Practical Management of Pain [6 ed.] 0323711014, 9780323711012, 9780323711029

Citation preview

Practical Management of Pain

Practical Management of Pain

SIXTH EDITION

Honorio T. Benzon, MD

Charles E. Argoff, MD

Professor Department of Anesthesiology Northwestern University Feinberg School of Medicine Chicago, Illinois

Professor of Neurology Albany Medical College Vice Chair Department of Neurology Director, Comprehensive Pain Center Director, Pain Management Fellowship Albany Medical Center Albany, New York

James P. Rathmell, MD, MBA Chair Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Leroy D. Vandam Professor of Anaesthesia Harvard Medical School Boston, Massachusetts

Christopher L. Wu, MD Clinical Professor of Anesthesiology Department of Anesthesiology Hospital for Special Surgery; Clinical Professor of Anesthesiology Department of Anesthesiology Weill Cornell Medicine New York City, New York

Dennis C. Turk, PhD John and Emma Bonica Professor of Anesthesiology & Pain Research Department of Anesthesiology & Pain Medicine University of Washington Seattle, Washington

Robert W. Hurley, MD, PhD Professor Associate Dean Department of Anesthesiology Department of Neurobiology and Anatomy Wake Forest University School of Medicine; Executive Director Pain Service Line Atrium Health - Wake Forest Baptist Winston Salem, North Carolina

Andrea L. Chadwick, MD, MSc, FASA Associate Professor Department of Anesthesiology, Pain, and Perioperative Medicine University of Kansas School of Medicine Kansas City, Kansas

PRACTICAL MANAGEMENT OF PAIN, SIXTH EDITION



Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 ISBN: 978-0-323-71101-2

Copyright © 2023 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In particular, because of rapid advances in the medical sciences, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors, or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2014, 2008, 2000, 1992, and 1986.

Executive Content Strategist: Michael Houston Senior Content Development Specialist: Lisa Barnes Publishing Services Manager: Shereen Jameel Senior Project Manager: Manikandan Chandrasekaran Design Direction: Margaret Reid

2

 

3

 

4

 

5

 

6

 

7

 

8

 

9

 

Last digit is the print number:

 

Printed in India 1

To my wife, Juliet – thank you for your encouragement and support. To our children and their spouses – Hazel and Paul, Hubert and Natalie. To our grandchildren – Annalisa and Jonathan, Hunter and Jackson. To my co-editors for working with me over three editions. To all authors who took time off their busy schedules to write their chapters. To all patients with pain – with basic, translational, and clinical advances, we hope your suffering will be better understood and treated. Honorio T. Benzon To Nori Benzon, who, through yet another revision of this text, this one during the course of a pandemic, led the project with patience, persistence, and kindness; it is a great privilege to work with you. To my wife and children – Bobbi, Lauren, James, and Cara – thank you for your tremendous support. James P. Rathmell This work is dedicated to my parents (Shy-Hsien and Tsai-Lien), children (Emily and Alex), partner (Cynthia Cummis), and mentors. I am grateful for their continued support and encouragement. Christopher L. Wu To my many mentors, collaborators, and colleagues; way too many to list, but all of whom have contributed greatly to my understanding of the people and especially the plight of people who experience persistent pain. They have truly enriched my journey. And with gratitude to LORRAINE, more than a wife, a partner, and my best friend; for her consistent and unyielding patience, tolerance, and sacrifices throughout our marriage. Dennis C. Turk To my wife and best friend Pat – what an adventure we are having together! To our children David, Melanie, and Emily – it has been a joy to watch you grow into unique and amazing adults. To Nori Benzon – for asking me to be a part of this project and for his persistence and diligence in assuring its completion in such a dignified manner. To each of the co-editors – I am so grateful to have had the opportunity to work with and learn from you as we completed this venture together. And to those who experience acute and chronic pain – it is my sincere hope that our ongoing determination to better understand the multiple mechanisms of pain and how to best treat painful conditions will lead to greater pain relief and less suffering. Charles E. Argoff To my wife and best friend, Meredith, for her unending support. To my daughter, Alexandra, and sons, Sebastian and Gibson, my greatest joys. To my parents, Morrison and Brenda, and my sister, Erin, who have always kept me grounded. To my mentors, Donna Hammond, Steve Cohen, and Chris Wu, for fostering my interests and, when needed, reining me in. To my collaborators, for questioning every sentence I put down on paper. Robert W. Hurley To my wife and best friend, Carrie, for showing me the power of authenticity and how embodying that principle allows one to fulfill their greatest potential in life and work. You are my why. To my children, Stellan and Emmett, your support of mommy’s “doctor work” is infinitely appreciated. Keep reaching for the stars; there is no limit to what you can achieve if you are true to yourself. To Nori Benzon, Rob Hurley, Dan Clauw, Nirmala Abraham, Chad Brummett, and Talal Khan, my mentors, sponsors, and cheerleaders. I have nothing but deep gratitude for the support, guidance, and friendship you have bestowed upon me over the years. To the patients who enrich my life by entrusting me to care for them, thank you for your strength despite adversity, vulnerability, and willingness to embark on a journey of healing with me. Andrea L. Chadwick

Contributors

Gregory A. Acampora, MD Faculty Psychiatrist Department of Psychiatry Massachusetts General Hospital; Assistant Professor of Psychiatry Harvard Medical School; Consultant Psychiatrist Department of Anesthesiology Critical Care and Pain Medicine Massachusetts General Hospital Boston, Massachusetts Meredith C.B. Adams, MD, MS Assistant Professor Department of Anesthesiology Wake Forest Baptist Health Winston-Salem, North Carolina Deepti Agarwal, MD Lake Forest Hospital Assistant Professor of Clinical Anesthesiology Northwestern University Feinberg School of Medicine Chicago, Illinois Aurelio Alonso, DDS, MS, PhD Assistant Professor Director of Orofacial Pain Department of Anesthesiology, Division of Pain Medicine, Center for Translational Pain Medicine Duke Innovative Pain Therapies Duke University Durham, North Carolina Thomas Anthony Anderson, PhD, MD Associate Professor Department of Anesthesiology, Perioperative and Pain Medicine Stanford School of Medicine Stanford, California Magdalena Anitescu, MD, PhD, FASA Professor of Anesthesia and Pain Medicine Section Chief, Pain Management Director, Multidisciplinary Pain Medicine Fellowship Department of Anesthesia and Critical Care University of Chicago Medicine Chicago, Illinois

vi

Charles E. Argoff, MD Professor of Neurology Albany Medical College Vice Chair Department of Neurology Director, Comprehensive Pain Center Director, Pain Management Fellowship Albany Medical Center Albany, New York Javier De Andrés Ares, MD, PhD, FIPP Chair, Pain Unit Pain Unit-Anesthesia Hospital Universitario La Paz Madrid, Spain Ralf Baron, MD Professor and Chair Division of Neurological Pain Research and Therapy Department of Neurology University Hospital Schleswig-Holstein Campus Kiel Kiel, Germany Declan Barry, PhD Director APT Foundation Pain Treatment Services; Associate Professor Department of Psychiatry and Child Study Center Yale School of Medicine New Haven, Connecticut Himayapsill Batista Quevedo, PharmD PGY2 Pain and Palliative Care Pharmacy Resident Department of Pharmacy Albany Straton VA Medical Center Albany, New York Mark Beitel, PhD Director of Research Pain Treatment Service The APT Foundation; Associate Research Scientist Child Study Center; Assistant Clinical Professor Department of Psychiatry, and Lecturer, Ethnicity, Race, and Migration Yale University New Haven, Connecticut

Contributors

Fabrizio Benedetti, MD Professor Department of Neuroscience University of Turin Medical School Turin, Italy; Director Medicine & Physiology of Hypoxia Plateau Rosà, Switzerland John C. Benson, MD Assistant Professor Department of Radiology Mayo Clinic Rochester, Minnesota Honorio T. Benzon, MD Professor Department of Anesthesiology Northwestern University Feinberg School of Medicine Chicago, Illinois Hubert A. Benzon, MD Attending Anesthesiologist Department of Pediatric Anesthesiology Ann & Robert H. Lurie Children’s Hospital of Chicago Associate Professor of Anesthesiology Northwestern University Feinberg School of Medicine Chicago, Illinois Anuj Bhatia, MBBS, MD, PhD, FRCPC, FRCA, FFPMRCA Associate Professor Department of Anesthesia and Pain Medicine University of Toronto University Health Network - Toronto Western Hospital, Women’s College Hospital Toronto, Ontario, Canada Ravneet Bhullar, BSc, MD, FASA Associate Professor and Director Division of Chronic Pain Management Department of Anesthesiology Albany Medical Center Albany, New York Klaus Bielefeldt, MD, PhD Professor Medicine (Gastroenterology) George E. Wahlen Department of Veterans Affairs Medical Center University of Utah Medical School Salt Lake City, Utah Anna Blanchfield Department of Neuroscience and Experimental Therapeutics Albany Medical College Albany, New York Milana Bochkur Dratver, BS, MS Medical Student Department of Urology Massachusetts General Hospital Boston, Massachusetts

vii

Staja Q. Booker, PhD, RN Assistant Professor Department of Biobehavioral Nursing Science College of Nursing University of Florida Gainesville, Florida Kim J. Burchiel, MD, FACS John Raaf Professor Department of Neurological Surgery Professor, Department of Anesthesiology and Perioperative Medicine Oregon Health & Science University Portland, Oregon Nicholas E. Burjek, MD Assistant Professor of Anesthesiology Department of Anesthesiology Ann & Robert H. Lurie Children’s Hospital of Chicago Northwestern University Feinberg School of Medicine Chicago, Illinois Yi Cai, MD Fellow, Pain Medicine Department of Anesthesiology University of San Diego San Diego, California Kenneth D. Candido, MD Chairman, Department of Anesthesiology Illinois Masonic Hospital Clinical Professor of Anesthesiology University of Illinois at Chicago Chicago, Illinois Andrea L. Chadwick, MD, MSc, FASA Associate Professor Department of Anesthesiology, Pain, and Perioperative Medicine University of Kansas School of Medicine Kansas City, Kansas Ronil V. Chandra, MBBS, MMed, FRANZCR, CCINR Associate Professor Department of NeuroInterventional Radiology Monash Health; Associate Professor Faculty of Medicine, Nursing and Health Sciences Monash University Melbourne, Australia Kailash Chandwani, MD Medical Director Pain Management UNC Health Southeastern Lumberton, North Carolina Andrew K. Chang, MD, MS Vincent P. Verdile, MD, ‘84 Endowed Chair for Emergency Medicine Vice Chair of Research and Academic Affairs Professor of Emergency Medicine Albany Medical Center Albany, New York

viii

Contributors

Yun-Yun K. Chen, MD Department of Anesthesiology Perioperative and Pain Medicine Brigham and Women’s Hospital Boston, Massachusetts Jianguo Cheng, MD, PhD Professor of Anesthesiology Director, Pain Management Cleveland Clinic Cleveland, Ohio Delia Chiaramonte, MD, MS Division Chief Integrative and Palliative Medicine, Gilchrist/Greater Baltimore Medical Center Affiliate Assistant Professor Department of Pharmacy Practice and Science, University of Maryland Baltimore, Maryland Roger Chou, MD Professor Department of Medical Informatics and Clinical Epidemiology Oregon Health & Science University Director Pacific Northwest Evidence-based Practice Center Oregon Health & Science University Portland, Oregon Daniel J. Clauw, MD Professor of Anesthesiology Department of Medicine (Rheumatology) and Psychiatry Director, Chronic Pain and Fatigue Research Center University of Michigan Medical School Ann Arbor, Michigan Steven P. Cohen, MD Chief, Pain Medicine Department of Anesthesiology & Critical Care Medicine Johns Hopkins Medical Institutions; Professor Department of Anesthesiology, Neurology and Physical Medicine & Rehabilitation and Psychiatry & Behavioral Sciences Johns Hopkins School of Medicine Baltimore, Maryland; Professor Anesthesiology and Physical Medicine & Rehabilitation Walter Reed National Military Medical Center Uniformed Services University of the Health Sciences Bethesda, Maryland Heather A. Columbano, MD Assistant Professor Department of Anesthesiology Medical Director of Spine Medicine Associate Program Director Pain Fellowship Atrium Health Wake Forest Baptist Winston-Salem, North Carolina Silvie Cooper, PhD Lecturer (Teaching) Applied Health Research

University College London London, Great Britain; Visiting Research Scholar Department of Sociology University of Witwatersrand Johannesburg, South Africa David Copenhaver, MD, MPH Chief, Pain Medicine Division Director of Cancer Pain Management Director of Pain Medicine Tele-Health; Professor Division of Pain Medicine Department of Anesthesiology and Pain Medicine Department of Neurological Surgery Lawrence J. Ellison Ambulatory Care Center Sacramento, California Megan H. Cortazzo, MD Associate Professor of Physical Medicine and Rehabilitation Department of PM&R University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Samantha Curran, BS Clinical Research Assistant Department of Anesthesiology Brigham & Women’s Hospital Boston, Massachusetts Chris D’Adamo, MD Assistant Professor Departments of Family and Community Medicine and Epidemiology and Public Health Center for Integrative Medicine University of Maryland School of Medicine Baltimore, Maryland Dana Dailey, PT, PhD Assistant Professor Department of Physical Therapy St. Ambrose University Davenport, Iowa; Research Scientist Physical Therapy and Rehabilitation Sciences University of Iowa Iowa City, Iowa Carlton D. Dampier, MD Professor Department of Pediatrics Emory University School of Medicine Atlanta, Georgia Elise J.B. De, MD, FACS FACS Associate Professor Surgery Harvard Medical School; Department of Urology Massachusetts General Hospital Boston, Massachusetts

Contributors

James Deering, MD Carolinas Pain Institute and Chronic Pain Research Institute Winston-Salem, North Carolina Lauriane Delay, PhD Postdoctoral Researcher Department Anesthesiology University of California, San Diego San Diego, California; Department of Pharmacology NeuroDol Clermont-Ferrand Auvergne, France David J. Derrico, RN, MSN, CNE Assistant Clinical Professor Department of Biobehavioral Nursing Science University of Florida College of Nursing Gainesville, Florida Anthony H. Dickenson, BSc, PhD Professor of Neuropharmacology Department of Neuroscience Physiology and Pharmacology University College London London, Great Britain Felix E. Diehn, MD Associate Professor Department of Radiology Division of Neuroradiology Mayo Clinic Rochester, Minnesota Massimiliano DiGiosia, DDS Associate Professor Diagnostic Sciences Adams School of Dentistry-University of North Carolina Chapel Hill, North Carolina Ryan S. D’Souza, MD Assistant Professor Director of Neuromodulation Department of Anesthesiology and Perioperative Medicine Mayo Clinic Hospital Rochester, Minnesota Robert Duarte, MD Montefiore Medical Center Bronx, New York Andrew Dubin, MD, MS Professor of Physical Medicine and Rehabilitation Department of Physical Medicine and Rehabilitation University of Florida Gainesville, Florida Lauren K. Dunn, MD, PhD Associate Professor Department of Anesthesiology University of Virginia Charlottesville, Virginia

ix

Robert R. Edwards, PhD Associate Professor Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Lori-Ann Edwards, MB, BS Resident Department of Anesthesiology Temple University Hospital Philadelphia, Pennsylvania Dalya Elhady, MD Fellow Department of Pain Medicine The University of Texas MD Anderson Cancer Center Interventional Pain Specialist Private Practice Houston, Texas Bonnie S. Essner, PhD Assistant Professor Department of Psychiatry and Behavioral Sciences Northwestern University Feinberg School of Medicine Pritzker Department of Psychiatry and Behavioral Health Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois Scott M. Fishman, MD Professor and Executive Vice-Chair Department of Anesthesiology and Pain Medicine University of California, Davis School of Medicine; Chief, Pain Medicine Department of Pain Medicine/Anesthesiology University of California, Davis School of Medicine; Director Center for Advancing Pain Relief University of California, Davis Sacramento, California Dermot Fitzgibbon, MB, BCh, BAO Professor Department of Anesthesiology & Pain Medicine University of Washington School of Medicine; Medical Director Seattle Cancer Care Alliance Seattle, Washington Grace Forde, MD Director of Neurological Services Neurology-Pain Management North American Partners In Pain Management Lake Success, New York Elisa Frisaldi, PhD Research Fellow in Neurophysiology Department of Neuroscience University of Turin Medical School Turin, Italy

x

Contributors

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB Clinical Pharmacy Specialist and Founder/Former Director PGY2 Pain & Palliative Care Pharmacy Residency Pharmacy Department Stratton VA Medical Center Albany, New York; Adjunct Associate Professor Pharmacy Practice Western New England University College of Pharmacy Springfield, Massachusetts; Adjunct Associate Professor Pharmacy Practice Albany College of Pharmacy and Health Sciences Albany, New York; President Remitigate Therapeutics Delmar, New York Timothy Furnish, MD Clinical Professor Department of Anesthesiology University of California, San Diego Health San Diego, California Katherine E. Galluzzi, DO, CMD, FACOFPd Professor and Chair Department of Geriatric and Palliative Medicine Philadelphia College of Osteopathic Medicine Philadelphia, Pennsylvania Marina Gaeta Gazzola, BS MD Student Yale School of Medicine; Research Assistant the APT Foundation New Haven, Connecticut Katherine Gentry, MD, MA Assistant Professor, Anesthesiology and Pain Medicine University of Washington School of Medicine Affiliate Faculty, Treuman Katz Center for Pediatric Bioethics Seattle Children’s Hospital Christopher Gilmore, MD Carolinas Pain Institute Center for Clinical Research Winston-Salem, North Carolina Gilson Gonçalves dos Santos, PhD Department of Anesthesiology University of California San Diego, California Debra B. Gordon, RN, DNP, FAAN Co-Director Harborview Integrated Pain Care Program Department of Anesthesiology & Pain Medicine University of Washington Seattle, Washington

Carlos E. Guerrero, MD, FIPP Anesthesiologist and Pain Management Specialist University Hospital Fundacion Santa Fe Bogota, Colombia; Professor Universidad El Bosque Professor Universidad de los Andes Bogota, Colombia Amit Gulati, MD Associate Attending Anesthesiology and Critical Care Memorial Sloan Kettering Cancer Center New York, New York Amir Hadanny, MD Department of Neurosurgery Albany Medical Center Albany, New York Thomas Hadjistavropoulos, PhD, ABPP, FCAHS Professor and Research Chair in Aging and Health Department of Psychology and Centre on Aging Health University of Regina Regina, Saskatchewan, Canada Carlyle Peters Hamsher, MD Assistant Professor Department of Anesthesiology Atrium Health Wake Forest Baptist Winston Salem, North Carolina Michael C. Hanes, MD Jax Spine & Pain Centers Jacksonville, Florida Gretchen Hermes, MD, PhD Medical Director APT Foundation; Assistant Professor Department of Psychiatry Yale University School of Medicine New Haven, Connecticut Keela A. Herr, PhD, RN, AGSF, FGSA, FAAN Kelting Professor & Associate Dean for Faculty College of Nursing The University of Iowa Iowa City, Iowa Louise Hillen, MD Associated Anesthesiologists, P.A. Plymouth, Minnesota Joshua A. Hirsch, MD Vice-Chair Department of Radiology Harvard Medical School Department of Radiology Massachusetts General Hospital Boston, Massachusetts

Contributors

Marshall T. Holland, MD, MS Assistant Professor of Neurosurgery Department of Neurosurgery University of Alabama at Birmingham Marnix E. Heersink School of Medicine The University of Alabama at Birmingham Birmingham, Alabama Rebecca Hoss, PharmD SUD and Analgesia Pharmacy Specialist Department of Pharmacy University of California Medical Center Sacramento, California Margaret Hsu, MD Assistant Professor Department of Anesthesiology University of Washington Medical System Seattle, Washington

Charles Inturrisi, PhD Professor Department of Pharmacology Weill Cornell Medicine New York, New York Mohammed A. Issa, MD Clinical Instructor Departments of Anesthesiology and Psychiatry Brigham and Women’s Hospital, Harvard Medical School Boston, Massachusetts Robert N. Jamison, PhD Professor Departments of Anesthesiology and Psychiatry Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Yul Huh, MD Center for Translational Pain Medicine Department of Anesthesiology Duke University Medical Center Durham, North Carolina

Ru-Rong Ji, PhD Professor and Director Center for Translational Pain Medicine Department of Anesthesiology Duke University Medical Center Durham, North Carolina

Christine L. Hunt, DO, MS Assistant Professor Pain Medicine Department Mayo Clinic Jacksonville, Florida

Rebecca L. Johnson, MD, FASA Associate Professor of Anesthesiology Department of Anesthesiology and Perioperative Medicine Mayo Clinic Rochester, Minnesota

Marc A. Huntoon, MD Professor with Tenure Department of Anesthesiology Vice Chair Department of Anesthesiology, VCU Health, Virginia Commonwealth University Richmond, Virginia

Jatin Joshi, MD Assistant Professor Department of Anesthesiology Weill Cornell Medicine New York, New York

Robert W. Hurley, MD, PhD Professor Associate Dean Department of Anesthesiology Department of Neurobiology and Anatomy Wake Forest University School of Medicine; Executive Director Pain Service Line Atrium Health - Wake Forest Baptist Winston Salem, North Carolina Frank J.P.M. Huygen, MD, PhD, FFPMCAI (hon) Professor and Chair Department of Anesthesiology and Pain Medicine Erasmusmc University Hospital Rotterdam, The Netherlands; Professor Department of Anesthesiology and Pain Medicine University Medical Center Utrecht Utrecht, The Netherlands

Leonardo Kapural, MD, PhD Director Carolinas Pain Institute at Brookstown Wake Forest Baptist Health; Professor of Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina Robert D. Kerns, PhD Professor of Psychiatry Neurology and Psychology Yale University New Haven, Connecticut Dost Khan, MD Assistant Professor Department of Anesthesiology Northwestern University Feinberg School of Medicine Chicago, Illinois

xi

xii

Contributors

Olga Khazen Department of Neuroscience and Experimental Therapeutics Albany Medical College Albany, New York Jessica Kruse, MA Doctoral Candidate Ferkauf Graduate School of Psychology Yeshiva University New York, New York Nebojsa Nick Knezevic, MD, PhD Vice-Chair for Research and Education Associate Program Director Department of Anesthesiology Advocate Illinois Masonic Medical Center; Clinical Professor Department of Anesthesiology University of Illinois; Clinical Professor Department of Surgery University of Illinois Chicago, Illinois Preetma Kaur Kooner, MD Assistant Professor Department of Anesthesiology and Pain Medicine University of Washington Seattle, Washington Evangeline P. Koutalianos, MD Assistant Professor of Physical Medicine & Rehabilitation SUNY Upstate Medical University Syracuse, New York

Julian Maingard, BBiomedSc, MBBS, FRANZCR, CCINR, EBIR Consultant Interventional Neuroradiologist Austin Health; Consultant Interventional Neuroradiologist St Vincent’s Health; Senior Lecturer Faculty of Medicine, Nursing and Health Sciences Monash University Melbourne, Australia; Senior Lecturer School of Medicine Deakin University Una E. Makris, MD, MSc Associate Professor Department of Internal Medicine University of Texas Southwestern Medical Center; Staff Physician Medical Service, Rheumatology North Texas Health Care System Dallas, Texas Khalid Malik, MD, MBA, FRCS Professor Department of Anesthesiology Division Chief, Pain Medicine University of Illinois Chicago, Illinois Timothy P. Maus, MD Professor of Radiology Department of Radiology Mayo Clinic Rochester, Minnesota

Christopher M. Lam, MD Assistant Professor Department of Anesthesiology, Pain and Perioperative Medicine University of Kansas School of Medicine Kansas City, Kansas

Zachary L. McCormick, MD Associate Professor Chief, Spine and Musculoskeletal Medicine Division Department of Physical Medicine and Rehabilitation University of Utah School of Medicine Salt Lake City, Utah

Daniel B. Larach, MD, MTR, MA Assistant Professor Department of Anesthesiology Vanderbilt University School of Medicine Nashville, Tennessee

Anne Marie McKenzie-Brown, MD Associate Professor Department of Anesthesiology Emory University School of Medicine Atlanta, Georgia

James Littlejohn, MD, PhD Assistant Professor of Clinical Anesthesiology Division of Critical Care Medicine Weill Cornell Medicine New York, New York

Samantha M. Meints, PhD Clinical Pain Psychologist Department of Anesthesiology Perioperative and Pain Medicine Brigham and Women’s Hospital; Instructor Harvard Medical School Boston, Massachusetts

Mary Leemputte, MD Fellow in Pain medicine Massachusetts General Hospital Boston, Massachusetts

Matthew Meroney, MD Associate Professor Department of Anesthesiology University of Florida College of Medicine Gainesville, Florida

Contributors

Jee Youn Moon, MD, PhD, FIPP, CIPS Associate Professor Department of Anesthesiology and Pain Medicine Seoul National University College of Medicine Seoul, Korea Juan C. Mora, MD Assistant Professor Department of Anesthesiology University of Florida College of Medicine Gainesville, Florida Brian Morrison, DC Baltimore, Maryland Natalie Moryl, MD Memorial Sloan Kettering Cancer Center New York, New York Jana M. Mossey, PhD, MPH, MSN Professor Emerita Epidemiology and Biostatistics, Dornsife School of Public Health Drexel University Philadelphia, Pennsylvania Tasha B. Murphy, PhD Behavioral Medicine Research Group School of Social Work University of Washington Seattle, Washington Antoun Nader, MD Professor of Anesthesiology and Orthopedic Surgery Department of Anesthesiology Northwestern University Chicago, Illinois Geeta Nagpal, MD Associate Professor Department of Anesthesiology Northwestern Memorial Hospital Chicago, Illinois Lynn Nakad, MSN, RN Research Assistant University of Iowa College of Nursing Iowa City, Iowa Mithun Nambiar, MBBS, BMedSc Department of NeuroInterventional Radiology, Monash Health; Adjunct Lecturer Faculty of Medicine, Nursing and Health Sciences Monash University Melbourne, Australia Captain, Royal Australian Army Medical Corps, Australian Defence Force

Ariana M. Nelson, MD Associate Professor Anesthesiology and Perioperative Medicine Division of Pain Medicine University of California, Irvine Irvine, California; Physician, Aerospace Medicine Research Exploration Medical Capability Element NASA (National Aeronautics and Space Administration) Diane Novy, MD Professor Department of Anesthesiology The University of Texas-Houston Health Science Center Department of Psychiatry and Behavioral Sciences The University of Texas-Houston Health Science Center University Center for Pain Medicine and Rehabilitation at Hermann Hospital Houston, Texas Shannon Nugent, PhD Assistant Professor Department of Psychiatry Oregon Health and Science University Portland, Oregon Akiko Okifuji, PhD Professor Division of Pain Medicine Department of Anesthesiology University of Utah Salt Lake City, Utah Dikachi Osaji, BA, MS Research Department of Anesthesia, Perioperative and Pain Medicine Brigham and Women’s Hospital Boston, Massachusetts Jan Alberto Paredes Mogica, MD Health Sciences Faculty of Medicine Anahuac University Huixquilucan, Mexico Sagar S. Parikh, MD Interventional Pain Physician Pain Fellowship Program Director JFK Johnson Rehabilitation Institute Hackensack Meridian Healt Hoboken, New Jersey Ryan Patel, BA, PhD Research associate Department of Neuroscience, Physiology and Pharmacology University College London London, Great Britain Feyce M. Peralta, MD, MS Associate Professor Department of Anesthesiology Northwestern University Feinberg School of Medicine Chicago, Illinois

xiii

xiv

Contributors

Julie G. Pilitsis, MD, PhD Chair and Professor Department of Neuroscience & Experimental Therapeutics Albany Medical College Professor of Neurosurgery Department of Neurosurgery Albany Medical College Albany, New York Mohammad Piracha, MD New York Presbyterian/Weill Cornell Medical Center Department of Anesthesiology New York, New York

Mohammed I. Ranavaya II, MD Resident Physician- General Surgery University of Louisville Hiram C. Polk, Jr., MD Department of Surgery Louisville, Kentucky Ahmed M. Raslan, MD Associate Professor Department of Neurological Surgery Oregon Health & Science University Portland, Oregon

Andrew J. B. Pisansky, MD, MS Assistant Professor Department of Anesthesiology Vanderbilt University Nashville, Tennessee

James P. Rathmell, MD, MBA Chair Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Leroy D. Vandam Professor of Anaesthesia Harvard Medical School Boston, Massachusetts

Markus Ploner, PhD, Dr.med. Professor of Human Pain Research Department of Neurology, Center for Interdisciplinary Pain Medicine, and TUM-Neuroimaging Center Technical University of Munich Munich, Germany

Mathieu Roy, PhD Assistant Professor Department of Psychology Alan Edwards Center for Research on Pain McGill University Montreal, Canada

Elisabeth B. Powelson, MD Clinical Instructor Department of Anesthesiology & Pain Medicine University of Washington Seattle, Washington

John E. Rubin, MD Instructor in Anesthesiology Division of Regional Anesthesiology and Acute Pain Medicine Department of Anesthesiology Weill Cornell Medicine New York, New York

David A. Provenzano, MD Pain Diagnostics and Interventional Care Sewickley, Pennsylvania Rene Przkora, MD, PhD Professor Department of Anesthesiology University of Florida College of Medicine Gainesville, Florida Jamila I. Ranavaya, BS, MD Resident Physician Combined Internal Medicine-Pediatrics Residency Joan C. Edwards School of Medicine at Marshall University Huntington, West Virginia Mohammed I. Ranavaya, MD, JD Professor and Chief Division of Occupational Medicine Joan C. Edwards School of Medicine at Marshall University; President American Board of Independent Medical Examiners; Medical Director Appalachian Institute of Occupational and Environmental Medicine Huntington, West Virginia

Juliane Sachau, MD Resident Division of Neurological Pain Research and Therapy Department of Neurology University Hospital Schleswig-Holstein Campus Kiel Kiel, Germany Patrick Schober, MD, PhD Amsterdam University Medical Center Bijlmer, Amsterdam, The Netherlands Kristin L. Schreiber, MD, PhD Associate Professor Anesthesiology, Perioperative, and Pain Medicine Brigham and Women’s Hospital Boston, Massachusetts Elizabeth K. Seng, PhD Associate Professor Ferkauf Graduate School of Psychology Yeshiva University; Research Associate Professor Albert Einstein College of Medicine Bronx, New York

Contributors

Ravi Shah, MD Associate Professor of Anesthesiology Department of Pediatric Anesthesiology Ann & Robert H. Lurie Children’s Hospital Northwestern University Chicago, Illinois Aziz Shaibani, MD Director Nerve and Muscle Center of Texas Houston Neurocare Clinical Professor of Medicine Baylor College of Medicine Houston, Texas Liang Shen, MD, MPH Assistant Professor of Clinical Anesthesiology Department of Anesthesiology Weill Cornell Medicine New York, New York Stephen D. Silberstein, MD Professor Department of Neurology Thomas Jefferson University; Director Jefferson Headache Center Thomas Jefferson University Hospital Philadelphia, Pennsylvania Priyanka Singla, MBBS, MD Resident Department of Anesthesiology University of Virginia Charlottesville, Virginia Lee-Anne Slater, MBBS (Hons), FRANZCR, MMed, CCINR Consultant Interventional Neuroradiologist Monash Health; Senior Lecturer Faculty of Medicine, Nursing and Health Sciences Monash University Melbourne, Australia Kathleen A. Sluka, PT, PhD Professor Department of Physical Therapy and Rehabilitation Science Department of Neuroscience and Pharmacology Pain Research Program University of Iowa Iowa City, Iowa Brett R. Stacey, MD Professor Department of Anesthesiology & Pain Medicine Division Chief, Pain Medicine Department of Anesthesiology & Pain Medicine University of Washington Seattle, Washington Steven P. Stanos, DO Executive Medical Director, Rehabilitation & Performance Medicine Swedish Pain Services Swedish Heatlh System Seattle, Washington

Jordan Starr, MD Acting Assistant Professor Department of Anesthesiology and Pain Medicine University of Washington Seattle, Washington Kylie Steinhilber, MA Department of Psychology Suffolk University Boston, Massachusetts Natalie H. Strand, MD Associate Professor Anesthesiology and Pain Medicine Department of Anesthesiology, Division of Pain Medicine Mayo Clinic Phoenix, Arizona Mark D. Sullivan, MD, PhD Professor Department of Psychiatry and Behavioral Sciences Adjunct Professor, Anesthesiology and Pain Medicine Adjunct Professor, Bioethics and Humanitie University of Washington Seattle, Washington Santhanam Suresh, MD, MBA, FAAP Arthur C. King Professor Department of Pediatric Anesthesiology Senior Vice-President, Chief of Provider Integration Ann & Robert H Lurie Children’s Hospital of Chicago Professor of Anesthesiology & Pediatrics Northwestern University’s Feinberg School of Medicine Chicago, Illinois David J. Tauben, MD Clinical Professor Emeritus Department of Medicine, Division of General Medicine Department of Anesthesia and Pain Medicine University of Washington Seattle, Washington Gregory W. Terman, MD, PhD Professor Department of Anesthesiology and Pain Medicine University of Washington Seattle, Washington Reda Tolba, MD Department Chair Pain Management Anesthesiology Institute, Cleveland Clinic Abu Dhabi, UAE; Clinical Professor of Anesthesiology Cleveland Clinic Lerner College of Medicine Cleveland Clinic Foundation Cleveland, Ohio Dennis C. Turk, PhD John and Emma Bonica Professor of Anesthesiology & Pain Research Department of Anesthesiology & Pain Medicine University of Washington Seattle, Washington

xv

xvi

Contributors

Mark D. Tyburski, MD Co-Chief, Department of Pain Medicine The Permanente Medical Group Sacramento/Roseville, California Etienne Vachon-Presseau, PhD Faculty of Dentistry Alan Edwards Center for Research on Pain McGill University Montreal, Quebec, Canada Koen van Boxem, MD, PhD, FIPP Department of Anesthesiology Critical Care and Multidisciplinary Pain Center Ziekenhuis Oost-Limburg Lanaken - Genk, Belgium; Department of Anesthesiology and Pain Medicine Maastricht University Medical Center Maastricht, The Netherlands

Jeanine A. Verbunt, MD, PhD Department of Rehabilitation Medicine Research School CAPHRI Maastricht University Maastricht, The Netherlands; Adelante Centre of Expertise in Rehabilitation and Audiology Hoensbroek, The Netherlands Thomas R. Vetter, MD, MPH Professor Department of Surgery and Perioperative Care Department of Population Health Dell Medical School at the University of Texas at Austin Austin, Texas Elayne Viera, MD Postgraduate Program on Physical Education Universidade Católica de Brasília Taguatinga, Brazil

Maarten van Eerd, MD, PhD, FIPP Department of Anesthesiology and Pain Management Amphia Ziekenhuis Breda, The Netherlands; Leiden University Medical Centre (LUMC), Department of Anesthesiology, Intensive Care and Pain Medicine Leiden, The Netherlands

Daniela Vivaldi, DDS Clinical Associate Department of Anesthesiology, Division of Pain Medicine, Center for Translational Pain Medicine Duke Innovative Pain Therapy Duke University Durham, North Carolina

Jan van Zundert, MD, PhD, FIPP Professor in Pain Medicine Department of Anesthesiology and Pain Medicine Maastricht University Medical Center Maastricht, The Netherlands; Head of Multidisciplinary Pain Centre Department of Anesthesiology, Critical Care and Pain Medicine Ziekenhuis Oost-Limburg Lanaken - Genk, Belgium

Iris Vuong, MD Resident in Internal Medicine Department of Internal Medicine University of California, Davis School of Medicine Sacramento, California

Carol G.T. Vance, PT, PhD Department of Physical Therapy and Rehabilitation Science University of Iowa Iowa City, Iowa Department of Physical Therapy St Ambrose University Davenport, Iowa

Graham Wagner, MD Assistant Professor Department of Physical Medicine and Rehabilitation University of Utah Salt Lake City, Utah Sayed E. Wahezi, MD Associate Professor Department of Rehabilitation Medicine Program Director, Pain Medicine Fellowship Montefiore Medical Center Bronx, New York

Thibaut Vanneste, MD Department of Anesthesiology, and Multidisciplinary Pain Center Ziekenhuis Oost-Limburg Lanaken - Genk, Belgium; Department of Anesthesiology and Pain Medicine Maastricht University Medical Center Maastricht, The Netherlands

Gary A. Walco, PhD Professor Department of Anesthesiology and Pain Medicine University of Washington; Director of Pain Medicine Department of Anesthesiology and Pain Medicine Seattle Children’s Hospital Seattle, Washington

Angelica A. Vargas, MD Assistant Professor of Anesthesiology Northwestern University Feinberg School of Medicine; Department of Pediatric Anesthesiology Ann & Robert H. Lurie Children’s Hospital Chicago, Illinois

Mark S. Wallace, MD Professor Department of Anesthesiology University of California, San Diego Health System San Diego, California

Contributors

David Andrew Walsh, PhD, FRCP Professor of Rheumatology Department of Academic Rheumatology University of Nottingham Nottingham, Great Britain Ning Nan Wang, MDCM, FRCPC Clinical Fellow Anesthesiology and Pain Medicine Toronto Western Hospital Toronto, Ontario, Canada Ajay Wasan, MD, MSc Professor Department of Anesthesiology and Psychiatry University of Pittsburgh Pittsburgh, Pennsylvania Erica L. Wegrzyn, BS, PharmD Clinical Pharmacy Specialist, Pain Management Stratton VA Medical Center Albany, New York Karin N. Westlund, PhD Professor and Vice-Chair for Research Department of Anesthesiology and Critical Care Medicine University of New Mexico Health Science Center Albuquerque, New Mexico David A. Williams, PhD Professor Department of Anesthesiology University of Michigan Ann Arbor, Michigan Harriet Wittink, MD Professor and Chair Lifestyle and Health Research Group Utrecht University of Applied Sciences Utrecht, The Netherlands

Christopher L. Wu, MD Clinical Professor of Anesthesiology Department of Anesthesiology Hospital for Special Surgery; Clinical Professor of Anesthesiology Department of Anesthesiology Weill Cornell Medicine New York City, New York Tony L. Yaksh, PhD Professor Department of Anesthesiology University of California San Diego La Jolla, California Nantthasorn Zinboonyahgoon, MD Associate Professor Chief, Division of Pain Medicine Department of Anesthesiology Faculty of Medicine Siriraj Hospital Mahidol University Bangkok, Thailand Xander Zuidema, MD, PharmD Department of Anesthesiology and Pain Management Diakonessenhuis Utrecht Utrecht, The Netherlands; Department of Anesthesiology and Pain Management Academic Medical Center Maastricht Maastricht, The Netherlands

xvii

Preface

The Practical Management of Pain, first published in 1986, is one of the established textbooks on pain management. In 2008, several of the current editors took over editorial leadership of the fourth edition of the book. As pain is multidimensional, starting in the fourth edition and continuing in the present edition, we the editors, represent several disciplines related to pain: anesthesiology, neurology, and psychology. The Practical Management of Pain has evolved due to our increasing understanding of pain and its underlying mechanisms, which is reflected throughout this volume. Topics such as local anesthetics, neuraxial anesthesia, technique of peripheral nerve blocks, and associated topics were discontinued to focus on pain-related topics. In this updated and expanded edition, we have enlisted an outstanding set of clinicians and researchers with considerable expertise in all facets of pain and its management to provide contemporary information as to why and how best to evaluate and treat patients experiencing pain. We believe that this volume truly represents state-of-the-art knowledge and understanding of pain and its management.

To represent the growing body of knowledge in the field, we have added Andrea Chadwick to this edition. Dr. Chadwick brings particular expertise in the areas of fibromyalgia, nonopioid management of pain, radiation exposure, among other topics. The production of a textbook involves the contributions, encouragement, and support of a number of people. We thank the authors, Michael Houston, Lisa Barnes, Manikandan Chandrasekaran, Baljinder Kaur of Aptara, and everyone related to the development of this edition. Honorio T. Benzon, MD James P. Rathmell, MD Christopher L. Wu, MD Dennis C. Turk, PhD Charles E. Argoff, MD Robert W. Hurley, MD, PhD Andrea L. Chadwick, MD

xix

 

Part 1: General Considerations

Classification of Acute Pain and Chronic Pain Syndromes, 11



2

Juan C. Mora, Rene Przkora, Matthew Meroney

Organizing an Inpatient Acute Pain Service, 16



3



14

15

Preetma Kaur Kooner, Gregory W. Terman Steven P. Stanos

16

Quality Assessment, Improvement, and Patient Safety in Pain Management, 67

James P. Rathmell, Anne Marie McKenzie-Brown

 

Part 2: Basic Considerations Neurophysiology of Pain: Peripheral, Spinal, Ascending, and Descending Pathways, 95



8

Karin N. Westlund

 

18

19 20



11

Individual Differences in Experience and Treatment of Pain: Race, Ethnicity, and Sex, 138 Samantha M. Meints, Dikachi Osaji, Kylie Steinhilber, Robert R. Edwards



12

21

Neuroimaging Techniques, 125

Biomarkers of Pain: Quantitative Sensory Testing, Conditioned Pain Modulation, Punch Skin Biopsy, 290 Juliane Sachau, Ralf Baron

22



Mathieu Roy, Étienne Vachon-Presseau, Markus Ploner, Ariana M. Nelson

Radiologic Assessment of Patient With Spine Pain, 232 Felix E. Diehn, John C. Benson, Timothy P. Maus

Psychological and Behavioral Assessment, 299 Jessica Kruse, Robert D. Kerns, Elizabeth K. Seng

23





10

Electromyography and Evoked Potentials, 219 Andrew Dubin



Tony L. Yaksh, Gilson Gonçalves dos Santos, Lauriane Delay, Elayne Viera

History and Physical Examination of the Patient With Pain, 207 Charles E. Argoff, Grace Forde, Sayed E. Wahezi, Robert Duarte

Neurochemistry of Nociception, 110



9

Part 3: Clinical Evaluation and Assessment

Education, Training, and Certification in Pain Medicine, 87



7



Debra B. Gordon, James P. Rathmell

Placebo and Nocebo Effects in Clinical Trials and Clinical Practice, 194 Fabrizio Benedetti, Elisa Frisaldi, Aziz Shaibani





6

17



Thomas R. Vetter

Mechanism-Based Treatment and Precision Medicine, 183 Jianguo Cheng, Yul Huh, Ru-Rong Ji

The Healthcare Policy of Pain Management, 57



5

Comprehensive Approach to Evaluating Patients With Chronic Pain, 173 Dennis C. Turk, Brett R. Stacey, Elisabeth B. Powelson



Interdisciplinary Pain Management, 39



4

Psychosocial and Psychiatric Aspects of Chronic Pain, 159 Dennis C. Turk, Tasha B. Murphy



Natalie Moryl, Charles Inturrisi

Pharmacogenetics in Pain Management, 151 Erica L. Wegrzyn, Himayapsill Batista Quevedo, Jeffrey Fudin, Charles E. Argoff

History Is a Distillation of Rumor, 3



1

13



Contents

Disability Assessment, 315 Mohammed I. Ranavaya, Mohammed I . Ranavaya II, Jamila I. Ranavaya

Communication and Clinician Relationships to Improve Care for Patients With Chronic Pain, 146 David J. Tauben, Mark D. Sullivan

xxi

xxii

Contents

Part 4:  Clinical Conditions: Evaluation and Treatment 24 Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia, 333 Nantthasorn Zinboonyahgoon, Yun-Yun K. Chen, Kristin L. Schreiber

25 Evaluation and Pharmacologic Treatment of Postoperative Pain, 347 Lauren K. Dunn, Priyanka Singla

26 Regional and Multimodal Treatments of Perioperative Pain, 355 Ryan S. D’Souza, Rebecca L. Johnson

27 Evaluation and Treatment of Postoperative Pain in Patients With Opioid Use Disorder, 374 Yi Cai, Gregory A. Acampora, T. Anthony Anderson

28 Evaluation and Treatment of Acute Pain in Children, 385 Ravi Shah, Santhanam Suresh, Nicholas E. Burjek

29 Low Back Pain Disorders, 396 Khalid Malik, Ariana M. Nelson

30 Buttock and Sciatica Pain, 413 Graham Wagner, Ariana M. Nelson, Steven P. Cohen, Zachary L. McCormick

31 Facet Pain: Pathogenesis, Diagnosis, and Treatment, 432 Steven P. Cohen, Javier De Andrés Ares

32 Neurosurgical Approaches to Pain Management, 453 Marshall T. Holland, Ahmed M. Raslan, Kim J. Burchiel

33 Evaluation and Treatment of Cancer-Related Pain, 461 Dermot Fitzgibbon, Margaret Hsu

34 Evaluation and Treatment of Neuropathic Pain Syndromes, 479 Christopher M. Lam, Andrea L. Chadwick, Robert W. Hurley

35 Evaluation and Treatment of Complex Regional Pain Syndrome, 500 Frank J.P.M. Huygen

36 Evaluation and Treatment of Pain in Selected Neurologic Disorders, 507 Amir Hadanny, Anna Blanchfield, Olga Khazen, Charles E. Argoff, Julie G. Pilitsis

37 Chronic Widespread Pain, 520 Meredith C.B. Adams, Daniel J. Clauw

38 Headache Management, 530 Stephen D. Silberstein

39 Cervicogenic Headache, Post-meningeal Puncture Headache, and Spontaneous Intracranial Hypotension, 545 Lori-Ann Edwards, Louise Hillen, Deepti Agarwal, Dost Khan, Reda Tolba

40 Orofacial Pain, 560 Aurelio Alonso, Massimiliano DiGiosia, Daniela Vivaldi

41 Visceral Pain, 582 Klaus Bielefeldt

42 Pelvic Pain, 593 Jan Alberto Paredes Mogica, Milana Bochkur Dratver, Elise J.B. De

43 Pediatric Chronic Pain Management, 620 Angelica A. Vargas, Ravi Shah, Bonnie S. Essner, Santhanam Suresh

44 Geriatric Pain Management, 637 Keela A. Herr, Staja Q. Booker, Lynn Nakad, David J. Derrico

45 Managing Pain During Pregnancy and Lactation, 647 Geeta Nagpal, Feyce M. Peralta, James P. Rathmell

46 Rheumatologic Conditions, 663 David Andrew Walsh

47 Pain Management in Patients With Comorbidities, 675 Natalie H. Strand, Andrea L. Chadwick

Part 5:  Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues 48 Major Opioids and Chronic Opioid Therapy, 689 David Copenhaver, Rebecca Hoss, Megan H. Cortazzo, Iris Vuong, Scott M. Fishman

49 Minor Analgesics: Non-Opioid and Opioid Formulations, 703 Steven P. Stanos, Mark D. Tyburski, Sagar S. Parikh

50 The U.S. Opioid Crisis and the Legal and Legislative Implications, 720 Jordan Starr, Mohammed A. Issa, Ajay Wasan

51 Evaluation for Opioid Management: Opioid Misuse Assessment Tools and Drug Testing in Pain Management, 727 Robert N. Jamison, Samantha Curran

52 Pain and Addictive Disorders: Challenge and Opportunity, 734 Shannon Nugent, Mark Beitel, Gretchen Hermes, Marina Gaeta Gazzola, Declan Barry

53 Anti-depressants, 743 Anthony H. Dickenson, Ryan Patel, Charles E. Argoff

Contents

54 Adjunct Medications for Pain Management, 752 Daniel B. Larach, Andrea L. Chadwick, Charles E. Argoff, Robert W. Hurley

55 Skeletal Muscle Relaxants, 763 Ravneet Bhullar, Evangeline P. Koutalianos, Charles E. Argoff, Andrew Dubin

56 Cannabinoids for Pain Management, 769 Ning Nan Wang, Anuj Bhatia

57 Topical Analgesics, 777 Magdalena Anitescu, Charles E. Argoff

58 Psychological Approaches in Pain Management, 782 Dennis C. Turk, Akiko Okifuji

59 Evidence-Based Rehabilitation Approaches to Acute and Chronic Pain Management, 792 Dana Dailey, Kathleen A. Sluka, Carol G.T. Vance

60 Physical Rehabilitation for Patients With Chronic Pain, 800 Harriet Wittink, Jeanine A. Verbunt

61 The Integrative Approach to Pain Management, 809 Delia Chiaramonte, Brian Morrison, Chris D’Adamo

62 Patient Education and Self-Management, 823 David A. Williams, Silvie Cooper

xxiii

69 Minimally Invasive Procedures for Vertebral Compression Fractures, 939 Mithun Nambiar, Lee-Anne Slater, Joshua A. Hirsch, Ronil V. Chandra, Julian Maingard

70 Biopsychosocial Pre-screening for Spinal Cord and Peripheral Nerve Stimulation Devices, 950 Andrew J.B. Pisansky, Ajay Wasan, Mohammed A. Issa

71 Spinal Cord Stimulation, Peripheral Nerve Stimulation, Restorative Neurostimulation, Deep Brain Stimulation, and Motor Cortex Stimulation, 957 Leonardo Kapural, James Deering, Christopher Gilmore

72 Intrathecal Drug Delivery, 963 Timothy Furnish, Carlyle Peters Hamsher, Mark S. Wallace

73 Radiation Safety and Radiographic Contrast Agents, 980 James P. Rathmell, Honorio T. Benzon

74 Infection and Anticoagulation Considerations in Pain Procedures, 996 Michael C. Hanes, Honorio T. Benzon, David A. Provenzano

Part 7:  Pain Management in Special Situations and Special Topics 75 Pain Management in Primary Care, 1015 Katherine E. Galluzzi

Part 6:  Neural Block and Interventional Techniques

76 Pain Management in the Emergency Department, 1034

63 Neurolytic Agents, Neuraxial Neurolysis, and Neurolysis of Sympathetic Axis for Cancer Pain, 835

77 Management of Pain in Sickle Cell Disease, 1039

Heather A. Columbano, Amit Gulati, Robert W. Hurley

64 Head and Neck Blocks, 857 Antoun Nader, Jee Youn Moon, Mary Leemputte, Kenneth D. Candido

65

Interlaminar and Transforaminal Therapeutic Epidural Injections, 874 Ariana M. Nelson, Honorio T. Benzon, Magdalena Anitescu, Marc A. Huntoon

66

Radiofrequency Treatment, 892 Koen van Boxem, Maarten van Eerd, Thibaut Vanneste, Xander Zuidema, Jan van Zundert

67 Pain Interventions for the Knee, Hip, and Shoulder, 908 Christine L. Hunt, David A. Provenzano, Kailash Chandwani

68 Myofascial Injections and Fascial Plane Blocks for Perioperative and Chronic Pain Management, 924 Ariana M. Nelson, Carlos E. Guerrero, Andrea L. Chadwick

Andrew K. Chang Carlton D. Dampier

78 Burn Pain, 1045 Jatin Joshi, Mohammad Piracha, Christopher L. Wu

79 Pain Evaluation and Management in Patients With Limited Ability to Communicate Because of Dementia, 1052 Thomas Hadjistavropoulos, Una E. Makris

80 Disparities in Pain Care: Descriptive Epidemiology-Potential for Primary Prevention, 1059 Jana M. Mossey

81 Pain Management in the Critically Ill Patient, 1069 Liang Shen, John E. Rubin, James Littlejohn

82 Pain Management at the End of Life and Home Care for the Terminally Ill Patient, 1076 Dalya Elhady, Diane Novy

xxiv

Contents

Part 8:  Research, Ethics, Healthcare Policy, and Future Directions in Pain Management 83 Clinical Trial Design Methodology and Data Analytic Strategies for Pain Outcome Studies, 1095 Nebojsa Nick Knezevic, Patrick Schober, Roger Chou, Thomas R. Vetter

84 Outcome Domains and Measures in Acute and Chronic Pain Clinical Trials, 1111 Honorio T. Benzon, Hubert A. Benzon, Dennis C. Turk

85 Ethical Issues in Pain Research, 1123 Katherine Gentry, Gary A. Walco

86 Treatment Development: Directions and Areas in Need of Investigation, 1128 Steven P. Cohen, Nebojsa Nick Knezevic, David A. Williams, Christopher L. Wu

Index, 1139

1

History Is a Distillation of Rumor

NATALIE MORYL, CHARLES INTURRISI

THOMAS CARLYLE (1795-1881) Management of pain, such as the management of any disease, is as old as the human race. In the view of Christians, the fall of Adam and Eve in the Garden of Eden produced a long life of suffering pain for men and women. This act allegedly sets the stage for several disease concepts, including the experience of pain in labor and delivery, the concept that hard work is painful, the notion that blood, sweat, and tears are needed to produce fruit; the introduction of pain and disease to human existence; establishment of the fact that hell and its fires are painful; and the expectation that heaven is pure, delightful, spiritually pleasing, and of course, pain free. From a historical perspective, humans have deliberately and knowingly inflicted on one another many experiences associated with pain—from the earliest wars to the more recent irrational shooting incidents in Sandy Hook Elementary School in Newtown, Connecticut, and Marjory Stoneman Douglas High School in Parkland, Dallas from the scourging of Jesus to contemporary strife in the Middle East, the Rwandan genocide, the Irish “religious” fratricide, and the conflicts in Bosnia and the Balkans. All wars, including the great wars, World War I and World War II, the American Civil War, the Korean War, and the Vietnam War, have been associated with untold pain, suffering, and death. In these concepts, pain is viewed as a negative experience and one that is associated with disease and death. Many diseases, including infections, plagues, and genetic and acquired disorders, including cancer and COVID-19, can cause significant pain. In contrast to acute pain that may teach us a lesson, that is, we would not touch a hot stove the second time after the initial touch brings sharp short-lived pain, chronic pain offers no such benefits. It interferes with our quality of life, sleep, work, and enjoyment of life and often causes anxiety, depression, and decreased mobility, which may precipitate or worsen other medical conditions resulting from inactivity. Most recently, social media has created a platform for those who may ordinarily suffer in silence the freedom to share and open up about their suffering and pain. Social media has become a powerful tool for people with pain to share their stories and reach new audiences across the globe, creating new patient communities. This has empowered patients with pain to set up new expectations during treatment of conditions commonly associated with pain, such as cancer, diabetes, HIV, and others. Medical and technological advances in the 21st century have changed the outcomes of many diseases and the probability of survivorship. Cultural and religious changes in many societies have also changed the way patients view the disease. Various advocacy groups have empowered patients and caregivers to

change what is viewed as acceptable during various treatments. Patients’ experience has been gaining priority not only for patients but also for research, clinicians, and the medical system overall. Originally conceived in 2001 by the National Institutes of Health, the patient-reported outcomes measurement information system (PROMIS) has involved hundreds of medical researchers and psychometricians and received approximately $250 million in funding.1,2 Further research showed that not only patients wanted to drive communications by reporting their distress with pain and other symptoms, but both caregivers and clinicians found regular communications from the patient reporting pain and other symptoms useful for clinical care. This chapter focuses on some of the major historical events that have led to the current conceptualization of pain and its treatment as an independent specialty in modern medicine.

Pain and Religion The early concept of pain as a form of punishment from supreme spiritual beings for sin and evil activity is as old as the human race. In the book of Genesis, God told Eve that following her fall from grace, she would endure pain during childbirth: “I will greatly multiply your pain in childbearing; in pain you shall bring forth children, yet your desire shall be for your husband, and he shall rule over you” (Genesis 3:16). This condemnation led early Christians to accept pain as a normal consequence of Eve’s action and to view this consequence as being directly transferred to them. Thus any attempt to decrease the pain associated with labor and delivery was treated by early Christians with disapproval and disapproval. It was not until 1847, when Queen Victoria was administered chloroform by James Simpson for the delivery of her eighth child, Prince Leopold, that contemporary Christians and, in particular, Protestants accepted the notion that it was not heretical to promote painless childbirth as part of the obstetric process. From the Old Testament, Job has been praised for his endurance of pain and suffering. While Job’s friends wondered whether these tribulations were an indication that he had committed some great sin for which God was punishing him (Job x:17), Job was considered a faithful servant by God, not guilty of any wrongdoing. He was described as a man who was “blameless and upright” and one who feared God and turned away from evil.3 In the 5th century, St. Augustine wrote that “all diseases of Christians are to be ascribed to demons; chiefly do they torment the fresh baptized, yea, even the guiltless newborn infant,” thus implying that not even innocent infants escape the work of demons. In the 1st century, many Christians were rebuked and 3

4

PA RT 1 General Considerations

suffered ruthless persecution, including death, because of their belief in Jesus as the Messiah. Some who were subsequently described as martyrs endured their suffering in the belief that they did it for the love of Christ, and they felt that their suffering identified them with Christ’s suffering on the cross during his crucifixion.4 This may be the earliest example of the value of psychotherapy as an important modality in managing pain. Thus some present-day cancer patients with strong religious beliefs view their pain and suffering as part of their journey toward eternal salvation. This concept has led to several scientifically conducted and government-sponsored studies evaluating intercessory prayer as an effective modality for controlling cancer pain. To fully appreciate the historical concept of pain, it is important to reflect on the origins of the term “pain patient.” The word pain comes from the Latin word poena, which means that “punishment.” The word patient is derived from the Latin word patior, meaning “to endure suffering or pain.” Thus it is not too outrageous to appreciate that in ancient days persons who experienced pain were interpreted to have received punishment in the form of suffering that was either dispensed by the gods or offered up to appease the gods for transgressions.5,6 In some cultures, the tribal concept of pain came from the belief that it resulted from an “intrusion” from outside the body. These “intruders” were thought to be evil spirits sent by the gods as a form of punishment. In this setting, the role of medicine men and shamans flourished because these were the persons assigned to treat the pain syndromes associated with internal disease. Since it was thought that spirits entered the body by different avenues, the rational approach to therapy was aimed at blocking the particular pathway chosen by the spirit. In Egypt, the left nostril was considered to be the specific site where the disease entered. This belief was confirmed by Papyri and Berlin, who stated that the treatment of headache involved expulsion of the offending spirit by sneezing, sweating, vomiting, urination, and even trephination.7,8 In New Guinea, it was believed that evil spirits entered via a spear or an arrow, which then produced spontaneous pain.7 Thus it was common for the shaman to occasionally purge the evil spirit from a painful offending wound and neutralize it with his special powers or special medicines. Egyptians treat some forms of pain by placing an electric fish from the Nile over the wounds to control pain.8,9 The resulting electrical stimulation that produced relief of pain actually works by a mechanism similar to transcutaneous electrical nerve stimulation (TENS), which is frequently used today to treat pain. The Papyrus of Ebers, an ancient Egyptian manuscript, contains a wide variety of pharmacologic information and describes many techniques and recipes, some of which still have validity.8,9 Early Native Americans believed that pain was experienced in the heart, whereas the Chinese and India identified multiple points in the body where pain might originate or might be selfperpetuating.10 Consequently, attempts were made to drain the body of these “pain points” by inserting needles, a concept that may have given birth to the principles of acupuncture therapy, which is well over 2000 years old.11 The ancient Greeks were the first to consider pain to be a sensory function that might be derived from peripheral stimulation.12 In particular, Aristotle believed that pain was a central sensation arising from some form of stimulation of the flesh, whereas Plato hypothesized that the brain was the destination of all peripheral stimulation. Aristotle advanced the notion that the heart was the origin or processing center for pain. He based his hypothesis on the concept that an excess of vital heat was conducted by the blood

to the heart, where pain was modulated and perceived. Because of his great reputation, many Greek philosophers followed Aristotle and embraced the notion that the heart was the center for pain processing.13 In contrast, another Greek philosopher, Stratton, and other distinguished Egyptians, including Herophilus and Eistratus, disagreed with Aristotle and proposed the concept that the brain was the site of pain perception, as suggested by Plato. Their theories were reinforced by actual anatomic studies showing the connections between the peripheral and central nervous systems.14 Nevertheless, controversies between the opposing theories of the brain and the heart as the center for pain continued. It was not until 400 years later that the Roman philosopher Galen rejuvenated the works of the Egyptians Herophilus and Eistratus and greatly re-emphasized the model of the central nervous system. Although Galen’s work was compelling, he received little recognition until the 20th century. Toward the period of the Roman Empire, steady progress was made in understanding pain as a sensation similar to other sensations in the body. Developments in anatomy and, to a lesser extent, in physiology helped establish that the brain, not the heart, was the center for the processing of pain.15 While these advances were taking place, simultaneous advances were occurring in the development of therapeutic modalities, including the use of drugs (e.g. opium), as well as heat, cold, massage, trephination, and exercise, to treat painful illnesses. These developments led to the establishment of the principles of surgery for treating diseases. Electricity was first used by the Greeks of that era, as they exploited the power of the electrogenic torpedo fish (Scribonius longus) to treat the pain of arthritis and headache. Electrostatic generators, such as the Leyden jar, were used in the late Middle Ages, resulting in the re-emergence of electrotherapy as a modality for managing medical problems, including pain. However, there was a relative standstill in the development of electrotherapy as a medical modality until the electric battery was invented in the 19th century. Several attempts have been made to revive its use as an effective medical modality, but these concepts did not catch on and were largely used only by charlatans and obscure scientists and practitioners. Over the centuries, many modes of anesthesia/analgesia have been developed and refined so that their mortality and morbidity have become negligible. General anesthesia was formally discovered by William Morton in 1846. In 1847, while even the concept of analgesia for the relief of labor pain was considered heretical and unchristian, Simpson used chloroform to provide anesthesia for the labor pains of Queen Victoria during the delivery of her eighth child, Prince Leopold.9 This action helped legitimize the practice of pain relief during childbirth. Around the same time, a hollow needle and syringe were invented. Many local anesthetic agents have been discovered in this era. In 1888, Corning described using a local anesthetic, cocaine, to treat nerve pain. Techniques for local and regional anesthesia for both surgery and pain disorders have proliferated rapidly. The history of anesthesia is full of instances wherein attempts to relieve pain were initially met with resistance and sometimes violence. In the mid-19th century, Crawford Long from the state of Georgia in the United States attempted to develop and provide anesthesia, but contemporary Christians of that state considered him a heretic for his scholarly activity. As a result, he had to flee for his life from Georgia to Texas. Although surgical anesthesia was well-developed in the late 19th century, religious controversy over its use required Pope Pius XII to give his approval before anesthesia could be used extensively for surgical procedures.6 Pope Pius XII wrote, “The patient, desirous of avoiding or relieving pain, may

 

CHAPTER 1

History Is a Distillation of Rumor

5

without any disquietude of conscience, use the means discovered by science which in themselves are not immoral.” More recently, the Church endorsed palliative care, including pain management using high-dose opioids or sedatives at the end of life (even if lifeshortening) as long as the palliative therapies were proportionate and used to treat refractory symptoms in a terminally ill patient. Pope John Paul II stated: “Moreover, while patients in need of pain killers should not be made to forego the relief that they can bring, the dose should be effectively proportionate to the intensity of their pain and its treatment.” (http://www.ldysinger.stjohnsem. edu/@magist/1978_JP2/Addresses/04_11_pal-care.htm).

a curse in that it biased the medical community for more than half a century into believing that pain pathways and their interruption were the total answer to the pain puzzle. This trend began in the late 19th century by Letievant, who first described specific neurectomy techniques for treating neuralgic pain.23 Afterward various surgical interventions for chronic pain were developed and used, including rhizotomy, cordotomy, leukotomy, tractotomy, myelotomy, and several other operative procedures designed to interrupt the central nervous system and consequently reduce pain.24 Most of these techniques were abysmal failures that did not relieve pain and occasionally resulted in more pain than previously present.

Pain and Pain Theories

Pain as a Disease

Throughout the Middle Ages and the Renaissance, the debate on the origin and processing center of pain raged. Fortunes fluctuated between proponents of the brain theory and proponents of the heart theory, depending on which theory was favored. Heart theory proponents appeared to prosper when William Harvey, recognized for his discovery of the circulation, supported the heart as the focus for pain sensation. However, Descartes disagreed vehemently with the Harvey hypothesis, and his description of pain conducted from peripheral damage through nerves to the brain led to the first plausible pain theory, that is, the specificity theory.16 In his 1664 Treatise of Man, René Descartes traced a pain pathway and described pain as “a specific sensation, with its own sensory apparatus independent of touch and other senses.” In the 1850s, by examining the effect of incisions in the spinal cord, Schiff16 demonstrated that touch and pain were sensations independent of each other. He postulated that pain had its own specific nervous system pathways from the spinal cord that traveled to the brain. Further work along the same lines by Bliz,17 Goldscheider,18 and von Frey19 contributed to the concept that separate and distinct receptors exist for the modalities of pain, touch, warmth, and cold. During the 18th and 19th centuries, new inventions, new theories, and new thinking emerged. This period was known as the Scientific Revolution, and several important inventions took place, including the discovery of the analgesic properties of nitrous oxide, followed by the discovery of local anesthetic agents (e.g. cocaine). Anatomy has also developed rapidly as an important branch of science and medicine; most notably, the discovery of the anatomic division of the spinal cord into sensory (dorsal) and motor (ventral) divisions. In 1840 Mueller proposed that based on anatomic studies, there was a straight-through system of specific nerve energies in which specific energy from a given sensation was transmitted along sensory nerves to the brain.20 Mueller’s theories led Darwin to propose the intensive theory of pain,21 which maintained that the sensation of pain was not a separate modality but instead resulted from a sensory overload of sufficient intensity for any modality. This theory was modified by Erb22 and then expanded by Goldscheider18 to encompass the roles of both stimulus intensity and central summation of stimuli. Although the intensive theory was persuasive, the controversy continued, with the result that by the mid-20th century, the specificity theory was universally accepted as the more plausible theory of pain. With this official, though not unanimous blessing of the contemporary scientific community, strategies for pain therapy began to focus on identifying and interrupting pain pathways. This tendency was both a blessing and a curse. It was a blessing in that it led many researchers to explore surgical techniques that might interrupt pain pathways and consequently relieve pain, but it was

The cardinal features of disease as recognized by early philosophers included calor, rubor, tumor, and dolor. The English translation is heat, redness, swelling, and pain. One of the important highlights in the history of pain medicine was the realization that even though heat, redness, and swelling may disappear, pain can continue and be unresponsive on occasion to different therapeutic modalities. When pain persists long after the natural pathogenic course of disease has ended, a chronic pain syndrome develops with characteristic clinical features, including depression, disability, disuse, and decreased mobility, causing other medical conditions such as obesity and arthritis to worsen. The risk of another comorbidity of chronic pain increases with chronic opioid exposure that, in some instances, can be complicated by dependency and opioid use disorder, formally known as addiction. John Dryden once wrote, “For all the happiness mankind can gain is not in pleasure, but in rest from pain.” Thus many fatal nonpainful diseases are not as feared as relatively trivial, painful ones. Physicians and healers have focused their attention on managing pain. Thus in managing cancer, an important measure of successful treatment is the success with which any associated pain is managed. Although many technological advances have been made in medicine, it is only within the past 10 to 20 years that significant strides have been made in dealing with chronic pain as a disease entity per se—one requiring specialized assessment, workup, diagnosis, and specialized therapeutic interventions targeting the cause of pain and pain itself.

Pain in the 20th Century In 1907, Schlosser reported significant relief of neuropathic pain for long periods with the injection of alcohol into damaged and painful nerves. Reports of similar treatment came from the management of pain resulting from tuberculous and neoplastic invasion.25 In 1926 and 1928, Swetlow and White, respectively, reported on the use of alcohol injections into thoracic sympathetic ganglia to treat chronic angina. In 1931, Dogliotti described the injection of alcohol into the cervical subarachnoid space to treat pain associated with cancer.26 One consequence of war has been the development of new techniques and procedures to manage injuries. During World War I (1914-1918), numerous injuries were associated with trauma (e.g. dismemberment, peripheral vascular insufficiency, and frostbite). In World War II (1939-1946), peripheral vascular injuries as well as phantom limb phenomena, causalgia, and many sympathetically mediated pain syndromes occurred. Leriche developed the technique of sympathetic neural blockade with procaine to treat the causalgic injuries of war.27 John Bonica, himself an army surgeon during World War II, recognized the gross inadequacy of

6

PA RT 1 General Considerations

managing war injuries and other painful states of veterans with the existing uni-disciplinary approaches.28 This led him to propose the concept of multi-disciplinary, multimodal management of chronic pain, including behavioral evaluation and treatment. Bonica also highlighted the fact that all kinds of pain were being undertreated; his work has borne fruit in that he is universally considered the “father of pain,” and he was the catalyst for the formation of many established national and international pain organizations. Bonica’s lasting legacy is his historic volume The Management of Pain, first published in 1953. The clinic that he developed at the University of Washington in Seattle remains a model for the multi-disciplinary management of chronic pain. As a result of his work, the American Pain Society (APS) and the International Association for the Study of Pain (IASP) were formed. Anesthesiology was developed as a division of surgery and did not reach full autonomy until after World War II. With the discovery of new local anesthetics, regional anesthesia began to flourish in the United States. Bonica’s wife had a very difficult delivery, alerting Dr. Bonica to the gap in childbirth analgesia. He played a major role in advancing the safe use of epidural anesthesia to manage the pain associated with labor and delivery in the 20th century. Regional anesthesia suffered a significant setback in the United Kingdom with negative publicity surrounding the 1954 cases of Wooley and Roe, in whom serious and irreversible neurological damage occurred after spinal anesthesia. It took three more decades to fully overcome this setback and to see regional anesthesia widely accepted as safe and effective in the United Kingdom. Several persons contributed significantly to the development of regional anesthesia, including Corning, Quincke-August Bier, Pitkin, Etherington-Wilson, Barker, and Adriani. An outstanding contribution in the field of research was the development and publication of the gate control theory by Melzack and Wall in 1965.29 This theory, which was built on the preexisting and prevalent specificity and intensive theories of pain, provided a sound scientific basis for understanding pain mechanisms and for developing other concepts on which sound hypotheses could be developed. The gate control theory emphasizes the importance of both ascending and descending modulation systems and provides a solid framework for the management of different pain syndromes. The gate control theory almost single-handedly legitimized pain as a scientific discipline and led not only to many other research endeavors building on the theory but also to the maturity of pain medicine as a science.30 As a consequence, the American Academy of Pain Medicine (AAPM), the American Society of Regional Anesthesia and Pain Medicine, the IASP, and the World Institute of Pain (WIP) have become serious and responsible organizations that deal with various aspects of pain medicine, including education, science, certification, and credentialing of members of the specialty of pain medicine. Dr. Jan Sternsward, Chief of the Cancer Unit at the World Health Organization (WHO), collaborated with IASP to focus on cancer pain and palliative care for cancer patients worldwide. In 1982, representatives from IASP, including Drs. Mark Swerdlow, John Bonica, Robert Twycross, Kathleen Foley, and Fumi Takeda met in Italy and developed what eventually became the 1986 report entitled cancer pain relief. With IASP, WHO made a historic statement declaring pain relief a human right issue and called on member states to make pain-relieving drugs available, including oral morphine, which was on the WHO essential drug list. Memorial Sloan Kettering’s James Ewing Hospital (MSK) was a focal point for the main site to evaluate new analgesics in patients with cancer pain. A young internist, Dr. Raymond Houde, with the assistance of a research nurse, Ada Rogers, and a psychologist,

Stanley Wallenstein, began work on opioid pharmacology, including equianalgesic opioid doses in 1951. From Henry Beecher at Harvard and from his own experiments with student volunteers at Michigan, he learned that the perception of pain was modified by multiple variables—emotional state, expectations or fears for the future, previous medications or treatments, and the course of the disease itself. Houde’s meticulous and patient-sensitive methods were recognized in the late 1950s as the standard for analgesic trials. A neurologist, Kathleen Foley, brought together various programs to form the first designated pain service in a cancer setting in the United States. In addition to Dr. Houde and Ada Rogers, it included Charles Inturrisi, professor of pharmacology at Weill Cornell Medical College, and Gavril Pasternak, professor of neurology, who was developing a laboratory to study opiate receptors in the brain. This program combined basic and clinical research, along with a training program as well as a supportive care program for patients with complicated pain started by a PhD nurse practitioner, Nessa Coyle. Dr. Kathleen Foley published the first taxonomy of cancer pain syndromes.

Pain and the Impact of Psychology The history of pain medicine is incomplete without acknowledging the noteworthy contributions of psychologists. Their influential research and clinical activities have been an integral part of a revolution in the conceptualization of the pain experience.31 For example, in the early 20th century, the role of the cerebral cortex in the perception of pain was controversial because of a lack of understanding of the neuroanatomic pathways and the neurophysiologic mechanisms involved in pain perception.32,33 This controversy largely ended with the introduction of the gate control theory by Wall and Melzack in 1965.29 The gate control theory has stood the test of time in subsequent research using modern brainimaging techniques such as positron emission tomography, functional magnetic resonance imaging, and single-photon emission computed tomography have also described the activation of multiple cortical and subcortical sites of activity in the brain during pain perception. Further elaboration of the psychological aspects of the pain experience includes the three psychological dimensions of pain: sensory-discriminative, motivational-affective, and cognitive-evaluative.34 Psychological researchers have greatly advanced the field of pain medicine by reconceptualizing both the etiology of pain experience and treatment strategy. Early pain researchers conceptualized pain experience as a product of either somatic pathology or psychological factors. However, psychological researchers have convincingly challenged this misconception by presenting research that illustrates the complex interaction between biomedical and psychosocial factors.35–37 This biopsychosocial approach to pain encourages the realization that pain is a complex perceptual experience modulated by a wide range of biopsychosocial factors, including emotions, social and environmental contexts, and cultural background, as well as beliefs, attitudes, and expectations. As the acutely painful experience transitions into a chronic phenomenon, these biopsychosocial abnormalities develop permanency. Thus chronic pain affects all facets of a person’s functional universe at great expense to the individual and society. Consequently, logic dictates that this multimodal etiology of pain requires a multimodal therapeutic strategy for optimal cost-effective treatment outcomes.38,39 Additional contributions from the field of psychology include therapeutic behavioral modification techniques for pain

 

CHAPTER 1

management. Techniques such as cognitive behavioral intervention, guided imagery, biofeedback, and autogenic training are the direct results of using the concepts presented in the gate control theory. In addition, neuromodulatory therapeutic modalities such as TENS, peripheral nerve stimulation, spinal cord stimulation, and deep brain stimulation are also logical offspring of the concepts presented in the gate control theory. The evaluation of candidates for interventional medical procedures is another valuable historical contribution from the field of psychology. Not only is the psychologist’s expertise in the identification of appropriate patients valuable for the success of therapeutic procedural interventions for the management of pain, but the psychologist’s expertise is also helpful in identifying patients who are not appropriate candidates for procedural interventions. Thus psychologists have contributed positively to the cost effectiveness and utility of diagnostic and therapeutic pain medicine. Psychologists’ contribution to the care of patients with cancer pain is invaluable. Psychological research in cancer led by Dr. Jimmie Holland et al., MSK led to the development of a new field of psycho-oncology that is essential in addressing the pain and suffering of patients with cancer pain.

Pain and Pain Organizations World Health Organization (WHO) When diplomats met to form the United Nations in 1945, one of the things they discussed was the establishment of a global health organization. A year later, in New York, the International Health Conference in New York approved the Constitution of the WHO. In 1986, the WHO published the first analgesia step ladder and a detailed report on cancer pain relief, highlighting the prevalence and assessment of cancer pain, its undertreatment, recommended therapeutic modalities, and the need to educate healthcare workers and the general public. Among the few countries, the United States was represented by Dr. John J. Bonica, President of the IASP, and Dr. Kathleen Foley, Chair of the Pain Service, Department of Neurology, Sloan Kettering Cancer Center in New York.

History Is a Distillation of Rumor

7

Special interest groups within the IASP include pain in children, neuropathic pain, herbal medicine, and cancer pain. The IASP also promotes and administers chronic pain fellowship programs for deserving candidates worldwide.

The American Pain Society (APS) Spurred by the burgeoning public interest in pain management and research, as well as by the formation of the Eastern and Western United States Chapters of the IASP, the APS was formed in 1977 as a result of a meeting of the Ad Hoc Advisory Committee on the Formation of a National Pain Organization. Its main function was to carry out the mission of the IASP at a national level through interprofessional collaborations between basic and clinical pain researchers and clinicians. APS was dissolved in 2019 through Chapter 7 bankruptcy resulting from the OxyContin scandal. APS maintains that it was another victim of the opioid crisis after being “named a defendant in numerous spurious lawsuits related to opioids prescribing and abuse” Although APS has been dissolved, its journal, the Journal of Pain, continues independent of the APS that originated it. The United States Association for the Study of Pain is a new professional society for United States-based pain researchers.

Commission on the Accreditation of Rehabilitation Facilities In 1983, the Commission on Accreditation of Rehabilitation Facilities (CARF) was the first to offer a system of accreditation for pain clinics and pain treatment centers. The CARF model was based on a rehabilitation system that emphasized both physical and psychosocial rehabilitation of patients suffering from pain. CARF promoted multi-disciplinary pain management programs offering not only medical but also mandatory psychological and physical therapy modalities for the management of pain. Its major goals included objective measures such as increased physical function, reduced intake of medication, and return-to-work issues.

The American Academy of Pain Medicine (AAPM) The International Association for the Study of Pain (IASP) The IASP is the largest multi-disciplinary, international association in the field of pain. Founded in 1973 by John J. Bonica, MD, the IASP is a nonprofit professional organization dedicated to furthering research on pain and improving the care of patients experiencing pain. Membership is open to scientists, physicians, dentists, psychologists, nurses, physical therapists, and other health professionals actively engaged in pain and to those who have a special interest in the diagnosis and treatment of pain. The IASP has members of more than 100 national chapters. The goals and objectives of the IASP are to foster and encourage research on pain mechanisms and pain syndromes and improve the management of clinical pain. One of the instruments used to disseminate new information is the journal Pain. In addition, the IASP promotes and sponsors a highly successful biennial world congress, as well as other meetings. The IASP encourages the development of national chapters for the national implementation of the IASP’s international mission. In addition, the IASP encourages the adoption of a uniform classification, nomenclature, and definition of pain and pain syndromes.

AAPM was formed in 1983 at a meeting of the APS in Washington, DC, when a group of physicians formed a separate American Academy of Algology, later renamed the AAPM. Their goal was to address the deficiency in evaluating pain physicians’ competence by creating uniform standards for training and credentialing. AAPM sponsored the American College of Pain Medicine, which organized, developed, and administered the first credentialing examination in 1992. The American College of Pain Medicine is not now called the American Board of Pain Medicine (ABPM). The goals of the AAPM include the promotion of quality care through research, education, and reimbursement. The Clinical Journal of Pain, the initial journal of the AAPM, is not affiliated with any pain medicine society. The AAPMs present journal is Pain Medicine. Both journals are well-respected.

The American Society of Regional Anesthesia and Pain Medicine (ASRA) ASRA is the largest subspecialty medical society in anesthesiology and the leader in regional anesthesia and acute and chronic pain medicine. The society is based in the United States; other societies on regional anesthesia are based in Europe, Asia, and

8

PA RT 1 General Considerations

Latin America. The international societies of regional anesthesia have changed the name of their highly cited journal, Regional Anesthesia, to Regional Anesthesia and Pain Medicine.

The American Society of Interventional Pain Physicians (ASIPP) ASIPP is a national organization that represents the interests of interventional pain physicians. The society was founded in 1998 by Dr. L. Manchikanti and associates to improve the delivery of interventional pain management services in various settings, including hospitals, ambulatory surgical centers, and medical offices. ASIPP has become a successful advocate for the political and regulatory aspects of pain medicine. The ASIPP journal is indexed and called Pain Physician.

The American Academy of Hospice and Palliative Medicine (AAHPM) AAHPM was founded in 1988 as an Academy of Hospice Physicians, and in 1996 it changed its name to the AAHPM to reflect a goal of this organization to control pain and other symptoms not only at the end of life but throughout the disease trajectory, from diagnosis through survivorship or end of life. AAHPM works closely with the American Board of Hospice and Palliative Medicine and disseminates its research through affiliation with a wellestablished Journal of Pain and Symptom Management. The goals of the multi-disciplinary AAHPM include providing education and clinical practice standards, fostering research, and sponsoring public policy advocacy for the chronically and terminally ill and their families.

The American Academy of Orofacial Pain The American Academy of Orofacial Pain (AAOP) is an organization of healthcare professionals dedicated to the alleviation of pain and suffering through education, research, and patient care in the field of orofacial pain and associated disorders. The AAOP goals include the establishment of acceptable criteria for the diagnosis and treatment of orofacial pain and temporomandibular disorders, sponsorship of research, and annual meetings. Their journal, together with the European, Asian, Australian, and New Zealand Academy of Orofacial Pain, is the Journal of Oral and Facial Pain and Headache.

The American Academy of Pain Management (AAP Management) AAP Management was founded in 1988 and changed its name to the Academy of Integrative Pain Management (AIPM) in 2016. The AIPM has promoted an integrative, interdisciplinary model of pain management. The AIPM closed its operations in 2019.

American Society for Pain Management Nursing (ASPMN) Founded in 1990, ASPMN is an organization of professional nurses dedicated to providing access to specialized care for patients experiencing pain, providing education to the public regarding self-advocacy for their pain needs, and providing a network for nurses working in the pain management field. The ASPMN Journal is Pain Management Nursing.

The International Headache Society (IHS) The International Headache Society is based in London. Its leadership is worldwide and is known for their international classification of headache disorders, now in its third edition. Another notable guideline is their International Classification of Orofacial Pain. In addition, their journal, Cephalalgia, has a fairly high impact factor.

The World Institute of Pain (WIP) The WIP is an international organization that aims to promote the best practice of pain medicine throughout the world through training via international seminars and exchange of clinicians and education via newsletters, scientific seminars, and publications. One of the most important initiatives if the WIP is to develop an international examination process to certify qualified interventional pain physicians. After showing proficiency in both general pain knowledge and safe performance of interventional procedures, successful candidates are awarded the designation of Fellow of Interventional Pain Practice (FIPP). In addition, the journal of the WIP, Pain Practice, is indexed and has a very respectable impact factor.

The Spine Intervention Society (SIS) The SIS, formerly called the International Spine Injection Society, is known for its leadership in interventional pain medicine. Their landmark monograph, Practice Guidelines for Spinal Diagnostic and Treatment Procedures, is the gold standard for spine interventions. Together with the AAPM, their journal is Pain Medicine.

The International Neuromodulation Society (INS) Founded in 1989, INS is a unique multi-disciplinary, international society that consists of not only clinicians and scientists but also engineers dedicated to the scientific development and awareness of neuromodulation – the alteration of nerve activity through the delivery of electromagnetic stimulation or chemical agents to targeted sites of the body. The INS promotes the field through meetings and its journal Neuromodulation.

American Pain Foundation (APF) Founded in 1997 by the APS (see above for the current status of APS), APF was the first pain organization specifically formed to serve the interests of people with diverse disorders associated with the presence of significant pain. Its goals include patient education, promoting recognition of pain as a critical health issue, and patient access to proper medical care. Regrettably, the organization dissolved in early 2012 because of financial difficulties.

International Association of Hospice and Palliative Care (IAHPC)) IAHPC was founded in 1980. From this, the Academy of Hospice Physicians grew. Two new independent organizations were formed: the AAHPM and the International Hospice Institute and College. IAHPC serves as a global platform to inspire, inform, and empower individuals, governments, and organizations to increase access and optimize the practice of palliative care.

 

CHAPTER 1

The Worldwide Hospice Palliative Care Alliance (WHPCA) WHPCA is an international non-governmental organization that includes members from over 100 countries, focusing exclusively on hospice and palliative care development worldwide. International Children’s Palliative Care Network (ICPCN) The ICPCN is the only global organization working to improve access to palliative care for children. The ICPCN is recognized globally for its leadership, a wealth of educational resources, and a network of members in over 120 countries.

Pain and the Hospice Movement Hospice is a medieval term representing a welcome place of rest for pilgrims to the Holy Land. The concept of hospice dates back to the reign of Emperor Julian the Apostate, when Fabiola, a Roman matron, created a place for sick and healthy travelers and cared for the dying.40 In general, hospitals were regarded as Christian institutions, and in medieval times most hospitals were used as hospices and vice versa.41 The 17th century Catholic priest St. Vincent DePaul founded the Sisters of Charity in Paris as a home for the poor, the sick, and the dying. The movement grew, and the Protestant pastor Fliedner founded Kaiserwerth 100 years later. Nuns from both Sisters of Charity and Kaiserwerth accompanied Florence Nightingale to Crimea to care for wounded soldiers.42 In 1902, the Irish Sisters of Charity founded St. Joseph’s hospice. Fifty years later, Cecily Saunders became the founder and medical director of St. Christopher’s Hospice in England. She was initially trained as a nurse and served during World War II. After becoming injured, she received training as a social worker. She subsequently developed a keen interest in terminal cancer patients and underwent training in medical school to become a physician. She emphasized the importance of pain control at the end of life, believing patients’ pain reports, the need for frequent pain assessments, and the scheduling of opioids for chronic pain instead of administering them on an as-needed basis.43 For all her efforts and leadership, she is regarded as the “mother of palliative care” and was knighted for her contributions to the hospice movement and care of dying cancer patients. Dame Saunders’ teachings are endorsed by medical and nursing schools today.

Pain and Palliative Care Palliative care is a more recent specialty. The term palliative comes from Medieval Latin palliativus, “under cloak” or to cover, mitigate, or alleviate. Palliative care is provided to improve the quality of life of patients with serious or life-threatening diseases, such as cancer. The goal is to prevent or treat the symptoms and side effects of the disease as early as possible, in addition to any

History Is a Distillation of Rumor

9

related psychological, social, and spiritual problems. Pain management, research, education, and advocacy are integral parts of palliative care.

Opioid Crisis While trying to empower the patients to report pain and aiming at pain free outcomes of dental, surgical, and medical interventions and with pharma advertising directly to patients, opioid prescriptions and opioid overdoses started to increase, reaching the peak in 2017.44 The first wave was from abuse of prescription opioids that was addressed by the Center for Disease Control and state and institutional guidelines.45 Unfortunately, some of the patients with prescription opioid addiction went on to abuse street drugs, including heroin and illicit fentanyl. Pharmaceutical companies, sued by several state attorney generals, agreed to a master settlement to defray the cost of the opioid crisis. As a result, the prescription of non-opioids has increased, and the search for non-opioid analgesics has become a priority for research and pharmaceutical companies. Access to the treatment of opioid addiction has become one of the priorities of the federal government, resulting in buprenorphine-naloxone medicationassisted addiction treatment available through primary care and other certified clinicians. This has become an alternative to methadone maintenance clinics that are much more easily accessible to patients. Since COVID-19, there has been an increase in opioid overdose deaths.

Pain and the Future The contributions of the IASP, WIP, International Headache Society (IHS), AAPM, ASRA, ASIPP, and many other international, national, regional, state, and local organizations devoted to pain and pain management led to research, innovative techniques, new drug development, dissemination of knowledge, and local, national, and international networking. Pain practitioners and investigators are no longer isolated, and a flurry of published manuscripts and textbooks now cover a wide array of topics in pain medicine. Official credentialing is through the certificate of added qualification by the American Board of Anesthesiology. In addition, the WIP offers FIPP certification through examination. Some organizations are now offering certifications on basic knowledge and expertise in the use of ultrasound for interventional pain procedures. Giving the patient’s voice through patient-reported outcomes (PRO) and social networking led to new patient-healthcare provider relationships. Data on PROs and the increasing interest in cost effectiveness made it clear that the scientific community concerned with pain must develop reliable and reproducible outcome measures to maintain high quality, credibility, integrity, and competence in the management of pain.

Key Points • The word pain comes from the Latin word poena, which means “punishment.” The word patient is derived from the Latin word patior, meaning “to endure suffering or pain.” • The history of anesthesia is full of instances in which attempts to relieve pain were initially met with resistance and at times violence.

• Developments in anatomy and physiology helped establish that the brain, not the heart, was the center for processing pain. • The tenet of the specificity theory, proposed by Descartes and revised by Schiff, was that each sensory modality, including pain, was transmitted along an independent pathway.

10

PA RT 1 General Considerations

• The use of chloroform to provide anesthesia for the labor pains of Queen Victoria helped to legitimize the practice of pain relief during childbirth. • The clinic that Bonica developed at the University of ­Washington in Seattle remains a model for the multi-disciplinary management of chronic pain. • The pain program that was developed at the Memorial Sloan Kettering Cancer Center was the first cancer pain program to remain a model for multi-disciplinary pain and palliative care programs for management and research in cancer pain.

• An outstanding contribution in the field of research was the development and publication of the gate control theory by ­Melzack and Wall in 1965. • Psychological researchers have greatly advanced the field of pain medicine by reconceptualizing both the etiology of pain experience and treatment strategy. • Several organizations have advanced the science and practice of pain medicine, including the IASP, American Society of Regional Anesthesia and Pain Medicine, AAPM, ASIPP, WIP, SIS, IHS, and INS. Pain medicine practitioners are certified by the American Board of Anesthesiology and the ABPM.

Suggested Readings

Saunders C. The last stages of life. Am J Nurs. 1965;65:70. Turk DC. Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. Clin J Pain. 2002;18:355. Turk DC, Okifuji A. Psychological factors in chronic pain: evolution and revolution. J Consult Clin Psychol. 2002;70:678. Unruh AM. Voices from the past: ancient views of pain in childhood. Clin J Pain. 1992;8:247–254. Warfield C. History of pain relief. Hosp Pract. 1988;7:121–122.

Abram SE. 1992 bonica lecture. Advances in chronic pain management since gate control. Reg Anesth. 1993;18:66. Campbell L. History of the hospice movement. Cancer Nurs. 1986;9:333. Fordyce WE. Behavioral factors in pain. Neurosurg Clin N Am. 1991;2:749. Melzack R, Wall PD. Pain mechanisms: a new theory. Sci. 1965;150:971. Raj PP. 1990 Labat lecture. Pain relief: fact or fancy? Reg Anesth. 1990;15:157.

The references for this chapter can be found at ExpertConsult.com.

References 1. PROMIS Health Organization. Available at: http://www.promishealth.org. 2. Basch E, Stover AM, Schrag D, et al. Clinical utility and user perceptions of a digital system for electronic patient-reported symptom monitoring during routine cancer care: findings from the PRO-TECT trial. JCO Clin Cancer Inform. 2020;4:947. http://doi. org/10.1200/CCI.20.00081. 3. Unruh AM. Voices from the past: ancient views of pain in childhood. Clin J Pain. 1992;8:247. 4. Caton D. The secularization of pain. Anesthesiol. 1985;62:93. 5. Warfield CA. A history of pain relief. Hosp Pract (Off Ed). 1988;23:121. 6. Jaros JA. The concept of pain. Crit Care Nurs Clin North Am. 1991;3:1. 7. Procacci P, Maresca M. Pain concepts in Western civilization: a historical review. In: Benedetti C, ed. Advances in Pain Research and Therapy, Volume 7. Recent Advances in The Management of Pain. New York: Raven Press; 1984:1. 8. Todd EM. Pain: historical perspectives. In: Aronoff GM, ed. Evaluation and Treatment of Chronic Pain. Baltimore: Urban and Schwarzenberg; 1985:1. 9. Castiglioni A. A History of Medicine. New York: Alfred A Knopf; 1947. 10. Lin Y. The Wisdom of India. London: Joseph; 1949. 11. Veith I, Huang Ti Ne, Ching Su Wen. The Yellow Emperor’s Classic of Internal Medicine. Baltimore: William & Wilkins, 1949. 12. Bonica JJ. Evolution of pain concepts and pain clinics. In: Brena SF, Chapman SL eds. Chronic Pain: Management Principles (Clinics in Anaesthesiology). Philadelphia: W.B. Saunders; 1985. 13. Bonica JJ. The Management of Pain. Philadelphia: Lea and Febiger; 1953. 14. Rey R. History of Pain, XIII. Paris: Éditions La Découverte; 1993:19. 15. Keele KD. Anatomies of Pain. Oxford: Blackwell Science; 1957. 16. Schiff M. Lerbuch der Phusiologie der Muskel, und Nervenphysiologie. Lahr: M. Schauenburg; 1848. 17. Bliz M. Experimentelle beitrag zur lösung der frage über die spezifische energie der hautnerven. Z biol. 1884;20:141. 18. Goldscheider A. Die spezifische energie der gefuhlsnerven der haut. Monatsschr Prakt Germatol. 1884;3:282. 19. von Frey M. Ber verhandl konig sachs ges wiss. Beitr Zur Physiol des Schmerzsinnes. 1894;45:185. 20. Mueller J. W Baly (transl) Handbuch der Physiologie des Menschen. London: Taylor and Walton; 1840. 21. Darwin E. Zoonomia, or the Laws of Organic Life. London: J Johnson; 1794. 22. Erb WH. Krankheitender peripherischen cerebrosphinalen ner ven. In: Luckey G, ed. Some recent studies of pain. Am J Psychol. 1895;7:109.

23. Letievant E. Traites des Sections Nerveuses. Paris: J B Bailliere; 1873. 24. White JC, Sweet WH. Pain and the Neurosurgeon: a forty-year experience. Springfield, Illinois: Charles C Thomas; 1969. 25. Raj PP. History of pain management. In Practical Management of Pain. Chicago: Yearbook Medical Publishers; 1986:3. 26. Dogliotti AM. Traitement des syndromes douloureqx de la Peripherie par alcoholisation sub-arachnoidienne. Presse Med. 1931;39:1249. 27. Leriche R. Surgery of Pain. Baltimore: William & Wilkins; 1939. 28. Bonica JJ. Cancer pain. In: Bonica JJ, ed. The Management of Pain. 3rd ed. Philadelphia: Lea & Febiger; 1990:400. 29. Melzack R, Wall PD. Pain mechanisms: a new theory. Sci. 1965;150:971. 30. Abram SE. 1992 bonica lecture. Advances in chronic pain management since gate control. Reg Anesth. 1993;18:66. 31. Turk DC, Okifuji A. Psychological factors in chronic pain: evolution and revolution. J Consult Clin Psychol. 2002;70:678. 32. Head H, Holmes G. Sensory disturbances from cerebral lesions. Brain. 1911;34:102. 33. Marshall J. Sensory disturbances in cortical wounds with special reference to pain. J Neurol Neurosurg Psychiatry. 1951;14:187. 34. Melzack R, Casey KL. Sensory, motivational and central control determinants of pain: a new conceptual model. In: Kenshalo D, ed. The skin senses. Springfield, Illinois: Charles C. Thomas; 1968:423– 443. 35. Fordyce WE. Psychological factors in the failed back. Int Disabil Stud. 1988;10:29. 36. Fordyce WE. Behavioural science and chronic pain. Postgrad Med J. 1984;60:865. 37. Fordyce WE. Behavioral factors in pain. Neurosurg Clin N Am. 1991;2:749. 38. Turk DC. Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. Clin J Pain. 2002;18:355. 39. Turk DC. Chronic non-malignant pain patients and health economic consequences. Eur J Pain. 2002;6:353. 40. Craven J, Wald FS. Hospice case for dying patients. Am J Nurs. 1993;75:1816. 41. Allan N. Hospice to hospital in the near east: an instance of continuity and change in late antiquity. Bull Hist Med. 1990;64:446. 42. Campbell L. History of the hospice movement. Cancer Nurs. 1986;9:333. 43. Saunders C. The last stages of life. Am J Nurs. 1965;65:70. 44. Benzon HT, Anderson TA. Themed issue on the opioid epidemic: what have we learned? Where do we go from here?. Anesth Analg. 2017;125:1435. 45. Dowell D, Haegerich TM, Chou R. CDC guideline for pre scribing opioids for chronic pain-United States, 2016. JAMA. 2016;315:1624.

10.e1

2

Classification of Acute Pain and Chronic Pain Syndromes

JUAN C. MORA, RENE PRZKORA, MATTHEW MERONEY

Definition of Pain The International Association for the Study of Pain (IASP) updated the definition of pain in 2020. The previous definition remained unchanged for more than 40 years (originally released in 1979), but it provided a necessary and widely accepted description in the medical field. The 1979 definition of pain was as follows: “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1 One year later, with a better understanding of pain and new research, the IASP understood the necessity of modifying the definition. They created an expert task force comprising 14 members. After two years of discussion, the 2020 definition was updated to read: “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”2 This new definition includes those unable to articulate their pain verbally, such as infants and the elderly. It is also important to note a few items to make this definition complete:2 1. Pain is a personal experience influenced by biologic, psychological, and social factors. 2. Pain cannot be inferred solely from activity in sensory neurons or nociceptors. 3. Each individual will learn the concept of pain through life experiences. 4. The report of an experience of pain should be respected. 5. Despite having an important adaptive role, pain may have adverse effects on function and social and psychological wellbeing. 6. A verbal description is only one of several behaviors to express pain, and the inability to communicate does not negate the possibility of experiencing pain.

Taxonomy and Classification Taxonomy derives from the Greek words tasso (arrangement) and nomia (rules or law), and it is defined as an organization of concepts arranged using hierarchical relationships. The purpose of creating a medical classification is pragmatic and includes exchanging standardized information, facilitating statistical comparisons, and improving research at national and international levels.3 An ideal classification should be comprehensive, biologically plausible, reliable, and exhaustive, and each item should be independent and

mutually exclusive. However, achieving all of these can be challenging in medical taxonomy.3 Currently, there are multiple classifications, groupings, and descriptions of different medical disciplines. Perhaps the most well known is the International Classification of Diseases (ICD), which includes multiple diagnoses and is used worldwide. Classifications related to pain have also been developed. Currently, there is a classification for psychiatric conditions that can be found in the Diagnostic and Statistical Manual of Mental Disorders (DSM), fifth edition (V). The categorization of headaches can be found in the International Classification of Headache Disorders. The classification for acute pain can be found in the ACTTION-APSAAPM Acute Pain Taxonomy (see Section E, Acute Pain, for more on this workgroup). The classification of chronic pain was provided by the IASP.

International Classification of Diseases (ICD) In 1793, Dr. Francois Bossier de Sauvages de Lacroix, a French physician and botanist, developed a categorization of 10 main pathologic conditions, subdivided into 2,400 unique diseases. This is believed to be the origin of the ICD.4 In 1853, a plan was made to create a worldwide system for classifying causes of mortality during the International Statistical Congress. This work was completed in 1893 and named the “International List of Causes of Death.” This list was adopted by multiple countries, including the United States, and was updated every decade until 1938. In 1948, it was renamed the ICD when the World Health Organization took over this classification system, expanding the list to include not only mortality but also morbidity.4 The ICD-6 was the first version to include psychiatric disorders. Starting with the ICD-9 in 1977, the list included 4-digit-level categories and optional 5-digit subdivisions, resulting in a better level of detail. This was advanced in 1992 with the ICD-10 when an alphanumeric code was introduced, dramatically improving specificity and expanding it from 17,000 to approximately 155,000 codes.4 In this version, the conditions were classified by causal agents, systems of the body, symptom pattern, and type of psychiatric illness.3 The implementation of the ICD-10 in the United States was officially approved in 2015 with clinical modifications. The 11th and newest version of the ICD was released in 2018 and approved by the World Health Assembly in 2019. With the contribution of an IASP taskforce, this version is considered more flexible than its predecessor. It has vast advantages in terms 11

12

PA RT 1 General Considerations

Chronic pain

Chronic primary pain

Chronic cancerrelated pain

Chronic postsurgical or posttraumatic pain

Chronic neuropathic pain

Chronic secondary headache or orofacial pain

Chronic secondary visceral pain

Chronic secondary musculoskeletal pain

• Figure 2.1  International Classification of Diseases (ICD)-11 chronic pain terms.

of chronic pain definitions, given that in the past, this type of pain was associated with only a pathophysiologic mechanism, neglecting the psychological and social contributors.5 In practical terms, chronic pain is still defined as pain that persists over three months.5 An extremely relevant change is the differentiation of primary versus secondary pain syndromes, with the inclusion of the term “chronic primary pain.” This term is intended to group several poorly understood conditions with the important component of emotional distress and/or significant functional disability not accounted for by other diagnoses.5,6 Chronic pain would then be the parent code of seven children codes that comprise the most relevant groups of chronic pain conditions: chronic primary pain, chronic cancer-related pain, chronic postsurgical or post-traumatic pain, chronic neuropathic pain, chronic secondary headache or orofacial pain, chronic secondary visceral pain, and chronic secondary musculoskeletal pain (Fig. 2.1).5,6 These changes are promising to improve the acquisition of accurate epidemiologic data, provide adequate billing, and potentiate the development and implementation of new therapies for chronic pain conditions.

IASP Chronic Pain Classifications The initial attempts to describe the taxonomy of chronic pain came from the IASP and were spearheaded by Dr. John Bonica7 and Dr. Harol Merskey.8 This was first published in 1986, followed by a modification in 1994 and subsequent small updates. The group defined the temporality of chronic pain as pain that has been present for more than six months.8 Their classification method was based on a multiaxis approach, using the five main pain axes (Table 2.1). Combining various pain characteristics and the axes, which are signified by a specific number, would allow most existing pain syndromes to be represented by a five-digit code (Table 2.2).8 The first axis addresses the region (anatomic location) where the pain occurs and is chosen for practical purposes. Any chronic pain can be easily identifiable by the region of the body compared to identification by etiology, as the latter has proven very challenging and not always possible. Therefore the etiology was assigned TABLE Pain Axes 2.1 Axis I

Regions

Axis II

Systems

Axis III

Temporal characteristics of pain: pattern of occurrence

Axis IV

Patient’s statement of intensity

Axis V

Etiology

to the last axis of the list.9 The second axis represents the systems of the body that are involved in the pain (e.g., musculoskeletal, nervous, gastrointestinal) and provides the second digit of the code. The third axis describes the temporal characteristics of pain, with special attention to the pattern of occurrence (e.g., single episode, continuous, recurring, paroxysmal). The fourth axis deals with the patient’s statement of intensity and is intended to capture the patient’s own experience and report on the severity and duration of the pain. The fifth and last axes refer to the etiology of the pain and are possibly the ones with more challenges given the lack of understanding concerning the etiology of some painful conditions. It is not uncommon that this digit of the code is left unknown. At the end of this five-digit code, a letter can be added to increase the granularity of the taxonomy system. For example, the letter “a” could be added for acute, “s” for spinal pain, and “r” for radicular pain.8

Acute Pain This chapter would not be complete without addressing acute pain. The Acute Pain Medicine Shared Interest Group defines acute pain as “the physiologic response and experience to noxious stimuli that can become pathologic, is normally sudden in onset, time-limited, and motivates behaviors to avoid actual or potential tissue injuries.”10 It is part of the unavoidable core experiences and has been evolutionarily preserved to serve an essential role in protecting the host against multiple threats.11 Timing differentiation between acute and chronic pain has had multiple definitions in the past, ranging from seven, 14, and 90 days to six months,11–13 or when it persists past the normal time of healing.7 However, there has to be an understanding that the transition from acute to chronic pain is a continuum, and they are not completely separate entities. Determining the cutoff time between the two could be very challenging and almost impossible.11 Most taxonomy attempts have been performed mainly for chronic pain. However, acute pain has not yet been fully considered. Classifications of acute pain were mainly unidimensional, focusing on sensory experience (pain intensity) and the use of different scales for its measurement.11 Recent research has discussed that pain trajectories are an important concept and that there are multiple dimensions for acute pain.11,14–16 In 2016, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration, the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) collaborated to create the ACTTION-APS-AAPM Acute Pain Taxonomy, which provides a multidimensional classification for acute pain with five dimensions of pain, as described in Table 2.3. They also differentiate between acute pain as surgical/procedural (e.g., general surgery, dental surgery, orthopedic surgery) and nonsurgical

 

CHAPTER 2

13

Classification of Acute Pain and Chronic Pain Syndromes

TABLE IASP Axes with Codes 2.2

Axis I: Regions

Recurring regularly

5

Head, face, and mouth

000

Paroxysmal

6

Cervical region

100

Sustained with superimposed paroxysms

7

Upper shoulder and upper limbs

200

Other combinations

8

Thoracic region

300

None of the above

9

Abdominal region

400

Lower back, lumbar spine, sacrum, and coccyx

500

Axis IV: Patient’s Statement of Intensity: Time Since Onset of Pain        .

Lower limbs

600

Pelvic region

700

Anal, perineal, and genital region

800

More than three major sites

900

Axis II: Systems

Not recorded, not applicable, or not known

.0

Mild - One month or less

.1

Medium - One month to six months

.2

- More than six months

.3

- One month or less

.4

Nervous system (central, peripheral, and autonomic) and special senses; physical disturbance or dysfunction

00

Nervous system (psychological and social)*

10

Severe

Respiratory and cardiovascular systems

20

- One month to six months

.5

Musculoskeletal system and connective tissue

30

- More than six months

.6

Cutaneous and subcutaneous and associated glands (breast, apocrine, etc.)

40

- One month or less

.7

- One month to six months

.8

Gastrointestinal system

50

- More than six months

.9

Genito-urinary system

60

Axis V: Etiology

Other organs or viscera (e.g., thyroid, lymphatic, hemopoietic)

70

Genetic or congenital disorders

.00

Trauma, operation, burns

.01

Infective, parasitic

.02

Inflammatory (no known infective agent), immune reactions

.03

Neoplasm

.04

More than one system

80

Unknown

90

Axis III: Temporal Characteristics of Pain: Pattern of Occurrence        . Not recorded, not applicable, or not known

0

Toxic, metabolic, radiation

.05

Single episode, limited duration

1

Degenerative, mechanical

.06

Continuous or nearly continuous, nonfluctuating

2

Dysfunctional (including psychophysiologic)

.07

Continuous or nearly continuous, fluctuating severity

3

Unknown or other

.08

Recurring irregularly

4

Psychological origin (e.g., conversion hysteria)

.09

(e.g., neuropathic, ischemic, visceral, trauma, musculoskeletal), which allows physicians to identify conditions where it is possible to intervene before the onset of pain or tissue injury, potentially avoiding the progression to chronic pain.11

Headache Classification The International Classification of Headache Disorders 3rd edition must be mentioned when evaluating headaches. This classification has created an orderly taxonomy of typically poorly classified neurologic diseases. The intuitive 1- to 5-digit classification code (Table 2.4) caters to general practitioners and headache specialists

alike, and it allows for broad or specific diagnoses. The first digit determines the most general type of headache experienced by a patient. For example, (1) migraine, (2) tension-type headaches, and (3) trigeminal autonomic cephalalgias. More specific information leads to a more specific code: 1.2.3.1.1, which indicates familial hemiplegic migraine type 1.17

New Pain Classification Efforts have been made to expand the descriptive factors of chronic pain. Until recently, pain was divided into nociceptive and neuropathic groups. Nociceptive pain is known as pain that

14

PA RT 1 General Considerations

TABLE ACTTION-APS-AAPMa Acute Pain Taxonomy 2.3 Acute Pain Dimensions11

Dimensions

Description

#1: Core criteria

Specifies the inciting event, time from the event, and tissue involved.

#2: Common features

Characterizes the acute pain condition through common pain variables (symptoms, signs, quality).

#3: Modulating factors

Includes comorbidities (i.e., opioid tolerance) as well as sociodemographic, biopsychosocial, and surgical factors that may modulate the acute pain experience.

#4: Impact/functional consequences

Describes the recovery trajectory, including the interrelationship of the physical, social, psychologic, and vocational consequences resulting from the acute pain condition.

#5: Putative mechanisms

Includes the neurobiologic mechanisms related to the acute pain condition.

ACTTION, analgesics, and addiction clinical trial translations, innovations, opportunities, and networks; APS, American Pain Society; AAPM, American Academy of Pain Medicine

a

TABLE International Classification of Headache 2.4 Disorders 1. Migraine 1.1 Migraine without aura 1.2 Migraine with aura 1.2.1 Migraine with typical aura 1.2.1.1 Typical aura with headache 1.2.1.2 Typical aura without headache 1.2.2 Migraine with brainstem aura 1.2.3 Hemiplegic migraine 1.2.3.1 Familial hemiplegic migraine (FHM) 1.2.3.1.1 Familial hemiplegic migraine type 1 (FHM1) 1.2.3.1.2 Familial hemiplegic migraine type 2 (FHM2) 1.2.3.1.3 Familial hemiplegic migraine type 3 (FHM3) 1.2.3.1.4 Familial hemiplegic migraine, other loci 1.2.3.2 Sporadic hemiplegic migraine (SHM) 1.2.4 Retinal migraine From IHS Classification ICHD-3. Available at: https://ichd-3.org/1-migraine/. Accessed July 20, 2020.

arises from actual or threatened damage to non-neural tissue and is because of the activation of nociceptors, and neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system.18,19 A growing body of data has begun to show the need for a third descriptor of pain that occurs in patients who do not have acute tissue injury or signs of neuropathy.20 The term “nociplastic pain” is defined as pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.18,19 It has been created to describe dysfunction in nociceptive processing that results in hypersensi-

tivity to seemingly normal sensations. Chronic pain conditions that demonstrate evidence of altered nociceptive processing may include fibromyalgia,21 complex regional pain syndrome,22 irritable bowel syndrome,23 and visceral pain disorders,24,25 among others. These efforts are meant to address pain that may frequently be classified as “pain of unknown origin,” previously known as idiopathic pain. However, a distinction needs to be made that this new descriptor should be used when patients note altered nociception, and it would not be appropriate for a patient who notes pain without hypersensitivity. Critics of this new classification argue that nociceptive and neuropathic pain may be proven by the identification of damage to tissue or nervous structures. Proponents agree that no structural pathology accounts for the pain, but tests such as sensory testing,22,25–29 sensory-evoked potentials,30–32 and functional magnetic resonance imaging21,25,33,34 support altered nociceptive processing.

Psychiatric Aspects of Chronic Pain The diagnosis of chronic pain related to psychiatric disorders has recently been updated in the DSM-V. The DSM-IV contains somatization disorders, including hypochondriasis, pain disorder, and undifferentiated somatoform disorders that have been removed. These diagnoses were criticized because of their overlap and the resulting lack of clarity regarding the appropriate diagnosis. They required a specific number of complaints from four symptom categories and the need for somatic symptoms to be medically unexplained. The DSM-V replacement states that somatic symptom disorder encompasses somatic symptoms that create dysfunction or distress with significant thoughts, feelings, or behaviors focused on those symptoms for longer than six months. The requirement for medically unexplained symptoms was removed. Therefore the patient’s symptoms may be related to other medical conditions. This change aimed to reduce the number of disorders a patient may be diagnosed with while making criteria more straightforward for non-psychiatric care physicians.35 The psychiatric aspects of chronic pain have evolved consistent with the changes in the DSM-V described above, psychiatric aspects of chronic pain have evolved. The focus on determining whether the patient’s symptoms are medically unexplained, which in itself can be very challenging, has lessened, and more importance has been placed on symptoms. Generally, it is not recommended to give an individual a diagnosis of a mental disorder solely because a medical cause has yet to be established. This contrasts with previous methodologies that sought to categorize a patient’s pain as related to a known medical problem versus a psychological origin, as noted in the DSMIV. Several elements may contribute to somatic symptoms, including biologic vulnerability to increased pain,20 traumatic experiences, and learned behaviors (care obtained from illness), as well as cultural practices that negatively brand psychological complaints compared to physical ones. Significant data have disproved the mind-body dualism view that the mind and body are distinct and separable. Patients who suffer from both pain and depression have been found to experience reduced physical, mental, and social functioning compared to patients with only depression or pain. Therefore treatments such as cognitive behavioral therapy for a patient with depression may have a significant impact on pain.36 This being said, there are situations such as conversion disorder where it is possible to conclude that the patient’s symptoms are not possible when considering medical pathophysiology.

 

CHAPTER 2

International Psychiatric Classifications There are two main entities in world psychiatric classification: the DSM, created by the American Psychiatric Association, and the ICD, created by the World Health Organization. Notably, the DSM is used mainly by psychiatrists in the United States, and the ICD system is used globally and is intended for use by all health practitioners. The ICD-10 classification of mental and behavioral disorders preserves parallel categories to those used in the DSM-V, although the descriptions are often different. However, the ICD-10 classification does not use the “checklist approach,” but rather provides a general description and major criteria required.35,37 The ICD classification system has often been criticized for its representation of chronic pain.6,38 Specifically, it has been claimed that the system allows for the documentation of chronic pain but lacks the ability to directly connect it to an additional (i.e., psychological) diagnosis that may be its cause. This could have the effect of confusing other medical providers who may think that the chronic pain condition is not associated with another separate condition. For example, pain because of known or inferred psychophysiologic mechanisms such as muscle tension pain or migraine, which is still believed to have a psychogenic cause, is coded under psychological or behavioral factors associated with disorders or diseases classified elsewhere (e.g. muscle tension pain or migraine). Musculoskeletal pain is organized according to anatomic sites but does not reference the underlying mechanism of

Classification of Acute Pain and Chronic Pain Syndromes

15

pain.38 The ICD-10 classification does provide a separate category of pain disorder, somatoform disorders F45.41 (pain disorder exclusively related to psychological factors). In essence, this category corresponds to what the DSM-V now calls somatic symptom disorders. In the ICD-10, the predominant complaint is persistent, severe, and distressing pain that cannot be explained fully by a physiologic process or a physical disorder.37 The next iteration of the ICD, the 11th edition, to be released in 2022, has been created with the goal of further interconnectedness with DSM-V diagnoses to avoid a mismatch of mental pathologizing depending on which classification system is used. In evaluating disability caused by pain for psychiatric purposes, one can reasonably apply the criteria of the World Health Organization Disability Assessment Schedule, version 2.0. This was created to evaluate a patient’s ability to perform activities in six areas: understanding and communicating, getting around, selfcare, getting along with people, life activities, and participation in society. This test is based on the International Classification of Functioning, Disability, and Health, and can be used for any medical condition. It may be useful for an initial evaluation to help guide intervention based on high scores in a certain domain or may be repeated to track progress. The World Health Organization Disability Assessment Schedule, version 2.0, is endorsed in the DSM-V and is meant to replace the global assessment of functioning scale previously mentioned in the DSM-IV, which was dropped because of concerns over a lack of clarity regarding symptoms, suicide risk, and disabilities.35

Key Points • Pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling, that associated with, actual or potential tissue damage.” • Taxonomy is the organization of concepts arranged using hierarchical relationships. • The purpose of creating a medical classification is to exchange standardized information, facilitate statistical comparisons, and improve research at the national and international levels. • Medical classifications also provide guidance for billing and reimbursement. • Currently, multiple taxonomy systems classify medical conditions related to pain syndromes: ICD, chronic pain (IASP),

Suggested Readings American Psychiatric Association. Section II: somatic symptoms and related disorders. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington VA: American Psychiatric Association; 2013. Classification of Chronic Pain Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain Subcommittee on Taxonomy Pain Suppl. Pain Suppl. 1986;3:S1–S226. Hirsch JA, Nicola G, McGinty G, et al. ICD-10: History and context AJNR Am J Neuroradiol. 2016;37(4):596–599. IHS. Classification. ICHD-3. Available at: https://ichd-3.org/. International Association for the Study of Pain. IASP terminology. Available at: https://www.iasp-pain.org/terminology?navItemNumber=576.

• • • •

ACTTION-APS-AAPM Acute Pain, DSM, and the International Classification of Headache Disorders. The ICD-10 is currently used worldwide, and the ICD-11 version is intended to be adopted in the near future. The IASP classification of chronic pain uses five axes: anatomic location, systems involved, temporal characteristics, intensity, and etiology. Pain can be described as nociceptive, neuropathic, and nociplastic. Nociplastic pain is defined as pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence of disease or lesion of the somatosensory system causing pain.

Kent ML, Tighe PJ, Belfer I, et al. The ACTTION-APS-AAPM pain taxonomy (AAAPT) multidimensional approach for classifying acute pain conditions. Pain Med. 2017;18(5):947–958. Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain? Pain. 2016;157(7):1382–1386. Merskey H. The taxonomy of pain. Med Clin North Am. 2007;91(1):13–20, vii, vii. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain defines pain as concepts, challenges, and compromises. Pain. 2020;161(9):1976–1982. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or disease: The IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain. 2019;160(1):19–27. The references for this chapter can be found at ExpertConsult.com.

References 1. Pain terms: A list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy. Pain. 1979;6(3):249. 2. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises. Pain. 2020;161:1976–1982. 3. Merskey H. The taxonomy of pain. Med Clin North Am. 2007;91(1):13–20 vii, vii. 4. Hirsch JA, Nicola G, McGinty G, et al. ICD-10: History and context. AJNR Am J Neuroradiol. 2016;37(4):596–599. 5. Treede R-D, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003–1007. 6. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: The IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain. 2019;160(1):19–27. 7. Bonica JJ. The management of pain. South Med J. 1954;47(8):802. 8. Merskey H. Classification of chronic pain: Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. Pain Suppl. 1986;3:S1–S226. 9. Merskey H, ed. Taxonomy and classification of chronic pain syndromes. In Practical Management of Pain. New York: Elsevier; 2014. 10. Tighe P, Buckenmaier CC, Boezaart AP, et al. Acute pain medicine in the united states: A status report. Pain Med. 2015;16(9):1806–1826. 11. Kent ML, Tighe PJ, Belfer I, et  al. The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) multidimensional approach to classifying acute pain conditions. Pain Med. 2017;18(5):947–958. 12. Dworkin RH, Turk DC, Basch E, et al. Considerations for extrapolating evidence of acute and chronic pain analgesic efficacy. Pain. 2011;152(8):1705–1708. 13. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division. Board on Health Care Services; Committee on Evidence-Based Clinical Practice Guidelines for Prescribing Opioids for Acute Pain. Framing Opioid Prescribing Guidelines for Acute Pain: Developing the Evidence. Washington (DC): National Academies Press (US); 2019. 14. Mora JC, Antony AB, Smith CR. A better way to evaluate postoperative pain? Pain Med. 2018;19(12):2334–2335. 15. Kannampallil T, Galanter WL, Falck S, et al. Characterizing the pain score trajectories of hospitalized adult medical and surgical patients: A retrospective cohort study. Pain. 2016;157(12):2739–2746. 16. Althaus A, Arránz Becker O, Moser KH, et al. Postoperative pain trajectories and pain chronification: An empirical typology of pain patients. Pain Med. 2018;19(12):2536–2545. 17. The International Classification of Headache Disorders 3rd edition (ICHD-3). 2018. Cited July 27, 2020. Available at: https://ichd-3.org/. 18. International Association for the Study of Pain. IASP terminology. Updated December 14, 2017. Cited July 28, 2020. Available at: https://www.iasp-pain.org/Education/Content.aspx?ItemNumber =1698. 19. Trouvin AP, Perrot S. New concepts of pain. Best Pract Res Clin Rheumatol. 2019;33(3):101415. 20. Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain. 2016;157(7):1382–1386.

21. Jensen KB, Srinivasan P, Spaeth R, et al. Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia pain. Arthritis Rheum. 2013;65:3293–3303. 22. van Rooijen DE, Marinus J, van Hilten JJ. Muscle hyperalgesia is widespread in patients with complex regional pain syndrome. Pain. 2013;154(12):2745–2749. 23. Mertz H, Morgan V, Tanner G, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology. 2000;118(5):842–848. 24. Clemens JQ. Male and female pelvic pain disorders: Is it all in their heads? J Urol. 2008;179:813–814. 25. Wilder-Smith CH. The balancing act: Endogenous modu lation of pain in functional gastrointestinal disorders. Gut. 2011;60(11):1589–1599. 26. Blumenstiel K, Gerhardt A, Rolke R, et  al. Quantitative sensory testing profiles in chronic back pain are distinct from those in fibromyalgia. Clin J Pain. 2011;27(8):682–690. 27. Gierthmühlen J, Maier C, Baron R, et al. German Research Network on Neuropathic Pain. Sensory signs in complex regional pain syndrome and peripheral nerve injury. Pain. 2012;153(4):765–774. 28. Kosek E, Ekholm J, Nordemar R. A comparison of pressure pain thresholds in different tissues and body regions. Long-term reliability of pressure algometry in healthy volunteers. Scand J Rehabil Med. 1993;25(3):117–124. 29. Puta C, Schulz B, Schoeler S, et  al. Somatosensory abnormalities for painful and innocuous stimuli at the back and at a site distinct from the region of pain in chronic back pain patients. PLOS ONE. 2013;8(3):e58885. 30. Diers M, Koeppe C, Yilmaz P, et  al. Pain ratings and somatosensory evoked responses to repetitive intramuscular and intracutaneous stimulation in fibromyalgia syndrome. J Clin Neurophysiol. 2008;25(3):153–160. 31. Diers M, Koeppe C, Diesch E, et  al. Central processing of acute muscle pain in chronic low back pain patients: An EEG mapping study. J Clin Neurophysiol. 2007;24(1):76–83. 32. Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalogr Clin Neurophysiol. 1996;100(2):165–168 8617155. 33. Giesecke T, Gracely RH, Grant MAB, et al. Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum. 2004;50(2):613–623. 34. Maihöfner C, Forster C, Birklein F, Neundörfer B, Handwerker HO. Brain processing during mechanical hyperalgesia in complex regional pain syndrome: A functional MRI study. Pain. 2005;114(1-2):93–103. 35. American Psychiatric Association. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington VA: American Psychiatric Association; 2013. 36. Ishak WW, Wen RY, Naghdechi L, et  al. Pain and depression: A systematic review. Harv Rev Psychiatry. 2018;26(6):352–363. 37. World Health Organization. The ICD-10 Classification of Men tal and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization; 1992. 38. Perrot S, Cohen M, Barke A, et al. The IASP classification of chronic pain for ICD-11: Chronic secondary musculoskeletal pain. Pain. 2019;160(1):77–82.

15.e1

10 3

Organizing Chapter TitleantoInpatient Go Here Acute Pain Service CHAPTER AUTHOR

PREETMA KAUR KOONER, GREGORY W. TERMAN

The Rationale Over the last decade, several surgical practices and public health initiatives, in addition to drug and technology advancements, have impacted inpatient acute pain services worldwide, for example, the continued development and implementation of less invasive surgical techniques, such as arthroscopy. Laparoscopy and robot-assisted surgery have reduced post-surgical pain and allowed nearly two-thirds of surgeries to be performed on an outpatient basis.1 Nonetheless, moderate to severe pain is common after outpatient procedures as well,2 and pain is still a leading cause of why patients scheduled for outpatient surgery are unable to go home and remain as inpatients. Indeed, the last minute consults stating that “pain is the only thing keeping [patient name] here” has become an increasingly common refrain. In short, even if outpatient surgery pain is treated effectively in an institution, inpatient post-surgical patients can be expected to have high levels of pain on average, as more patients and procedures are deemed suitable for outpatient surgery. This may explain why pain after inpatient surgery has shown only a marginal reduction in patients suffering from moderate to severe pain, dropping from 80% in 19953 to 65% in 20154—despite an increase in inpatient pain services. Post-operative pain management in both inpatient and outpatient settings has also been complicated by the dramatic increase in opioid-related morbidity and mortality from both illicit and prescribed opioids, which have occurred since the turn of the century (the so called “opioid crisis”). Sometimes conflicting regulatory, legislative, insurance, and institutional policies, largely aimed at outpatient opioid prescribing, have proven, at best, difficult to remember and, at worst, impediments to patient-centered postoperative pain care. Both primary care services and the patients they care for are often reluctant to use opioid analgesics for fear of side effects. In this regard, it is necessary to remember that ineffective post-operative pain management is also associated with a variety of medical and economic “side effects,” including readmissions,5 patient dissatisfaction with medical care,6 possible transition to chronic pain,7 and extended lengths of treatment (which has been associated with opioid use disorder diagnoses).8 Moreover, with or without consistent evidence based policies and guidelines, achieving satisfactory acute pain management is challenging since patient post-operative analgesic requirements vary widely even following the same surgery. Several patient factors 16

have been reported to influence post-operative opioid requirements, including: • Preoperative pain sensitivity9 • Coexisting medical conditions and associated multiple drug administration4 • Pre-surgical opioid tolerance or history of drug abuse10 • Psychological factors, including catastrophizing, and anxiety11,12 • Age13 • Type of surgery10 Great care must be taken to consider all the characteristics mentioned above when deriving an analgesic plan for managing an individual’s response to a surgical insult. Such careful acute pain management does not include opioids and has never been involved. The time is long past when acute or chronic pain caregivers should think of “opioid treatment” and “pain management” as synonyms. However, how can we explain how the 2001 “pain is the fifth vital sign” campaign has, in retrospect, been vilified as a plot to increase opioid prescribing? A “vital sign” implies assessment, not a particular treatment—just as a heart rate of 100 may be treated quite differently in a fetus in utero than in a cardiac cripple. In summary, acute pain, if not pain in general, still suffers from a lack of careful assessment and functional goal-directed multimodal therapy. Despite repeated educational initiatives worldwide, including the International Association for the Study of Pain (IASP) Global Year Against Acute Pain in 2011, followed by the Global Year Against Pain After Surgery in 2017, and even the Global Year of Prevention of Pain in 2020. This chapter posits that investing in an inpatient-based acute pain service is still the best mechanism to ensure effective and safe acute pain care.

General Principles The sequelae associated with acute pain, including surgical procedures, result from various components of the stress response, including cardiopulmonary, infectious, and thromboembolic complications, cerebral dysfunction, nausea and gastrointestinal paresis, fatigue, and prolonged convalescence. Throughout the process of organizing an acute pain program, it is helpful to remember the following statements: • The post-operative pain management regimen should be designed with attention to providing patient comfort and

 

CHAPTER 3

inhibiting nociceptive impulses sufficient to allow appropriate rehabilitation. • A time-, energy-, and cost-effective acute pain program should optimally provide multimodal and multi-disciplinary interventions, including systemic and regional pharmacologic,14 and non-pharmacologic treatments,15,16 including stress reduction, transcutaneous electrical nerve stimulation, music therapy, and acupuncture. • Surgical stress responses are inhibited most effectively by the neuraxial administration of local anesthetics, and the administration of other agents—systemically, neuraxially, or perineurally—contribute little additional reduction of the endocrine (metabolic and catabolic) stress response following operative procedures.17,18 • Parenteral opioids exaggerate the perioperative immune depression already triggered by the neuroendocrine response to surgery, although the clinical relevance of this observation is controversial.19 Opioids administered into the epidural space have minor suppressive effects on surgically induced proinflammatory cytokines.20 • Effective analgesia can reduce post-operative morbidity and improve function. For example, thoracic epidural analgesia has been shown to improve post-operative spirometry and reduce pulmonary infections and atelectasis.21,22 The experience of a skilled anesthesiologist lends itself to providing leadership within an acute pain service. Anesthesiologists are proficient in the use of systemic and regional analgesic techniques, including peripheral and neuraxial nerve conduction blockade. They also often understand the surgical techniques and the insults that they impose and are frequently equipped with leadership skills for working within a multi-disciplinary team from their work in the operating room. Nonetheless, an anesthesiologist-based team is not the only service model. Nurse-based, anesthesiologist-supervised, inpatient acute pain services have also been demonstrated to provide safe and effective post-operative pain management.23,24 Regardless of the service model, nursing involvement in an inpatient acute pain service is essential. Bedside nurses’ impressions of a patient’s analgesic needs and recovery is an invaluable element in the decision making process for any given patient, and because it is the nurse who will ultimately be delivering the care, nurses must understand the analgesic plan, goals, policies, and procedures that might pertain to their pain care. Detailed practice guidelines and protocols can help streamline the ordering and implementation of patient care. Wellestablished protocols have been shown to reduce errors in realms outside pain management25 and decrease the cost associated with prescribing choices.26 At the University of Washington Medical Center, we have instituted multiple protocols, including order sets for patient-controlled analgesia (PCA), continuous and patient-administered epidural analgesia, ketamine and lidocaine infusions, and continuous perineural catheter infusions (Figs. 3.13.5). PCA and epidural analgesia protocols must include titration and bolus instructions to treat breakthrough or incident pain. Order sets should also include routine and specific monitoring orders, as well as treatment options for common and/or dangerous side effects (e.g. antiemetics and/or antipruritics, and opioid receptor antagonists to reverse respiratory depression). Ketamine, intravenous lidocaine, and perineural anesthetics are most frequently used as adjuncts to other analgesic therapies (e.g. PCA opioids and scheduled acetaminophen and/or nonsteroidal antiinflammatory drugs). The recovery room, intensive care unit, and medical/surgical floor nurses must be trained to be familiar with

Organizing an Inpatient Acute Pain Service

17

the order set parameters. In most cases, nurses can autonomously assess patients and implement changes that successfully achieve adequate analgesia with minimal side effects. An emerging area of concern for any anesthesiology-based pain service is the complexity of managing invasive pain management techniques (e.g. epidurals) in an era where an ever-increasing number of anticoagulants are given as treatment or prophylaxis for many medical and surgical indications. These indications include treatment of cardiac arrhythmias, valvular disease, and deep vein thrombosis prophylaxis. To aid in treating such patients with the least risk, the University of Washington Medical Center has designed institutional guidelines (based on national guidelines such as those of the American Society of Regional Anesthesia)27 for the management of indwelling neuraxial and peripheral nerve catheters in patients treated concomitantly with anticoagulants (see Chapter 74). This document was designed to address the placement, maintenance, and removal of catheters in several common anticoagulation scenarios. The intention of such guidelines, which are linked to the electronic medical record, is to distill the existing scientific evidence and opinion into a format that is easy to access and apply in the patient care workflow.

Identifying Service Leadership It is important to recognize at the outset of establishing a pain service that it is a major endeavor. Planning, design, and implementation of a successful service will require substantial human and material resources. If the need and desire for an acute pain service exist within a hospital facility, one must first elicit support from the anesthesiology department’s chairperson. Although multiple design models for acute pain management services are possible, most will require that an anesthesiologist be made available for some level of participation in the service. Unless resources allow an anesthesiologist to be easily released from operating room obligations, the staffing conflict presents a difficult challenge. An agreeable arrangement of service responsibilities must allow the anesthesiologist or his or her delegates to be available to provide safe and consistent care to whomever he or she is responsible, 24 h a day and seven days a week. Once the intradepartmental resource allocation issues have been discussed with the chairperson, the proposal to begin an acute pain service should be brought to the medical director as a representative of the facility’s administrative team. The commitment of the medical director to the project will be necessary to provide resources in the form of personnel and money. Appropriate leadership for acute pain services must be selected. Operating a service requires a diverse constellation of skills. The service director must have knowledge of the mechanisms of acute post-surgical pain and the methods of treatment, including opioid and non-opioid analgesics, epidural and peripheral nerve catheter placement and maintenance, and ketamine, lidocaine, and other adjuvant drug therapies, as well as treatments for the side effects of these therapies. An anesthesiologist is often the best fit because he or she has experience with these pharmacologic approaches. The recent formation of Accreditation Council for Graduate Medical Studies (ACGME) accredited fellowship programs, combining regional anesthesia and acute pain training, has been in direct response to this understanding that anesthesiology training results in clinicians well suited for providing acute pain management. Indeed, many early acute pain services, like the one started by Dr. Brian Ready at the University of Washington in the 1980s, grew out of the obstetric anesthesia team and the regional anesthetists working thereon. Nonetheless, it is important to distinguish

18

PA RT 1 General Considerations

between a regional anesthetist’s goal of keeping a patient comfortable enough to stay still for a painful procedure and an acute pain practitioner’s goal of keeping a patient comfortable enough to move during rehabilitation. Zero out of ten pain is rarely an option or goal for acute pain services. In this regard, as mentioned previously, non-pharmacologic therapies (including physical, psychological, and complementary medicine techniques) also play a role in acute pain treatment, although they are rarely used in the operating room. Acute pain service leaders must be aware of the value and indications for the full panoply of therapeutic strategies for pain. In addition to expertise in analgesic therapies, the success and stability of any new acute pain service will require that the service

director also possess certain nonclinical skills, including strong leadership, organizational, communication, and administrative abilities. The clinical success of an inpatient pain service demands the integration of multiple clinical disciplines, such as nursing, anesthesiology, medicine, physical therapy, and pharmacy. The service director must merge the strengths of these diverse professionals such that their efforts are collaborative—both outside of the normal silos inherent to patient care and without undue power struggles or inefficiencies that can arise within a multi-disciplinary team. In addition, the leader will need to understand the place of the acute pain service within the structure of the health care organization. The service should be seen as efficient and valuable to the hospital and its surgical services.

A

• Figure 3.1  A

and B, University of Washington Medical Center parenteral (intravenous/subcutaneous) patient-controlled analgesia standardized order set. Courtesy of University of Washington Medical Center, Seattle, Washington.

 

CHAPTER 3

Organizing an Inpatient Acute Pain Service

19

B • Figure 3.1, cont’d.

A clinical nurse specialist (CNS) or equivalent is an additional cornerstone on which to build any new inpatient pain service. The primary responsibility of the CNS is to provide ongoing education for intensive care, recovery rooms, and medical/surgical care nurses concerning pain protocols. At the University of Washington Medical Center, a CNS in pain has been a part of the acute pain service from day one (only four different individuals in 35 years). In addition to nursing education, the CNS is involved in equipment trialing and purchasing, order and policy development, committee work on pain-related (though not necessarily pain service-related) hospital committees, and helps to resolve

any conflicts that might arise between nursing and prescribing care team members. Over the years, the CNS’s salary has been shared to different degrees between departmental and hospital sources. More recently, pharmacists have begun to play a valuable role in inpatient pain services. Their understanding of drug actions, metabolism, interactions, and side effects has proven ideal for promoting safe pharmacologic pain management. Moreover, their knowledge of drug costs, prescription drug monitoring program benefits and weaknesses, and electronic health record ordering peculiarities have opened the door for practical teaching of

20

PA RT 1 General Considerations

trainees and more experienced practitioners alike. In our inpatient pain service, pharmacists seem to enjoy patient interactions (including symptom assessment and education) and have become vital parts of our multi-professional team.

Assessment of Need Once the challenge of implementing an acute pain service is accepted, and leadership is identified, assessment of specific needs for the service is mandatory. This might be accomplished by surveying the patient population, nurses, types of specialty services,

procedures commonly performed, and the people performing these procedures. Furthermore, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has set forth standards declaring the patient’s right to adequate pain assessment and treatment and has explicitly acknowledged that pain is a coexisting condition with many diseases and injuries that require explicit attention. Although JCAHO updated its pain-related requirements in 2017,28 the importance of pain assessment and therapy was not diminished, and the updates were mostly focused on safer opioid prescribing including teaching and practice of multimodal analgesic therapies. This encourages more hospital expertise in

A • Figure 3.2  A and B, University of Washington Medical Center epidural infusion standardized order set. Courtesy of University of Washington Medical Center, Seattle, Washington.

 

CHAPTER 3

Organizing an Inpatient Acute Pain Service

21

B • Figure 3.2, cont’d.

pain management, and on this basis, the mission statement of the service should be defined. Those planning the structure of the service might also consider whether they wish to distinguish between different types of pain management challenges or manage them as conglomerates. For example, the University of Washington Inpatient Pain Services is divided into three factions: acute pain, chronic/cancer pain, and interventional pain. The service was separated into these groups to preserve the continuity of care (e.g. inpatient admissions of patients followed by an outpatient cancer pain clinic), and more

practically manage the high volume of patients (when only a subset of practitioners on a service have the training or experience to perform certain interventional procedures). Admittedly, the boundaries between these categories are artificial and may overlap. For example, consider a patient with acute post-surgical pain superimposed on long-standing cancer pain or a patient who is now recovering from surgery to place an implanted epidural neuromodulating device for treating chronic pain. Whatever the organizational structure, an acute post-operative pain management service is likely to require 24 h a day and seven

22

PA RT 1 General Considerations

• Figure 3.3  University of Washington Medical Center intravenous ketamine infusion standardized order set. Courtesy of University of Washington Medical Center, Seattle, Washington.

days a week call coverage, with appropriate medical supervision. Immediate availability is important concerning patient safety and patient satisfaction. Inadequacy of pain relief has been highlighted as a quality-of-care measure and a focus on patients’ concerns. In a questionnaire survey, 57% of patients identified pain after surgery as their primary fear.3 Sadly, the removal of specific questions about pain management satisfaction from the Hospital Consumer Assessment of Healthcare Providers and Systems survey, because of unsubstantiated fears of opioid over-prescribing to improve survey scores, is a step back from incentivizing attention to pain hurdles patients face in recovering from painful conditions or procedures and offers another indication that the multimodal approach to

pain management is still not widely appreciated. Nonetheless, the competitive healthcare environment mandates that hospitals focus on the most important issues to patients. Favorable reports of patient satisfaction may encourage patients to seek services in a given hospital facility and encourage patient loyalty in return for additional medical care. Furthermore, according to one multicenter prospective cohort study,29 immediate post-operative patient satisfaction with care is a predictor of long-term, positively self-perceived health status. In short, for many hospitals, following JCAHO’s requirement to have a “leadership team that is responsible for pain management” is also simply put, the right thing to do for their patients.

 

CHAPTER 3

Organizing an Inpatient Acute Pain Service

23

PAIN SERVICE: Pain Management IV Lidocaine Continuous Infusion Orders Admit / Tx / Medication GENERAL GUIDELINES:1. No Titration or bolus. 2. No routine therapeutic drug level monitoring. 3. Generally used for 24-72 hours as an adjunct to existing pain treatments (including epidural, PCA and ketamine for analgesia). 4. Select dose below according to patient weight (MAXIMUM rate = 120 mg/hr Patient weight < 45 kg = Lidocaine 30 mg/hr IV infusion Lidocaine 2g in D5W (Dextrose 5% in Water) 250mL Comments: For PAIN. DO NOT titrate, DO NOT bolus Patient weight 45-55 kg = Lidocaine 75 mg/hr IV infusion Lidocaine 2g in D5W (Dextrose 5% in Water) 250mL Comments: For PAIN. DO NOT titrate, DO NOT bolus Patient weight 56-67 kg = Lidocaine 85 mg/hr IV infusion Lidocaine 2g in D5W (Dextrose 5% in Water) 250mL Comments: For PAIN. DO NOT titrate, DO NOT bolus Patient weight 68-80 kg = Lidocaine 100 mg/hr IV infusion Lidocaine 2g in D5W (Dextrose 5% in Water) 250mL Comments: For PAIN. DO NOT titrate, DO NOT bolus Patient weight > 80 kg = Lidocaine 120 mg/hr IV infusion Lidocaine 2g in D5W (Dextrose 5% in Water) 250mL Comments: For PAIN. DO NOT titrate, DO NOT bolus Vitals / Monitoring Vital Signs Lidocaine initiation: BP, HR, respiratory effort (rate, depth, regularity & effort), 02 sat, visual analogue scale (VAS) pain score q1h  2, then q2h  2, then q4h if stable Cardiac Monitoring It is the responsibility of the ordering provider to assure that a 12 lead EKG has been obtained within the previous 7 days and showed no contraindications (including 1st and 2 nd degree heart block) Neuro Checks Neuro checks and monitoring for adverse effects/toxicity signs including: disorientation,or confusion, slurred speech, dizziness, sedation, seizure q1h  2, then q2h  2, then q4h if stable Pt Care / Nursing Call Provider for the Following Vital Signs SBP> 160, SBP< 90, DBP< 50, RR< 8, and/or sedation scale > 2, if systolic BP is > or < 30 mm Hg from pre-infusion baseline parameters. New development of arrhythmia. CALL or page the Acute PAIN SERVICE (APS) and Primary Service Call Pain Service for the following signs or symptoms (see order comments) and STOP infusion immediately. Comments: Patient Assessments: 1) seizure 2) tremor 3) diplopia 4) metallic taste 5) numbness of tongue 6) tinnitus 7) muscle twitching. Provider should consider drawing lidocaine level STAT if side effects are severe. (Please note: this has no therapeutic consequence and is to rule out other etiologies) In the very rare event of Local Anesthetic-induced Systemic Toxicity (LAST) call a CODE BLUE immediately and implement: 1. Airway management to deliver Oxygen, 2. Seizure suppression with benzodiazepines, 3. Cardiopulmonary stabilization/resuscitation

• Figure 3.4  University of Washington Medical Center intravenous Lidocaine infusion standardized order set. Courtesy of University of Washington Medical Center, Seattle, Washington.

Definition of the Service Once the pain service mission statement has been formulated in response to the perceived institutional and community needs, leadership must define the resources that will be required to meet the needs. The resources and modalities that an acute pain service may use are diverse and depend on the patient population, the skills of the personnel, and the service’s therapeutic approach. Ideally, an

evidence based approach to the selection of treatment modalities that specifically evaluates the efficacy and cost-effectiveness of each therapy is used. The resources required to implement and operate an acute pain service will represent a synthesis of characteristics of the patient population, evidence based selection of therapeutic modalities, and consistency with the service’s mission. The feasibility of various treatment plans based on the availability of resources was defined by the IASP task force for the management

24

PA RT 1 General Considerations

• Figure 3.5  University

of Washington Medical Center peripheral nerve/wound infusion standardized order set. Courtesy of University of Washington Medical Center, Seattle, Washington.

of acute pain (Table 3.1). Individualized treatment of patients should ideally be evidence based (Table 3.2), and several organizations have published guidelines for acute pain treatment.30,31 A useful, more dynamic resource for evidence based post-operative pain management is the PROSPECT database32—hosted and updated by the European Society of Regional Anesthesia and Pain Therapy. This website (https://esraeurope.org/prospect/) offers procedure specific post-operative pain management (PROSPECT) recommendations based on evidence detailed on the site. Such recommended care mixes maximal improvements in patient outcomes with the most cost-effective care available. Indeed, many of the leaders of the PROSPECT

project have also spearheaded the so called ERAS (Enhanced Recovery After Surgery) movement to facilitate safe and efficient postsurgical rehabilitation, minimizing hospital stays and thus reducing costs.33 For example, Dr. Henri Kehlet (a general surgeon) has developed ERAS principles for more than 35 years—emphasizing rapid re-feeding after bowel surgery, including, in part, the use of neuraxial local anesthetics for post-operative pain. Such techniques require special resources in the form of medications, equipment, and personnel, and these must be anticipated and negotiated with the institution’s administrative, business, and clinical departments when designing the service structure.

 

CHAPTER 3

Organizing an Inpatient Acute Pain Service

TABLE Options for Acute Pain Treatment Based on Available Resources 3.1 TABLE Attention! When can you Safely do Neuraxial/Peripheral Nerve Procedures or Give Antithrombotic Agents? 3.1A NOTE: For Concerns Related to Bleeding or Traumatic Procedures, Contact Pain Service.

Precautions: Do NOT give MULTIPLE anticoagulants, including antiplatelet agents, concurrently in patients undergoing Neuraxial/Nerve Procedures. Delay restarting anticoagulants for 24 h after traumatic needle placement.

MEDICATION

PRIOR TO NEURAXIAL/NERVE PROCEDURE Minimum time between the last dose of antithrombotic agent AND neuraxial injection or neuraxial/ nerve catheter placement

B. WHILE NEURAXIAL/NERVE CATHETER IN PLACE Restrictions on the use of antithrombotic agents while neuraxial/nerve catheters are in place and prior to their removal

AFTER NEURAXIAL/NERVE PROCEDURE Minimum time between neuraxial injection or neuraxial/nerve catheter removal AND next dose of antithrombotic agent

ANTICOAGULANTS FOR VTE PROPHYLAXIS Heparin unfractionated 5000 units SQ Q8H or Q12H

Maybe give; no time restriction for neuraxial injection or neuraxial/nerve catheter placement Does not require Pain Service approval

* Heparin unfractionated 7500 units SQ Q8H

12 h

* Dalteparin (Fragmin) 5000 units SQ QDay

12 h - CrCl ≥30 mL/min 24 h - CrCl zero) counts as a symptom and clinically indicates the need for further suicide risk assessment and safety planning with the patient. The GAD-7 is a self-administered seven item screening measure for generalized anxiety disorder (GAD). The items assess the frequency of physiologic and cognitive anxiety symptoms in the past two weeks, and response options range in frequency from zero (not at all) to three (nearly every day). A final question assesses if these problems have interfered with daily activities.126 The GAD-7 was initially validated on primary care patients and was found to have excellent internal consistency (Cronbach’s alpha = 0.92), test-retest reliability (intraclass correlation = 0.83), and validity with established anxiety screening measures (intraclass correlation = 0.83).126 The GAD-7 has also been found to be valid and reliable in the general population,127 and patients with pain.128 The Beck anxiety inventory (BAI) is a 21 item self-report questionnaire that assesses the severity of anxiety symptoms, with

Psychological and Behavioral Assessment

309

items asking how much the symptoms bothered the respondent in the last two weeks from zero (not at all) to three (severely - it bothered me a lot). The measure focuses on the somatic symptoms of anxiety and was developed to discriminate anxiety disorders from depressive disorders, although it should not be used as a solo differential diagnostic tool.129 The summed score of response options can be interpreted using the following ranges: 0 to 7 minimal anxiety, 8 to 15 mild anxiety, 16 to 25 moderate anxiety, and 26 to 63 severe anxiety, with a score greater or equal to 16 indicating clinically significant anxiety.130,131 The BAI was initially validated on psychiatric patients with anxiety and depressive disorders and was found to have high internal consistency (Cronbach’s alpha = 0.92) and good test-retest reliability over one week (r = 0.75). The BAI’s reliability and validity have been examined across multiple care contexts, clinical populations, and racial and ethnic groups, and it has been translated into several languages.130,132–136 The pain anxiety symptom scale (PASS)137 was designed to assess the cognitive, physiologic, and behavioral domains of pain related fear. It includes 53 items distributed across four subscales measuring fear of pain, cognitive anxiety, somatic anxiety, and escape and avoidance. Respondents use zero (never) to six (always) scales to endorse the frequency of each of the symptoms. The PASS has been demonstrated to have adequate internal consistency,137 with indices of internal consistency ranging from 0.81 to 0.89 for each of the four scales and 0.94 for the total scale. Good predictive validity,138 and acceptable criterion validity have also been demonstrated.139 The PASS has been criticized for its poor prediction of disability relative to other pain related fear measures,139 and its factor structure has also been challenged.140 The Spielberger state-trait anxiety inventory (STAI)141 was designed to identify and quantify both situational anxiety (state) and dispositional anxiety (trait). The STAI consists of two 20 item self-report inventories of each of these constructs. Respondents rate the degree of agreement to brief statements (e.g. “I feel calm”) on four point scales ranging from “not at all” to “very much so” in terms of both their present state (state version) and their frequency over time (trait version). There is a high concordance between pain and anxiety as measured by the STAI,142 and it has been widely used in the pain literature. It has acceptable psychometric properties,139,141 and it is sensitive to change in anxiety as a function of pain treatment.143 The medical outcomes study short form health survey (SF-36)144 was developed as a general measure of perceived health status and is typically self-administered. The measure contains 36 items combined to form eight scales: physical functioning, physical role functioning, bodily pain, general health, vitality, social functioning, emotional role functioning, and mental health. Respondents use “yes-no” or five or six point scales to endorse the presence or degree of specific symptoms, problems, and concerns. Scores on the scales range from 0 to 100, with higher scores indicating better health status and functioning. The measure takes about 10 to 15 min to complete. The SF-36 has been extensively validated with large samples from the general population and across several demographic subgroups, including samples of healthy persons over 65.145 Estimates of internal consistency (alphas) for most samples range from 0.62 to 0.94 for the subscales, with most estimates ranging over 0.80. Test-retest coefficients ranged from 0.43 to 0.81 for six months and from 0.60 to 0.81 for two weeks.146 The SF-36 has been shown to correlate reasonably well with other criterion measures, measures of ability to work, utilization of healthcare

310

PA RT 3 Clinical Evaluation and Assessment

resources, and other clinically meaningful criteria such as “burden of care.”145–148 Factor analytic studies have supported the presence of two distinct factors labeled physical health and mental health functioning that account for 82% of the measure’s variance.148–150 In one multi-site trial of cognitive-behavior therapy, exercise, and their combination, for patients with Gulf War Illness that included chronic, diffuse musculoskeletal pain as a primary feature, each of these treatments was found to be associated with improvements in the mental health functioning component score.151 On a more negative note, Rogers and his colleagues reported that the SF-36 lacked reliability for the assessment of outcomes following multi-disciplinary pain treatment, and they questioned aspects of the measure’s validity in discriminating dimensions of functional limitations.152 Similar concerns about the sensitivity of the SF-36 to change have also been raised.153 Continued examination of the sensitivity of the SF-36 Mental Health Functioning component to change as a function of pain interventions is indicated.

Pain Beliefs and Coping The survey of pain attitudes (SOPA)154 was developed to measure beliefs about chronic pain. It included five domains: perceived ability to control pain (control), perceived level of pain related disability (disability), belief in medical cures for pain (medical cures), belief that others should be solicitous toward them when they are in pain (solicitude), and the importance of medication as a treatment for pain (medication). The measure was later expanded to include two new dimensions: belief in the influence of emotions on pain (emotions) and belief that pain indicates underlying physical damage that necessitates the limiting of physical activity (harm).155, 156 The final version of the SOPA has 57 items and employs a zero (this is very untrue for me) to four (this is very true for me) response scale. The SOPA is grounded in cognitive behavioral theory, which specifies that patients’ beliefs about their pain influence important pain related outcomes, including emotional and physical functioning. A 30 item brief form of the SOPA (the SOPA-B)157 and a 35 item short version (SOPA-R)158 are also available. Internal consistency alphas for the 57 item SOPA scales are good, ranging from 0.71 (control) to 0.81 (disability), and testretest stability ranged from 0.63 to 0.68.156 The shorter version of the SOPA, the SOPA-B, has demonstrated a seven-factor structure consistent with the original measure, adequate internal consistency (ranging from 0.56 ([medication] to 0.83 [solicitude]), and strong correlations with the corresponding SOPA scales (0.79–0.97).157 The original factor structure of the SOPA-R has largely been confirmed by other investigators, and the measure has demonstrated good internal consistency (0.65–0.84) except for the medication scale (0.49).159 The main strength of the various versions of the SOPA is their correlation with clinical treatment outcomes. The disability scale of the SOPA (the belief that one is disabled) has demonstrated significant correlations with physical and emotional functioning.156,159,160 The harm scale showed significant association with reported physical disability, and the medication scale was associated with treatment utilization.156 The most frequently used measure of the construct of “pain readiness to change” is the pain stages of change questionnaire (PSOCQ).161 The PSOCQ measures beliefs about the degree of patient personal responsibility for pain control and interest in making behavioral changes to cope with pain. The PSOCQ is a 30 item self-report measure composed of four distinct scales. The precontemplation scale measures the degree to which a patient

endorses little personal responsibility for pain control and no interest in making behavioral changes. Contemplation represents an increasing recognition of personal responsibility for pain control and interest in behavioral changes that support pain management. The action scale measures the extent to which patients believe that they are actively learning pain management skills. The maintenance scale quantifies patients’ degree of commitment to using self-management strategies in their daily life and a high degree of personal responsibility for pain management. A review of the empiric literature documents the reliability, and criterion, and concurrent validity of the measure.162 Internal consistencies of the four scales range from 0.77 to 0.86, and stability indices range from 0.74 to 0.88. However, the utility of the PSOCQ hinges on its ability to predict important treatment process variables. Thus far, research has been encouraging. For example, PSOCQ subscales (i.e. precontemplation, contemplation, action, and maintenance) predict completion of self-management treatment programs,163 and improvements in pain coping during treatment.164 Furthermore, changes in PSOCQ during treatment consistent with increased readiness to change or “forward stage movement” are associated with improvements in pain and physical and emotional functioning.163–166 However, the readiness to change model has not been without critics. For example, Strong and colleagues167 challenged the external validity of the PSOCQ and demonstrated that a measure of self-efficacy had greater predictive validity than the PSOCQ. The chronic pain coping inventory (CPCI)168 is a 64 item questionnaire designed to assess patients’ use of pain coping strategies. The questions contained in the scale fall into three broad categories and include eight subscales: wellness-focused or positive coping strategies (exercise, relaxation, task persistence, coping self-statements), illness-focused or negative coping strategies (guarding, asking for assistance, resting), and neutral coping strategies (seeking social support). Respondents report the number of days in the last week that they used each strategy. The CPCI subscales demonstrated good internal consistency (0.74–0.91) and test-retest reliability (0.65–0.90).168 Spouse report of patient disability and coping skill use was strongly associated with CPCI scales.168 Other studies have largely confirmed the initially specified eight-subscale factor structure.169,170 Studies have found various associations between CPCI subscales and patient adjustment and outcomes. However, overall, illness-focused coping strategies were found to be significantly associated with poorer patient adjustment and outcomes, and wellness-focused strategies were significantly associated with better patient adjustment and outcomes.169,171 An exception is relaxation, with some studies showing a counterintuitive association between relaxation and higher affective distress and lower pain control,169,171 and another showing no associations between relaxation and any patient adjustment or outcome variable examined.170 Importantly, even after controlling for pain severity and demographic factors, CPCI subscales were significant predictors of patient-reported physical functioning, mood, disability, and activity level.170 A six month longitudinal study of patients with low back pain following a work accident demonstrated that higher guarding scores were predictive of prolonged leave from work.171 The pain catastrophizing scale (PCS) is a 13 item scale designed to measure the extent to which patients engage in catastrophic thinking regarding their pain.172 Catastrophic thinking is characterized by thoughts that the pain is horrible, unbearable, and that the worst possible outcome of the patient’s pain will manifest.

 

CHAPTER 22

Patients record the frequency with which they experience thoughts and feelings described by items on a five point Likert-type scale ranging from zero (not at all) to four (all the time). Initial scale development occurred in an undergraduate sample.172 However, the PCS has demonstrated reliability and validity in both non-clinical and clinical samples. Factor analyses tend to identify three subscales: magnification, rumination, and helplessness.172–175 These factors have demonstrated gender invariance.174 However, evidence from a single study suggests that, particularly for African Americans, two subscales of rumination and magnification/helplessness might be more appropriate.176 Internal consistency coefficients range from 0.60 to 0.91 for subscales and from 0.87 to 0.95 for the full scale.172–175 The PCS has demonstrated validity through its association with catastrophic thought patterns identified through clinical interview,172 pain severity,173,175,176 pain interference,173 pain related disability,176 and mood and anxiety symptoms.173 Further, the PCS has demonstrated discriminant validity from affect,175 and psychological disturbance.173 The PCS has demonstrated responsiveness to cognitive behavioral and physical activity pain treatments and is considered an important mechanism of changes in these treatments.177–181 The PCS has also been translated into several languages.182–187 The chronic pain acceptance questionnaire (CPAQ) is a 20 item scale designed to measure chronic pain acceptance or the extent to which patients accept the inevitability of chronic pain and engages in activities despite experiencing pain.188 The recent interest in acceptance and commitment therapy as an effective psychological intervention for chronic pain has precipitated widespread use of the CPAQ.189 Patients respond to statements of acceptancerelated pain beliefs using a seven item Likert scale ranging from one (never true) to six (always true). The CPAQ has two subscales: engagement in activities and willingness to experience pain.188 Additional factor analyses have confirmed these two subscales with the scale as published,190 or with minor revision.191 Internal consistency coefficients of the total scale range from 0.72 to 0.91.188,190,192 Regarding validity, the CPAQ has been associated with lower pain severity and pain related disability, less healthcare utilization and medication use, lower self-reported depressive symptoms, pain related anxiety and pain catastrophizing, higher self-efficacy, and lower dysfunctional pain coping and social support interaction styles.192 The CPAQ has also demonstrated responsiveness to acceptance-based and cognitive behavioral pain treatment,190,193 as well as a yoga-based pain treatment.194 The CPAQ is available in an adolescent version195 and multiple languages.196,197 An eight item version of the CPAQ has demonstrated reasonable reliability (internal consistency coefficients = 0.77–0.89) and validity, as evidenced by relationships with pain severity and interference, pain treatment-seeking, and depressive and anxious symptoms.191

Quality of Care The quality of pain care offered to patients can differ substantially by institution, clinician, and individual patient experience. High quality pain care is thought to improve outcomes of pain treatment through a high quality patient-provider relationship and faithful administration of validated treatments.198 Any effort to improve the quality of pain care across a system must first begin with measurement. For this reason, the American Pain Society produced its first patient outcome questionnaire (APS-POQ) to assess multiple domains of quality of patient care.199 The most

Psychological and Behavioral Assessment

311

recent version of the measure, the APS-POQ-R,200 is a 12 item scale that assesses pain severity, the impact of pain on affect, sleep, and activity, side effects, satisfaction with information provided about pain treatment, shared decision making, and use of nonpharmacologic strategies. Patients circles or checks the statement that best applies to their pain management care (e.g. “were you allowed to participate in decisions about your pain treatment as much as you wanted to?” with responses ranging from zero “not at all” to ten “very much so”). In the initial development study, inpatients who had been in the hospital less than 72 h were administered the APS-POQ-R orally, evaluating the first 24 h of their hospital stay.200 Overall internal consistency was α = 0.86. Factor analysis identified five subscales that corresponded with the domains described above, with αs = 0.63-0.83. As with previous versions of the APS-POQ-R,199 higher pain severity was associated with higher interference with activities, adverse effects from pain treatments, and affective distress, and with lower satisfaction with pain care, providing preliminary evidence for validity.200 However, cross-cultural validity studies have found poor reliability and inconsistent factor structure in countries other than the United States.201,202 Findings suggested the APS-POQ-R may be most relevant to patients receiving care within the healthcare system in which it was developed (United States). In response to concerns about cross-cultural validity, the APS-POQ-R measure was adapted into the international pain outcomes questionnaire (IPO) by PAIN OUT, a multinational European project on postoperative pain management.203 The measure was developed in two phases, both with large samples (N = 5,134 & N = 4,590) for phases one and two, respectively. Factor analysis found that the final measure loaded on three factors: pain intensity and interference, adverse effects, and perceptions of care. While the IPO questionnaire provides a culturally sensitive alternative to the APS-POQ-R, further validation of the questionnaire across different languages is necessary, as the psychometric validity of the translated versions has not yet been reported. The pediatric American Pain Society patient outcomes questionnaire (pediatric APS-POQ) was recently developed to assess the six domains—pain intensity, functional interference, emotional response, side effects, perceptions of care, and usual pain— of pain management care in hospitalized pediatric patients.204 The pediatric APS-POQ was adapted from the APS-POQ-R: wording on items was adjusted for pediatrics, and some items were changed based on updates to the literature. Patient-report and parentalreport versions of the pediatric APS-POQ were developed and found to be highly correlated. The measure requires additional testing in more varied populations to establish psychometric validity, as it was developed on a predominately Caucasian, American sample (N = 232) of pediatric patients three years old or older without developmental delays and has not yet been validated in other populations. Additionally, during development, the measure was administered in interview format, and other methods of administration have not yet been validated.204

Special Patient Populations We will briefly review considerations for the psychological and behavioral assessment of pain in the pediatric and older adult populations. Pain is often poorly assessed and managed in these populations, and both require specific considerations and pain assessment measures.205–208 Further, a substantial proportion of children and older adults cannot self-report their pain, which poses significant limitations to pain assessment.207

312

PA RT 3 Clinical Evaluation and Assessment

Recent clinical practice recommendations for pain assessment in patients unable to self-report recommend following a hierarchy of pain assessment techniques: 1) be aware of potential causes of pain; 2) attempt self-report; 3) observe patient behaviors; 4) solicit proxy reporting of pain and behavior/activity changes; 5) attempt analgesic trial.207 Specific considerations within this hierarchy for pediatric and older adult patients unable to self-report are provided below. As this chapter focuses on the psychological and behavioral assessment of pain, particular attention will be given to these two steps of the hierarchy. Pain in pediatric patients presenting for health care is extremely common but is generally poorly assessed and treated.208,209 Clinical practice recommendations suggest considering pediatric patients by cognitive development status. Neonates and infants are unable to self-report as they are nonverbal. However, around the second year of life, children begin to be able to verbalize the presence of pain, and by age three can provide basic descriptions of their pain quality and quantity. Children ages three to six often conflate their affective pain experience with sensory pain symptoms and other aversive physical symptoms and demonstrate reporting bias, making interpretation of self-reported pain scores challenging.207 The “poker chip tool” (children are asked to pick the number of red poker chips from zero to four that best describe their pain intensity) is recommended for pain assessment in children three to four years old, the faces pain scale-revised is appropriate for children four to 12 years, and the VAS can be used in children eight years and older.207 Behavioral pain assessment in pediatric patients can also help identify pain. However, it is important to remember that pain behaviors, and scoring on pain behavior scales, do not necessarily directly correlate with experienced pain intensity. Pain behaviors observed in children differ between acute and chronic pain. In acute pain, facial expressions, physical activity, and crying and other verbalizations are often used as the basis for behavioral pain assessment. In contrast, children experiencing chronic pain tend to limit energy expenditure and display functional limitations. Multiple behavioral pain assessment tools exist for different pediatric

populations, including the CHEOPS: Children’s Hospital of Eastern Ontario pain scale, CHIPPS: children’s and infants’ postoperative pain scale, and FLACC: faces, legs, activity, cry, consolability, observational tool (see Herr et al. for further detail).207 The adolescent pediatric pain tool, based on the MPQ, can provide a useful evaluation of the affective and sensory qualities of pain in children eight years and older. Additionally, the PedsQL provides measures of physical, emotional, social, and academic functioning in children and has both parent and child report versions available. Measures of pediatric pain are discussed further in Chapters 28 and 43. An estimated 25% to 50% of older adults experience chronic pain. However, multiple barriers to effective pain assessment and management in older adults have been noted, including myths that pain is a normative part of the aging process, stoicism and tendency toward underreporting, fears of opioid addiction, and the increased prevalence of cognitive impairment.205 Prior to the clinical interview, sensory deficits should be assessed for, and sensory assistive devices should be used as indicated. As with all patients experiencing pain, older adults should receive measures of psychosocial and affective functioning in addition to pain specific self-report assessment measures (see Hadjistavropoulos et al. for a detailed consensus statement on pain assessment in older adults).205 Patients with mild to moderate cognitive impairment from dementia can often still self-report their pain, but as dementia progresses, patients’ ability to accurately self-report pain decreases.205 In these cases, observation of patient behaviors—facial expressions, verbalizations/utterances, activity changes, motor movements, and mental status changes—becomes the next best method of pain assessment. The presence of pain indicators should be assessed while patients are in motion, as pain is often less severe at rest.205 Behavioral pain assessment tools appropriate for older adults with dementia include the CNCPI: checklist of nonverbal pain indicators and the CPAT: certified nursing assistant pain assessment tool.205 Measures for the assessment of pain in older adults are discussed further in Chapters 44 and 84.

Conclusion This chapter provides an overview of the role of psychological and behavioral assessment in the context of the provision of comprehensive and integrative care to patients with painful medical conditions. Discussion of more general principles that can be used to guide decisions regarding psychological assessment of pain in the clinical setting was followed by a more detailed consideration of some of the most commonly employed standardized psychological assessment strategies. This review serves as a general guide to clinicians who are compelled by the value of more thorough consideration of psychosocial factors in the assessment of patients with pain that may be used to guide and evaluate pain care. Having acknowledged the potential value of such an approach, several relevant issues that may serve as cautionary notes and targets for future research and clinical investigation may be highlighted. Of particular note are the overall limitations of this field with regard to consideration of the influence of cultural, racial, ethnic, and other aspects of diverse society on the reliability and validity of existing psychological and behavioral assessment methods. Given a growing awareness and empirical evidence of reliable differences in the experience of pain among patients of differing racial/ethnic backgrounds, gender, and age, among other relevant

variables,210 caution is encouraged when employing most of the reviewed assessment strategies, and specific consideration of culturally specific norms for the measures is important. Already emphasized throughout this chapter is that several measures frequently used in this field were not originally developed for use with patients with painful conditions, and as a result, the validity of these methods is still subject to concern. The continued development and evaluation of psychological and assessment methods designed specifically for patients with painful conditions and the further evaluation of the psychometric properties of these measures are indicated. With increasing appreciation of differences in the experience of pain and its impact among patients with different conditions, specific examination of the psychometric properties among patients with similar disorders is encouraged. Consistent with this observation, the IMMPACT group, for example, although providing recommendations for the use of specific measures in the assessment of pain treatment effects, has encouraged the selection of measures that were developed and normed for a specific population (e.g. osteoarthritis patients) when such instruments are available. Another area for continued work is the importance of developing patient-oriented outcome measures. For example, one group

 

CHAPTER 22

uses a qualitative approach to collect information to develop measures of pain coping in older adults living in the community.211 Several other investigator groups are currently working on the development and validation of more comprehensive measures for assessing patient-oriented outcomes, and the future availability of these methods promises to provide alternatives to existing methods that may have increased sensitivity to important and meaningful changes in pain and its impact, at least from a patient’s perspectives. Clinicians must consider pragmatic issues related to the use of existing methods and measures for the psychological and behavioral assessment of patients with pain in the clinical setting. Response burden is an important factor to consider when selecting measures for use in the clinical setting. Clinicians are encouraged to consider specific objectives of the assessment and the importance of reaching a balance between the desire for a

Psychological and Behavioral Assessment

313

more thorough assessment and patient burden. Clinicians should also consider measurement precision, brevity, and costs of the assessment process in making decisions about the use of psychological assessment strategies. As already emphasized, the clinical interview and examination remain the core method for clinical assessment and should not be displaced by the use of questionnaires, diaries, and other methods. Finally, managed care reimbursement methodologies are, of course, critical to consider in most clinical settings. The potential value of incorporating assessment methods that permit a more comprehensive evaluation of the psychological and behavioral aspects of the experience of pain has been emphasized. As in most similar contexts, the “devil is in the details,” and clinicians and investigators alike are encouraged to consider a range of important issues when designing an assessment approach consistent with their goals and objectives.

Key Points • Chronic pain is challenging to assess because pain complaints are inherently subjective, and pain has a wide-ranging influence on patient functioning. • Psychological and behavioral assessment of pain serves several clinical goals: 1) providing information about a patient’s pain experiences, treatment histories, current, and past emotional and physical functioning, and beliefs about pain, 2) identifying the patient’s strengths and weaknesses, 3) identifying factors that contribute to the development and maintenance of problems in physical, social, and emotional functioning, 4) identifying comorbid psychiatric or behavioral conditions that may interfere with pain treatment, 5) determining if the patient is psychologically appropriate and likely to benefit from surgery or invasive procedure, and 6) providing a benchmark of the patient’s pain and functioning against which the efficacy of treatments can be measured. • Because of the wide range of clinical goals for psychological and behavioral assessment of pain, when making a request for psychological and behavioral assessment, it is necessary to explicitly state the reasons for the request or pose a question to be answered about the patient or their treatment. • A useful guide for the assessment of the multidimensional nature of pain is the IMMPACT group consensus statement on the core outcome domains that should be assessed when evaluating the efficacy of a pain treatment and recommended instruments for measuring those domains. The group has encouraged the selection of measures that were developed and normed for a specific population (e.g. low back pain patients) when such instruments are available. • The consistency, validity, and reliability of the numerous measurement tools have been noted in the following domains: pain intensity, personality, psychosocial impact, physical and social role functioning, emotional functioning, pain beliefs and coping, and quality of care (see Table 22.2). Several of these tools were not originally developed for use with patients with painful

•

•

•

•

•

•

conditions, and their validity has not been tested in specific pain populations. Technological advances, including smartphone apps and wearable technologies, allow for information about pain, sleep, physical and emotional functioning to be recorded prospectively and frequently in the patients’ natural environment. These devices provide objective measures of modifiable health behaviors and are useful tools for clinicians and patients. Pain intensity should not be used as a primary, unitary pain outcome measure as it does not directly correlate with pain related disability, and its measurement does not improve the quality of patient pain management. Patients with HICP, pain at least most days for ≥3 months with ≥1 activity limitation/participation restriction, experience worse outcomes. Subsequently, providers are encouraged to assess patients for HICP with the question, “Over the past six months, how often did pain limit your life or work activities? Would you say never, some days, most days, or every day?” Patients reporting pain related limitations most days or every day meet the criteria for HICP. Pain is often poorly assessed and managed in pediatric and older adult populations, and both require specific considerations and pain assessment measures, particularly for patients unable to self-report pain. In patients unable to self-report pain, it is recommended that providers follow a hierarchy of pain assessment techniques: 1) be aware of potential causes of pain; 2) attempt self-report; 3) observe patient behaviors; 4) solicit proxy reporting of pain and behavior/activity changes; 5) attempt analgesic trial. Areas for continued research include developing patientoriented outcome measures, evaluating standard measures in specific populations, and evaluating measures across diverse cultural populations, particularly those with limited communication capability.

314

PA RT 3 Clinical Evaluation and Assessment

Suggested Readings Beck AT, Ward CH, Mendelsohn M, Mock J, Erbaugh J. An inventory for measuring depression. JAMA Psychiatry. 1961;4(6):561–571. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1-2):9–19. Jensen MP KP, Huger R. The development and preliminary validation of an instrument to assess patients’ attitudes toward pain. J Psychsom Res. 1987;31(3):393–400. Jensen MP, Turner JA, Romano JM, Fisher LD. Comparative reliability and validity of chronic pain intensity measures. Pain. 1999;83(2):157–162.

Spielberger CD GR, Lushene R. Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press, 1970. Sullivan MJL, Bishop SC, Pivik J. The pain catastrophizing scale: Development and validation. Psychol Assess. 1995;7(4):524–532. Tellegen A, Ben-Porath YS. Mmpi-2-Rf (Minnesota Multiphasic Personality Inventory-2 Restructured Form): Technical Manual. Minneapolis, MN: University of Minnesota Press, 2008. Turk DC, Dworkin RH, Allen RR, et al. Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain. 2003;106(3):337–345. The references for this chapter can be found at ExpertConsult.com.

References 1. Pollard C. Preliminary validity study of the pain disability index. Percept Mot Skills. 1984;59:974. 2. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: A health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15(12):1833–1840. 3. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: The neuropathic pain scale. Neurol. 1997;48:332–338. 4. Heapy AA, Wandner L, Driscoll MA, et  al. Developing a typology of patient-generated behavioral goals for cognitive behavioral therapy for chronic pain (CBT-CP): Classification and predicting outcomes. J Behav Med. 2018;41(2):174–185. 5. Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: A state of the art. Pain. 2000;85:317–332. 6. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1-2):9–19. 7. Turk DC, Dworkin RH, Allen RR, et al. Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain. 2003;106(3):337–345. 8. Turk DC, Dworkin RH, Burke LB, et  al. Developing patientreported outcome measures for pain clinical trials: IMMPACT recommendations. Pain. 2006;125(3):208–215. 9. Holzman AD, Kerns RD, Turk DC. Pain assessment report. Personal communication, 1981. 10. Heaton RK LR, Getto CJ. A Manual for the Psychosocial Pain Inventory. Odessa, FL: Psychological assessment resources; 1985. 11. Shiffman S, Stone AA, Hufford MR. Ecological momentary assessment. Annu Rev Clin Psychol. 2008;4:1–32. 12. Kerns RD, Finn P, Haythornwaite J. Self-monitored pain intensity: Psychometric properties and clinical utility. J Behav Med. 1988;11(1):71–82. 13. Haythornthwaite JA, Hegel MT, Kerns RD. Development of a sleep diary for chronic pain patients. J Pain and Symptom Manag. 1991;6(2):65–72. 14. Heapy A, Sellinger J, Higgins D, Chatkoff D, Bennett TC, Kerns RD. Using interactive voice response to measure pain and quality of life. Pain Med. 2007;8(Suppl 3):S145–S154. 15. Bassett DR, Toth LP, LaMunion SR, Crouter SE. Step counting: A review of measurement considerations and health-related applications. Sports Med. 2017;47(7):1303–1315. 16. Geneen LJ, Moore RA, Clarke C, Martin D, Colvin LA, Smith BH. Physical activity and exercise for chronic pain in adults: An overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017;4:CD011279. 17. Ahles TA CD, Jensen L, Stukel T, Maurer LH, Keefe FJ. Development of a behavioral observation technique for the assessment of pain behaviors in cancer patients. Behav Ther. 1990;21: 449–460. 18. Anderson KOBL, McDaniel LK, Young LD, et al. The assessment of pain in rheumatoid patients: Validity of a behavioral observation method. Arthritis Rheum. 1987;30:36–43. 19. Keefe FJCD, Queen RT, Gil KM, et al. Osteoarthritic knee pain: A behavioral analysis. Pain. 1987;28(3):309–321. 20. Keefe FJBA. Development of an observation method for assessing pain behavior in chronic low back pain patients. Behav Ther. 1982;13:363–375. 21. Prkachin KM HE, Schultz I, Joy P, Hunt D. Real-time assessment of pain behavior during clinical assessment of low back pain patients. Pain. 2002;95:23–30. 22. Romano JMTJ, Friedman LS, Bulcroft RA, Jensen MP, Hops H. Observational assessment of chronic pain patient-spouse behavioral interactions. Behav Ther. 1991;22:549–567.

23. Keefe FJ, Williams DA, Smith SJ. Assessment of pain behaviors. In: Turk DC, Melzack R, eds. Handbook of pain assessment. New York: The Guilford Press; 2001. 24. Fordyce W. Behavioral Methods for Chronic Pain and Illness. St. Louis, MO: Mosby; 1976. 25. Turk DC, Meichenbaum D, Genest M. Pain and Behavioral Medicine: A Cognitive-Behavioral Perspective. NY: Guilford Press; 1983. 26. Leonard MT, Cano A, Johansen AB. Chronic pain in a couples context: A review and integration of theoretical models and empirical evidence. J Pain. 2006;7(6):377–390. 27. Kerns RD, Otis JD. Family therapy for persons experiencing pain: Evidence for its effectiveness. Semin Pain Med. 2003;1(2):79–89. 28. Newton-John TR, de C Williams AC. Chronic pain couples: Perceived marital interactions and pain behaviours. Pain. 2006;123(1-2): 53–63. 29. Kerns RD, Rosenberg R. Pain-relevant responses from significant others: Development of a significant-other version of the WHYMPI scales. Pain. 1995;61(2):245–249. 30. Schwartz L, Jensen MP, Romano JM. The development and psychometric evaluation of an instrument to assess spouse responses to pain and well behavior in patients with chronic pain: The spouse response inventory. J Pain. 2005;6(4):243–252. 31. Sharp T, Nicholas M. Assessing the significant others of chronic pain patients: The psychometric properties of significant other questionnaires. Pain. 2000;88(2):135–144. 32. Flor H, Kerns RD, Turk DC. The role of spouse reinforcement, perceived pain, and activity levels of chronic pain patients. J Psychosom Res. 1987;31(2):251–259. 33. Flor H. Psychophysiological assessment of the patient with chronic pain. In: Turk DC, Melzack R (eds). Handbook of Pain Assessment. New York: The Guilford Press; 2001. 34. Holroyd KA, Penzien DB, Hursey KG, et al. Change mechanisms in EMG biofeedback training: Cognitive changes underlying improvements in tension headache. J Consult Clin Psychol. 1984;52(6):1039. 35. Tracy LM, Ioannou L, Baker KS, Gibson SJ, Georgiou-Karistianis N, Giummarra MJ. Meta-analytic evidence for decreased heart rate variability in chronic pain implicating parasympathetic nervous system dysregulation. Pain. 2016;157(1):7–29. 36. Shaffer F, McCraty R, Zerr CL. A healthy heart is not a metronome: An integrative review of the heart’s anatomy and heart rate variability. Front Psychol. 2014;5:1040. 37. Shaffer F, Ginsberg J. An overview of heart rate variability metrics and norms. Front Public Health. 2017;5:258. 38. Berry ME, Chapple IT, Ginsberg JP, Gleichauf KJ, Meyer JA, Nagpal ML. Non-pharmacological intervention for chronic pain in veterans: A pilot study of heart rate variability biofeedback. GAHMJ. 2014;3(2):28–33. 39. Gass JJ, Glaros AG. Autonomic dysregulation in headache patients. AAPB. 2013;38(4):257–263. 40. Hallman DM, Olsson EM, Von Schéele B, Melin L, Lyskov E. Effects of heart rate variability biofeedback in subjects with stressrelated chronic neck pain: A pilot study. AAPB. 2011;36(2):71–80. 41. Committee APSQoC. Quality improvement guidelines for the treatment of acute pain and cancer pain. JAMA. 1995;274(23): 1874–1880. 42. Pitcher MH, Von Korff M, Bushnell MC, Porter L. Prevalence and profile of high-impact chronic pain in the United States. J Pain. 2019;20(2):146–160. 43. Mularski RA, White-Chu F, Overbay D, Miller L, Asch SM, Ganzini L. Measuring pain as the 5th vital sign does not improve quality of pain management. J Gen Intern Med. 2006;21(6):607–612. 44. Jensen MP, Karoly P. Self-report scales and procedures for assessing pain in adults. In: Turk DC, Melzack R (eds). Handbook of Pain Assessment. New York: The Guilford Press; 2001. 45. Jensen MP, Turner JA, Romano JM, Fisher LD. Comparative reliability and validity of chronic pain intensity measures. Pain. 1999;83(2):157–162. 314.e1

314.e2

References

46. Jamison RN, Gracely RH, Raymond SA, et al. Comparative study of electronic vs. paper VAS ratings: A randomized, crossover trial using healthy volunteers. Pain. 2002;99(1-2):341–347. 47. Bird M-L, Callisaya ML, Cannell J, Gibbons T, Smith ST, Ahuja KD. Accuracy, validity, and reliability of an electronic visual analog scale for pain on a touch screen tablet in healthy older adults: A clinical trial. I J Med Res. 2016;5(1):e4910. 48. Turnbull A, Sculley D, Escalona-Marfil C, et al. Comparison of a mobile health electronic visual analog scale app with a traditional paper visual analog scale for pain evaluation: Cross-sectional observational study. J Med Internet Res. 2020;22(9):e18284. 49. Melzack R. The McGill pain questionnaire: Major properties and scoring methods. Pain. 1975;1(3):277–299. 50. Adelmanesh F, Jalali A, Attarian H, et  al. Reliability, validity, and sensitivity measures of expanded and revised version of the short-form McGill pain questionnaire (SF-MPQ-2) in Iranian patients with neuropathic and non-neuropathic pain. Pain Med. 2012;13(12):1631–1638. 51. Arimura T, Hosoi M, Tsukiyama Y, et al. Pain questionnaire development focusing on cross-cultural equivalence to the original questionnaire: The Japanese version of the short-form McGill pain questionnaire. Pain Med. 2012;13(4):541–551. 52. LdCM Costa, Maher CG, McAuley JH, et al. The Brazilian-Portuguese versions of the McGill pain questionnaire were reproducible, valid, and responsive in patients with musculoskeletal pain. J Clin Epidemiol. 2011;64(8):903–912. 53. Hasvik E, Haugen AJ, Haukeland-Parker S, Rimehaug SA, Gjerstad J, Grøvle L. Cross-cultural adaptation and validation of the Norwegian short-form McGill pain questionnaire-2 in low back-related leg pain. Spine. 2019;44(13):E774–E781. 54. Wang J-L, Zhang W-J, Gao M, Zhang S, Tian D-H, Chen J. A cross-cultural adaptation and validation of the short-form McGill pain questionnaire-2: Chinese version in patients with chronic visceral pain. J Pain Res. 2017;10:121. 55. Melzack R. The short-form McGill pain questionnaire. Pain. 1987;30(2):191–197. 56. Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual analog scale for pain (vas pain), numeric rating scale for pain (nrs pain), McGill pain questionnaire (mpq), short-form McGill pain questionnaire (sf-mpq), chronic pain grade scale (cpgs), short form-36 bodily pain scale (sf-36 bps), and measure of intermittent and constant osteoarthritis pain (icoap). Arthritis Care Res. 2011;63(S11):S240–S252. 57. Dworkin RH, Turk DC, Trudeau JJ, et al. Validation of the shortform McGill pain questionnaire-2 (SF-MPQ-2) in acute low back pain. J Pain. 2015;16(4):357–366. 58. Katz J, Melzack R. The McGill pain questionnaire: Development, psychometric properties, and usefulness of the long form, short form, and short-form 2. In: Turk DC, Melzack R (eds). Handbook of Pain Assessment. 3rd ed. New York: Guilford Press; 2011. 59. Jensen MP, Miller L, Fisher LD. Assessment of pain during medical procedures: A comparison of three scales. Clin J Pain. 1998;14(4):343–349. 60. Dworkin RH, Turk DC, Revicki DA, et al. Development and initial validation of an expanded and revised version of the short-form McGill pain questionnaire (SF-MPQ-2). Pain. 2009;144(1-2): 35–42. 61. Lovejoy TI, Turk DC, Morasco BJ. Evaluation of the psychometric properties of the revised short-form McGill pain questionnaire. J Pain. 2012;13(12):1250–1257. 62. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of chronic pain and high-impact chronic pain among adults-United States, 2016. MMWR. 2018;67(36):1001. 63. Interagency Pain Research Coordinating Committee. National Pain Strategy: A Comprehensive Population Health-Level Strategy for Pain. Washington DC: Department of Health and Human Services; 2015. 64. Cleeland CS, Ryan KM. Pain assessment: Global use of the brief pain inventory. Ann Acad Med Singap. 1994;23(2):129–138.

65. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the Brief Pain Inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain. 2004;20(5):309–318. 66. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med. 2009;24(6):733–738. 67. Von Korff M, DeBar LL, Krebs EE, Kerns RD, Deyo RA, Keefe FJ. Graded chronic pain scale revised: Mild, bothersome, and highimpact chronic pain. Pain. 2020;161(3):651–661. 68. Kerns RD, Turk DC, Rudy TE. The west haven-yale multidimensional pain inventory (WHYMPI). Pain. 1985;23(4):345–356. 69. Riley III JL, Zawacki TM, Robinson ME, Geisser ME. Empirical test of the factor structure of the West Haven-Yale multidimensional pain inventory. Clin J Pain. 1999;15(1):24–30. 70. Turk DC, Rudy TE. Toward an empirically derived taxonomy of chronic pain patients: Integration of psychological assessment data. J Consult Clin Psychol. 1988;56(2):233. 71. Turk DC, Rudy TE. The robustness of an empirically derived taxonomy of chronic pain patients. Pain. 1990;43(1):27–35. 72. Kerns RD, Haythornthwaite J, Southwick S, Giller Jr E. The role of marital interaction in chronic pain and depressive symptom severity. J Psychosom Res. 1990;34(4):401–408. 73. TE R. Multiaxial assessment of pain: Multidimensional pain inventory. Computer Program Users’ Manual, Version 2.1. Pittsburgh, PA: Pain Evaluation and Treatment Institute; 1989. 74. Okifuji A, Turk DC, Eveleigh DJ. Improving the rate of classification of patients with the multidimensional pain inventory (MPI): Clarifying the meaning of “significant other”. Clin J Pain. 1999;15(4):290–296. 75. Bruehl S, Lofland KR, Sherman JJ, Carlson CR. The variable responding scale for detection of random responding on the multidimensional pain inventory. Psychol Assess. 1998;10(1):3–9. 76. Tait RC PC, Margolis RB, Duckro PN, Krause SJ. The pain disability index: Psychometric and validity data. Arch PhysMed Rehabil. 1987;68:438–441. 77. Grönblad M, Hupli M, Wennerstrand P, et  al. Intel-correlation and test-retest reliability of the pain disability index (PDI) and the Oswestry disability questionnaire (ODQ) and their correlation with pain intensity in low back pain patients. Clin J Pain. 1993;9(3): 189–195. 78. Grönblad M, Järvinen E, Hurri H, Hupli M, Karaharju EO. Relationship of the pain disability index (PDI) and the Oswestry disability questionnaire (ODQ) with three dynamic physical tests in a group of patients with chronic low-back and leg pain. Clin J Pain. 1994;10(3):197–203. 79. Askew RL, Cook KF, Keefe FJ, et al. A PROMIS measure of neuropathic pain quality. Value Health. 2016;19(5):623–630. 80. Amtmann D, Cook KF, Jensen MP, et al. Development of a PROMIS item bank to measure pain interference. Pain. 2010;150(1): 173–182. 81. Revicki DA, Chen WH, Harnam N, et al. Development and psychometric analysis of the PROMIS pain behavior item bank. Pain. 2009;146(1–2):158–169. 82. Fenton BW, Palmieri P, Diantonio G, Vongruenigen V. Application of patient reported outcomes measurement information system to chronic pelvic pain. J Minim Invasive Gynecol. 2011;18(2):189–193. 83. Askew RL, Cook KF, Revicki DA, Cella D, Amtmann D. Evidence from diverse clinical populations supported clinical validity of PROMIS pain interference and pain behavior. J Clin Epidemiol. 2016;73:103–111. 84. Stone AA, Broderick JE, Junghaenel DU, Schneider S, Schwartz JE. PROMIS fatigue, pain intensity, pain interference, pain behavior, physical function, depression, anxiety, and anger scales demonstrate ecological validity. J Clin Epidemiol. 2016;74:194–206. 85. Crins M, Roorda L, Smits N, et al. Calibration of the Dutch-Flemish PROMIS pain behavior item bank in patients with chronic pain. Eur J Pain. 2016;20(2):284–296.

References

86. Hinds PS, Nuss SL, Ruccione KS, et al. PROMIS pediatric measures in pediatric oncology: Valid and clinically feasible indicators of patient-reported outcomes. Pediatr Blood Cancer. 2013;60(3): 402–408. 87. Varni JW, Stucky BD, Thissen D, et al. PROMIS pediatric pain interference scale: An item response theory analysis of the pediatric pain item bank. J Pain. 2010;11(11):1109–1119. 88. Varni JW, Magnus B, Stucky BD, et al. Psychometric properties of the PROMIS® pediatric scales: Precision, stability, and comparison of different scoring and administration options. Qual Life Res. 2014;23(4):1233–1243. 89. Bergner M BR, Carter WB, Gilson BS. The sickness impact profile: Development and final revision of a health status measure. Med Care. 1981;19:787–805. 90. Sanders SH, Brena SF. Empirically derived chronic pain patient subgroups: The utility of multidimensional clustering to identify differential Treatment effects. Pain. 1993;54(1):51–56. 91. Roland M, Morris R. A study of the natural history of back pain: Part 1: Development of a reliable and sensitive measure of disability in low-back pain. Spine. 1983;8(2):141–144. 92. Tellegen A, Ben-Porath YS. MMPI-2-RF (Minnesota Multiphasic Personality Inventory-2 Restructured Form): Technical Manual. Minneapolis: University of Minnesota Press; 2008. 93. Bradley LA, NL McKendree-Smith. Assessment of psychological status using interviews and self-report instruments. In: Turk DC, Melzack R (eds). Handbook of Pain Assessment. New York: Guilford Press; 2001 second edition. 94. Pincus T, Callahan LF, Bradley LA, Vaughn WK, Wolfe F. Elevated MMPI scores for hypochondriasis, depression, and hysteria in patients with rheumatoid arthritis reflect disease rather than psychological status. Arthritis Rheum. 1986;29(12):1456–1466. 95. McCord DM, Drerup LC. Relative practical utility of the Minnesota multiphasic personality inventory-2 restructured clinical scales versus the clinical scales in a chronic pain patient sample. J Clin Exp. 2011;33(1):140–146. 96. Tarescavage AM, Scheman J, Ben-Porath YS. Reliability and validity of the Minnesota multiphasic personality inventory-2-restructured form (MMPI-2-RF) in evaluations of chronic low back pain patients. Psychol Assess. 2015;27(2):433. 97. Millon T, Green CJ, Meagher RB. Millon Behavioral Health Inventory Manual. Interpretive Scoring Systems. Minneapolis, MN; 1982. 98. Gatchel RJ, Deckel AW, Weinberg N, Smith JE. The utility of the millon behavioral health inventory in the study of chronic headaches. J Headache Pain. 1985;25(1):49–54. 99. Herron L, Turner JA, Ersek M, Weiner P. Does the millon behavioral health inventory (MBHI) predict lumbar laminectomy outcome? A comparison with the Minnesota multiphasic personality inventory (MMPI). Clin Spine Surg. 1992;5(2):188–192. 100. Gatchel RJ, Mayer TG, Capra P, Barnett J, Diamond P. Millon behavioral health inventory: Its utility in predicting physical function in patients with low back pain. Arch Phys Med. 1986;67(12):878–882. 101. Beck AT, Ward CH, Mendelsohn M, Mock J, Erbaugh J. An inventory for measuring depression. JAMA Psychiatry. 1961;4(6): 561–571. 102. Yonkers KASJ. Mood disorders measures. In: American Psychiatric Association Handbook of Psychiatric Measures. Washington DC: American Psychiatric Association; 2000. 103. Beck AT SR, Garbin MG. Psychometric properties of the Beck depression inventory: Twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77–100. 104. Moran PW, Lambert MJ. A review of current assessment tools for monitoring changes in depression. In: Lamber ER, Christiensen SD (eds). The Assessment of Psychotherapy and Outcomes. New York: Wiley; 1983. 105. Burns JW JB, Mahoney N, Devine J, Pawl R. Cognitive and physical capacity process variables predict long-term outcome after treatment for chronic pain. J Consult Clin Psychol. 1998;66:434–439.

314.e3

106. CL K. How chronic pain patients cope with pain: Relation to treatment outcome in a multidisciplinary pain clinic. Cog Ther Res. 1992;16:669–685. 107. Marhold C LS, Melin L. A cognitive-behavioral return-to-work program: Effects on pain patients with a history of long-term versus short-term sick leave. Pain. 2001;91:155–163. 108. Nicholas MK WP, Goyen J. Operant-behavioral and cogni tive-behavioral treatment for chronic low back pain. Pain. 1991;48:339–347. 109. Richardson IH, Richardson PH, ACdC Williams, Featherstone J, Harding VR. The effects of a cognitive-behavioural pain management programme on the quality of work and employment status of severely impaired chronic pain patients. Disabil Rehabil. 1994;16(1):26–34. 110. Radloff LS, Locke BZ. Center for epidemiologic studies depression scale (CES-D). In: Handbook of Psychiatric Measures. Washington, DC: American Psychiatric Association; 2000. 111. Roberts RE. Reliability of the CES-D scale in different ethnic contexts. Psychiatry Res. 1980;2(2):125–134. 112. Blalock SJ. Validity of the center for epidemiological studies depression scale in arthritis populations. Arthritis and Rheum. 32(8):991–997. 113. Brown GK. A causal analysis of chronic pain and depression. J Abnorm Psych. 1989;99(2):127–137. 114. Magni G, Caldieron C, Rigatti-Luchini S, Merskey H. Chronic musculoskeletal pain and depressive symptoms in the general population. An analysis of the 1st national health and nutrition examination survey data. Pain. 1990;43(3):299–307. 115. Turk DC. Detecting depression in chronic pain patients: Adequacy of self-reports. Behav Res Ther. 1994;32(1):9–16. 116. Nielson WR, Walker C, McCain GA. Cognitive behavioral treatment of fibromyalgia syndrome: Preliminary findings. J Rheumatol. 1992;19(1):98–103. 117. Turner JA. Effectiveness of behavioral therapy for chronic low back pain: A component analysis. J Consult Clin Psych. 1990;58(5):573–579. 118. Yesavage JA. Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res. 1982; 17(1):37–49. 119. Sheikh JI, Yesavage JA. Geriatric depression scale (GDS): Recent evidence and development of a shorter version. Clin Gerontol. 1986;5(1–2):165–173. 120. Brink TL, Yesavage JA, Lum O, Heersema PH, Adey M, Rose TL. Screening tests for geriatric depression. Clin Gerontol. 2008;1(1):37–43. 121. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: Validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606– 613. 122. Martin A, Rief W, Klaiberg A, Braehler E. Validity of the brief patient health questionnaire mood scale (PHQ-9) in the general population. Gen Hosp Psychiatry. 2006;28(1):71–77. 123. Huang FY, Chung H, Kroenke K, Delucchi KL, Spitzer RL. Using the patient health questionnaire-9 to measure depression among racially and ethnically diverse primary care patients. J Gen Intern Med. 2006;21(6):547–552. 124. Gilbody S, Richards D, Brealey S, Hewitt C. Screening for depression in medical settings with the patient health questionnaire (PHQ): A diagnostic meta-analysis. J Gen Intern Med. 2007;22(11):1596–1602. 125. Seo JG, Park SP. Validation of the patient health questionnaire-9 (PHQ-9) and PHQ-2 in patients with migraine. J Headache Pain. 2015;16:65. 126. Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: The GAD-7. Arch Intern Med. 2006;166(10):1092–1097. 127. Löwe B, Decker O, Müller S, et al. Validation and standardization of the generalized anxiety disorder screener (GAD-7) in the general population. Med Care. 2008:266–274. 128. Seo J-G, Park S-P. Validation of the generalized anxiety disorder-7 (GAD-7) and GAD-2 in patients with migraine. J Headache Pain. 2015;16(1):97.

314.e4

References

129. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: Psychometric properties. J Consult Clin Psychol. 1988;56(6):893. 130. Bardhoshi G, Duncan K, Erford BT. Psychometric meta-analysis of the English version of the Beck anxiety inventory. J Couns Dev. 2016;94(3):356–373. 131. Beck AT, Steer RA. Beck Anxiety Inventory: BAI: Psychological Corporation; 1993. 132. Muntingh AD, van der Feltz-Cornelis CM, van Marwijk HW, Spinhoven P, Penninx BW, van Balkom AJ. Is the beck anxiety inventory a good tool to assess the severity of anxiety? A primary care study in the Netherlands study of depression and anxiety (NESDA). BMC Fam Pract. 2011;12(1):66. 133. Osman A, Hoffman J, Barrios FX, Kopper BA, Breitenstein JL, Hahn SK. Factor structure, reliability, and validity of the Beck Anxiety Inventory in adolescent psychiatric inpatients. J Clin Psychol. 2002;58(4):443–456. 134. Wetherell JL, Areán PA. Psychometric evaluation of the Beck anxiety inventory with older medical patients. Psychol Assess. 1997;9(2):136. 135. Ulusoy M, Sahin NH, Erkmen H. The Beck anxiety inventory: Psychometric properties. J Cogn Psychother. 1998;12(2):163–172. 136. Fydrich T, Dowdall D, Chambless DL. Reliability and validity of the Beck anxiety inventory. J Anxiety Disorder. 1992;6(1):55–61. 137. McCracken LM, Zayfert C, Gross RT. The pain anxiety symptoms scale: Development and validation of a scale to measure fear of pain. Pain. 1992;50(1):67–73. 138. McCracken LM. Pain-related anxiety predicts non-specific physical complaints in persons with chronic pain. Behav Res Ther. 36(6):621–630. 139. McCracken LM. The assessment of anxiety and fear in persons with chronic pain: A comparison of instruments. Behav Res Ther. 34(11-12): 927–933. 140. Larsen DK, Taylor S, Asmundson GJG. Exploratory factor analysis of the pain anxiety symptoms scale in patients with chronic pain complaints. Pain. 1997;69(1):27–34. 141. Spielberger CD GR, Lushene R. Manual for the State-Trait Anxiety Inventory. Palo Alto: Consulting Psychologists Press; 1970. 142. Polatin PB. Psychiatric illness and chronic low-back pain. The mind and the spine-which goes first? Spine. 1976;18(1):66–71. 143. Bradley LA. Effects of psychological therapy on pain behavior of rheumatoid arthritis patients. treatment outcome and six-month followup. Arthritis and Rheum. 30(10):1105–1114. 144. Ware JES. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care. 1992; 30(6). 145. Kazis LE, Clark J, et al. Health-related quality of life in patients served by the Department of Veterans Affairs results from the veterans health study. Arch Intern Med. 1960;158(6). 146. McHorney CA, Ware JE, Lu JFR, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care. 1994;32(1):40–66. 147. McHorney CA, Ware JE, Raczek AE. The MOS 36-item shortform health survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31(3):247–263. 148. Ware Jr. SF-36 health survey update. Spine. 2000;25(24). 149. Kazis LE SK, Rogers W, Lee A, Ren XS, Miller D. Health Status and Outcomes of Veterans: Physical and Mental Component Summary Scores (Sf-36V). 1998 National Survey of Ambulatory Care Patients. Mid-Year Executive Report. Washington, D.C. and Bedford: Office of Performance and Quality, Health Assessment Project, Center for Health Quality Outcomes and Economic Research, HSR&D Service, Veterans Administration, 1998. 150. Ware JEKM, Keller SD. SF-36 Physical and Mental Health Summary Scales: A Users Manual. Boston: Health Assessment Lab, New England Medical Center; 1994.

151. Donta ST, Clauw DJ, Engel J, Charles C, et al. Cognitive behavioral therapy and aerobic exercise for Gulf War veterans’ illnesses: A randomized controlled trial. JAMA. 2003;289(11):1396–1404. 152. Rogers WH, Wagner A, Cynn D, Carr DB. Assessing individual outcomes during outpatient multidisciplinary chronic pain treatment by means of an augmented SF-36. Pain Med. 2000;1(1):44–54. 153. McHorney C TA. Individual-patient monitoring in clini cal practice: Are available health status surveys adequate? QOL Research.4(4):293-307. 154. Jensen MP KP, Huger R. The development and preliminary validation of an instrument to assess patients’ attitudes toward pain. J Psychsom Res. 31(3):393–400. 155. Jensen MP KP. Revision and Cross-Validation of The Survey of Pain Attitudes. 10th Annual Scientific Sessions of The Society of Behavioral Medicine, San Francisco, CA; 1989. 156. Jensen MP, Turner JA, Romano JM, Lawler BK. Relation ship of pain-specific beliefs to chronic pain adjustment. Pain. 1994;57(3):301–309. 157. Tait RC, Chibnall JT. Development of a brief version of the survey of pain attitudes. Pain. 1997;70(2):229–235. 158. Jensen MP TJ, Romano JM. Pain belief assessment: A comparison of the short and long versions of the surgery of pain attitudes. J Pain. 1(2):138–150. 159. Strong J, Ashton R, Chant D. Pain intensity measurement in chronic low back pain. Clin J Pain. 1991;7(3):209–218. 160. Jensen MP KP. Control beliefs, coping efforts, and adjustment to chronic pain. J Consult Clin Psychol. 59(3):431–438. 161. Kerns RD, Rosenberg R, Jamison RN, Caudill MA, Haythornthwaite J. Readiness to adopt a self-management approach to chronic pain: The pain stages of change questionnaire (PSOCQ). Pain. 1997;72(1):227–234. 162. Kerns RD. A critical review of the pain readiness to change model. J Pain. 5(7):357–367. 163. Kerns RD, Rosenberg R. Predicting responses to self-management treatments for chronic pain: Application of the pain stages of change model. Pain. 2000;84(1):49–55. 164. Biller N AP, Caudill M, Federman C, Guberman C. Predicting completion of a cognitive-behavioral pain management program by initial measures of a chronic pain patient’s readiness for change. Clin J Pain. 2000;16(4). 165. Jensen MP, Nielson WR, Kerns RD. Toward the develop ment of a motivational model of pain self-management. J Pain. 2003;4(9):477–492. 166. Glenn B BJ. Pain self-management in the process and outcome of multidisciplinary treatment of chronic pain: Evaluation of a stage of change model. J Behav Med. 2003;26(5):417–433. 167. Strong J WK, Smith G, McKenzie I, Ryan W. Treatment outcome in individuals with chronic pain: Is the pain stages of change questionnaire (PSOCQ) a useful tool? Pain. 97(1):65–73. 168. Jensen MP, Turner JA, Romano JM, Strom SE. The chronic pain coping inventory: Development and preliminary validation. Pain. 1995;60(2):203–216. 169. Hadjistavropoulos HD, MacLeod FK, Asmundson GJG. Validation of the chronic pain coping inventory. Pain. 1999;80(3):471–481. 170. Tan G NQ, Anderson KO, Jensen M, Thornby J. Further validation of the chronic pain coping inventory. J Pain. 6(1):29–40. 171. Truchon M, Côté D. Predictive validity of the chronic pain coping inventory in subacute low back pain. Pain. 2005;116(3):205–212. 172. Sullivan MJL, Bishop SC, Pivik J. The pain catastrophizing scale: Development and validation. Psychol Assess. 1995;7(4):524–532. 173. Osman B, Kopper Hauptmann, Jones O’Neill. Factor structure, reliability, and validity of the pain catastrophizing scale. J Behav Med. 1997;20(6):589–605. 174. D’Eon JL HC, Ellis JA. Testing factorial validity and gender invariance of the pain catastrophizing scale. J Behav Med. 2004;27(4):361–372. 175. Osman B, Gutierrez Kopper, Merrifield Grittman. The pain catastrophizing scale: Further psychometric evaluation with adult samples. J Behav Med. 2000;23(4):351–365.

References

176. Chibnall JT, Tait RC. Confirmatory factor analysis of the pain catastrophizing scale in African American and Caucasian workers’ compensation claimants with low back injuries. Pain. 2005;113(3):369–375. 177. Jensen MP TJ, Romano JM. Changes in beliefs, catastrophizing, and coping are associated with improvement in multidisciplinary pain treatment. J Consult Clin Psychol. 2001;69(4):655–662. 178. Burns JW KA, Bruehl S, Harden RN, Lofland K. Do changes in cognitive factors influence outcome following multidisciplinary treatment for chronic pain? A cross-lagged panel analysis. J Consult Clin Psychol. 2003;71(1):81–91. 179. Spinhoven P, ter Kuile M, Kole-Snijders AMJ, Hutten Mansfeld M, den Ouden DJ, Vlaeyen JWS. Catastrophizing and internal pain control as mediators of outcome in the multidisciplinary treatment of chronic low back pain. Eur J Pain. 2004;8(3):211–219. 180. Smeets RJEM, Vlaeyen JWS, Kester ADM, Knottnerus JA. Reduction of pain catastrophizing mediates the outcome of both physical and cognitive-behavioral treatment in chronic low back pain. J Pain. 2006;7(4):261–271. 181. Thorn BE, Pence LB, Ward LC, et al. A randomized clinical trial of targeted cognitive behavioral treatment to reduce catastrophizing in chronic headache sufferers. J Pain. 2007;8(12):938–949. 182. Van Damme S, Crombez G, Bijttebier P, Goubert L, Van Houdenhove B. A confirmatory factor analysis of the pain catastrophizing scale: Invariant factor structure across clinical and non-clinical populations. Pain. 2002;96(3):319–324. 183. Meyer K, Sprott H, Mannion AF. Cross-cultural adaptation, reliability, and validity of the German version of the pain catastrophizing scale. J Psychosom Res. 2008;64(5):469–478. 184. García Campayo J, Rodero B, Alda M, Sobradiel N, Montero J, Moreno S. Validation of the Spanish version of the pain catastrophizing scale in fibromyalgia. Med Clin (Barc). 2008;131(13):487–492. 185. Yap JCLJ, Chen PP, Gin T, et al. Validation of the Chinese pain catastrophizing scale (HK-PCS) in patients with chronic pain. Pain Med. 2008;9(2):186–195. 186. Miró J, Nieto R, Huguet A. The Catalan version of the pain catastrophizing scale: A useful instrument to assess catastrophic thinking in whiplash patients. J Pain. 2008;9(5):397–406. 187. Din FM, Hoe VC, Chan C, Muslan M. Cultural adaptation and psychometric assessment of Pain Catastrophizing Scale among young healthy Malay-speaking adults in military settings. QOL Research. 2015;24(5):1275–1280. 188. McCracken LM, Vowles KE, Eccleston C. Acceptance of chronic pain: Component analysis and a revised assessment method. Pain. 2004;107(1):159–166. 189. Veehof MM, Oskam M-J, Schreurs KMG, Bohlmeijer ET. Acceptance-based interventions for the treatment of chronic pain: A systematic review and meta-analysis. Pain. 2011;152(3):533–542. 190. Vowles KE, McCracken LM, McLeod C, Eccleston C. The chronic pain acceptance questionnaire: Confirmatory factor analysis and identification of patient subgroups. Pain. 2008;140(2):284–291. 191. Fish RA, McGuire B, Hogan M, Morrison TG, Stewart I. Validation of the chronic pain acceptance questionnaire (CPAQ) in an internet sample and development and preliminary validation of the CPAQ-8. Pain. 2010;149(3):435–443. 192. Reneman MF, Dijkstra A, Geertzen JHB, Dijkstra PU. Psychometric properties of chronic pain acceptance questionnaires: A systematic review. Eur J Pain. 2010;14(5):457–465. 193. Wetherell JL, Afari N, Rutledge T, et al. A randomized, controlled trial of acceptance and commitment therapy and cognitivebehavioral therapy for chronic pain. Pain. 2011;152(9):2098– 2107. 194. Curtis K, Osadchuk A, Katz J. An eight-week yoga intervention is associated with improvements in pain, psychological functioning

314.e5

and mindfulness, and changes in cortisol levels in women with fibromyalgia. J Pain Res. 2011;4:189–201. 195. McCracken LM, Gauntlett-Gilbert J, Eccleston C. Acceptance of pain in adolescents with chronic pain: Validation of an adapted assessment instrument and preliminary correlation analyses. Eur J Pain. 2010;14(3):316–320. 196. González Menéndez A, Fernández García P, Torres Viejo I. Acceptance of chronic pain in fibromyalgia patients: Adaptation of chronic pain acceptance questionnaire (CPAQ) in a Spanish population. Psicothema. 2010;22(4):997–1003. 197. Bernini O, Pennato T, Cosci F, Berrocal C. The psychometric properties of the chronic pain acceptance questionnaire in Italian patients with chronic pain. J Health Psychol. 2010;15(8):1236–1245. 198. Blumenthal D. Part 1: Quality of care- what is it? New Eng J Med. 1996;335(12):891–894. 199. Standards APSCoQA. American Pain Society quality assurance standards for the relief of acute pain and cancer pain. Paper presented at: Ith World Congress on Pain, Seattle, WA; 1991. 200. Gordon DB, Polomano RC, Pellino TA, et  al. Revised American Pain Society patient outcome questionnaire (APS-POQ-R) for quality improvement of pain management in hospitalized adults: Preliminary psychometric evaluation. J Pain. 2010;11(11):1172–1186. 201. Botti M, Khaw D, Jørgensen EB, Rasmussen B, Hunter S, Redley B. Cross-cultural examination of the structure of the revised American Pain Society patient outcome questionnaire (APS-POQ-R). J Pain. 2015;16(8):727–740. 202. Zoëga S, Ward S, Gunnarsdottir S. Evaluating the quality of pain management in a hospital setting: Testing the psychometric properties of the Icelandic version of the revised American Pain Society patient outcome questionnaire. Pain Manag Nurs. 2014;15(1):143–155. 203. Rothaug J, Zaslansky R, Schwenkglenks M, et  al. Patients’ perception of postoperative pain management: Validation of the international pain outcomes (IPO) questionnaire. J Pain. 2013;14(11):1361–1370. 204. Kaczynski K, Ely E, Gordon D, et al. The pediatric American Pain Society patient outcomes questionnaire (Pediatric APS-POQ): Development and initial psychometric evaluation of a brief and comprehensive measure of pain and pain outcomes in hospitalized youth. J Pain. 2020;21(5-6):633–647. 205. Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain. 2007;23:S1–S43. 206. Herr K, Coyne PJ, McCaffery M, Manworren R, Merkel S. Pain assessment in the patient unable to self-report: Position statement with clinical practice recommendations. Pain Manage Nurs. 2011;12(4):230–250. 207. Herr K, Coyne PJ, Ely E, Gélinas C, Manworren RC. Pain assessment in the patient unable to self-report: Clinical practice recommendations in support of the ASPMN 2019 position statement. Pain Manag Nurs. 2019;20(5):404–417. 208. McGrath PJ, Walco GA, Turk DC, et al. Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J Pain. 2008;9(9):771–783. 209. Beltramini A, Milojevic K, Pateron D. Pain assessment in newborns, infants, and children. Pediatr Ann. 2017;46(10):e387–e395. 210. Otis J CL, Kerns RD. The influence of family and culture on pain. In: Breitbart RDW (ed). Psychosocial and Psychiatric Aspects of Pain: A Handbook for Health Care Providers. Seattle, WA: International Association for the Study of Pain Press; 2003. Psychosocial and psychiatric aspects of pain: a handbook for health care providers. 27. 211. Barry LC, Gill TM, Kerns RD, Reid MC. Identification of painreduction strategies used by community-dwelling older persons. J Gerontol. 2005;60(12):1569–1575.

23

Disability Assessment

MOHAMMED I . RANAVAYA, MOHAMMED I. RANAVAYA II, JAMILA I. RANAVAYA

Introduction The transition from acute to chronic pain and disability because of multiple factors has been well documented in the literature.1 According to a morbidity and mortality weekly report from the Centers for Disease Control and Prevention (CDC), one in four United States adults, 61 million Americans, have a disability that impacts major life activities.2 These numbers are likely to increase in the next few decades with our aging generation of baby boomers currently living with potentially disabling conditions.3 Continued advancements in medical and surgical technologies enable increased survival after catastrophic injuries and illnesses and may help mitigate the disabling consequences, as well as allow for an increased prevalence of disability within our society. Persons with disabilities face greater barriers to health care than do those without disabilities.4 Impairment and disability resulting from claims of functional losses secondary to chronic pain continue to challenge pain medicine specialists and independent medical examiners because of the problem’s polemic nature. The decade long opioid epidemic has led some in the medical community to question the very existence of disability from chronic pain and the very basis of it as a specific disease entity. Everything about disabling chronic nonmalignant pain engenders controversy except for the suffering associated with the diagnosis and the isolation, frustration, and marginalization experienced by these patients. Physicians dealing with the evaluation and treatment of patients with chronic nonmalignant pain and disabling conditions can expect to be called upon occasionally to formally evaluate the impairment and disability of these patients for legal purposes, mainly for receiving benefits under many disability compensation systems. This skill is not taught in any medical education or residency training.5 The treating pain medicine specialist must become familiar with and adapt their practice to better address patient needs associated with these assessment requests by gaining greater knowledge and understanding of the concepts and terminology of disablement and the practices of impairment rating and disability evaluation. The scientific approach to impairment and disability differs from the legal.6 To deal with this disparity between law and medicine, a pain medicine specialist must understand the fundamentals of the disability and compensation system, the nuances of legal procedure, and their duties and rights within the legal system. This chapter intends to educate and provide critical information, principles, and practical knowledge unique to the emerging field of

disability medicine essential for pain medicine professionals looking to enhance their skills and empower themselves with knowledge, skills, and abilities to further care for their patients. The intention is to not only provide a brief historical and conceptual overview of models of disablement and United States disability systems but also to familiarize the processes and tools available for impairment rating and disability determination and to examine the medical-legal pitfalls and ramifications of these clinical activities. At the conclusion of this chapter, there are also suggestions and recommendations for further reading and available training in disability evaluation.

United States Disability and Personal injuries Compensation Systems Historical Perspective It is written in the Bible that “if any would not work, neither should he eat.”7 Hence there has been a long-standing expectation among individuals within society that members must contribute individually to benefit and share collectively. It appears equally valid that individual members who cannot contribute because of disability may be exempt from such expectation and yet still enjoy benefits to which other group members are entitled. It is also possible for an individual to exploit society through unfair and exaggerated claims of disability, which becomes an issue of social justice. Although social justice systems compensate in some way for bodily illness or injury, they must also afford protection against benefits being paid to those who choose not to be productive and fake or exaggerate their disability. Various legal disability and compensation systems provide rules defining disability and entitlement as well as procedures for determining who qualifies as disabled. These rules are intended to provide fair and equitable distribution of limited system resources to those whose needs are greatest and whose disabilities are most compelling.8 Within the United States, various disability and compensation systems have arisen to ensure that members of society with a medically determinable impairment that may lead to disability have recourse to compensation from various avenues. This includes state tort laws to provide compensation for personal injuries from intentional or negligent acts of others and state and federal workers’ compensation laws for work related injuries and illnesses, social security disability benefits, veterans’ benefits, and social

315

316

PA RT 3 Clinical Evaluation and Assessment

welfare programs where appropriate. These systems have diverse historical origins and statutory requirements. Consequently, there remains considerable variability between them concerning definitions of disability, entitlement, benefits, claims application procedures, adjudication, and the role and relative weight given to medical versus administrative deliberations.

Contemporary Perspective The United States legal system is complex because of its large territory (50 state jurisdictions plus two commonwealth territories). However, as it relates to disability and compensation of individuals, it is essentially based on two basic types of law: federal and state statutory (legislative) laws and common law (judicial precedent). Both federal and state statutory laws are then mainly adjudicated through administrative law, which has a modified evidentiary and procedural process for ease of judicial administration.9 The administrative law decisions are then subject to review by various state and federal courts upon appeal by parties. The common law claims of personal injuries, for example, from motor vehicle accidents to slip and fall claims seeking compensation are mainly based on state tort laws.

Tort Law All states in the United States, under their common law, recognize physical or psychological injury as a personal injury for which monetary damages can be awarded under the law of torts. Common law is a system of law in the United States inherited from the British colonial period based on previous legal judgments (precedent setting cases), which is a defining characteristic of common law sometimes referred to as “judge made law.” This is contrasted with statutory law, which is adopted through the legislative process, and regulations enacted by the executive branch. A majority of the United States contract, property, and tort law are based on common law. Under tort law, a claim is usually made against the defendant for personal injury arising out of negligence and, in some instances, an intentional act. Common examples include those claims arising out of motor vehicle accidents, slip and fall claims against property owners (both private and business), defective products, medical negligence, hospital and nursing home negligence, assault claims, and work related injuries outside of the aegis of workers’ compensation. Plaintiffs are entitled to monetary awards for both actual and general damages (e.g. pain and suffering, nonpecuniary damages). The severity of the injury and its outcome in the form of physical or mental impairment and or disability is the main driver for the compensation. Physicians who have not participated in the medical care of the patients are retained by both sides as independent medical examiners (as expert witnesses) to evaluate the plaintiff’s claims of personal injury by performing an independent medical examination (IME). The physician is typically required to evaluate the causation, the nature and the severity of the injury, the exacerbation or aggravation of the preexisting pathologic condition, if any, and apportionment. Sometimes, the physician may also be called on to comment on the necessity of the treatment previously provided or future treatment proposed for the condition under question. In addition to the tort claims that may arise from a personal injury caused by motor vehicle accidents, slip and fall, medical malpractice, or defective products are adjudicated in the individual state court system. The following are other contemporary disability compensation systems in the United States.

State Workers’ Compensation Systems The workers’ compensation system is statutory law administered by a governing board or agency in each state, commonly referred to as an industrial commission, Bureau of Workers’ compensation or commission, which oversees various public/private combinations of workers’ compensation systems in that state. In nearly all states, workers’ compensation insurance is available through private insurance companies that underwrite the risk of occupational injury/ disease in a particular occupation or industry in return for payment of a premium paid by the employer. A few states have a state-owned monopoly insurance fund that employers must pay into unless they qualify as a self-insurer. Large employers with sufficient financial strength can also self-insure and are responsible for paying the claims through a third party administrator who administers these self-insured workers’ compensation programs.10 An injured worker is entitled to three types of benefits: medical and rehabilitation expenses, wage loss benefits, and survivor benefits. In the event of death, the surviving spouse and/or children are entitled to survivor benefits. Coverage for medical and rehabilitative expenses is 100% for authorized services. Wage loss benefits are paid according to four separate levels of work disability. Temporary disability occurs for the duration of the treatment period and may be total (employee is incapable of any work) or partial (employee may resume “modified duty” with restrictions). General damages for pain and suffering and punitive damages for employer negligence are not available in workers’ compensation schemes, and negligence is generally not an issue in these cases unless the employer had wanton, reckless disregard to workplace safety, or intentionally caused injury. Thus a workers’ compensation system is desirable for employers because the cost of workers’ compensation insurance is predictable and can be passed on to the consumer within the cost of goods. In contrast, the employer avoids the potential risk of expensive and time-consuming common law litigation as well as financial insolvency that could result from a substantial jury award. The workers’ compensation statutes in various states may have some subtle differences from each other. However, fundamental features are common to all of these statutory schemes: • A no-fault system for injuries arising out of and in the course of employment. • Compulsory insurance is required for employers with very few exceptions. • Exclusive legal remedy for employees for work related injuries/ illnesses with few exceptions. • The injured worker retains the right to sue any third party liable for injury. • Dispute resolution through administrative law adjudication with less rigorous rules of procedure and evidence than the civil court system. • Expedited benefits for medical and rehabilitation treatment with wage replacement during the temporary disability phase. • Final compensation for permanent partial and permanent total disability. Under the workers’ compensation system, upon completion of the treatment phase under a claim, a physician must determine the point of maximum medical improvement (MMI) so case closure can occur. The employee may receive monetary compensation for permanent total or partial disability. Generally, this is a lump sum payout calculated according to a predetermined formula specific to each jurisdiction. It considers the value of the “whole person impairment” as several weeks’ pay multiplied by the average

 

CHAPTER 23

weekly wage up to a cap, and then multiplies by the impairment percentage of the “whole person” based almost always on a certain edition of American Medical Association (AMA) Guides to the Evaluation of Permanent Impairment as prescribed by the relevant law or regulation. Medical determination of physical or psychological impairment is almost always performed at MMI by a physician skilled in the use of the AMA Guides, as impairment is only determinable by medical means. In contrast, disability requires consideration of numerous other non-medical factors. However, in some cases, the physician is empowered to render an opinion regarding the nature and extent of medically determined impairment resulting in disability.

Federal Workers’ Compensation Systems In the United States, federal workers’ compensation laws provide no fault based compulsory broad coverage of injuries and illnesses arising out of and in the course of employment for over 2.9 million federal employees. The United States Department of Labor (USDOL) maintains exclusive jurisdiction over these programs subject to judicial review. The major federal workers’ compensation programs are administered by the Office of Workers’ Compensation Programs (OWCP), an agency within the USDOL. One of the major federal programs, the Federal Employee’s Compensation Act (FECA), covers federal employees in more than 70 different agencies along with several other worker groups adopted by Congress in various acts of expansion of the federal authority.11 Additionally, the Longshore and Harbor Workers’ Compensation Act, Energy Employees Occupational Illness Compensation Act, and Federal Black Lung Program (coal mine workers’ compensation) are other federally mandated compensation acts administered by the OWCP. These four major federal workers’ compensation programs provide wage replacement benefits, medical treatment, vocational rehabilitation, and other benefits to injured workers that experience work related injury or occupational disease or their dependents.12 USDOL also oversees the Defense Based Act (DBA) that provides workers’ compensation protection to civilian employees working outside the United States on military bases or under a contract with the United States government for public works or national defense. Similar programs that cover a specialized group of workers, such as the Non-Appropriated Fund Instrumentalities Act (NAFIA) and Outer Continental Shelf Lands Act (OCSLA), exist but are beyond the scope of this discussion. Other federally mandated workers’ compensation programs include the Federal Employers Liability Act (FELA), commonly known as the Railroad Worker Act, and the Jones Act (Merchant Marine Act). FELA provides disability benefits to employees of the interstate railroad industry for job-related injuries. It is the only remedy for injured railroad workers employed by a common carrier railroad. It is a fault-based system, and the injured railroad worker must sue the railroad in civil court (similar to negligent tort action) to prove that the injury was caused in whole or in part by the negligence of an agent, employee, or contractor of the railroad or from faulty equipment. The civil action can be brought in either a state or federal court, and the case is tried in front of a judge and jury. The monetary damages awarded against the negligent railroad are generally much higher than those of other no fault based state or workers’ compensation systems.13 The Merchant Marine Act of 1920, also known as the Jones Act, allows civilian sailors, while in the service of a ship in the United States navigable waters and between United States ports,

Disability Assessment

317

to claim compensation for injuries resulting from the unseaworthiness of the vessel on which they served or negligence of a ship’s owner, agents, and employees. It operates similar to FELA, and the claimant must bring suit in civil court against the master or owner of the ship to collect monetary compensation.

Social Security Disability Benefits Program The Social Security Administration (SSA) manages the largest federally mandated disability insurance program in the United States, providing benefits to approximately half of all persons who qualify as disabled under its two titles. Social Security Disability Income (SSDI; Title 2) covers individuals who are disabled (unable to engage in substantial gainful activity) because of a medically determinable physical or mental impairment that has lasted or is likely to last for more than 12 months or is likely to result in death.14 It is currently funded by a payroll tax contributed to by both the employer and, while gainfully employed, the employee. Selfemployed workers are also required to contribute to the system. Benefits are available to those individuals who have worked in a qualified job for a requisite period, paid into the social security system, and subsequently become disabled before age 65 years. SSDI benefits are provided to those considered totally incapacitated and extend to their surviving spouse and children. Benefits are paid as a monthly stipend, and beneficiaries may receive payments until age 65 years, after which they are eligible for social security retirement benefits. Supplemental Security Income (SSI; Title 16) is a second disability benefits program within the SSA, which operates as a federal-state partnership providing SSI benefits to disabled individuals whose income and assets meet minimum criteria according to a means test. It is funded through general revenue (i.e. income tax revenues) and does not require work history for eligibility. Most SSI recipients are below the federal poverty income threshold and must remain below that threshold to continue receiving SSI, but this is not the case with SSDI.15 The SSI provides income for medically indigent persons who are blind, disabled, or older (>65 years of age). SSI also provides assistance to children if they have “medically determinable impairments of comparable severity” to an adult’s and if the impairment “limits the child’s ability to function independently, appropriately, and effectively in an ageappropriate manner.”16 SSI operates as a federal-state partnership and, in addition to the means test, also requires that a “medically determinable impairment” be established. When an applicant submits an SSI application, and nonmedical eligibility has been established, the application is forwarded to their state Disability Determination Service (DDS) for further medical review. The SSI has its own set of medical criteria, the “listing of impairments,” which, if met or equaled, will cause an automatic award of benefits. There are separate listings for adults and children arranged by body system. Each listing typically contains a diagnosis and some clinical markers of severity. If listing criteria are not met, the applicant can appeal based on “residual functional capacity.” Physicians, including the patient’s treating physician, who assist applicants when filing for SSDI or SSI disability, should be familiar with the “five-step” appeals process and the listings themselves.17 They may be asked to provide the DDS evaluating team with a statement about the patient’s ability to do work related activities and backed by objective evidence. They may also be asked to comment on an applicant’s physical and psychological capacities and limitations. If the condition in question does not

318

PA RT 3 Clinical Evaluation and Assessment

meet or equal the listings, to assist the DDS evaluating team in estimating the claimant’s “residual functional capacities.”

Disability Benefits Under the Veterans Benefits Laws The Veterans Benefits Administration (VBA) within the Veterans Health Administration (VHA) oversees the Department of Veterans Affairs’ (VA) compensation and pension program (C&P) providing service to United States veterans.18 Eligibility for VA disability benefits is based on discharge from active military service (full-time service to the army, navy, air force, marines, or coast guard, or as a commissioned officer of the Public Health Service, the Environmental Services Administration, or the National Oceanic and Atmospheric Administration). Only honorable and general discharges (as opposed to dishonorable or bad-conduct discharges) qualify. Entitlement to compensation is determined by the Adjudication Division of the C&P Service within the VBA. It is classified as service connected if the disability relates directly to injury or disease incurred while on active duty or as a direct result of VA care or as nonservice connected if determined to have not been incurred while on active duty. Presumptive service connection applies to various conditions, such as chronic diseases (e.g. hypertension, diabetes mellitus) or tropical diseases (e.g. malaria), and qualifies for compensation if such conditions manifest themselves within one year of discharge from active duty. Disability compensation is paid as a monthly stipend to veterans who are disabled because of service connected injury or disease. The amount of compensation received depends on the amount of impairment caused by the injury or disease where the rating percentages themselves are expressed according to “the average impairment in earning capacity resulting from such disease and injuries and their residual conditions in civil occupations.” Disability compensation is not subject to federal or state income tax, it varies according to the number of dependents, and it is regularly adjusted to reflect changes in the cost of living. Benefits may also include disability pensions for veterans of low income according to a means test, who are permanently and totally disabled, and who have experienced 90 days or more of active duty, at least one day of which was during wartime. Other benefits include insurance benefits, specially adapted housing, motor vehicle modifications, and durable medical equipment. The benefit amount is based on the VA Schedule of Rating Disabilities (VASRD), a graduated scale from 10% to 100% (in increments of 10%) depending on the degree of the veteran’s disability based on medical evidence. The multiple percentages are combined using a combined rating chart similar to the combined values chart in the AMA Guides to Evaluation of Permanent Impairment.19 VA C&P examinations may be performed by physicians, nurse practitioners, physician assistants, psychologists, optometrists, audiologists, and “other qualified” clinical personnel. The VHA oversees and ensures that C&P examiners are adequately qualified, and all C&P examination reports must be assigned by a physician or psychologist. The physician examiner is asked to render an opinion as to the diagnosis of the ratable condition, to address permanency of the condition, and to opine as to whether the individual with the condition is considered totally disabled (fails to meet minimal employability criteria), which is defined as physical inability to be employable at a sedentary level, or psychiatric or

psychological inability to be employed in a loosely supervised situation with minimal exposure to the public. Physician disability evaluations are generally performed at VHA facilities with the automated medical information exchange data processing system and associated disability examination worksheets disability based questionnaires (DBQ) and the VA’s schedule of rating disabilities.20 The adjudication division of the C&P programs, through its rating officers (rater), determines the nature and amount of entitlement benefits, which include monthly disability payments to the veteran or the veteran’s spouse, child, or parent in the event of a service connected death. Additional benefits include hospitalization and medical care, orthotic and prosthetic devices, durable medical equipment, and allowances for adaptive modifications to the veteran’s home and/or motor vehicle where necessary. Title 38 of the Code of Federal Regulations contains both the VA’s schedule for rating disabilities in Part 4 and other VA regulations about compensation and pension in Part 3. The schedule is organized according to 16 body parts and systems.

Private Disability Benefit Systems According to some estimates,21 about 40 million Americans are covered by private short and long term disability insurance that pays replacement income in the event of a temporary or permanent disability that prevents the insured from working. Private disability insurance generally available through the workplace is a contract between the insurer and insured. Specific contractual language governs the criteria for eligibility, entitlement, and benefits. The injured party must complete a certain waiting period (usually three months), after which the long term disability policy takes effect. Such policies may be group policies (more affordable) with coverage to individuals who cannot perform their usual and customary job during a finite period (typically two to three years). Subsequently, disability benefits may continue only if the individual can be determined unable to perform any occupation according to the definitions and provisions of their policy. Private disability generally pays up to 60% of the individual’s wages (to a cap) and may have a built-in cost of living allowance to adjust for inflation.

Working Terminology and Definitions Physicians performing impairment and disability evaluations must be familiar with precise meanings and definitions of the terms impairment and disability, as well as the fundamental requirements, nuances, and jurisdictional variations of the particular disability system within which they are working. See Table 23.1 for a comparison between various disability compensation systems in the United States and a section on working terminology and definitions. To effectively communicate medical and other scientific information to claims examiners, claims managers, lawyers, and adjudicators, doctors must become familiar with the important definitions and terminology that are commonly used in disability assessment and medicolegal practice, as some are “terms of art” having specific meanings within the field of disability medicine that differ from their traditional meanings.22 This section defines common medicolegal terms that physicians dealing with disability evaluation should be familiar with and includes annotations for better understanding.

 

CHAPTER 23

TABLE 23.1

Disability Assessment

319

Comparison of Major Disability Compensation Systems in United States

Compensation System

Eligible Individuals

Adjudicating Body

Rating Schedule

Employability Status

State tort laws

Personal injuries resulting from negligence or intentional acts of others

State court system by civil actions (lawsuits)

Jury award for both compensatory and general damages, i.e. pain and suffering

Based on state tort law

Damages for various pecuniary and non-pecuniary losses

Lump sum award

State workers’ compensation

Workers injured out of and in the course of employment in a particular state. Excludes federal employees

Individual state worker’s comp statutes

AMA Guides in most states; particular edition of Guides prescribed by law. Few states have their own rating guide

Return to work in one’s own occupation, or in modified duty, if available

Medical and rehabilitation benefits, wage loss benefits. Survivor’s benefits. Permanent partial or total disability benefits

Determined by statute

Social security

Workers 12 months

Monthly stipend

There is an annually adjusted cap on benefits

Federal employees’ compensation act (FECA)

Federal employees, including the United States postal service, peace corps

United States department of labor (USDOL)– office of workers’ compensation prog. (OWCP)

AMA Guides sixth edition

Loss of earnings (no schedule loss) because of disability resulting from personal injury sustained while in the performance of duty

66.6%–75% of wages, reasonable medical care. Lump sums not available

75% of wages if worker married or has dependents

Longshore and harbor workers’ compensation program

Maritime employees such as seamen, longshoremen, harbor workers, ship workers (not seamen)

Office of workers’ compensation programs in the United States department of labor

AMA Guides 6th edition

Wage loss and schedule loss benefits for injuries arising out of and in the course of employment

Full medical care, death benefits, lump sum awards, 66.6% of weekly wages

200% of the current national average weekly wage

FELA-railroad workers’ act and Jones Act for seamen

Railroad workers and seamen

Federal or state court system by civil actions (lawsuits)

Jury award for both compensatory and general damages, i.e. pain and suffering

Based on FELA or Jones Act as the case may be

Damages for various pecuniary and non-pecuniary losses

Lump sum award

Benefits

Maximum Monthly Benefit

Continued

320

PA RT 3 Clinical Evaluation and Assessment

TABLE 23.1

Comparison of Major Disability Compensation Systems in United States—cont’d

Compensation System

Eligible Individuals

Adjudicating Body

Rating Schedule

Employability Status

Veterans disability programs

Honorable or general discharge from the armed forces or a survivor of a veteran

Adjudication division of the compensation and pension service of the veterans benefits administration

VA schedule for rating disabilities (VASRD)(Ref)

Wage loss and schedule loss for the average person unable to follow a substantially gainful occupation

Disability pension, death benefits, hospitalization, medical care, orthotics, prosthetics, durable medical goods, adaptive modifications

Variable based on rating and other criteria

Private disability insurance

Individual covered under a long term disability insurance plan after a wait period of short term disability defined by the policy

Long term private disability insurance company

Based on the contractual language of the disability insurance policy

Inability to engage in own occupation up to 3 years, or in any occupation, after that, depending on the individual policy

Wage loss compensation

Generally, 60% of previous income

Benefits

Maximum Monthly Benefit

© 2019 ACIME, Inc. Reproduced with permission from ACIME, Inc. All rights reserved.

Key Terminology and Definition Abnormal illness behavior: Conscious or unconscious, intentional or unintentional exaggeration or fabrication of symptoms and/ or physical findings because of psychological, social, financial, or other reasons. Accommodation: In the context of the Americans with Disabilities Act, any modification of the workplace or a specific job that allows a person with a disability to perform essential functions of a job and/or able to be gainfully employed. Activities of Daily Living (ADLs): Basic self-care activities performed in one’s personal sphere (e.g. feeding, bathing, hygiene, dressing). Instrumental ADLs (IADLs) are complex self-care activities that may be delegated to others (e.g. financial management, medications, meal preparation). ADLs do not include highly individualized work duties. Adjudicate: To make a formal judgment on a disputed matter through judicial authority. Administrative hearing: An oral proceeding similar to a trial with the presentation of testimony and evidence before an administrative hearing officer or a law judge. Unlike a trial, an administrative hearing is usually less formal and shorter in duration with abbreviated procedural rules. Administrative law: The body of law that governs all the activities of administrative agencies of government, including rule making, adjudication, or the enforcement of specific regulatory mandates given by the legislative bodies. Affidavit: A written statement under oath for use as evidence in a legal proceeding subject to the penalty of perjury for falsehood as if giving false evidence in court. Aggravation: Permanent worsening of a preexisting condition. Allegation: A claim or assertion of a fact by a party in a legal proceeding made without proof.

Apportion/Apportionment: To divide something proportionally, such as allocating contributions among various causes of disease or impairment. The first step in causation apportionment is scientifically-based causation analysis.23 Second, one must allocate responsibility among the probable causes and select apportionment percentages consistent with the medical literature and facts of the case in question. Arbitrary, unscientific apportionment estimates, which are nothing more than speculations, must be avoided. Case law: Accumulated decisions and holdings by appellate courts interpreting and applying legal principles, common law, statutes, or provisions of a constitution in previous cases. The aggregate of reported cases sets the precedents (authority) that must be followed as the law (binding) by the lower courts within the same jurisdiction when deciding subsequent cases with similar issues or facts in similar cases. The legal principle stare decisis (Latin for “to stand by the things decided”) requires that similar cases be treated alike to create stability and predictability in common law. Cause/Causation: In general, anything that produces an effect. In medicine, cause refers to an identifiable factor (e.g. trauma, toxic, or infectious exposure) that results in injury or illness. The cause or causes must be scientifically probable following causation analysis. Cause of action: Legal grounds for which a plaintiff can sue in court for the legal wrong the defendant is alleged to have caused. A specific legal theory upon which a plaintiff can legally sue and seek legal remedy. Some examples are medical malpractice, intentional infliction of emotional distress, battery, false imprisonment, or breach of contract. Civil action: A legal proceeding (lawsuit) by a party to enforce, redress or protect private rights and mostly seek relief in the form of the monetary damage award. These suits most often

 

CHAPTER 23

are between private parties, although governments and corporations may be parties to a civil lawsuit. Claim adjuster: Usually an insurance company employee or an independent agent who investigates insurance claims to determine the extent of the insuring company’s liability, assesses the amount of compensation to be paid and negotiates and settles claims against the insured. Combined Values Chart: A method used in the AMA’s Guides to the Evaluation of Permanent Impairment (AMA Guides) to combine two or more impairment percentages, derived from the formula A + B (1 – A) = Combined Values of A and B. Combining, as opposed to adding, ensures that the total value will not exceed 100% whole person impairment and considers the impact of impairment from one body part on impairment of another body part. Compensable injury: Workers’ Compensation statutes define this as an injury or illness arising out of and in the course of employment. Contingency fee: A charge or fee, the collection of which is based upon the client winning or settling the case. Contract: A legally binding and enforceable agreement made between parties. Cross examination: The interrogation under oath to test the truthfulness of witness testimony in a legal proceeding (deposition or trial) by challenging or probing the testimony given during the direct examination that precedes the cross examination. Damages: In law, damages are monetary sums awarded by a court in a civil action as compensation to someone who has been injured or suffered loss because of the wrongful conduct of another party. In a tort action, damages are meant to restore an injured party to the position before being harmed, which in addition to being compensatory (reimbursement for actual losses such as lost income and medical expenses), also include general damages that are non-economic (non-pecuniary) losses, such as pain and suffering, mental anguish, loss of life’s enjoyment, loss of consortium, and so on. Deposition: A process of taking testimony under oath of a witness (deponent) by oral interrogations outside the trial by an attorney for the parties involved in civil litigation. Usually, depositions for a physician witness are done as pre-trial fact findings in which the retaining counsel asks questions (direct examination), and the other side then tests the truth of the witness statements by cross examination. The questions are asked by attorneys in the same manner as if the witness was testifying in a live trial. The proceeding is recorded by a court reporter, and a transcript of the testimony is produced that may be submitted as evidence or used to impeach the witness at trial by confronting the witness with inconsistencies in statements. Direct examination: The primary or initial questioning (also known as examination in chief ) of a witness by the party that has called that witness to give evidence that supports their case. Disability: An umbrella term for activity limitations and/or participation restrictions in an individual with a health condition, disorder, or disease. The definition may differ and be more specific in certain compensation systems. For example, the United States SSA defines disability as the inability to engage in substantial gainful activity because of a medically determinable physical or mental impairment that has lasted for 12 months or likely to result in death. Exacerbation: Temporary worsening of a preexisting condition. Following a transient increase in symptoms, signs, disability, and/or impairment, the person recovers to her baseline status, or what it would have been had the exacerbation never occurred.

Disability Assessment

321

Expert witness: A person tendered as a witness in a legal proceeding stipulated as having special knowledge, education, training, experience, or skill in a field for which she may give testimony if it assists the trier of fact (jury or the judge) in determining the truth of a matter. Impairment: A significant deviation, loss, or loss of use of any body structure or function in an individual with a health condition, disorder, or disease. Impairment evaluation: The acquisition, recording, assessment, and reporting of medical evidence, performed by a licensed physician, using a standard method such as described in the AMA’s Guides to the Evaluation of Permanent Impairment (AMA Guides), to determine permanent impairment associated with a physical or mental condition. Malingering: According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), malingering is not a psychiatric condition but rather a conscious and intentional production of false or grossly exaggerated physical or psychological problems motivated by external incentives such as avoiding military duty or work, obtaining financial compensation, evading criminal prosecution, or obtaining drugs. MMI: Also known as the maximum degree of medical improvement, it is the point at which a condition has stabilized and is unlikely to change (improve or worsen) substantially in the next year, with or without treatment. While symptoms and signs of the condition may wax and wane over time, further overall recovery or deterioration is not anticipated. Simply put, the person is now as good as they are going to get, signifying that the injured person can exit the temporary disablement stage of recovery, facilitating claim settlement and case closure. MMI does not preclude the deterioration of a condition that is expected to occur over time, i.e. beyond 12 months; neither does it preclude allowances for ongoing follow-up or maintenance medical care, should such care be indicated based on current evidencebased practice generally accepted by the scientific community. However, both the name given to and exact definition of this status vary depending on the jurisdiction. Among the numerous synonyms for MMI are (in alphabetical order): ascertainable loss, end of healing, fixed and stable, maximum cure, the maximum degree of medical improvement, maximum medical healing, maximum medical recovery, maximum medical rehabilitation, maximum medical stability, medical end result, medical stability, medical stabilization, medically stable, medically stationary, permanent and stationary, and stable and ratable. Negligence: Failing to exercise the degree of care that a reasonably prudent person would exercise under the same or similar circumstances. It can also be thought of as a breach of legal duty that causes an injury resulting in liability to the injured party. Pecuniary: Pertaining to money as in pecuniary damages awarded for actual monetary losses. Permanent impairment: The impairment present at the point of MMI. Reasonable degree of medical certainty/probability: Two phrases commonly used in medicolegal reports and expert testimony to express the idea that their opinions are based on at least a 51% probability conveying that the opinions are “more probable than not” correct or true. Rules of civil procedure: A body of law that provides the rules that courts must follow when adjudicating civil lawsuits. Stare decisis: Latin for “to stand by the things decided” or also “let the decision stand.” A legal principle requiring courts to apply the same approach and rationale of the legal principles

322

PA RT 3 Clinical Evaluation and Assessment

as decided in similar prior cases setting precedent. See also case law. Statute: A written law enacted by a legislative body (state or federal) that declares, forbids, or commands something specific to achieve a specified legislative objective. Subjective: In health care, refers to that which is perceived, reported, and/or demonstrated by a patient but cannot be verified by an examiner on physical examination or via diagnostic tests. The adjective is most commonly used in the context of symptoms such as pain, but many physical findings are also subjective, including tenderness, range of motion, and strength. Subpoena: An official written command issued in judicial process directing the person to appear at a certain time and place to give testimony under oath or provide documents in her possession or control (subpoena duces tecum) that may help resolve an issue in a pending litigation. Whole person impairment: A concept described in AMA Guides that relates the impact of the impairments from various body parts on the individual’s overall ability to perform ADLs, excluding work.

Models and Classification of Disablement Models of Disability The “medical model” of disability was the paradigm for understanding disablement throughout much of the 19th and 20th centuries, during which causation of disability was directly viewed in terms of the underlying pathology (impairment) arising through illness or disease. Management of disability was closely linked to the diagnosis and treatment of the underlying pathology, long considered the purview of the physician examiner, who then became empowered to rate and diagnose and treat the disabling condition (impairment). Anatomic and physiologic objectivity is the conceptual lynchpin of the medical model of disability described above.24 This model worked well for conditions whereby the diagnosis was unambiguous, and the pathology was well understood, and where treatment strategies and end points were often well established and clearly understood.25 Today, the medical model still serves as the basis for social security disability determinations as described in some of the compensation systems in section III above. The “social model” of disability grew out of the disability advocacy movement of the 1970s and 1980s and was founded on the notion that society imposes disability upon individuals with impairments by failing to address their special needs in terms of priority awareness, environmental access, and infrastructural accommodation for major life activities. The resulting disability was viewed in terms of restrictions imposed upon the impaired individual ranging from individual and institutional prejudicial thinking and discrimination, architectural and other physical barriers to access and transportation, educational segregation, and the lack of accommodation in the workplace.26 An understanding of the social model has helped foster strategies to better neutralize social barriers to individuals with impairments, enabling them and minimizing their disability. The “biopsychosocial model” of disability27 is now widely accepted as the preferred conceptual model of disablement. It simultaneously recognizes the contributions of medical, social, personal, and psychological determinants of disability. The biologic component refers to the physical and/or mental aspects of an individual’s health condition. The psychological component recognizes personal and psychological factors that are impacting that

individual’s functioning. The social component recognizes contextual and environmental factors that may also affect functioning in each case.28

Classifications of Disablement The most commonly used, contemporary, internationallyaccepted definitions, terminologies, and classification of disablement have been created by the World Health Organization, the origins of which can be traced to the work of Bertillon’s Classification of Causes of Death (1893), which later was expanded into the International Statistical Classification of Diseases, Injuries and Causes of Death.29 In 1948 the World Health Organization took over this effort, which ultimately led to creating the International Classification of Impairments, Disabilities and Handicaps (ICIDH) in 1980.30 This system applied a model of disablement with four ordinal domains linked in a linear relationship as follows (Fig. 23.1). Pathology - “a disease or trauma acting at a tissue anatomical or physiological level to potentially alter the structure and/or function of an organ.” Impairment - “any loss or abnormality of psychological, physiological or anatomical structure or function and resulting from a pathology.” Impairment occurs at an organ system level. Disability - “any restriction or lack (resulting from impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.” Disability is commonly conceptualized in terms of limitations on activities within one’s sphere, including mobility (transfers and ambulation) and selfcare (activities of daily living or ADLs). Handicap - “a disadvantage for an individual that limits or prevents the fulfillment of a role that is normal (depending upon age, sex, social and cultural factors) for that individual.” There were several shortcomings of the ICIDH system. It was rooted in the medical model of disease whose limitations are described above. The linearity of the system implies a unidirectional and causal relationship among its elements which may not always be the case. It inadequately accounted for various modifiers (e.g. personal, environmental), which could influence the magnitude of disability.31 For example, other work showed that environmental factors played a key role in determining outcomes of disability that could be studied independently.32 Subsequent work by the Institute of Medicine (IOM)33 and the National Center for Medical Rehabilitation Research,34 expanded upon the view that resulting disability was the product of the individual with an impairment interacting with their environment in each specific case. Additional attention was given to the role of personal modifiers (e.g. lifestyle choices, belief systems, entitlement, and coping abilities) affecting outcomes of disability for individual cases.35 Pathology

Impairment

Disability

Handicap

The underlying disease or diagnosis

The immediate physiologic consequences, symptoms, and signs

The functional consequences, abilities lost

The social and societal consequences, freedoms lost

• Figure 23.1  World Health Organization’s international classification of ill-

ness. (Reproduced with permission from World Health Organization. International Classification of Impairments, Disabilities and Handicaps: A Manual of Classification Relating to the Consequences of Disease. Geneva, Switzerland: World Health Organization; 1980. Figure 2*.)

 

CHAPTER 23

Health Condition (Disorder or Disease)

Body Functions and Structures

Participation

Activities

Environmental Factors

Disability Assessment

Within this conceptual framework, the disabling consequences of impairment may be amplified or mitigated by factors unique to the individual with a health condition, interacting with their environment and according to personal choice. To illustrate the importance of environmental factors, consider Fig. 23.3. Despite its superiority as a classification system, shortcomings of the ICF can be noted. The distinctions between activities and participations are often blurred, and inadequate attention has thus far been given to quality of life (QOL) measures (e.g. life satisfaction, burden of care) in the model itself.

Measuring Disability for Compensation Purposes

Personal Factors

• Figure 23.2  Components and interactions of the World Health Organiza-

tion’s international classificaion of funtioning. (Reproduced with permission from World Health Organization. International Classification of Functioning, Disabilities and Health: ICF. Geneva, Switzerland: World Health Organization; 2001.)

The International Classification of Functioning, Disabilities, and Health (ICF)36 is depicted in Fig. 23.2. The ICF has replaced the ICIDH and portrays an interactive (as opposed to linear) association between an individual with a health condition, the functional consequences of their impairment, and contextual factors of a personal and environmental nature. The ICF classification system embraces the biopsychosocial model of disease described earlier, considering environmental and personal modifiers of functional outcomes in any given case. The components of disablement according to the ICF classification system include: Body functions and body structures: physiologic functions and body parts, respectively. Activity: the execution of a task or action by an individual (typically within their personal sphere). Participation: involvement in a life situation (typically within a social sphere). Impairments: problems in body function or structure such as a significant deviation or loss. Activity limitations: difficulties an individual may have in executing activities. Participation restrictions: problems an individual may experience in involvement in life situations.

Social justice requires that individual group members contribute productively to the common good of the whole. However, provisions must be made to exempt this requirement and support those incapable of such productivity by virtue of age, illness, or disability. A related expectation is that individuals who incur loss or disablement because of illness or injury are thereby entitled to some compensation for their losses. Within our social system, there are many different disability compensation systems (see section III above) designed to compensate individuals for such losses. They share a common conceptual and operational platform in which the initial estimate of physical and/or psychological loss can be translated into an estimate of functional and economic losses expressed in monetary terms. By convention, the severity of the physical and psychological loss is operationally defined and measured in terms of a medical impairment rating at an organ system level. That is typically expressed as a percentage of regional loss of the affected body part(s) and can be further extrapolated to the body as a whole. The severity of functional and, hence, economic loss associated with this impairment percentage is further estimated in terms of a disability rating expressed as a percentage of the economic worth of the “whole person.” The disability rating is operationally derived from the impairment percentage and is at once intended to reflect direct economic losses, non-economic losses, and negative impact on QOL in terms of a monetary sum. The whole person value and magnitude of awards vary according to the disability system in question, and disability payments may be awarded as lump sum payments or on an annuity basis. III Work Disability IIIA Loss of Earning Capacity

I Medical Impairment IA Anatomic Loss

IB Functional Loss

II Functional Limitations

IIIB Actual Loss of Earnings

IV Nonwork Disability

V Quality of Life

• Figure 23.3  Disabling

323

consequences of an injury or disease. (Reproduced with permission from McGeary M, Ford M, McCutchen SR, et al. (eds). IOM Committee on Medical Evaluation of Veterans for Disability Compensation. A 21st Century System for Evaluating Veterans for Disability Benefits. The Rating Schedule. Washington, DC: The National Academies Press; 2007, pp. 117.)

324

PA RT 3 Clinical Evaluation and Assessment

THE “PERSON” (with potentially disabling conditions)

Physical Environment

Social Environment

DISABILITY

Amount of disability is proportional to the amount of displacement in the mat.

ENVIRONMENT The Strength/resilience of the flexible mat (environment) is a function of social support, culture, physical barriers, assistive technology.

Physical Environment

Social Environment

DISABILITY

• Figure 23.4  Reproduced

with permission from the Institute of Medicine. Enabling America: Assessing the Role of Rehabilitation Science and Engineering. Washington, DC: The National Academies Press, 1997. doi:10.17226/5799.

The IOM37 has recently developed a generalized model to demonstrate the essential features common to all disability systems. Individuals seeking compensation and meeting criteria of entitlement must demonstrate losses according to five domains of interest (see Fig. 23.4). The first of these, Medical Impairment, traditionally carries the most weight for several reasons. It is largely anatomically and physiologically based and, hence, can readily be measured in objective terms. Objectivity enables codification of the disability and fosters standardization, reliability, and reproducibility of measurement according to some uniform scale. Impairment can be measured and expressed in terms of anatomic or functional losses. The second domain of interest, functional limitations, can be expressed and measured in terms of basic ADLs and/or instrumental (advanced) activities of daily living (IADLs). ADLs include basic self-care activities such as feeding, toileting, grooming, bathing, hygiene, and dressing—activities that generally occupy our personal sphere. IADLs require greater cognitive and physical capacity and include such activities as meal preparation, driving, managing finances, medications, and one’s daily routine. The third domain, Work Disability, can be understood in terms of loss of earning capacity (an actuarial determination of negative impact on employability and earnings brought about by work restrictions because of the impairment, and other considerations such as age, baseline employment, and earnings history, availability of accommodation and alternative job opportunities, and other local factors). It can also be understood in terms of actual loss of earnings directly attributable to the impairment.

A fourth domain, non-work disability, includes losses in terms of inability to visit friends and relatives, engage in communal activities, hobbies, or other recreational pursuits because of barriers of access or performance attributable to the impairment. A fifth domain, QOL, includes losses attributable to diminished life satisfaction, self-esteem, and increased burden of care in terms of treatment compliance and caregiver support. The metrics whereby each of these constructs is defined and measured vary and remain incompletely understood. This is partly because of persisting confusion of terminology, definitions, and criteria of impairment and disability across the various systems and the continuing emphasis upon objective, medically determined impairment as the prime determinant of disablement. Unfortunately, there is also a lack of agreement upon the metrics whereby the impairment ratings themselves are determined between and even within the various disability systems of interest. For example, United States workers’ compensation jurisdictions show considerable variability in terms of their acceptance or rejection of standard and uniform impairment rating guides and those that mandate or recommend the use of the same variable in the choice of reference. Even in the case of the American Medical Association Guides to the Evaluation of Permanent Impairment (AMA Guides), the actual edition chosen for reference varies from state to state.38 The same is true for the international use of the AMA Guides where in many countries (e.g. Australia, Netherlands, South Africa), the various editions are used in motor vehicle accidents and other personal injury claims to determine the injury severity (a threshold) before access to benefits for general damages (non-pecuniary, non-economic losses) is granted.39

 

CHAPTER 23

The importance of the impairment rating to cash awards also varies within and between the various disability systems, as a closer examination of the United States workers’ compensation (WC) system illustrates. Operationally, the WC system awards cash benefits according to three basic approaches: The first of these, the impairment approach, awards benefits in direct relationship to the percentage of impairment rating. The second, the loss of earning capacity approach, requires that the injured worker have an impairment rating but then bases the actual amount of cash benefits on the estimate of associated loss of earning capacity. The third approach, the actual wage loss approach, requires the worker to have both an impairment and loss of earning capacity and then base the amount of cash benefits on demonstrating the actual loss of workers’ earnings.40 The mechanism of WC cash benefits are awarded is further complicated by distinguishing between various types of injuries as scheduled vs. unscheduled. Scheduled injuries typically affect the upper or lower extremities and are listed as percentage of extremity; unscheduled injuries affect the spine, nervous system, or other organ systems and are awarded as a percentage of the “whole person.”41 Although the impairment rating is the common factor in disability determinations as cash benefits, it is not the sole factor. However, in practice, many jurisdictions implement procedural shortcuts whereby the impairment rating percentage becomes a direct surrogate for the disability rating according to a predetermined formula that multiplies the impairment percentage times several weeks wages (up to a cap) times a percentage (generally two-thirds to three-fourths) of the average weekly wage (up to a cap) and resulting in a lump sum pay out. The adequacy of applying the impairment rating as an operational surrogate measure of disability continues to be a subject of debate. Implications for pain sufferers can be noted: The metrics for medical impairment rating clearly favor and emphasize objective over subjective criteria. As such, painful entities such as headache, fibromyalgia, or low back pain often occur in the absence of objective, verifiable pathology or may present in a setting where objective clinical findings are most consistent with normal anatomic variation and the aging process and may be of little or no clinical significance to the individual’s actual complaints. Impairment ratings in such cases are ineffective since minimal or no rating percentage is currently allowed in relation to any apparent (and often profound) negative impact that these conditions may be having upon ADLs. The disablement, and ensuing losses in such cases, potentially become more evident if viewed in terms of QOL. There are well respected psychometric instruments now available to measure the QOL. Notable examples include the quality of wellbeing (QWB) scale, the WHOQOL-100, and the QOL index (QLI).42 Unfortunately, such metrics are not familiar tools to the typical rating physician and are not routinely taken into account by the rating systems per se. Consequently, losses in terms of QOL remain largely unaccounted for by the rating practice summarized above.

American Medical Association Guides The process whereby disability determinations are made requires that an initial impairment rating be made according to standard and specific medical criteria. Since the physician is empowered and charged to render such ratings, the AMA has produced a rating manual to assist physicians in this regard. The American Medical Association Guides to the Evaluation of Permanent Impairment (AMA Guides) is a standardized, objective reference for this purpose, initially published in 1971 as a compilation of a series of impairment rating articles for different organ systems that were

Disability Assessment

325

published in the Journal of the American Medical Association from 1958–1970. It has periodically been updated and revised to the most current AMA Guides, sixth edition published in 2008.43 The AMA Guides is recognized nationally and globally as the preferred reference for medical impairment ratings. Various editions are required or recommended by statute in the majority of United States WC jurisdictions. To date, the AMA Guides, sixth edition has recently been adopted by 19 jurisdictions in the United States and is the reference mandated by the USDOL in the various disability systems outlined above. It is also adopted and used internationally in WC and personal injury claims, including nine of ten Canadian provinces and all three Canadian territories, the Netherlands, South Africa, Australia, New Zealand, Malaysia, Korea, Hong Kong, and the Middle east. The United Nations peacekeeping operations also use the AMA Guides, sixth edition to adjudicate personal injury claims arising from peacekeeping mission assignments. The AMA Guides, sixth edition builds upon the precedent of the previous edition of the Guides in placing increasing emphasis upon a diagnosis-based approach, with particular emphasis on musculoskeletal impairment ratings of the spine and extremities. Diagnosis-based impairment (DBI) grids are provided for each anatomic region (cervical spine, thoracic spine, lumbar spine and pelvis for the spine; digits/hand, wrist, elbow, and shoulder for the upper extremity; and foot & ankle, knee, and hip for the lower extremity). Each grid has five potential impairment classes (Class 0–4) consistent with the ICF classification system, and each covers a broad and precise array of diagnoses ranging from soft tissue conditions (non-specific, chronic, or recurrent) to muscle-tendon and/ or motion-segment injuries (sprains, strains, tendinopathy), and to ligament, bone, and joint injuries (fractures, dislocations, arthrodesis). The impairment rating is a two-step process whereby an initial assignment to an impairment class requires the rating examiner to identify the most appropriate diagnosis. Each diagnostic-based impairment class has an available range of impairment values with an initial “default” mid-range value. The rating is then adjusted within-range as a second step, using three separate criteria to validate the diagnosis and severity (functional history, examination findings, and clinical test results) of the condition and by using a simple triangulation method enables a final numerical adjustment upward for less-favorable outcomes or downward for more optimal outcomes according to the specific result in each case.44

Medicolegal Constructs and Constraints In general, the pain practitioner has unique legal liabilities that include administrative, civil, and criminal liability exposure both at the state and federal level, the discussion of which is beyond the scope of this chapter. Alternatively, a brief overview of the interaction between impairment and disability assessor and the law is indicated. The pain practitioner participating in such evaluation is encouraged to become familiar with the emerging field of disability medicine described as a sub-specialty of clinical medical practice that encompasses identifying, predicting, preventing, assessing, evaluating, and managing impairment and disability in both human individuals and populations.45

The IME IME: A (usually) one-time evaluation performed by a physician examiner who is not treating the patient or claimant to answer specific questions posed by the referring party, including MMI

326

PA RT 3 Clinical Evaluation and Assessment

determination, impairment rating, and return to work restrictions, if applicable.46 IMEs are examinations performed by a physician who is not involved in the person’s care to clarify medical and job issues. IMEs are performed to provide information to case management and for evidence in hearings and other legal proceedings. IMEs are a component of most WC statutes, although the specifics vary by state and country. They are performed at several stages during the cycle of injury/illness, treatment, rehabilitation, and return to work. The key issues associated with an IME differ from clinical consultations in role and focus. In the WC arena, IMEs may be performed any time there is a dispute, concern, or question regarding the medical treatment or condition of the injured worker. These issues include such topics as: 1. Diagnosis, proximate causation, and work-relatedness of an illness or injury. 2. Current and proposed medical treatment or diagnostic efforts. 3. Appropriate work and general activity level during treatment. 4. Stability of the medical condition and status regarding maximal medical improvement. 5. Identification of other non-medical factors that can have a significant impact on the outcome of the medical condition or treatment. 6. Impairment rating and related disability issues under certain circumstances. 7. Ability to return to work (fitness for duty) and reasonable accommodation. IMEs can help to untangle the complex relationship between pathology (a medical condition or diagnosis), impairment (an anatomic or functional abnormality or loss), activity limitations (a reduction in ADLs that can be assessed by functional metrics), and participation restrictions (a reduction in the ability to perform socially-defined activities or roles). The opinions outlined in the IME report are expected to be expressed in terms of medical probability vs. medical possibility in all cases, where the following definitions apply: Medical Possibility: Something could occur because of a particular cause (probability less than or equal to 50%). Medical Probability: Something is more likely to occur than not (probability exceeds 50%).47

Physician Testimony and Liabilities The IME is a form of expert witness testimony that embraces the important task of assessing a claimant’s health in accordance with their legal rights, entitlement, and potential for monetary gain. The independent medical examiner, acting as an agent to the consulting party rather than as a patient advocate, also bears the risk of becoming a target for allegations of wrongdoing leveled by the disgruntled claimant. From a legal perspective, an independent medical examiner or a disability evaluator is essentially an expert witness. As such, and until recently, the expert had enjoyed essentially the same type of immunity as to any other witness in the judicial process. This immunity from civil liability ran quite deep and included protection from claims of defamation and negligence. The witness immunity can be traced back to the 16th century English common law.48 The idea behind witness immunity was to ensure that the witness would speak freely when giving testimony.49 Subsequently, the American courts considered the issue of witness immunity to be so important that it was maintained even when there might be negligence.50 Traditionally, the argument for such immunity

has been that expert witnesses are an important part of the legal system, and in the interest of justice, expert witnesses need to be protected from liability. Several state courts have affirmed the concept of witness immunity for reasons of public policy because, without immunity, there would be a loss of objectivity, and the fear of infinite vexation would have a chilling effect on the witness and the reluctance to testify.51 The United States Supreme Court, in the 1980s, confirmed the importance of witness immunity in two cases. In Briscoe,52 the court noted that a witness who knows that he might be forced to defend a subsequent lawsuit and perhaps to pay damages might be inclined to shade his testimony in favor of the potential plaintiff, to magnify uncertainties and thus to deprive the finder of the fact (judge or jury) of candid, objective, and undistorted evidence. In Mitchell,53 the United States Supreme Court reasoned that witness immunity is important because the judicial process is an arena of open conflict, and in virtually every case there is, if not always a winner, at least one loser. The court noted that it is inevitable that many of those who lose will pin the blame on witnesses and would bring suit against them in an effort to re-litigate the underlying conflict. The continuous theme that ran through these cases emphasized that the object of immunity is not to protect those whose conduct is open to criticism but those who would be subject to unjustified and vexatious claims by disgruntled litigants.  However, recent development in the law of liability of expert witnesses in the past two decades has caused many cracks in the expert witness armor. The legal liabilities of the independent medical examiner as an expert witness are mainly grounded in legal theories (referred to in legal parlance as causes of action) of tort law and to some extent in contract law by which the injured party as a plaintiff may bring a lawsuit against a healthcare provider. It should be noted that a liability claim against a practitioner can be and is usually brought simultaneously under several legal theories. The plaintiff hopes to win under any or all of these claims leading to the recovery of a monetary award from the defendant practitioner. Insert Table 23.2 here: The underlying principle of the common law (both law of tort and contracts) is to provide a venue for a person who has suffered damages because of an action or inaction by others to seek redress for his or her grievance in the courtroom. The tort law has been described as a great equalizer as it gives the individual an ability to bring a potentially mightier wrongdoer (referred to in legal parlance as tortfeasor) before the bar on a more equal footing for the wrongs that may have been done to her and secure compensation for her loss. Obviously, the law cannot make the tortfeasor undo the injury or harm but makes them pay monetary compensation for both intentional wrongs (for example, defamation, assault, and battery) and unintentional (e.g. negligence). The law of tort shifts the burden of the cost of the injury or damages to the responsible party and serves to prevent similar harm to other members of society through enforced accountability. The idea is to make the offensive, and undesirable behavior costly to the tortfeasor and, in principle, serves to deter others from engaging in behaviors such as the defendant in the future.54 Traditionally, the healthcare provider’s liability to their patients arises out of medical malpractice claims. The term malpractice refers to any professional misconduct that encompasses an unreasonable lack of skill or unfaithfulness in carrying out professional or fiduciary duties.55 Under the theory of negligence, the law of

 

CHAPTER 23

TABLE 23.2

Legal Theories of Causes of Action Against IME Doctors/Expert Witnesses

A. Intentional Tortes 1. Assault 2. Battery 3. Intentional infliction of emotional distress 4. False imprisonment 5. Defamation 6. Invasion of privacy 7. Fraud and misrepresentation 8. Conspiracy 9. Bad faith 10. Deceptive trade practices B. Unintentional Tortes 1. Ordinary negligence 2. Professional malpractice 3. Failure to warn 4. Wrongful death 5. Loss of chance of recovery or survival 6. Vicarious liability for the acts of others 7. Negligent referral 8. Failure to diagnosis 9. Failure to inform C. Actions Under Law of Contract 1. Breach of contract 2. Breach of warranty 3. Abandonment D. Miscellaneous Causes of Action 1. Deceptive trade practices 2. Violation of a statute or regulation

torts is the most common basis for a medical malpractice action against a healthcare provider. However, under this action, the plaintiff must prove that the practitioner had a duty to the patient and breached that duty because of which (causation) harm or damage occurred. Until recently, the medical malpractice actions against the IME doctors and expert witnesses failed because of a lack of doctor/ patient relationship with the examinee/plaintiff.56 The continuous theme that ran through the cases across various jurisdictions in the United States was that as long as the IME doctor neither offered to nor intended to treat the individual examinee, there was a lack of doctor/patient relationship, which prevented the medical malpractice cause of action.57 Many potential cases were either not filed because of prevailing notions among the legal community based on the previous case law, or cases when filed were dismissed upon pre-trial motions from the defendants.58,46–48 However, this has changed significantly in the past two decades with increasing case law from various jurisdictions holding independent medical examiners and expert witnesses accountable for the alleged harm suffered by the plaintiff/examinee. This was initially done under the cause of action of simple negligence and outside of the law of torts for medical malpractice.49 More recently, at least two state Supreme Courts have allowed the civil action against the IME doctors to proceed under the traditional medical malpractice theory. The legal commentators have observed that this increasing erosion of immunity from civil action for the independent medical examiner as an expert witness is because of the proliferation and growth of the litigation/ expert witness industry, as well as the courts’ perception of lack of protection of injured party from unscrupulous witnesses and the inadequacy of the traditional safeguards against expert witness

Disability Assessment

327

malfeasance from potential prosecution for perjury and inadequate cross examination. The beginning of this trend of judicial hostility toward expert witness immunity can be traced back to the mid-1990s when the state courts in the United States started holding independent medical examiners and expert witnesses without any doctor/patient relationship accountable to their examinee in ordinary negligence. This trend began in Colorado with the Greenberg59 case. Several other jurisdictions have since followed.  The Virginia Supreme Court in Harris60 held as a matter of the first impression (making new precedent) that a doctor could be sued for malpractice for the negligent performance of a doctor’s mental and physical examination of a party during an IME. Similarly, the Court of Appeals in Arizona in the Stanley61 case found that a formal doctor/patient relationship is not the only source of a doctor’s duty toward a patient and that the doctor owed a duty of care to the patient despite the absence of a formal doctor/patient relationship. The Arizona Supreme Court took it a notch further in Ritchie62 and allowed for medical malpractice to go forward despite no doctor/patient relationship, essentially stating that the court can envision no public benefit in not holding a doctor accountable to a duty to conform to the legal standard of reasonable care. As can be seen from above, under case law of various jurisdictions in the United States, the expert witnesses’ (as well as IME doctors’) immunity, traditionally enjoyed up until recently against various legal causes of action, is now rapidly eroding. The news from the other side of the Atlantic is even worse. In a recent decision by the United Kingdom Supreme Court in Jones,63 the United Kingdom Supreme Court practically stripped the expert witness from all immunities that are available to the fact witnesses, generally. After a lengthy discussion, the majority of the Jones court concluded that they see no public policy reason to justify immunity for the expert witness. While this recent decision in the United Kingdom has no authority in the United States jurisprudence, it is nonetheless regarded by some as a persuasive argument. In summary, the pain practitioner should be aware of the legal liabilities in the overall practice of their subspecialty and the additional liabilities entailed with exposure to independent medical examinations and expert witness work. Even though the recent case law in some jurisdictions has significantly removed the traditional immunity from medical malpractice claims against providers with no doctor/patient relationship with their examinees. In American jurisprudence, there remains a great need for expert medical witness service. Practitioners attracted to disability assessment and inclined to serve as independent medical examiners are encouraged to attend several of the high-quality training programs offered in the United States to independent medical examiners and expert witnesses to empower them with the knowledge, skills, and abilities necessary to practice as an independent medical examiner and/or expert witness in the field of disability medicine.

Implications for Disability Assessment of Chronic Pain An important point of this chapter can best be made by drawing into focus the distinction between impairment ratings and disability ratings as they pertain to the issue of pain. The construct of impairment is conceptually and operationally grounded in

328

PA RT 3 Clinical Evaluation and Assessment

the medical model of disease discussed earlier. Impairment is codified and systematically defined according to a predetermined set of objective and measurable criteria for each organ system. Conditions that affect one or more organ systems and manifest themselves in terms of objective, measurable organ system pathology are infinitely ratable according to these organ systems. The painful experience that often accompanies specific pathology can and should be accounted for in some systematic manner and included in such ratings. However, pain can occur in the absence of observed pathology specific to the organ system, and chronic painful conditions transcend the organ system boundaries of the individual and can perhaps be best described and understood in terms of the biopsychosocial model described above.54,64 Global pain or other chronic painful conditions not attributable to any specific organ system pathology according to the impairment rating method alluded to above can perhaps be more adequately accounted for by adopting and applying QOL measures.65 Such metrics have the necessary empirical foundation from which to develop standards for losses in terms of non-vocational function, life satisfaction, and burden of care and medical compliance needed to maintain optimal function in the presence of chronic pain and other disabling conditions. Such metrics, when properly applied, can and should enable modification of any disability payment as a percentage add-on or standalone cash award according to specifications of each disability system. Perhaps the disabling consequences of chronic painful conditions can be more favorably captured in overall disability determinations at the point of final integration of the impairment rating, functional outcomes, and other relevant disability criteria as evidenced through such QOL assessments. QOL measures are important factors in determining impairment and ultimately disability, as pain is a subjective experience and thus hard to quantify outside of the patient’s description. Pain affects all aspects of life, which in the long term increases depression and anxiety. This is underscored by the fact that many of the patients with chronic pain do not seek out a physician’s help because their pain cannot be relieved. Therefore it is important to make the experience of pain easier to bear, and QOL measures allow a validated approach to reach that goal and assess a patient’s function in the context of their illness.66 When choosing a QOL measurement tool, it is important to determine the objective of the tool. Some tools are very narrow in their measurement and only examine certain aspects of a patient’s life, such as those that measure health-related QOL, which the CDC defines as “an individual’s or group’s perceived physical and mental health over time.” Others are disease specific such as the gastrointestinal QOL index (GIQLI), the asthma quality of life questionnaire, and the stroke specific QOL scale.67 It is important to note that these questionnaires examine the patients’ QOL in the context of the disease rather than examining the patients’ overall QOL, which can be a limitation in assessing the true QOL of the patient. Some QOL measurement tools are very broad, and rather than looking at the QOL from the standpoint of disease, examine the patients’ QOL holistically. The downside to such a QOL measurement is that it can be difficult to administer because of the potential for large question numbers and length of completion. To counteract that and still measure a patient’s general QOL, several QOL tools have been developed using data from the larger tool items to create smaller, easier to use ones. One

such example is the medical outcome study short-form 36 (MOS SF-36). This tool measures eight aspects of the patient’s life over 36 questions.68 Because of QOL being influenced by cultural and societal values, some measurement tools also account for those. An example of such a tool would be the World Health Organization’s QOL instrument developed by the World Health Organization. This tool seeks to create a QOL evaluation that spans different cultures and languages. It covers six total domains: physical capacity, psychological, level of independence, social relationships, environment, and spirituality/religion/personal beliefs. To allow the cross cultural application, it allows additional questions that apply to the culture to which the patient belongs. This helped to produce a 100 questions test called the WHOQOL-100.69 A shorter version was also developed called the WHOQOL-26 BREF, which is shorter and maybe more practical to administer. It should be noted that there are other QOL measures that are used in clinical trials. These are discussed in Chapter 84. The use of a suitable QOL as a tool for disability assessment of pain must recognize that a valid disability assessment of pain may require a skill set and applied metrics beyond those typically embodied by the physician disability examiner. Until this ideal can be more closely achieved, the role of pain as a contributor to disability can be most properly accounted for in two ways: Pain directly affecting impairment can be viewed in terms of functional outcomes accompanying specific impairment, as it is now possible, using the DBI approach outlined above for impairment rating as put forward in the AMA Guides, sixth edition, to modify the “expected” impairment rating upwards using a functionally-based “grade modifier” sensitive to pain and other limiters of function, to award additional impairment for pain-associated loss of function. Alternatively, in cases where a specific diagnosis is lacking, and pain appears to be the primary problem, the AMA Guides, sixth edition currently offers a “stand alone” assessment of pain that awards up to 3% loss to the whole person where pain is not effectively rated elsewhere. Additional work is needed to perfect our current disability infrastructure to further enhance the relevance, validity, and reliability of medical impairment ratings and provide alternative metrics to expand and modify disability determinations to properly account for functional losses because of chronic pain.

Resources Available to the Physician Disability Examiner Several educational venues and reference resources are available to enable interested physicians to gain the additional necessary knowledge, expertise, and credentials to perform impairment ratings, disability evaluations, and IMEs competently and authoritatively. These include training programs, credentialing, and certification by examination, as well as several reference texts as listed below: 1. American Board of Independent Medical Examiners: www. abime.org 2. American College of Independent Medical Examiners: www. acime.org 3. American College of Occupational and Environmental Medicine: www.acoem.org 4. American Medical Association: www.ama-assn.org

 

CHAPTER 23

Disability Assessment

329

Key Points • A pain specialist must understand the impairment and disability system they will be working with to be successful. • Historically, there have been systems in place to provide for those unable to work because of disability. These date back to biblical times and continue into the present with various laws at state and federal levels, including social security and WC and compensation for personal injuries arising out of the negligence of others. • State WC has three kinds of benefits: medical and rehabilitation expenses, wage loss benefits, and survivor benefits. • State tort law allows for monetary awards for both mental and physical damage, given that it can be proven that another was at fault. • Federal worker’s compensation systems are governed by the USDOL with administration done by the OWCP (a subagency of the USDOL) and include FECA, Longshore and Harbor WC Act, Energy Employees Occupational Illness Compensation Act, Federal Black Lung Program, DBA, NAFIA, OCSLA. The other federal laws not under USDOL providing compensation include FELA (Railroad Worker Act and the Jones/Merchant Marine Act). • SSDI covers those who are disabled because of a medically determined physical or mental impairment that lasted or likely to last greater than 12 months or end in death. • SSI provides income for those below the poverty line who are blind, disabled, children, or older than 65 years. • Eligibility for veterans’ benefits is based on how the veteran was discharged and whether the disability was service connected, nonservice connected, or presumptive service connected.

• Private disability insurance are usually group policies and available through the workplace. They are split into short term (three months) and long term (two to three years) before reevaluation for lifetime benefits. • The “medical model” of disability defined disability as being because of underlying pathology from illness or disease and relied on diagnosis and treatment of pathology. The “social model” of disability defines disability as the failure of society to address the disabled individual’s special needs regarding priority awareness, environmental access, and infrastructural accommodation for major life activities. • The ICIDH considered a disability to be four linear linked domains: pathology, impairment, disability, and handicap. The ICF, which replaced it, focused on an interactive association between an individual and their disability, including the functional consequences of their impairment and the context of personal versus environmental nature. ICF focused on activity, participation, impairments, activity limitations, and participation restrictions. • Pain medicine practitioners should focus more on QOL measures, and the tools available are helpful when evaluating chronic pain and resulting impairment and Disability. • The AMA Guides are essential to describing an impairment in many legal jurisdictions. • One key difference between independent examiners and everyday patient interactions is that there is no patient-physician relationship between an independent medical examiner and the examinee. • There are multiple ways to become proficient in medicolegal and disability ratings, particularly training courses.

Suggested Readings

Rondinelli RD, Genovese E, Katz RT, et al. (eds). Guides to the Evaluation of Permanent Impairment. 6th ed. Chicago, IL: American Medical Association; 2008, pp. 612. Young Casey C, Greenberg MA, Nicassio PM, et al. Transition from acute to chronic pain and disability: A model including cognitive, affective, and trauma factors. Pain. 2008;134:69–79.

American Medical Association. Guides to the Evaluation of Permanent Impairment. 6th ed. Chicago: American Medical Association; 2008. Field MJ, Jette AM. (eds). The Future of Disability in America. Washington, DC: The National Academies Press; 2007. Ranavaya MI. Physician’s Guide to Medicolegal Practice. 1st ed. Chicago, IL: American Medical Association; 2019.

The references for this chapter can be found at ExpertConsult.com.

References 1. Casey CY, Greenberg MA, et al. Transition from acute to chronic pain and disability: A model including cognitive, affective, and trauma factors. Pain. 2008;134(1-2):69–79. 2. Okoro CA, Hollis ND, Cyrus AC, Griffin-Blake S. Prevalence of disabilities and health care access by disability status and type among adults - United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67:882–887. doi:10.15585/mmwr.mm6732a3external icon. 3. Centers for Disease Control. Available at: https://www.cdc.gov/ media/releases/2018/p0816-disability.html. 4. Office of the Surgeon General. The Surgeon General’s Call to Action to Improve the Health and Wellness of Persons with Disabilities. Rockville, MD: Office of the Surgeon General; 2005. 5. Ranavaya MI. Impairment and disability evaluation training in US medical education: A survey of family medicine residency cur-ricula and attitudes. Disabil Med. 2008;6:3–7. 6. Ranavaya M. Physician’s Guide to Medicolegal Practice. 1st ed. American Medical Association; 2019. 7. 2 Thessalonians 3:10: “For even when we were with you, we gave you this command: anyone”. 8. Ranavaya MI, Rondinelli RD. The major US disability and compensation systems: origins and. 9. Ranavaya MI. Methodology of personal injury assessment and disability compensation systems in the United States. In: S Ferrara, R Boscolo-Berto, G Viel (eds). Personal Injury and Damage Ascertainment Under Civil Law. Cham, Switzerland: Springer. doi: 10.1007/978-3-319-29812-2_31. 10. Ranavaya MI. Methodology of personal injury assessment and disability compensation systems in the United States. In: Ferrara SD (ed). International Academy of Legal Medicine (Ialm) Monograph. New York, NY: Springer Publishing Co; 2016. 11. 39 J. The European influence on workers’ compensation reform in the United States. Environ Health. 2011;10:103. 12. Rondinelli RD, Ranavaya MI. Practical aspects of impairment rating and disability determination. In: Cifu DX (ed). Braddom’s Physical Medicine & Rehabilitation. 6th ed. Philadelphia, PA: Elsevier; 2020. 13. Ranavaya MI, Rondinelli RD. Review of major disability and compensation systems in the USA. Disability Med. 2009;7(3):2. 14. Social Security Administration. Disability evaluation under social security. Available at: https://www.ssa.gov/disability/professionals/ bluebook. 15. Social Security Administration. Disability evaluation under Social Security: Listing of impairments- adult listings (part A). Available at: https://www.ssa.gov/disability/professionals/bluebook/ AdultListings.htm. 16. Social Security Administration. Disability evaluation under social security: Listing of impairments-childhood listings (part B). Available at: https://www.ssa.gov/disability/professionals/bluebook/ ChildhoodListings.htm. 17. Social Security Administration. Disability evaluation under social security. Available at: https://www.ssa.gov/disability/professionals/ bluebook. 18. United States Department of Veterans Affairs. 38 CFR book C, schedule for rating disabilities. Available at: https://www.benefits. va.gov/warms/bookc.asp. 19. Rondinelli R, Ranavaya M, et al. Disability assessment. In: Benzon HT, Rathmell JP, Wu CL, et al. (eds). Practical Management of Pain. 5th ed. Philadelphia: Elsevier-Mosby; 2013. 20. Veterans Benefits Administration. Schedule for rating disabilities. Section 1155, title 38 CFR, pensions, bonuses, and veterans’ relief. 21. Bureau of Labor Statistics, US Department of Labor. The benefits of working for a small business. The Economics Daily. Available at: https://www.bls.gov/opub/ted/2018/the-benefits-of-working-for-asmall-business.htm?view_full. 22. Lezzoni LI, Freedman VA. Turning the disability tide: The importance of definitions. JAMA. 2008;299:332–334.

23. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965;58:295–300. 24. Rondinelli RD. Changes for the new AMA guides to Impairment ratings, sixth edition: Implications and applications for physician disability evaluations. PM&R. 2009;1(7):643–656. 25. Wadell G, Burton AK, Aylward M. A biopsychosocial model of sickness and disability. Guides Newsletter. 2008:1–20 May-June. 26. Oliver M. Understanding Disability. From Theory to Practice. New York, NY: St. Martin’s Press; 1996:30–42. 27. Engle GL. The need for a new medical model: A challenge for biomedicine. Sci. 1977;196:129–136. 28. Wadell G, Burton AK. Concepts of Rehabilitation for the Management of Common Health Problems. London: The Stationary Office; 2004. 29. World Health Organization. History of the development of the ICD. Available at: https://www.who.int/classifications/icd/en/HistoryOfICD.pdf. 30. World Health Organization. International Classification of Impairments, Disabilities and Handicaps: A Manual of Classification Relating to the Consequences of Disease. Geneva, Switzerland: World Health Organization; 1980. 31. Whiteneck G. Conceptual models of disability; past, present, and future. In: Field MJ, Jette AM, Martin L (eds). Workshop on Disability in America. A New Look. Washington, DC: The National Academies Press; 2006:50–66. 32. Nagi S. Disability and Rehabilitation: Legal, Clinical, and Self-Concepts and Measurement. Columbus OH: Ohio State University Press; 1969. 33. Pope AM, Tarlov AR. Disability in America: Toward a National Agenda of Prevention. Washington, DC: National Academy Press; 1991. 34. National Institutes of Health. Research Plan for the National Center for Medical Rehabilitation Research. Washington, DC: United States Department of Health and Human Services; 1993. 35. Fougeyrollas P. Documenting environmental factors for preventing the handicap creation process: Quebec contributions relating to ICIDH and social participation of people with functional differences. Disability Rehabil. 1995;17:145–153. 36. World Health Organization. International Classification of Functioning, Disabilities and Health: ICF. Geneva, Switzerland: World Health Organization; 2001. 37. McGeary M, Ford M, McCutchen SR, et  al. IOM Committee on Medical Evaluation of Veterans for Disability Compensation. A 21st Century System for Evaluating Veterans for Disability Benefits. The Rating Schedule. Washington, DC: The National Academies Press; 2007:92–138. 38. Ranavaya MI. Physician’s Guide to Medicolegal Practice. 1st ed. Chicago, IL: American Medical Association. 39. Ranavaya ML, Brigham C. International use of the AMA guides to the evaluation of permanent impairment. AMA Guides Newsletter. 2020 Apr/May. 40. Burton Jr JF. Workers’ compensation cash benefits. Part one: The building blocks. Workers’ Compensation Policy Rev. 2008;8(2): 15–28. 41. Burton Jr JF. Workers’ compensation cash benefits. Part two: Cash benefit systems and criteria for evaluation. Workers’ Compensation Policy Rev. 2008;8(6):13–31. 42. Murphy PA, Williams JM. Assessment of Rehabilitative and Quality hf Life Issues in Litigation. Boca Raton, FLA: CRC Press LLC; 1999. 43. American Medical Association. Guides to the Evaluation of Permanent Impairment. 6th ed. Chicago: American Medical Association; 2008. 44. Rondinelli R, Eskay-Auerbach M, Ranavaya M, et al. Commentary on NCCI report. AMA guides Newsletter. 2012. 45. Ranavaya ML. Presidential address. American Academy of Disability Evaluating Physicians. 1997. 46. Ranavaya MI, Andersson GB. The impairment and disability evaluations. In: Mayer TG, Gatchel RJ, Polatin PB (eds). Occupational Musculoskeletal Disorders: Function, Outcomes & Evidence. Philadelphia, PA: Lippincott Williams & Wilkins; 2001. 330.e1

330.e2

References

47. Rondinelli RD, Ranavaya M. Disability assessment. In: Benzon HT, Rathmell JP, Wu CL, Turk DC, Argoff CE, Hurley RW (eds). Practical Management of Pain. 5th ed. Philadelphia, PA: ElsevierMosby; 2013:257–268. 48. Cutler v. Dixon, 76 Eng Rep. 886 (QB 1585). 49. Henderson v. Broomhead, 157. Eng Rep. 1859;964:967–968 Ex. 50. Clark v. Grigson, 579 SW 2d 263 (Tex 1978). 51. Bruce v. Byrne-Stevens & Assoc Engineers Inc. 776 P2d 666,667 (Wash 1989). 52. Briscoe v. LaHue, 460 US 325 (1983). 53. Mitchell v. Forsyth, 472 US 511 (1985). 54. Keeton WP, Dobbs DB, Keeton RE, et al. Prosser and Keeton on the Law Of Torts. 5th ed. St. Paul, MN: West Group Publisher; 1984. 55. Sanbar S, Firestone M, eds. Legal Medicine. 7th ed. Schaumburg, IL: Am College Legal Med; 2007. 56. Rand v. Miller, 408 S E 2d 655 (W. Va.1991). 57. Johnston v. Sibley, 588 S.W.2d 135 (Tex. Civ. App. 1977). 58. Craddock v. Gross, 504 A.2d 1300, 1302 (Pa.Super.Ct. 1986). 59. Greenberg v. Perkins, 845 P.2d 530, 538 (Colo 1993). 60. Harris v. Kreutzer, 624 S.E.2d 24, 27 (Va. 2006). 61. Stanley v. McCarver, 208 Ariz. 219, 226. 92 P.3d 849, 856. 62. Ritchie v. Krasner, (No.1.CA-CV08-0099. Filed April 21, 2009).

6 3. Jones v. Karney, 2011, UKSC 13. 64. Turk DC, Monarch ES. Biopsychosocial perspective on chronic pain. In: Turk DC, Gatchel RJ (eds). Psychological Approaches to Pain Management: A Practitioner’s Handbook. 2nd ed. Guilford, NY: Guilford Press; 2002:3–29. 65. Katz N. The impact of pain management on quality of life. J Pain Symptom Manage. 2002;24(1 Suppl):S38–S47. doi:10.1016/s08853924(02)00411-6. 66. Health-Related Quality of Life (HRQOL). Centers for Disease Control and Prevention, 31 Oct. 2018. Available at: www.cdc.gov/ hrqol/index.htm. 67. Haraldstad K, Wahl A, Andenæs R, et al. LIVSFORSK network. A systematic review of quality of life research in medicine and health sciences. Qual Life Res. 2019;28(10):2641–2650. doi:10.1007/ s11136-019-02214-9. 68. Ware Jr JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–483. 69. World Health Organization. WHOQOL User Manual - Programme on Mental Health. Division of Mental Health and Prevention of Substance Abuse - World Health Organization; 2012.

24

Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

NANTTHASORN ZINBOONYAHGOON, YUN-YUN K. CHEN, KRISTIN L. SCHREIBER

Chronic post-surgical pain (CPSP) is a growing area of study in pain medicine.1 An increasing number of patients undergoing surgery each year,2 multiplied by a variable reported incidence (5%–85%),3 produces an increased number of patients with new chronic pain. In recognition of CPSP as an important global health problem, the International Association for the Study of Pain (IASP) named 2017 the Global Year Against Pain After Surgery.4 In the upcoming International Classification of Disease (ICD-11), which is expected to be implemented in January 2022 by the World Health Organization, CPSP is recognized as one of the seven major types of chronic pain (MG 30.XX) under distinct codes for “chronic postsurgical pain” (MG 30.21), “chronic postsurgical or posttraumatic pain, unspecified” (MG30.2Z), and “other specified chronic postsurgical or posttraumatic pain” (MG30.2Y).5,6 CPSP is a distinct subset of chronic posttraumatic pain, the definition of which is “pain developing or increasing in intensity after a tissue injury (involving any trauma including.”6 The code for chronic posttraumatic pain also includes persistent pain after trauma, spinal cord injury, nerve injuries, and burn injury.6 Publications regarding CPSP have grown exponentially over the last decade, from 178 publications by 2009 to 938 publications by 2019,7 providing a strong but heterogeneous and complex body of evidence. This chapter will cover the definition, incidence, and proposed pathophysiology of CPSP, summarize what is known about potential risk factors that may aid prediction, and outline strategies for preventive efforts.

2) The duration of two months may be too short to be considered as chronic pain in some cases, and thus the required duration of pain should be extended to at least three–six months. 3) Rather than simply categorizing pain as absence/presence, pain severity and impact should be considered, with CPSP defined as pain that the patient feels has at least a minimal impact on quality of life. 4) CPSP commonly develops immediately after surgery but may also develop after a pain-free period, possibly because of the delayed onset of neuropathic pain after nerve injuries (inguinal hernia repair, breast surgery with axillary dissection). 5) The CPSP may involve locations outside the surgical site. For example, patients suffering from persistent pain after breast cancer surgery report pain not only at the breast or axilla, both in the upper medial arm,10 likely because of intercostobrachial neuralgia from axillary node dissection.11 IASP updated the definition of CPSP in 2017:12 “Chronic post-surgical pain is chronic pain developing or increasing in intensity after a surgical procedure and persisting beyond the healing process, i.e. at least three months after surgery.” The pain is either localized to the surgical field, projected to the innervation territory of a nerve situated in this area, or referred to a dermatome (after surgery/injury to deep somatic or visceral tissues). Other causes of pain, such as infection and malignancy, need to be excluded, and pain continuing from a preexisting pain problem. Depending on the type of surgery, CPSP often includes elements of neuropathic pain (Table 24.1). These newly proposed criteria provide a more comprehensive picture of CPSP and may be used as diagnostic criteria in the ICD-11 coding system.

Definition of CPSP

Incidence of CPSP

The concept of CPSP is pain that lasts longer than the physiologic healing process after surgery. Simple diagnostic criteria for CPSP were proposed by Macrae8 in 2001 as pain developing after a surgical procedure of at least two months duration, with other causes for the pain having been excluded (e.g. continuing malignancy or chronic infection), including the possibility that the pain continues from a preexisting problem. However, there have been additions and modifications to this simple definition, including:9 1) Many patients already experience pre-surgical pain. To define CPSP for patients who already had pre-surgical pain, post-surgical pain should have increased severity and/or be accompanied by a change in location or character.

Having a well-developed definition and standard diagnostic criteria has assisted the visibility and recognition of CPSP, which had previously been underestimated.13 However, the diagnostic criteria for CPSP do not specify a clinically meaningful pain severity to define CPSP. Even with these more closely defined diagnostic criteria, variation in cut points for the severity constituting clinically significant pain and at timepoints chosen to study CPSP likely contributes to the wide range of reported incidence of CPSP in the literature. Studies have used different definitions to denote clinically meaningful CPSP, ranging from anything >0/10 on the pain scale to only considering pain >3 or >4/10 as significant.10 Frequency may be variable (constant vs. intermittent), and the

Introduction

333

334

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 24.1

Evolution of the Definition and Diagnostic Criteria of Chronic Post-surgical Pain

Macrae 20018

Werner and Kongsgaard 20149

IASP 20196

(1) The pain should have developed after a surgical procedure. (2) The pain should be of at least two months duration. (3) Other causes for the pain should be excluded, e.g. continuing malignancy (after surgery for cancer) or chronic infection. (4) The possibility that the pain is continuing from a preexisting problem should be explored, and exclusion attempted. (There is an obvious grey area here in that surgery may exacerbate a preexisting condition but attributing escalating pain to the surgery is clearly not possible as natural deterioration cannot be ruled out.)

(1) The pain develops after a surgical procedure or increases in intensity after the surgical procedure. (2) The pain should be of at least three to six months’ duration and significantly affect the HR-QOL. (3) The pain is either a continuation of acute postsurgery pain or develops after an asymptomatic period. (4) The pain is either localized to the surgical field, projected to the innervation territory of a nerve in the surgical field, or referred to a dermatome (after surgery in deep somatic or visceral tissues). (5) Other causes of the pain should be excluded, e.g. infection or continuing malignancy in cancer surgery.

The pain that develops or increases in intensity after a surgical procedure or a tissue injury and persists beyond the healing process, i.e. at least three months after the initiating event. The pain has to be localized to the surgical field or area of injury, projected to the innervation territory of a nerve situated in this area, or referred to a dermatome or Head’s zone (after surgery/injury to deep somatic and visceral tissues). Other causes of pain, such as preexisting pain conditions or infections, or malignancy, have to be excluded in all cases of chronic posttraumatic and post-surgical pain.

quality of the pain may depend on its location and the exact mixture of its mechanistic basis. From mild to debilitating pain, this range of severity correspondingly results in varying degrees of negative impact on quality of life.14 Thus the estimates for the incidence of CPSP vary substantially even among studies using the same procedure (Table 24.2),15,16 according to the methodologic differences in defining CPSP by TABLE 24.2

Incidence of Chronic Post-surgical Pain by Operation and Pain Intensity and Proportion of Neuropathic Pain

Type of Surgery

Incidence of All CPSP

Incidence of Severe CPSP (>5/10 of 10/10)

Proportion of Neuropathic Pain in CPSP

Amputation

30%–85%

5%–10%

80%

Cesarean delivery

6%–55%

5%–10%

50%

Cholecystectomy

3%–50%

Not reported

Not reported

Coronary bypass

30%–50%

5%–10%

Not reported

Craniotomy

7%–30%

25%

Not reported

Dental surgery

5%–13%

Not reported

Not reported

Hip arthroplasty

27%

6%

Not reported

Inguinal herniotomy

5%–63%

2%–4%

80%

Knee arthroplasty

13%–44%

15%

6%

Melanoma resection

9%

Not reported

Not reported

Mastectomy

11%–57%

5%–10%

65%

Sternotomy

7%–17%

Not reported

Not reported

Thoracotomy

5%–65%

10%

45%

Vasectomy

0%–37%

Not reported

Not reported

With permission from Schug et al.12

pain intensity (Table 24.2),6 and by time (Fig. 24.1), and across study samples.16 The procedures with the highest reported incidence of CPSP include thoracotomy (5%–65%), mastectomy (11%–57%), and amputation (30%–85%). These procedures also have a higher prevalence of moderate to severe pain (5%–10%) than herniotomy (2%–4%)12 and seem to have more neuropathic characteristics (66%–68% for thoracotomy and mastectomy) than hip or knee arthroplasty (6%).15 Although cross-sectional studies are the most common, some longitudinal studies have tracked the incidence of CPSP at later time points and generally show a decrease over time. For example, the incidence of CPSP after thoracotomy in the study by Montes et al. showed 38% at four months, 19% at 12 months, and 13% at 24 months.16 A similar mean trajectory of CPSP has been reported after hysterectomy and hernia repair (Fig. 24.1).16 In contrast, other studies have suggested a relatively low but stable incidence beyond three months, as in the case of mastectomy, where both cross-sectional studies querying patients at six months to six years,17 and longitudinal studies out to 12 months,18 suggest a similar incidence of about 30% reporting pain of ≥3/10 or more. A more in-depth analysis, taking interpatient variability into account, suggests that there may be multiple pain trajectories within the first year after surgery, depending on severity, experienced by different subgroups of patients.19 A large international study averaging across multiple surgical types showed an overall incidence of CPSP of 41% (95% CI 38–43) at six months and 35% (95% CI 32–39) at one year. However, patients with severe pain (NRS ≥6/10), who also reported greater pain interference with activities and mood than patients with more moderate pain, represented only 2% of patients in the same study (95% CI 1–3).14

Proposed Mechanisms of CPSP Surgical injury leads to acute postoperative pain that may be nociceptive, inflammatory, and/or neuropathic when viewed according to classic pain categorizations. However, the exact mechanism(s) involved in the pathophysiology leading to the maintenance or chronification of post-surgical pain is not well established and may vary according to nature of the injury and tissues involved. Three important mechanistic concepts that may be important for understanding the chronification of pain after

CHAPTER 24  Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

335

• Figure 24.1  Incidence of chronic post-surgical pain after hernia repair, hysterectomy, and thoracotomy at different time points after surgery. With permission from Montes et al.16

surgery include neuroplasticity, nerve injury, and opioid-induced hyperalgesia.

Neuroplasticity Neuroplasticity is a term that describes the adaptability within the structure and function of the nervous system, a quality that fundamentally underlies several crucial tasks of the nervous system, such as learning and memory, and also includes self-preservation from noxious stimuli.20 The intense nociceptive and inflammatory stimuli from tissue injury that occurs during surgery is a message that the nervous system cannot evolutionarily afford to ignore. The nervous system response to tissue injury can be regarded as functional neuroplasticity. Increased pain immediately after surgery can drive adaptive behaviors that facilitate healing. However, these processes, when sustained or solidified into CPSP, represent a maladaptive change. Surgical injury of tissues leads to a local release of inflammatory and other mediators and creates an acidic and often locally ischemic environment. These mediators activate peripheral nociceptors both directly through binding of mediators and by decreasing the threshold to activation by other stimuli, making normally painful stimuli more painful (hyperalgesia) and painful nonpainful stimuli (allodynia) at the site of injury (primary hyperalgesia and allodynia, limited to injury site).3 intense and maintained nociceptive input from the periphery also activates central nociceptive pathways, starting at the level of the dorsal horn,21 and modulating descending facilitation and inhibition from supraspinal centers,22 and cortex.23 This multi-level activation contributes to increased sensitivity at the primary site and sites distal to the injury (secondary hyperalgesia), otherwise known as central sensitization (Fig. 24.2). Changes in receptor and gene expression in the dorsal root ganglion contribute to this prolonged excitability of primary nociceptors (peripheral sensitization) and thus enhanced transmission of the nociceptive signal.3 Correspondingly, the continued transmission of this nociceptive input can cause transcriptional changes at the level of the spinal cord that underlie central sensitization.3 The N-methyl-d-aspartate (NMDA) receptor plays a pivotal role

in the amplification of pain and central sensitization at the level of the spinal cord, as evidenced in pre-clinical and human models.24 The application of NMDA receptor antagonists to prevent hyperalgesia in experimental models25 provided hope for a similar outcome in humans. Some studies showed that NMDA receptor antagonism with agents such as ketamine might modify the incidence or intensity of CPSP in clinical application.26 Additionally, the response from surrounding immune, stromal, and glial cells in the periphery and spinal cord causally contributes to and sustains peripheral and central sensitization, influencing the extent and duration of pain and its transition to a more chronic state.3 In keeping with the idea of noxious nociceptive input from the periphery driving central sensitization, efforts to interrupt the intense nociceptive signal have long been viewed as a way to prevent pain amplification and nervous system plasticity (preventive analgesia, sometimes called preemptive analgesia). The concept of preemptive analgesia was described in 1983 as an early analgesic intervention initiated before a nociceptive stimulus, which may “preempt” the development of persistent pain.27 However, clinical studies comparing analgesics given before vs. immediately following an injury failed to strongly confirm the idea of preemption.28 The subsequent concept of preventive analgesia recognized the need to extend the time window of intervention to cover not only the initial intense nociceptive stimulation (during injury or hours after injury) but also the ongoing inflammation and aberrant firing of injured nerves at later time points (days after injury), when ongoing nociception has not yet abated.29,30 The impact of regional anesthesia (nerve blocks),31 and pharmacologic agents such as ketamine,26 and lidocaine,32 have been often studied, with mixed but promising results in preventing CPSP. The definitions of these concepts are summarized in Table 24.3.

Opioid-Induced Hyperalgesia Opioids have long been commonly used as potent analgesics. However, when used chronically and at high doses, analgesic efficacy may diminish, disappear, or even lead to increased pain. This paradoxical phenomenon, where opioids lead to a hyperalgesic state, is called opioid-induced hyperalgesia.36

336

PA RT 4 Clinical Conditions: Evaluation and Treatment

Cortex

4

Thalamus Hypothalamus

Limbic system

Brain stem Spinal Cord

3 Dorsal root ganglion 2

Nerve

Surgical nerve injury 1

• Figure 24.2  Sites and possible mechanisms responsible for chronic post-surgical pain: (1) Tissue and

nerve injuries signal intense pain stimuli and peripheral sensitization; (2) changes in the sensitivity in the dorsal root ganglion producing central sensitization; (3) brainstem descending controls modulate pain transmission in spinal cord; (4) limbic system, hypothalamus, and cortex contribute to altered mood and behavior. Modified with permission from Kehlet et al.3

TABLE 24.3

Terms and Definitions

Term

Definition

Preemptive analgesia

An intervention initiated before a nociceptive stimulus, aimed at significantly decreasing or eliminating the nociceptive stimulus to the point that it does not lead to central sensitization and prolonged pain.30,33

Preventive analgesia

An intervention that is initiated before a nociceptive stimulus and continues until the majority of nociceptive stimuli have abated.30,34

Peripheral sensitization

Changes in the peripheral nociceptor and its milieu that lower the pain threshold and lead to a greater response for any given stimulus.30,35

Central sensitization

Changes in the central nervous system at the level of the spinal cord or higher that result in pain hypersensitivity.3,30

Opioid-induced hyperalgesia (OIH) can be conceptualized as secondary hyperalgesia. The mechanism underlying OIH likely involves transcriptional changes leading to an imbalance between pro and antinociceptive pathways,37 including µ-opioid signaling, pronociceptive ion channel modulation, and microglial activation.38 Chronic exposure to opioids has been shown to result in µ-opioid receptor phosphorylation by G-protein coupled receptor

kinases, which leads to β-arresting-2 recruitment, µ-opioid receptor endocytosis, and receptor unavailability.38,39 A systematic review of clinical studies suggests that high intraoperative doses of remifentanil are associated with small but significant increases in acute pain after surgery. 40 Even lower dose and briefer exposures to remifentanil (0.1 mcg/kg/min for 30 min) have been associated with OIH.41 In pre-clinical studies, the hyperalgesic effect of a single dose of fentanyl can last for three weeks.36 OIH may potentially augment hyperalgesia from tissue injuries itself, making opioid-sparing strategies such as multimodal analgesia especially important in treating both acute postoperative pain and CPSP. Ketamine, an NMDA receptor antagonist, has been shown to decrease β-arresting-2 transcription in mice42 and to clinically decrease punctate hyperalgesia in humans who received remifentanil.41 Within a clinical context, it may be challenging to distinguish OIH from opioid tolerance, inadequate analgesia, and changes in underlying disease pathology. However, it may be suggested by altered sensory processing such as allodynia and hyperalgesia and worsening pain with further doses of opioids.38 Assessing specifically for signs of OIH early after surgery may allow a better determination of the extent to which OIH contributes to CPSP.

Nerve Injury Peripheral nerves are among the tissues that can be injured by surgery. Peripheral nerve injury is often considered a central contributor to the mechanistic basis of CPSP. As outlined in the

CHAPTER 24  Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

neuroplasticity section above, peripheral nerves contribute fundamentally to carrying an augmented message of pain after any tissue injury, whether the nerves themselves have sustained structural damage. However, pre-clinical studies have shown that a variety of damage to peripheral nerves may cause increased and spontaneous firing of action potentials, changes in gene expression including up and downregulation of neurotransmitters, and immune system activation after injury. These changes occur at the dorsal root ganglion level but reverberate to the dorsal horn and higher centers.3 Neuropathic pain in the context of CPSP can be defined in various ways, although typically utilizing questionnaires such as the DN4, S-LANSS, and painDETECT, or by including similar questions in a surgery specific questionnaire.43 The presence of pain features of a certain quality (e.g. burning, tingling, stabbing) are indicators of nerve injury. Based on these definitions, the prevalence of neuropathic pain in CPSP varies from 6% to 68% among various surgeries,15 although the highest reported ranges appear after thoracic and breast surgery and lowest after hip or knee replacement.15 While more extensive nerve damage is associated with a higher incidence of CPSP,3 higher pain severity,44 and functional impairment,14 nerves are rarely injured in isolation, and causation cannot be inferred from this correlation.

Risk Factors and Prediction of CPSP Many putative factors have been linked to the incidence of CPSP and its severity, impact, and related complications, such as persistent opioid use. These factors may allow further insight into the mechanism underlying CPSP and have been put to practical use to estimate the risk of CPSP in many predictive models.

Risk Factors for Developing CPSP Although surgical injury, by definition, is the inciting event for CPSP, the surgical extent is not always the best predictor of greater incidence and severity of CPSP. Chronic pain is a complex interaction between nociception and an individual’s life. Many factors beyond the degree of tissue injury are formative to the individual experience Timing

Preoperave

of pain after surgery, including genetic, psychological, and social factors. The biopsychosocial model of pain, which includes biophysical differences between individuals (genetic variation, baseline nociceptive sensitivity, opioid dependence), and differences in psychosocial factors known to be involved in the processing of pain (anxiety, depression, coping strategies, social support), provides a comprehensive picture of the risk and predictive model for CPSP (Fig. 24.3).

Surgical Factors Tissue and nerve injury in each procedure must also be considered as part of the biologic variation that occurs between individuals undergoing surgery. Certain procedures are associated with different ranges of CPSP incidence,12,16 typically with procedures of greater extent associated with higher rates. Surgical factors associated with CPSP include longer duration of surgery, low (vs. high) volume of surgical center, open (vs. laparoscopic) approach for some operations such as inguinal hernia repair,46–48 and intraoperative nerve damage.21 Tissue injury is not necessarily limited to the initial surgical injury. For example, patients who underwent repeated inguinal hernia repair were more likely to develop moderate or severe pain.49 Similarly, and patients who received radiotherapy after breast cancer surgery had a higher likelihood of CPSP in a metaanalysis (odds ratio [OR] = 1.35[1.16–1.57]),50 possibly because of the increased incidence of tissue fibrosis, neural entrapment, and impaired glenohumeral motion.51 Patients Characteristics Age and Sex

Younger age and female sex are associated with an increased risk of CPSP.12,21 A multivariable analysis by Montes et al. found that, compared to older patients (>64 years), younger patients had a greater incidence of CPSP (OR 3.1 [2.4–4.0] for 18–50-yearolds, and OR 1.6 [1.2–2.1] for 51–64 patients).16 Similarly, in a meta-analysis of 30 studies involving 19,813 patients undergoing breast cancer surgery, the absolute risk of CPSP increased 7% [5%, 9%] for every ten years decreased from age 70.50

Surgery (Intraoperave)

Postoperave

Recovery (> 3 months postop)

Events Paent preparaon for surgery

Scheduled surgical Injury

Acute postsurgical pain

Chronic postsurgical pain

Response to injury, plascity underlying chronificaon

Risk Factors

Assessment and Treatment

Biophysical: Surgical approach Age Sex Genec variaon Opioid dependence Nocicepve sensivity Tendency towards pain centralizaon

Individualized procedural risk straficaon

337

Psychosocial: Anxiety, depression Sleep disturbance Pain catastrophizing Somazaon Healthcare access Coping strategies Social support

Regional Anesthesia Mulmodal Analgesia Minimize opioid-induced hyperalgesia Biophysical and psychosocial tesng, support and treatment Minimally invasive technique & decreased duraon

• Figure 24.3  The comprehensive risk factors in the biopsychosocial model for developing chronic postsurgical pain. Chen Y-YK, Boden KA, Schreiber KL. The role of regional anaesthesia and multimodal analgesia in the prevention of chronic post-surgical pain: a narrative review. Anaesthesia. 2021;76(1):8–17.45

338

PA RT 4 Clinical Conditions: Evaluation and Treatment

Preoperative Pain

Preexisting pain at the surgical site represents sensitization of nociceptors in the area,21 and further nociceptive input from surgical injury likely further augments this sensitization in an additive or supra-additive fashion.49 Chronic pain in nonsurgical areas is also an important risk factor, indicating a tendency toward amplification of the pain signal over endogenous pain inhibition,16,52 or central sensitization.53 Other studies have associated longer duration and higher intensity of preoperative pain with the development and persistence of CPSP.21,54 One study reported a slightly higher risk of CPSP for preoperative pain at the surgical site than preoperative pain at a remote site. However, both surgical site and generalized pain appear to be robust predictors of CPSP.52 A multivariable analysis from a large observational multinational study showed the presence of chronic preoperative pain at any site is the strongest predictor of CPSP at 12 months after surgery (OR 1.89 [1.12–3.18]).14 Preoperative pain, either at the surgical site or chronic pain at another site, are consistently included among the key predictors in most prediction models for CPSP.14,16,18,54–56 Preoperative Opioid Use

Long term opioid use for the treatment of chronic pain may increase the risk of CPSP, either as a marker of preoperative chronic pain severity or OIH, or both.57 However, whether opioid use serves as a causal contributor to CPSP or is simply a common coincidental finding because of chronic pain is still unknown. In one cohort study, preoperative opioids were associated with CPSP on a simple univariable analysis (relative risk [RR] 2.0 [1.2–3.3]). However, when other factors, including preoperative pain status, were included in the multivariate analysis, preoperative opioid use was no longer a significant predictor (RR 1.3 [0.8–1.9]).58

Psychological and Social Factors The experience of pain involves a complex interaction between nociception and psychology. The impact of psychological factors on acute postoperative pain, CPSP, and other types of chronic pain is well documented. An earlier meta-analysis indicated an important association of psychological factors including depression, psychological vulnerability, and stress with CPSP after various surgeries, including thoracotomy, mastectomy, hernia repair, and orthopedic surgery.59 Then an even broader investigation of psychological factors including both state and trait anxiety or depression, pain catastrophizing, sleep disturbance, somatization, positive and negative affect, coping strategies, and expectations found an association of higher psychological distress with greater incidence and severity of CPSP.10,17,60–63 In particular, pain catastrophizing, defined as a tendency to magnify, ruminate, or feel helpless in the face of painful sensations,62 has proven an interesting and consistent correlate of CPSP,17,61 and chronic pain generally.64 A meta-analysis showed a strong association between pain catastrophizing and CPSP (pooled OR of the minimum effect of 2.13 [1.26, 3.59]).61 Psychological factors can be assessed perioperatively with validated questionnaires such as the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) short forms for depressive symptoms, anxiety, and sleep disturbance,65 the Brief Symptom Index (BSI)-Somatization Scale for somatization,66 or questionnaires such as the Pain Catastrophizing Scale.67 Social and sociodemographic factors may also influence pain experiences, including resources and access to care. Socioeconomic factors and disability status have been variably implicated as risk factors in systematic reviews and meta-analyses.12 Lower

educational and employment status have been associated with vulnerability to developing chronic pain.68–71 The contribution of social factors to CPSP risk has been understudied compared to biologic and psychological constructs.72 However, social interactions appear to also play an important role in modulating pain and the ability to cope with chronic pain,73 although the interaction of social and psychological factors, both complex and difficult to study, may also be important. Several studies suggest that a more insecure attachment style is associated with greater distress, lower self-efficacy to decrease pain, greater pain catastrophizing, more disability because of pain, and greater pain sensitivity.74

Acute Postoperative Pain Greater nociceptor activation leads, on the one hand, to more severe acute pain, but also to a greater likelihood of central sensitization, which may contribute to the development of CPSP.14,16 Thus greater acute postoperative pain is cited as a risk factor in many studies and is often included in models of CPSP prediction.14,50,56 In one meta-analysis, acute postoperative pain severity was associated with an OR of 1.16 [1.03,1.30] and an absolute risk increase of 3% [1%, 6%] for every 1-cm increment on a 10-cm visual analog scale.50 Besides acute pain severity per se, the percentage of time in severe pain on day one after surgery has also been shown to be strongly associated with moderate to severe pain from CPSP (NRS ≥3/10) at 6 and 12 months after surgery (Fig. 24.4).14 However, the severity and daily duration of acute postoperative pain may also be viewed as reflecting patient susceptibility to pain amplification, which also underlies the propensity toward central sensitization and the development of CPSP.14 Acute pain is less of a predictor than a temporal correlate of the same process involved in the development of CPSP. It is yet unclear whether adequate or inadequate perioperative analgesia could meaningfully affect CPSP development,3 and in light of the goals of providing analgesia in the perioperative period, this principle may be difficult or unethical to prove. Provision of excellent acute postoperative pain control leads to a better experience for the patient, both in terms of satisfaction and perioperative recovery,75 independent of whether it may prevent CPSP. Other Factors Genetic Variations

Clinical and pre-clinical studies have linked genetic factors to chronic pain. Many single nucleotide polymorphisms (SNPs), including catechol-O-methyltransferase (COMT), GTP cyclohydrolase 1 (GCH1), and DA receptor 2 (DRD2), have been linked with the risk of CPSP,76

• Figure 24.4  The incidence of moderate to severe chronic post-surgical

pain (≥3/10) at 6 and 12 months and the percentage of time in severe pain at postoperative day one. With permission from Fletcher et al.14

CHAPTER 24  Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

but a definitive genetic profile of elevated CPSP is still the object of much ongoing research. One analysis of a larger set of 90 SNPs, including those aforementioned, selected based on functional genetic variants associated with pain sensitivity and chronic pain conditions, failed to show significant differences in allele frequencies between patients with and without CPSP.16 However, this is likely to be an area of continued interest, particularly as larger collaborative studies emerge. Quantitative Sensory Testing

Quantitative sensory testing (QST) of an individual’s response to standardized pain stimuli may help to characterize overall pain susceptibility.77 Many studies have shown the predictive value of QST for CPSP after thoracotomy,52 shoulder surgery,78 and mastectomy.10 Nevertheless, the application of QST in the clinical setting is still limited, and a relatively small pool of studies have investigated the predictive potential of these modalities, with somewhat variable QST protocols employed. Given that the application of QSTs is somewhat time consuming and requires access to standardized equipment and specially trained personnel,79 future development of practical bedside tests is needed to offer a more practical application of QST to CPSP prediction,80 and to determine whether these tests add predictive power independent of other measured risk factors.

Risk Factors for Other CPSP-Related Outcomes Risk Factors for Pain Interference From CPSP As pain is a multidimensional experience, measures of pain severity alone are insufficient to estimate the impact of pain,81 especially when pain persists. Greater pain interference after surgery (a subscale of the Brief Pain Inventory) is closely associated with greater reported CPSP severity and the presence of neuropathic characteristics at 6 and 12 months.14 Preoperatively assessed characteristics including state anxiety, preoperative pain status, and

moderate to severe acute postoperative pain predicted greater CPSP interference.54 A prospective longitudinal examination of a comprehensive set of preoperative variables (demographic, biomedical, and psychosocial factors) allowed an assessment of these variables’ independent predictive potential for CPSP, including both pain measures of severity and impact on physical, cognitive, and emotional functioning impact.18 Interestingly, predictors of severity and predictors of impact were only partially overlapping and depended on whether a surgery-specific questionnaire or a more general pain questionnaire was used (Fig. 24.5). Consistent independent predictors across pain outcomes included preoperative surgical area pain, less formal education, and greater baseline sleep disturbance, while pain catastrophizing, affect, younger age, higher body mass index, and chemotherapy were more consistently predictive of pain impact, but not severity.

Risk Factors for Persistent Postoperative Opioid Use Rates of new persistent opioid use, defined as use for over 90 days after surgery in opioid-naïve patients, were 5.9% for minor surgeries and 6.5% for major surgeries (non-operative control arm 0.4%) according to a large study of 36,177 patients undergoing various procedures in the United States.82,83 As the prevalence was similar between minor and major surgeries (OR 1.04 [0.93,1.18]), these findings suggest that prolonged opioid use after surgery cannot be simply explained by the extent of surgical injury. The multivariable analysis revealed that significant risk factors for persistent opioid use included tobacco use, alcohol and substance abuse disorders, mood disorder, anxiety, and preoperative chronic pain, thus including many of the same risk factors associated with CPSP. Risk Factors for Neuropathic Features Involved in CPSP Neuropathic features, such as burning, pins and needles, and stabbing, are often coincident with CPSP, with a reported range from 6% to 80%.12,15 These features are also often associated with a Breast Cancer Pain Questionnaire (BCPQ) Physical, Cognitive, & Emotional Impact Model Fit: Cog/Emot Impact Age

Model Fit: PSI

Observed

40

Depression

20

Somatization

%RMSE:17.6

40

Predicted

Preop Pain Model Fit: BPI Mean

%RMSE:13.3

20

30 40 Predicted

50

Model Fit: BPI Functional Impact

Sleep

10

30

BMI Chemo Catastrophizing Affect

Education

60 8 100 120 0

20

40

20

0 0

50

Opioid use

ALND

Observed

Breast Cancer Pain Questionnaire (BCPQ) Pain Severity Index 120 100 80 60

339

80

6 4

Opioid use

2 %RMSE:22.2

0 2

4

6 8 Predicted

Observed

Other pain

60 40 20 %RMSE:19.8

0

10

12

0

20

40 Predicted

Brief Pain Inventory BPI mean

• Figure 24.5

Brief Pain Inventory BPI Interference

Assessment of comprehensive set of biopsychosocial risk factors for independent association with different post-surgical pain outcomes at one year. Schreiber KL, Zinboonyahgoon N, Flowers KM. Prediction of Persistent Pain Severity and Impact 12 months after Breast Surgery using Comprehensive Preoperative Assessment of Biopsychosocial Pain Modulators. Ann Surg Oncol 28, 5015–5038 (2021). https://doi.org/10.1245/s10434-020-09479-218  

Observed

8

60

80

340

PA RT 4 Clinical Conditions: Evaluation and Treatment

more pronounced functional impairment.14 Similar to the close relationship between acute and chronic pain severity, early neuropathic features (on postoperative day two) are strongly associated with persistent post-surgical neuropathic features at later time points (two months), OR 4.22 [2.19–8.12].84

100% 82%

80%

68%

Previous research has uncovered many candidate risk factors through cross-sectional and prospective longitudinal studies of CPSP. Recognizing the interrelatedness of many of these candidate risk factors, several groups have worked to identify independent predictors using multivariable regression models. Such multivariable prediction modeling aims to achieve the most accurate prediction while reducing the number of predictors to a manageable set. These models may gain a better understanding of the mechanisms underlying CPSP and enrich preventive interventional CPSP trials. A risk index for CPSP was developed by Althaus et al. in 2012,56 which included several previous and acute pain-related variables (preoperative pain in the operative area, other preoperative pain, acute post-surgical pain) and two variables related to physical and psychological stress (answering yes to a question about capacity overload/overstrain, and answering yes to having one of the following: sleeping disorder, exhaustibility/exhaustion, frightening thoughts, dizziness, tachycardia, feeling of being misunderstood, trembling hands, or intake of sleeping/sedation pills). This risk index was used to classify patients into low risk (zero to one risk factor), moderate risk (two risk factors), and high risk of developing CPSP (three–five risk factors presented) (Fig. 24.6). In this model, when including acute pain and other preoperative pain variables in the model, other predictors such as sex and type of surgery, minimally invasive versus open, did not emerge as independent predictors from the multivariable analysis process. In 2015, Montes et al.16 developed a predictive model from a large prospective multicenter cohort study that enrolled 2,929 patients scheduled for various surgical procedures (vaginal hysterectomy, abdominal hysterectomy, hernia repair, and thoracotomy). The resultant multivariable model included six predictors: preoperative pain at the surgical site, preoperative pain at another

71%

60% 40%

Prediction Models

TABLE 24.4

Chronic post-surgical pain

20%

30%

37%

12%

0% 0

1 2 3 4 Number of risk factors presented (0-5)

5

• Figure 24.6  The probability for developing chronic post-surgical pain

at six months according to risk index by Althaus’s model. With permission from Althaus et al.56

body site, more extensive surgery (higher risk for thoracotomy), younger age, and overall physical and mental condition (SF-12 physical and mental score subscales) (Table 24.4). Taken together, these factors predicted the risk of developing CPSP at four months after surgery with reasonable accuracy (approximately 70%), even when the procedure type was excluded. One advantage of a model that includes only factors known before the procedure is that it may allow the clinician to develop preventive plans for high-risk individuals in the preoperative period. This model was applied for validation at additional hospital centers and reported a similar accuracy of prediction, demonstrating reasonable geographic and temporal generalizability across populations of comparable patients.85

Prevention of CPSP Considering the putative mechanisms and modulators of CPSP, many therapies aimed at modulating or preventing CPSP involve aspects of this proposed pathophysiology, targeting events in peripheral tissues, including nerves at the site of injury, as well as events at the spinal cord or above (Table 24.5). The strategies include early and aggressive pain control by analgesic and regional anesthesia, modification of the surgical approach, and psychological-behavioral adaptation.

Comparison of Two Models to Predict the Development of Chronic Post-surgical Pain (CPSP)

Model

Althaus et al. 201156

Montes et al. 201516

Study design

150 patients undergoing various types of surgery

Prospective multicenter cohort, 2929 patients undergoing vaginal hysterectomy, abdominal hysterectomy, hernia repair, or thoracotomy

Factors

1. 2. 3. 4. 5.

1. 2. 3. 4. 5. 6.

Risk calculation

Summation of the five risk factors and classify them into low, moderate, and high risk of developing CPSP six months after surgery.

Capacity overload (+)* Preoperative pain, surgical site (+) Other chronic preoperative pain (+) Postoperative acute pain (+) Comorbid stress symptoms (+)

Surgical procedure (+,–) Age (–) SF-12 physical (–) SF-12 mental (–) Preoperative pain, surgical site (+) Preoperative pain, other sites (+)

Complex equation from six factors calculating the risk of developing CPSP four months after surgery in 73% of the patients.

(+) increased risk, (–) decreased risk, *capacity overload = answering yes to having one of the following: sleeping disorder, exhaustibility/exhaustion, frightening thoughts, dizziness, tachycardia, feeling of being misunderstood, trembling hands, or intake of sleeping/sedation pills.

CHAPTER 24  Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

TABLE 24.5

341

Targets to Prevent Chronic Post-surgical Pain (CPSP): Various Interventions Can Act at Several Targets Along the Pain Pathway Initiated by Surgical Injury to Prevent CPSP

Targets and Risk Factors

Intervention

Peripheral tissues, including nerves

Modification of surgical approach

Peripheral nerve activation

Regional anesthesia

Local inflammatory response and neurogenic inflammation

Regional anesthesia Anti-inflammatory (COX-2, NSAIDs, acetaminophen)

Peripheral nerve sensitization and continued ectopic firing

Regional anesthesia Cav α2-δ ligands (gabapentin, pregabalin)

Changes in gene expression at dorsal root ganglion

Regional anesthesia Corticosteroids (dexamethasone) Anti-inflammatory (COX-2, NSAIDs)

Central sensitization

Regional anesthesia NMDA antagonists (ketamine, magnesium, dextromethorphan, amantadine) Corticosteroids α-2 adrenergic agonists (clonidine, dexmedetomidine) Opioid receptor agonists

Descending facilitation from the brainstem

Anti-inflammatory (COX-2, NSAIDs, acetaminophen) Anti-depressant

Limbic system and hypothalamus

Psychological-behavioral interventions Anti-depressants Anxiolytics

Cortical pain processing

Assessment and pre-screening Psychological-behavioral interventions Setting appropriate expectations

Genomic DNA leading to a predisposition to chronic pain

Assessment and pre-screening

COX-2, Cyclooxygenase-2; NMDA, N-methyl-d-aspartate; NSAIDs, nonsteroidal anti-inflammatory drugs. Chen Y-YK, Boden KA, Schreiber KL. The role of regional anaesthesia and multimodal analgesia in the prevention of chronic post-surgical pain: a narrative review. Anaesthesia. 2021;76(1):8–17.

Analgesics and Regional Anesthesia As the severity of acute pain after surgery is strongly associated with CPSP, excellent perioperative pain control is a logical goal. Early and proactive perioperative pain management using a combination of different analgesic agents and techniques (multimodal analgesia) has been applied to this goal, with varying effects and conclusiveness.

Analgesics Systemic Lidocaine Lidocaine is classically known to block voltage-gated sodium channels when administered in direct proximity to nerves. However, additional mechanisms of action may include modulation of hyperpolarization-activated cyclic nucleotide-gated channels, transient receptor potential ion channels, and certain G-proteincoupled receptors (GPCRs),86,87 when administered systemically via the intravenous route. Administration of intravenous lidocaine is associated with analgesia beyond the duration of its pharmacokinetics, possibly by its impact on immune and neural targets and by reduction of central sensitization.86 A recent meta-analysis including six high-quality post-surgical studies using 1.5–2 intravenous lidocaine bolus over 10–15 min, then 1.5–2 mg/kg/h infusion until the end or 1–2 h after the operation,32 found that perioperative lidocaine administration reduced the incidence of CPSP at three and six months after surgery (OR 0.29 [0.18 to 0.48]).32 Intravenous lidocaine was also associated with a

trend toward lower pain scores (Fig. 24.7). There were no reported adverse events of systemic lidocaine in these studies, although only one study reported lidocaine plasma levels.88 The subgroup analysis for lidocaine infusion in a meta-analysis by Weinstein31 also showed a preventive effect for CPSP after breast cancer surgery (Table 24.6).

Ketamine As NMDA receptors play a pivotal role in central sensitization,89,90 the NMDA receptor antagonist ketamine has been frequently studied for its utility in the prevention of CPSP.26,91,92 A metaanalysis by Chapparo showed that perioperative infusion of ketamine decreased the incidence of CPSP (any value greater than 0/10) at six months, compared to a placebo (OR 0.50, [0.33, 0.76]), and the number needed to treat to prevent one patient from moderate to severe CPSP was 10.83 [5.7–109].26 The analysis did not show a preventive effect of ketamine at three months and was underpowered to determine a preventive effect at 12 months because of heterogeneity. Subsequent meta-analyses by McNicol et al.92 and Klatt et al.91 were not supportive of a long-term preventive effect for ketamine, again possibly because of heterogeneity in study design and definition of CPSP (Table 24.6), as most of the trials included were small, the populations heterogenous, and ketamine used in varying protocols (intravenous bolus 0.2–1 mg/kg or infusion 0.05–0.25 mg/ kg/h).92 An important consideration for studying the prevention of clinically meaningful CPSP (pain of at least 3/10 or higher) is that the majority of subjects entering the study do not develop the

342

PA RT 4 Clinical Conditions: Evaluation and Treatment

Experimental Study or Subgroup

Control

Odds Ratio

Experimental

Odds Ratio

Events Total Events Total Weight M-H, Random, 95% Cl

Study or Subgroup Mean

M-H, Random, 95% Cl

Control

SD Total Mean

Mean Difference

SD Total Weight

Jendoubi 2017

1

20

9

20

5.1%

0.06 [0.01, 0.58]

Choi 2016

1.5 0.74

41

Grigoras 2012

2

17

9

19

8.3%

0.15 [0.03, 0.83]

Grigoras 2012

1.2

4.4

17

2.1

5.3

19

14.2%

–0.90 [–4.07, 2.27]

Choi 2016

6

41

16

43

21.8%

0.29 [0.10, 0.84]

Kendall 2017

1.7 2.96

62

1.5 2.22

59

28.4%

0.20 [–0.73, 1.13]

Terkawi 2014

4

34

8

27

13.9%

0.32 [0.08, 1.20]

Kendall 2017

8

62

17

59

28.4%

0.37 [0.14, 0.93]

Kim 2017

8.9

39

39

27.0% –3.80 [–4.96, –2.64]

Kim 2017

7

39

14

39

22.5%

0.39 [0.14, 1.11]

207 100.0%

0.29 [0.18, 0.48]

2.3

Total (95% Cl) Total (95% CI)

213

3 1.48

12.7

2.9

159

43

28

160 100.0%

–1.55 [–3.16, 0.06]

Heterogeneity: Tau2 = 2.15; Chi2 = 27.98, df = 3 (P < 0.00001); l2 = 89% –4

73

Heterogeneity: Tau2 = 0.00; Chi2 = 2.98, df = 5 (P = 0.70); l2 = 0% Test for overall effect: Z = 4.84 (P < 0.00001)

IV, Random, 95% Cl

30.5% –1.50 [–2.00, –1.00]

Test for overall effect: Z = 1.89 (P = 0.06) Total events

Mean Difference

IV, Random, 95% Cl

–2

0

Favours [experimental] 0.05

0.2

1

5

2

4

Favours [control]

20

Favours [experimental] Favours [control]

Figure 2. Effect of perioperative lidocaine infusions on CPSP in all surgery types, CPSP, chronic postsurgical pain.

Figure 3. Effect of perioperative lidocaine infusions on pain intensity using the total score derived from the short-form McGill Pain Questionnaire.

• Figure 24.7  Effect of lidocaine infusion on incidence (left) and intensity (right) of chronic post-surgical pain. With permission from Bailey et al.32

TABLE 24.6

Meta-analyses of Pharmacologic Agents to Prevent Chronic Post-surgical Pain

Medication

Surgery

Odds Ratio (95% Confidence Interval)

Lidocaine

Breast

0.24 [0.08–0.69]

I2 = 0%

97

Any pain, three to six months

Weinstein 201831

Breast, thyroid, kidney

0.29 [0.18–0.48]

I2 = 0%

420

Three to six months

Bailey 201832

Amputation, breast, thoracic, orthopedics, abdomen/pelvis

0.50 [0.33–0.76]

I2 = 0%

516

Any pain, six months

Chapparo 201326

Amputation, breast, thoracic, orthopedics, hemorrhoid, mixed

0.84 [0.70–1.01]

I2 = 15%

771

Any pain, three to six months

McNicol 201492

breast, thyroid, cardiac, cesarean section, gyn, orthopedics, abdomen

0.52 [0.07–0.98]

I2 = 30.5%

356

Three to six months

Clarke 201294

Amputation, breast, thoracic, cardiac, cesarean section

0.97 [0.59–1.59]

I2 = 0%

280

Any pain, three months

Chapparo 201326

Cardiac, orthopedics

0.09 [0.02–0.79]

I2 = 0%

285

Three to six months

Clarke 201294

Orthopedics, cardiac, spine, thyroid

0.60 [0.39–0.93]

I2 = 28.5%

439

Any pain, three months

Chapparo 201326

Orthopedics, cardiac, spine, thyroid, thoracic, abdomen

0.87 [0.66–1.14]

I2 = 43%

1,884

Any pain, three months

Martinez 201795

Ketamine

Gabapentin

Pregabalin

outcome (if only 35% develop CPSP); thus many studies are underpowered. Studies employing screening to enrich preventive trials with patients at higher risk of CPSP are needed to confirm the efficacy of ketamine in preventing CPSP. Meanwhile, ketamine is also increasingly being used to treat already established chronic pain,89 including CPSP, although little is known about the efficacy and duration of the effect of such treatments. Other NMDA receptor antagonists, including dextromethorphan, magnesium, memantine, and nitrous oxide, have shown some benefit in acute postoperative pain, but their role in CPSP is largely unknown.26,79 A small randomized controlled trial showed that women treated with memantine had a modest reduction in pain (p  =  0.017) and reduced referral for postoperative neuropathic pain treatment (p = 0.040) three months after mastectomy.93

Heterogeneity

N

Pain Score and Followup (Months)

References

Gabapentinoids Gabapentinoids, including gabapentin and pregabalin, reduce pain by inhibiting the α2δ subunit of presynaptic voltage-gated calcium channels, which are upregulated after injury, forming a rational target for prevention.79 However, the clinical evidence for their potential to prevent CPSP is still mixed.26,94–96

Gabapentin Most clinical trials failed to demonstrate a reduction in the incidence of CPSP with gabapentin at three and six months. Although a meta-analysis by Clarke et al.94 (pooled data from eight studies) showed marginal benefit over placebo (OR 0.52 [0.27–0.98]), subsequent meta-analyses by Chaparro et al.26 (ten trials) and Verret et al.96 (27 trials for gabapentinoids, risk ratio, 0.89 [0.74–1.07])

CHAPTER 24  Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

did not support its preventive effect. Some studies with relatively high doses of gabapentin (1,200–1,800 mg/day) have suggested an analgesic effect, but these doses are associated with significant side effects such as sedation, dizziness, and visual trouble.79

Pregabalin The evidence for the preventive effect of pregabalin was also mixed. The early meta-analysis by Chapparo (five trials) and Clarke (three trials) appeared promising,26,94 with OR 0.60 [0.39–0.93] and OR 0.09 [0.02–0.79], respectively. However, several negative unpublished trials were not included, and subsequent additional negative studies contributed further evidence against a preventive effect.95,96 This included a meta-analysis of 18 trials in which pregabalin failed to demonstrate effectiveness in preventing CPSP (Table 24.6).95 Similar to gabapentin, pregabalin was also associated with significant sedation and decreased satisfaction.79

Other Pharmacologic Agents Peripheral and central sensitization involves the activation of inflammatory mediators and changes in the plasticity of multiple receptors along the pain pathway, with many corresponding potential pharmacologic targets aimed at preventing CPSP.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) The inflammatory state from surgery leads to upregulation of several mediators, including cyclooxygenase-2 (COX-2) and prostaglandins, which can drive both peripheral and central sensitization.97 COX inhibitors and classical NSAIDs help reduce the intensity of acute pain but still lack high quality clinical evidence showing as preventive for CPSP.79,98 α-2 Adrenergic Agonists The activation of α-2 adrenoceptors spinally results in analgesia and may show important synergism with spinal opioids. However, antagonism of these receptors outside of the spinal cord results in side effects, including sedation and reduction of sympathetic tone.99 The most commonly studied α-2 adrenoceptor agonists are clonidine and dexmedetomidine. One study showed that dexmedetomidine infusions during breast surgery reduced chronic pain intensity three months postoperatively.100 A few studies investigating systemic or neuraxial clonidine reported efficacy in preventing CPSP. However, these studies were small, preliminary, uncontrolled, and did not have CPSP as a primary outcome.79 Despite the potential of α-2 agonists for acute postoperative pain,101 evidence is currently too limited to draw a conclusion regarding the preventive effect of CPSP. Based on available data, there is very limited evidence on the preventive effects of CPSP available for other drugs, including mexiletine, acetaminophen, corticosteroids, and opioids.79,98 High-quality, well-controlled, enriched, and stratified studies are needed to confirm or refute the efficacy of these agents.

Regional Anesthesia Regional anesthesia (RA), including both peripheral nerve or neuraxial blocks, aims to inhibit nociceptive impulse transmission. Because RA reduces pain signals transmitted to the spinal cord and supraspinal and cortical nociceptive centers, it may also indirectly prevent glial cell activation and minimize the synaptic plasticity of neurons, thus decreasing central nervous system sensitization. Reduction of central sensitization with RA has been

343

demonstrated in several animal models in the acute phase.13 Local anesthetics may also have anti-inflammatory properties, which could also decrease sensitization. Animal models and in vitro studies have suggested that local anesthetics may reduce ectopic firing of neurons, expression of cytokines and other inflammatory mediators, and decrease neutrophil priming.13,30 When used in combination with other multimodal analgesics, RA serves as a potent tool that affects many targets along the pain pathway, as shown in Table 24.5. Beyond the theoretical and pre-clinical benefits, growing clinical evidence of the potential preventive impact of RA on CPSP is especially clear for breast and thoracic surgery. A meta-analysis by Weinstein et al.31 showed that a variety of regional anesthetic techniques, including epidural block, peripheral nerve block, and local infiltration, are associated with a lower risk of CPSP (Fig. 24.8). Subgroup analysis also showed independent preventive effects for breast surgery, thoracic surgery, and cesarean delivery (Table 24.7). Breast surgery has been the most widely studied surgical intervention for the impact of RA on CPSP. A meta-analysis31 showed an overall benefit for CPSP from local anesthetics in multiple modes of administration, including intravenous lidocaine, local infiltration, paravertebral block, and multimodal block (intercostal block, intercostobrachial nerve block) despite the high degree of heterogeneity (OR 0.43[0.28–0.68], p = 0.0003) (Table 24.7). Subgroup analyses also showed a preventive effect for paravertebral blocks and some promise of less common alternative approaches, including intercostal and pectoral nerve-2 (PECS 2) blocks.102,103 A preventive effect of RA for post-thoracotomy persistent pain has been shown in a meta-analysis that favor regional anesthesia (epidural analgesia, five studies; intercostal nerve block and wound irrigation, one study each) with an OR of 0.52 [0.32– 0.84] (p = 0.008).31 Epidural block showed the greatest preventive effect for CPSP, while other modalities, including continuous wound irrigation and intercostal nerve blocks, were less effective (Table 24.7).104,105 Nevertheless, this analysis did not include paravertebral blocks. Paravertebral blocks have been shown to provide efficacy equivalent to epidural blocks for the management of thoracic surgical pain, and paravertebral blocks may also reduce the incidence and/or intensity of CPSP.105–107 Overall, a reduction in CPSP after cesarean delivery is associated with RA use (transverse abdominis plane [TAP] blocks, intraperitoneal installation, or local infiltration) (OR 0.46 [0.28–0.78], p = 0.004) (Table 24.7).31 However, the number needed to treat to prevent one case of CPSP is much higher than mastectomy or thoracotomy (19 versus 7 and 7, respectively), mainly because of the lower incidence of CPSP after cesarean delivery. The role of RA in other surgical procedures, including limb amputation, cardiac surgery, laparotomy, hernia repair, prostatectomy, and hysterectomy, is informed by a smaller pool of randomized controlled studies available for review, supporting CPSP prevention by RA for these operations is less clear. A growing body of evidence regarding pharmacologic and interventional measures, such as RA, to prevent CPSP is welcome. However, while evidence is needed to inform clinical practice, the heterogeneity of design, definition, and methods makes the cogent interpretation of this evidence challenging. As the definition of CPSP is not universal (pain intensity and time after surgery), the estimated incidence in each study can vary considerably, from to 70%–80% in some studies, with more conservative estimates in the 20%–30% range. Although the performance of metaanalyses may abrogate this problem to some extent, the heterogeneity of studies in the pool often makes the results inconclusive.

344

PA RT 4 Clinical Conditions: Evaluation and Treatment

Favours regional Conventional Pain Control Odds Ratio Events Total Events Total Weight M.H, Random, 95% CI

Study or Subgroup

1.3.1 Paravertebral block Kairaluoma 2006 Ibarra 2011 Lee 2013 Karmakar 2014 Lam 2015 Oacio 2016 Subtotal (95% Cl)

2 5 9 35 4 3

30 15 25 117 18 32 237

10 7 11 21 5 7

30 14 26 60 18 34 182

4.3% 4.7% 6.0% 8.0% 4.6% 4.8% 32.5%

0.14 [0.03, 0.72] 0.50 [0.11, 2.24] 0.77 [0.25, 2.37] 0.79 [0.41, 1.54] 0.74 [0.16, 3.38] 0.40 [0.09, 1.70] 0.61 [0.39,0.97]

19 27 46

4.0% 5.3% 9.3%

0.15 [0.03, 0.83] 0.32 [0.08, 1.20] 0.24 [0.08, 0.69]

48 15 108 30 201

7.2% 4.0% 8.3% 4.3% 23.9%

1.03 [0.44, 2.40] 0.75 [0.14,4.17] 1.36 [0.76, 2.43] 0.12 [0.02, 0.62] 0.76 [0.32, 1.77]

22 21 24 30 60 30 187

4.2% 5.4% 6.1% 5.8% 7.2% 5.8% 34.4%

0.08 [0.01, 0.41] 0.32 [0.09, 1.17] 2.46 [0.80, 7.55] 0.20 [0.06, 0.66] 0.20 [0.09, 0.47] 0.20 [0.06, 0.66] 0.29 [0.12, 0.73]

616

100.0%

0.43 [0.28, 0.68]

Odds Ratio M.H, Random, 95% CI

Total events 58 61 Heterogeneity: Tau2 = 0.00; Chi2 = 4.32, df = 5 (P = 0.50); l2 = 0% Test for overall effect: Z = 2.10 (P = 0.04) 1.3.2 Intravenous lidocaine Grigoras 2012 2 17 9 Terkawi 2015b 4 34 8 Subtotal (95% Cl) 51 Total events 6 17 Heterogeneity: Tau2 = 0.00; Chi2 = 0.47, df = 1 (P = 0.49); l2 = 0% Test for overall effect: Z = 2.66 (P = 0.008) 1.3.3 Multimodal block Fassoulaki 2001 30 46 31 Micha 2012 3 14 4 Albi-Feldzer 2013 37 111 29 2 30 11 Tecirli 2014 201 Subtotal (95% Cl) Total events 72 75 Heterogeneity: Tau2 = 0.42; Chi2 = 7.73, df = 3 (P = 0.05); l2 = 61% Test for overall effect: Z = 0.64 (P = 0.52) 1.3.4 Local infiltration Fassoulaki 2000 Fassoulaki 2005 Baudry 2008 Strazisar 2012 Besic 2014 Strazisar 2014 Subtotal (95% Cl)

10 6 16 5 10 5

23 20 29 30 60 30 192

20 12 8 15 30 15

Total events 52 100 Heterogeneity: Tau2 = 0.92; Chi2 = 17.87, df = 5 (P = 0.003); l2 = 72% Test for overall effect: Z = 2.62 (P = 0.009) Total (95% Cl)

681

188 253 Total events Heterogeneity: Tau2 = 0.55; Chi2 = 46.20, df = 17 (P = 0.0002); l2 = 63% Test for overall effect: Z = 3.63 (P = 0.0003)

0.1

Test for subgroup differences: Chi2 = 4.83, df = 3 (P = 0.18), l2 = 37.9%

0.2 0.5 1 2 5 10 Favours regional Favours conventional

• Figure 24.8 

Forest plot and subgroup analysis of the effect of local anesthetics and regional anesthesia on postmastectomy pain at three to 12 months. With permission from Weinstein et al.31

TABLE 24.7

The Effect of Regional Anesthesia on Prevention of Chronic Post-surgical Pain in Mastectomy, Thoracotomy, and Cesarean Delivery Odds Ratio (95% Confidence Interval)

NNT (95% Confidence Interval)

Heterogeneity

N

Follow-Up (Month)

Paravertebral, nerve block, local infiltrate, intravenous lidocaine

0.43 (0.28–0.68)

7 (6–13)

I2 = 72%

1297

Three to 12 months

Paravertebral

0.61 (0.39–0.97)

NA

I2 = 0%

419

Three to 12 months

Thoracotomy

Epidural analgesia, intercostal block, wound irrigation

0.52 (0.32–0.84)

7 (4–23)

I2 = 14%

499

Three to 18 months

Cesarean section

TAP block*, intraperitoneal installation or local infiltration

0.46 (0.28–0.78)

19 (14–49)

I2 = 0%

551

Three to eight months

Surgery Mastectomy

Regional Anesthetic Technique

TAP block, Transversus abdominis plane block. With permission from Weinstein et al.31

CHAPTER 24  Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

As surgical techniques and instrumentation have improved over time, the degree of surgical extent may be quite different between studies over time (e.g. reduction in the performance of radical or even radical mastectomy in the case of breast cancer, although all surgeries were grouped together as breast surgery).

Surgical Technique Modification Surgical factors, including a greater degree of tissue or nerve injury, have been variably associated with increased incidence and severity of CPSP. Some evidence suggests that more minimally invasive surgical approaches may result in lower CPSP incidence, such as vaginal vs. abdominal hysterectomy, which is associated with a lower incidence of CPSP at all time points (Fig. 24.1).16 Laparoscopic inguinal hernia repair is associated with less acute and chronic post-surgical pain than open inguinal hernia repair.46–48 In breast cancer surgery, axillary lymph node dissection (ALND) is a consistent risk factor for CPSP across many studies and metaanalyses (compared to sentinel node biopsy or no axillary procedure).18,108 Injury of the intercostobrachial nerve (ICBN) has been cited as a likely mechanism of CPSP after ALND because the ICBN traverses the axillary lymph node bed. Studies showing preservation of the ICBN during ALND are associated with a reduced incidence109 and severity110 of CPSP, and less sensory deficit, without a significant increase in total surgery time.111 In other cases, the surgical extent appears to play a less important role. Patients who undergo breast-conserving surgery (lumpectomy) do not have lower rates of CPSP than patients undergoing total mastectomy, especially when measured at later time points (> one year).10 Less invasive surgery has also not consistently resulted in a lower incidence of CPSP in the case of thoracic surgery, especially at later time points. Compared to open thoracotomy, video-assisted thoracoscopic surgery is variably associated with a lower incidence of CPSP at six months,112,113 but similar incidence at one year.113 Laparoscopic cholecystectomy also tends toward reduced rates of moderate to severe CPSP, but overall laparoscopic and minimally invasive procedures versus open for cholecystectomy are associated with similar incidences of CPSP, with a similar result for colectomy.14 These modest effects of surgical modification underline the importance of considering other risk factors in the biopsychosocial model to understand and prevent CPSP.

Psychological Intervention Many psychological factors such as anxiety, depression, and pain catastrophizing are associated with a higher risk of CPSP. Psychological treatments such as cognitive-behavior therapy or acceptance and commitment therapy are associated with improved pain related outcomes in patients with chronic pain.34,114–117 Increasingly, these strategies are employed as a possible preventive measure in

345

the perioperative period, with some studies indicating that preoperative psychological interventions, such as brief acceptance-based psychological intervention,118 along with the routine pre-surgical protocol or pain education,119 can improve pain related outcomes, analgesic demand, anxiety,118 and pain intensity,119 in the acute postoperative period. However, the effect of these behavioral interventions on the prevention of CPSP remains largely unknown. Understanding an individual patient’s psychological profile may facilitate the rational application of behaviorally based preventive strategies. One study that stratified the results of a regional anesthetic based on whether patients scored higher or lower on a measure of pain catastrophizing suggested that RA (paravertebral block) provided analgesic benefit for mastectomy patients was more pronounced among patients with higher baseline catastrophizing scores.120 More research on the differential effect of traditional or non-traditional preventive interventions for CPSP among patients with different risk factors is needed to tailor treatment according to individual risk.

Future Directions CPSP is an active area of study, with much left to be understood, from understanding the underlying mechanisms to identifying the best preventive strategies. Having a consistent taxonomy, definition, and diagnostic criteria for CPSP is an important first step to better delineate its true incidence, temporal characteristics, and impact. Although evidence consistently shows a strong association between acute post-surgical pain and CPSP, and this risk factor dominates many of the prediction models developed up to this point, it is unclear whether acute pain should be considered a temporal correlate of chronic pain or a truly modifiable risk factor. Providing excellent control of acute postoperative pain is unquestionably an important goal in its own right, and thus proving causality may be challenging. Viewing CPSP through the lens of the biopsychosocial model, it seems clear that CPSP, like many types of chronic pain, is a complex reaction to the physical injury of surgery, which is influenced by biologic, psychological, social, and psychosocial factors. Comprehensive assessment of a wide range of putative factors from this biopsychosocial model, including pain sensitivity and psychological and genetic factors, may allow greater fidelity of risk assessment and specific preventive, personalized preventive strategies based on an individual’s profile.121 Long-term pain outcomes other than severity, including functional impairment and impact, and long term opioid use, should also be included in efficacy studies. Testing novel preventive measures, including psychological interventions, new pharmacologic agents, or combinations of multimodal analgesia, will continue to advance the capacity to prevent CPSP. Preoperative evaluation and consultation will continue to be essential to the design of preventive trials and clinical care planning.122

Summary CPSP has a high impact on a patient’s quality of life and is a common untoward consequence after surgery. CPSP is defined as pain developing or increasing in intensity after a surgical procedure and persisting beyond three months. Proposed mechanisms include nerve injury, peripheral and central neuroplasticity, and possibly OIH. As the type of operation and degree of tissue injury cannot solely explain the risk of CPSP, additional risk factors from the biopsychosocial model, including preexisting pain and pain

sensitivity, as well as contributing psychosocial factors, may allow for a more comprehensive explanation and prediction of CPSP. Clinical evidence regarding the efficacy of preventive measures has been mixed, but mainly positive for systemic lidocaine, ketamine, RA, and surgical technique modification for certain procedures. Although our understanding of CPSP has grown tremendously over the years, more studies are needed to understand this complex phenomenon.

346

PA RT 4 Clinical Conditions: Evaluation and Treatment

Key Points • CPSP is a relatively common consequence of surgery and may negatively impact patients’ quality of life. Effective prevention of CPSP is an important clinical goal, as informed by a growing body of studies. • CPSP is defined as chronic pain that develops or increases in severity after a surgical procedure, which persists beyond the healing process, typically at least three months or longer. CPSP is most commonly localized to the surgical field, but may also include pain within the innervation territory of a nerve affected by the surgery. Other causes must be excluded from the diagnosis of CPSP to be made. • The mechanism by which CPSP develops is not completely understood, but it likely includes nerve injury and neuroplasticity and may involve OIH. Preventive analgesia, opioid-sparing strategies, and modification of surgical techniques may modify the transmission of the nociceptive signal and subsequent maladaptive plasticity in the peripheral and central nervous systems. • Risk factors for CPSP may be categorized using the biopsychosocial model, ranging from biologic factors such as sur-

gical extent, genetics, age, sex, preexisting pain, and pain modulation, to psychological and social factors such as anxiety, depression, catastrophizing, coping strategies, and community support and resources. Recognizing and measuring these baseline factors may inform the assessment of CPSP risk. Some general and procedure-specific predictive models using some of these risk factors have been proposed to help stratify risk and tailor preventive measures. • Preventive measures may include minimally invasive surgery, aggressive acute postoperative pain control, and preventive analgesia. Several perioperative pharmacologic interventions such as ketamine, lidocaine infusion, and RA appear promising for the prevention of CPSP, although the evidence remains somewhat mixed. • Successful preventive treatment for CPSP likely depends on identifying the type of pain, recognizing the type of individual, and employing a multimodal, multi-disciplinary, and personalized approach to tailor treatments according to individual risk factors.

Suggested Readings

Partridge A, Pusic A, Golshan M, Edwards RR. Prediction of Persistent Pain Severity and Impact 12 Months After Breast Surgery Using Comprehensive Preoperative Assessment of Biopsychosocial Pain Modulators. Ann Surg Oncol. 2021 Jan 15. PMID: 33452600. Schug SA, Lavand’homme P, Barke A, Korwisi B, Rief W, Treede RD. The IASP classification of chronic pain for ICD-11: Chronic postsurgical or posttraumatic pain. Pain. 2019;160(1):45–52. Weinstein EJ, Levene JL, Cohen MS, et al. Local anesthetics and regional anesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children. Cochrane Database Syst Rev. 2018;4(4):CD007105. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306(5944):686–688.

Haroutiunian S, Nikolajsen L, Finnerup N, Jensen T. Neuropathic component in persistent postsurgical pain: A systematic literature review Pain. 2013;154(1):95–102. Katz J, Clarke H, Seltzer Z. Review article: Preventive analgesia: quo vadimus. Anesth Analg. 2011;113(5):1242–1253. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: Risk factors and prevention Lancet. 2006;367(9522):1618–1625. Mogil JS. Social modulation of and pain in humans and rodents Pain. 2015;156. Raja SN, Sivanesan E, Guan Y. Central sensitization, n-methyl-d-aspartate receptors, and human experimental pain models: Bridging the gap between target discovery and drug development. Anesthesiol. 2019;131(2):233–235. Schreiber KL, Zinboonyahgoon N, Flowers, KM, Hruschak, V, Fields, KG, Patton, ME, Schwartz, E, Azizoddin,D, Soens,M, King T,

The references for this chapter can be found at ExpertConsult.com.

References 1. Macrae W, Davies H. Chronic postsurgical pain. In: Crombie IK, Linton S, Croft P, Von Korff M, LeResche L (eds). Epidemiology of Pain. Seattle, WA: IASP Press; 1999. 2. Weiser TG, Haynes AB, Molina G, et al. Estimate of the global volume of surgery in 2012: An assessment supporting improved health outcomes. Lancet. 2015;385:S11 -S. 3. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: Risk factors and prevention. Lancet. 2006;367(9522):1618–1625. 4. IASP. Pain after surgery: 2017 global year against pain after surgery. Available at: https://www.iasp-pain.org/GlobalYear/AfterSurgery. 5. World Health Organization. ICD-11 coding tool. Available at: https://icd.who.int/ct11/icd11_mms/en/release. 6. Schug SA, Lavand’homme P, Barke A, Korwisi B, Rief W, Treede RD. The IASP classification of chronic pain for ICD-11: Chronic postsurgical or posttraumatic pain. Pain. 2019;160(1):45–52. 7. National Library of Medicine. PubMed.gov: Chronic postsurgical pain. Available at: https://pubmed.ncbi.nlm.nih.gov/?term=chronic +postsurgical+pain&filter=years.1975–2019. 8. Macrae WA. Chronic pain after surgery. Br J Anaesth. 2001;87(1): 88–98. 9. Werner MU, Kongsgaard UE. Defining persistent postsurgical pain: Is an update required? Br J Anaesth. 2014;113(1):1–4. 10. Schreiber KL, Martel MO, Shnol H, et al. Persistent pain in postmastectomy patients: Comparison of psychophysical, medical, surgical, and psychosocial characteristics between patients with and without pain. Pain. 2013;154(5):660–668. 11. Jung BF, Ahrendt GM, Oaklander AL, Dworkin RH. Neuropathic pain following breast cancer surgery: Proposed classification and research update. Pain. 2003;104(1):1–13. 12. Schug SA, Bruce J. Risk stratification for the development of chronic postsurgical pain. Pain. Rep. 2017;2(6):e627. 13. Crombie IK, Davies HT, Macrae WA. Cut and thrust: Antecedent surgery and trauma among patients attending a chronic pain clinic. Pain. 1998;76(1-2):167–171. 14. Fletcher D, Stamer UM, Pogatzki-Zahn E, et  al. Chronic postsurgical pain in Europe: An observational study. Eur J Anaesth. 2015;32(10):725–734. 15. Haroutiunian S, Nikolajsen L, Finnerup N, Jensen T. The neuropathic component in persistent postsurgical pain: A systematic literature review. Pain. 2013;154(1):95–102. 16. Montes A, Roca G, Sabate S, et  al. Genetic and clinical factors associated with chronic postsurgical pain after hernia repair, hysterectomy, and thoracotomy: A two-year multicenter cohort study. Anesthesiol. 2015;122(5):1123–1141. 17. Belfer I, Schreiber KL, Shaffer JR, et al. Persistent postmastectomy pain in breast cancer survivors: Analysis of clinical, demographic, and psychosocial factors. J Pain. 2013;14(10):1185–1195. 18. Schreiber KL, Zinboonyahgoon N, Flowers, KM, Hruschak, V, Fields, KG, Patton, ME, Schwartz, E, Azizoddin,D, Soens,M, King T, Partridge A, Pusic A, Golshan M, Edwards RR. Prediction of Persistent Pain Severity and Impact 12 Months After Breast Surgery Using Comprehensive Preoperative Assessment of Biopsychosocial Pain Modulators. Ann Surg Oncol. 2021 Jan 15. PMID: 33452600. 19. Miaskowski C, Cooper B, Paul SM, et al. Identification of patient subgroups and risk factors for persistent breast pain following breast cancer surgery. J Pain. 2012;13(12):1172–1187. 20. Zilles K. Neuronal plasticity as an adaptive property of the central nervous system. Ann Anatom. 1992;174(5):383–391. 21. Katz J, Seltzer ZE. Transition from acute to chronic postsurgical pain: Risk factors and protective factors. Expert Rev Neurother. 2009;9(5):723–744. 22. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest. 2010;120(11):3779–3787. 23. Ching YY, Wang C, Tay T, et  al. Altered sensory insular connectivity in chronic postsurgical pain patients. Front Hum Neurosci. 2018;12:483.

24. Raja SN, Sivanesan E, Guan Y. Central sensitization, n-methyl-daspartate receptors, and human experimental pain models: Bridging the gap between target discovery and drug development. Anesthesiol. 2019;131(2):233–235. 25. Martin E, Narjoz C, Decleves X, et  al. Dextromethorphan analgesia in a human experimental model of hyperalgesia. Anesthesiol. 2019;131(2):356–368. 26. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev. 2013;2013(7):Cd008307. 27. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306(5944):686–688. 28. Vadivelu N, Mitra S, Schermer E, Kodumudi V, Kaye AD, Urman RD. Preventive analgesia for postoperative pain control: A broader concept. Local Reg Anesth. 2014;7:17–22. 29. Katz J, Clarke H, Seltzer Z. Review article: Preventive analgesia: quo vadimus? Anesth Analg. 2011;113(5):1242–1253. 30. Perkins F, Franklin J. Prediction and prevention of persistent postsurgical pain. In: Practical Management of Pain. 5th ed. Philadelphia: Mosby; 2013, pp. 298–303. 31. Weinstein EJ, Levene JL, Cohen MS, et al. Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children. Cochrane Database Syst Rev. 2018(6). 32. Bailey M, Corcoran T, Schug S, Toner A. Perioperative lidocaine infusions for the prevention of chronic postsurgical pain: A systematic review and meta-analysis of efficacy and safety. Pain. 2018;159(9):1696. 33. Kissin I. Weiskopf Richard B. Preemptive analgesia. Anesthesiol. 2000;93(4):1138–1143. 34. Clarke H, Poon M, Weinrib A, Katznelson R, Wentlandt K, Katz J. Preventive analgesia and novel strategies for the prevention of chronic postsurgical pain. Drugs. 2015;75(4):339–351. 35. Woolf CJ, Ma Q. Nociceptors-noxious stimulus detectors. Neuron. 2007;55(3):353–364. 36. Simonnet G, Laboureyras E. Predisposing factors for chronic postsurgical pain. In: Chronic Postsurgical Pain. Paris: Springer; 2013. 37. Velayudhan A, Bellingham G, Morley-Forster P. Opioid-induced hyperalgesia. CEACCP. 2013;14(3):125–129. 38. Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia—when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet. 2019;393(10180):1558–1568. 39. Roeckel L-A, Le Coz G-M, Gavériaux-Ruff C, Simonin F. Opioidinduced hyperalgesia: Cellular and molecular mechanisms. Neurosci. 2016;338:160–182. 40. Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: A systematic review and a meta-analysis. Br J Anaesth. 2014;112(6):991–1004. 41. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schüttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiol. 2003;99(1):152–159. 42. Ohnesorge H, Feng Z, Zitta K, Steinfath M, Albrecht M, Bein B. Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice. PLoS One. 2013;8(11):e79567. 43. Mejdahl MK, Christensen KB, Andersen KG. Development and validation of a screening tool for surgery-specific neuropathic pain: Neuropathic pain scale for postsurgical patients. Pain Phys. 2019;22(2):E81–E90. 44. Dualé C, Ouchchane L, Schoeffler P, Dubray C. Neuropathic aspects of persistent postsurgical pain: A French multicenter survey with a 6-month prospective follow-up. J Pain. 2014;15(1): 24 e1-.e0. 45. Chen YK, Boden KA, Schreiber KL. The role of regional anaesthesia and multimodal analgesia in the prevention of chronic postoperative pain: A narrative review. Anaesthesia. 2021 Jan;76 Suppl 1:8-17. doi: 10.1111/anae.15256. PMID: 33426669 Review. 346.e1

346.e2

References

46. McCormack K, Scott NW, Go PM, Ross S, Grant AM. Laparoscopic techniques versus open techniques for inguinal hernia repair. Cochrane Database Syst Rev. 2003(1):Cd001785. 47. Schmedt CG, Sauerland S, Bittner R. Comparison of endoscopic procedures vs Lichtenstein and other open mesh techniques for inguinal hernia repair: A meta-analysis of randomized controlled trials. Surg Endosc. 2004;19(2):188–199. 48. Neumayer L, Giobbie-Hurder A, Jonasson O, et al. Open mesh versus laparoscopic mesh repair of inguinal hernia. New Eng J Med. 2004;350(18):1819–1827. 49. Callesen T, Bech K, Kehlet H. Prospective study of chronic pain after groin hernia repair. Br J Surg. 1999;86(12):1528–1531. 50. Wang L, Guyatt GH, Kennedy SA, et  al. Predictors of persistent pain after breast cancer surgery: A systematic review and meta-analysis of observational studies. CMAJ. 2016;188(14):E352–E361. 51. Tait RC, Zoberi K, Ferguson M, et al. Persistent post-mastectomy pain: Risk factors and current approaches to treatment. J Pain. 2018;19(12):1367–1383. 52. Yarnitsky D, Crispel Y, Eisenberg E, et  al. Prediction of chronic postoperative pain: Preoperative DNIC testing identifies patients at risk. Pain. 2008;138(1):22–28. 53. Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization in patients with painful knee osteoarthritis. Pain. 2010;149(3):573–581. 54. VanDenKerkhof EG, Peters ML, Bruce J. Chronic pain after surgery: Time for standardization? A framework to establish core risk factor and outcome domains for epidemiological studies. Clin J Pain. 2013;29(1):2–8. 55. Meretoja TJ, Andersen KG, Bruce J, et al. Clinical prediction model and tool for assessing risk of persistent pain after breast cancer surgery. J Clin Oncol. 2017;35(15):1660–1667. 56. Althaus A, Hinrichs-Rocker A, Chapman R, et al. Development of a risk index for the prediction of chronic postsurgical pain. Eur J Pain. 2012;16(6):901–910. 57. Lavand’homme P, Thienpont E. Pain after total knee arthroplasty: A narrative review focusing on the stratification of patients at risk for persistent pain. Bone Joint J. 2015;97-b(Suppl A):45–48 10. 58. VanDenKerkhof EG, Hopman WM, Goldstein DH, et al. Impact of perioperative pain intensity, pain qualities, and opioid use on chronic pain after surgery: A prospective cohort study. Reg Anesth Pain Med. 2012;37(1):19–27. 59. Hinrichs-Rocker A, Schulz K, Järvinen I, Lefering R, Siman ski C, Neugebauer EA. Psychosocial predictors and correlates for chronic post-surgical pain (CPSP)-a systematic review. Eur J Pain. 2009;13(7):719–730. 60. Miaskowski C, Paul SM, Cooper B, et al. Identification of patient subgroups and risk factors for persistent arm/shoulder pain following breast cancer surgery. Eur J Oncol Nurs. 2014;18(3):242–253. 61. Edwards RR, Mensing G, Cahalan C, et al. Alteration in pain modulation in women with persistent pain after lumpectomy: Influence of catastrophizing. J Pain. Symptom Manage. 2013;46(1):30–42. 62. Theunissen M, Peters ML, Bruce J, Gramke HF, Marcus MA. Preoperative anxiety and catastrophizing: A systematic review and meta-analysis of the association with chronic postsurgical pain. Clin J Pain. 2012;28(9):819–841. 63. Schreiber KL, Kehlet H, Belfer I, Edwards RR. Predicting, preventing and managing persistent pain after breast cancer surgery: The importance of psychosocial factors. Pain Manag. 2014;4(6):445–459. 64. Sullivan MJ, Thorn B, Haythornthwaite JA, et al. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain. 2001;17(1):52–64. 65. Cella D, Riley W, Stone A, et  al. The patient-reported outcomes measurement information system (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008. J Clin Epidemiol. 2010;63(11):1179–1194. 66. Durá E, Andreu Y, Galdón MJ, et al. Psychological assessment of patients with temporomandibular disorders: Confirmatory analysis of the dimensional structure of the brief symptoms inventory 18. J Psychosom Res. 2006;60(4):365–370.

67. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: Development and validation. Psychol Assess. 1995;7(4):524–532. 68. Núñez-Cortés R, Chamorro C, Ortega-Palavecinos M, et al. Social determinants associated to chronic pain after total knee arthroplasty. Int Orthop. 2019;43(12):2767–2771. 69. Davies KA, Silman AJ, Macfarlane GJ, et  al. The association between neighbourhood socioeconomic status and the onset of chronic widespread pain: Results from the EPIFUND study. Eur J Pain. 2008;13(6):635–640. 70. Grol-Prokopczyk H. Sociodemographic disparities in chronic pain, based on 12-year longitudinal data. Pain. 2017;158(2): 313–322. 71. Janevic MR, McLaughlin SJ, Heapy AA, Thacker C, Piette JD. Racial and socioeconomic disparities in disabling chronic pain: Findings from the health and retirement study. J Pain. 2017;18(12): 1459–1467. 72. Krahé C, Springer A, Weinman JA, Fotopoulou A. The social modulation of pain: Others as predictive signals of salience -a systematic review. Front Hum Neurosci. 2013;7:386. 73. Mogil JS. Social modulation of and by pain in humans and rodents. Pain. 2015:156. 74. Schreiber KL, Belfer I, Miaskowski C, Schumacher M, Stacey BR, Van De Ven T. AAAPT diagnostic criteria for acute pain following breast surgery. J Pain. 2020;21(3–4):294–305. 75. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131–157. 76. van Reij RRI, Joosten EAJ, van den Hoogen NJ. Dopaminergic neurotransmission and genetic variation in chronification of postsurgical pain. Br J Anaesthes. 2019;123(6):853–864. 77. Greenspan JD. Quantitative assessment of neuropathic pain. Curr Pain Headache Rep. 2001;5(2):107–113. 78. Gwilym SE, Oag HC, Tracey I, Carr AJ. Evidence that central sensitisation is present in patients with shoulder impingement syndrome and influences the outcome after surgery. J Bone Joint Surg Br. 2011;93(4):498–502. 79. Richebé P, Capdevila X, Rivat C. Persistent postsurgical pain: Pathophysiology and preventative pharmacologic considerations. Anesthesiol. 2018;129(3):590–607. 80. Koulouris AE, Edwards RR, Dorado K, et al. Reliability and validity of the Boston bedside quantitative sensory testing battery for neuropathic pain. Pain Med. 2020;21(10):2336–2347. 81. Cleeland C. Symptom assessment questionnaires: The brief pain inventory user’s guide 2009. Available at: https://www.mdanderson. org/research/departments-labs-institutes/departments-divisions/ symptom-research/symptom-assessment-tools.html. 82. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152(6):e170504. 83. Brummett CM, Moser SE, Nallamothu BK. Errors in analysis in study of new persistent opioid use after surgery. JAMA Surg. 2019;154(3):268–269. 84. Beloeil H, Sion B, Rousseau C, et  al. Early postoperative neuropathic pain assessed by the DN4 score predicts an increased risk of persistent postsurgical neuropathic pain. Eur J Anaesthesiol. 2017;34(10):652–657. 85. Montes A, Roca G, Cantillo J, Sabate S. Presurgical risk model for chronic postsurgical pain based on 6 clinical predictors: A prospective external validation. Pain. 2020;161(11):2611–2618. 86. Hermanns H, Hollmann MW, Stevens MF, et al. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: A narrative review. Br J Anaesth. 2019;123(3):335–349. 87. Reddi D, Curran N. Chronic pain after surgery: Pathophysiology, risk factors and prevention. Postgrad Med J. 2014;90(1062):222– 227 quiz 6.

References

88. Grigoras A, Lee P, Sattar F, Shorten G. Perioperative intravenous lidocaine decreases the incidence of persistent pain after breast surgery. Clin J Pain. 2012;28(7):567–572. 89. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):521– 546. 90. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44(3):293–299. 91. Klatt E, Zumbrunn T, Bandschapp O, Girard T, Ruppen W. Intra-and postoperative intravenous ketamine does not prevent chronic pain: A systematic review and meta-analysis. Scand J Pain. 2015;7(1):42–54. 92. McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent postsurgical pain. Acta Anaesthesiol Scand. 2014;58(10):1199–1213. 93. Morel V, Joly D, Villatte C, et al. Memantine before mastectomy prevents post-surgery pain: A randomized, blinded clinical trial in surgical patients. PLoS One. 2016;11(4):e0152741. 94. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: A combined systematic review and metaanalysis. Anesth Analg. 2012;115(2):428–442. 95. Martinez V, Pichard X, Fletcher D. Perioperative pregabalin administration does not prevent chronic postoperative pain: Systematic review with a meta-analysis of randomized trials. Pain. 2017;158(5):775–783. 96. Verret M, Lauzier F, Zarychanski R, et al. Perioperative use of gabapentinoids for the management of postoperative acute pain: A systematic review and meta-analysis. Anesthesiol. 2020;133(2):265–279. 97. Pak DJ, Yong RJ, Kaye AD, Urman RD. Chronification of pain: Mechanisms, current understanding, and clinical implications. Curr Pain Headache Rep. 2018;22(2):1–6. 98. Thapa P, Euasobhon P. Chronic postsurgical pain: Current evidence for prevention and management. Korean J Pain. 2018;31(3):155– 173. 99. Fairbanks CA, Stone LS, Kitto KF, Nguyen HO, Posthumus IJ, Wilcox GL. Alpha(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exper Ther. 2002;300(1):282–290. 100. Jain G, Bansal P, Ahmad B, Singh DK, Yadav G. Effect of the perioperative infusion of dexmedetomidine on chronic pain after breast surgery. Indian J Palliat Care. 2012;18(1):45–51. 101. Blaudszun G, Lysakowski C, Elia N, Tramèr MR. Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: Systematic review and meta-analysis of randomized controlled trials. Anesthesiol. 2012;116(6):1312–1322. 102. Al Ja’bari A, Robertson M, El-Boghdadly K, Albrecht E. A randomised controlled trial of the pectoral nerves-2 (PECS-2) block for radical mastectomy. Anaesth. 2019;74(10):1277–1281. 103. Fujii T, Shibata Y, Akane A, et  al. A randomised controlled trial of pectoral nerve-2 (PECS 2) block vs. serratus plane block for chronic pain after mastectomy. Anaesth. 2019;74(12):1558–1562. 104. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain. 1996;12(1):50–55.

346.e3

105. Liu FF, Liu XM, Liu XY, et al. Postoperative continuous wound infusion of ropivacaine has comparable analgesic effects and fewer complications as compared to traditional patient-controlled analgesia with sufentanil in patients undergoing non-cardiac thoracotomy. Int J Clin Exp Med. 2015;8(4):5438–5445. 106. Li XL, Zhang Y, Dai T, Wan L, Ding GN. The effects of preoperative single-dose thoracic paravertebral block on acute and chronic pain after thoracotomy: A randomized, controlled, double-blind trial. Med. 2018;97(24):e11181. 107. Yeung JH, Gates S, Naidu BV, Wilson MJ, Gao Smith F. Paravertebral block versus thoracic epidural for patients undergoing thoracotomy. Cochrane Database Syst Rev. 2016;2(2):Cd009121. 108. Wang L, Cohen JC, Devasenapathy N, et al. Prevalence and intensity of persistent postsurgical pain following breast cancer surgery: A systematic review and meta-analysis of observational studies. British journal of anaesthesia: BJA. 2020;125(3):346–357. 109. Taylor KO. Morbidity associated with axillary surgery for breast cancer. ANZ J Sug. 2004;74(5):314–317. 110. Maycock LA, Dillon P, Dixon JM. Morbidity related to intercostobrachial nerve damage following axillary surgery for breast cancer. Breast. 1998;7(4):209–212. 111. Torresan RZ, Cabello C, Conde DM, Brenelli HB. Impact of the preservation of the intercostobrachial nerve in axillary lymphadenectomy due to breast cancer. Breast J. 2003;9(5):389–392. 112. Bayman EO, Parekh KR, Keech J, Selte A, Brennan TJ. A prospective study of chronic pain after thoracic surgery. Anesthesiol. 2017;126(5):938–951. 113. Landreneau RJ, Mack MJ, Hazelrigg SR, et  al. Prevalence of chronic pain after pulmonary resection by thoracotomy or videoassisted thoracic surgery. J Thorac. Cardiovasc Surg. 1994;107(4): 1079–1086. 114. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: A meta-analytic review. Pain. 1992;49(2):221–230. 115. Morley S, Eccleston C, Williams A. Systematic review and metaanalysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain. 1999;80(1):1–13. 116. Vowles KE, McCracken LM. Acceptance and values-based action in chronic pain: A study of treatment effectiveness and process. J Consult Clin Psychol. 2008;76(3):397–407. 117. Wetherell JL, Afari N, Rutledge T, et  al. A randomized, controlled trial of acceptance and commitment therapy and cognitive-behavioral therapy for chronic pain. Pain. 2011;152(9): 2098–2107. 118. Fernández MD, Luciano C, Valdivia-Salas S. Impact of acceptancebased nursing intervention on postsurgical recovery: Preliminary findings. Span J Psychol. 2012;15(3):1361–1370. 119. Lin LY, Wang RH. Abdominal surgery, pain and anxiety: Preoperative nursing intervention. J Adv Nurs. 2005;51(3):252–260. 120. Zinboonyahgoon N, Vlassakov K, Lirk P, et al. Benefit of regional anaesthesia on postoperative pain following mastectomy: The influence of catastrophising. Br J Anaesth. 2019;123(2):e293– e302. 121. Zinboonyahgoon N, Patton ME, Chen YK, Edwards RR, Schreiber KL. Persistent Post-Mastectomy Pain: The Impact of Regional Anesthesia Among Patients with High vs Low Baseline Catastrophizing. Pain Med. 2021;22(8):1767–1775. doi: 10.1093/ pm/pnab039. PMID: 33560352. 122. Kalso EIV. Persistent post-surgery pain: Research agenda for mechanisms, prevention, and treatment. Br J Anaesth. 2013;111(1):9–12.

25

Evaluation and Pharmacologic Treatment of Postoperative Pain

LAUREN K. DUNN, PRIYANKA SINGLA

Pain after a surgical procedure is inevitable. However, as stated by Haruki Murakami, “Suffering is optional.” Management of postoperative pain has come a full circle. The Joint Commission recognized the underassessment and undertreatment of pain in 2000 and introduced the concept of pain as the fifth vital sign.1 However, the emphasis of The Joint Commission on the use of opioids for pain control has been criticized as a contributing factor in the prescription opioid epidemic that the modern world is facing.2 Enhanced recovery pathways involving multimodal analgesia with emphasis on limiting opioids have become the cornerstone of managing pain in the postoperative setting. A majority of patients who undergo surgery report inadequate pain control.3 Causes of ineffective pain control include lack of accurate assessment and patient factors such as fear of adverse effects or addiction from medications.4 Poorly controlled pain increases the incidence of postoperative complications such as pneumonia, delirium, delayed wound healing, and evolution of acute pain into chronic pain,5,6 while optimal pain control improves patient satisfaction and enhances the quality of recovery.4,7 Pain management is an important ethical responsibility of every clinician. Adequate pain control requires finesse to find the delicate balance between minimizing immediate adverse effects and preventing long term dependence on opioids. Many institutions have developed standardized guidelines for perioperative analgesia in the form of enhanced recovery after surgery (ERAS) protocols. The acute pain service is an integral part of most anesthesiology departments, with a focus on providing optimal pain management in the postoperative period. Assessment and management of pain in opioid dependent patients and pain in children are beyond the scope of this chapter and are discussed in Chapters 27 and 28, respectively. Management of postoperative pain starts with an accurate assessment. Guidelines from the American Pain Society recommend that “clinicians use a validated pain assessment tool to track responses to postoperative pain treatments and adjust treatment plans accordingly.”3 Effective pain management takes into account the surgical procedure performed and individual patient factors such as comorbidities and the use of preoperative narcotics.3 The goal of pain assessment is to determine the analgesic requirements of the patient and if there is a need to change the treatment plan.3 Evaluation of pain can be extremely challenging as pain is largely subjective.4,8 There are multiple evaluation tools available for postoperative pain assessment. However, most require patient

participation, which can be difficult in the immediate postoperative period when the patient is still emerging out of anesthesia. Comprehensive postoperative pain assessment includes several components. Although severity is the most easily quantifiable measure, attention should be paid to other characteristics of pain, including location, quality, onset, progression, radiation, aggravating and relieving factors, and effects of therapy.3 Pain symptoms that are at an inappropriate site or of unexpected severity based on the surgical procedure performed should be investigated for causes other than the surgery itself.3,4 Unexpectedly high pain can be because of opioid tolerance, anxiety, a new medical problem unrelated to surgery, or a potential complication from the surgery itself.3

Evaluation of Pain Using Pain Scales Numerous self-reported pain scales have been developed to quantify the severity of pain (Table 25.1). Among the most frequently used scales are: Visual Analog Scale (VAS) Numeric Rating Scale (NRS) Verbal Rating Scale (VRS)

Visual Analog Scale VAS is measured by drawing a 10 cm or 100 mm straight line. This line is anchored at each end by a perpendicular line that represents two extremes of pain—no pain on the left end and most intense pain imaginable on the right end. The patient is asked to make a mark at a point on the line, which represents the patient’s level of perceived pain intensity, and the scale is scored by measuring the distance from the end with no pain to the patient’s mark.9–12 The line may be depicted with a horizontal or vertical orientation, though a horizontal line is generally preferred.10 The VAS has often been recommended as the measure of choice for assessment of pain intensity.10 It has been suggested that a single VAS score is probably not the most accurate measure of a patient’s pain but is probably within the range of +/–20 mm.13 A change of 10 mm out of 100 mm pain VAS is considered the minimal clinically important difference, i.e. the minimal change in a pain VAS score that would indicate a significant change in a patient’s pain intensity, and the VAS of 33 or less signifies acceptable pain control after surgery.14,15 VAS is sensitive to treatment effects10 and shows ratio level scoring properties.10,16 The reliability of VAS depends on the patient’s 347

348

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 25.1

Commonly Used Scales for Postoperative Assessment of Pain

Pain Scale

Range

Advantage

Disadvantage

Visual Analog Scale

0–10 (cm) 0–100 (mm)

Sensitive to treatment effect Shows ratio level scoring property

Requires visual motor coordination from the patient

Numeric Rating Scale

0–5(6) 0–10(11) 0–20(21) 0–100(101)

Verbally scored Easy to administer High compliance Sensitive to treatment effect

Lacks ratio level scoring property

Verbal Rating Scale

No pain to most intense pain

Easy to understand Better compliance in elderly

Requires patient familiarity with adjectives Interval between adjectives not equal

ability to place a mark at the intended spot and requires visual and motor coordination.11 VAS may be challenging to obtain in patients with cognitive impairment,10 and freedom of choice provided by VAS could be confusing for some patients.12 VAS shows a good correlation with NRS in patients with arthritis.12 However, its usefulness may be limited in the immediate postoperative period, especially in phase 1 of recovery when the patient may have residual effects of anesthesia, blurred vision, or nausea.13 Nonetheless, it is a simple, useful, and valid tool to assess and reassess a patient’s pain and response to therapy if the problems intrinsic to the score itself are considered.13

Numerical Rating Scale NRS consists of a numeric scale ranging from 0 to 10, 0 to 20, or 0 to 100.3,9,10,17,18 Zero represents no pain, whereas the higher end (10, 20, or 100) represents the most intense pain. NRS can be administered verbally or in a written format.10,17 When presented graphically, the numbers are often enclosed in boxes, and the scale is referred to as an 11 or 21-point box scale depending on the number of levels of discrimination offered to the patient.17 Its advantages include that it is simple, easily understood by the patient, and is easily administered and scored by the caregiver.10 It is a valid tool with a high compliance rate and good consistency over time, which correlates positively with other measures of pain and shows sensitivity to treatments.8,10 The principal limitation of NRS is that it does not have ratio qualities, implying that the difference between two and four and the difference between four and six may not represent equivalent intervals in terms of scaling of the intensity of pain.10 Its major advantage over VAS is that it can be used in patients with visual impairment by recording verbal responses.17 One author has described the successful use of a six-point NRS (0-5) during the postoperative period in patients with dementia.17 The six-point NRS is a simplified version of NRS 11.17 It was reported to be reliable, valid, and much easier to administer in patients with dementia.17 The 100 mm VAS and NRS 11 are the most commonly used scales for postoperative pain assessment.14 A limitation of both scores is that the definition of worst imaginable pain differs among individuals.10 This can be taken care of by providing the patient with some context of the worst imaginable pain.

Verbal Rating Scale The VRS comprises a list of adjectives that describe increasing levels of pain.9,18 The most common words used are no pain, mild pain, moderate pain, and severe or intense pain.18 To simplify the documentation, each adjective is assigned a number. The least intensity (no pain) is assigned the number 0, with subsequent intensity assigned one number higher.9,18 The strengths of VRS include its simplicity, ease of administration, and scoring.10 It is straightforward for patients to comprehend, which is important in the very early postoperative period and is most easily understood by patients with cognitive impairment.19,20 VRS has much superior compliance rates in the elderly than other scales.10 One of the pitfalls of this scale is that the interval between each adjective is not equal.18 Also, the patient must be familiar with words used to describe the pain and should be able to choose the one that describes his/her pain accurately.10

Clinical Evaluation of Pain Along with self-reporting of pain, patients should be observed for clinical signs of distress that include:8 • facial expression of pain, such as grimacing; • audible expression of pain, such as moaning or crying; • ambulation in the form of limping or posture, e.g. lying in a fetal position; and • avoidance of activities or specific movements. Assessment tools such as the behavioral pain scale (BPS) and critical-care pain observation tool (CPOT) can help clinicians assess pain control in patients with cognitive impairment or sedation.3,21 The CPOT has four components22,23—facial expression, body movements, resistance to passive flexion, and compliance to the ventilator in intubated patients or vocalization in extubated patients. The scale is scored from zero to eight, with zero being no pain and eight being maximum possible pain (Table 25.2).23 The BPS has three components—facial expression, upper limb movements, and compliance with mechanical ventilation, scored on a scale of one to four.23–25 BPS scores range from three (no pain) to 12 (maximum pain) (Table 25.3).23 Both scales are used routinely in the intensive care unit to assess pain in intubated and sedated patients. Increases in heart rate and blood pressure have been suggested as sympathetic responses to noxious stimuli. However, caution must be used when interpreting changes in these vital signs that may also be influenced by other factors, such as postoperative use of vasopressors and inotropes. Behavioral and physiologic indicators are especially important indices for the assessment of pain in patients who are unable to self-report.22

Functional Assessment of Pain Another objective way to access pain is to ascertain the extent to which pain interferes with functional ability after surgery.4 It may vary with the type of surgery performed. Some examples include taking a deep breath and performing incentive spirometry after abdominal surgery, participating in physical therapy after musculoskeletal or spine surgery, or swallowing after tonsillectomy.3,4 NRS 11 can be used to assess the impact of pain on functional ability with similar anchors as pain (0= does not interfere, 10= completely interfere).8 However, objective measures should not be used as the sole criterion for assessing pain in patients who can participate in assessment as there is marked interindividual variability in pain behaviors at a similar level of pain.3

 

CHAPTER 25

TABLE 25.2

Evaluation and Pharmacologic Treatment of Postoperative Pain

349

Critical-Care Pain Observation Tool (CPOT)23

Component

Description

Score

Facial expression

No muscular tension observed

Relaxed 0

Presence of frowning, brow lowering, orbit tightening, and levator contraction

Tense 1

All of the above facial movements plus eyelid tightly closed

Grimacing 2

Does not move at all

Absence of movements 0

Slow, cautious movements; touching or rubbing the pain site; seeking attention through movements

Protection 1

Pulling tube, attempting to sit up, moving limbs/thrashing, not following commands, striking at staff, trying to climb out of bed

Restlessness 2

No resistance to passive movements

Relaxed 0

Resistance to passive movements

Tense, rigid 1

Strong resistance to passive movements, inability to complete them

Very tense, rigid 2

Alarms not activated, easy ventilation

Tolerating ventilator or movement 0

Tolerating ventilator or movement

Coughing but tolerating 1

Asynchrony: blocking ventilation, alarms frequently activated

Fighting ventilator 2

Body movements

Muscle tension evaluation by passive flexion and extension of upper extremities Compliance with ventilator

Total zero to eight, with zero being no pain and eight being maximum possible pain. Adapted from Rijkenberg S, Stilma W, Bosman RJ, van der Meer NJ, van der Voort PHJ. Pain measurement in mechanically ventilated patients after cardiac surgery: comparison of the behavioral pain scale (BPS) and the critical-care pain observation tool (CPOT). J Cardiothorac Vasc Anesth. 2017;31(4):1227–1234.

TABLE 25.3

Behavioral Pain Scale (BPS)23

Component

Assessment

Compliance with mechanical ventilation

Tolerating movement

1

Coughing but tolerating ventilation most of the time

2

Fighting ventilator

3

Unable to control ventilation

4

Relaxed

1

Partially tightened

2

Fully tightened

3

Grimacing

4

Pharmacologic Treatment of Pain

No movement

1

Partially bent

2

Fully bent with finger flexion

3

Permanently retracted

4

Pharmacologic treatment of postoperative pain has traditionally favored the use of opioids as the primary analgesic treatment. However, with the growing realization of the adverse effects of opioids, including nausea, vomiting, constipation, urinary retention, respiratory depression, sedation,28 and risk for opioid dependence,3 the practice is slowly changing to optimize the use of non-opioid medications first. The ideal treatment of postoperative pain involves the use of multimodal analgesia regimens. Multimodal analgesia is defined as using multiple analgesic agents and techniques that act in a synergistic or additive manner.3 The multimodal approach aims to target multiple different pain receptors within both the central and peripheral nervous systems to provide maximal pain relief and minimize adverse effects.3 Multimodal analgesia is discussed in depth in Chapter 26. Many enhanced recovery (ERAS) protocols

Facial expression

Upper limb movements

Score

patient can be evaluated better by trending pain scores on a graph instead of looking at individual numbers.19 The effectiveness and adverse effects of analgesic medications should be evaluated at frequent intervals, and appropriate adjustments should be made to the regimen for each patient.3 Pharmacokinetic principles such as route of administration and time to achieve peak analgesic effect should be kept in mind when evaluating the response to medications. Most oral analgesics require 1 to 2 h to reach peak effect, whereas for analgesics administered parenterally, it is 15 to 30 min.3 An important part of the evaluation is a documented follow-up assessment to note the efficacy of the therapy and the patient’s satisfaction with it.3,4 Pain should be assessed at rest and with activity. The goal should be optimum pain control with activity, which is often more difficult to achieve.3,19,26,27

BPS scores range from 3 (no pain) to 12 (maximum pain). Adapted from Rijkenberg S, Stilma W, Bosman RJ, van der Meer NJ, van der Voort PHJ. Pain measurement in mechanically ventilated patients after cardiac surgery: comparison of the behavioral pain scale (BPS) and the critical-care pain observation tool (CPOT). J Cardiothorac Vasc Anesth. 2017;31(4):1227–1234.

Assessment of pain requires frequent reassessment, guided by response to therapy and the type of surgical procedure.3 It has been suggested that the progress of pain relief of an individual

350

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 25.4

Systemic Opioid and Nonopioid Analgesic Options

Agent

Delivery

Analgesic Ceiling

Opioids

PO, IV PCA, IM

Acetaminophen

Side Effects

Comments

No

Induced hyperalgesia, nausea, vomiting, sedation, respiratory depression, pruritus, constipation, urinary retention

Side effects limit full their analgesic potential

PO, IV

Yes

Hepatotoxicity

Coadministration with opioids appears to provide opioid-sparing analgesia but may not reduce opioid-related side effects

NSAIDs

PO, IV, IM

Yes

Renal, GI, platelet inhibition, inhibition of bone healing, inhibition of osteogenesis, cardiovascular

Coadministration with opioids appears to provide opioid-sparing analgesia but may not reduce opioid-related side effects

COX-2 inhibitors

PO

Yes

Renal, cardiovascular, inhibition of bone healing, inhibition of osteogenesis

Coadministration with opioids appears to provide opioid-sparing analgesia but may not reduce opioid-related side effects

Ketamine (low dose)

IV

Yes

No cognitive impairments or psychotomimetic effects are seen with dosing of 0.25 mg/kg

May attenuate both postoperative pain and chronic pain; may attenuate opioidinduced hyperalgesia

Gabapentin and pregabalin

PO

Unknown

Dizziness, somnolence, ataxia, memory impairment, weight gain, edema, altered vision

May be useful for acute analgesia and chronic antihyperalgesia, pending further study

COX, Cyclooxygenase; IM, intramuscular; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; PCA, patient-controlled analgesia; PO, per oral. (printed with permission from Hanna MN et al. In: H Benzon et al. (eds) Practical management of pain, 5th edition. Philadelphia: Elsevier, 2014, pp. 271–297).

incorporated multimodal analgesia to minimize opioid use and facilitate pain control and recovery. Recently, the American Pain Society published updated guidelines for the management of postoperative pain.3 These guidelines provide the reference for clinicians treating postoperative pain to devise a plan, individualized based on patient’s expectations, comorbidities, and the surgical procedure. Pharmacotherapy for pain can be broadly divided into opioid and non-opioid medications (Table 25.4). Non-opioid pain medications should be the first line of treatment for postoperative pain. It is a heterogeneous group of medications with a diverse mechanism of actions and includes: • Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen • Local anesthetic agents: lidocaine • Ketamine • Gabapentin, pregabalin • Alpha two agonists

Acetaminophen and Non-steroidal Anti-inflammatory Drugs Acetaminophen (Paracetamol) is an integral part of any multimodal analgesia regimen. It is the most commonly prescribed analgesic for the treatment of acute pain.29 Its mechanism of action is not precisely understood. It has been found to cross the blood-brain barrier.30 There are several possible explanations for its mechanism, including inhibition of central prostaglandin synthesis,29–33 inhibition of central nitric oxide generation via inhibition of N‐methyl‐d‐aspartat (NMDA) e or substance P,29,34 activation of descending serotonergic pathways, and inhibiting the uptake of endocannabinoids from the extracellular space.29,31,35,36

It can be administered orally, rectally, or intravenously (IV). The peak acetaminophen plasma concentration occurs 3 to 4 h after a rectal dose, 45 to 60 min after an oral dose, and 15 min after IV infusion.37–39 IV paracetamol may be more than suitable in patients in whom faster onset is desirable and oral route is not available.29 However, the cost of the IV formulation may be a limiting factor as well as its availability. The dosage for oral and IV acetaminophen in adults is 1 gram every 4 to 6 h, not to exceed 4 grams in a 24 h period. Once the patient can tolerate oral drugs, oral acetaminophen can be scheduled every 4–6 h to ensure therapeutic plasma levels. Acetaminophen can be administered rectally as an alternative to the oral route. However, its main disadvantage is unpredictable bioavailability.40,41 Acetaminophen is metabolized in the liver and excreted by the kidney. The dose interval should be at least 6 h in patients with renal insufficiency (creatinine clearance 70 or creatinine clearance < 30 mL/min)b Fentanyl 25 mcg IV prn or hydromorphone 0.2 mg IV prn for pain score> four Oxycodone 5–10 mg PO every 4 hours prn and/or hydromorphone 1–2 mg PO every 4 hours prn when taking oral medications Ketamine 10 mg IV every 5 minutes for severe pain (7–10) and consideration of initiating ketamine infusion 0.1–0.3 mg/kg/h for persistent severe postoperative pain There is currently weak evidence for preoperative caffeine. Source: Hampl et  al. Perioperative administration of caffeine tablets for the prevention of postoperative headaches.  Can J Anaesth. 1995;42(9):789–792.

a

b

Careful patient selection for NSAID therapy is warranted; in certain patient populations undergoing colorectal surgery (e.g. Crohn’s disease and ulcerative colitis), NSAIDs may be contraindicated.

PO, Mouth; IV, intravenous; PCA, patient-controlled analgesia; prn, as needed; GFR, glomerular filtration rate; PNB, peripheral nerve blockade. A sample multimodal pathway adapted from Panchamia et al. A 3-arm randomized clinical trial comparing interscalene blockade techniques with local infiltration analgesia for total shoulder arthroplasty. J Shoulder Elbow Surg. 2019;28(10):e325-e338.

Regional Anesthesia Techniques

Spinal Analgesia

The aforementioned ERAS pathways and the regional anesthetic techniques described below should be tailored to the individual patient while keeping in mind the surgical type, side effects of the individual medications, and the patient’s comorbidities.35 The regional anesthetic blocks described below include neuraxial regional techniques as well as peripheral/perineural nerve blocks commonly performed in the perioperative setting and may serve as rescue blocks for postoperative pain management in the wards and beyond. The goal of this section is not to provide a comprehensive list but instead provide examples of common regional anesthetic blocks and to appraise the evidence in the literature for their analgesic efficacy in the perioperative setting.

While intrathecal local anesthetic administration is often used as the primary anesthetic for many surgeries (e.g. cesarean deliveries, certain abdominal procedures) instead of general anesthesia, the focus of this section will be on intrathecal medications for postoperative analgesia only. Intrathecal opioids are potent, centrally acting analgesic drugs and are commonly administered to provide intraoperative and postoperative analgesia. When administering neuraxial opioids, it is important to consider the lipophilic properties of opioids. Studies have demonstrated that the liposolubility of intrathecal opioids is inversely proportional to spinal selectivity and spinal-mediated analgesia, which is higher for hydrophilic opioids than for other more lipophilic opioids.41 While all opioids administered intrathecally produce some degree of spinal-mediated analgesia, hydrophilic opioids provide primarily spinal-mediated analgesia, while lipophilic opioids tend to provide analgesia via either a spinal or systemic mechanism.42 Hydrophilic opioids, including morphine and hydromorphone, remain in the cerebrospinal fluid (CSF) for a long duration and can produce a delayed but longer duration of analgesia. Because of this property, hydrophilic opioids may have a higher incidence of delayed respiratory depression because of greater CSF spread.43 Intrathecal morphine may lead to severe respiratory depression lasting up to 24 hours.43 The respiratory

Neuraxial Analgesia Generally, neuraxial techniques provide better analgesia than systemic opioids and have the advantage of decreasing adverse perioperative pathophysiology (e.g. stress response) while improving patient outcomes. For instance, continuous epidural infusion has been shown to be associated with decreased pulmonary,36 cardiovascular,37–39 and gastrointestinal40 complications in high-risk patients after high-risk procedures. Below, we describe the spinal (intrathecal), epidural, and caudal anesthesia techniques.

 

CHAPTER 26

Regional and Multimodal Treatments of Perioperative Pain

359

TABLE Enhanced Recovery Pathway for Colorectal Surgery 26.3 Preoperative Fluid and carbohydrate loading,a and avoidance of prolonged fasting Caffeine 200 mg PO if the patient reports regular caffeine intake Antibiotic prophylaxis Thromboprophylaxis Acetaminophen (paracetamol) 1000 mg PO Celecoxib 200–400 mg PO (adjusted for age, creatinine clearance, and weight) Consider granisetron 1 mg IV or scopolamine patch if the patient reports a history of severe PONV Intraoperative Administration of short-acting anesthetic agents (e.g. fentanyl IV or remifentanil IV) Utilization of regional anesthetic techniques (may consider neuraxial analgesia, liposomal bupivacaine wound infiltration, and various truncal blocks such as TAP blocks and rectus abdominis sheath block) Avoidance of excessive fluid administration Maintenance of normothermia Re-dose Acetaminophen (paracetamol) 1000 IV if 6 hours since preoperative dose Ketorolac 7.5–15 mg IV (adjusted for age, creatinine clearance, and weight) at skin closure; avoid if age > 70 or creatinine clearance < 30 mL/min) Avoidance of surgical drain placement PONV prophylaxis: dexamethasone 4–8 mg IV at induction, ondansetron 4 mg IV at the end of the case (if the patient has two or more PONV risk factors,b consider the addition of droperidol 0.625 mg IV or promethazine 12.5 mg IV or haloperidol 1–2 mg IV at the end of the case) Postoperative Maintenance of continuous regional anesthetic technique (e.g. epidural catheter) Early removal of urinary catheter Early oral nutrition Bowel regimen and agents to promote stimulation of gut mobility Early mobilization Use of non-opioid analgesics: Re-dose acetaminophen (paracetamol) 1000 IV every 6 hours until the patient starts taking oral medications Re-dose ketorolac 7.5–15 mg IV every 6 hours up (up to five doses maximum; adjusted for age, creatinine clearance, and weight) at skin closure; avoid if age > 70 or creatinine clearance < 30 mL/min) Oxycodone 5–10 mg PO every 4 hours prn when taking oral medications a

Source describing evidence on preoperative carbohydrate loading. Bilku et al. Role of preoperative carbohydrate loading: a systematic review. Ann R Coll Surg Engl. 2014;96(1):15–22.

b

PONV risk factors include female sex, young to middle age, history of PONV or motion sickness, and non-smoking status.

PO, Mouth; IV, intravenous; PCA, patient-controlled analgesia; prn, as needed; PONV, postoperative nausea, and vomiting; TAP, transversus abdominis plane.

depression after intrathecal morphine administration usually follows a biphasic pattern with an initial onset in the first 1–3 hours and a late-onset at 6–12 hours because of their hydrophilic nature and cephalad spread.43 On the other hand, lipophilic opioids, such as fentanyl and sufentanil, have a faster onset of action but a shorter duration of analgesia because of more rapid diffusion from CSF.41 Common side effects of all intrathecal opioids include pruritus in up to 60% of patients,44,45 nausea and vomiting in over 50% of patients,46 and urinary retention in up to 80% of patients.47 There is limited evidence on the use of other intrathecal medications for postoperative pain control, including α-2-agonists,48 steroids,49 and neostigmine.50 A randomized clinical study by

Sarma and colleagues showed that a low dose of intrathecal dexmedetomidine or clonidine with bupivacaine produced a shorter onset and longer duration of motor and sensory blockade than bupivacaine alone in lower limb surgeries.48 Another prospective, double-blind study51 showed that intrathecal dexmedetomidine with bupivacaine provided earlier onset of sensory and motor block, longer duration of analgesia, and preserved hemodynamic stability compared to bupivacaine alone in infraumbilical surgeries. Of all adjuvants for neuraxial analgesia, only clonidine is approved by the FDA.52 Future well-designed randomized controlled trials (RCTs) assessing postoperative analgesia with intrathecal adjuvant medications are warranted.

360

PA RT 4 Clinical Conditions: Evaluation and Treatment

In summary, intrathecal administration of lipophilic opioids produces short-term analgesia for approximately 1–4 hours and may be helpful for immediate postoperative pain. Although hydrophilic intrathecal opioids provide longer duration analgesia (for up to 24 hours) useful for more invasive and painful surgeries, we recommend that it be limited to patients expected to remain hospitalized in an appropriately monitored setting for at least one postoperative day.

Epidural Analgesia Continuous epidural analgesia offers postoperative pain management for a longer duration than a single injection spinal injection and analgesia superior to systemic opioids.53 In terms of pharmacokinetics, medications placed in the epidural space must cross the dura prior to reaching the spinal cord.54 In addition, because of the high vascularity of the epidural space, there may be a significant redistribution of epidural medications into the systemic circulation.54 Furthermore, the presence of epidural fat may serve as a repository for lipophilic drugs.54 Notably, compared to the intrathecal space, significantly larger amounts of medication need to be delivered via the epidural route to obtain equivalent analgesic efficacy because diffusion of drugs across the dura is concentration and time dependent.54 This pharmacokinetic concept is complex and involves inherent drug properties, primarily lipophilicity. For instance, lipophilic opioids (fentanyl and sufentanil) readily cross the dura to reach spinal cord receptors, whereas hydrophilic opioids (morphine) would cross the dura more slowly; thus when calculating the epidural dose for a medication that is equianalgesic to the intrathecal route, a higher epidural dose would be required for hydrophilic medications than for lipophilic medications. As a general rule of thumb, 10 mg of epidural morphine (hydrophilic opioid) would be equianalgesic to 0.1 mg of intrathecal morphine (10:1 ratio), whereas 33 mcg of epidural fentanyl would be equianalgesic to 6–10 mcg of intrathecal fentanyl (5:1 to 3:1 ratio).55 However, further well-designed dosing studies are warranted to validate these findings. Typically, epidural local anesthesia with or without opioids offers better physiologic benefits after most surgeries than opioids alone and may decrease opioid-related side effects. The choice of local anesthetic may vary based on provider preference, but a local anesthetic with a longer duration of action with preferential sensory blockade and limited motor blockade is preferable for postoperative analgesia.56 However, in certain circumstances, such as persistent hypotension, epidural opioids alone may be more advantageous because of sympathectomy often associated with epidural local anesthetic. When initiating epidural analgesia, small epidural bolus doses (5–10 mL) are usually administered first over a short period of 5–10 minutes to achieve an adequate depth of analgesia prior to initiating a continuous epidural infusion rate that can be titrated to effect. Furthermore, different delivery modes of epidural analgesia may be instituted, including fixed continuous infusion or patient-controlled epidural analgesia (PCEA). Similar to intravenous patient-controlled analgesia (PCA), PCEA allows analgesic requirements to be individualized to the needs of the patient and improves patient satisfaction.57,58 Various combination settings may be employed, including continuous epidural infusion rate with PCEA together or a programmed intermittent epidural bolus technique with PCEA.

Similar to the intrathecal route, there is limited evidence of certain epidurally delivered adjuvant medications. Clonidine may provide analgesia via the epidural route by activating the descending noradrenergic pathway but may be limited by hypotension, bradycardia, and sedation.59 Epinephrine may increase the intensity of sensory blockade when administered with a local anesthetic.60 In summary, continuous epidural analgesia provides superior analgesia and better patient outcomes than intravenous opioids and can provide postoperative pain control with epidural local anesthetic alone or a combination of epidural local anesthetic and opioids. Continuous infusion and other delivery modes can provide prolonged postoperative analgesia and may be titrated to an analgesic effect.

Caudal Analgesia Caudal analgesia involves injection through the sacrococcygeal ligament with entrance into the epidural space.61 There is limited utility of caudal analgesia for acute postoperative pain control in adult patients because it is more technically challenging to perform caudal injection compared to lumbar or thoracic epidural blocks. Caudal analgesia is useful in the pediatric population and provides excellent postoperative analgesia for inguinal hernia repair, urologic interventions (e.g. circumcision, hypospadias correction, orchidopexy), anal atresia repair, and lower extremity surgeries.62,63 Additional details on pediatric analgesia may be found in Chapter 28.

Complications With Neuraxial Techniques The most common risks from neuraxial analgesia include hypotension, nausea and vomiting, and back pain.64 Transient neurological syndrome (TNS) is severe lower back pain localized in the buttocks and lower extremities after recovery from spinal anesthesia with no evidence of localized nerve damage.65 Risk factors for TNS include intrathecal lidocaine administration, lithotomy position, and ambulatory surgery.65–67 Postdural puncture headache (PDPH) is because of lumbar puncture with subsequent CSF leak through the puncture site causing symptoms related to traction of pain-sensitive central nervous system structures.68 To decrease the risk of PDPH, it is recommended to use a non-cutting needle.68 When utilizing a pencil-point spinal needle, a meta-analysis by Zorrilla-Vaca et al. demonstrated no difference in PDPH rates between 22-gauge and 25-gauge needles. Thus this study concluded that providers might consider using larger-caliber pencil-point spinal needles in all but the youngest patients to maximize technical proficiency instead of risking a failed spinal anesthetic by using a smaller sized spinal needle.68 Epidural catheters may be misplaced or may migrate after placement,69 leading to ineffective or inadequate analgesic coverage. Epidural placement closer to one side may result in a one-sided blockade with inadequate coverage of the contralateral side. Inadvertent placement of an epidural catheter in the subdural space may lead to unpredictable block characteristics, including an inappropriately high block because of extensive spread, delayed onset, segmental distribution, and potential for motor blockade.70 The feared complication is total spinal anesthesia, which occurs if excess local anesthetic is administered intrathecally, leading to coma, paralysis, hypotension, bradycardia, and apnea.71 Other rare adverse events include infection, hematoma, and nerve injury.69

 

CHAPTER 26

Regional and Multimodal Treatments of Perioperative Pain

361

Peripheral Nerve Blockade Utilization of peripheral nerve blockade in the perioperative setting is associated with adequate pain control, reductions in hospital length of stay, decreased hospital costs, better rehabilitation, and other improved postsurgical outcomes.72,73 Peripheral nerve blockade can be established with a single injection of local anesthetic or with a continuous infusion through a perineural catheter. A perineural catheter with continuous infusion may provide equivalent analgesia to an epidural for certain surgeries while carrying fewer side effects than epidural analgesia.74 Patients may be discharged home with continuous local analgesic medications delivered via a perineural catheter and may remove the perineural catheter themselves without requiring a hospital visit.75,76 Techniques for peripheral nerve blockade localization include paresthesia, peripheral nerve stimulator, and UGRA, although there has been a recent preference for UGRA. UGRA may be associated with a greater block success rate, faster onset of sensory block, fewer needle passes, and less discomfort during the block.77,78 Lidocaine and mepivacaine are commonly used to provide short to intermediate duration peripheral nerve blockade.79 In contrast, bupivacaine, levobupivacaine, and ropivacaine are preferred for longer duration peripheral nerve blockade.80,81 Other adjuvant medications are not currently approved but are commonly added to local anesthetics, including epinephrine82 (detects inadvertent intravascular uptake, denser and prolonged blockade related to vascular constriction) and clonidine (prolongs the duration of analgesia with added risks for hypotension and cardiac arrhythmias).83,84 Below, we discuss various peripheral nerve blocks of the upper extremity, lower extremity, and trunk.

Lower Extremity Peripheral Nerve Blocks The ventral rami from the lumbar plexus (L1–4) and the sacral plexus (L4–5, S1–3) provide innervation to the lower extremity.85 The specific nerves derived from the lumbar plexus (Fig. 26.1) include the lateral femoral cutaneous nerve (L2–3), obturator nerve (L2–4), femoral nerve (L2–4); the lumbar plexus also gives rise to the iliohypogastric, ilioinguinal, and genitofemoral nerves, which innervate the inguinal and genital areas.85 The sciatic nerve (L4–5, S1–3) is derived from the sacral plexus.

Lumbar Plexus Block The lumbar plexus is triangular-shaped, with the femoral nerve situated in the middle, the lateral cutaneous femoral nerve situated laterally, and the obturator nerve situated medially in the plexus.86 When the local anesthetic is injected within the psoas muscle, there is cephalad spread of the local anesthetic to the lumbar nerve roots. Hence, the term “psoas compartment” block is often used interchangeably with “lumbar plexus block.”86,87 Since lumbar plexus blockade covers both the femoral and obturator nerves, it provides surgical anesthesia and postoperative analgesia for surgeries of the hip joint (e.g. total hip arthroplasty, hip arthroscopy) and knee joint (total knee arthroplasty, multi-ligament reconstruction, and ligament repair surgeries) in conjunction with a sacral plexus block.88,89 In certain invasive knee surgeries where coverage from the obturator nerve is not required, it may be technically easier to perform a femoral nerve block instead of a lumbar plexus block.90 Compared to hip surgery patients who did not receive any nerve blockade, those who received lumbar plexus blockade

• Figure 26.1  Lumbar Plexus. (Adapted from 20th United States edition of Gray’s Anatomy of the Human Body [No copyright needed as the image is available in the public domain].)

experienced decreased intraoperative blood loss, decreased postoperative opioid consumption, improved patient satisfaction, earlier postoperative ambulation, and improved participation in physical therapy and rehabilitation.89,91,92 Compared to epidural analgesia, continuous lumbar plexus blockade may be associated with less motor blockade, faster time to ambulation, and fewer overall complications.93 Thus the lumbar plexus block may play a pivotal role in ERAS protocols for hip surgery. By itself, the lumbar plexus block is unlikely to provide complete anesthesia for hip surgeries because the sacral plexus provides innervation to the posteromedial capsule of the hip.94 Compared with general anesthesia, a combination of lumbar plexus and parasacral blocks for hip surgeries in elderly patients may be utilized as the primary anesthetic and is associated with less hypotension, shorter hospital length of stay, fewer intensive care unit admissions, and improved patient satisfaction.95,96

Femoral Nerve Block The femoral nerve is the largest nerve from the lumbar plexus.97,98 It travels in the groove between the psoas muscle and iliacus muscle, passes under the inguinal ligament, and presents at the femoral triangle where it runs laterally to the femoral vessels (Fig. 26.2).97,98 The femoral nerve then divides into anterior and posterior terminal branches, with anterior branches providing mainly cutaneous innervation and posterior branches providing primarily motor innervation.99 The femoral nerve provides motor and sensory innervation to the skin and muscles of the anterior compartment of the thigh (e.g. quadriceps muscle), while its terminal branch (saphenous nerve) provides sensory innervation only to the medial portion of the leg from below the knee to the

362

PA RT 4 Clinical Conditions: Evaluation and Treatment

Saphenous Nerve Block

• Figure 26.2  Femoral Nerve. (Courtesy of Mayo Clinic.)

big toe.99 Given the proximity of the femoral nerve to the artery, which is located in a separate sheath about 1 cm apart, accidental intravascular injection and hematoma formation are potential complications during blockade.100 Femoral nerve blockade provides excellent postoperative analgesia for mid-femur and knee surgeries, such as total knee arthroplasty (TKA), and may also be a satisfactory analgesic alternative to posterior lumbar plexus blockade for hip arthroplasty.101 Because blockade occurs distally to the lumbar plexus, there is preservation of the hip flexion and hip adduction function, but patients cannot perform knee extension (function of quadriceps muscle).102 While femoral nerve blockade may be utilized as the sole regional analgesic modality for knee surgeries, it is commonly supplemented with sciatic nerve blockade to provide coverage of the posterior aspect of the knee (e.g. TKA surgery, anterior cruciate ligament [ACL] surgery with hamstring autograft) or for below the knee procedures.103,104 Similarly, if more proximal coverage of the medial compartment of the knee is required, supplementation with an obturator nerve block may be desirable.105 Compared to systemic pharmacologic therapy alone in patients undergoing TKA, studies and systematic reviews demonstrate that both single injection and continuous femoral nerve blockade are associated with superior analgesia.73,106,107 Patients receiving femoral nerve blockade may also experience faster time to ambulation, improved knee flexion, reduced intraoperative and postoperative bleeding, quicker recovery, and decreased hospital length of stay.73,106–108 Compared with surgeon-performed periarticular injection after TKA, continuous femoral nerve blockade may be associated with lower opioid consumption and improved recovery after six weeks.109 Studies have also compared epidural analgesia versus continuous femoral nerve blockade after TKA, demonstrating that femoral nerve blockade provides equivalent postoperative analgesia, rehabilitation indices, and hospital duration of stay, but with fewer side effects (e.g. pruritus, postoperative nausea and vomiting, and dizziness).110–112

The saphenous nerve is a distal sensory branch of the femoral nerve that innervates the medial portion of the leg, medial calf, medial malleolus, and anteromedial foot.113,114 Depending on the nature of the surgery and the location where analgesia is desired, the saphenous nerve may be blocked in several different locations, including perifemoral, subsartorial, transarterial, block at the medial femoral condyle, below the knee, paravenous approach, and at the medial malleolus.115 Below, we focus on the subsartorial approach and discuss the saphenous nerve block at the medial malleolus in the “ankle block” section. The subsartorial approach to the saphenous nerve block (proximal, mid-thigh approach in the middle third of the thigh) may be performed in patients who have undergone knee arthroplasty. This technique is often called the “adductor canal block.” The adductor canal is a triangular-shaped canal with borders formed by the vastus medialis laterally, adductor longus or magnus medially, and roofed medially by the sartorius muscle, and can be visualized as a round hyperechoic structure anterior to the femoral artery using ultrasonographic guidance.116,117 Given that femoral nerve blockade leads to quadriceps muscle weakness and impairment of early mobilization, the acute pain interventionalist now more often substitutes the adductor canal block for postoperative analgesia for TKA because it provides sensory blockade while sparing quadriceps strength and facilitating rehabilitation.118 Similarly, a meta-analysis on patients undergoing ACL repair also demonstrated that adductor canal blockade is associated with similar analgesic requirements and short-term preservation of quadriceps muscle strength (24–48 hours) compared to femoral nerve blockade.119 However, reports of significant quadriceps muscle weakness from local anesthetic spread in an adductor canal block have been described.120 Risk factors, including advanced age, eliminationrelated activities (e.g. while in the bathroom, going to and from the bathroom, while using bedside commode), and intermediate phase of recovery (late postoperative day one to postoperative day three), also make patients vulnerable to fall after orthopedic surgery, and fall prevention strategies should be an institutional priority.121

Fascia Iliaca Block The fascia iliaca is derived from fascicular aponeurotic sheets of the psoas and iliacus muscles. It is hypothesized that since there are multiple peripheral nerves enclosed within the fascia iliaca compartment in close proximity, including the femoral, lateral femoral cutaneous, genitofemoral, and obturator nerves, a high volume injection of local anesthetic may block all these peripheral nerves with one injection along this fascial plane.122,123 Studies have demonstrated that the fascia iliaca block may provide adequate analgesia after hip, knee, and femoral shaft surgery.124,125 A loss-of-resistance technique may be used to block the fascia iliaca compartment. However, studies have demonstrated that ultrasound guidance increases block success rates and the percentage of patients experiencing blockade of the femoral, obturator, and lateral femoral cutaneous nerves.126 Compared to systemic opioid therapy alone, fascia iliaca block may provide superior pain relief postoperatively after hip surgery127–130 and femoral fracture surgery.131

Sciatic Nerve Block The sciatic nerve is the largest of the peripheral nerves supplying the lower extremity and provides innervation to the posterior thigh, leg below the knee, except for its medial portion (supplied

 

CHAPTER 26

by the saphenous nerve), and the foot. It is commonly blocked either via the subgluteal or popliteal approach (discussed below). Sciatic nerve blockade provides excellent coverage for all foot and ankle surgeries132,133 and is often performed in conjunction with femoral or lumbar plexus blocks for postoperative analgesia after hip or knee surgeries.104 However, sciatic nerve blockade is often accompanied by hamstring muscle weakness, limiting its utility in many distal foot and ankle surgeries where postoperative weakness is undesirable.134 Phantom limb pain following below-knee or above-knee amputation may significantly improve with continuous sciatic nerve blockade.135 Compared to femoral nerve blockade alone, both a femoral nerve block and sciatic nerve block provide superior postoperative analgesia and reduce postoperative opioid consumption.136,137 Furthermore, a meta-analysis revealed that patients undergoing TKA who received sciatic nerve blockade as an adjunct to femoral nerve block reported lower postoperative pain scores and consumed fewer opioids up to 24 hours postoperatively compared to those who received femoral nerve blockade with local infiltration analgesia.138

Popliteal Sciatic Nerve Block The popliteal fossa is bordered superomedially by the semimembranosus and semitendinosus muscles, superolaterally by the biceps femoris, and inferiorly by the two heads of the gastrocnemius muscle. Within the popliteal fossa, the sciatic nerve is located posterolateral to the popliteal vessels (Fig. 26.3). Compared to the subgluteal approach to sciatic nerve blockade, the more distal location of popliteal sciatic nerve blockade preserves hamstring muscle strength and may facilitate earlier ambulation.134 Pertaining to the technique

• Figure 26.3

 

Regional and Multimodal Treatments of Perioperative Pain

363

of performing popliteal block, studies have demonstrated higher sensory block success, reduced time to perform the block, reduced risk of vascular puncture, and requirement for less local anesthetic with ultrasonographic guidance versus peripheral nerve stimulation techniques.139,140 When popliteal sciatic blockade is performed using ultrasonographic guidance, performing the block separately for the tibial and common peroneal nerves at the bifurcation may be associated with faster block onset and denser motor block compared to a prebifurcation popliteal sciatic blockade.141,142 Popliteal sciatic nerve blockade provides excellent analgesia and surgical anesthesia for surgeries below the knee joint, notably foot and ankle surgery.143,144 While an ankle block may be pursued for foot surgeries, a popliteal block is preferable when the surgery involves the use of a calf tourniquet. Supplementation with a saphenous nerve block is required for coverage of the medial aspect of the leg. Compared to single injection popliteal sciatic nerve blockade for foot and ankle surgery, continuous infusion of local anesthetic is associated with lower postoperative pain scores at 24 and 48 hours.144 Although popliteal sciatic nerve blockade is primarily utilized for below the knee procedures, the combination of a popliteal sciatic nerve block and an adductor canal block may provide sufficient analgesia after TKA.145 Furthermore, a combination of continuous popliteal sciatic and continuous femoral nerve block may improve postoperative pain control during movement following ankle surgery.146

Ankle Block The ankle block involves injection at multiple sites around the ankle and foot to block several peripheral nerve targets (Fig. 26.4). These include derivatives from the sciatic nerve (deep fibular/

Popliteal Nerve. (Courtesy of Mayo Clinic.)

364

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Figure 26.4  Ankle Block. (Henry Gray, Anatomy of the Human Body, 20e, Lea & Febiger, 1918.)

peroneal, superficial fibular/peroneal, sural, and posterior tibial nerves) and one derivative from the femoral nerve (saphenous nerve), which innervates the medial side of the ankle and foot.147 This provides excellent surgical anesthesia and postoperative analgesia for surgeries of the foot, particularly surgeries not requiring calf tourniquet application. Since motor blockade is often unnecessary, high volumes of lower concentrations of local anesthetics may be administered to provide adequate sensory blockade; hence, the term “volume-block” is often used to describe the ankle block. Epinephrine is not recommended for use in ankle blocks, particularly if a circumferential infiltration technique around the ankle is used. The ankle block is ideal for ambulatory surgeries as patients may still ambulate with assistance, facilitating earlier discharge with adequate pain control.148 The ankle block may be performed using either a landmarkbased approach or an ultrasound guided approach. Compared to the landmark approach, the use of an ultrasound for ankle block may be associated with a higher block success rate, although the lower local anesthetic volume in ultrasound guided injections may compromise postoperative analgesia in the first 24 hours.148,149 In a study comparing spinal anesthesia and ankle block, ankle block was associated with lower pain scores and longer time to first need for analgesics but was associated with a longer time to sensory block.150

Upper Extremity Peripheral Nerve Blocks The brachial plexus is formed by the anterior rami of the cervical nerves from C5–C8 and the first thoracic spinal nerve (T1) and provides motor and sensory innervation to the upper extremity. The brachial plexus consists of five roots, three trunks, six divisions, three cords, and five terminal branches (Fig. 26.5). The terminal branches include the radial, median, ulnar, musculocutaneous, and axillary nerves.151 Depending on the nature and location of the upper extremity surgery, blockade of the brachial plexus can be targeted at any of these levels to provide surgical anesthesia and postoperative analgesia. Ultrasound allows reliable visualization of the brachial plexus. It may be associated with an increase in overall block success rate, quicker block performance time, use of less local anesthetic, faster onset of motor and sensory block, and minimal side effects when compared to traditional landmark-based and nerve stimulation techniques.152–155

Interscalene Block An interscalene block is performed at the distal roots/proximal trunk level of the brachial plexus and provides excellent analgesia for shoulder and upper arm surgeries.151 It is effective in providing a complete block of the superior and middle trunks, but coverage

 

CHAPTER 26

Regional and Multimodal Treatments of Perioperative Pain

365

• Figure 26.5  Brachial

Plexus. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

of the inferior trunk is frequently missed, thus making the interscalene block an unsuitable option for forearm and hand procedures that require ulnar nerve coverage.156 If an interscalene block is performed for elbow procedures, additional supplemental nerve blocks may be required, including the intercostobrachial nerve block to cover the medial aspect of the arm, as well as the medial antebrachial cutaneous and ulnar nerve blocks to cover the medial aspect of the forearm. The spread of local anesthetic injectate in an interscalene block consistently spreads to cover the supraclavicular nerve (C3–4), which provides innervation to the cape of the shoulder.157 If paresthesia or nerve stimulation technique is utilized, the desired response is preferably a paresthesia or motor twitch of the upper arm or hand. However, the stimulus of the deltoid/anterior shoulder may be acceptable.158 If the contraction of the diaphragm is sometimes visualized as hiccups, this indicates phrenic nerve stimulation from a needle that is placed too anterior. If the needle is placed too posteriorly, stimulation of the dorsal scapular nerve may elicit rhomboid muscle movement.159 The interscalene block should be avoided in patients with impaired pulmonary function because the phrenic nerve is usually blocked using this technique.160 The interscalene nerve block should not be performed in a patient under general anesthesia or deep sedation because of the risk of syrinx and other major neurological complications, including intrathecal and epidural injection.161 Other potential complications from interscalene block include intravascular injection, particularly into the vertebral artery, pneumothorax, and Horner’s syndrome.160 Nerve injury may potentially occur in the dorsal scapular nerve, leading to a dull ache in the medial scapula and weakness of the rhomboid and levator scapulae muscles.162 Nerve injury is also possible to

the long thoracic nerve, resulting in chronic shoulder pain and serratus muscle weakness.162–164 A meta-analysis revealed that patients undergoing arthroscopic shoulder surgery who received an interscalene block with general anesthesia experienced lower pain scores up to one day postoperatively, lower intraoperative systolic blood pressure, shorter extubation time, and a lower rate of adverse events compared to general anesthesia alone.165 Compared to systemic opioids, interscalene block is associated with superior analgesia, less postoperative opioid consumption, and less incidence of opioid-related side effects.166 Patients may maintain the continuous perineural local anesthetic infusion via an interscalene catheter while at home with a portable infusion pump, allowing better pain control and improvement in rehabilitation indices with greater shoulder range of motion.167,168 If there is concern for respiratory insufficiency in a patient undergoing shoulder surgery, an anterior suprascapular nerve block or a supraclavicular block approach may be pursued instead of an interscalene approach. However, even the more distal supraclavicular approach is associated with phrenic nerve blockade.169 A meta-analysis of patients undergoing shoulder surgery revealed that patients receiving a supraclavicular block reported similar postoperative pain scores and postoperative opioid consumption but with lower rates of hemidiaphragmatic paresis and Horner’s syndrome compared to those receiving an interscalene block.170

Supraclavicular Block A supraclavicular block is commonly known as the “spinal of the arm” because the brachial plexus in this approach is tightly packed and can achieve quick, reliable, and dense blockade with little to

366

PA RT 4 Clinical Conditions: Evaluation and Treatment

no sparing after local anesthetic infiltration.171 The supraclavicular block is performed at the distal trunks/proximal cords level of the brachial plexus172 and provides surgical anesthesia and postoperative analgesia for surgeries of the hand, forearm, and arm. While studies have shown that supraclavicular block may provide analgesia similar to that of an interscalene block,170 other studies recommend supplementing the supraclavicular block with a separate superficial cervical plexus block of the supraclavicular nerve (C3–C4) to provide coverage of the shoulder cape.151,173 In addition, supplementation with an intercostobrachial nerve block to provide coverage of the medial arm may be required for elbow surgeries or tourniquet application. A feared complication from a supraclavicular block is pneumothorax, which may occur if the needle angle is aimed at the apex of the lung. The supraclavicular approach carries the highest risk for pneumothorax among all brachial plexus block techniques.174,175 Phrenic nerve blockade occurs commonly, although not as common as in the interscalene approach, and thus may be avoided in those with impaired pulmonary function.176 Hematoma may occur in the supraclavicular approach, commonly because of puncture of the subclavian artery.177 Higher local anesthetic volumes should be avoided because ischemic compression within the tightly packed supraclavicular space is possible and may lead to indirect nerve injuries. Direct injury to the suprascapular nerve may also occur and manifests with shoulder pain and weakness of the supraspinatus and infraspinatus muscles.178 Although the supraclavicular block is considered to be the approach that provides the fastest and most reliable onset of dense blockade, RCTs have demonstrated that ultrasound guided brachial plexus blocks via the supraclavicular, infraclavicular, and axillary approaches all led to similar success rates, pain scores, and total anesthesia-related times.179,180 Studies have also investigated the addition of dexmedetomidine adjuvant to supplement local anesthetic in supraclavicular blocks, demonstrating that it leads to improved analgesia with shorter onset time and longer duration compared to local anesthetic (ropivacaine) alone.181 Furthermore, there was no difference in the rates of bradycardia or hypotension.181 In terms of technique, UGRA and nerve stimulation techniques are considered superior to the blind technique because of a higher success rate and decreased rate of complications.182

Infraclavicular Block The infraclavicular block is performed at the level of the brachial plexus cords, and either a single injection or continuous catheter infusion provides surgical anesthesia and postoperative analgesia for arm, elbow, forearm, and hand procedures.151,183 The three cords (lateral, posterior, and medial) are named in relation to the axillary artery, but substantial variation in the true location of the cords in relation to the axillary artery may be present at the coracoid level.184 Of all the brachial plexus block techniques, the infraclavicular approach likely allows for a more secure insertion site for catheters.151 While there are three main approaches to the infraclavicular block described (coracoid, lateral sagittal, and vertical approach), the coracoid approach may be preferable to some because of the clear anatomic landmarks and the lateral entry point reducing the probability for pneumothorax and hemidiaphragmatic paresis.185 However, the evidence on a preferred technique is limited, which is an area for future investigation. Complications may include hematoma and vascular puncture, particularly of the axillary artery or vein, LAST potential,

especially because of the need for a high volume of local anesthetic injectate, and sparing of the radial nerve distribution in the single injection technique.186 Compared to the supraclavicular and interscalene approach, there is a lower incidence of pneumothorax or inadvertent neuraxial injection with the infraclavicular approach because it is more distant from the lung and neuraxis.187 The infraclavicular block is also suitable for patients with pulmonary insufficiency, as phrenic nerve blockade is markedly reduced compared to supraclavicular and interscalene techniques.188 As aforementioned, an infraclavicular approach for arm surgeries provides equivalent regional anesthesia and analgesia compared to other brachial plexus blocks.179,180 However, when comparing an infraclavicular continuous catheter infusion to a supraclavicular continuous catheter infusion, the former is associated with superior analgesia.189 Compared to general anesthesia with volatile anesthetic for ambulatory hand and wrist surgery, infraclavicular nerve block as the primary anesthetic was associated with lower postoperative pain scores, decreased time to ambulation, and lower post-anesthesia care unit admissions.190 Placement of an infraclavicular catheter with continuous local anesthetic infusion may result in less dynamic postoperative pain, reduced postoperative opioid requirements, and less sleep disturbance compared to placebo infusion.191 Studies have also investigated the addition of dexmedetomidine adjuvant to supplement local anesthetic in infraclavicular blocks, demonstrating that it leads to increased duration of analgesia and enhancement of sensory and motor blockade, lower postoperative pain scores, and reduction in postoperative opioid requirements compared to local anesthetic (bupivacaine) alone.192

Axillary Block The axillary block is performed at the level of the terminal nerves surrounding the axillary artery, consisting of the radial, ulnar, and median nerves. However, with ultrasound guidance, a more proximal cord/terminal nerve block is possible. The relationship of the musculocutaneous nerve deserves special attention with the axillary approach because it courses away from the axillary artery and is located in the belly of the coracobrachialis muscle.193,194 Thus a separate injection into the coracobrachialis muscle or ultrasound guided perineural injection of the musculocutaneous nerve is warranted during an axillary block.193,194 The axillary block provides surgical anesthesia and postoperative analgesia for hand and arm surgery and can be blocked through various techniques, including paresthesia, nerve stimulation, perivascular, trans-arterial, and ultrasound guided.151,195,196 If an axillary block is utilized for primary surgical anesthesia, supplementation of the musculocutaneous, intercostobrachial, medial brachial cutaneous, and medial antebrachial cutaneous nerves are warranted to prevent tourniquet pain. A review by Chin et al. demonstrated that the multiple injection technique for axillary block improved the block success rate, although the block time was longer than that with single- and double-injection techniques.197 Compared to general anesthesia alone for ambulatory hand surgery, an axillary block for surgical anesthesia provides superior postoperative pain control, decreases postoperative opioid requirement, and increases the time to first analgesic medication request.198,199 Potential complications include LAST, postoperative neuropathy, hematoma, and vascular puncture, particularly the axillary artery. Pulmonary complications are rare, and this block is preferable in patients with pulmonary insufficiency undergoing distal arm, forearm, and hand surgery.

 

CHAPTER 26

Regional and Multimodal Treatments of Perioperative Pain

367

Bier Block

Transversus Abdominis Plane (TAP) Block

Intravenous regional anesthesia, also known as the Bier block, provides surgical anesthesia and a bloodless surgical field for shorter duration distal extremity surgeries.200 The Bier block may also be utilized to treat certain chronic pain conditions, including complex regional pain syndrome.201 The mechanism of action involves the diffusion of local anesthetic from the veins to the nerves.202 The local anesthetic of choice commonly used in Bier blocks is lidocaine. Long-acting local anesthetic agents, including bupivacaine, are not appropriate for Bier blocks.203,204 It is recommended that the tourniquet remain inflated at least twice the systolic blood pressure for 30 minutes prior to deflation.200,205 However, seizures have been reported even with a tourniquet time as long as 60 minutes with the use of the lowest effective dose of lidocaine.206 In the event of Bier block failure, surgeon-administered infiltration of local anesthetic at the surgical site or conversion to general anesthesia may be performed. The Bier block is relatively contraindicated in localized or systemic infections, peripheral vascular disease, sickle cell anemia, presence of arteriovenous fistulas, and lack of IV access. Side effects include phlebitis and LAST, which may be because of improper technique or tourniquet failure, nerve injury, compartment syndrome, and tourniquet pain. In addition to local anesthetic infusion, other studies have also evaluated other adjuvants to the Bier block, including opioids, steroids (e.g. dexamethasone, methylprednisolone), α-2-agonists (dexmedetomidine, clonidine), ketamine, and NSAIDs, notably ketorolac.202,207,208 Of all opioids, some studies have described the efficacy of only meperidine,209 while the remaining opioids are considered non-effective adjuvants.204 Dexmedetomidine at a dose of 1 mcg/kg and clonidine at a dose of 1 mcg/kg may be associated with improved tourniquet tolerance and reduced postoperative analgesic requirements.210 Furthermore, 100 mcg/ kg of ketamine has been shown to also reduce postoperative analgesic requirements and improve tourniquet pain.211 Up to 24 hours of reduced postoperative analgesic requirements may also be observed with a combination of dexamethasone and lidocaine versus plain lidocaine alone.212

The (TAP) block has been used for postoperative analgesia after abdominal and gynecological surgeries, including hernia repairs, hysterectomies, appendectomy, and laparoscopic surgeries. The inclusion of TAP blocks in multimodal analgesia protocols is associated with a decrease in postoperative pain scores, opioid consumption, earlier ambulation, and shorter duration of hospital stay following laparoscopic cholecystectomy and appendectomy, as well as various laparotomy cases.214,219–223 An RCT demonstrated that bilateral TAP blocks after abdominal hernia repair are associated with decreased time to ambulation and improved discharge readiness.224 TAP blocks may obviate the need for neuraxial anesthesia and may be an option in the obese population, where neuraxial techniques may be challenging.220 The TAP block covers nerves derived from the anterior rami of T7-L1 that provide sensation to the anterolateral abdominal wall skin, muscle, and parietal peritoneum (Fig. 26.6). Although statistically significant improvements in analgesia after TAP blocks for abdominal surgeries have been reported, these associations may only reflect a clinically modest benefit; thus this technique is not recommended for routine practice.213 Furthermore, the TAP block may be limited in certain postsurgical settings, including coverage of midline incisional pain,214 and presence of significant visceral pain,225 and thus the implementation of a multimodal analgesia protocol is often necessary in these settings. The TAP block should not be performed anteriorly in the abdominal wall because of concern for inadequate spread.226 Furthermore, performing the block posterior to the midaxillary line has the advantage of targeting the lateral cutaneous branches prior to exiting the TAP.227 Subcostal TAP blocks may provide analgesia for midline supraumbilical surgeries and upper abdominal incisions. The success of the block is dependent on the extensive spread of local anesthetic to traverse nerves across the abdominal wall; thus a high volume of dilute, long-acting local anesthetic (about 20 mL on each side) is preferred.227,228 Adverse events may include damage to the viscera, retroperitoneal hematoma, nerve injury (e.g. femoral nerve palsy), and intravascular injection.214 Caution is also advised when performing right-sided TAP blocks because of the proximity of the liver and the potential for liver injury in those with hepatomegaly.

Fascial Plane/Truncal Nerve Blocks With the widespread use of ultrasonography, fascial plane blockade has been applied to various surgical procedures and acute pain management strategies.213 A combination of systemic analgesic medications with truncal blocks of the abdomen, chest wall, or paraneuraxial nerves may offer similar analgesic efficacy and a lower risk profile when compared to neuraxial techniques.214 The most common truncal blocks performed in the perioperative setting include the transversus abdominis plane (TAP), rectus sheath, ilioinguinal/iliohypogastric, intercostal, and paravertebral blocks. While most truncal blocks were initially described in the literature through landmark-based techniques,215,216 the advent of ultrasonography has renewed interest in truncal blocks. It has improved the placement of local anesthetic in the appropriate location while avoiding injury to surrounding structures.217 Unlike other peripheral nerve blocks, truncal nerve blocks are usually performed along muscular or fascial planes that spread to traversing nerves; thus visualization of the individual nerve or nerve plexus is not a requirement.218

Ilioinguinal and Iliohypogastric Nerve Block The ilioinguinal and iliohypogastric nerve blocks provide postoperative analgesia following inguinal hernia repair, cesarean section, and other lower abdominal and inguinal surgeries. These nerves originate from the anterior ramus of the L1 nerve root and arise from the lateral border of the psoas muscle.229 The iliohypogastric nerve travels superior to the ilioinguinal nerve and may give off lateral cutaneous branches that travel through the internal and external oblique muscles.229 Thus these truncal nerves should be approached more proximally to avoid sparing of these lateral cutaneous branches.229 The injectate is placed along the same plane as the TAP block (described above), although the optimal point of needle entry is 2.5 mm from the anterior superior iliac spine (ASIS) along a trajectory connecting the ASIS and the umbilicus.214,230 Complications may include visceral damage, femoral nerve palsy, retroperitoneal hematoma, intravascular injection, and vascular injury, particularly of the inferior epigastric vessels that travel close to the ilioinguinal and iliohypogastric nerves.214

368

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Figure 26.6  Abdominal Wall Innervation. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

In an RCT comparing a landmark-based technique versus ultrasound guidance for ilioinguinal/iliohypogastric nerve blocks in children undergoing unilateral inguinal surgery, use of ultrasound was associated with lower sevoflurane requirement intraoperatively, lower pain scores, decreased requirement for analgesics in the post-anesthesia care unit and increased parent satisfaction despite using a lower dose of local anesthetic to perform the block.231 A meta-analysis comparing ilioinguinal/iliohypogastric nerve block versus TAP blocks for inguinal herniorrhaphy revealed that both techniques were associated with similar postoperative opioid consumption and patient satisfaction. In contrast, the ilioinguinal/iliohypogastric cohort reported better analgesic efficacy at 6 and 8 hours postoperatively compared to the TAP block cohort.232 In patients with cervical cancer undergoing surgery, the addition of ilioinguinal/iliohypogastric blocks with general anesthesia compared to general anesthesia alone was associated with decreased intraoperative propofol and sufentanil requirements, decreased postoperative pain scores, and longer time until the administration of first postoperative analgesic medication.233

Rectus Sheath Block The rectus sheath block provides postoperative analgesia for midline abdominal and periumbilical surgeries. The location of local anesthetic deposition is beneath the rectus abdominis muscle, which traverses the anterior intercostal nerves from T9 to T11.234,235 Specifically, the needle tip should be between the rectus abdominis muscle and the double layer that is created by the

transversalis fascia and aponeurosis of the transversus abdominis muscle.236 It is important to note that above the arcuate line, both the aponeurosis of the transversus abdominis muscle and the transversalis fascia separates the rectus abdominis from the abdominal cavity. However, caudal to the arcuate line, the rectus abdominis muscle is only separated from the abdominal cavity by the transversalis fascia.237 Furthermore, rectus sheath blocks would only provide coverage for midline abdominal surgeries, and the presence of lateral incisions would need to be supplemented with a TAP block (discussed above). Similar to the TAP block, the rectus abdominis sheath block does not provide analgesia for visceral pain. The use of ultrasound is recommended as one study demonstrated that 21% of rectus sheath blocks performed using a landmark-based loss-of-resistance approach led to intraperitoneal needle entry.238 Other risks include infection, post-procedural pain, LAST, visceral organ damage, and intravascular injection, particularly in superior or inferior epigastric vessels.213,239 Compared to patients undergoing abdominal surgeries who did not receive any block or received a sham block, those who received preoperative rectus sheath blocks generally had lower intraoperative anesthetic requirements, decreased postoperative analgesic requirement and opioid consumption, and decreased postoperative pain scores.240,241 Furthermore, the combination of the TAP block and rectus sheath block may improve postoperative pain, reduce analgesic requirements, and accelerate postoperative recovery after major abdominal surgeries.242 In certain high-risk patients with limited cardiovascular reserve, case reports of using

 

CHAPTER 26

rectus sheath blocks as the primary surgical anesthetic for standard periumbilical surgery have been reported.236

Thoracic Paravertebral Block The thoracic paravertebral block provides postoperative analgesia for cardiac and thoracic procedures, including thoracotomy, nephrectomy, rib fractures, chest tube insertion, and breast surgeries. Bilateral thoracic paravertebral continuous catheters are particularly useful when the placement of an epidural catheter is difficult or not pursued. A thoracic paravertebral block may also be performed in the chronic pain setting in cases of complex regional pain syndrome.243 The proposed mechanism of the thoracic paravertebral block is the direct spread of local anesthetic into the spinal nerves, lateral tracking of local anesthetic toward intercostal nerves, and medial tracking of local anesthetic into the intervertebral foramina (Fig. 26.7).244 Several factors may impact the efficacy of the paravertebral block. However, a successful block is usually correlated with inferior needle advancement to the transverse process, medially directed bevel, large-volume and higher speed of injection to overcome negative intrathoracic pressures, absence of surgical emphysema from subcutaneous air, absence of fracture or blood in the intercostal space, and absence of anatomical abnormalities such as foraminal stenosis, disc herniation, and facet joint hypertrophy.244–246 Adverse effects may include procedural pain, LAST because of large volumes, nerve injury, pneumothorax, hypotension from neuraxial spread, potential for total spinal blockade, and potential for quadriceps muscle weakness if the block is inadvertently placed below L1 with resultant femoral nerve blockade.244,247 While the efficacy of analgesia from a paravertebral block may be similar to that of an epidural block, the paravertebral block may allow for a more targeted coverage (e.g. unilateral block),

Regional and Multimodal Treatments of Perioperative Pain

369

less sympathectomy, lower rates of failed block, and lower rates of side effects including urinary retention, nausea and vomiting, and hypotension.244,248,249 Furthermore, continuous paravertebral anesthetic infusions are associated with superior postoperative analgesia, greater preservation of lung function, and fewer side effects than interpleural analgesia for thoracic surgery.250,251

Intercostal Nerve Block The intercostal nerve block provides postoperative analgesia for upper abdominal and thoracic surgeries and surgical anesthesia for minor surgical chest or abdominal procedures (Fig. 26.8).252,253 Intercostal nerve blocks may also provide analgesia for rib fractures, chest tube placements, and gastrostomy tube placements.254 The mechanism of action is the direct local anesthetic effect on intercostal nerves. However, if a catheter is inserted medially at the angle of the rib and if the catheter lies medially to the border of the intercostalis intimus muscle, local anesthetic may spread to the paravertebral space.255 Above the T7 level, an intercostal nerve block may be technically challenging to perform because of the scapula; thus if analgesia is desired above T7, alternative modalities such as a paravertebral block or epidural catheter should be pursued. Because of the significant vascularity within the intercostal space, systemic concentrations of local anesthetic are high following intercostal nerve blocks, and caution must be exercised when performing multiple-level intercostal nerve blocks.256 Furthermore, peak serum local anesthetic concentrations may not be reached until 15–20 minutes post-procedure, and thus the patient should be monitored for LAST during this interval.256 Although rare, pneumothorax is a serious potential complication after intercostal block, with an overall incidence of 8.7% per patient and 1.4% per intercostal nerve block.257

• Figure 26.7  Paravertebral Space Anatomy. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

370

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Figure 26.8  Intercostal Nerve. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

An RCT in patients undergoing video-assisted thoracoscopic surgery reported that the addition of an intercostal nerve block was associated with better postoperative analgesia and less morphine consumption in the early postoperative period (6 hours) compared to those who did not receive an intercostal nerve block.258 This is consistent with another study reporting improved postoperative analgesia and quality of life after patients received intercostal nerve blockade for percutaneous nephrolithotomy.253

Erector Spinae Plane Block The erector spinae plane block (ESPB) is a relatively novel interfascial plane block initially described in the setting of chronic thoracic neuropathic pain and video-assisted thoracoscopic surgery.259 The deep needle approach to ESPB, which is the recommended approach, involves local anesthetic injection deep to the three erector spinae muscles (iliocostalis, longissimus, and spinalis) but superficial to the thoracic transverse processes.259 The superficial approach involves local anesthetic injection between the erector spinae muscle and the rhomboid major muscle.260 When utilizing the deep approach, studies have demonstrated injectate spread from C7 to T8 on the right side and T1 to T8 on the left side within the paraspinous gutter and lateral spread toward the transverse processes.259,261 Owing to its relative distance from the pleura, major blood vessels, and spinal cord compared to the paravertebral block, the ESPB provides a favorable adverse risk profile. Furthermore, unlike neuraxial analgesia, ESPB may be performed in patients with thoracic vertebral fractures.262 ESPB has been described as an effective analgesic modality for rib fractures as well as a variety of surgeries, including thoracic surgery (e.g. video-assisted thoracoscopy, thoracotomy), cardiovascular surgery (e.g. aortic valve replacement), breast and thoracic mass surgery, open abdominal and laparoscopic surgery, and spinal surgery. Given the novelty of this fascial plane block, most of the evidence for its use in postoperative analgesia consists of case reports and small retrospective studies. A cohort study in patients with traumatic rib fractures who received ESPB showed

significant improvement in incentive spirometry and reduction in pain scores with no hemodynamic instability. While there was a reduction in opioid intake, this did not reach statistical significance.263 Although complications specific to the ESPB are rare, there have been reported cases of pneumothorax,264 bilateral lower extremity weakness,265 and LAST with central nervous system effects.266 It is recommended that those receiving an ESPB at the lower thoracic or lumbar levels be evaluated for motor weakness after completion of the block.267 The potential for block failure or lack of analgesic efficacy has been reported in several studies, although risk factors have yet to be identified.266,268 Future studies are warranted to characterize differences in the ESPB approach (superficial vs. deep technique), optimal volume and concentration of local anesthetic, timing of block, respiratory function, and efficacy of unilateral and bilateral ESPB for various surgical indications.

Modes of Local Anesthetic Delivery There are many variations in the delivery of local anesthetic to the block target site. The most basic is the single injection of local anesthetic, which is commonly performed for intrathecal analgesia and various peripheral nerve blocks. Single injection blocks are performed for ambulatory and short-duration procedures and typically provide short-term surgical anesthesia and analgesia depending on the local anesthetic medication injected. For instance, a single injection of peripheral nerve block with bupivacaine provides longer postoperative analgesia than intermediateacting agents such as lidocaine. If a catheter is placed for continuous infusion of local anesthesia, different delivery settings, including continuous infusion, intermittent bolus dosing, or a combination of both, may be pursued. Intermittent bolus dosing may be categorized as either manually delivered intermittent bolus dosing or programmable intermittent bolus dosing. Studies have examined PCEA, which provides excellent analgesia for various surgeries and is

 

CHAPTER 26

associated with few complications.269 While many RCTs have compared intermittent bolus dosing and continuous infusion delivery modes, a recent systematic review demonstrated limited evidence and reported no differences between intermittent bolus dosing over continuous infusion modes in truncal and peripheral nerve blocks.270 For certain ambulatory surgeries, the patient may be discharged home with a perineural catheter in place and an ongoing continuous local anesthetic infusion for prolonged postoperative analgesia.75,271 If the patient is discharged with a continuous perineural local anesthetic infusion, it is important to educate the patient on potential risks, potential for LAST, signs of infection and bleeding, and vigilance for other concerns. Suppose the patient manifests any signs or symptoms of LAST or other adverse events from regional anesthesia. In that case, the patient should stop the local anesthetic infusion, contact the acute pain service (if available at their hospital), and consider transport to the emergency department for further evaluation.

Special Patient Populations

Regional and Multimodal Treatments of Perioperative Pain

371

contralateral phrenic nerve palsy) may not tolerate the reduction in pulmonary function from ipsilateral phrenic nerve blockade.281,283 Although ultrasonography, low-volume local anesthetic infiltration, and digital pressure above the injection site have been implemented, these techniques have not been associated with reduced phrenic nerve palsy.281,284 Alternative peripheral nerve blocks may be utilized, including direct local anesthetic infiltration at the surgical site, Bier block, infraclavicular block, and axillary block, all of which carry a much lower risk for phrenic nerve palsy.281,285 In terms of neuraxial blockade, the presence of a high spinal or epidural anesthesia may decrease expiratory reserve volume and vital capacity and reduce the ability to forcefully exhale, cough, or clear pulmonary secretions.286 This is usually because of paralysis of the abdominal muscles.286 A study in elderly patients with poor respiratory reserve who received spinal anesthesia with a level above T6 demonstrated significant decreases in forced expiratory volume in one second (FEV1), forced vital capacity, and forced expiratory flow 25%–75%.287 Tidal volume is typically not impacted unless the phrenic nerve (C3–5) is affected by higher neuraxial blockade.286

Obese Patients

Trauma and Critically Ill Patients

Obesity may present unique challenges in terms of perioperative analgesia. A significant proportion of obese patients have obstructive sleep apnea (OSA) and, vice versa, up to 90% of OSA patients may have obesity.272 Thus pain management plans for patients with severe obesity, morbid obesity, or OSA include a multimodal analgesia approach that avoids or limits sedating medications and systemic opioids and utilizes regional anesthesia modalities.273,274 This is consistent with the guidelines from the ASA Task Force on perioperative management of OSA patients.275 A study by Batistich and colleagues demonstrated that administration of regional anesthesia and systemic non-opioid analgesia to morbidly obese patients undergoing bariatric surgery decreased the requirement for systemic opioids.276 If sedative medications and systemic opioids are administered, obese patients and patients with OSA should be monitored for respiratory depression during the first 24 hours postoperatively, and providers should consider instituting continuous and/or remote pulse oximetry.275,277 Furthermore, regional anesthesia may be more technically challenging and associated with block failure in obese patients. Nielsen et al. demonstrated that obese patients were 1.62 times more likely than non-obese patients to experience block failure.278 Finally, the regional anesthesiologist must consider the elevated risk for anticoagulation needs in the obese population postoperatively.279 Refer to the section below regarding “Patients on Anticoagulation.”

Trauma and critically ill patients experience an amplified inflammatory response, which may activate peripheral nociceptors and initiate neurogenic inflammation that increases the release of certain nociceptive neurotransmitters such as substance P and calcitonin gene-related peptide.288 Undertreatment of pain in trauma and critically ill patients is a major concern. It may be attributed to the inability to perform a proper pain assessment, concern for unstable hemodynamics, fear of sedation and analgesia masking and interfering with the diagnosis of underlying injuries, the misconception that sleep implies lack of pain, concern for addiction, and the misconception that trauma patients do not recall painful episodes.289–291 After establishing stable hemodynamics, cautious analgesic administration is indicated and may even make the patient more cooperative after adequate pain control is achieved, permitting further assessment and detection of unrecognized injuries. This may be especially critical in assessing cervical spine injuries because distracting injuries may interfere with accurate diagnosis.292 Peripheral nerve blockade and neuraxial techniques play an important role and may reduce the need for opioids and other sedative agents. Various regional anesthesia techniques may offer significant analgesia depending on the location of the injury. Brachial plexus blocks, lower extremity blocks, and neuraxial blocks may provide analgesia to the upper extremity, lower extremity, and thoracic/truncal injuries, respectively. With rib fractures, neuraxial analgesia, paravertebral blocks, ESPB, and intercostal blocks offer significant analgesia, decrease the need for opioids, and may be associated with improved respiratory indices by preventing splinting (improved oxygenation, tidal volume, and inspiratory force; decreased atelectasis and ventilation/perfusion mismatch).293–295 If neuraxial blockade is pursued, the proceduralist should ensure definitive spinal cord injury clearance. Furthermore, in patients with head trauma and the potential for elevated intracranial pressure, neuraxial techniques may not be an option because of the potential for herniation of the brain and cerebral structures as well as expansion of intracranial hematomas.296 Additionally, coagulopathy is common in patients with polytrauma, which would be a contraindication to neuraxial analgesia. It is also recommended

Patients with Pulmonary Disease Patients with pulmonary disease and respiratory insufficiency may benefit from utilizing regional anesthesia and avoiding sedative medications and general anesthesia.280 However, the adverse effect profile of certain regional techniques may be detrimental to a patient with existing pulmonary disease and merits discussion. Ipsilateral phrenic nerve palsy is a common complication in brachial plexus blocks and almost always occurs in interscalene blocks.281,282 While healthy patients may compensate for the decrease in pulmonary function, patients with cardiopulmonary disorders and moderate to severe respiratory dysfunction (e.g. severe chronic obstructive pulmonary disease, preexisting

372

PA RT 4 Clinical Conditions: Evaluation and Treatment

that certain peripheral nerve blocks performed close to the neuraxis (e.g. lumbar plexus block, paravertebral blocks) and at noncompressible sites (e.g. infraclavicular nerve block) be avoided in polytrauma cases with coagulopathy. Finally, hemorrhagic shock and hemodynamic instability are commonly present in trauma patients, leading to ischemia and multiple-organ dysfunction.297 Ketamine and various non-opioid analgesics have been shown to provide effective analgesia with limited effects on hemodynamics.298 Furthermore, sympathectomy from neuraxial local anesthetics may be undesirable in trauma patients with hemodynamic instability; in such cases, opioid-only infusions may be utilized with a better hemodynamic profile.

Patients on Anticoagulation The incidence of bleeding complications from neuraxial blocks is unknown, but some sources cite an incidence of one in 150,000 epidural blocks and one in 220,000 spinal blocks.299 This risk is elevated in certain populations, such as those taking anticoagulants and those with coagulopathy disorders. Guidelines on performing regional anesthetic techniques are based on guidelines derived from a retrospective analysis of observational data and pharmacologic dosing studies.299 There are no laboratory models available, and prospective randomized studies are not possible because of ethical reasons and the requirement for very large sample sizes. Finally, this issue is further compounded by medicationrelated factors (duration of therapy, degree of anticoagulation),

procedure-related factors (location of regional block, need for catheter placement), patient-specific factors (obesity, advanced age, personal or family history of coagulopathy, trauma, pregnancy), surgery-related factors, and other pharmacologic factors (concomitant use of herbal medications that increase the risk of bleeding, polypharmacy, and drug-drug interactions), all of which may impact bleeding risk.299 As previously mentioned, certain regional techniques are less suitable for patients with potential coagulopathy and increased risk for bleeding, including neuraxial analgesia, nerve blocks performed close to the neuraxis (e.g. lumbar plexus block, paravertebral blocks), and peripheral nerve blocks performed at non-compressible sites (e.g. infraclavicular nerve block). The proceduralist should also refer to recommendations and guidelines published by reputable societies such as the American Society of Regional Anesthesia (ASRA) and the European Society of Regional Anesthesia (ESRA) regarding discontinuation of anticoagulation perioperatively and for high-risk regional anesthetic procedures.300,301 Variations between the two practice recommendations have been narrowed as members of the ESRA anticoagulation Writing Committee helped formulate the latest edition of the ASRA guidelines.300,301 A thorough risk-benefit analysis of performing regional anesthesia in anti-coagulated patients is warranted and should be individualized. Further details on the implications of anticoagulation from common pain related procedures are included in Chapter 74.

Conclusion With the increased implementation of ERAS and multimodal analgesia pathways in the perioperative setting, studies continue to show improvements in patient-reported pain scores, improvements in rehabilitation, and decreased hospital stays. Acute pain proceduralists should consider for each patient a unique and individualized treatment plan while taking into

account the nature of the surgery, anatomic location, procedural factors, expected hospital duration, and side effect profile. Unless contraindicated, multimodal pathways should always include NSAIDs or acetaminophen and utilize regional anesthetic techniques.

Key Points • While opioids remain the mainstay of postoperative analgesia for moderate to severe pain, multimodal analgesia is recommended and includes other non-opioid analgesics with different mechanisms of action. • Neuraxial analgesia provides superior pain control over systemic opioids for various abdominal, thoracic, and lower extremity surgeries. This route of analgesia is not suitable in certain scenarios, including therapeutic anti-coagulation, bleeding disorders, certain neuroanatomic abnormalities, elevated intracranial pressure, and intracranial hematoma. • Lumbar plexus blocks provide analgesia for hip and knee procedures, while the psoas compartment block is considered an advanced regional anesthetic block because of its proximity to the neuraxis as well as its non-compressible location. • Sciatic nerve blockade may be performed through various approaches, including parasacral, subgluteal, and popliteal, as well as surgical anesthesia and postoperative analgesia for TKA and below the knee surgeries. • The interscalene brachial plexus block provides analgesia for shoulder surgeries, supraclavicular block provides analgesia for upper arm and elbow surgeries, while both infraclavicular and

•

•

•

•

axillary blocks provide analgesia for elbow, forearm, and hand surgeries. Depending on the approach to brachial plexus blockade, sparing of various nerves may occur, including the ulnar nerve (interscalene block), musculocutaneous nerve (axillary block), and intercostobrachial nerve (spared in all brachial plexus blocks). The transversus abdominus plane, rectus abdominus, and ilioinguinal/iliohypogastric nerve blocks provide somatic pain coverage of the abdominal wall but do not provide visceral pain coverage. Neuraxial analgesia, paravertebral blocks, and intercostal blocks may provide analgesia for breast, thoracic, cardiac, and upper abdominal surgeries, although more side effects are associated with neuraxial techniques. Administration of opioid analgesics and regional anesthesia warrants special consideration of the adverse effect profile in certain at-risk populations, including obese patients, patients with OSA, trauma and critically ill patients, patients with pulmonary disease, patients with bleeding disorders, or those taking anticoagulant medications.

 

CHAPTER 26

Regional and Multimodal Treatments of Perioperative Pain

373

Acknowledgments The authors acknowledge that some of this chapter’s information has been modified from previous editions of Practical Management of Pain, including “Postoperative Pain and Other Acute Pain Syn-

dromes” authored by Drs. Marie N. Hanna, Jean-Pierre P. Ouanes, and Vicente Garcia Tomas.

Suggested Readings

offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005;103(6):1296–1304. Ilfeld BM. Continuous peripheral nerve blocks: An update of the published evidence and comparison with novel alternative analgesic modalities. Anesth Analg. 2017;124(1):308–335. Liu SS. Evidence basis for ultrasound-guided block characteristic onset, quality, and duration. Reg Anesth Pain Med. 2016;41(2):205–220. Melnyk M, Casey RG, Black P, Koupparis AJ. Enhanced recovery after surgery (ERAS) protocols: Time to change practice? Can Urol Assoc J. 2011;5(5):342–348. Neal JM, Brull R, Horn JL, et al. The second American Society of Regional Anesthesia and Pain Medicine evidence-based medicine assessment of ultrasound-guided regional anesthesia: Executive summary. Reg Anesth Pain Med. 2016;41(2):181–194. Salinas F, Tran D, Benzon HT, Neal J. Lower extremity regional anesthesia: Essentials of our current understanding. Reg Anesth Pain Med. 2019;44:143–180. The references for this chapter can be found at ExpertConsult.com.

American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: An updated report by the American Society of Anesthesiologists task force on acute pain management. Anesthesiology. 2012;116(2):248–273. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5):588–593. Chin KJ, McDonnell JG, Carvalho B, Sharkey A, Pawa A, Gadsden J. Essentials of our current understanding: Abdominal wall blocks. Reg Anesth Pain Med. 2017;42(2):133–183. Clarke H, Poon M, Weinrib A, Katznelson R, Wentlandt K, Katz J. Preventive analgesia and novel strategies for the prevention of chronic post-surgical pain. Drugs. 2015;75(4):339–351. Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine

References 1. American Society of Anesthesiologists task force on acute pain management. Practice guidelines for acute pain management in the perioperative setting: An updated report by the American Society of Anesthesiologists task force on acute pain management. Anesthesiology. 2012;116(2):248–273. 2. Steglitz J, Buscemi J, Ferguson MJ. The future of pain research, education, and treatment: A summary of the IOM report “relieving pain in America: A blueprint for transforming prevention, care, education, and research.” Transl Behav Med. 2012;2(1):6–8. 3. Ballantyne JC, Carr DB, Chalmers TC, Dear KB, Angelillo IF, Mosteller F. Postoperative patient-controlled analgesia: Metaanalyses of initial randomized control trials. J Clin Anesth. 1993;5(3): 182–193. 4. Gan TJ. Poorly controlled postoperative pain: Prevalence, consequences, and prevention. J Pain Res. 2017;10:2287–2298. 5. Desborough JP. The stress response to trauma and surgery. Br J Anaesth. 2000;85(1):109–117. 6. Wilmore DW. From Cuthbertson to fast-track surgery: 70 years of progress in reducing stress in surgical patients. Ann Surg. 2002;236(5):643–648. 7. Holte K, Kehlet H. Postoperative ileus: A preventable event. Br J Surg. 2000;87(11):1480–1493. 8. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77(5):1048– 1056. 9. Clarke H, Poon M, Weinrib A, Katznelson R, Wentlandt K, Katz J. Preventive analgesia and novel strategies for the prevention of chronic post-surgical pain. Drugs. 2015;75(4):339–351. 10. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg. 2005;101(5):1427–1432. 11. Hebl JR, Dilger JA, Byer DE, et  al. A pre-emptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery. Reg Anesth Pain Med. 2008;33(6):510–517. 12. Neal JM. Ultrasound-guided regional anesthesia and patient safety: Update of an evidence-based analysis. Reg Anesth Pain Med. 2016;41(2):195–204. 13. Neil MJ, Macrae WA. Post surgical pain- the transition from acute to chronic pain. Rev Pain. 2009;3(2):6–9. 14. Raja SN, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology. 1988;68(4):571–590. 15. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306(5944):686–688. 16. Dai YQ, Jin DZ, Zhu XZ, Lei DL. Triptolide inhibits COX-2 expression via NF-kappa B pathway in astrocytes. Neurosci Res. 2006;55(2):154–160. 17. Buvanendran A, Kroin JS, Berger RA, et al. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology. 2006;104(3):403–410. 18. Reuben SS, Buvanendran A, Kroin JS, Steinberg RB. Postop erative modulation of central nervous system prostaglandin E2 by cyclooxygenase inhibitors after vascular surgery. Anesthesiology. 2006;104(3):411–416. 19. Caumo W, Schmidt AP, Schneider CN, et al. Preoperative predictors of moderate to intense acute postoperative pain in patients undergoing abdominal surgery. Acta Anaesthesiol Scand. 2002;46(10):1265–1271. 20. Shinn HK, Kim BG, Jung JK, Kwon HU, Yang C, Won J. Prolonged hemidiaphragmatic paresis following continuous interscalene brachial plexus block: A case report. Medicine (Baltimore). 2016;95(24):e3891. 21. Neal JM, Bernards CM, Hadzic A, et al. ASRA practice advisory on neurologic complications in regional anesthesia and pain medicine. Reg Anesth Pain Med. 2008;33(5):404–415.

22. Garimella V, Cellini C. Postoperative pain control. Clin Colon Rect Surg. 2013;26(3):191–196. 23. Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: A metaanalysis. Anesth Analg. 2005;100(3):757–773 table of contents. 24. Ghezzi F, Cromi A, Bergamini V, et  al. Preemptive port site local anesthesia in gynecologic laparoscopy: A randomized, controlled trial. J Minim Invas Gynecol. 2005;12(3):210–215. 25. Tierney S, Perlas A. Informed consent for regional anesthesia. Curr Opin Anaesthesiol. 2018;31(5):614–621. 26. D’Souza RS, Johnson RL, Bettini L, Schulte PJ, Burkle C. Room for improvement: A systematic review and meta-analysis on the informed consent process for emergency surgery. Mayo Clin Proc. 2019;94(9):1786–1798. 27. Mulroy MF, Weller RS, Liguori GA. A checklist for performing regional nerve blocks. Reg Anesth Pain Med. 2014;39(3):195–199. 28. Henshaw DS, Turner JD, Dobson SW, et al. Preprocedural checklist for regional anesthesia: Impact on the incidence of wrong site nerve blockade (an 8-year perspective). Reg Anesth Pain Med. 2019 Jan 13;rapm-2018-000033. 29. Helander EM, Menard BL, Harmon CM, et al. Multimodal analgesia, current concepts, and acute pain considerations. Curr Pain Headache Rep. 2017;21(1):3. 30. Melnyk M, Casey RG, Black P, Koupparis AJ. Enhanced recovery after surgery (ERAS) protocols: Time to change practice? Can Urol Assoc J. 2011;5(5):342–348. 31. Lassen K, Soop M, Nygren J, et  al. Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) group recommendations Arch Surg. 2009;144(10): 961–969. 32. El-Boghdadly K, Pawa A, Chin KJ. Local anesthetic systemic toxicity: Current perspectives. Local Reg Anesth. 2018;11:35–44. 33. Weaver JM. Calculating the maximum recommended dose of local anesthetic. J Calif Dent Assoc. 2007;35(1):61–63. 34. Förster JG, Rosenberg PH. Clinically useful adjuvants in regional anaesthesia. Curr Opin Anaesthesiol. 2003;16(5):477–486. 35. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5): 588–593. 36. Pöpping DM, Elia N, Marret E, Remy C, Tramèr MR. Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic surgery: A meta-analysis. Arch Surg. 2008;143(10):990–999 discussion 1000. 37. Nishimori M, Low JH, Zheng H, Ballantyne JC. Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev. 2012;7(7):CD005059. 38. Liu SS, Block BM, Wu CL. Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery: A metaanalysis. Anesthesiology. 2004;101(1):153–161. 39. Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: A meta-analysis. Anesth Analg. 2001;93(4):853–858. 40. Jørgensen H, Wetterslev J, Møiniche S, Dahl JB. Epidural local anaesthetics versus opioid-based analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery. Cochrane Database Syst Rev. 2000;4(4):CD001893. 41. Bujedo BM, Santos SG, Azpiazu AU. A review of epidural and intrathecal opioids used in the management of postoperative pain. J Opioid Manag. 2012;8(3):177–192. 42. Cooper DW. Can epidural fentanyl induce selective spinal hyperalgesia? Anesthesiology. 2000;93(4):1153–1154. 43. Sultan P, Gutierrez MC, Carvalho B. Neuraxial morphine and respiratory depression: Finding the right balance. Drugs. 2011;71(14):1807–1819. 44. Walder B, Schafer M, Henzi I, Tramèr MR. Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand. 2001;45(7):795–804. 373.e.1

373.e.2

References

45. Kjellberg F, Tramèr MR. Pharmacological control of opioid-induced pruritus: A quantitative systematic review of randomized trials. Eur J Anaesthesiol. 2001;18(6):346–357. 46. Bucklin BA, Chestnut DH, Hawkins JL. Intrathecal opioids versus epidural local anesthetics for labor analgesia: A meta-analysis. Reg Anesth Pain Med. 2002;27(1):23–30. 47. Gedney JA, Liu EH. Side-effects of epidural infusions of opioid bupivacaine mixtures. Anaesthesia. 1998;53(12):1148–1155. 48. Sarma J, Narayana PS, Ganapathi P, Shivakumar MC. A comparative study of intrathecal clonidine and dexmedetomidine on characteristics of bupivacaine spinal block for lower limb surgeries. Anesth Essays Res. 2015;9(2):195–207. 49. Naghibi T, Dobakhti F, Mazloomzadeh S, Dabiri A, Molai B. Comparison between intrathecal and intravenous betamethasone for post-operative pain following cesarean section: A randomized clinical trial. Pak J Med Sci. 2013;29(2):514–518. 50. Klamt JG, Slullitel A, Garcia IV, Prado WA. Postoperative analgesic effect of intrathecal neostigmine and its influence on spinal anaesthesia. Anaesthesia. 1997;52(6):547–551. 51. Patro SS, Deshmukh H, Ramani YR, Das G. Evaluation of dexmedetomidine as an adjuvant to intrathecal bupivacaine in infraumbilical surgeries. J Clin Diagn Res. 2016;10(3):UC13–UC16. 52. Hassenbusch SJ, Gunes S, Wachsman S, Willis KD. Intrathecal clonidine in the treatment of intractable pain: A phase I/II study. Pain Med. 2002;3(2):85–91. 53. Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA, Wu CL. Efficacy of postoperative epidural analgesia: A meta-analysis. JAMA. 2003;290(18):2455–2463. 54. Bernards CM, Shen DD, Sterling ES, et  al. Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 2): Effect of epinephrine. Anesthesiology. 2003;99(2):466–475. 55. Kim DD, Patel A, Sibai N. Conversion of intrathecal opioids to fentanyl in chronic pain patients with implantable pain pumps: A retrospective study. Neuromodulation. 2019;22(7):823–827. 56. Zaric D, Nydahl PA, Philipson L, Samuelsson L, Heierson A, Axelsson K. The effect of continuous lumbar epidural infusion of ropivacaine (0.1%, 0.2%, and 0.3%) and 0.25% bupivacaine on sensory and motor block in volunteers: A double-blind study. Reg Anesth. 1996;21(1):14–25. 57. Ferrante FM, Lu L, Jamison SB, Datta S. Patient-controlled epidural analgesia: Demand dosing. Anesth Analg. 1991;73(5):547–552. 58. Hwang BY, Kwon JY, Jeon SE, et  al. Comparison of patient controlled epidural analgesia with patient-controlled intravenous analgesia for laparoscopic radical prostatectomy. Korean J Pain. 2018;31(3):191–198. 59. Paech MJ, Pavy TJ, Orlikowski CE, Lim W, Evans SF. Postoperative epidural infusion: A randomized, double-blind, dose-finding trial of clonidine in combination with bupivacaine and fentanyl. Anesth Analg. 1997;84(6):1323–1328. 60. Sakaguchi Y, Sakura S, Shinzawa M, Saito Y. Does adrenaline improve epidural bupivacaine and fentanyl analgesia after abdominal surgery? Anaesth Intensive Care. 2000;28(5):522–526. 61. Eastwood D, Williams C, Buchan I. Caudal epidurals: The whoosh test. Anaesthesia. 1998;53(3):305–307. 62. Sivashankar KR, Dass SK. Caudal analgesia for postoperative pain relief in children. Med J Armed Forces India. 1996;52(4):242–244. 63. Dalens B, Hasnaoui A. Caudal anesthesia in pediatric surgery: Success rate and adverse effects in 750 consecutive patients. Anesth Analg. 1989;68(2):83–89. 64. Rhee WJ, Chung CJ, Lim YH, Lee KH, Lee SC. Factors in patient dissatisfaction and refusal regarding spinal anesthesia. Korean J Anesthesiol. 2010;59(4):260–264. 65. Forget P, Borovac JA, Thackeray EM, Pace NL. Transient neurological symptoms (TNS) following spinal anaesthesia with lidocaine versus other local anaesthetics in adult surgical patients: A network meta-analysis. Cochrane Database Syst Rev. 2019;12:CD003006. 66. Pollock JE. Transient neurologic symptoms: Etiology, risk factors, and management. Reg Anesth Pain Med. 2002;27(6):581–586.

67. Freedman JM, Li DK, Drasner K, Jaskela MC, Larsen B, Wi S. Transient neurologic symptoms after spinal anesthesia: An epidemiologic study of 1,863 patients. Anesthesiology. 1998;89(3):633–641. 68. Zorrilla-Vaca A, Mathur V, Wu CL, Grant MC. The impact of spinal needle selection on postdural puncture headache: A metaanalysis and metaregression of randomized studies. Reg Anesth Pain Med. 2018;43(5):502–508. 69. Crosby ET. Epidural catheter migration during labour: An hypothesis for inadequate analgesia. Can J Anaesth. 1990;37(7):789–793. 70. Asato F, Nakatani K, Matayoshi Y, Katekawa Y, Chinen K. Development of a subdural motor blockade. Anaesthesia. 1993;48(1):46–49. 71. Foster LA, Deutz CK, Hutchins JL, Allen JA. Total spinal and brainstem anesthesia as complication of paravertebral ropivacaine administration. Neurol Clin Pract. 2017;7(5):430–432. 72. Liu JL, Wang XL, Gong MW, et  al. Comparative outcomes of peripheral nerve blocks versus general anesthesia for hip fractures in geriatric Chinese patients. Patient Prefer Adherence. 2014;8: 651–659. 73. Capdevila X, Barthelet Y, Biboulet P, Ryckwaert Y, Rubenovitch J, d’Athis F. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology. 1999;91(1):8–15. 74. Fowler SJ, Symons J, Sabato S, Myles PS. Epidural analgesia compared with peripheral nerve blockade after major knee surgery: A systematic review and meta-analysis of randomized trials. Br J Anaesth. 2008;100(2):154–164. 75. Visoiu M, Joy LN, Grudziak JS, Chelly JE. The effectiveness of ambulatory continuous peripheral nerve blocks for postoperative pain management in children and adolescents. Paediatr Anaesth. 2014;24(11):1141–1148. 76. Ludot H, Berger J, Pichenot V, Belouadah M, Madi K, Malinovsky JM. Continuous peripheral nerve block for postoperative pain control at home: A prospective feasibility study in children. Reg Anesth Pain Med. 2008;33(1):52–56. 77. Fredrickson MJ, Ball CM, Dalgleish AJ. A prospective randomized comparison of ultrasound guidance versus neurostimulation for interscalene catheter placement. Reg Anesth Pain Med. 2009;34(6):590–594. 78. Salinas FV. Ultrasound and review of evidence for lower extremity peripheral nerve blocks. Reg Anesth Pain Med. 2010;35(2 Suppl): S16–S25. 79. Buettner J, Klose R, Hoppe U, Wresch P. Serum levels of mepivacaine-HCl during continuous axillary brachial plexus block. Reg Anesth. 1989;14(3):124–127. 80. Casati A, Vinciguerra F, Scarioni M, et al. Lidocaine versus ropivacaine for continuous interscalene brachial plexus block after open shoulder surgery. Acta Anaesthesiol Scand. 2003;47(3):355–360. 81. Becker DE, Reed KL. Local anesthetics: Review of pharmacological considerations. Anesth Prog. 2012;59(2):90–101 quiz 102-103. 82. Mezzatesta JP, Scott DA, Schweitzer SA, Selander DE. Continuous axillary brachial plexus block for postoperative pain relief. Intermittent bolus versus continuous infusion. Reg Anesth. 1997;22(4): 357–362. 83. Singelyn FJ, Seguy S, Gouverneur JM. Interscalene brachial plexus analgesia after open shoulder surgery: Continuous versus patientcontrolled infusion. Anesth Analg. 1999;89(5):1216–1220. 84. Pöpping DM, Elia N, Marret E, Wenk M, Tramèr MR. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: A meta-analysis of randomized trials. Anesthesiology. 2009;111(2):406–415. 85. Brejt N, Berry J, Nisbet A, Bloomfield D, Burkill G. Pelvic radiculopathies, lumbosacral plexopathies, and neuropathies in oncologic disease: A multidisciplinary approach to a diagnostic challenge. Cancer Imaging. 2013;13(4):591–601. 86. Mannion S, Barrett J, Kelly D, Murphy DB, Shorten GD. A description of the spread of injectate after psoas compartment block using magnetic resonance imaging. Reg Anesth Pain Med. 2005;30(6):567–571.

References

87. Chayen D, Nathan H, Chayen M. The psoas compartment block. Anesthesiology. 1976;45(1):95–99. 88. Luber MJ, Greengrass R, Vail TP. Patient satisfaction and effectiveness of lumbar plexus and sciatic nerve block for total knee arthroplasty. J Arthroplasty. 2001;16(1):17–21. 89. Goytizolo EA, Stundner O, Rúa SH, et al. The effect of regional analgesia on vascular tone in hip arthroplasty patients. HSS J. 2016;12(2):125–131. 90. Kaloul I, Guay J, Côté C, Fallaha M. The posterior lumbar plexus (psoas compartment) block and the three-in-one femoral nerve block provide similar postoperative analgesia after total knee replacement. Can J Anaesth. 2004;51(1):45–51. 91. Stevens RD, Van Gessel E, Flory N, Fournier R, Gamulin Z. Lumbar plexus block reduces pain and blood loss associated with total hip arthroplasty. Anesthesiology. 2000;93(1):115–121. 92. Guay J, Johnson RL, Kopp S. Nerve blocks or no nerve blocks for pain control after elective hip replacement (arthroplasty) surgery in adults. Cochrane Database Syst Rev. 2017;10:CD011608. 93. Türker G, Uçkunkaya N, Yavaşçaoğlu B, Yilmazlar A, Ozçelik S. Comparison of the catheter-technique psoas compartment block and the epidural block for analgesia in partial hip replacement surgery. Acta Anaesthesiol Scand. 2003;47(1):30–36. 94. de Leeuw MA, Zuurmond WW, Perez RS. The psoas compartment block for hip surgery: The past, present, and future. Anesthesiol Res Pract. 2011;2011:159541. 95. Naja Z, el Hassan MJ, Khatib H, Ziade MF, Lönnqvist PA. Combined sciatic-paravertebral nerve block vs. general anaesthesia for fractured hip of the elderly. Middle East J Anaesthesiol. 2000;15(5):559–568. 96. Petchara S, Paphon S, Vanlapa A, Boontikar P, Disya K. Combined lumbar-sacral plexus block in high surgical risk geriatric patients undergoing early hip fracture surgery. Malays Orthop J. 2015;9(3):28–34. 97. Wong TL, Kikuta S, Iwanaga J, Tubbs RS. A multiply split femoral nerve and psoas quartus muscle. Anat Cell Biol. 2019;52(2): 208–210. 98. Jakubowicz M. Topography of the femoral nerve in relation to components of the iliopsoas muscle in human fetuses. Folia Morphol (Warsz). 1991;50(1-2):91–101. 99. Refai NA, Tadi P. Anatomy, Bony Pelvis and Lower Limb, Thigh Femoral Nerve. 2020 Oct 27. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 32310525. 100. Idestrup C, Sawhney M, Nix C, Kiss A. The incidence of hematoma formation in patients with continuous femoral catheters following total knee arthroplasty while receiving rivaroxaban as thromboprophylaxis: An observational study. Reg Anesth Pain Med. 2014;39(5):414–417. 101. Ilfeld BM, Mariano ER, Madison SJ, et  al. Continuous femoral versus posterior lumbar plexus nerve blocks for analgesia after hip arthroplasty: A randomized, controlled study. Anesth Analg. 2011;113(4):897–903. 102. Koh IJ, Choi YJ, Kim MS, Koh HJ, Kang MS, In Y. Femoral nerve block versus Adductor Canal Block for analgesia after total knee arthroplasty. Knee Surg Relat Res. 2017;29(2):87–95. 103. Ben-David B, Schmalenberger K, Chelly JE. Analgesia after total knee arthroplasty: Is continuous sciatic blockade needed in addition to continuous femoral blockade? Anesth Analg. 2004;98(3): 747–749 table of contents. 104. Williams BA, Kentor ML, Vogt MT, et al. Femoral-sciatic nerve blocks for complex outpatient knee surgery are associated with less postoperative pain before same-day discharge: A review of 1,200 consecutive cases from the period 1996-1999. Anesthesiology. 2003;98(5):1206–1213. 105. Macalou D, Trueck S, Meuret P, et al. Postoperative analgesia after total knee replacement: The effect of an obturator nerve block added to the femoral 3-in-1 nerve block. Anesth Analg. 2004;99(1): 251–254. 106. Singelyn FJ, Deyaert M, Joris D, Pendeville E, Gouverneur JM. Effects of intravenous patient-controlled analgesia with morphine,

373.e.3

continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg. 1998;87(1):88–92. 107. Paul JE, Arya A, Hurlburt L, et al. Femoral nerve block improves analgesia outcomes after total knee arthroplasty: A meta-analysis of randomized controlled trials. Anesthesiology. 2010;113(5):1144–1162. 108. Chelly JE, Greger J, Gebhard R, et al. Continuous femoral blocks improve recovery and outcome of patients undergoing total knee arthroplasty. J Arthroplasty. 2001;16(4):436–445. 109. Carli F, Clemente A, Asenjo JF, et al. Analgesia and functional outcome after total knee arthroplasty: Periarticular infiltration vs continuous femoral nerve block. Br J Anaesth. 2010;105(2):185–195. 110. Vishwanatha S, Kalappa S. Continuous femoral nerve block ade versus epidural analgesia for postoperative pain relief in knee surgeries: A randomized controlled study. Anesth Essays Res. 2017;11(3):599–605. 111. Nishio S, Fukunishi S, Juichi M, et  al. Comparison of continuous femoral nerve block, caudal epidural block, and intravenous patient-controlled analgesia in pain control after total hip arthroplasty: A prospective randomized study. Orthop Rev (Pavia). 2014;6(1):5138. 112. Sundarathiti P, Ruananukul N, Channum T, et  al. A comparison of continuous femoral nerve block (CFNB) and continuous epidural infusion (CEI) in postoperative analgesia and knee rehabilitation after total knee arthroplasty (TKA). J Med Assoc Thai. 2009;92(3):328–334. 113. Mercer D, Morrell NT, Fitzpatrick J, et al. The course of the distal saphenous nerve: A cadaveric investigation and clinical implications. Iowa Orthop J. 2011;31:231–235. 114. Kapoor R, Adhikary SD, Siefring C, McQuillan PM. The saphenous nerve and its relationship to the nerve to the vastus medialis in and around the adductor canal: An anatomical study. Acta Anaesthesiol Scand. 2012;56(3):365–367. 115. Benzon HT, Sharma S, Calimaran A. Comparison of the different approaches to saphenous nerve block. Anesthesiology. 2005;102(3):633–638. 116. Thiayagarajan MK, Kumar SV, Venkatesh S. An exact localization of adductor canal and its clinical significance: A cadaveric study. Anesth Essays Res. 2019;13(2):284–286. 117. Wong WY, Bjørn S, Strid JM, Børglum J, Bendtsen TF. Defining the location of the adductor canal using ultrasound. Reg Anesth Pain Med. 2017;42(2):241–245. 118. Gao F, Ma J, Sun W, Guo W, Li Z, Wang W. Adductor canal block versus femoral nerve block for analgesia after total knee arthroplasty: A systematic review and meta-analysis. Clin J Pain. 2017;33(4):356–368. 119. Smith JH, Belk JW, Kraeutler MJ, Houck DA, Scillia AJ, McCarty EC. Adductor canal versus femoral nerve block after anterior cruciate ligament reconstruction: A systematic review of Level I randomized controlled trials comparing early postoperative pain, opioid requirements, and quadriceps strength. Arthroscopy. 2020;36(7):1973–1980. 120. Chen J, Lesser JB, Hadzic A, Reiss W, Resta-Flarer F. Adductor canal block can result in motor block of the quadriceps muscle. Reg Anesth Pain Med. 2014;39(2):170–171. 121. Johnson RL, Duncan CM, Ahn KS, Schroeder DR, Horlocker TT, Kopp SL. Fall-prevention strategies and patient characteristics that impact fall rates after total knee arthroplasty. Anesth Analg. 2014;119(5):1113–1118. 122. Dalens B, Vanneuville G, Tanguy A. Comparison of the fascia iliaca compartment block with the 3-in-1 block in children. Anesth Analg. 1989;69(6):705–713. 123. Winnie AP, Ramamurthy S, Durrani Z. The inguinal paravascular technic of lumbar plexus anesthesia: The “3-in-1 block.” Anesth Analg. 1973;52(6):989–996. 124. Jones MR, Novitch MB, Hall OM, et al. Fascia iliaca block, history, technique, and efficacy in clinical practice. Best Pract Res Clin Anaesthesiol. 2019;33(4):407–413.

373.e.4

References

125. Capdevila X, Biboulet P, Bouregba M, Barthelet Y, Rubenovitch J, d’Athis F. Comparison of the three-in-one and fascia iliaca compartment blocks in adults: Clinical and radiographic analysis. Anesth Analg. 1998;86(5):1039–1044. 126. Dolan J, Williams A, Murney E, Smith M, Kenny GN. Ultrasound guided fascia iliaca block: A comparison with the loss of resistance technique. Reg Anesth Pain Med. 2008;33(6):526–531. 127. Thompson J, Long M, Rogers E, et al. Fascia iliaca block decreases hip fracture postoperative opioid consumption: A prospective randomized controlled trial. J Orthop Trauma. 2020;34(1):49–54. 128. Ma Y, Wu J, Xue J, Lan F, Wang T. Ultrasound-guided continuous fascia iliaca compartment block for pre-operative pain control in very elderly patients with hip fracture: A randomized controlled trial. Exp Ther Med. 2018;16(3):1944–1952. 129. Stevens M, Harrison G, McGrail M. A modified fascia iliaca compartment block has significant morphine-sparing effect after total hip arthroplasty. Anaesth Intensive Care. 2007;35(6):949–952. 130. Foss NB, Kristensen BB, Bundgaard M, et  al. Fascia iliaca compartment blockade for acute pain control in hip fracture patients: A randomized, placebo-controlled trial. Anesthesiology. 2007;106(4):773–778. 131. Wathen JE, Gao D, Merritt G, Georgopoulos G, Battan FK. A randomized controlled trial comparing a fascia iliaca compartment nerve block to a traditional systemic analgesic for femur fractures in a pediatric emergency department. Ann Emerg Med. 2007;50(2):162–171 171.e161. 132. di Benedetto P, Casati A, Bertini L. Continuous subgluteus sciatic nerve block after orthopedic foot and ankle surgery: Comparison of two infusion techniques. Reg Anesth Pain Med. 2002;27(2): 168–172. 133. di Benedetto P, Casati A, Bertini L, Fanelli G, Chelly JE. Postoperative analgesia with continuous sciatic nerve block after foot surgery: A prospective, randomized comparison between the popliteal and subgluteal approaches. Anesth Analg. 2002;94(4):996–1000 table of contents. 134. Evans H, Steele SM, Nielsen KC, Tucker MS, Klein SM. Peripheral nerve blocks and continuous catheter techniques. Anesthesiol Clin North Am. 2005;23(1):141–162. 135. Pinzur MS. Sciatic nerve block for residual limb pain following below-knee amputation. Contemp Orthop. 1991;22(3):290–292. 136. Zorrilla-Vaca A, Li J. The role of sciatic nerve block to complement femoral nerve block in total knee arthroplasty: A meta-analysis of randomized controlled trials. J Anesth. 2018;32(3):341–350. 137. Abdallah FW, Madjdpour C, Brull R. Is sciatic nerve block advantageous when combined with femoral nerve block for postoperative analgesia following total knee arthroplasty? a meta-analysis. Can J Anaesth. 2016;63(5):552–568. 138. Zhang Z, Yang Q, Xin W, Zhang Y. Comparison of local infiltration analgesia and sciatic nerve block as an adjunct to femoral nerve block for pain control after total knee arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(19):e6829. 139. Perlas A, Brull R, Chan VW, McCartney CJ, Nuica A, Abbas S. Ultrasound guidance improves the success of sciatic nerve block at the popliteal fossa. Reg Anesth Pain Med. 2008;33(3):259–265. 140. Cao X, Zhao X, Xu J, Liu Z, Li Q. Ultrasound-guided technology versus neurostimulation for sciatic nerve block: A meta-analysis. Int J Clin Exp Med. 2015;8(1):273–280. 141. Buys MJ, Arndt CD, Vagh F, Hoard A, Gerstein N. Ultrasoundguided sciatic nerve block in the popliteal fossa using a lateral approach: Onset time comparing separate tibial and common peroneal nerve injections versus injecting proximal to the bifurcation. Anesth Analg. 2010;110(2):635–637. 142. Faiz SHR, Imani F, Rahimzadeh P, Alebouyeh MR, Entezary SR, Shafeinia A. Which ultrasound-guided sciatic nerve block strategy works faster? Prebifurcation or separate tibial-peroneal nerve block? A randomized clinical trial. Anesthesiol Pain Med. 2017;7(4):e57804.

143. Zaric D, Boysen K, Christiansen J, Haastrup U, Kofoed H, Rawal N. Continuous popliteal sciatic nerve block for outpatient foot surgery–a randomized, controlled trial. Acta Anaesthesiol Scand. 2004;48(3):337–341. 144. Ma HH, Chou TA, Tsai SW, Chen CF, Wu PK, Chen WM. The efficacy and safety of continuous versus single-injection popliteal sciatic nerve block in outpatient foot and ankle surgery: A systematic review and meta-analysis. BMC Musculoskelet Disord. 2019;20(1):441. 145. Seo JH, Seo SS, Kim DH, BY Park, Park CH, Kim OG. Does combination therapy of popliteal sciatic nerve block and adductor canal block effectively control early postoperative pain after total knee arthroplasty? Knee Surg Relat Res? 2017;29(4):276–281. 146. Blumenthal S, Borgeat A, Neudörfer C, Bertolini R, Espinosa N, Aguirre J. Additional femoral catheter in combination with popliteal catheter for analgesia after major ankle surgery. Br J Anaesth. 2011;106(3):387–393. 147. Delbos A, Philippe M, Clément C, Olivier R, Coppens S. Ultrasound-guided ankle block. History revisited. Best Pract Res Clin Anaesthesiol. 2019;33(1):79–93. 148. Fredrickson MJ, White R, Danesh-Clough TK. Low-volume ultrasound-guided nerve block provides inferior postoperative analgesia compared to a higher-volume landmark technique. Reg Anesth Pain Med. 2011;36(4):393–398. 149. Chin KJ, Wong NW, Macfarlane AJ, Chan VW. Ultrasoundguided versus anatomic landmark-guided ankle blocks: A 6-year retrospective review. Reg Anesth Pain Med. 2011;36(6):611–618. 150. Urfalioglu A, Gokdemir O, Hanbeyoglu O, et al. A comparison of ankle block and spinal anesthesia for foot surgery. Int J Clin Exp Med. 2015;8(10):19388–19393. 151. Neal JM, Gerancher JC, Hebl JR, et al. Upper extremity regional anesthesia: Essentials of our current understanding, 2008. Reg Anesth Pain Med. 2009;34(2):134–170. 152. Alfred VM, Srinivasan G, Zachariah M. Comparison of ultrasound with peripheral nerve stimulator-guided technique for supraclavicular block in upper limb surgeries: A randomized controlled trial. Anesth Essays Res. 2018;12(1):50–54. 153. Honnannavar KA, Mudakanagoudar MS. Comparison between conventional and ultrasound-guided supraclavicular brachial plexus block in upper limb surgeries. Anesth Essays Res. 2017;11(2):467–471. 154. Gelfand HJ, Ouanes JP, Lesley MR, et  al. Analgesic efficacy of ultrasound-guided regional anesthesia: A meta-analysis. J Clin Anesth. 2011;23(2):90–96. 155. Fredrickson MJ, Kilfoyle DH. Neurological complication analysis of 1000 ultrasound guided peripheral nerve blocks for elective orthopaedic surgery: A prospective study. Anaesthesia. 2009;64(8): 836–844. 156. Vaid VN, Shukla A. Inter scalene block: Revisiting old technique. Anesth Essays Res. 2018;12(2):344–348. 157. Urmey WF, Grossi P, Sharrock NE, Stanton J, Gloeggler PJ. Digital pressure during interscalene block is clinically ineffective in preventing anesthetic spread to the cervical plexus. Anesth Analg. 1996;83(2):366–370. 158. Roch JJ, Sharrock NE, Neudachin L. Interscalene brachial plexus block for shoulder surgery: A proximal paresthesia is effective. Anesth Analg. 1992;75(3):386–388. 159. Bollini CA, Urmey WF, Vascello L, Cacheiro F. Relationship between evoked motor response and sensory paresthesia in interscalene brachial plexus block. Reg Anesth Pain Med. 2003;28(5):384–388. 160. Bowens C, Sripada R. Regional blockade of the shoulder: Approaches and outcomes. Anesthesiol Res Pract. 2012;2012:971963. 161. Yanovski B, Gaitini L, Volodarski D, Ben-David B. Catastrophic complication of an interscalene catheter for continuous peripheral nerve block analgesia. Anaesthesia. 2012;67(10):1166–1169. 162. Kim YD, Yu JY, Shim J, Heo HJ, Kim H. Risk of encountering dorsal scapular and long thoracic nerves during ultrasound-guided interscalene brachial plexus block with nerve stimulator. Korean J Pain. 2016;29(3):179–184.

References 373.e.5

163. Borgeat A, Tewes E, Biasca N, Gerber C. Patient-controlled interscalene analgesia with ropivacaine after major shoulder surgery: PCIA vs PCA. Br J Anaesth. 1998;81(4):603–605. 164. Borgeat A, Schäppi B, Biasca N, Gerber C. Patient-controlled analgesia after major shoulder surgery: Patient-controlled interscalene analgesia versus patient-controlled analgesia. Anesthesiology. 1997;87(6):1343–1347. 165. Yan S, Zhao Y, Zhang H. Efficacy and safety of interscalene block combined with general anesthesia for arthroscopic shoulder surgery: A meta-analysis. J Clin Anesth. 2018;47:74–79. 166. Klein SM, Grant SA, Greengrass RA, et  al. Interscalene brachial plexus block with a continuous catheter insertion system and a disposable infusion pump. Anesth Analg. 2000;91(6):1473–1478. 167. Ilfeld BM, Morey TE, Wright TW, Chidgey LK, Enneking FK. Continuous interscalene brachial plexus block for postoperative pain control at home: A randomized, double-blinded, placebo-controlled study. Anesth Analg. 2003;96(4):1089–1095 table of contents. 168. Ilfeld BM, Vandenborne K, Duncan PW, et al. Ambulatory continuous interscalene nerve blocks decrease the time to discharge readiness after total shoulder arthroplasty: A randomized, triple-masked, placebo-controlled study. Anesthesiology. 2006;105(5):999–1007. 169. Auyong DB, Yuan SC, Choi DS, Pahang JA, Slee AE, Hanson NA. A double-blind randomized comparison of continuous interscalene, supraclavicular, and suprascapular blocks for total shoulder arthroplasty. Reg Anesth Pain Med. 2017;42(3):302–309. 170. Schubert AK, Dinges HC, Wulf H, Wiesmann T. Interscalene versus supraclavicular plexus block for the prevention of postoperative pain after shoulder surgery: A systematic review and meta-analysis. Eur J Anaesthesiol. 2019;36(6):427–435. 171. Kohli S, Yadav N, Prasad A, Banerjee SS. Anatomic variation of subclavian artery visualized on ultrasound-guided supraclavicular brachial plexus block. Case Rep Med. 2014;2014:394920. 172. Brown DL, Cahill DR, Bridenbaugh LD. Supraclavicular nerve block: Anatomic analysis of a method to prevent pneumothorax. Anesth Analg. 1993;76(3):530–534. 173. Ryu T, Kil BT, Kim JH. Comparison between ultrasound-guided supraclavicular and interscalene brachial plexus blocks in patients undergoing arthroscopic shoulder surgery: A prospective, randomized, parallel study. Medicine (Baltimore). 2015;94(40):e1726. 174. Gupta K, Bhandari S, Singhal D, Bhatia PS. Pneumothorax following ultrasound guided supraclavicular brachial plexus block. J Anaesthesiol Clin Pharmacol. 2012;28(4):543–544. 175. Kumari A, Gupta R, Bhardwaj A, Madan D. Delayed pneumothorax after supraclavicular block. J Anaesthesiol Clin Pharmacol. 2011;27(1):121–122. 176. Erickson JM, Louis DS, Naughton NN. Symptomatic phrenic nerve palsy after supraclavicular block in an obese man. Orthopedics. 2009;32(5):368. 177. Singh SK, Katyal S, Kumar A, Kumar P. Massive hemothorax: A rare complication after supraclavicular brachial plexus block. Anesth Essays Res. 2014;8(3):410–412. 178. Draeger RW, Messer TM. Suprascapular nerve palsy following supraclavicular block for upper extremity surgery: Report of 3 cases. J Hand Surg Am. 2012;37(12):2576–2579. 179. Tran DQ, Russo G, Muñoz L, Zaouter C, Finlayson RJ. A prospective, randomized comparison between ultrasound-guided supraclavicular, infraclavicular, and axillary brachial plexus blocks. Reg Anesth Pain Med. 2009;34(4):366–371. 180. Stav A, Reytman L, Stav MY, et al. Comparison of the supraclavicular, infraclavicular and axillary approaches for ultrasound-guided brachial plexus block for surgical anesthesia. Rambam Maimonides Med J. 2016;7(2). 181. Dai W, Tang M, He K. The effect and safety of dexmedetomidine added to ropivacaine in brachial plexus block: A metaanalysis of randomized controlled trials. Medicine (Baltimore). 2018;97(41):e12573. 182. Duncan M, Shetti AN, Tripathy DK, Roshansingh D, Krishnaveni N. A comparative study of nerve stimulator versus ultrasound-guided

supraclavicular brachial plexus block. Anesth Essays Res. 2013;7(3): 359–364. 183. Chelly JE, Ben-David B, Williams BA, Kentor ML. Anesthesia and postoperative analgesia: Outcomes following orthopedic surgery. Orthopedics. 2003;26(8 Suppl):s865–s871. 184. Sauter AR, Smith HJ, Stubhaug A, Dodgson MS, Klaastad Ø. Use of magnetic resonance imaging to define the anatomical location closest to all three cords of the infraclavicular brachial plexus. Anesth Analg. 2006;103(6):1574–1576. 185. Rodríguez J, Bárcena M, Alvarez J. Restricted infraclavicular distribution of the local anesthetic solution after infraclavicular brachial plexus block. Reg Anesth Pain Med. 2003;28(1):33–36. 186. Arcand G, Williams SR, Chouinard P, et  al. Ultrasound-guided infraclavicular versus supraclavicular block. Anesth Analg. 2005; 101(3):886–890 table of contents. 187. Sanchez HB, Mariano ER, Abrams R, Meunier M. Pneumothorax following infraclavicular brachial plexus block for hand surgery. Orthopedics. 2008;31(7):709. 188. Petrar SD, Seltenrich ME, Head SJ, Schwarz SK. Hemidiaphragmatic paralysis following ultrasound-guided supraclavicular versus infraclavicular brachial plexus blockade: A randomized clinical trial. Reg Anesth Pain Med. 2015;40(2):133–138. 189. Mariano ER, Sandhu NS, Loland VJ, et  al. A randomized comparison of infraclavicular and supraclavicular continuous peripheral nerve blocks for postoperative analgesia. Reg Anesth Pain Med. 2011;36(1):26–31. 190. Hadzic A, Arliss J, Kerimoglu B, et al. A comparison of infraclavicular nerve block versus general anesthesia for hand and wrist day-case surgeries. Anesthesiology. 2004;101(1):127–132. 191. Ilfeld BM, Morey TE, Enneking FK. Continuous infraclavicular brachial plexus block for postoperative pain control at home: A randomized, double-blinded, placebo-controlled study. Anesthesiology. 2002;96(6):1297–1304. 192. Ammar AS, Mahmoud KM. Ultrasound-guided single injection infraclavicular brachial plexus block using bupivacaine alone or combined with dexmedetomidine for pain control in upper limb surgery: A prospective randomized controlled trial. Saudi J Anaesth. 2012;6(2):109–114. 193. Buchanan TS, Erickson JC. Selective block of the brachialis motor point. An anatomic investigation of musculocutaneous nerve branching. Reg Anesth. 1996;21(2):89–92. 194. Spence BC, Sites BD, Beach ML. Ultrasound-guided musculocutaneous nerve block: A description of a novel technique. Reg Anesth Pain Med. 2005;30(2):198–201. 195. Yamamoto K, Tsubokawa T, Shibata K, Kobayashi T. Area of paresthesia as determinant of sensory block in axillary brachial plexus block. Reg Anesth. 1995;20(6):493–497. 196. Liu FC, Liou JT, Tsai YF, et al. Efficacy of ultrasound-guided axillary brachial plexus block: A comparative study with nerve stimulator-guided method. Chang Gung Med J. 2005;28(6):396–402. 197. Chin KJ, Handoll HH. Single, double or multiple-injection techniques for axillary brachial plexus block for hand, wrist or forearm surgery in adults. Cochrane Database Syst Rev. 2011;7(7): CD003842. 198. Chan VW, Peng PW, Kaszas Z, et al. A comparative study of general anesthesia, intravenous regional anesthesia, and axillary block for outpatient hand surgery: Clinical outcome and cost analysis. Anesth Analg. 2001;93(5):1181–1184. 199. McCartney CJ, Brull R, Chan VW, et al. Early but no long-term benefit of regional compared with general anesthesia for ambulatory hand surgery. Anesthesiology. 2004;101(2):461–467. 200. Vaughn N, Rajan N, Darowish M. Intravenous regional anesthesia using a forearm tourniquet: A safe and effective technique for outpatient hand procedures. Hand (N Y). 2020;15(3):353–359. 201. Eckmann MS, Ramamurthy S, Griffin JG. Intravenous regional ketorolac and lidocaine in the treatment of complex regional pain syndrome of the lower extremity: A randomized, double-blinded, crossover study. Clin J Pain. 2011;27(3):203–206.

373.e.6

References

202. Bansal A, Gupta S, Sood D, Kathuria S, Tewari A. Bier’s block using lignocaine and butorphanol. J Anaesthesiol Clin Pharmacol. 2011;27(4):465–469. 203. Kalso E, Rosenberg PH. Bupivacaine and intravenous regional anaesthesia–a matter of controversy. Ann Chir Gynaecol. 1984; 73(3):190–196. 204. Flamer D, Peng PW. Intravenous regional anesthesia: A review of common local anesthetic options and the use of opioids and muscle relaxants as adjuncts. Local Reg Anesth. 2011;4:57–76. 205. Dekoninck V, Hoydonckx Y, Van de Velde M, et al. The analgesic efficacy of intravenous regional anesthesia with a forearm versus conventional upper arm tourniquet: A systematic review. BMC Anesthesiol. 2018;18(1):86. 206. Guay J. Adverse events associated with intravenous regional anesthesia (Bier block): A systematic review of complications. J Clin Anesth. 2009;21(8):585–594. 207. Viscomi CM, Friend A, Parker C, Murphy T, Yarnell M. Ketamine as an adjuvant in lidocaine intravenous regional anesthesia: A randomized, double-blind, systemic control trial. Reg Anesth Pain Med. 2009;34(2):130–133. 208. Kumar A, Sharma D, Datta B. Addition of ketamine or dexmedetomidine to lignocaine in intravenous regional anesthesia: A randomized controlled study. J Anaesthesiol Clin Pharmacol. 2012;28(4):501–504. 209. Acalovschi I, Cristea T. Intravenous regional anesthesia with meperidine. Anesth Analg. 1995;81(3):539–543. 210. Sardesai SP, Patil KN, Sarkar A. Comparison of clonidine and dexmedetomidine as adjuncts to intravenous regional anaesthesia. Indian J Anaesth. 2015;59(11):733–738. 211. Gorgias NK, Maidatsi PG, Kyriakidis AM, Karakoulas KA, Alvanos DN, Giala MM. Clonidine versus ketamine to prevent tourniquet pain during intravenous regional anesthesia with lidocaine. Reg Anesth Pain Med. 2001;26(6):512–517. 212. Bigat Z, Boztug N, Hadimioglu N, Cete N, Coskunfirat N, Ertok E. Does dexamethasone improve the quality of intravenous regional anesthesia and analgesia? A randomized, controlled clinical study. Anesth Analg. 2006;102(2):605–609. 213. Chin KJ, McDonnell JG, Carvalho B, Sharkey A, Pawa A, Gadsden J. Essentials of our current understanding: Abdominal wall blocks. Reg Anesth Pain Med. 2017;42(2):133–183. 214. Urits I, Ostling PS, Novitch MB, et  al. Truncal regional nerve blocks in clinical anesthesia practice. Best Pract Res Clin Anaesthesiol. 2019;33(4):559–571. 215. Rafi AN. Abdominal field block: A new approach via the lumbar triangle. Anaesthesia. 2001;56(10):1024–1026. 216. Richardson J, Lönnqvist PA. Thoracic paravertebral block. Br J Anaesth. 1998;81(2):230–238. 217. Abrahams M, Derby R, Horn JL. Update on ultrasound for truncal blocks: A review of the evidence. Reg Anesth Pain Med. 2016;41(2):275–288. 218. Go R, Huang YY, Weyker PD, Webb CA. Truncal blocks for perioperative pain management: A review of the literature and evolving techniques. Pain Manag. 2016;6(5):455–468. 219. Dai C, Zhang K, Huang J. The efficacy of transversus abdominis plane block for abdominal hysterectomy post-operative analgesia. Cureus. 2018;10(8):e3131. 220. Jakobsson J, Wickerts L, Forsberg S, Ledin G. Transversus abdominal plane (TAP) block for postoperative pain management: A review. F1000Res. 2015;4 F1000 Faculty Rev-1359. 221. McDonnell JG, O’Donnell B, Curley G, Heffernan A, Power C, Laffey JG. The analgesic efficacy of transversus abdominis plane block after abdominal surgery: A prospective randomized controlled trial. Anesth Analg. 2007;104(1):193–197. 222. Carney J, Finnerty O, Rauf J, Curley G, McDonnell JG, Laffey JG. Ipsilateral transversus abdominis plane block provides effective analgesia after appendectomy in children: A randomized controlled trial. Anesth Analg. 2010;111(4):998–1003.

223. Bharti N, Kumar P, Bala I, Gupta V. The efficacy of a novel approach to transversus abdominis plane block for postoperative analgesia after colorectal surgery. Anesth Analg. 2011;112(6): 1504–1508. 224. Jain S, Kalra S, Sharma B, Sahai C, Sood J. Evaluation of ultrasound-guided transversus abdominis plane block for postoperative analgesia in patients undergoing intraperitoneal onlay mesh repair. Anesth Essays Res. 2019;13(1):126–131. 225. Lissauer J, Mancuso K, Merritt C, Prabhakar A, Kaye AD, Urman RD. Evolution of the transversus abdominis plane block and its role in postoperative analgesia. Best Pract Res Clin Anaesthesiol. 2014;28(2):117–126. 226. Hebbard P, Fujiwara Y, Shibata Y, Royse C. Ultrasound-guided transversus abdominis plane (TAP) block. Anaesth Intensive Care. 2007;35(4):616–617. 227. Tsai HC, Yoshida T, Chuang TY, et al. Transversus abdominis plane block: An updated review of anatomy and techniques. BioMed Res Int. 2017;2017:8284363. 228. Moeschler SM, Murthy NS, Hoelzer BC, Gazelka HM, Rho RH, Pingree MJ. Ultrasound-guided transversus abdominis plane injection with computed tomography correlation: A cadaveric study. J Pain Res. 2013;6:493–496. 229. Chakraborty A, Khemka R, Datta T. Ultrasound-guided truncal blocks: A new frontier in regional anaesthesia. Indian J Anaesth. 2016;60(10):703–711. 230. van Schoor AN, Bosman MC, Bosenberg AT. Revisiting the anatomy of the ilio-inguinal/iliohypogastric nerve block. Paediatr Anaesth. 2013;23(5):390–394. 231. Nan Y, Zhou J, Ma Q, Li T, Lian QQ, Li J. Application of ultrasound guidance for ilioinguinal or iliohypogastric nerve block in pediatric inguinal surgery. Zhonghua Yi Xue Za Zhi. 2012;92(13):873–877. 232. Zhou Y, Chen M, Zhang Y, Zhou H, Yu X, Chen G. Ilioinguinal/iliohypogastric nerve block versus transversus abdominis plane block for pain management following inguinal hernia repair surgery: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2019;98(42):e17545. 233. Gu J, Hao C, Yan X, Xuan S. Applied analysis of ultrasound-guided ilioinguinal and iliohypogastric nerve blocks in the radical surgery of aged cervical cancer. Oncol Lett. 2017;13(3):1637–1640. 234. Stecco C, Azzena GP, Macchi V, et  al. Rectus abdominis muscle innervation: An anatomical study with surgical implications in DIEP flap harvesting. Surg Radiol Anat. 2018;40(8):865–872. 235. Yang JD, Hwang HP, Kim JH, et  al. Development of the rectus abdominis and its sheath in the human fetus. Yonsei Med J. 2012;53(5):1028–1035. 236. Quek KH, Phua DS. Bilateral rectus sheath blocks as the single anaesthetic technique for an open infraumbilical hernia repair. Singapore Med J. 2014;55(3):e39–e41. 237. Monkhouse WS, Khalique A. Variations in the composition of the human rectus sheath: A study of the anterior abdominal wall. J Anat. 1986;145:61–66. 238. Dolan J, Lucie P, Geary T, Smith M, Kenny GN. The rectus sheath block: Accuracy of local anesthetic placement by trainee anesthesiologists using loss of resistance or ultrasound guidance. Reg Anesth Pain Med. 2009;34(3):247–250. 239. Seidel R, Wree A, Schulze M. Does the approach influence the success rate for ultrasound-guided rectus sheath blocks? An anatomical case series. Local Reg Anesth. 2017;10:61–65. 240. Hong S, Kim H, Park J. Analgesic effectiveness of rectus sheath block during open gastrectomy: A prospective double-blinded randomized controlled clinical trial. Medicine (Baltimore). 2019;98(15):e15159. 241. Kartalov A, Jankulovski N, Kuzmanovska B, et al. The effect of rectus sheath block as a supplement of general anesthesia on postoperative analgesia in adult patient undergoing umbilical hernia repair. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2017;38(3): 135–142.

References

242. Zhu JL, Wang XT, Gong J, Sun HB, Zhao XQ, Gao W. The combination of transversus abdominis plane block and rectus sheath block reduced postoperative pain after splenectomy: A randomized trial. BMC Anesthesiol. 2020;20(1):22. 243. Park JS, Kim YH, Jeong SA, Moon DE. Ultrasound-guided aspiration of the iatrogenic pneumothorax caused by paravertebral block- a case report. Korean J Pain. 2012;25(1):33–37. 244. Batra RK, Krishnan K, Agarwal A. Paravertebral block. J Anaesthesiol Clin Pharmacol. 2011;27(1):5–11. 245. Ben-Ari A, Moreno M, Chelly JE, Bigeleisen PE. Ultrasoundguided paravertebral block using an intercostal approach. Anesth Analg. 2009;109(5):1691–1694. 246. Wardhan R, Kantamneni S. The challenges of ultrasound-guided thoracic paravertebral blocks in rib fracture patients. Cureus. 2020;12(4):e7626. 247. Dizdarevic A, Fernandes A. Thoracic paravertebral block, multimodal analgesia, and monitored anesthesia care for breast cancer surgery in primary lateral sclerosis. Case Rep Anesthesiol. 2016;2016:6301358. 248. Saito T, Den S, Cheema SP, et al. A single-injection, multi-segmental paravertebral block-extension of somatosensory and sympathetic block in volunteers. Acta Anaesthesiol Scand. 2001;45(1):30–33. 249. Davies RG, Myles PS, Graham JM. A comparison of the analgesic efficacy and side-effects of paravertebral vs epidural blockade for thoracotomy–a systematic review and meta-analysis of randomized trials. Br J Anaesth. 2006;96(4):418–426. 250. Ballantyne JC, Carr DB, de Ferranti S, et  al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: Cumulative meta-analyses of randomized, controlled trials. Anesth Analg. 1998;86(3):598–612. 251. Richardson J, Sabanathan S, Mearns AJ, Shah RD, Goulden C. A prospective, randomized comparison of interpleural and paravertebral analgesia in thoracic surgery. Br J Anaesth. 1995;75(4): 405–408. 252. Atanassoff PG, Alon E, Pasch T, Ziegler WH, Gautschi K. Intercostal nerve block for minor breast surgery. Reg Anesth. 1991;16(1):23–27. 253. Honey RJ, Ghiculete D, Ray AA, Pace KT. A randomized, doubleblinded, placebo-controlled trial of intercostal nerve block after percutaneous nephrolithotomy. J Endourol. 2013;27(4):415–419. 254. Truitt MS, Murry J, Amos J, et al. Continuous intercostal nerve blockade for rib fractures: Ready for primetime? J Trauma. 2011;71(6):1548–1552 discussion 1552. 255. Zinboonyahgoon N, Luksanapruksa P, Piyaselakul S, et  al. The ultrasound-guided proximal intercostal block: Anatomical study and clinical correlation to analgesia for breast surgery. BMC Anesthesiol. 2019;19(1):94. 256. Tucker GT, Moore DC, Bridenbaugh PO, Bridenbaugh LD, Thompson GE. Systemic absorption of mepivacaine in commonly used regional block procedures. Anesthesiology. 1972;37(3): 277–287. 257. Shanti CM, Carlin AM, Tyburski JG. Incidence of pneumothorax from intercostal nerve block for analgesia in rib fractures. J Trauma. 2001;51(3):536–539. 258. Ahmed Z, Samad K, Ullah H. Role of intercostal nerve block in reducing postoperative pain following video-assisted thoracoscopy: A randomized controlled trial. Saudi J Anaesth. 2017;11(1):54–57. 259. Forero M, Adhikary SD, Lopez H, Tsui C, Chin KJ. The erector spinae plane block: A novel analgesic technique in thoracic neuropathic pain. Reg Anesth Pain Med. 2016;41(5):621–627. 260. Jain K, Jaiswal V, Puri A. Erector spinae plane block: Relatively new block on horizon with a wide spectrum of application- a case series. Indian J Anaesth. 2018;62(10):809–813. 261. Chin KJ, Adhikary S, Sarwani N, Forero M. The analgesic efficacy of pre-operative bilateral erector spinae plane (ESP) blocks in patients having ventral hernia repair. Anaesthesia. 2017;72(4): 452–460.

373.e.7

262. Hamilton DL, Manickam B. Erector spinae plane block for pain relief in rib fractures. Br J Anaesth. 2017;118(3):474–475. 263. Adhikary SD, Liu WM, Fuller E, Cruz-Eng H, Chin KJ. The effect of erector spinae plane block on respiratory and analgesic outcomes in multiple rib fractures: A retrospective cohort study. Anaesthesia. 2019;74(5):585–593. 264. Ueshima H. Pneumothorax after the erector spinae plane block. J Clin Anesth. 2018;48:12. 265. Selvi O, Tulgar S. Ultrasound guided erector spinae plane block as a cause of unintended motor block. Rev Esp Anestesiol Reanim. 2018;65(10):589–592. 266. Tulgar S, Selvi O, Senturk O, Serifsoy TE, Thomas DT. Ultrasound-guided erector spinae plane block: Indications, complications, and effects on acute and chronic pain based on a single-center experience. Cureus. 2019;11(1):e3815. 267. Tulgar S, Ahiskalioglu A, De Cassai A, Gurkan Y. Efficacy of bilateral erector spinae plane block in the management of pain: Current insights. J Pain Res. 2019;12:2597–2613. 268. Luis-Navarro JC, Seda-Guzmán M, Luis-Moreno C, Chin KJ. Erector spinae plane block in abdominal surgery: Case series. Indian J Anaesth. 2018;62(7):549–554. 269. Kim SH, Yoon KB, Yoon DM, Kim CM, Shin YS. Patient-controlled epidural analgesia with ropivacaine and fentanyl: Experience with 2,276 surgical patients. Korean J Pain. 2013;26(1):39–45. 270. Jagannathan R, Niesen AD, D’Souza RS, Johnson RL. Intermittent bolus versus continuous infusion techniques for local anesthetic delivery in peripheral and truncal nerve analgesia: The current state of evidence. Reg Anesth Pain Med. 2019;44(4):447–451. 271. Chung D, Lee YJ, Jo MH, et  al. The ON-Q pain management system in elective gynecology oncologic surgery: Management of postoperative surgical site pain compared to intravenous patientcontrolled analgesia. Obstet Gynecol Sci. 2013;56(2):93–101. 272. Benumof JL. Obstructive sleep apnea in the adult obese patient: Implications for airway management. J Clin Anesth. 2001;13(2):144–156. 273. Wiesel S, Fox GS. Anaesthesia for a patient with central alveolar hypoventilation syndrome (Ondine’s curse). Can J Anaesth. 1990;37(1):122–126. 274. Ingrande J, Brodsky JB, Lemmens HJ. Regional anesthesia and obesity. Curr Opin Anaesthesiol. 2009;22(5):683–686. 275. Gross JB, Bachenberg KL, Benumof JL, et  al. Practice guidelines for the perioperative management of patients with obstructive sleep apnea: A report by the American Society of Anesthesiologists task force on perioperative management of patients with obstructive sleep apnea. Anesthesiology. 2006;104(5):1081–1093 quiz 1117-1088. 276. Batistich S, Kendall A, Somers S. Analgesic requirements in morbidly obese patients. Anaesthesia. 2004;59(5):510–511. 277. Kaw R, Gali B, Collop NA. Perioperative care of patients with obstructive sleep apnea. Curr Treat Options Neurol. 2011;13(5):496–507. 278. Nielsen KC, Guller U, Steele SM, Klein SM, Greengrass RA, Pietrobon R. Influence of obesity on surgical regional anesthesia in the ambulatory setting: An analysis of 9,038 blocks. Anesthesiology. 2005;102(1):181–187. 279. Freeman AL, Pendleton RC, Rondina MT. Prevention of venous thromboembolism in obesity. Expert Rev Cardiovasc Ther. 2010; 8(12):1711–1721. 280. Battaglini D, Robba C, Rocco PRM, De Abreu MG, Pelosi P, Ball L. Perioperative anaesthetic management of patients with or at risk of acute distress respiratory syndrome undergoing emergency surgery. BMC Anesthesiol. 2019;19(1):153. 281. Guirguis M, Karroum R, Abd-Elsayed AA, Mounir-Soliman L. Acute respiratory distress following ultrasound-guided supraclavicular block. Ochsner J. 2012;12(2):159–162. 282. Urmey WF, Talts KH, Sharrock NE. One hundred percent incidence of hemidiaphragmatic paresis associated with interscalene brachial plexus anesthesia as diagnosed by ultrasonography. Anesth Analg. 1991;72(4):498–503.

373.e.8

References

283. Hood J, Knoblanche G. Respiratory failure following brachial plexus block. Anaesth Intensive Care. 1979;7(3):285–286. 284. Rau RH, Chan YL, Chuang HI, et  al. Dyspnea resulting from phrenic nerve paralysis after interscalene brachial plexus block in an obese male–a case report. Acta Anaesthesiol Sin. 1997;35(2):113–118. 285. Klein SM, Evans H, Nielsen KC, Tucker MS, Warner DS, Steele SM. Peripheral nerve block techniques for ambulatory surgery. Anesth Analg. 2005;101(6):1663–1676. 286. Saraswat V. Effects of anaesthesia techniques and drugs on pulmonary function. Indian J Anaesth. 2015;59(9):557–564. 287. Oğurlu M, Sen S, Polatli M, Sirthan E, Gürsoy F, Cildağ O. The effect of spinal anesthesia on pulmonary function tests in old patients. Tuberk Toraks. 2007;55(1):64–70. 288. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413(6852):203–210. 289. Zohar Z, Eitan A, Halperin P, et  al. Pain relief in major trauma patients: An Israeli perspective. J Trauma. 2001;51(4):767–772. 290. Cohen SP, Christo PJ, Moroz L. Pain management in trauma patients. Am J Phys Med Rehabil. 2004;83(2):142–161. 291. Neighbor ML, Honner S, Kohn MA. Factors affecting emergency department opioid administration to severely injured patients. Acad Emerg Med. 2004;11(12):1290–1296. 292. Heffernan DS, Schermer CR, Lu SW. What defines a distracting injury in cervical spine assessment? J Trauma. 2005;59(6): 1396–1399. 293. Wu CL, Jani ND, Perkins FM, Barquist E. Thoracic epidural analgesia versus intravenous patient-controlled analgesia for the treatment of rib fracture pain after motor vehicle crash. J Trauma. 1999;47(3):564–567.

294. Karmakar MK, Critchley LA, Ho AM, Gin T, Lee TW, Yim AP. Continuous thoracic paravertebral infusion of bupivacaine for pain management in patients with multiple fractured ribs. Chest. 2003;123(2):424–431. 295. Osinowo OA, Zahrani M, Softah A. Effect of intercostal nerve block with 0.5% bupivacaine on peak expiratory flow rate and arterial oxygen saturation in rib fractures. J Trauma. 2004;56(2): 345–347. 296. Allen DJ, Chae-Kim SH, Trousdale DM. Risks and complications of neuraxial anesthesia and the use of anticoagulation in the surgical patient. Proc (Bayl Univ Med Cent). 2002;15(4):369–373. 297. Seyfer AE, Seaber AV, Dombrose FA, Urbaniak JR. Coagu lation changes in elective surgery and trauma. Ann Surg. 1981;193(2):210–213. 298. Yousefifard M, Askarian-Amiri S, Rafiei Alavi SN, et al. The efficacy of ketamine administration in prehospital pain management of trauma patients; a systematic review and meta-analysis. Arch Acad Emerg Med. 2020;8(1):e1. 299. Krombach JW, Dagtekin O, Kampe S. Regional anesthesia and anticoagulation. Curr Opin Anaesthesiol. 2004;17(5):427–433. 300. Gogarten W, Vandermeulen E, Van Aken H, et  al. Regional anaesthesia and antithrombotic agents: Recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010; 27(12):999–1015. 301. Horlocker TT, Vandermeuelen E, Kopp SL, Gogarten W, Leffert LR, Benzon HT. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (fourth edition). Reg Anesth Pain Med. 2018;43(3):263–309.

10 27

Evaluation and Chapter Title toTreatment Go Here of Postoperative Pain in Patients With Opioid Use Disorder CHAPTER AUTHOR

YI CAI, GREGORY A. ACAMPORA, T. ANTHONY ANDERSON

Background Because of the dramatic increase in the number of opioid related deaths since 1999, the opioid epidemic was declared a “public health emergency” in the United States on October 26, 2017.1 The opioid abuse epidemic arose in part from a lack of acknowledgment about the high addiction potential of opioids along with aggressive widespread pharmaceutical company marketing of prescription opioids for both acute and chronic pain treatment in the late 1990s.2,3 This led to pervasive opioid diversion, opioid abuse, and a rapid rise in opioid overdoses, leading to over 47,000 people in the United States dying from an opioid overdose in 2017.4 As seen in Fig. 27.1, from 2010–2015 the annual number of deaths from prescription opioids remained relatively stable. However, overdose deaths from illicit opioids (heroin followed by highpotency synthetic opioids such as fentanyl) nearly tripled. This large increase in illicit opioid use was driven in part by people prescribed opioids and who subsequently developed opioid use disorder (OUD).5,6 OUD is defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, criteria as having at least two of the criteria illustrated in Table 27.1. As of 2015, two million Americans aged 12 years or older had an OUD involving prescription opioids, and nearly 600,000 had an OUD involving heroin. Opioid-attributable deaths increased 292% between 2001 and 2016.7 In 2016, the approximate person-years of lives lost in the United States from opioid-attributable deaths was 1.68 million (5.2 per 1000 population),7 and opioid overdose was linked to an average of two-thirds of the 175 daily deaths related to all drug overdoses in the United States.8 The economic burden of prescription opioid abuse in 2013 was estimated to be almost $80 billion.9 The global burden of disease from opioid related conditions approaches 11 million life-years lost from health problems, disabilities, and early death.10 Some patients are at a higher risk of developing OUD, and widely available scoring systems such as the opioid risk tool (ORT) were developed to screen for the likelihood of aberrant behavior. These criteria included a personal history or family history of illicit substance use, comorbid psychological disorder, age between 16 and 45 years, and history of preadolescent sexual abuse (Table 27.2).11 One study found that patients who were younger, had comorbid depression, used psychotropic medications, and 374

were impaired by pain had a significantly increased risk of developing OUD (odds ratio of eight).6 Comorbid chronic pain (CP) and substance use disorders (SUD) are very common. Chronic non-cancer pain (CNCP) is common among patients treated for SUD, and SUD is common among those treated for CNCP. The lifetime prevalence of CP in patients with SUD is over 50% and as high as 75% in those actively treated for SUD. The overall prevalence of current SUD among patients with CNCP is as high as 48%, and the lifetime prevalence of any SUD in those CNCP is as high as 74%.12–14 SUD may result from substances used to cope with pain symptoms, and/or substance use-related injury may lead to CP conditions.15,16 However, many experts now believe that a diathesis-stress model best explains these comorbidities. Patients have preexisting, semi-dormant characteristics of the individual before the onset of CP, which are then activated and exacerbated by the stress of this chronic condition, eventually resulting in diagnosable psychopathology.17 Several studies have examined the chronologic relationship between CNCP and SUD with conflicting evidence.18–21 The management of pain in patients with SUD, specifically OUD, has not been investigated in detail. Studies published on the co-management of OUD and CNCP suggest the use of 1) multi-disciplinary care teams, 2) stepped care models, and 3) multimodal treatments with a combination of nonpharmacologic, non-opioid pharmacologic, and buprenorphine or methadone.22–25 In 2012, the Center for Substance Abuse Treatment published a thorough set of recommendations for managing CP in patients with SUD based on expert recommendations.26 It is critical to understand that the risk of death in adults with SUD is significantly higher than in those without; even patients undergoing SUD treatment have a mortality rate approximately four times that of the general United States population,27 while those with OUD also have a significantly elevated mortality rate.28 Even those with OUD and treated with an opioid agonist have a significantly higher death rate from drug abuse and other causes than the general population.29 Thus in those patients being actively treated for OUD, relapse may be lethal. Clinicians must be aware that pain management in patients with active addiction or in treatment, especially treatment involving opioids, is perilous. This chapter will review the latest evidence for the management of acute postoperative pain in patients with comorbid OUD.

 

CHAPTER 27

Evaluation and Treatment of Postoperative Pain in Patients With Opioid Use Disorder

375

Three Waves in the Rise in Opioid Overdose Deaths 12

Other Synthetic Opioids

Deaths per 100,000 population

10

e.g. Tramadol and Fentanyl, prescribed or illicitly manufactured 8

6

Heroin Commonly Prescribed Opioids

4

Natural & Semi-Synthetic Opioids and Methadone

Wave 1: Rise in Prescription Opioid Overdose Deaths

Wave 2: Rise in Heroin Overdose Deaths

2018

2017

2016

2015

2014

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

0

1999

2

Wave 3: Rise in Synthetic Opioid Overdose Deaths SOURCE: National Vital Statistics System Mortality File.

• Figure 27.1  The three waves of the rise of opioid overdose deaths with Wave 1 because of a rise in

prescription opioids, Wave 2 because of illicit drugs such as heroin, and Wave 3 because of synthetic opioid usage, such as fentanyl. Image available at: https://www.cdc.gov/drugoverdose/epidemic/index.html.

TABLE 27.1

DSM-V Criteria for Opioid Use Disorder

Opioids are often taken in larger amounts or over a longer period than was intended. There is a persistent desire or unsuccessful efforts to cut down or control opioid use. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects. Craving, or a strong desire or urge to use opioids. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids. Important social, occupational, or recreational activities are given up or reduced because of opioid use. Recurrent opioid use in situations in which it is physically hazardous. Continued opioid use despite having a persistent or recurrent physical or psychological problem likely to have been caused or exacerbated by the substance. Exhibits tolerance.* Exhibits withdrawal.* *This criterion is not considered for those taking opioids solely under appropriate medical supervision. At least two of the criteria should be observed within 12 months. If two or three Items cluster together in the same 12 months, the disorder is mild; if four or five items cluster, the disorder is moderate; and if six or more items cluster, the disorder is severe. These criteria are from the Diagnostic and Statistical Manual of Mental Disorders, fifth edition.195

Given the paucity of published evidence on this topic, recommendations from experts in the field and data from the management of perioperative pain alone are extrapolated to the care of patients with comorbid SUD.

Management of Opioid Use Disorder The Substance Abuse and Mental Health Services Administration (SAMHSA) has determined that the combination of medication assisted treatment (MAT) and cognitive behavior

therapy should be used to manage patients with OUD.30 The three medications approved by the United States Food and Drug Administration for MAT are methadone, buprenorphine, or naltrexone. The outcomes of MAT treatment in patients with OUD are dramatic; patients who use methadone have retention rates of 60%–84%,31,32 and patients who use buprenorphine have similar results.33,34 Importantly, mortality rates also decrease with the use of these medications. In a well-cited randomized placebo control trial comparing buprenorphine to a placebo, the

376

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 27.2

The Opioid Risk Tool

Family History of Substance Abuse

superior perioperative analgesia compared to opioid-based management of acute pain and should be strongly considered when possible as part of the multimodal pain management plan for patients who undergo surgery.

Female

Male

Alcohol

1

3

Illegal drugs drugs Prescription

24

34

Challenges of Postoperative Pain Management in Patients With Opioid Use Disorder

Alcohol

3

3

Illegal drugs

4

4

Prescription drugs

5

5

Age between 16-45 years

1

1

History of preadolescent sexual abuse

3

0

ADD, OCD, bipolar schizophrenia

2

2

Depression

1

1

There are many challenges in treating acute pain in patients with OUD, including withdrawal, tolerance, hyperalgesia because of chronic opioid exposure, and comorbid psychological conditions, including the risk of relapse. Withdrawal. Withdrawal during hospitalization can occur after underdosing inpatient opioids and/or sudden discontinuation of a misused drug if illicit drug use is not known, such as in an unconscious patient or one who voluntarily withholds details of their history. Withdrawal and severity may be diagnosed using the Clinical Opiate Withdrawal Scale (Fig. 27.2) using symptoms such as dysphoric mood, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, pupillary dilation or piloerection or sweating, diarrhea, yawning, fever, or insomnia. The time to onset of withdrawal symptoms depends on the type of opioid used. Short acting opioids such as heroin have an onset of withdrawal at 8–24 h after last use and may last 4–10 days. Long-acting opioids such as methadone have an onset of withdrawal symptoms 12-48 h after last use and may last 10–20 days. Hyperalgesia. Hyperalgesia is an increased sensitivity to painful stimuli. Patients with OUD report a pain sensitivity increase of 42%–72% compared with controls.37,38 The mechanisms of hyperalgesia can be attributed to central activation of N-methyld-aspartate (NMDA) receptors and protein kinase C, upregulation of spinal dynorphin, and apoptosis of spinal dorsal horn neurons.39–41 Patients with OUD maintained on methadone may be hyperalgesic and cross-tolerant to the anti-nociceptive effects of very high plasma morphine concentrations. Higher morphine doses may achieve pain relief, although there is a risk of respiratory compromise.42 Tolerance. Tolerance is thought to involve opioid receptor desensitization, internalization, and downregulation, whereas dependence and withdrawal are primarily because of opioid receptor counter adaptation.43 Clinically, which is defined as an increasing requirement of a drug to gain the same effect. However, different opioids develop tolerance at different rates and different degrees; this is called differential tolerance.44 For opioids, the development of tolerance is most profound for analgesia, followed by respiratory depression, and finally peripheral effects such as decreased gastrointestinal motility. Thus patients with OUD will be tolerant to the analgesic effects of opioids but may still have an increased risk of respiratory depression if the pain is treated with opioids.44 Psychological Comorbidities. There is a high association of substance use disorder with CP despite the absence of clearcut directional causality.45,46 Patients with CP often have SUD involving other substances such as benzodiazepines, alcohol, and cannabis.47–49 CP patients also have a high incidence of psychological comorbidities, including major depressive disorder, anxiety spectrum disorders, post-traumatic stress disorder, and risk of suicide.50 Data suggests that CP is a significant independent risk factor for suicidality.51 Predictors of suicidality included frequent intermittent pain, sleep problems, and feeling negative about selfmental health. Interestingly, pain duration, intensity/severity, or type were unrelated to suicide risk.

Personal history of substance abuse

Psychological disease

Total score Opioid risk tool may be used to screen patients and indicates the risk of opioid use. A ccore of zero to three indicates low risk, a score of four to seven indicates moderate risk, and a score higher than eight indicates high risk. Adapted from Webster and Webster 2015.11

placebo group dropout rate was 100% by the second month, with all subjects demonstrating urine samples positive for drug use and mortality rate of 20%.32 Buprenorphine-treated patients demonstrated a 75% retention rate and a mortality of 0% at one year.33 A meta-analysis assessing methadone versus buprenorphine treatment for patients with OUD found that subjects who received 8–12 mg/day buprenorphine had 1.26 times the relative risk of discontinuing treatment and 8.3% more positive urinalyses than subjects receiving 50–80 mg/day methadone.34 However, different dropout rates have been observed with other doses of methadone. For example, patients who receive doses of less than 60 mg of methadone are significantly more likely to drop off treatment than those who received doses of 80 mg or more.35

Acute Pain Treatment Goals The appropriate management of new-onset pain in patients with OUD depends on the origin of pain (i.e. new postoperative acute pain versus acute on chronic exacerbation). As recommended above, management should include a multispecialty approach and multimodal pharmacologic and nonpharmacologic treatments. The goals of treating acute pain in patients with OUD are to prevent withdrawal, provide adequate analgesia, and avoid triggering a relapse if a patient is in recovery (or worsening of the disorder if a patient has active addiction). The most common causes of acute pain include surgery, fracture, dental work, cuts, and burns. Patients taking opioids to control CP, OUD, or illegitimately should not be intentionally weaned off opioids during an acute pain episode because of the risk of withdrawal and presumed hyperalgesia. A multimodal regimen, including nonpharmacologic therapies, regional anesthesia, and/ or non-opioid medications, may reduce the need for additional opioid medications.36 Continuous regional anesthesia provides

 

CHAPTER 27

Evaluation and Treatment of Postoperative Pain in Patients With Opioid Use Disorder

Patient’s Namef

Date and Time:

377

:

Reason for this assessment: Resting Pulse Rate:

beats/min.

Measured after patient is sitting or lying for 1 min. 0 pulse rate 80 or below 1 pulse rate 81-100 2 pulser rate, 101-120 4 pulse rate greater than 120

Sweating: over past 1/2 hour not accounted for by room temperature or patient activity.

GI Upset: over last 1/2 hour 0 no GI symptoms 1 stomach cramps 2 nausea or loose stool 3 vomiting or diarrhea 5 multiple episodes of diarrhea or vomiting

Tremor observation of outstretched hands 0 no tremor

0 no report of chills or flushing 1 subjective report of chills or flushing 2 flushed or observable moistness on face 3 beads of sweat on brow or face 4 sweat streaming off face

1 tremor can be felt, but not observed

Restlessness Observation during assessment 0 able to sit still 1 reports difficulty sitting still, but is able to do so 3 frequent shifting or extraneous movements of legs/arms 5 unable to sit still for more than a few seconds

Yawning Observation during assessment 0 no yawning 1 yawning once or twice during assessment 2 yawning three or more times during assessment 4 yawning several times/minute

Pupil size

Anxiety or Irritability

0 pupils pinned or normal size for room light 1 pupils possibly larger than normal for room light 3 pupils moderately dilated 5 pupils so dilated that only the rim of the iris is visible

0 none 1 patient reports increasing irritability or anxiousness 2 patient obviously irritable or anxious 4 patient so irritable or anxious that participation in the assessment is difficult

Bone or Joint Aches If patient was having pain previously, only the additional component attributed to opiates withdrawal is scored 0 not present 1 mild diffuse discomfort 2 patient reports severe diffuse aching of joints/muscles 4 patient is rubbing joints or muscles and is unable to sit still because of discomfort

2 slight tremor observable 4 gross tremor or muscle twitching

Gooseflesh Skin 0 skin is smooth 3 piloerection of skin can be felt or hairs standing up on arms 5 prominent piloerection

Runny Nose or Tearing Not accounted for by cold symptoms or allergies 0 not present 1 nasal stuffiness or unusually moist eyes 2 nose running or tearing 4 nose constantly running or tears streaming down cheeks

Total Score: The total score is the sum of all 11 items Initials of person completing assessment:

Score: 5–12 = mild; 13–24 = moderate; 25–36 = moderately severe; more than 36 = severe withdrawal

• Figure 27.2  The

Clinical Opiate Withdrawal Scale (COWS). COWS is an 11 item scale designed to monitor the symptoms and severity of opiate withdrawal over time. Score: 5–12, mild; 13–24, moderate; 25–36, moderately severe; >36, severe withdrawal. Revised from Wesson and Ling 2003.194

Evaluation of Patients With Opioid Use Disorder who Present for Surgery Evaluation of both inpatients and outpatients with OUD is best accomplished using a multispecialty approach, including psychiatry, psychology, social work, physical therapy, and/or pain management specialists. Similar to the evaluation of patients with CP and SUD, patients should undergo a comprehensive assessment that includes their substance use history, whether they have active

addiction or are in treatment, their comorbidities (including CP history and psychiatric history), a physical examination, and the patient’s current mental status.52 A thorough history and physical examination should include prescription-controlled medication use (which should be verified according to the state’s prescription drug monitoring program), the dose of medications taken, use of recreational drugs, pain goals, withdrawal symptoms such as nausea, vomiting, diarrhea, anxiety, and shivering (Table 27.3), and even potentially a urine toxicology screen for controlled and

378

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 27.3

Symptoms of Opioid Withdrawal, Grouped Into Categories Based on the Organ System Affected

Table 3. Opioid Withdrawal Symptoms Gastrointestinal distress

Abdominal cramps Diarrhea Nausea Vomiting

Flu-like symptoms

Lacrimation, rhinorrhea, diaphoresis, shivering, piloerection

Sympathetic arousal

Mydriasis Hypertension Tachycardia Tremor Myalgia/arthralgia

Psychological symptoms

Anxiety Irritability Dysphoria Insomnia Agitation

Other

Yawning, sneezing

illicit medications. If the patient had a history of CP, the baseline pain intensity at rest and during activity should also be assessed. In patients admitted for non-elective surgical procedures, perioperative (particularly post-surgical) withdrawal symptoms should be anticipated. For patients who will require postoperative pain management with opioids postoperatively, especially those who will be discharged with an opioid prescription, screening for opioid abuse risk may occur. While it is assumed that a history of OUD predicts increased risk, the degree of risk can be further anticipated with a simple screening tool. For example, the “ORT” scores patients based on their family history of substance use, personal history of substance use, age, history of preadolescent sexual abuse, and psychological disease.11

Patients With OUD in Remission who Present for Surgery Patients with OUD in remission and without medication treatment may no longer have signs and symptoms of physical dependence, but will continue to be susceptible to triggers. Triggers for relapse include stress (i.e. surgery) and administration of the agents of abuse (i.e. opioids). Thus these patients are at a particularly high risk of relapse.  Anxiety surrounding surgery, perioperative concerns (e.g. financial, social, and/or professional), and postoperative pain are stressors that can trigger drug cravings and relapse,53 as may poor pain control, if it occurs perioperatively.54,55 An acute pain consultation, even prior to surgery, can help with the development of a safe and effective perioperative pain plan, which may include regional anesthesia, multimodal pharmacologic therapy, and discharge planning.56 Discharge planning may include storage and disposal of unused opioids and enlisting the help of a responsible friend or family member to assist in managing the patient’s opioid use. Overdose prevention education and naloxone prescription should be considered.57 Management of postoperative pain in patients with OUD on MAT should start with the continuation of the home medication

treatment regimen. Therapy should be based on the degree of expected pain, which depends on the type of surgery and includes, as appropriate, non-opioid adjuvant therapies, regional anesthesia, and nonpharmacologic therapies. Additional opioids can be added, but only when the benefits are deemed greater than the risk. If additional opioids are added, a postoperative tapering plan should be developed to discontinue them after the perioperative phase. Moreover, clear communication should be undertaken with the patient to set expectations and prevent opioid escalation. Multi-disciplinary discharge planning is critical.58

Postoperative Pain Management Techniques for Patients With Opioid Use Disorder Non-opioid Pharmacologic Treatment Patients on high-dose opioids have a high occupancy rate of opioid receptors, and thus non-opioid methods of pain control allow for the treatment of pain using medications that interact with different pain receptors. The type of medication should be tailored to the type of pain, inflammatory, nociceptive, or neuropathic pain. The use of non-opioid analgesics decreases the need for additional opioids. Most of the available evidence for the efficacy of non-opioid analgesics in reducing and improving perioperative pain is not available in patients with OUD. However, many pain experts recommend maximizing the perioperative use of non-opioid analgesics in patients with OUD when possible. Using a combination of analgesic medications with different mechanisms of action may decrease pain, improve functional outcomes, reduce opioid requirements, and decrease the duration of hospital stay. Although not well studied, even if individual medications only provide mild to moderate improvements in pain outcomes, a combination of agents may have an additive or synergistic effect on postoperative pain.

Intravenous Lidocaine The pain-alleviating effects of systemic lidocaine in patients with CP conditions have been noted in patients with spinal cord injury,59 diabetic neuropathy,60 central pain syndrome,61 chronic regional pain syndrome,62 and postherpetic neuralgia.63 One of the proposed pathophysiologic mechanisms of neuropathic pain is the upregulation of sodium channels in nociceptors. The change in channel density on nociceptor membranes creates an electrochemical environment that causes neurons to reach their depolarization threshold more rapidly, which leads to increased nociceptive signaling. Lidocaine acts as a sodium channel blocker and can modulate neuropathic pain by decreasing the function of these sodium channels, reversing the effects of sodium channel upregulation.64 While the quality of the evidence is limited and results are variable, lidocaine has been demonstrated to improve postoperative pain scores, decrease opioid consumption, decrease nausea, decrease the duration of hospitalization, and decrease the length of ileus in patients undergoing open or laparoscopic surgery.65 For instance, Koppert et al. reported a 35% reduction in morphine consumption between 0 to 72 h after surgery in 40 patients undergoing major abdominal surgery.66 A continuous lidocaine infusion may take 4 to 8 h to achieve a steady state; the context sensitive half-life is 20–40 min after a three day infusion and does not accumulate in healthy individuals.67 However, pain benefits can persist for many hours or even days after the termination of the infusion, partially because of the anti-inflammatory effects of lidocaine,

 

CHAPTER 27

Evaluation and Treatment of Postoperative Pain in Patients With Opioid Use Disorder

which block the activation of polymorphonuclear granulocytes, thus dampening the cascade of inflammatory responses.65,68 A randomized clinical trial of 180 patients with OUD who underwent orthopedic surgery under general anesthesia were randomly allocated to receive an intravenous infusion of lidocaine, ketamine, or a placebo. Patients who received lidocaine had lower numeric pain scores and opioid consumption 24 h postoperatively than both the ketamine and placebo groups.69 In addition, patients in the lidocaine group were less restless, calmer, and less drowsy than patients in the ketamine and control group. A 2018 Cochrane review assessed the efficacy of perioperative lidocaine and included 68 randomized controlled trials; the authors concluded that it was uncertain if systemic lidocaine had a clinical impact on pain scores or opioid consumption. The study found a reduction in ileus with a risk ratio 0.37 (95% confidence interval [CI] 0.15 to 0.87), a reduction of time to first bowel movement by a mean of -7.92 h (95% CI -12.71 to -3.13), and a reduction in postoperative nausea with a risk ratio of 0.78 (95% CI 0.67 to 0.91).70

N-methyl-d-aspartate (NMDA) Receptor Antagonists Examples: ketamine, methadone, memantine, amantadine, dextromethorphan. NMDA receptor antagonists modulate nociception in spinal pain fibers and the central nervous system. Ketamine is the most commonly used NMDA antagonist. At subanesthetic doses, ketamine has been used as an analgesic and to prevent central sensitization,71 and the spreading of pain sensitivity beyond the original site of injury in the form of secondary hyperalgesia and allodynia. Ketamine can be administered intravenously to both inpatients and outpatients. It can also be used orally and intranasally but is commonly administered intravenously perioperatively. Inpatient delivery and monitoring (e.g. the level of care required, such as telemetry) will depend on institutional protocols. A meta-analysis assessing the efficacy of perioperative ketamine reported a decrease in morphine consumption at 24 h (15.7 mg) and a slight decrease in pain scores at 48 h postoperatively.72 A meta-analysis assessing the utility of perioperative ketamine included 47 studies in subjects without OUD and found that its use decreased opioid consumption and the time to first analgesic need in the included studies, but with the greatest efficacy in thoracic, abdominal, and orthopedic surgeries. Despite using fewer opioids, 25 out of 32 treatment groups (78%) experienced less pain than the placebo group at some point postoperatively.73 In patients without OUD taking opioids for CP, a ketamine infusion has been found to decrease average pain scores compared to a placebo, without a change in opioid consumption.74 Dextromethorphan is a common antitussive medication and an NMDA antagonist; its affinity with the NMDA receptor is lower than that of ketamine. A meta-analysis of randomized, doubleblinded, placebo-controlled trials of subjects without OUD noted that perioperative dextromethorphan use reduced postoperative opioid consumption at 24 to 48 h and pain scores at 1, 4, 6, and 24 h.75 In a meta-analysis of multimodal preemptive analgesic adjuncts in subjects without OUD benefit was found for preemptive nonsteroidal anti-inflammatory drugs, epidural analgesia, and local anesthetic infiltration, but the effects of ketamine and dextromethorphan were determined to be equivocal.76 α-2 Agonists

Examples: Dexmedetomidine, clonidine. a-2 Agonists act on the a2 receptors of the peripheral and central nervous systems, resulting in sedation, hypnosis, anxiolysis,

379

sympatholysis, and analgesia.77,78 2 Agonists appear to potentiate the analgesic effects of opioids.79 In a meta-analysis of 28 randomized controlled trials, patients without OUD treated with dexmedetomidine perioperatively reported lower pain intensity at 1 h postoperatively and reduced postoperative opioid consumption at 24 h postoperatively compared to a placebo. In addition, patients demonstrated a lower risk for nausea in the postanesthesia care unit (PACU).77 In another meta-analysis of 30 trials analyzing both clonidine and dexmedetomidine, both were found to reduce morphine use after surgery. A decrease in morphine use was observed for dexmedetomidine from to 2–24 h postoperatively, with a cumulative decrease in morphine of 30%. The decrease in morphine use was observed for clonidine from 12–24 h postoperatively, with a cumulative morphine decrease of 25%.78 The degree of morphine sparing was stronger than what has been reported with acetaminophen,80,81 but weaker than with ketamine,72 or nonsteroidal anti-inflammatory drugs.81 α

Gabapentinoids

Examples: gabapentin, pregabalin. Anti-convulsants are typically prescribed for the management of neuropathic pain and have demonstrated efficacy in reducing perioperative pain.82–86 Surgical tissue injury produces neuroplastic changes leading to spinal sensitization, hyperalgesia, and allodynia.87,88 Anti-convulsant drugs may be important in the modulation of these postoperative neural changes by suppression of sodium channel and calcium channel activity and suppression of the glutamate action on the NMDA receptor in both the peripheral and central nervous systems.89 Gabapentin is an anti-convulsant that blocks the -2-d subunits of voltage-dependent calcium ion channels and has been found to reduce postoperative pain and opioid requirements when administered as a single 300–1200 mg dose in patients without OUD.83,84,90,91 In meta-analyses of spine surgery patients without OUD, gabapentin was found to decrease pain, opioid use, and urinary retention.91,92 However, in a meta-analysis assessing the effect of gabapentin after total knee arthroplasty, no difference in pain scores was found compared to a placebo.93 Pregabalin is similar in mechanism to gabapentin but is more potent with fewer side effects.94 Pregabalin has been found to have similar benefits to gabapentin perioperatively.85,95,96 In a systematic review, pregabalin improved postoperative analgesia and reduced morphine equivalent postoperatively than with a placebo.85,97 Similarly, in a meta-analysis of knee arthroplasty, pain was reduced by approximately 0.5 on an 11 point numeric rating scale.93  A meta-analysis of patients undergoing hysterectomy concluded that pregabalin decreased pain, morphine consumption, and postoperative nausea and vomiting (PONV).98,99 When 100–300 mg is used, no difference in acute pain outcomes have been found when a single preoperative dose of pregabalin is given or multiple doses perioperatively.85 In a meta-analysis of studies in which patients underwent bariatric surgery, a single preoperative dose of 75 mg pregabalin did not improve pain relief, quality of postoperative recovery, or reduction in opioid consumption.100 However, this may have been because of the low dosage and large volume of distribution in the patient population. This is supported by a dose study in spine surgery patients in which 150 mg pregabalin administered before surgery and 12 h after surgery resulted in decreased opioid consumption. However, the lower dose of 75 mg before and after surgery produced no significant opioid-sparing effect.101 Regrettably, both gabapentin and pregabalin have an α

380

PA RT 4 Clinical Conditions: Evaluation and Treatment

emerging potential for misuse, particularly in individuals with OUD,102 and there may be an increase in the risk of respiratory depression when administered in combination with opioids.103 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Examples: ketorolac, celecoxib, naproxen, ibuprofen. In meta-analyses of trials with subjects without OUD, postoperative administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to decrease pain across a wide range of surgeries, including lumbar spine surgery,104 laparoscopic cholecystectomies,105 and cesarean deliveries,106 but not dental surgery.107 Ketorolac is a non-selective cyclooxygenase (COX)-1 inhibitor that has been found to decrease postoperative pain, and some studies have found a decrease in the need for opioids by 25%– 45%.108–111 Traditionally, 15–30 mg is administered intravenously to adults every 6–8 h. Even 10–15 mg ketorolac is effective in decreasing pain after spine surgery patients and in patients who present to the emergency department with pain.112,113 Other medications such as celecoxib,114,115 naproxen,116,117 and ibuprofen118,119 have also been shown to decrease postoperative pain. In a study assessing postoperative pain management and comparing ibuprofen 400 mg, oxycodone 5 mg, the combination of ibuprofenoxycodone 400 mg–5 mg, and a placebo, the number needed to treat (NNT) for a 50% pain reduction was similar for ibuprofen and ibuprofen-oxycodone (NNT 2.3 [2.0–2.8]) than with oxycodone alone (NNT 2.9 [2.3–4]), and the combination of ibuprofen-oxycodone provided analgesia for longer than oxycodone alone.120 In another study, the NNT for a 50% pain reduction was 2.9, for ketoprofen 50 mg, 2.5, ibuprofen 400 mg, and 2.7 for diclofenac 50 mg.121

Acetaminophen

Examples: N-acetyl-para-aminophenol (APAP), acetaminophen. The mechanism of action of acetaminophen may involve inhibition of peroxidase reactions in the prostaglandin synthesis pathway.122 A single dose of acetaminophen prior to surgery provides 4 h of effective analgesia for approximately half of patients with acute postoperative pain. The NNT with acetaminophen postoperative is five to prevent one rescue medication administration over 4–6 h.123 Intravenous acetaminophen has been shown to reduce visual analog pain scores by 1.6 (95% CI, 1.0–2.2) and decrease morphine consumption by 30% in the first 4 h after surgery compared to a placebo.124 In a separate study, acetaminophen led to a morphine sparing effect of 20% in the first 24 h postoperatively.80 While acetaminophen has been found to be efficacious by itself, a Cochrane review found that ibuprofen combined with acetaminophen provided better analgesia than either drug alone at the same dose and with a smaller chance of an adverse event.125 In a randomized controlled trial of intravenous ibuprofen versus acetaminophen in bariatric patients without OUD, both drugs reduced morphine consumption to similar degrees, but ibuprofen was superior in terms of pain relief.118

Muscle Relaxants

Examples: baclofen, diazepam, carisoprodol, tizanidine, methocarbamol. While there is evidence that gamma-aminobutyric acid (GABA)–acting muscle relaxants hinder the release of substance P in animal models,126,127 evidence for their efficacy in reducing postoperative pain is lacking. Muscle relaxants should not be stopped perioperatively because of the risk of withdrawal. In 2020, an active clinical trial assessed

the effect of a single oral dose of baclofen on postoperative pain and opioid consumption in non–opioid-naïve patients.128 Intrathecal baclofen as an adjuvant in spinal anesthesia for total knee arthroplasty, decreased postoperative opioid usage, and decreased persistent post-surgical pain at three months after surgery.129 Diazepam binds to GABAA receptors and potentiates GABAergic activity by increasing chloride conductance, resulting in presynaptic inhibition in the spinal cord. Diazepam is the only benzodiazepine that has been approved by the Food and Drug Administration for the treatment of spasticity and muscle spasms and is commonly prescribed for these symptoms. However, it is rarely recommended as a first line agent because of the risks of sedation and the potential for dependence or abuse. No published studies have assessed the efficacy of methocarbamol for postoperative pain, but one study assessing its efficacy after a traumatic injury did not find improved pain control during the first three days of hospitalization.130 Administration of 4 mg tizanidine prior to laparoscopic cholecystectomy was found in one study to reduce postoperative pain, opioid consumption, and the length of stay in the postoperative recovery unit.131 In another study, the use of tizanidine after hernia repair decreased pain, increased time to first analgesic, and decreased total analgesic use postoperatively.132 Caffeine

Caffeine is a naturally occurring compound that acts on the central nervous system as a stimulant, and its anti-nociceptive actions have been linked to the antagonism of the adenosine receptors and blocking sites of prostaglandin synthesis.133 A Cochrane review of caffeine as an analgesic adjuvant found caffeine combined with commonly used non-opioid analgesics (e.g. aspirin, NSAIDs, acetaminophen) to improve the duration and efficacy of analgesia without increasing side effects, and about 5%–10% more patients achieved a >50% pain relief with the addition of caffeine, leading to an NNT for caffeine alone to be 15.134 Another Cochrane review assessing the efficacy of ibuprofen plus caffeine found the combination of 200 mg ibuprofen and 100 mg caffeine to have an NNT of 2.1 to achieve a >50% pain reduction.135 In a 2019 Phase I trial, caffeine ingestion with aspirin or paracetamol was not found to alter the blood serum concentrations of those agents, suggesting caffeine enhances the analgesic efficacy of these drugs by pharmacodynamic rather than pharmacokinetic interactions.136

Esmolol

The analgesic effects of β-blockers have been reported in the treatment of allodynia in humans.137 β-Blockers are also used to reduce the stress response and decrease the need for opioids following surgery.138 A meta-analysis found that intraoperative esmolol use reduced intraoperative and PACU opioid consumption, with no change in PACU pain scores.139 In bariatric surgery patients without OUD, patients who received intraoperative esmolol infusion had similar pain scores compared to those who received epidural analgesia; the two groups also exhibited similar rates of PONV.140 In elective laparoscopic cholecystectomy, intraoperative esmolol infusion was not inferior to lidocaine infusion in terms of opioid requirement and pain severity in the first 24 h after surgery.141

Dexamethasone

Steroids are useful as adjuvant therapy for CP conditions, including metastatic bone pain, neuropathic pain, and visceral pain. Corticosteroids have been shown to reduce inflammation, edema, and spontaneous discharge in an injured nerve, which reduces

 

CHAPTER 27

Evaluation and Treatment of Postoperative Pain in Patients With Opioid Use Disorder

381

neuropathic pain.142 Dexamethasone is the most commonly used corticosteroid because of its lack of mineralocorticoid effects, long half-life, and higher potency than other corticosteroids. Several meta-analyses assessing the efficacy of dexamethasone for perioperative pain management have concluded that it effectively reduces postoperative pain and opioid consumption.143–145

associated with lower pain scores, reduced opioid consumption, and a higher range of motion at 24 h compared to a placebo or no injection.158 In lumbar spine surgery, a meta-analysis found that postoperative intramuscular local anesthetic infiltration resulted in a prolonged time to first analgesic and a significantly reduced postoperative opioid demand.159

Lidocaine Patches

Nonpharmacologic Analgesia Treatment

Transdermal lidocaine has been used to treat both acute and CP. Transdermal lidocaine has been found to be effective for the relief of pain in patients with postherpetic neuralgia and diabetic neuropathy.146 In a study of patients who received a midline incision for gynecologic surgery, lidocaine patches applied to the incision resulted in reduced postoperative pain scores at rest. However, it did not result in reduced pain scores with activity, morphine consumption, or duration of hospital stay.147 However, a metaanalysis that assessed its efficacy in the management of acute postoperative pain did not find a significant benefit for pain, opioid consumption, or hospital length of stay.148

Cannabinoids

In 2020, many clinical trials assessing the use of cannabinoids for acute and CP were conducted at clinicaltrials.gov. Cannabinoids may help manage some types of CP. A Cochrane review of cannabis-based medicines for neuropathic pain concluded that a higher proportion of patients experienced >50% pain relief compared with a placebo (21% versus 17%).149 However, at this time, evidence for the efficacy of cannabinoids in managing postoperative pain suggests that they are not helpful.150

Overall, there is a paucity of studies assessing many different nonpharmacologic techniques for the treatment of postoperative pain. However, acupuncture and some mind-body therapies (MBTs) have been assessed for the treatment of pain. MBTs include hypnosis, meditation, cognitive behavior therapy, and guided imagery; these modalities have been shown to have a moderate effect on pain outcomes.160 In a meta-analysis of 29 randomized controlled trials of patients without OUD, hypnosis was found to decrease postprocedural pain compared to standard care.161 A Cochrane review suggested the efficacy of distraction, hypnosis, CBT, and breathing interventions for helping children with needle-related pain or distress. Unfortunately, the quality of evidence was low to very low.162 Children who received acupuncture may have decreased postoperative pain and analgesic consumption with higher patient and parent satisfaction scores and no adverse outcomes.163,164 A systematic review concluded that adults treated with acupuncture for the management of postoperative pain had lower opioid consumption, lower pain scores, and lower incidences of nausea, dizziness, sedation, pruritus, and urinary retention.165

Opioids Regional Anesthesia: Neuraxial Blockade, Peripheral Nerve Blocks, and Local Infiltration The use of regional anesthesia in patients with OUD who undergo surgery has not been extensively studied. However, there is significant evidence for the efficacy of regional anesthesia in improving postoperative pain compared to parenteral opioids.151 Therefore most experts recommend the use of continuous regional anesthesia for patients with OUD who present for surgery when possible. Epidural analgesia, regardless of the location of catheter placement, time of pain assessment, or infusing agent, provides better postoperative analgesia than parenteral opioids and IV patient-controlled analgesia (PCA).152,153 A  Cochrane database review of nine randomized controlled trials showed that continuous epidural analgesia provided superior pain control 72 h after abdominal surgery compared with IV PCA alone.154 A metaanalysis of elderly patients undergoing abdominal surgery found that the addition of epidural opioids to local anesthetics results in improved postoperative pain control.155 Peripheral nerve blocks for surgery of the extremities are also beneficial for managing postoperative pain. Specific regional anesthetic techniques have been discussed in detail elsewhere. For all surgeries, continuous peripheral nerve block, regardless of catheter location, provides superior postoperative analgesia, decreased opioid usage, and decreased opioid-related side effects than with opioid analgesia.156 For abdominal surgery, transversus abdominus plane (TAP) blocks lead to a lower postoperative requirement for morphine at 24 and 48 h than with placebo.157 If regional anesthesia is not used, infiltration of local anesthetics into the surgical area may provide some pain relief.158,159 In a meta-analysis of total knee arthroplasty patients, periarticular local anesthetic infiltration was

For patients who present for surgery who are prescribed opioids (non-MAT) chronically preoperatively, opioid medications should be continued perioperatively. If a patient cannot take oral medications post-procedurally, the oral morphine equivalent can be converted into a parenterally dosed opioid and administered on a scheduled basis. For patients with a history of OUD, a perioperative pain management plan that includes opioids should be developed by a multi-disciplinary care team. Opioids should be utilized after all other pain management strategies have been exhausted. The lowest effective dose of opioids should be used, and prescribed opioids should be scheduled rather than as needed. For inpatient management, intravenous PCA is an effective method with high patient satisfaction in the emergency department (ED) and hospital.166 For PCA to be most efficacious, patients should be counseled on the importance of delivering a self-bolus prior to painful stimulation, such as physical therapy or dressing changes. If the dose is not adequate to facilitate function, future doses can include a higher rescue bolus from the PCA machine or nursing staff prior to painful stimulation. For opioid tolerant patients, the starting dose recommendation is higher than that of opioid-naïve patients, although no firm consensus or guidelines are available. High opioid receptor affinity drugs, such as fentanyl, are preferred if patients are on MAT. The use of a PCA with basal infusion typically depends on provider preference and institution culture. Once patients can tolerate oral intake postoperatively, the total dose of opioids required to provide adequate pain control should be calculated. Considering this, baseline home opioid medications should be restarted, plus additional opioids to manage acute pain. Given that patients with OUD have physiologic and psychological dependence, conversion to a non-injectable formulation is ideal. Providers must recognize that higher doses of opioids are

382

PA RT 4 Clinical Conditions: Evaluation and Treatment

often needed in the setting of both hyperalgesia and opioid tolerance, and it is important to find a balance between the use of higher doses and respiratory depression. For all scenarios, a bowel regimen should be administered to aid gastrointestinal motility. According to the Centers of Disease Control (CDC) recommendations in 2016, providers should consider offering outpatient naloxone when there are increased risk factors of overdose or concurrent benzodiazepine use.167 For inpatient care, naloxone orders should be in place, so it is immediately available for use by staff. Most states have laws designed to protect healthcare professionals from civil and criminal liabilities for prescribing and dispensing naloxone.168,169

S A M P L E A C U T E PA I N R E G I M E N F O R O P I O I D T O L E R A N T PAT I E N T S • Calculate home regimen OME; continue fentanyl patch

• • • • •

or other long-acting meds for baseline control if patient able to tolerate PO intake Consider increasing home scheduled opioids by 30% Add short acting opioids to cover acute pain (10%– 20% of 24 h baseline home dose), dosed PRN Q1-4 h If opt for PCA, may use hydromorphone, fentanyl, or morphine Avoid basal infusions unless a pain specialist agrees Reduce dose of new opioid by 30%–50% when switching from one opioid to another to account for tolerance

Postoperative Pain Management in Patients Taking Medication Assisted Treatment for Opioid Use Disorder Patients on MAT for OUD, such as buprenorphine, methadone, or naloxone, require special consideration. As naloxone is an opioid receptor antagonist, it cannot be used to assist with acute pain management and should be discontinued perioperatively after consultation with an addiction specialist. Methadone and buprenorphine are dosed daily for addiction treatment, but their analgesic properties last 6–8 h; thus the continuation of outpatient dosing regimens for addiction is not sufficient for acute perioperative pain management. Patients on MAT require a pain management service consultation, and the physician prescribing the patient’s MAT should be contacted.

Methadone Methadone is a long-acting opioid receptor agonist that reduces opioid cravings by maintaining high levels of opioid tolerance and reducing the euphoric effects of subsequent shorter-acting opioids. As a controlled substance with a potential for abuse, it is only administered by certified SAMHSA opioid treatment programs (OTP). In patients admitted to the hospital, providers should contact the methadone treatment program to verify the dose of the patient and continue that dose in the inpatient setting, including the day of surgery.170–172 If postoperative oral methadone is not feasible, oral methadone may be switched to the intravenous formulation; the conversion ratio will depend on the patient’s baseline dose.170,173,174 Consultation with a pain specialist is recommended. Non-opioid analgesics, including regional anesthesia, should be employed, and conventional opioid agonists may be used to supplement pain control.171,172 The provider may

also increase the daily methadone dose by 25%–30%, given in divided doses three to four times/day, allowing five to seven days between dose titration.175 If doses are increased, intermittent electrocardiograms should occur as QT prolongation is a side effect of methadone, especially postoperatively when patients are more susceptible to electrolyte derangement.176 In addition, monitoring for respiratory depression should occur.176,177 Prior to discharge, patients should have a follow-up with their OTP for resumption of methadone. The final postoperative methadone daily dose used should also be communicated with the OTP. In opioid-naïve patients, methadone has been repeatedly proven to be a highly effective analgesic for controlling perioperative pain.178,179 Thus if additional opioids are required for postoperative pain management in patients with OUD, strong consideration should be given to using methadone, both in patients taking methadone for MAT (as above, increased, divided doses) and those who are not.

Buprenorphine Buprenorphine is a semi-synthetic partial μ opioid receptor (MOR) agonist and an antagonist of the k-opioid receptor that can be prescribed in a clinician’s office for medically supervised opioid maintenance. Although the half-life of buprenorphine is only 3 h, it has a very high affinity for, and a slow dissociation rate from, the opioid receptors to which it binds, leading to a long functional half-life.180 Buprenorphine is used to treat CP and OUD. In 2007, the World Health Organization (WHO) recognized buprenorphine and buprenorphine-naloxone as a treatment for opioid dependence, including both drugs in the 15th WHO Model List of Essential Medicines. By 2017, at the height of the opioid abuse crisis, 14.6 million buprenorphine prescriptions were dispensed in the United States.181 With such a high number of prescriptions, many institutions have developed their own protocol for dealing with patients on buprenorphine who present for surgery.57 Buprenorphine’s high affinity for the opioid receptor can be a challenge for treating acute pain, and there continues to be disagreement between practitioners about which has higher priority, acute pain management or continued OUD treatment. In 2017, a well-cited article in Anesthesiology separated those on buprenorphine who were expected to have mild postoperative pain and moderate to severe pain postoperatively. The authors suggested that for patients with moderate-severe pain expected, tapering and cessation of buprenorphine should occur prior to elective surgery, and expectations should be for higher opioid use postoperatively.182 The authors further suggested that multimodal analgesia should be maximized for all patients, including regional anesthesia, and follow up should be coordinated with the buprenorphine provider. In 2018, guidelines were established by the pain physician. Based on a review of 12 articles, providers were advised to discontinue buprenorphine three to five days preoperatively for patients with expected moderate-to-severe postoperative pain and to prescribe full opioid agonists until surgery.183 However, discontinuation of buprenorphine in the highly stressful, emotionally charged perioperative period risks precipitation of OUD relapse.184 If postoperative pain is expected to be mild, most providers suggest continuing the baseline dose of buprenorphine and supplementing with multimodal analgesics.182 If postoperative pain is expected to be mild-moderate, some clinicians suggest increasing the daily dose of buprenorphine (maximum 32 mg/day) and giving it in divided doses every 6–8 h.183,185 Literature from 2019 and 2020 suggests that if moderate-to-severe postoperative pain is expected, buprenorphine should be continued, but decreased to 12–16 mg/day preoperatively (for those taking >16 mg/day).182,186–188 Continuing buprenorphine

 

CHAPTER 27

Evaluation and Treatment of Postoperative Pain in Patients With Opioid Use Disorder

383

Surgery with Mild pain Moderate to Severe pain

Continue BUP home dose throughout perioperative period

BUP daily dose >8 mg?

no

yes Dose >16 mg daily?

PRE-OP PHASE

no

yes

Continue BUP home dose including day before surgery

DAY OF SURGERY and early postoperative period

As surgical pain subsides

Titrate down BUP dose to 16 mg day before surgery [ideally 8 mg BID]

BUP 8 mg day of surgery [may use 4] THEN 8 mg daily [ideally 4 mg BID] Add full agonist opioid (FAO) as needed Taper off FAO Resume home BUP dose [may modify]

DACCPM Guideline for Perioperative Buprenorphine Management. March 2018 (Ga rev. July 2020)

• Figure 27.3  The protocol implemented at Massachusetts General Hospital (MGH) in March 2018. BID, “Bis en die” (twice/day); BUP, buprenorphine; DACCPM, department of anesthesia, critical care, and pain management at MGH; mg, milligram; PRE-OP, preoperative. Adapted with permission from Acampora et al. 2020.186

perioperatively, even at a lower than normal dose, should continue to provide OUD relapse risk mitigation. On the day of surgery and in the acute postoperative phase, if moderate-to-severe postoperative pain is expected and the daily dose is >16 mg, buprenorphine can be divided into two doses186 (Fig. 27.3). A daily dose of buprenorphine 16 mg binds to approximately 70%–90% of μ-opioid receptors.189 For patients 1) who were administered monthly buprenorphine injections, 2) were scheduled for elective surgery, 3) whose daily dose of buprenorphine is >16 mg, and 4) are expected to have moderate-to-severe postoperative pain, it may be prudent to switch the patient to daily buprenorphine. For patients using the buprenorphine month implant, as the daily dose is about 8 mg/day once steady state is achieved after four weeks,190 it should probably be continued. When pain subsided postoperatively, if additional opioid agonists were prescribed, they should be tapered and discontinued with a return to the patient’s preoperative buprenorphine dose. A detailed plan should be developed preoperatively with the patient’s prescription of buprenorphine.

Naltrexone Naltrexone is an opioid antagonist that competitively binds to opioid μ receptors and can be taken as an oral formulation or a monthly intramuscular injection. Perioperative planning is ideal for discussing the risks and benefits of different options with the patient. Postoperative pain management is a clinical challenge for patients receiving naltrexone for the treatment of OUD and should include preoperative communication with the patient’s naltrexone prescription.191 For those who are on an oral formulation, naltrexone should be discontinued 72 h before surgery. For those prescribed subcutaneous injections, surgery should be scheduled for at least four weeks after the last injection. If emergency surgery is performed while the patient is on naltrexone, higher doses of opioids are required to overcome its MOR antagonist activity.192 In contrast, when naltrexone does not occupy the receptors, opioid analgesics can elicit an exaggerated response because of opioid receptor upregulation, resulting in more exaggerated responses to opioid medications.193

Conclusions Postoperative pain management in patients with OUD is complex and benefits from a cooperative multi-disciplinary treatment plan. The perioperative period is a vulnerable time for patients with OUD, as they may face adverse judgment and undertreatment of their pain because of the presence of opioid tolerance, hyperalgesia, withdrawal, and likely comorbid psychiatric disorders. A multimodal approach to pain management in patients who present for surgery with a history of OUD is highly recommended. This multimodal approach should include, as appropriate, nonpharmacologic therapies, regional anesthesia, and non-opioid analgesics. Opioid analgesics should be used only when necessary and after a risk-benefit analysis. For patients who undergo surgery with MAT for OUD, methadone should be continued perioperatively. However, to provide adequate analgesia, methadone

should be administered in divided doses, not once a day. There is compelling evidence that methadone improves postoperative pain compared to other opioids in opioid-naïve patients who undergo surgery. Thus for patients with OUD, consideration should be given to increasing the patient’s baseline dose of methadone postoperatively, when appropriate, to improve postoperative pain management. Many pain specialists now suggest that for patients with OUD managed with buprenorphine and who present for surgery, buprenorphine should be continued perioperatively to decrease the risk of OUD relapse and allow for adequate pain management. Patients with OUD who present for surgery must be closely monitored, and a perioperative strategy, including an opioid taper plan for those who require additional opioids, should be developed preoperatively.

384

PA RT 4 Clinical Conditions: Evaluation and Treatment

Key Points • Over 2.1 million Americans (0.7%) and 16 million people worldwide have OUD. • Patients with OUD have a significantly increased mortality risk than those without OUD. • Acute pain management for patients with OUD must occur within a risk minimization framework. • Treatment for OUD should continue to occur during the perioperative period, especially MAT, as it has been shown to be the most efficacious in preventing relapse. • Management of postoperative pain in patients with OUD necessitates an interdisciplinary care team.

Suggested Readings Bech AB, Clausen T, Waal H, et al. Mortality and causes of death among patients with opioid use disorder receiving opioid agonist treatment: A national register study. BMC Health Serv Res. 2019;19(1):440. Bradley H Lee, Kanupriya K Kumar, Emily C Wu, Christopher L Wu. Role of regional anesthesia and analgesia in the opioid epidemic Regional Anesthesia & Pain Medicine Apr 2019;44(4):492–493. doi: 10.1136/rapm-2018-100102. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8(7):573–582. Florence CS, Zhou C, Luo F, Xu L. The economic burden of prescription opioid overdose, abuse, and dependence in the United States in 2013. Med Care. 2016;54(10):901–906. United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for

• Perioperative challenges when managing pain in patients with OUD include hyperalgesia, opioid tolerance, the potential for withdrawal, and a high incidence of additional psychiatric comorbidities. • Evaluation of patients presenting for surgery with OUD should include questions regarding whether the patient is in remission or not, past and current illicit substance use, and the amount and type of current substance use, including medication-assisted therapy. • Postoperative pain management should maximize regional anesthesia, non-opioid pharmacologic, and nonpharmacologic therapies before opioid analgesics are employed.

Substance Abuse Treatment. Managing chronic pain in adults with or without recovery from substance use disorders. Rockville, MD: United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment; 2013. Quinlan J, Cox F. Acute pain management in patients with drug dependence syndrome. Pain Rep. 2017;2(4):e611. Ward EN, Quaye AN, Wilens TE. Opioid use disorders: Perioperative management of a special population Anesth Analg. 2018;127(2): 539–547. Webster LR, Webster RM Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the opioid risk tool Pain Med. 2005;6(6):432–442. The references for this chapter can be found at ExpertConsult.com

References 1. Jones MR, Viswanath O, Peck J, Kaye AD, Gill JS, Simopoulos TT. A brief history of the opioid epidemic and strategies for pain medicine. Pain Ther. 2018;7(1):13–21. 2. Morone NE, Weiner DK. Pain as the fifth vital sign: Exposing the vital need for pain education. Clin Ther. 2013;35(11):1728–1732. 3. Van Zee A. The promotion and marketing of oxycontin: Commercial triumph, public health tragedy. Am J Public Health. 2009;99(2): 221–227. 4. US Department of Health and Human Services, Centers for Disease Control. CDC/NCHS NVSS, mortality. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control; 2018. Available at: https://wonder.cdc.gov. 5. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8(7):573–582. 6. Boscarino JA, Rukstalis M, Hoffman SN, et al. Risk factors for drug dependence among outpatients on opioid therapy in a large US health-care system. Addiction. 2010;105(10):1776–1782. 7. Gomes T, Tadrous M, Mamdani MM, Paterson JM, Juurlink DN. The burden of opioid-related mortality in the United States. JAMA Netw Open. 2018;1(2):e180217. 8. Dowell D, Noonan RK, Houry D. Underlying factors in drug overdose deaths. JAMA. 2017;318(23):2295–2296. 9. Florence CS, Zhou C, Luo F, Xu L. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care. 2016;54(10):901–906. 10. Degenhardt L, Whiteford H, Hall WD. The global burden of disease projects: What have we learned about illicit drug use and dependence and their contribution to the global burden of disease? Drug Alcohol Rev. 2014;33(1):4–12. 11. Webster LR, Webster RM. Predicting aberrant behaviors in opioidtreated patients: Preliminary validation of the opioid risk tool. Pain Med. 2005;6(6):432–442. 12. John WS, Wu LT. Chronic non-cancer pain among adults with substance use disorders: Prevalence, characteristics, and association with opioid overdose and healthcare utilization. Drug Alcohol Depend. 2020;209:107902. 13. Morasco BJ, Gritzner S, Lewis L, Oldham R, Turk DC, Dobscha SK. Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder. Pain. 2011;152(3):488–497. 14. Hser Y-I, Mooney LJ, Saxon AJ, Miotto K, Bell DS, Huang D. Chronic pain among patients with opioid use disorder: Results from electronic health records data. J Subst Abuse Treat. 2017;77:26–30. 15. Ilgen MA, Perron B, Czyz EK, McCammon RJ, Trafton J. The timing of onset of pain and substance use disorders. Am J Addict. 2010;19(5):409–415. 16. Alford DP, German JS, Samet JH, Cheng DM, Lloyd-Travaglini CA, Saitz R. Primary care patients with drug use report chronic pain and self-medicate with alcohol and other drugs. J Gen Intern Med. 2016;31(5):486–491. 17. Dersh J, Polatin PB, Gatchel RJ. Chronic pain and psychopathology: Research findings and theoretical considerations. Psychosom Med. 2002;64(5):773–786. 18. Polatin PB, Kinney RK, Gatchel RJ, Lillo E, Mayer TG. Psychiatric illness and chronic low-back pain. The mind and the spine–which goes first? Spine (Phila Pa 1976). 1993;18(1):66–71. 19. Gatchel RJ, Polatin PB, Mayer TG. The dominant role of psychosocial risk factors in the development of chronic low back pain disability. Spine (Phila Pa 1976). 1995;20(24):2702–2709. 20. Brown RL, Patterson JJ, Rounds LA, Papasouliotis O. Sub stance abuse among patients with chronic back pain. J Fam Pract. 1996;43(2):152–160. 21. Akhtar E, Ballew AT, Orr WN, Mayorga A, Khan TW. The prevalence of post-traumatic stress disorder symptoms in chronic pain

patients in a tertiary care setting: A cross-sectional study. Psychosom. 2019;60(3):255–262. 22. Ballantyne JC, LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. Pain. 2007;129(3):235–255. 23. Clark MR, Stoller KB, Brooner RK. Assessment and management of chronic pain in individuals seeking treatment for opioid dependence disorder. Can J Psychiatry. 2008;53(8):496–508. 24. Hojsted J, Sjogren P. An update on the role of opioids in the management of chronic pain of nonmalignant origin. Curr Opin Anaesthesiol. 2007;20(5):451–455. 25. Speed TJ, Parekh V, Coe W, Antoine D. Comorbid chronic pain and opioid use disorder: Literature review and potential treatment innovations. Int Rev Psychiatry. 2018;30(5):136–146. 26. Center for Substance Abuse Treatment. Managing chronic pain in adults with or in recovery from substance use disorders. Treatment improvement protocol (TIP) series54. Rockville, MD: Substance Abuse and Mental Health Services Administration (United States); 2012. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK92054/. 27. Lindblad R, Hu L, Oden N, Wakim P, Rosa C, VanVeldhuisen P. Mortality rates among substance use disorder participants in clinical trials: Pooled analysis of twenty-two clinical trials within the national drug abuse treatment clinical trials network. J Subst Abuse Treat. 2016;70:73–80. 28. Larney S, Tran LT, Leung J, et al. All-cause and cause-specific mortality among people using extra medical opioids: A systematic review and meta-analysis. JAMA Psychiatry. 2019. 29. Bech AB, Clausen T, Waal H, Saltyte Benth J, Skeie I. Mortality and causes of death among patients with opioid use disorder receiving opioid agonist treatment: A national register study. BMC Health Serv Res. 2019;19(1):440. 30. United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Medication and counseling treatment. 2020. Available at: https://www.samhsa.gov/ medication-assisted-treatment/treatment. 31. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Methadone dose and treatment outcome. Drug Alcohol Depend. 1993;33(2): 105–117. 32. Garcia-Portilla MP, Bobes-Bascaran MT, Bascaran MT, Saiz PA, Bobes J. Long term outcomes of pharmacological treatments for opioid dependence: Does methadone still lead the pack? Br J Clin Pharmacol. 2014;77(2):272–284. 33. Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: A randomised, placebo-controlled trial. Lancet. 2003;361(9358):662–668. 34. Barnett PG, Rodgers JH, Bloch DA. A meta-analysis comparing buprenorphine to methadone for treatment of opiate dependence. Addiction. 2001;96(5):683–690. 35. Caplehorn JR, Bell J. Methadone dosage and retention of patients in maintenance treatment. Med J Aust. 1991;154(3):195–199. 36. Mitra S, Sinatra RS. Perioperative management of acute pain in the opioid-dependent patient. Anesthesiol. 2004;101(1):212–227. 37. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study. J Pain. 2006;7(1):43–48. 38. Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain. 2001;90(1-2):91–96. 39. Gardell LR, Wang R, Burgess SE, et al. Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci. 2002;22(15):6747–6755. 40. Vanderah TW, Gardell LR, Burgess SE, et al. Dynorphin promotes abnormal pain and spinal opioid anti-nociceptive tolerance. J Neurosci. 2000;20(18):7074–7079.

384.e1

384.e2

References

41. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: Implications in morphine tolerance and abnormal pain sensitivity. J Neurosci. 2002;22(18):8312–8323. 42. Athanasos P, Smith CS, White JM, Somogyi AA, Bochner F, Ling W. Methadone maintenance patients are cross-tolerant to the antinociceptive effects of very high plasma morphine concentrations. Pain. 2006;120(3):267–275. 43. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiol. 2011; 115(6):1363–1381. 44. Hayhurst CJ, Durieux ME. Differential opioid tolerance and opioid-induced hyperalgesia: A clinical reality. Anesthesiol. 2016; 124(2):483–488. 45. Hser YI, Mooney LJ, Saxon AJ, Miotto K, Bell DS, Huang D. Chronic pain among patients with opioid use disorder: Results from electronic health records data. J Subst Abuse Treat. 2017;77:26–30. 46. Kaye AD, Jones MR, Kaye AM, et al. Prescription opioid abuse in chronic pain: An updated review of opioid abuse predictors and strategies to curb opioid abuse: Part 1. Pain Physician. 2017;20(2S): S93–S109. 47. Cunningham JL, Craner JR, Evans MM, Hooten WM. Benzodiazepine use in patients with chronic pain in an interdisciplinary pain rehabilitation program. J Pain Res. 2017;10:311–317. 48. Zale EL, Maisto SA, Ditre JW. Interrelations between pain and alcohol: An integrative review. Clin Psychol Rev. 2015;37:57–71. 49. Hasin DS, Shmulewitz D, Cerdá M, et al. U.S. adults with pain, a group increasingly vulnerable to nonmedical cannabis use and cannabis use disorder: 2001–2002 and 2012–2013. Am J Psychiatry. 2020;177(7):611–618. 50. Hooten WM. Chronic pain and mental health disorders: Shared neural mechanisms, epidemiology, and treatment. Mayo Clin Proc. 2016;91(7):955–970. 51. Racine M. Chronic pain and suicide risk: A comprehensive review. Prog Neuropsychopharmacol. Biol Psychiatry. 2018;87(Pt B):269– 280. 52. United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment. Managing chronic pain in adults with or in recovery from substance use disorders. Rockville, MD: United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment; 2013. 53. Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. N Engl J Med. 2016;374(4):363–371. 54. Tsui JI, Lira MC, Cheng DM, et  al. Chronic pain, craving, and illicit opioid use among patients receiving opioid agonist therapy. Drug Alcohol Depend. 2016;166:26–31. 55. Larson MJ, Paasche-Orlow M, Cheng DM, Lloyd-Travaglini C, Saitz R, Samet JH. Persistent pain is associated with substance use after detoxification: A prospective cohort analysis. Addiction. 2007;102(5):752–760. 56. Stromer W, Michaeli K, Sandner-Kiesling A. Perioperative pain therapy in opioid abuse. Eur J Anaesthesiol. 2013;30(2):55–64. 57. Ward EN, Quaye AN, Wilens TE. Opioid use disorders: Perioperative management of a special population. Anesth Analg. 2018;127(2):539–547. 58. Quinlan J, Cox F. Acute pain management in patients with drug dependence syndrome. Pain Rep. 2017;2(4):e611. 59. Tremont-Lukats IW, Hutson PR, Backonja MM. A randomized, double-masked, placebo-controlled pilot trial of extended IV lidocaine infusion for relief of ongoing neuropathic pain. Clin J Pain. 2006;22(3):266–271. 60. Wallace MS, Laitin S, Licht D, Yaksh TL. Concentration-effect relations for intravenous lidocaine infusions in human volunteers: Effects on acute sensory thresholds and capsaicin-evoked hyperpathia. Anesthesiol. 1997;86(6):1262–1272.

61. Attal N, Gaude V, Brasseur L, et al. Intravenous lidocaine in central pain: A double-blind, placebo-controlled, psychophysical study. Neurol. 2000;54(3):564–574. 62. Wallace MS, Ridgeway BM, Leung AY, Gerayli A, Yaksh TL. Concentration-effect relationship of intravenous lidocaine on the allodynia of complex regional pain syndrome types I and II. Anesthesiol. 2000;92(1):75–83. 63. Baranowski AP, De Courcey J, Bonello E. A trial of intravenous lidocaine on the pain and allodynia of postherpetic neuralgia. J Pain Symptom Manage. 1999;17(6):429–433. 64. Kvarnstrom A, Karlsten R, Quiding H, Gordh T. The analgesic effect of intravenous ketamine and lidocaine on pain after spinal cord injury. Acta Anaesthesiol Scand. 2004;48(4):498–506. 65. Dunn LK, Durieux ME. Perioperative use of intravenous lidocaine. Anesthesiol. 2017;126(4):729–737. 66. Koppert W, Weigand M, Neumann F, et al. Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth Analg. 2004;98(4):1050–1055 table of contents. 67. Eipe N, Gupta S, Penning J. Intravenous lidocaine for acute pain: An evidence-based clinical update. BJA Education. 2016;16(9): 292–298. 68. Hollmann MW, Herroeder S, Kurz KS, et al. Time-dependent inhibition of G protein-coupled receptor signaling by local anesthetics. Anesthesiol. 2004;100(4):852–860. 69. Sahmeddini MA, Khosravi MB, Farbood A. Comparison of perioperative systemic lidocaine or systemic ketamine in acute pain management of patients with opioid use disorder after orthopedic surgery. J Addict Med. 2019;13(3):220–226. 70. Weibel S, Jelting Y, Pace NL, et  al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database Syst Rev. 2018;6:CD009642. 71. Yaksh TL, Hua XY, Kalcheva I, Nozaki-Taguchi N, Marsala M. The spinal biology in humans and animals of pain states generated by persistent small afferent input. Proc Natl Acad Sci U S A. 1999;96(14):7680–7686. 72. Elia N, Tramer MR. Ketamine and postoperative pain- a quantitative systematic review of randomised trials. Pain. 2005;113(1-2): 61–70. 73. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58(10):911–923. 74. Barreveld AM, Correll DJ, Liu X, et  al. Ketamine decreases postoperative pain scores in patients taking opioids for chronic pain: Results of a prospective, randomized, double-blind study. Pain Med. 2013;14(6):925–934. 75. King MR, Ladha KS, Gelineau AM, Anderson TA. Perioperative dextromethorphan as an adjunct for postoperative pain: A metaanalysis of randomized controlled trials. Anesthesiol. 2016;124(3): 696–705. 76. Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: A metaanalysis. Anesth Analg. 2005;100(3):757–773 table of contents. 77. Schnabel A, Meyer-Friessem CH, Reichl SU, Zahn PK, PogatzkiZahn EM. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain. 2013;154(7):1140–1149. 78. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: Systematic review and meta-analysis of randomized controlled trials. Anesthesiol. 2012;116(6):1312–1322. 79. Grosu I, de Kock M. New concepts in acute pain management: Strategies to prevent chronic postsurgical pain, opioid-induced hyperalgesia, and outcome measures. Anesthesiol Clin. 2011;29(2):311–327. 80. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: Meta-analysis of randomized controlled trials. BJA: Br J Anaesth. 2005;94(4): 505–513.

References

81. Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiol. 2005;103(6):1296–1304. 82. Gilron I. Review article: The role of anticonvulsant drugs in postoperative pain management: A bench-to-bedside perspective. Can J Anaesth. 2006;53(6):562–571. 83. Nir RR, Nahman-Averbuch H, Moont R, Sprecher E, Yarnitsky D. Preoperative preemptive drug administration for acute postoperative pain: A systematic review and meta-analysis. Eur J Pain. 2016;20(7):1025–1043. 84. Arumugam S, Lau CS, Chamberlain RS. Use of preoperative gabapentin significantly reduces postoperative opioid consumption: A meta-analysis. J Pain Res. 2016;9:631–640. 85. Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: A systematic review and meta-analysis. Br J Anaesth. 2015;114(1):10–31. 86. Doleman B, Heinink TP, Read DJ, Faleiro RJ, Lund JN, Williams JP. A systematic review and meta-regression analysis of prophylactic gabapentin for postoperative pain. Anaesth. 2015;70(10):1186–1204. 87. Pogatzki-Zahn EM, Segelcke D, Schug SA. Postoperative painfrom mechanisms to treatment. Pain Rep. 2017;2(2):e588. 88. Zahn PK, Brennan TJ. Primary and secondary hyperalgesia in a rat model for human postoperative pain. Anesthesiol. 1999;90(3): 863–872. 89. Perucca E. An introduction to antiepileptic drugs. Epilepsia. 2005; 46(Suppl 4):31–37. 90. Jiang Y, Li J, Lin H, et al. The efficacy of gabapentin in reducing pain intensity and morphine consumption after breast cancer surgery: A meta-analysis. Med. 2018;97(38):e11581. 91. Liu B, Liu R, Wang L. A meta-analysis of the preoperative use of gabapentinoids for the treatment of acute postoperative pain following spinal surgery. Med. 2017;96(37):e8031. 92. Han C, Kuang MJ, Ma JX, Ma XL. The efficacy of preoperative gabapentin in spinal surgery: A meta-analysis of randomized controlled trials. Pain Physician. 2017;20(7):649–661. 93. Hamilton TW, Strickland LH, Pandit HG. A meta-analysis on the use of gabapentinoids for the treatment of acute postoperative pain following total knee arthroplasty. J Bone Joint Surg Am. 2016;98(16):1340–1350. 94. Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45(Suppl 6):13–18. 95. Agarwal A, Gautam S, Gupta D, Agarwal S, Singh PK, Singh U. Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy. Br J Anaesth. 2008;101(5):700–704. 96. Hwang SH, Park IJ, Cho YJ, Jeong YM, Kang JM. The efficacy of gabapentin/pregabalin in improving pain after tonsillectomy: A meta-analysis. Laryngoscope. 2016;126(2):357–366. 97. Jiang HL, Huang S, Song J, Wang X, Cao ZS. Preoperative use of pregabalin for acute pain in spine surgery: A meta-analysis of randomized controlled trials. Med. 2017;96(11):e6129. 98. Wang YM, Xia M, Shan N, et  al. Pregabalin can decrease acute pain and postoperative nausea and vomiting in hysterectomy: A meta-analysis. Med. 2017;96(31):e7714. 99. Li S, Guo J, Li F, Yang Z, Wang S, Qin C. Pregabalin can decrease acute pain and morphine consumption in laparoscopic cholecystectomy patients: A meta-analysis of randomized controlled trials. Med.. 2017;96(21):e6982. 100. Martins MJ, Martins C, Castro-Alves LJ, et  al. Pregabalin to improve postoperative recovery in bariatric surgery: A parallel, randomized, double-blinded, placebo-controlled study. J Pain Res. 2018;11:2407–2415. 101. Kim JC, Choi YS, Kim KN, Shim JK, Lee JY, Kwak YL. Effective dose of peri-operative oral pregabalin as an adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery. Spine (Phila Pa 1976). 2011;36(6):428–433.

384.e3

102. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs. 2017;77(4):403–426. 103. Cavalcante AN, Sprung J, Schroeder DR, Weingarten TN. Multimodal analgesic therapy with gabapentin and its association with postoperative respiratory depression. Anesth Analg. 2017;125(1):141–146. 104. Zhang Z, Xu H, Zhang Y, et  al. Nonsteroidal antiinflammatory drugs for postoperative pain control after lumbar spine surgery: A meta-analysis of randomized controlled trials. J Clin Anesth. 2017;43:84–89. 105. Qiu J, Xie M, Qu R. The influence of etoricoxib on pain control for laparoscopic cholecystectomy: A meta-analysis of randomized controlled trials. Surg Laparosc Endosc Percutan Tech. 2019;29(3):150–154. 106. Zeng AM, Nami NF, Wu CL, Murphy JD. The analgesic efficacy of nonsteroidal antiinflammatory agents (NSAIDs) in patients undergoing cesarean deliveries: A meta-analysis. Reg Anesth Pain Med. 2016;41(6):763–772. 107. Costa FW, Esses DF, de Barros, Silva PG, et al. Does the preemptive use of oral nonsteroidal antiinflammatory drugs reduce postoperative pain in surgical removal of third molars? A meta-analysis of randomized clinical trials. Anesth Prog. 2015;62(2):57–63. 108. De Oliveira Jr GS, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: A meta-analysis of randomized trials. Anesth Analg. 2012;114(2):424–433. 109. Chen JY, Ko TL, Wen YR, et al. Opioid-sparing effects of ketorolac and its correlation with the recovery of postoperative bowel function in colorectal surgery patients: A prospective randomized double-blinded study. Clin J Pain. 2009;25(6):485–489. 110. Pavy TJ, Paech MJ, Evans SF. The effect of intravenous ketorolac on opioid requirement and pain after cesarean delivery. Anesth Analg. 2001;92(4):1010–1014. 111. Chen JY, Wu GJ, Mok MS, et  al. Effect of adding ketorolac to intravenous morphine patient-controlled analgesia on bowel function in colorectal surgery patients- a prospective, randomized, double-blind study. Acta Anaesthesiol Scand. 2005;49(4):546–551. 112. Duttchen KM, Lo A, Walker A, et al. Intraoperative ketorolac dose of 15mg versus the standard 30mg on early postoperative pain after spine surgery: A randomized, blinded, non-inferiority trial. J Clin Anesth. 2017;41:11–15. 113. Motov S, Yasavolian M, Likourezos A, et al. Comparison of intravenous ketorolac at three single-dose regimens for treating acute pain in the emergency department: A randomized controlled trial. Ann Emerg Med. 2017;70(2):177–184. 114. Huang YM, Wang CM, Wang CT, Lin WP, Horng LC, Jiang CC. Perioperative celecoxib administration for pain management after total knee arthroplasty- a randomized, controlled study. BMC Musculoskelet Disord. 2008;9:77. 115. Mammoto T, Fujie K, Mamizuka N, et al. Effects of postoperative administration of celecoxib on pain management in patients after total knee arthroplasty: Study protocol for an open-label randomized controlled trial. Trials. 2016;17:45. 116. Mason L, Edwards JE, Moore RA, McQuay HJ. Single-dose oral naproxen for acute postoperative pain: A quantitative systematic review. BMC Anesthesiol. 2003;3(1):4. 117. Derry C, Derry S, Moore RA, McQuay HJ. Single dose oral naproxen and naproxen sodium for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009(1):CD004234. 118. Erdogan Kayhan G, Sanli M, Ozgul U, Kirteke R, Yologlu S. Comparison of intravenous ibuprofen and acetaminophen for postoperative multimodal pain management in bariatric surgery: A randomized controlled trial. J Clin Anesth. 2018;50:5–11. 119. Ahiskalioglu EO, Ahiskalioglu A, Aydin P, Yayik AM, Temiz A. Effects of single-dose preemptive intravenous ibuprofen on postoperative opioid consumption and acute pain after laparoscopic cholecystectomy. Med. 2017;96(8):e6200. 120. Derry S, Derry CJ, Moore RA. Single dose oral ibuprofen plus oxycodone for acute postoperative pain in adults. Cochrane Database Syst Rev. 2013(6):CD010289.

384.e4

References

121. Gaskell H, Derry S, Wiffen PJ, Moore RA. Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults. Cochrane Database Syst Rev. 2017;5:CD007355. 122. Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther. 2006;79(1):9–19. 123. Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database Syst Rev. 2008(4):CD004602. 124. McNicol ED, Tzortzopoulou A, Cepeda MS, Francia MB, Farhat T, Schumann R. Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: A systematic review and meta-analysis. Br J Anaesth. 2011;106(6):764–775. 125. Derry CJ, Derry S, Moore RA. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane Database Syst Rev. 2013(6):CD010210. 126. Ray NJ, Jones AJ, Keen P. GABAB receptor modulation of the release of substance P from capsaicin-sensitive neurons in the rat trachea in vitro. Br J Pharmacol. 1991;102(4):801–804. 127. Hwang AS, Wilcox GL. Baclofen, gamma-aminobutyric acid B receptors and substance P in the mouse spinal cord. J Pharmacol Exp Ther. 1989;248(3):1026–1033. 128. Mandabach M. Baclofen as a perioperative analgesic adjuvant. Available at: https://clinicaltrials.gov/ct2/show/NCT03720717. NLM Identifier: NCT03720717. 129. Sanders JC, Gerstein N, Torgeson E, Abram S. Intrathecal baclofen for postoperative analgesia after total knee arthroplasty. J Clin Anesth. 2009;21:486–492 7a. 130. Aljuhani O, Kopp BJ, Patanwala AE. Effect of methocarbamol on acute pain After traumatic injury. Am J Ther. 2017;24(2):e202–e206. 131. Talakoub R, Abbasi S, Maghami E, Zavareh SM. The effect of oral tizanidine on postoperative pain relief after elective laparoscopic cholecystectomy. Adv Biomed Res. 2016;5:19. 132. Yazicioglu D, Caparlar C, Akkaya T, Mercan U, Kulacoglu H. Tizanidine for the management of acute postoperative pain after inguinal hernia repair: A placebo-controlled double-blind trial. Eur J Anaesthesiol. 2016;33(3):215–222. 133. Sawynok J. Caffeine and pain. Pain. 2011;152(4):726–729. 134. Derry CJ, Derry S, Moore RA. Caffeine as an analgesic adjuvant for acute pain in adults. Cochrane Database Syst Rev. 2012(3): CD009281. 135. Derry S, Wiffen PJ, Moore RA. Single dose oral ibuprofen plus caffeine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2015(7):CD011509. 136. Weiser T, Weigmann H. Effect of caffeine on the bioavailability and pharmacokinetics of an acetylsalicylic acid-paracetamol combination: Results of a phase I study. Adv Ther. 2019;36(3):597–607. 137. Ernberg M, Lundeberg T, Kopp S. Effect of propranolol and granisetron on experimentally induced pain and allodynia/hyperalgesia by intramuscular injection of serotonin into the human masseter muscle. Pain. 2000;84(2-3):339–346. 138. Stein C, Kopf A. Miller’s Anesthesia. Philadelphia, PA: Churchill Livingstone; 2010:1797–1817. 139. Gelineau AM, King MR, Ladha KS, Burns SM, Houle T, Anderson TA. Intraoperative esmolol as an adjunct for perioperative opioid and postoperative pain reduction: A systematic review, meta-analysis, and meta-regression. Anesth Analg. 2018;126(3):1035–1049. 140. Casalino S, Fabozzi M, Millo P, Cena A, Angellotti A, Albani A. Esmolol vs epidural anesthesia in bariatric surgery: Pain control and postoperative outcome: 1AP1-1. Eur J Anaesthesiol. 2011;28:6–7. 141. Bajracharya JL, Subedi A, Pokharel K, Bhattarai B. The effect of intraoperative lidocaine versus esmolol infusion on postoperative analgesia in laparoscopic cholecystectomy: A randomized clinical trial. BMC Anesthesiol. 2019;19(1):198. 142. Watanabe S, Bruera E. Corticosteroids as adjuvant analgesics. J Pain Symptom Manage. 1994;9(7):442–445.

143. De Oliveira Jr GS, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: A meta-analysis of randomized controlled trials. Anesthesiol. 2011;115(3):575–588. 144. Fan Z, Ma J, Kuang M, et al. The efficacy of dexamethasone reducing postoperative pain and emesis after total knee arthroplasty: A systematic review and meta-analysis. Int J Surg. 2018;52:149–155. 145. Fan ZR, Ma J, Ma XL, et  al. The efficacy of dexamethasone on pain and recovery after total hip arthroplasty: A systematic review and meta-analysis of randomized controlled trials. Med. 2018;97(13):e0100. 146. Mick G, Correa-Illanes G. Topical pain management with the 5% lidocaine medicated plaster–a review. Curr Med Res Opin. 2012;28(6):937–951. 147. Lau LL, Li CY, Lee A, Chan SK. The use of 5 % lidocaine medicated plaster for acute postoperative pain after gynecological surgery: A pilot randomized controlled feasibility trial. Med. 2018;97(39):e12582. 148. Bai Y, Miller T, Tan M, Law LS, Gan TJ. Lidocaine patch for acute pain management: A meta-analysis of prospective controlled trials. Curr Med Res Opin. 2015;31(3):575–581. 149. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabisbased medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3:CD012182. 150. Abdallah FW, Hussain N, Weaver T, Brull R. Analgesic efficacy of cannabinoids for acute pain management after surgery: A systematic review and meta-analysis. Reg Anesth Pain Med. 2020;45(7):509–519. 151. Bradley H Lee, Kanupriya K Kumar, Emily C Wu, Christopher L Wu Role of regional anesthesia and analgesia in the opioid epidemic Regional Anesthesia & Pain Medicine Apr 2019;44(4):492–493. doi: 10.1136/rapm-2018-100102. 152. Wu CL, Cohen SR, Richman JM, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: A metaanalysis. Anesthesiol. 2005;103(5):1079–1088 quiz 1109-1010. 153. Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan Jr JA, Wu CL. Efficacy of postoperative epidural analgesia: A meta-analysis. JAMA. 2003;290(18):2455–2463. 154. Werawatganon T, Charuluxanun S. Patient controlled intrave nous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database Syst Rev. 2005(1):CD004088. 155. Mann C, Pouzeratte Y, Boccara G, et al. Comparison of intravenous or epidural patient-controlled analgesia in the elderly after major abdominal surgery. Anesthesiol. 2000;92(2):433–441. 156. Richman JM, Liu SS, Courpas G, et al. Does continuous peripheral nerve block provide superior pain control to opioids? A metaanalysis. Anesth Analg. 2006;102(1):248–257. 157. Charlton S, Cyna AM, Middleton P, Griffiths JD. Perioperative transversus abdominis plane (TAP) blocks for analgesia after abdominal surgery. Cochrane Database Syst Rev. 2010(12):CD007705. 158. Seangleulur A, Vanasbodeekul P, Prapaitrakool S, et al. The efficacy of local infiltration analgesia in the early postoperative period after total knee arthroplasty: A systematic review and meta-analysis. Eur J Anaesthesiol. 2016;33(11):816–831. 159. Perera AP, Chari A, Kostusiak M, Khan AA, Luoma AM, Casey ATH. Intramuscular local anesthetic infiltration at closure for postoperative analgesia in lumbar spine surgery: A systematic review and meta-analysis. Spine (Phila Pa 1976). 2017;42(14):1088–1095. 160. Garland EL, Brintz CE, Hanley AW, et al. Mind-body therapies for opioid-treated pain: A systematic review and meta-analysis. JAMA Intern Med. 2019. 161. Kendrick C, Sliwinski J, Yu Y, et al. Hypnosis for acute procedural pain: A critical review. Int J Clin Exp Hypn. 2016;64(1):75–115. 162. Birnie KA, Noel M, Chambers CT, Uman LS, Parker JA. Psychological interventions for needle-related procedural pain and distress in children and adolescents. Cochrane Database Syst Rev. 2018;10:CD005179.

References

163. Tsao GJ, Messner AH, Seybold J, Sayyid ZN, Cheng AG, Golianu B. Intraoperative acupuncture for posttonsillectomy pain: A randomized, double-blind, placebo-controlled trial. Laryngoscope. 2015;125(8):1972–1978. 164. Gilbey P, Bretler S, Avraham Y, Sharabi-Nov A, Ibrgimov S, Luder A. Acupuncture for posttonsillectomy pain in children: A randomized, controlled study. Paediatr Anaesth. 2015;25(6):603–609. 165. Sun Y, Gan TJ, Dubose JW, Habib AS. Acupuncture and related techniques for postoperative pain: A systematic review of randomized controlled trials. Br J Anaesth. 2008;101(2):151–160. 166. Ballantyne JC, Carr DB, Chalmers TC, Dear KB, Angelillo IF, Mosteller F. Postoperative patient-controlled analgesia: Metaanalyses of initial randomized control trials. J Clin Anesth. 1993; 5(3):182–193. 167. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain - United States, 2016. MMWR. 2016; 65(1):1–49. 168. Prescription Drug Abuse Policy System NOPL, 2017. Available at: www.pdaps.org. 169. Walley AY, Xuan Z, Hackman HH, et  al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: Interrupted time series analysis. BMJ. 2013;346:f174. 170. Sen S, Arulkumar S, Cornett EM, et  al. New pain management options for the surgical patient on methadone and buprenorphine. Curr Pain Headache Rep. 2016;20(3):16. 171. Peng PW, Tumber PS, Gourlay D. Review article: Periopera tive pain management of patients on methadone therapy. Can J Anaesth. 2005;52(5):513–523. 172. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. 2006;144(2):127–134. 173. Gonzalez-Barboteo J, Porta-Sales J, Sanchez D, Tuca A, GomezBatiste X. Conversion from parenteral to oral methadone. J Pain Palliat Care Pharmacother. 2008;22(3):200–205. 174. Walker PW, Palla S, Pei BL, et al. Switching from methadone to a different opioid: What is the equianalgesic dose ratio? J Palliat Med. 2008;11(8):1103–1108. 175. Taveros MC, Chuang EJ. Pain management strategies for patients on methadone maintenance therapy: A systematic review of the literature. BMJ Support Palliat Care. 2017;7(4):383–389. 176. Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: A clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15(4):321–337. 177. Cornett EM, Kline RJ, Robichaux SL, et al. Comprehensive perioperative management considerations in patients taking methadone. Curr Pain Headache Rep. 2019;23(7):49. 178. D’Souza RS, Gurrieri C, Johnson RL, Warner N, Wittwer E. Intraoperative methadone administration and postoperative pain control: A systematic review and meta-analysis. Pain. 2020;161(2):237–243. 179. Machado FC, Vieira JE, de Orange FA, Ashmawi HA. Intraoperative methadone reduces pain and opioid consumption in acute postoperative pain: A systematic review and meta-analysis. Anesth Analg. 2019;129(6):1723–1732.

384.e5

180. Cowan A, Lewis JW, Macfarlane IR. Agonist and antagonist properties of buprenorphine, a new anti-nociceptive agent. Br J Pharmacol. 1977;60(4):537–545. 181. U.S. Department of Justice Drug Enforcement Administration Diversion Control Division Drug & Chemical Evaluation Section. Drug Enforcement Administration. Buprenorphine. Available at: http://www.deadiversion.usdoj.gov/drug_chem_info/buprenorphine.pdf. 182. Anderson TA, Quaye ANA, Ward EN, Wilens TE, Hilliard PE, Brummett CM. To stop or not, that is the question: Acute pain management for the patient on chronic buprenorphine. Anesthesiol. 2017;126(6):1180–1186. 183. Jonan AB, Kaye AD, Urman RD. Buprenorphine formulations: Clinical best practice strategies recommendations for perioperative management of patients undergoing surgical or interventional pain procedures. Pain Physician. 2018;21(1):E1–E12. 184. Bentzley BS, Barth KS, Back SE, Book SW. Discontinuation of buprenorphine maintenance therapy: Perspectives and outcomes. J Subst Abuse Treat. 2015;52:48–57. 185. Childers JW, Arnold RM. Treatment of pain in patients taking buprenorphine for opioid addiction #221. J Palliat Med. 2012; 15(5):613–614. 186. Acampora GA, Nisavic M, Zhang Y. Perioperative buprenorphine continuous maintenance and administration simultaneous with full opioid agonist: Patient priority at the interface between medical disciplines. J Clin Psychiatry. 2020;81(1). 187. Lembke A, Ottestad E, Schmiesing C. Patients maintained on buprenorphine for opioid use disorder should continue buprenorphine through the perioperative period. Pain Med. 2019;20(3):425–428. 188. Goel A, Azargive S, Lamba W, et al. The perioperative patient on buprenorphine: A systematic review of perioperative management strategies and patient outcomes. Can J Anaesth. 2019;66(2):201– 217. 189. Greenwald MK, Johanson CE, Moody DE, et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacol. 2003;28(11):2000–2009. 190. Titan Pharmaceuticals Inc. Probuphine [prescribing information]. South San Francisco, CA: Titan Pharmaceuticals Inc; 2019. 191. Vickers AP, Jolly A. Naltrexone and problems in pain management. BMJ. 2006;332(7534):132–133. 192. Dean RL, Todtenkopf MS, Deaver DR, et  al. Overriding the blockade of anti-nociceptive actions of opioids in rats treated with extended-release naltrexone. Pharmacol Biochem Behav. 2008;89(4):515–522. 193. Yoburn BC, Sierra V, Lutfy K. Simultaneous development of opioid tolerance and opioid antagonist-induced receptor upregulation. Brain Res. 1990;529(1-2):143–148. 194. Wesson DR, Ling W. The clinical opiate withdrawal scale (COWS). J Psychoactive Drugs. 2003;35(2):253–259. 195. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Arlington, VA: American Psychiatric Association; 2013.

28

Evaluation and Treatment of Acute Pain in Children

RAVI SHAH, SANTHANAM SURESH, NICHOLAS E. BURJEK

Recognition and treatment of acute pain is a vital component of pediatric medicine.1,2 Adequate pain control is necessary to prevent adverse neurohormonal and developmental changes in response to painful stimuli.3–5 Fortunately, advances in pharmacologic therapy and regional anesthesia techniques have helped expand the scope of pediatric acute pain management.6 In addition, the establishment of pediatric acute pain services has played an important role in ensuring timely and consistent care of children.7,8

Developmental Neurobiology of Pain The study of pain in neonates has been a significant focus in the field of neuroscience. Nociceptive pathways are well developed even at birth, resulting in hormonal, metabolic, cardiorespiratory, emotional, and behavioral changes in response to painful stimuli.9 A study of brain perfusion in response to pain has demonstrated significant changes in perfusion with noxious stimuli versus nonnoxious stimuli.10 Newborn rats appear to have a significant proliferation of A and C fibers with a pattern of hyperalgesia developing at sites exposed to painful stimuli.11 Analogously, human neonates exposed to repeated heel sticks develop cutaneous hyperalgesia, which can be reversed with topical local analgesia.12 Therefore it is a misconception that pain control is less important in neonates and small children because they cannot form memories of painful experiences or communicate discomfort. Adequate analgesia can limit the immediate and long term effects of noxious stimuli, and treatment of pain in young patients should receive the same level of attention as in adults.

Assessment of Pediatric Acute Pain Reliable assessment of pain level is essential for effective management.13 Unfortunately, pediatric patients may be too young, developmentally immature, or unwilling to adequately communicate their pain level.14 Assessment of acute pain in such patients often relies on observer reports, whereas older children may use self-report measures (see Table 28.1).15–30 Observational pain assessment tools rely on the interpretation of pain related activity such as body movements, facial expression, and vocalizations; physiologic changes such as heart rate and oxygen saturation; and the child’s behavioral state. These measures have been designed to assess procedural pain (e.g. premature infant pain profile [PIPP],16 neonatal facial coding system [NFCS]17) or postoperative pain (e.g. Children’s Hospital of Eastern Ontario pain scale [CHEOPS],31

toddler-preschooler postoperative pain scale [TPPPS]).23 The FLACC scale (faces, legs, activity, cry, consolability) is a tool that can be used for all ages,32,33 while the revised FLACC (rFLACC) scale incorporates additional observable behaviors to improve validity in children with cognitive impairment (see Table 28.2).34 The rFLACCs ease of use and validation in patients with a wide range of ages and cognitive levels make it a practical choice for assessment of patients who cannot self-report. Observational assessment tools have limits in their specificity, particularly when including physiologic parameters that can vary because of conditions not associated with pain. Despite their intrinsic limits, these scales have been shown to have construct validity and internal and interrater reliability.18–22,24–30 Developmentally appropriate children five years and older can typically provide self-reports on one of several validated visual analog (e.g. colored analog scale [CAS]26) or faces scales (e.g. faces pain scale-revised [FPS-R],19,35 Oucher21) (Fig. 28.1). McGrath and Hillier36 developed a separate facial affective scale designed to measure pain affect, as distinct from pain intensity. Interestingly, the faces scales anchored with a smiling face produce higher pain ratings than do those anchored with a neutral face.37 Discordance between an observer’s ratings of a child’s pain and the child’s selfreport is well described.38,39 Therefore the child’s self-reported pain level should be considered the “gold standard” whenever it can reliably be obtained.40 The majority of pediatric pain assessment measures that have been developed focus on acute, procedure-related pain.41,42 Alterations in the behavioral and sensory aspects of pain that can habituate when pain becomes chronic may not be captured by these measurement scales.38 A systematic evaluation of chronic pain in children is beyond the scope of this chapter (see Chapter 42).

Nonmedical Management of Pediatric Acute Pain Management of pain through nonmedical techniques (e.g. environmental and behavioral strategies) has proved effective in modulating pain, both independently and in conjunction with pharmacologic interventions in children.43–47 Cognitive behavior therapy (e.g. relaxation, problem solving, cognitive coping skills) and distraction techniques such as deep breathing, cartoon videos, party blowers, and hypnosis have strong empirical support for their efficacy in easing procedure-related pain in children.48–51 385

386

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 28.1

Clinical Measurements of Pediatric Acute Pain

Age Group

Measure

Type of Measurement

Type of Pain

Neonates and infants

Premature infant pain profile (PIPP) (preterm and full-term neonates)16

Behavioral, physiologic, gestational age

Procedural

Neonatal facial coding system (NFCS) (preterm and full-term neonates, infants ≤18 months)17

Behavioral

Procedural

COMFORT scale (zero to three years)18

Behavioral, physiologic

Procedural, postoperative

Behavioral

Postoperative

Faces scales

Self-report

Procedural, postoperative

Oucher (≥ three years)21

Self-report

Procedural

Poker chip tool (four to eight years)22

Self-report

Procedural

Toddler-preschooler postoperative pain scale (TPPPS) (one to five years)23

Behavioral

Postoperative

Children’s Hospital of Eastern Ontario pain scale (CHEOPS) (one to seven years)24

Behavioral

Postoperative

Children’s and infants’ postoperative pain scale (CHIPPS) (zero to four years)25

Behavioral, physiologic, alertness, calmness

Postoperative

rFLACC scale (two months to seven years)32–34

Behavioral

Postoperative

Colored analog scale (CAS) (≥ five years)

26

Self-report

Procedural, recurrent, chronic

26,27

Visual analog scale (VAS) (≥ five years)

Self-report

Procedural, recurrent, chronic

Faces pain scale

Self-report

Procedural, recurrent, chronic

Non-communicating children’s pain checklistpostoperative version (NCCPC-PV), non-communicating children’s pain checklist-R (NCCPC-R)28,29

Behavioral

Procedural, postoperative injury, pain related to a chronic medical condition

VAS30

Self-report

Procedural

Behavioral

Postoperative

rFLACC scale (two months to seven years) Toddlers and preschoolers

School-age children and adolescents

Non-communicating children, children with cognitive impairment

19,20

rFLACC scale

TABLE 28.2

32–34

32,34

Revised FLACC Behavioral Pain Scale

Categories

Scoring 0

Scoring 1

Scoring 2

Face

No particular expression or smile

Occasional grimace or frown, withdrawn, disinterested, appears sad or worried

Frequent to constant frown, clenched jaw, quivering chin, distressed-looking face; expression of fright or panic

Legs

Normal position or relaxed, usual tone and motion to limbs

Uneasy, restless, tense, occasional tremors

Kicking or legs drawn up, marked increase in spasticity, constant tremors or jerking

Activity

Lying quietly, normal position, moves easily; regular rhythmic respirations

Squirming, shifting back and forth, tense, tense, or guarded movements; mildly agitated (e.g. head back and forth, aggression); shallow, splinting respirations, intermittent sighs

Arched, rigid, or jerking, severe agitation; head banging; shivering (not rigors); breath holding, gasping or sharp intake of breaths, severe splinting

Cry

No cry (awake or asleep)

Moans or whimpers, occasional complaint, occasional verbal outburst or grunt

Crying steadily, screams or sobs, frequent complaints, repeated outbursts, constant grunting

Consolability

Content, relaxed

Reassured by occasional touching, hugging, being talked to; distractible

Difficult to console or comfort, pushing away caregiver, resisting care or comfort measures

Non-italicized text denotes the original FLACC descriptors. Italicized text denotes behaviors that were added for the revised FLACC scale, improving validity for assessment of children with cognitive impairment.34

 

CHAPTER 28

Evaluation and Treatment of Acute Pain in Children

387

Which face shows how much hurt you have now?

0 No hurt

1 Hurts a little bit

2 Hurts a little more

• Figure 28.1  Distraction methods are hypothesized to work by engaging children and redirecting their attention away from the pain, thereby reducing perceived pain intensity and inhibiting the neural activity that underlies pain perception.52–58 Complementary and alternative medicine techniques such as acupuncture have also been described as potential treatments of acute pain in children.59,60 Recent studies have identified preoperative risk factors for worse postoperative pain, including patient behaviors such as catastrophizing and psychological and somatic symptoms such as depression and fatigue.61–63 Additional research is needed to determine whether psychological and other nonpharmacologic interventions may be beneficial for this pain-vulnerable group of children.

Pain Treatment Modalities Acute pain in infants and children may result from several causes, including surgery, trauma, sickle cell vaso-occlusive episodes, and oncologic processes and treatments. Non-opioid analgesics can provide adequate control of mild pain with minimal side effects.64

3 Hurts even more

4 Hurts a whole lot

5 Hurts worse

Faces pain scale.

For moderate to severe pain, a multimodal strategy that incorporates non-opioid analgesics, opioids, and regional anesthesia is preferred. Multimodal analgesia involves multiple agents working synergistically at different biologic locations along the pain pathway (Fig. 28.2).65 This allows improved pain control with reduced side effects (sedation, respiratory depression, nausea, pruritis, ileus) that can occur with the higher doses required when opioids are used alone for treatment of severe pain.66,67 Patient factors such as comorbidities, developmental level, opioid use history, and ability to take oral medications must be considered along with pain cause, severity, location, and expected duration when developing an optimal analgesia plan.

Non-opioid Analgesics Sucrose Oral administration of glucose and sucrose can provide mild analgesia, as opioid peptides in the ventral striatum and cingulate gyrus may play a role in regulating positive responses to energy-rich food sources.68,69 A Cochrane database review suggested that sucrose

• Figure 28.2  The pain pathway and locations of action for various analgesics. (© David Klemm).

388

PA RT 4 Clinical Conditions: Evaluation and Treatment

may be effective in reducing procedural pain in neonates.70 Doses in the range of 0.01–0.1 g can be used to reduce procedural pain in infants younger than six months.71

Acetaminophen Acetaminophen is commonly used in children to reduce or eliminate pain from a variety of conditions.72 It can be administered via the oral, rectal, and intravenous routes. There is no evidence to suggest the superior analgesic effect of one route over another when appropriately dosed, and the oral route is the most cost effective.73 The rectal and intravenous routes are used for patients unable to take oral medications, as is often the case in the perioperative period. Higher rectal doses (i.e. 30–40 mg/kg loading dose followed by 15–20 mg/kg maintenance doses at 4–6 h intervals in children over two years old) are required to produce therapeutic serum concentrations in the majority of patients, and there is large interindividual pharmacokinetic variability.74,75 Intravenous acetaminophen has more predictable bioavailability and achieves maximum concentration more rapidly than rectal dosing, and therefore may be the preferred non-oral route for administration to hospital inpatients.76 While rare, hepatotoxicity is a dose-dependent risk with acetaminophen use.77 Compared to older children, neonates exhibit decreased acetaminophen clearance because of renal and hepatic immaturity. Doses should be reduced, especially in preterm infants.78 Another potential source of overdose is inadvertent administration from multiple sources, including over-the-counter cold remedies and fixed-dose opioid combinations, both of which often contain acetaminophen. All medications being taken by a patient, including those available without a prescription, should be carefully reviewed before recommending acetaminophen (Table 28.3).

TABLE 28.3

Nonsteroidal Anti-inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in children and can be administered via oral, intravenous, or intramuscular routes. NSAIDs are an effective treatment for various pain states and have been shown to be more effective than opioids for mild traumatic musculoskeletal pain in children.79 When used in the postoperative setting, NSAIDs can produce analgesia equivalent to a dose of opioid, and their use with or without additional opioids has been associated with less nausea, vomiting, respiratory depression, and other adverse events.72,80,81 Ketorolac is commonly used in children and can be administered via intravenous or intramuscular routes. The clinical significance of the effects of NSAIDs on platelet function remains controversial, which has led to its avoidance by some for procedures with a significant risk of postoperative bleeding. Known side effects, including bleeding, renal toxicity, and gastritis, are more likely to occur with prolonged administration and in the presence of coexisting disease. Adverse events are more common in neonates; NSAIDs should be used cautiously in patients less than six months of age and avoided in patients less than 21 days old or 37 weeks post gestational age.82,83 Evidence from animal models has caused concern that NSAIDs may interfere with osteogenesis. However, studies of children receiving a short course of NSAIDs, including ketorolac, after spinal fusion or operative fracture repair do not appear to be at increased risk for bone nonunion.84,85 Aspirin, a unique NSAID that irreversibly inhibits cyclooxygenase (COX)-1 and COX-2, should not be routinely used as an analgesic in patients under the age of 18 years because of the risk of Reye’s syndrome, a serious acute encephalopathy.86

Non-opioid Analgesic Dosing

Medication

Dose

Dosing Interval (h)

Maximum Daily Dose (mg/kg)

Maximum Daily Dose (mg)

Acetaminophen* (oral)

10–15 mg/kg

4–6

75

3000

Acetaminophen* (IV)

15 mg/kg

6

75

3000

Acetaminophen* (rectal)

30–40 mg/kg as loading dose, 15–20 mg/kg maintenance

6

75

3000

Ibuprofen

5–10 mg/kg

6–8

40

2400

Ketorolac (IV)

0.5 mg/kg

6

2

120

Celecoxib (oral)

10–25 kg: 50 mg >25 kg: 100 mg

12

Gabapentin (oral)

50 kg: 300–600 mg

8

Pregabalin (oral)

50 kg: 50 mg

8–12

Ketamine (infusion)

0.1–0.2 mg/kg/h

Continuous

Diazepam (oral, IV)

0.05–0.1 mg/kg

6–8

^ ^,#

*Dose should be decreased in preterm and term neonates. ^ #

Use with caution in neonates 1 cm RF group had had ≥ 50% pain reduction

Salman et al.90

Prospective, randomized, comparative, study, n = 15

Conventional RF of the L4, L5 dorsal rami, and S1−S3 lateral branches versus intra-articular steroid injection

53% of patients in the RF group obtained >50% pain reduction

Unable to analyze the control group because of a small number of participants

Zheng et al.104

Prospective, randomized, controlled, n = 155

Palisading bipolar RF versus celecoxib

Mean VAS −1.9 at three months and −2.2 at six months with RF group over the control group

Prior diagnosis of ankylosing spondylitis

Cooled RF of the L5 dorsal ramus and S1−3 lateral branches

Mean VAS −4.0 at one month with similar results seen at six and 12 months

All patients had positive blocks of SIJ or medial/ lateral branches

Pragmatic Studies

Observational Studies Stelzer et al.105

Retrospective chart review, n = 109

Continued

424

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 30.3

Efficacy and Effectiveness of Radiofrequency Lesioning of the Sacral Lateral Branch Nerves—cont’d

Author

Study Design

Treatments

Results

Comments

Reddy et al.106

Retrospective chart review, n = 16

“Simplicity” conventional RF of peripheral nerves at S1−S4

Mean NRS −4.5 at 12 months

Patients included all had a diagnostic and therapeutic SIJ injection with ≥50% NRS reduction and for ≥ six months

Romero et al.107

Prospective, observational study, n = 32

Conventional RF of the L5 dorsal ramus and S1−3 lateral branches

Mean NRS −4.6 at six months and −3.7 at 18 months

SIJ pain confirmed by positive intra-articular block

Ho et al.92

Retrospective chart review, n = 20

Cooled RF of the L5 dorsal ramus and S1−3 lateral branches

Mean NRS −4.9 at three months, −4.4 at 12 months, and −4.3 at 24 months

SIJ pain confirmed by positive intra-articular block

Stelzer et al.93

Retrospective chart review, n = 126

Cooled RF of the L5 dorsal ramus and S1−3 lateral branches

Mean VAS −6.2 in the subgroup with follow up from four to six months, −5.5 in the subgroup with follow up from six to 12 months, and −3.9 in the subgroup with follow up >12 months

SIJ pain confirmed by positive intra-articular block

Gevargez et al.62

Prospective, observational study, n = 38

Conventional RF in the dorsal interosseous ligament and of L5 dorsal ramus (CT-guided)

At three months, 13 of 38 patients had no pain, 12 of 38 had substantially reduced pain

SIJ pain confirmed by positive intra-articular block (CT-guided)

Cohen and Abdi 75

Retrospective chart review, n = 9

Conventional RF of L4, L5 dorsal rami, and S1−S3 lateral branches

Eight of nine patients reported 50% or greater pain relief at the nine month follow up. One of nine had a 40% improvement

All patients had a positive response to diagnostic blocks of L4 and 5 dorsal rami and S1−3 lateral branches

Yin et al.50

Retrospective chart review, n = 14

Conventional RF of L5 dorsal ramus and S1−3 lateral branches

Nine of 14 with 60% or greater patient-perceived improvement with >50% decrease in pain scores at six months

All patients had dual positive SIJ steroid injections

Karaman et al.91

Prospective observational study, n = 15

Cooled RF of the L5 dorsal ramus and S1−3 lateral branches

At six months, 80% had >50% pain relief, 87% had a 10-point decrease in ODI

SIJ pain confirmed by positive intra-articular block

CT, Computed tomography; NRS, numeric rating scale; ODI, Oswestry disability index; RF, radiofrequency; SIJ, sacroiliac joint; VAS, visual analog scale.

in structure,118 and mobility119 of the sacrococcygeal articulation, as well as dimensions and angulation120,121 of the coccyx itself. Sensory innervation of the coccyx is primarily derived from the sacrococcygeal plexus, which originates from the lower sacral nerve roots. Anteriorly, this is comprised of the coccygeal nerves and the ventral rami of S4 and S5, while the dorsal rami of S4 and S5 and the coccygeal nerves contribute to innervation.122 The sacrococcygeal plexus innervates the following anterior structures: the pubococcygeus muscle, ischiococcygeus muscle, coccygeus muscle, and a portion of the levator ani, external anal sphincter, sacrococcygeal and coccygeal ligaments, sacrococcygeal joint, and coccygeal periosteum. Posterior structures innervated by the sacrococcygeal plexus include the dorsal periosteum, overlying skin, and soft tissue.122–126 Sympathetic anatomic innervation from the paravertebral sympathetic trunk contributes to the ganglion impar, located on the ventral surface of the coccyx, and visceral pain from the rectum may refer to this region via nociceptive input from the ganglion

impar.127 Pain from other pelvic viscera may also refer to the coccygeal region via the hypogastric plexus or pelvic splanchnic nerves.122 Aside from being the insertion point of muscles, tendons, and ligaments, the coccyx supports pelvic floor and anal function and provides structural support in the sitting position in conjunction with the ischial tuberosities.108

Presentation Coccydynia classically presents as pain in the region of the tailbone, but other aspects of the history may be helpful, including pain with sitting, reclining, defecation, or intercourse.108 Acute onset after a posterior fall could indicate a traumatic etiology. Tenderness to palpation over the coccyx is often present but not requisite, as pain of radicular or visceral origin can refer to this region. Hypermobility of the sacrococcygeal articulation can be diagnosed via rectal examination. Imaging with plain film radiographs, CT,

• Figure 30.15  Posterior view of the bony sacrococcygeal junction. Red

arrow, sacrococcygeal articulation. (From White TD, Folkens PI. Pelvic girdle: sacrum, coccyx, & os coxae. In: TD White, PI Folkens (eds). The Human Bone Manual. 1st ed. Burlington, MA: Academic Press; 2005: 241–253.)

or MRI may help in diagnosing fractures, dislocations, cysts (pilonidal, Tarlov), or masses.

Treatment Conservative treatment of coccydynia can be initiated with mechanical support such as modified wedge-shaped, “U”-shaped, or donut cushions that offload pressure over the tender region. Adjusting seating surfaces and workplace ergonomic changes may also offer benefits. Cold and heat therapies are reasonable options. Pharmacologic therapy with NSAIDs and, to a lesser extent, tricyclic anti-depressants have been studied, but the studies were small and the data inconsistent.128,129 Topical analgesics have been shown to be beneficial in arthritis but have not been studied directly in this patient population. As in other pain states, opioid therapy should only be considered after the failure of conservative therapy and should be used cautiously outside of the acute phase. Physical therapies, such as massage, manual manipulation, and modalities have been utilized with varying degrees of success. It is thought that these therapies may relieve pain because of inflammation, muscle spasm, ligament pain, and dislodgement of the coccyx.108 Maigne et al. compared intrarectal manipulation to shortwave diathermy, with significantly more patients experiencing ≥50% pain relief in the intrarectal manipulation group at one and six months.130 In 2015, Lin et al. compared extracorporeal shockwave therapy to physiotherapy (short wave diathermy or inferential current) with significantly greater mean pain relief in the former group, but no difference in Oswestry disability index scores at eight weeks.131 Regarding interventional procedures, there are a myriad of described treatments of coccydynia, most commonly injection of steroids and local anesthetics. There is no clear consensus on the best target for injection, although it is generally accepted that

 

CHAPTER 30

Buttock and Sciatica Pain

425

because of the close proximity of the pelvic viscera anteriorly, fluoroscopic or ultrasound guidance should be utilized. Overall, the body of literature surrounding treating coccydynia is low to very low quality because of small sample sizes and methodologic shortcomings. In 1991, Wray et al. randomized 120 patients to receive steroid injections or manipulation. They reported a mean pain reduction of 60% in the steroid group versus 85% in the manipulation group, and the follow up period was unclear in their report.132 In a small study of 14 patients, Mitra et al. reported that 50% of patients experienced at least 50% pain relief with steroid and local anesthetic injections over and around the coccyx at three weeks.133 Pulsed radiofrequency treatment of the posterior coccygeal nerves innervating the coccyx was performed in ten patients with a mean improvement in pain of 75% at six months.134 A study evaluating thermal radiofrequency ablation of the posterior coccygeal nerves in nine patients reported a mean improvement in pain of 55%, with follow up varying between two months and two years.135 In this study, conventional radiofrequency ablation was found to be superior to pulsed RF, and those who responded to prognostic blocks fared better than those who did not receive pretreatment local anesthetic blocks. The ganglion impar, which is the terminal pelvic segment of the sympathetic trunk lying just anterior to the coccyx and accessed via the sacrococcygeal articulation, has also been a target for intervention in patients with pain referred from the pelvic viscera, typically in the setting of malignancy. Gunduz et al. performed ganglion impar blocks in 19 patients, with 95% experiencing ≥50% pain relief at a mean follow up of 17 months.136 Thermal radiofrequency ablation of the ganglion impar has also been described, with a mean improvement at six months in 10 patients, being 66% for pain and 50% for function.137 Chemoneurolysis of the ganglion impar has also been described in case reports and small case series, the largest of which showed 73% mean pain relief at four months in 28 patients treated with CT-guided ethanol injections.138,139 It must be noted that a major potential complication of ganglion impar ablation is anal sphincter incompetence, so a thorough risk/benefit discussion with the patient is imperative. Neuromodulation has also been used to treat chronic coccydynia. Improvement in pain with stimulation of the sacral nerve roots via the sacral hiatus in the epidural space has been described.140 Stimulation of the S3 nerve root via the S3 foramen141 and stimulation of the thoracic dorsal columns,142 both of which were effective in providing pain relief. For patients with pain refractory to more conservative measures, surgical coccygectomy is the last resort treatment option. While numerous studies have reported significant benefits of coccygectomy (more than half of all patients in every published study have derived benefit), the majority of these studies were retrospective, observational, and uncontrolled, thus limiting the ability to draw firm conclusions from their results.135 As with non-operative interventions for coccydynia, the body of literature for surgical intervention is low to very low quality because of small sample sizes and methodologic shortcomings.

Piriformis Syndrome Epidemiology Piriformis syndrome (PS) was first described143 in 1947 and is relatively uncommon, generally reported as affecting only 5% to 8% of a population. However, the prevalence may be as high as 36% in patients who are referred for back or leg pain.144–147 It should

426

PA RT 4 Clinical Conditions: Evaluation and Treatment

be considered in the differential diagnosis of patients who present with unilateral buttock and/or leg pain. However, because its clinical presentation often overlaps with other sources of buttock pain, it is commonly misdiagnosed.144,147,148

Anatomy of the Piriformis Muscle and the SN The piriformis muscle originates from the anterior surface of the S2-S4 sacral vertebrae, the capsule of the SIJ, and the gluteal aspect of the ilium near the iliac spine.149 The broad origin of the muscle tapers becomes smaller in caliber and tendinous as it courses through the greater sciatic foramen and inserts on the piriformis fossa on the medial aspect of the greater trochanter of the femur (Fig. 30.16). The piriformis is typically innervated by the superior gluteal nerve,150 and the principal function of the muscle is to abduct and externally rotate the femur. Neurovascular structures close to the piriformis muscle include the posterior femoral cutaneous nerve, gluteal nerves, gluteal vessels, and the SN, most relevant to our discussion.151 Formed from the ventral rami (L4-S3) of the lumbosacral plexus, the SN is approximately 2 cm in diameter as it exits the pelvis via the greater sciatic foramen. This large mixed nerve contains motor fibers that supply the posterior thigh, hip, and knee, and sensory fibers that supply the entire surface of the leg distal to the knee, except for the anteromedial calf and medial aspect of the foot.151 Typically, the SN passes inferior to the piriformis muscle, but deviations in this anatomic relationship are relatively common, and prevalence rates have been described as 6% or up to 22%.152–155 The Beason and Anson classification system156 describes these six possible anatomic relationships between the

TABLE 30.4

Beason and Anson Classification for the Anatomic Relationship between the Sciatic Nerve (n.) and Piriformis Muscle (m.)

Beason and Anson Classification Normal anatomy

Type 1

Undivided sciatic n. passes inferior to undivided m

Proximal division

Type 2

One division passes through, and one inferior to m

Aberrant route

Type 3

One division passes inferior and one superior to m

Type 4

One division passes inferior and one superior to the m

Normal division

Type 5

Sciatic n. passes through the m

Aberrant route

Type 6

Sciatic n. passes superior to the m

piriformis muscle and the SN (Table 30.4). According to a recent study, the prevalence of the most common relationship types A (the entire SN passes inferior to the piriformis muscle), B (the SN is split, with a portion piercing the piriformis and a portion passing inferior to the muscle), and C (the SN is split, with a portion passing superior to and a portion passing inferior to the piriformis) were 74%, 22%, and 3%, respectively (Fig. 30.17).157 Anatomic variants are thought to increase the likelihood of developing PS, given that an abnormal course of the SN or smaller divisions would be more susceptible to compression or irritation from muscular hypertrophy than a large-caliber undivided SN.152,158,159 Indeed, variability in morphometric measurements of the lower limbs correlates with anatomic variations in the relationship of the piriformis muscle with the SN.144 However, the significance of variant anatomy regarding the likelihood of developing PS is disputed, given the results of a cadaveric surgical case series and a prospective MRI study on living patients,160 both of which showed similar rates of aberrant anatomy in patients with or without symptoms of PS.

Pathophysiology

• Figure 30.16 

Posterior view of the sacrum, ilium, and greater trochanter of the femur, illustrating the course of the piriformis muscle, sciatic nerve, and the site of injection (marked “X”). SI, Sacroiliac. (From Benzon HT, Katz JA, Benzon HA, et  al. Piriformis syndrome: anatomic considerations, a new injection technique, and a review of the literature. Anesthesiol. 2003; 98:1442–1448.)

The clinical presentation of PS likely has a somatic component, from myofascial pain in the buttock musculature, and depending on the relationship between the muscle and nerve, in some cases, a neuropathic component is present from irritation or compression of the SN. Affected patients had a median age of 50,161 and females were more affected than males. Risk factors for PS include pelvic/buttock trauma,147 hypertrophy or spasm of the piriformis or gemelli muscles,149 female sex assigned at birth, pregnancy, anatomic variants in the relationship between the piriformis and SN, true or apparent leg length inequality (at least 0.5 inches in difference),154 obesity, hypertonicity, lumbar hyperlordosis, infection, and mass effect from space occupying lesions.161 Although a history of trauma can be elicited in 50% of cases of PS,162 trauma isolated exclusively from the piriformis muscle is rare. Instead, the reported injury is generally mild and deemed to be a sequela of heavy manual labor or strenuous athletic activity that often occurs several months prior to the onset of pain. However, the pathophysiologic relationship between physical stress and muscle pain that occurs months later is debatable. Because of diffuse muscular involvement, some authors now favor the

 

CHAPTER 30

Buttock and Sciatica Pain

427

• Figure 30.17  Beason and Anson types for the relationship of the piriformis muscle and the sciatic nerve. (Credit: Sophie Sha.)

term “deep gluteal syndrome” rather than PS.163 However, both terminologies describe a syndrome in which trauma leads to the release of inflammatory mediators, including histamine, bradykinin, and serotonin, which then irritates the buttock musculature and/or the SN.152,164 This irritation then leads to further spasm or inflammation of the musculature in a classic pain cascade cycle that leads to chemical or anatomic irritation of the SN as it passes between the piriformis muscle and the bony pelvis.165

Presentation In a review of 55 studies, the most common features of a patient with PS were:166 • buttock pain • external tenderness over the greater sciatic notch • aggravation of pain with prolonged sitting • augmentation of pain with maneuvers that increase tension on the piriformis muscle Patients with PS tend to describe pain centered on the buttock and extending from the origin of the muscle at the sacrum to the insertion of the muscle on the medial aspect of the greater trochanter.144,147,152 Pain is often aggravated by prolonged sitting, especially on hard surfaces or with motor activity involving the affected limb, as in driving or biking, and when rising from a seated position.144,147 Radiation of pain to the ipsilateral distal leg is thought to be present if the SN is significantly irritated.147,152 Physical examination may reveal pelvic tilt, a palpable spindleshaped mass in the buttock, and tenderness to external palpation or on pelvic/rectal examination, given the proximity of the piriformis to the lateral pelvic wall. The pain can be aggravated by the Valsalva maneuver or flexion, adduction, and internal rotation (FAIR) of the hip-maneuvers that stretch the muscle. If the hip is flexed over 90°,

the piriformis is elongated with external rotation, and thus the heelcontralateral knee maneuver may reproduce pain. However, the use of these physical exam maneuvers is not always reliable.167 Although PS is a clinical diagnosis, it is also a diagnosis of exclusion from other sources of buttock pain. Therefore diagnostic modalities such as electromyography (EMG), CT, and MRI may assist in diagnosis. EMG can demonstrate a delay in the patient’s H-reflex during the FAIR maneuver compared with the patient’s H-reflex in an anatomically neutral position.168 Patients with PS more consistently have electrophysiologic abnormalities in the peroneal H-reflex (prolongation by three standard deviations for definitive diagnosis)169 than the tibial nerve H-reflex.170 Although imaging is often negative, CT and MRI may demonstrate enlargement of the piriformis muscle. Magnetic resonance neurography is a more sensitive modality for detecting signal changes in the SN under a hypertrophied piriformis muscle. However, this imaging modality is not universally available, and most insurance companies do not routinely authorize its use.171 Lastly, ultrasonographic diagnosis of PS is an emerging technique that is being increasingly utilized. Patients with symptomatic PS will demonstrate increased thickness and cross-sectional area of the muscle than asymptomatic individuals.172,173

Treatment As with most pain syndromes, the initial treatment is conservative. Oral nonsteroidal anti-inflammatory medications (NSAIDs) and muscle relaxants are used to reduce inflammation and muscle spasms, respectively, and can be used in conjunction with a course of physical therapy (PT) to improve therapeutic effects. Conventional PT consists of FAIR of the hip followed by pressure applied to the piriformis muscle.144,147 Exercises such as hip flexion, adduction, and external rotation (ADD stretch), hip flexion, external rotation,

428

PA RT 4 Clinical Conditions: Evaluation and Treatment

and adduction (ExR stretch) increase the piriformis length by 30% to 40% compared to conventional PT. Treatment with NSAIDs, muscle relaxants, and PT is successful in 75% to 80% of patients.174

Techniques of Piriformis Muscle and Perisciatic Nerve Injections The remaining subset of patients are candidates for injection therapy,175 which can consist of medication administration or dry needling.176 Injections are typically performed with image guidance, and fluoroscopy, ultrasonography,177,178 and EMG are often used either alone or in combination.179 CT and MRI guidance are other options and can better target the tendinous portion of the external rotators of the hip,180 but their use is infrequent because of increased radiation exposure and logistical difficulties, respectively. Fluoroscopy is the most commonly used method for imageguided injections. After positioning the patient prone, the needle was advanced coaxially into the muscle belly of the piriformis at 1 to 2 cm lateral and 1 to 2 cm caudal to the inferior border of the SIJ. Contrast dye can then be applied, and if an appropriate myogram is visualized, the injectate is administered (Fig. 30.18). In addition to fluoroscopy,152,179 EMG can be used to identify a motor-evoked response from the SN. The needle can then be withdrawn at least 0.3 cm to administer a portion of injectate perisciatically. Then, the needle can again be withdrawn an additional 1 cm to the belly of the piriformis muscle and the remaining injectate administered.152 Pain providers offering piriformis injections are increasingly using ultrasound guidance,181 which is considered more accurate182 and avoids radiation or contrast exposure. Several ultrasound-guided methods exist, most of which rely on the identification of the inferior/lateral border of the sacrum. Subsequently, the pain providers scanned laterally with the ultrasound probe from the sacral hiatus until the piriformis is identified as a hyperechoic mass deep to the gluteus maximus and an ovoid-shaped SN visible either adjacent to or embedded within the muscle.177 An alternate approach identifies the PSIS and the posterior inferior iliac spine and then scans inferiorly from the lateral sacrum to the greater sciatic notch plane

• Figure 30.18  Fluoroscopic image of the insulated needle in the piriformis muscle with the muscle being outlined by the injected radiopaque dye.

• Figure 30.19  (A) Longitudinal ultrasound view of the piriformis during

needle placement using a medial-to-lateral approach parallel to the long axis of the transducer. The proximal end of the needle has been digitally enhanced to highlight the needle trajectory. (B) Post-injection tenogram at the level of the greater sciatic foramen. Anechoic injectate (FLUID) within the piriformis tendon sheath lies superficial and deep to the hyperechoic tendon. RT PIR LG, Right side, piriformis, longitudinal view; TIP, needle tip. (From Smith J, Hurdle MF, Locketz AJ, et al. Ultrasound-guided piriformis injection: technique description and verification. Arch Phys Med Rehabil. 2006;87:1664–1667.)

(Fig. 30.19).178 Ultrasound can also guide needle placement and the administration of medications, or simply needle placement for dry needling technique.176,183 Studies have found no difference in pain or satisfaction outcomes when the piriformis is injected with fluoroscopic versus ultrasound guidance.184 The injectate is typically composed of a particulate steroid formulation combined with a local anesthetic. In a randomized, doubleblind study performed in 47 patients with PS, there was no difference in pain scores up to three months after injection in patients who received local anesthetic only versus local anesthetic with steroid.185 Patients may also receive botulinum toxin if the response to steroids and local anesthetics is transient. The use of botulinum toxin to treat refractory PS is supported by randomized controlled and observational studies.186 The toxin blocks the release of acetylcholine at the neuromuscular junction, resulting in prolonged relaxation, which causes increased fatty infiltration of the piriformis and concomitant reduction in thickness and volume of the muscle.171,187 The duration of the effect depends on the rate of neuromuscular sprouting and reinnervation of the muscle. However, botulinum toxin typically confers relief for greater than six weeks188 and lacks the side effects of steroid administration, making it an attractive alternative injectate. Risks of botulinum injection include plexopathy, polyradiculoneuritis, and local psoriasiform dermatitis.189–191 The most invasive option for the management of PS includes surgical release, in which the distal piriformis tendon is resected

at the femoral insertion site to decompress the SN. Other musculature of the buttocks can compensate for the loss of this muscle function, and surgery has become less invasive with advances in technique192 surgical management is effective in approximately 75% of patients.193 If symptoms recur, they are typically because of incomplete tendon release or scar/hematoma formation.194

Non-Piriformis Muscle Pain Pathology involving muscles besides the piriformis may present as low back and/or buttock pain. Mechanical pain involving muscles and other soft tissue in the buttock may manifest as a dull, aching pain worsened by weight bearing, activities, and sometimes sitting. Depending on the source of pain and the anatomic location of the SN in relation to the structure, patients may also experience true sciatic neuropathy, or “pseudo sciatica,” which presents as pain extending into the posterolateral thigh region. There are reports of pain derived from the gemelli-obturator internis muscle complex, which consists of the obturator internis muscle and bursa, superior and inferior gemelli, and the tendinous insertion of the complex on the greater trochanter. The obturator internis originates from the pelvic surface of the obturator membrane and the surrounding bones. The superior and inferior gemelli originate from the ischial spine and tuberosity, respectively, and are inserted on the medial aspect of the greater trochanter after merging with the tendon of the obturator internis. Pain arising from the gemelli-obturator complex may manifest as an aching pain in the retrotrochanteric region that extends into the hip and posterolateral thigh.195,196 In some individuals, movement may bring the SN into juxtaposition with the obturator-gemelli complex (i.e. tendon). An anatomic study performed in cadavers and human volunteers showed that internal rotation of the hip could result in deviation of the nerve course, causing symptoms of sciatic neuropathy.195,197 Tendonitis, muscle tears, and spasms of the quadratus femoris can manifest as buttock pain, groin pain, hip pain, and “sciatica,” depending on the anatomic relationship with the SN or its branches.198–200 The gluteal muscles and their tendinous insertions are also a potential source of buttock and lateral hip pain.201–203 The gluteus maximus, which extends and laterally rotates the hip, is the largest muscle in the buttock-hip region, originating from the sacrotuberous ligament and inserting into the iliotibial band. The gluteus medius muscle arises from the ilium, attaches to the lateral greater trochanteric, and functions to stabilize the femur and pelvis during weight bearing. Pathology of the gluteus minimus, which originates from the external iliac fossa and inserts on the anterior facet of the greater trochanter, most often occurs in conjunction with disorders involving the gluteus medius tendon. The gluteus minimus is involved in internal hip rotation and abduction. For muscles, activities that involve their function may exacerbate pain from overuse injuries, while activities that stretch the muscles may worsen pain arising from muscle spasms. The treatment of muscle pain depends on the pathology and may consist of rest for overuse injuries, stretching exercises for muscle spasms, PT and exercises to address biomechanical precipitating factors, and nonsteroidal anti-inflammatory drugs for inflammatory processes. Injections have also been employed for both diagnostic and therapeutic purposes.199,204 In refractory cases of SN entrapment, surgical decompression may be indicated.198 Trigger point injections may be considered when myofascial pain is suspected. This concept and technique are discussed in Chapter 68. For non-piriformis trigger point injections, studies have found

 

CHAPTER 30

Buttock and Sciatica Pain

429

greater short-term benefit with the injection of substances than dry needling, with little difference in outcomes between injectates.205,206

Ischial Bursitis In ischial bursitis, also termed ischial-gluteal bursitis, the fluidfilled sac (the non-pathologic bursa contains minimal fluid) that separates the ischial tuberosity from the gluteus maximus muscle becomes inflamed. Although the epidemiology is unknown, it is estimated to account for less than 1% of cases of low back or buttock pain. Risk factors for ischial bursitis include obesity, autoimmune diseases, excessive or inappropriate exercise, and a sedentary lifestyle characterized by long periods of sitting; hence, the colloquial nickname “weaver’s bottom.”207 The typical presentation of ischial bursitis is gluteal or upper posterior thigh pain, often provoked or exacerbated by exercise or prolonged sitting. On physical examination, tenderness to palpation was a prominent objective sign. MRI can be helpful in the diagnosis and may show low or intermediate signal intensity on T1 and T2 hyperintensity in the region of the ischial bursa.208 The treatment of ischial bursitis is symptom-oriented and may include ergonomic modification, PT, NSAIDs, and steroid injections.209 Surgical resection of the bursa may be performed for refractory cases.210

Techniques of Ischial Bursa Injection Ischial Bursa Injection Under Ultrasound The patient was positioned in the contralateral decubitus position. With an ultrasound-guided injection, the ischial tuberosity was palpated, and a curvilinear probe was placed axially over the ischial tuberosity. In this view, the ischial tuberosity, hamstring tendons, gluteus maximus, and SN can all be visualized (Fig. 30.20). Flexion of the knee and hip decreases the distance between the bursa and skin compared to hip and knee extension. Using a sterile technique, the needle is passed through the skin in an in-plane approach, traversing the gluteus maximus toward the ischial tuberosity. When the needle tip is clearly visualized in

• Figure 30.20  Ultrasound image demonstrating a needle within the is-

chial bursa. The gluteus maximus muscle is above the needle tip, and the hamstring tendon origin is below the needle tip. The arrow indicates the needle tip; the top is superficial; the bottom is deep; the left is medial (MED), and the right is lateral. ISCH, Ischium; SCN, sciatic nerve. (From Wisniewski SJ, Hurdle M, Erickson JM, Finnoff JT, Smith J. Ultrasoundguided ischial bursa injection: technique and positioning considerations. PMR. 2014;6(1):56–60.)

430

PA RT 4 Clinical Conditions: Evaluation and Treatment

the region of the ischial bursa, an injectate of local anesthetic and particulate steroid is administered into the bursa.211

Ischial Bursa Injection Under Fluoroscopy A fluoroscopically guided ischial bursa injection was performed with the patient in the prone position and the fluoroscope image intensifier oriented in the cephalocaudad position. A 22 or 25

gauge Quincke needle was introduced perpendicular to the skin on the inferior portion of the buttock and directed in a coaxial fashion toward the ischial tuberosity. After contact with the bone, the needle was withdrawn 1 mm, and contrast dye was administered. If vascular uptake is absent and a fill pattern consistent with a filling of the ischial bursa is noted, then an injectate of particulate steroid and local anesthetic is administered.

Summary Comments Much like pain in the lower back, pain in the buttock is derived from numerous anatomic pain generators (Table 30.5). When considered as an entity separate from LBP, the benign sources of buttock pain include the SIJ and associated structures, termed the SIJC, the coccyx and assoTABLE 30.5

ciated soft tissues, the deep external hip rotator muscles including the piriformis muscle along with the SN, and other soft tissues of the buttock region. The diagnosis and management of these pain generators differ markedly and are discussed in detail in this chapter.

Presentation of Different Etiologies of Buttock Pain

Condition

Historical Findings

Pain Pattern

Physical Exam Findings

Imaging/Diagnostic Findings

Sacroiliac joint complex pain

Trauma to back or pelvis Spinal deformity Prior spinal surgery Leg length discrepancy Patient points to pain over the PSIS or sacral sulcus May be pain with walking, prolonged sitting, rising from sitting Female gender Onset during pregnancy or childbirth

Pain largely below L5 level Radiation to the groin or posterior thigh to the upper calf

Three or more positive physical exam findings Tenderness to palpation over the posterior joint, PSIS, sacral sulcus Absence of neurologic signs

Imaging is typically normal or shows mild osteoarthritis Plain film radiographs and CT may show changes to the joint space, bone erosions, subchondral sclerosis, and bony malalignment MRI can show intra-articular fluid signal, soft tissue and bone edema, fatty infiltration, and joint erosions Radionucleotide bone scan can show active areas of increased metabolic uptake

Piriformis pain

Trauma to pelvis or buttocks Overuse (athlete, laborer) Leg length discrepancy Pain with prolonged sitting, particularly on hard surfaces, or rising from a seated position

Pain in the buttocks radiating to the greater trochanter If the sciatic nerve is irritated, radiating pain down the posterior ipsilateral thigh

Tenderness to palpation in the buttocks; may have a palpable tender point Provocative maneuvers include hip flexion, adduction, and/or internal rotation Numbness in the ipsilateral leg is rare Normal reflexes

MRI may show an enlarged piriformis, the relationship of the muscle to the sciatic nerve, or localized inflammation CT may show traumatic sequelae, pelvic visceral or soft tissue masses EMG - fibular H-reflex may be prolonged

Coccydynia

Trauma to the tailbone Prolonged sitting on hard surfaces

By definition, pain is in the area overlying or immediate to the coccyx Pain may be vague if referred from the pelvic viscera or sacral nerve roots

Tenderness to palpation over the coccyx or sacrococcygeal junction Hypermobility of the coccyx on rectal exam Dislodgement of the coccyx

Plain film radiographs, CT, or MRI, may help in diagnosing fracture, dislocation, cysts (pilonidal, Tarlov), or masses

Ischial bursitis

Exacerbated by prolonged sitting (“weavers bottom”), or exercise Might be concomitant with obesity, sedentary lifestyle, or autoimmune disease

Pain in the lower buttocks over the ischial tuberosity Proximal posterior thigh pain

Tenderness to palpation over the ischial tuberosity Pain with end-range hip flexion

Ultrasound may show fluid within the bursa MRI may show bursitis or proximal hamstrings/gluteal tendinopathy

Non-piriformis muscle pain

Dependent on the structure(s) involved: may be pain with activity, weight bearing, or sitting Trauma to the gluteal region

Dependent on the structure(s) involved: pain may be in the deep or superficial gluteal musculature, at the attachments on the greater trochanter, radiation into the hip or lateral thigh. If the sciatic nerve is irritated, radiating pain down the posterior ipsilateral thigh

Dependent on the structure(s) involved: may exhibit tenderness to palpation of the deep or superficial gluteal musculature over the posterior or greater trochanter May exhibit pain with internal rotation or hip flexion

Ultrasound may show tendinopathy or hematoma Plain film radiographs and CT may show fracture MRI may show tendinopathy or another soft tissue injury

CT, Computed tomography; EMG, electromyography; MRI, magnetic resonance imaging; PSIS, posterior superior iliac spine.

 

CHAPTER 30

Buttock and Sciatica Pain

431

Key Points • The causes of pain localized to the buttocks are diverse and often challenging to diagnose. • The SIJC consists of the SIJ and anterior and posterior stabilizing ligaments. The sensory innervation of these structures is complex. • The SIJC pain is felt in the SIJ area and can radiate to the lateral hip, posterolateral thigh, posterior leg, and groin. • The common tests that confirm the presence of SIJC pain include the FABER-Patrick, Gaenslen, Yeoman, Gillet, sacroiliac shear, pelvic distraction, pelvic compression, and thigh thrust tests. • The diagnosis of SIJC pain is based on the patient’s history, symptoms, physical examination maneuvers, elimination of the other causes of buttock pain, and a positive response to an SIJ injection. • Relief from the SIJ or SIJ and periarticular injection with local anesthetic and steroids can be temporary. More prolonged relief can be obtained by thermal RF lesioning of the SIJ or the lateral branches of the primary ramus of the L5-S3 nerves. The literature supports periforaminal RFA and sacral lateral crest strip lesion RFA techniques as successful methods to relieve pain from the SIJC. • Coccydynia most commonly occurs after trauma, with women more often affected than men. • Visceral pain may refer to the area of the coccyx via the ganglion impar, hypogastric plexus, or pelvic splanchnic nerves.

• Interventional treatment for coccydynia can be performed with sacrococcygeal joint injection, radiofrequency ablation of the coccygeal nerves, ganglion impar injection or radiofrequency ablation, and surgery with coccygectomy. • PS is located in the buttocks and radiates to the ipsilateral hip. It may radiate to the leg if the SN is compressed or irritated. • Physical examination signs to confirm PS include the Pace, Lasègue, and Freiberg signs. • The diagnosis of PS is usually based on the presence of the above symptoms and positive provocative tests. • Perisciatic and piriformis muscle injections of steroids and local anesthetics may result in relief that lasts several months. If the relief is transient, injections of botulinum toxin may provide longer relief. • Non-piriformis muscle pain may present similar to PS, as an aching pain that worsens with sitting or movements, with or without sciatica, depending on the relationship of the gemelliobturator muscle complex with the SN. • Similar to PS, injections may be indicated for diagnostic and therapeutic purposes in individuals who fail to respond to conservative therapy. • Ischial bursitis, also known as “weaver’s bottom,” typically presents as an aching pain in the lower buttock region and worsens with sitting or certain activities. Treatments include NSAIDs, ergonomic modification, PT, and steroid injections.

Suggested Readings

Laslett M, Aprill CN, McDonald B, Young SB. Diagnosis of sacroiliac joint pain: Validity of individual provocation tests and composites of tests. Man Ther. 2005;10(3):207–218. Lirette LS, Chaiban G, Tolba R, et al. Coccydynia an overview of the anatomy, etiology, and treatment of coccyx pain. Ochsner J. 2014;14(1):84–87. Misirlioglu TO, Akgun K, Palamar D, Erden MG, Erbilir T. Piriformis syndrome: Comparison of the effectiveness of local anesthetic and corticosteroid injections: A double blinded, randomized controlled study. Pain Phys. 2015;18(2):163–171. Roberts SL, Stout A, Loh EY, et al. Anatomical comparison of radiofrequency ablation techniques for sacroiliac joint pain. Med. 2018;19(10):1924–1943. Schneider BJ, Rosati R, Zheng P, McCormick ZL. Challenges in diagnosing sacroiliac joint pain: A narrative review. PMR. 2019;11(Suppl 1):S40–S45. Scott NA, Guo B, Barton PM, Gerwin RD. Trigger point injections for chronic non-malignant musculoskeletal pain: A systematic review. Pain Med. 2009;10(1):54–69. Wan-Ae-Loh P, Huanmanop T, Agthong S, Chentanez V. Evaluation of the sciatic nerve location regarding its relationship to the piriformis muscle. Folia Morphol (Warsz). 2020;79(4):681–689.

Bogduk N. International Spine Intervention S, Standards C. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. San Francisco: International Spine Intervention Society; 2013. Chen Y, Huang-Lionnet JHY, Cohen SP. Radiofrequency ablation in coccydynia: A case series and comprehensive, evidence-based review. Pain Med. 2017;18(6):1111–1130. Cohen SP, Chen Y, Neufeld NJ. Sacroiliac joint pain: A comprehensive review of epidemiology, diagnosis, and treatment. Expert Rev Neurother. 2013;131–99–116. Dreyfuss P, Henning T, Malladi N, et al. The ability of multi-site, multidepth sacral lateral branch blocks to anesthetize the sacroiliac joint complex. Pain Med. 2009;10(4):679–688. Ferreira F, Pedro A. Ganglion impar neurolysis in the management of pelvic and perineal cancer-related pain. Case Rep Oncol. 2020;13(1): 29–34. Johnson DB, Varacallo M. Ischial bursitis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020. Available at: https:// www.ncbi.nlm.nih.gov/books/NBK482285/. Kennedy DJ, Engel A, Kreiner DS, Nampiaparampil D, Duszynski B, MacVicar J. Fluoroscopically guided diagnostic and therapeutic intraarticular sacroiliac joint injections: A systematic review. Pain Med. 2015;16(8):1500–1518.

The references for this chapter can be found at ExpertConsult.com.

References 1. Cohen SP, Chen Y, Neufeld NJ. Sacroiliac joint pain: A comprehensive review of epidemiology, diagnosis and treatment. Expert Rev Neurother. 2013;13(1):99–116. 2. Kennedy DJ, Engel A, Kreiner DS, Nampiaparampil D, Duszynski B, MacVicar J. Fluoroscopically guided diagnostic and therapeutic intra-articular sacroiliac joint injections: A systematic review. Pain Med. 2015;16(8):1500–1518. 3. Sakamoto N, Yamashita T, Takebayashi T, Sekine M, Ishii S. An electrophysiologic study of mechanoreceptors in the sacroiliac joint and adjacent tissues. Spine (Phila Pa 1976). 2001;26(20):E468– E471. 4. Chou LH, Slipman CW, Bhagia SM, et  al. Inciting events initiating injection-proven sacroiliac joint syndrome. Pain Med. 2004;5(1):26–32. 5. Cohen SP, Strassels SA, Kurihara C, et al. Outcome predictors for sacroiliac joint (lateral branch) radiofrequency denervation. Reg Anesth Pain Med. 2009;34(3):206–214. 6. Schwarzer AC, Aprill CN, Bogduk N. The sacroiliac joint in chronic low back pain. Spine (Phila Pa 1976). 1995;20(1):31–37. 7. Filipec M, Jadanec M, Kostovic-Srzentic M, van der Vaart H, Matijevic R. Incidence, pain, and mobility assessment of pregnant women with sacroiliac dysfunction. Int J Gynaecol Obstet. 2018;142(3):283–287. 8. Ostgaard HC, Andersson GB, Karlsson K. Prevalence of back pain in pregnancy. Spine (Phila Pa 1976). 1991;16(5):549–552. 9. Kiapour A, AbdElgawad AA, Goel VK, Souccar A, Terai T, Ebraheim NA. Relationship between limb length discrepancy and load distribution across the sacroiliac joint – a finite element study. J Orthop Res. 2012;30(10):1577–1580. 10. Longo UG, Loppini M, Berton A, Laverde L, Maffulli N, Denaro V. Degenerative changes of the sacroiliac joint after spinal fusion: An evidence-based systematic review. Br Med Bull. 2014;112(1):47–56. 11. Borowsky CD, Fagen G. Sources of sacroiliac region pain: Insights gained from a study comparing standard intra-articular injection with a technique combining intra- and peri-articular injection. Arch Phys Med Rehabil. 2008;89(11):2048–2056. 12. Murakami E, Tanaka Y, Aizawa T, Ishizuka M, Kokubun S. Effect of periarticular and intraarticular lidocaine injections for sacroiliac joint pain: Prospective comparative study. J Orthop Sci. 2007;12(3):274–280. 13. Hartung W, Ross CJ, Straub R, et al. Ultrasound-guided sacroiliac joint injection in patients with established sacroiliitis: Precise IA injection verified by MRI scanning does not predict clinical outcome. Rheumatol (Oxf Engl). 2010;49(8):1479–1482. 14. Cohen SP, Bicket MC, Kurihara C, et al. Fluoroscopically guided vs landmark-guided sacroiliac joint injections: A randomized controlled study. Mayo Clin Proc. 2019;94(4):628–642. 15. Szadek KM, Hoogland PV, Zuurmond WW, de Lange JJ, Perez RS. Nociceptive nerve fibers in the sacroiliac joint in humans. Reg Anesth Pain Med. 2008;33(1):36–43. 16. Kurosawa D, Murakami E, Aizawa T. Referred pain location depends on the affected section of the sacroiliac joint. Eur Spine J. 2015;24(3):521–527. 17. Murakami E, Aizawa T, Noguchi K, Kanno H, Okuno H, Uozumi H. Diagram specific to sacroiliac joint pain site indicated by onefinger test. J Orthop Sci. 2008;13(6):492–497. 18. Slipman CW, Jackson HB, Lipetz JS, Chan KT, Lenrow D, Vresilovic EJ. Sacroiliac joint pain referral zones. Arch Phys Med Rehabil. 2000;81(3):334–338. 19. Fortin JD, Aprill CN, Ponthieux B, Pier J. Sacroiliac joint: Pain referral maps upon applying a new injection/arthrography technique. Part II: Clinical evaluation. Spine (Phila Pa 1976). 1994;19(13):1483–1489. 20. Kurosawa D, Murakami E, Aizawa T. Groin pain associated with sacroiliac joint dysfunction and lumbar disorders. Clin Neurol Neurosurg. 2017;161:104–109.

21. Hodge JC, Bessette B. The incidence of sacroiliac joint disease in patients with low-back pain. Can Assoc Radiol J. 1999;50(5):321–323. 22. Laslett M, Aprill CN, McDonald B, Young SB. Diagnosis of sacroiliac joint pain: Validity of individual provocation tests and composites of tests. Man Ther. 2005;10(3):207–218. 23. Szadek KM, van der Wurff P, van Tulder MW, Zuurmond WW, Perez RS. Diagnostic validity of criteria for sacroiliac joint pain: A systematic review. J Pain. 2009;10(4):354–368. 24. Bernard TN, Cassidy JD. The sacroiliac joint syndrome. In: Frymoyer JW, Ducker TB (eds). The Adult Spine: Principles and Practice. New York: Raven Press; 1991:2107–2130. 25. Bernard TN, Kirkaldy-Willis WH. Managing Low Back Pain. New York: Churchill Livingstone; 1999. 26. Dreyfuss P, Dryer S, Griffin J, Hoffman J, Walsh N. Positive sacroiliac screening tests in asymptomatic adults. Spine (Phila Pa 1976). 1994;19(10):1138–1143. 27. Eskander JP, Ripoll JG, Calixto F, et al. Value of examination under fluoroscopy for the assessment of sacroiliac joint dysfunction. Pain Phys. 2015;18(5):E781–E786. 28. Elgafy H, Semaan HB, Ebraheim NA, Coombs RJ. Computed tomography findings in patients with sacroiliac pain. Clin Orthop Relat Res. 2001;382(382):112–118. 29. Maigne JY, Boulahdour H, Chatellier G. Value of quantitative radionuclide bone scanning in the diagnosis of sacroiliac joint syndrome in 32 patients with low back pain. Eur Spine J. 1998;7(4):328–331. 30. Schneider BJ, Rosati R, Zheng P, McCormick ZL. Challenges in diagnosing sacroiliac joint pain: A narrative review. PMR. 2019;11(Suppl 1):S40–S45. 31. Slipman CW, Sterenfeld EB, Chou LH, Herzog R, Vresilovic E. The value of radionuclide imaging in the diagnosis of sacroiliac joint syndrome. Spine (Phila Pa 1976). 1996;21(19):2251–2254. 32. Arnbak B, Jurik AG, Jensen TS, Manniche C. Association between inflammatory back pain characteristics and magnetic resonance imaging findings in the spine and sacroiliac joints. Arthritis Care Res (Hoboken). 2018;70(2):244–251. 33. Fortin JD, Washington WJ, Falco FJ. Three pathways between the sacroiliac joint and neural structures. AJNR Am J Neuroradiol. 1999;20(8):1429–1434. 34. Maigne JY, Aivaliklis A, Pfefer F. Results of sacroiliac joint double block and value of sacroiliac pain provocation tests in 54 patients with low back pain. Spine (Phila Pa 1976). 1996;21(16):1889–1892. 35. Added MAN, de Freitas DG, Kasawara KT, Martin RL, Fukuda TY. Strengthening the gluteus maximus in subjects with sacroiliac dysfunction. Int J Sports Phys Ther. 2018;13(1):114–120. 36. Bhatia A, Engle A, Cohen SP. Current and future pharmacological agents for the treatment of back pain. Expert Opin Pharmacother. 2020;21(8):857–861. 37. Miles D, Bishop M. Use of manual therapy for posterior pelvic girdle pain. PMR. 2019;11(Suppl 1):S93–S97. 38. Maugars Y, Mathis C, Berthelot JM, Charlier C, Prost A. Assessment of the efficacy of sacroiliac corticosteroid injections in spon­ dylarthropathies: A double-blind study. Br J Rheumatol. 1996;35(8): 767–770. 39. Luukkainen R, Nissilä M, Asikainen E, et al. Periarticular corticosteroid treatment of the sacroiliac joint in patients with seronegative spondylarthropathy. Clin Exp Rheumatol. 1999;17(1):88–90. 40. Luukkainen RK, Wennerstrand PV, Kautiainen HH, Sanila MT, Asikainen EL. Efficacy of periarticular corticosteroid treatment of the sacroiliac joint in non-spondylarthropathic patients with chronic low back pain in the region of the sacroiliac joint. Clin Exp Rheumatol. 2002;20(1):52–54. 41. Yang AJ, McCormick ZL, Zheng PZ, Schneider BJ. Radiofrequency ablation for posterior sacroiliac joint complex pain: A narrative review. PMR. 2019;11(Suppl 1):S105–S113. 42. Yson SC, Sembrano JN, Jr Polly DW. Sacroiliac joint fusion: Approaches and recent outcomes. PMR. 2019;11(Suppl 1):S114– S117. 431.e1

431.e2

References

43. Medicine CoP, Anesthesiologists ASo. Statement on anesthetic care during interventional pain procedures for adults; 2016. Available at: https://www.asahq.org. 44. Cohen SP, Hameed H, Kurihara C, et  al. The effect of sedation on the accuracy and treatment outcomes for diagnostic injections: A randomized, controlled, crossover study. Pain Med. 2014;15(4):588–602. 45. Rosenberg JM, Quint TJ, de Rosayro AM. Computerized tomographic localization of clinically guided sacroiliac joint injections. Clin J Pain. 2000;16(1):18–21. 46. Stelzer W, Stelzer D, Stelzer E, et al. Success rate of intra-articular sacroiliac joint injection: Fluoroscopy vs ultrasound guidance- a cadaveric study. Pain Med. 2019;20(10):1890–1897. 47. Bydon M, Macki M, De la Garza-Ramos R, et al. The cost-effectiveness of CT-guided sacroiliac joint injections: A measure of QALY gained. Neurol Res. 2014;36(10):915–920. 48. Bogduk N. International Spine Intervention S, Standards C. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. San Francisco: International Spine Intervention Society; 2004. 49. Fenton DS, Czervionke LF. Image-Guided Spine Intervention. Philadelphia, PA: Saunders; 2003. 50. Yin W, Willard F, Carreiro J, Dreyfuss P. Sensory stimulationguided sacroiliac joint radiofrequency neurotomy: Technique based on neuroanatomy of the dorsal sacral plexus. Spine (Phila Pa 1976). 2003;28(20):2419–2425. 51. Dreyfuss P, Dreyer SJ, Cole A, Mayo K. Sacroiliac joint pain. J Am Acad Orthop Surg. 2004;12(4):255–265. 52. Ebraheim NA, Xu R, Nadaud M, Huntoon M, Yeasting R. Sacroiliac joint injection: A cadaveric study. Am J Orthop (Belle Mead NJ). 1997;26(5):338–341. 53. Cohen SP, Bhaskar A, Bhatia A, et al. Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group. Reg Anesth Pain Med. 2020;45(6):424–467. 54. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9(2):105–121. 55. Pekkafahli MZ, Kiralp MZ, Başekim CC, et  al. Sacroiliac joint injections performed with sonographic guidance. J Ultrasound Med. 2003;22(6):553–559. 56. Harmon D, O’Sullivan M. Ultrasound-guided sacroiliac joint injection technique. Pain Phys. 2008;11(4):543–547. 57. Klauser A, De Zordo T, Feuchtner G, et  al. Feasibility of ultrasound-guided sacroiliac joint injection considering sonoanatomic landmarks at two different levels in cadavers and patients. Arthritis Rheum. 2008;59(11):1618–1624. 58. Jee H, Lee JH, Park KD, Ahn J, Park Y. Ultrasound-guided versus fluoroscopy-guided sacroiliac joint intra-articular injections in the noninflammatory sacroiliac joint dysfunction: A prospective, randomized, single-blinded study. Arch Phys Med Rehabil. 2014;95(2):330–337. 59. De Luigi AJ, Saini V, Mathur R, Saini A, Yokel N. Assessing the accuracy of ultrasound-guided needle placement in sacroiliac joint injections. Am J Phys Med Rehabil. 2019;98(8):666–670. 60. Perry JM, Colberg RE, Dault SL, Beason DP, Tresgallo RA. A cadaveric study assessing the accuracy of ultrasound-guided sacroiliac joint injections. PMR. 2016;8(12):1168–1172. 61. Bollow M, Braun J, Taupitz M, et al. CT-guided intraarticular corticosteroid injection into the sacroiliac joints in patients with spondyloarthropathy: Indication and follow-up with contrast-enhanced MRI. J Comput Assist Tomogr. 1996;20(4):512–521. 62. Gevargez A, Groenemeyer D, Schirp S, Braun M. CT-guided percutaneous radiofrequency denervation of the sacroiliac joint. Eur Radiol. 2002;12(6):1360–1365. 63. Pulisetti D, Ebraheim NA. CT-guided sacroiliac joint injections. J Spinal Disord. 1999;12(4):310–312. 64. Hansen HC. Is fluoroscopy necessary for sacroiliac joint injections? Pain Phys. 2003;6(2):155–158.

65. Kennedy DJ, Shokat M, Visco CJ. Sacroiliac joint and lumbar zygapophysial joint corticosteroid injections. Phys Med Rehabil Clin N Am. 2010;21(4):835–842. 66. Kim WM, Lee HG, Jeong CW, Kim CM, Yoon MH. A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain. J Altern Complement Med. 2010;16(12):1285–1290. 67. Hansen H, Manchikanti L, Simopoulos TT, et  al. A systematic evaluation of the therapeutic effectiveness of sacroiliac joint interventions. Pain Phys. 2012;15(3):E247–E278. 68. Braun J, Bollow M, Seyrekbasan F, et al. Computed tomography guided corticosteroid injection of the sacroiliac joint in patients with spondyloarthropathy with sacroiliitis: Clinical outcome and followup by dynamic magnetic resonance imaging. J Rheumatol. 1996;23(4):659–664. 69. Fischer T, Biedermann T, Hermann KG, et al. Sacroiliitis in children with spondyloarthropathy: Therapeutic effect of CT-Guided intraarticular corticosteroid injection. RoFo. 2003;175(6):814–821. 70. Hawkins J, Schofferman J. Serial therapeutic sacroiliac joint injections: A practice audit. Pain Med. 2009;10(5):850–853. 71. Liliang PC, Lu K, Weng HC, Liang CL, Tsai YD, Chen HJ. The therapeutic efficacy of sacroiliac joint blocks with triamcinolone acetonide in the treatment of sacroiliac joint dysfunction without spondyloarthropathy. Spine (Phila Pa 1976). 2009;34(9):896–900. 72. Ojala R, Klemola R, Karppinen J, Sequeiros RB, Tervonen O. Sacro-iliac joint arthrography in low back pain: Feasibility of MRI guidance. Eur J Radiol. 2001;40(3):236–239. 73. Pereira PL, Günaydin I, Trübenbach J, et  al. Interventional MR imaging for injection of sacroiliac joints in patients with sacroiliitis. AJR Am J Roentgenol. 2000;175(1):265–266. 74. Sadreddini S, Noshad H, Molaeefard M, Ardalan MR, Ghojazadeh M, Shakouri SK. Unguided sacroiliac injection: Effect on refractory buttock pain in patients with spondyloarthropathies. Presse Med. 2009;38(5):710–716. 75. Cohen SP, Abdi S. Lateral branch blocks as a treatment for sacroiliac joint pain: A pilot study. Reg Anesth Pain Med. 2003;28(2):113–119. 76. Dreyfuss P, Snyder BD, Park K, Willard F, Carreiro J, Bogduk N. The ability of single site, single depth sacral lateral branch blocks to anesthetize the sacroiliac joint complex. Pain Med. 2008;9(7): 844–850. 77. Dreyfuss P, Henning T, Malladi N, Goldstein B, Bogduk N. The ability of multi-site, multi-depth sacral lateral branch blocks to anesthetize the sacroiliac joint complex. Pain Med. 2009;10(4): 679–688. 78. Grob KR, Neuhuber WL, Kissling RO. Innervation of the sacroiliac joint of the human. Z Rheumatol. 1995;54(2):117–122. 79. Kapural L, Stojanovic M, Sessler DI, Bensitel T, Zovkic P. Cooled radio frequency (RF) of L5 dorsal ramus for RF denervation of the sacroiliac joint: Technical report. Pain Med. 2010;11(1):53–57. 80. Kapural L. Sacroiliac joint radiofrequency denervation: Who benefits? Reg Anesth Pain Med. 2009;34(3):185–186. 81. Roberts SL, Stout A, Loh EY, Swain N, Dreyfuss P, Agur AM. Anatomical comparison of radiofrequency ablation techniques for sacroiliac joint pain. Pain Med. 2018;19(10):1924–1943. 82. Cohen SP, Hurley RW, 3rd Buckenmaier CC, Kurihara C, Morlando B, Dragovich A. Randomized placebo-controlled study evaluating lateral branch radiofrequency denervation for sacroiliac joint pain. Anesthesiol. 2008;109(2):279–288. 83. Cosman Jr ER, Gonzalez CD. Bipolar radiofrequency lesion geometry: Implications for palisade treatment of sacroiliac joint pain. Pain Pract. 2011;11(1):3–22. 84. Roberts SL, Burnham RS, Agur AM, Loh EY. A cadaveric study evaluating the feasibility of an ultrasound-guided diagnostic block and radiofrequency ablation technique for sacroiliac joint pain. Reg Anesth Pain Med. 2017;42(1):69–74. 85. Patel N, Gross A, Brown L, Gekht G. A randomized, placebo-controlled study to assess the efficacy of lateral branch neurotomy for chronic sacroiliac joint pain. Pain Med. 2012;13(3):383–398.

References

86. Provenzano DA, Lassila HC, Somers D. The effect of fluid injection on lesion size during radiofrequency treatment. Reg Anesth Pain Med. 2010;35(4):338–342. 87. Provenzano DA, Lutton EM, Somers DL. The effects of fluid injection on lesion size during bipolar radiofrequency treatment. Reg Anesth Pain Med. 2012;37(3):267–276. 88. Burnham RS, Yasui Y. An alternate method of radiofrequency neurotomy of the sacroiliac joint: A pilot study of the effect on pain, function, and satisfaction. Reg Anesth Pain Med. 2007;32(1):12–19. 89. van Tilburg CW, Schuurmans FA, Stronks DL, Groeneweg JG, Huygen FJ. Randomized sham-controlled double-blind multicenter clinical trial to ascertain the effect of percutaneous radiofrequency treatment for sacroiliac joint pain: Three-month results. Clin J Pain. 2016;32(11):921–926. 90. Salman OH, Gad GS, Mohamed AA, Rafae HH, Abdelfatah AM. Randomized, controlled blind study comparing sacroiliac intraarticular steroid injection to radiofrequency denervation for sacroiliac joint pain. Egypt J Anaesth. 2016;32(2):219–225. 91. Karaman H, Kavak GO, Tüfek A, et  al. Cooled radiofrequency application for treatment of sacroiliac joint pain. Acta Neurochir (Wien). 2011;153(7):1461–1468. 92. Ho KY, Hadi MA, Pasutharnchat K, Tan KH. Cooled radiofrequency denervation for treatment of sacroiliac joint pain: Two-year results from 20 cases. J Pain Res. 2013;6:505–511. 93. Stelzer W, Aiglesberger M, Stelzer D, Stelzer V. Use of cooled radiofrequency lateral branch neurotomy for the treatment of sacroiliac joint-mediated low back pain: A large case series. Pain Med. 2013;14(1):29–35. 94. Stout A, Dreyfuss P, Swain N, Roberts S, Loh E, Agur A. Proposed optimal fluoroscopic targets for cooled radiofrequency neurotomy of the sacral lateral branches to improve clinical outcomes: An anatomical study. Pain Med. 2018;19(10):1916–1923. 95. Shih CL, Shen PC, Lu CC, et al. A comparison of efficacy among different radiofrequency ablation techniques for the treatment of lumbar facet joint and sacroiliac joint pain: A systematic review and meta-analysis. Clin Neurol Neurosurg. 2020;195:105854. 96. Chen CH, Weng PW, Wu LC, Chiang YF, Chiang CJ. Radiofrequency neurotomy in chronic lumbar and sacroiliac joint pain: A meta-analysis. Med (Baltim). 2019;98(26):e16230. 97. Juch JNS, Maas ET, Ostelo RWJG, et  al. Effect of radiofrequency denervation on pain intensity among patients with chronic low back pain: The mint randomized clinical trials. JAMA. 2017;318(1):68–81. 98. Kapural L, Provenzano D, Re NS, Juch JNS, et al. Effect of radio frequency denervation on pain intensity among patients with chronic low back pain: The mint randomized clinical trials. JAMA Neuromodulat. 2017;20(8):68–81 844;318(1. 99. McCormick ZL, Vorobeychik Y, Gill JS, et al. Guidelines for composing and assessing a paper on the treatment of pain: A practical application of evidence-based medicine principles to the mint randomized clinical trials. Pain Med. 2018;19(11):2127–2137. 100. Irwin RW, Watson T, Minick RP, Ambrosius WT. Age, body mass index, and gender differences in sacroiliac joint pathology. Am J Phys Med Rehabil. 2007;86(1):37–44. 101. Mehta V, Poply K, Husband M, Anwar S, Langford R. The effects of radiofrequency neurotomy using a strip-lesioning device on patients with sacroiliac joint pain: Results from a single-center, randomized, sham-controlled trial. Pain Phys. 2018;21(6):607–618. 102. Dutta K, Dey S, Bhattacharyya P, Agarwal S, Dev P. Comparison of efficacy of lateral branch pulsed radiofrequency denervation and intraarticular depot methylprednisolone injection for sacroiliac joint pain. Pain Phys. 2018;21(5):489–496. 103. Cánovas Martínez L, Orduña Valls J, Paramés Mosquera E, Lamelas Rodríguez L, Rojas Gil S, Domínguez García M. Sacroiliac joint pain: Prospective, randomised, experimental and comparative study of thermal radiofrequency with sacroiliac joint block. Rev Esp Anestesiol Reanim. 2016;63(5):267–272. 104. Zheng Y, Gu M, Shi D, Li M, Ye L, Wang X. Tomography-guided palisade sacroiliac joint radiofrequency neurotomy versus celecoxib

431.e3

for ankylosing spondylitis: A open-label, randomized, and controlled trial. Rheumatol Int. 2014;34(9):1195–1202. 105. Stelzer W, Stelzer V, Stelzer D, Braune M, Duller C. Influence of BMI, gender, and sports on pain decrease and medication usage after facet-medial branch neurotomy or SI joint lateral branch cooled RF-neurotomy in case of low back pain: Original research in the Austrian population. J Pain Res. 2017;10:183–190. 106. Anjana Reddy VS, Sharma C, Chang KY, Mehta V. ‘Simplicity’ radiofrequency neurotomy of sacroiliac joint: A real life 1-year follow-up UK data. Br J Pain. 2016;10(2):90–99. 107. Romero FR, Vital RB, Zanini MA, Ducati LG, Gabarra RC. Longterm follow-up in sacroiliac joint pain patients treated with radiofrequency ablative therapy. Arq Neuro Psiquiatr. 2015;73(6):476–479. 108. Lirette LS, Chaiban G, Tolba R, Eissa H. Coccydynia: An overview of the anatomy, etiology, and treatment of coccyx pain. Ochsner J. 2014;14(1):84–87. 109. Fogel GR, Cunningham 3rd PY, Esses SI. Coccygodynia: Evaluation and management. J Am Acad Orthop Surg. 2004;12(1):49–54. 110. Kaushal R, Bhanot A, Luthra S, Gupta PN, Sharma RB. Intrapartum coccygeal fracture, a cause for postpartum coccydynia: A case report. J Surg Orthop Adv. 2005;14(3):136–137. 111. Maigne JY, Doursounian L, Chatellier G. Causes and mechanisms of common coccydynia: Role of body mass index and coccygeal trauma. Spine (Phila Pa 1976). 2000;25(23):3072–3079. 112. Maigne JY, Rusakiewicz F, Diouf M. Postpartum coccydynia: A case series study of 57 women. Eur J Phys Rehabil Med. 2012;48(3): 387–392. 113. Schapiro S. Low back and rectal pain from an orthopedic and proctologic viewpoint; with a review of 180 cases. Am J Surg. 1950;79(1):117–128 illust. 114. Deniz R, Ozen G, Yilmaz-Oner S, et  al. Ankylosing spondylitis and a diagnostic dilemma: Coccydynia. Clin Exp Rheumatol. 2014;32(2):194–198. 115. Cockbain AJ, Morrison CP, Davies JB. Coccydynia secondary to a large pelvic tumor of anorectal origin. Spine J. 2011;11(7):683. 116. Kim HS, Yang SH, Park HJ, Park HB, Cho HS. Glomus tumor as a cause of coccydynia. Skelet Radiol. 2013;42(10):1471–1473. 117. Pennekamp PH, Kraft CN, Stütz A, Wallny T, Schmitt O, Diedrich O. Coccygectomy for coccygodynia: Does pathogenesis matter? J Trauma. 2005;59(6):1414–1419. 118. Postacchini F, Massobrio M. Idiopathic coccygodynia. Analysis of fifty-one operative cases and a radiographic study of the normal coccyx. J Bone Joint Surg Am. 1983;65(8):1116–1124. 119. Maigne JY, Guedj S, Straus C. Idiopathic coccygodynia. Lateral roentgenograms in the sitting position and coccygeal discography. Spine (Phila Pa 1976). 1994;19(8):930–934. 120. Woon JT, Perumal V, Maigne JY, Stringer MD. CT morphology and morphometry of the normal adult coccyx. Eur Spine J. 2013;22(4):863–870. 121. Woon JT, Stringer MD. Clinical anatomy of the coccyx: A systematic review. Clin Anat. 2012;25(2):158–167. 122. Standring S, Gray H. Gray’s Anatomy: The Anatomical Basis of Clinical Practice. Edinburgh: Churchill Livingstone; 2008. 123. Barber MD, Bremer RE, Thor KB, Dolber PC, Kuehl TJ, Coates KW. Innervation of the female levator ani muscles. Am J Obstet Gynecol. 2002;187(1):64–71. 124. Moore KL, Agur AMR, Dalley AF. Essential Clinical Anatomy. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 125. Sato K. A morphological analysis of the nerve supply of the sphincter ani externus, levator ani and coccygeus (author’s transl). Kaibogaku Zasshi. 1980;55(3):187–223. 126. Woon JT, Stringer MD. Redefining the coccygeal plexus. Clin Anat. 2014;27(2):254–260. 127. Walters A, Muhleman M, Osiro S, et al. One is the loneliest number: A review of the ganglion impar and its relation to pelvic pain syndromes. Clin Anat. 2013;26(7):855–861. 128. Hodges SD, Eck JC, Humphreys SC. A treatment and outcomes analysis of patients with coccydynia. Spine J. 2004;4(2):138–140.

431.e4

References

129. Maigne JY, Pigeau I, Aguer N, Doursounian L, Chatellier G. Chronic coccydynia in adolescents. A series of 53 patients. Eur J Phys Rehabil Med. 2011;47(2):245–251. 130. Maigne JY, Chatellier G, Faou ML, Archambeau M. The treatment of chronic coccydynia with intrarectal manipulation: A randomized controlled study. Spine (Phila Pa 1976). 2006;31(18):E621–E627. 131. Lin SF, Chen YJ, Tu HP, et al. The effects of extracorporeal shock wave therapy in patients with coccydynia: A randomized controlled trial. PLoS One. 2015;10(11):e0142475. 132. Wray CC, Easom S, Hoskinson J. Coccydynia. Aetiology and treatment. J Bone Joint Surg Br. 1991;73(2):335–338. 133. Mitra R, Cheung L, Perry P. Efficacy of fluoroscopically guided steroid injections in the management of coccydynia. Pain Phys. 2007;10(6):775–778. 134. Atim A, Ergin A, Bilgiç S, Deniz S, Kurt E. Pulsed radiofrequency in the treatment of coccygodynia. Agri. 2011;23(1):1–6. 135. Chen Y, Huang-Lionnet JHY, Cohen SP. Radiofrequency ablation in coccydynia: A case series and comprehensive, evidence-based review. Pain Med. 2017;18(6):1111–1130. 136. Gunduz OH, Sencan S, Kenis-Coskun O. Pain relief due to Transsacrococcygeal ganglion impar block in chronic coccygodynia: A pilot study. Pain Med. 2015;16(7):1278–1281. 137. Demircay E, Kabatas S, Cansever T, Yilmaz C, Tuncay C, Altinors N. Radiofrequency thermocoagulation of ganglion impar in the management of coccydynia: Preliminary results. Turk Neurosurg. 2010;20(3):328–333. 138. Agarwal-Kozlowski K, Lorke DE, Habermann CR, Am Esch JS, Beck H. CT-guided blocks and neuroablation of the ganglion impar (Walther) in perineal pain: Anatomy, technique, safety, and efficacy. Clin J Pain. 2009;25(7):570–576. 139. Ferreira F, Pedro A. Ganglion impar neurolysis in the management of pelvic and perineal cancer-related pain. Case Rep Oncol. 2020;13(1):29–34. 140. Lee DW, Lai A. Sacral burst neuromodulation via caudal approach as a treatment for chronic coccydynia. Neuromodulat. 2019;22(8):992–994. 141. Hope ER, Gruber DD. Coccygeal fracture pain cured by sacral neuromodulation: A case report. Neuromodulat. 2013;16(6):614–617. 142. Yakovlev A, Resch B. Spinal cord stimulation for the treatment of coccydynia following traumatic closed fracture of sacrum and coccyx and rectal tear. Pain Pract. 2012;12(s1):182. 143. Robinson DR. Pyriformis syndrome in relation to sciatic pain. Am J Surg. 1947;73(3):355–358. 144. Barton PM. Piriformis syndrome: A rational approach to management. Pain. 1991;47(3):345–352. 145. Boyajian-O’Neill LA, McClain RL, Coleman MK, Thomas PP. Diagnosis and management of piriformis syndrome: An osteopathic approach. J Am Osteopath Assoc. 2008;108(11):657–664. 146. Papadopoulos EC, Khan SN. Piriformis syndrome and low back pain: A new classification and review of the literature. Orthop Clin North Am. 2004;35(1):65–71. 147. Parziale JR, Hudgins TH, Fishman LM. The piriformis syndrome. Am J Orthop (Belle Mead NJ). 1996;25(12):819–823. 148. Durrani Z, Winnie AP. Piriformis muscle syndrome: An underdiagnosed cause of sciatica. J Pain Symptom Manage. 1991;6(6):374–379. 149. Wun-Schen C. Bipartite piriformis muscle: An unusual cause of sciatic nerve entrapment. Pain. 1994;58(2):269–272. 150. Iwanaga J, Eid S, Simonds E, Schumacher M, Loukas M, Tubbs RS. The majority of piriformis muscles are innervated by the superior gluteal nerve. Clin Anat. 2019;32(2):282–286. 151. Giuffre BA, Jeanmonod R. Anatomy, sciatic nerve. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2020. 152. Benzon HT, Katz JA, Benzon HA, Iqbal MS. Piriformis syndrome: Anatomic considerations, a new injection technique, and a review of the literature. Anesthesiol. 2003;98(6):1442–1448. 153. Michel F, Decavel P, Toussirot E, et al. The piriformis muscle syndrome: An exploration of anatomical context, pathophysiological

hypotheses and diagnostic criteria. Ann Phys Rehabil Med. 2013;56(4):300–311. 154. Natsis K, Totlis T, Konstantinidis GA, Paraskevas G, Piagkou M, Koebke J. Anatomical variations between the sciatic nerve and the piriformis muscle: A contribution to surgical anatomy in piriformis syndrome. Surg Radiol Anat. 2014;36(3):273–280. 155. Smoll NR. Variations of the piriformis and sciatic nerve with clinical consequence: A review. Clin Anat. 2010;23(1):8–17. 156. Beaton LE, BJ Anson. The relation of the sciatic nerve and of its subdivisions to the piriformis muscle. Anat Rec. 1937;70(1):1–5. 157. Wan-Ae-Loh P, Huanmanop T, Agthong S, Chentanez V. Evaluation of the sciatic nerve location regarding its relationship to the piriformis muscle. Folia Morphol (Warsz). 2020;79(4):681–689. 158. Barbosa ABM, Santos PVD, Targino VA, et al. Sciatic nerve and its variations: Is it possible to associate them with piriformis syndrome? Arq Neuro Psiquiatr. 2019;77(9):646–653. 159. Khan H, Ling S, Ali S, et al. Sciatic nerve variants in patients diagnosed with sciatica: Is there a correlation? J Comput Assist Tomogr. 2019;43(6):953–957. 160. Bartret AL, Beaulieu CF, Lutz AM. Is it painful to be different? Sciatic nerve anatomical variants on MRI and their relationship to piriformis syndrome. Eur Radiol. 2018;28(11):4681–4686. 161. Shah SS, Consuegra JM, Subhawong TK, Urakov TM, Manzano GR. Epidemiology and etiology of secondary piriformis syndrome: A single-institution retrospective study. J Clin Neurosci. 2019;59:209–212. 162. Pace JB, Nagle D. Piriform syndrome. West J Med. 1976;124(6):435– 439. 163. Kizaki K, Uchida S, Shanmugaraj A, et al. Deep gluteal syndrome is defined as a non-discogenic sciatic nerve disorder with entrapment in the deep gluteal space: A systematic review. Knee Surg Sports Traumatol Arthrosc. 2020;28(10):3354–3364. 164. Jankiewicz JJ, Hennrikus WL, Houkom JA. The appearance of the piriformis muscle syndrome in computed tomography and magnetic resonance imaging. A case report and review of the literature. Clin Orthop Relat Res. 1991;262(262):205–209. 165. Hallin RP. Sciatic pain and the piriformis muscle. Postgrad Med. 1983;74(2):69–72. 166. Hopayian K, Song F, Riera R, Sambandan S. The clinical features of the piriformis syndrome: A systematic review. Eur Spine J. 2010;19(12):2095–2109. 167. Robinson LR. Is the FAIR-test a fair method of detecting piriformis syndrome? Muscle Nerve. 2019;60(3):E20. 168. Fishman LM, Zybert PA. Electrophysiologic evidence of piriformis syndrome. Arch Phys Med Rehabil. 1992;73(4):359–364. 169. Najdi H, Mouarbes D, Abi-Akl J, Karnib S, Chamsedine AH, Jawish R. EMG in piriformis syndrome diagnosis: Reliability of peroneal H-reflex according to results obtained after surgery, Botox injection and medical treatment. J Clin Neurosci. 2019;59:55–61. 170. Jawish RM, Assoum HA, Khamis CF. Anatomical, clinical and electrical observations in piriformis syndrome. J Orthop Surg Res. 2010;5:3. 171. Yang HE, Park JH, Kim S. Usefulness of magnetic resonance neurography for diagnosis of piriformis muscle syndrome and verification of the effect after botulinum toxin type A injection: Two cases. Med (Baltim). 2015;94(38):e1504. 172. Wu YY, Guo XY, Chen K, He FD, Quan JR. Feasibility and reliability of an ultrasound examination to diagnose piriformis syndrome. World Neurosurg. 2020;134:e1085–e1092. 173. Zhang W, Luo F, Sun H, Ding H. Ultrasound appears to be a reliable technique for the diagnosis of piriformis syndrome. Muscle Nerve. 2019;59(4):411–416. 174. Fishman LM, Dombi GW, Michaelsen C, et  al. Piriformis syndrome: Diagnosis, treatment, and outcome - a 10-year study. Arch Phys Med Rehabil. 2002;83(3):295–301. 175. Terlemez R, Erçalık T. Effect of piriformis injection on neuropathic pain. Agri. 2019;31(4):178–182.

References

176. Tabatabaiee A, Takamjani IE, Sarrafzadeh J, Salehi R, Ahmadi M. Ultrasound-guided dry needling decreases pain in patients with piriformis syndrome. Muscle Nerve. 2019;60(5):558–565. 177. Chen CP, Shen CY, Lew HL. Ultrasound-guided injection of the piriformis muscle. Am J Phys Med Rehabil. 2011;90(10):871–872. 178. Smith J, Hurdle MF, Locketz AJ, Wisniewski SJ. Ultrasoundguided piriformis injection: Technique description and verification. Arch Phys Med Rehabil. 2006;87(12):1664–1667. 179. Fishman SM, Caneris OA, Bandman TB, Audette JF, Borsook D. Injection of the piriformis muscle by fluoroscopic and electromyographic guidance. Reg Anesth Pain Med. 1998;23(6):554–559. 180. Masala S, Crusco S, Meschini A, Taglieri A, Calabria E, Simonetti G. Piriformis syndrome: Long-term follow-up in patients treated with percutaneous injection of anesthetic and corticosteroid under CT guidance. Cardiovasc Intervent Radiol. 2012;35(2):375–382. 181. Bardowski EA, Byrd JWT. Piriformis injection: An ultrasoundguided technique. Arthrosc Tech. 2019;8(12):e1457–e1461. 182. Finnoff JT, Hurdle MF, Smith J. Accuracy of ultrasound-guided versus fluoroscopically guided contrast-controlled piriformis injections: A cadaveric study. J Ultrasound Med. 2008;27(8):1157–1163. 183. Fusco P, Di Carlo S, Scimia P, Degan G, Petrucci E, Marinangeli F. Ultrasound-guided dry needling treatment of myofascial trigger points for piriformis syndrome management: A case series. J Chiropr Med. 2018;17(3):198–200. 184. Fowler IM, Tucker AA, Weimerskirch BP, Moran TJ, Mendez RJ. A randomized comparison of the efficacy of 2 techniques for piriformis muscle injection: Ultrasound-guided versus nerve stimulator with fluoroscopic guidance. Reg Anesth Pain Med. 2014;39(2): 126–132. 185. Misirlioglu TO, Akgun K, Palamar D, Erden MG, Erbilir T. Piriformis syndrome: Comparison of the effectiveness of local anesthetic and corticosteroid injections: A double-blinded, randomized controlled study. Pain Phys. 2015;18(2):163–171. 186. Santamato A, Micello MF, Valeno G, et  al. Ultrasound-guided injection of botulinum toxin type A for piriformis muscle syndrome: A case report and review of the literature. Toxins (Basel). 2015;7(8):3045–3056. 187. Gulledge BM, Marcellin-Little DJ, Levine D, et al. Comparison of two stretching methods and optimization of stretching protocol for the piriformis muscle. Med Eng Phys. 2014;36(2):212–218. 188. Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain. 2000;85(1-2):101–105. 189. Al-Al-Shaikh M, Michel F, Parratte B, Kastler B, Vidal C, Aubry S. An MRI evaluation of changes in piriformis muscle morphology induced by botulinum toxin injections in the treatment of piriformis syndrome. Diagn Interv Imaging. 2015;96(1):37–43. 190. Fishman LM, Anderson C, Rosner B. Botox and physical therapy in the treatment of piriformis syndrome. Am J Phys Med Rehabil. 2002;81(12):936–942. 191. Waseem Z, Boulias C, Gordon A, Ismail F, Sheean G, Furlan AD. Botulinum toxin injections for low-back pain and sciatica. Cochrane Database Syst Rev. 2011;1(1):CD008257. 192. Dezawa A, Kusano S, Miki H. Arthroscopic release of the piriformis muscle under local anesthesia for piriformis syndrome. Arthroscopy. 2003;19(5):554–557. 193. Benson ER, Schutzer SF. Posttraumatic piriformis syndrome: Diagnosis and results of operative treatment. J Bone Joint Surg Am. 1999;81(7):941–949.

431.e5

194. Kobbe P, Zelle BA, Gruen GS. Case report: Recurrent piriformis syndrome after surgical release. Clin Orthop Relat Res. 2008;466(7):1745–1748. 195. Balius R, Susín A, Morros C, Pujol M, Pérez-Cuenca D, SalaBlanch X. Gemelli-obturator complex in the deep gluteal space: An anatomic and dynamic study. Skelet Radiol. 2018;47(6):763–770. 196. Cox JM, Bakkum BW. Possible generators of retrotrochanteric gluteal and thigh pain: The gemelli-obturator internus complex. J Manipulative Physiol Ther. 2005;28(7):534–538. 197. Filler AG, Gilmer-Hill H. Piriformis syndrome, obturator internus syndrome, pudendal nerve entrapment, and other pelvic entrapments. In: Winn RH, ed. Youmans Neurological Surgery. Philadelphia: Elsevier Saunders; 2011:2447–2455. 198. Bano A, Karantanas A, Pasku D, Datseris G, Tzanakakis G, Katonis P. Persistent sciatica induced by quadratus femoris muscle tear and treated by surgical decompression: A case report. J Med Case Rep. 2010;4:236. 199. Girolami M, Tonetti L, Pipola V, et al. Quadratus femoris muscle causing deep gluteal syndrome: A rare cause of refractory sciatica of extraspinal origin in the presence of an anatomic variation. J Back Musculoskelet Rehabil. 2019;32(4):667–670. 200. Klinkert Jr P, Porte RJ, de Rooij TP, de Vries AC. Quadratus femoris tendinitis as a cause of groin pain. Br J Sports Med. 1997;31(4):348–349. 201. Bewyer D, Chen J. Gluteus medius tendon rupture as a source for back, buttock and leg pain: Case report. Iowa Orthop J. 2005;25:187–189. 202. Hoffman DF, Sellon JL, Moore BJ, Smith J. Sonoanatomy and pathology of the gluteus minimus tendon. J Ultrasound Med. 2020;39(4):647–657. 203. Reiman MP, Bolgla LA, Loudon JK. A literature review of studies evaluating gluteus maximus and gluteus medius activation during rehabilitation exercises. Physiother Theor Pract. 2012;28(4):257–268. 204. Chen B, Rispoli L, Stitik T, Leong M. Successful treatment of gluteal pain from obturator internus tendinitis and bursitis with ultrasound-guided injection. Am J Phys Med Rehabil. 2017;96(10):e181–e184. 205. Kamanli A, Kaya A, Ardicoglu O, Ozgocmen S, Zengin FO, Bayik Y. Comparison of lidocaine injection, botulinum toxin injection, and dry needling to trigger points in myofascial pain syndrome. Rheumatol Int. 2005;25(8):604–611. 206. Scott NA, Guo B, Barton PM, Gerwin RD. Trigger point injections for chronic non-malignant musculoskeletal pain: A systematic review. Pain Med. 2009;10(1):54–69. 207. Van Mieghem IM, Boets A, Sciot R, Van Breuseghem I. Ischiogluteal bursitis: An uncommon type of bursitis. Skelet Radiol. 2004;33(7): 413–416. 208. Akisue T, Yamamoto T, Marui T, et al. Ischiogluteal bursitis: Multimodality imaging findings. Clin Orthop Relat Res. 2003;406(406): 214–217. 209. Johnson DB, Varacallo M. Ischial bursitis. In: StatPearls [Internet]. StatPearls Publishing; 2020. Available at: https://www.ncbi.nlm. nih.gov/books/NBK482285/. 210. Hitora T, Kawaguchi Y, Mori M, et  al. Ischiogluteal bursitis: A report of three cases with MR findings. Rheumatol Int. 2009;29(4): 455–458. 211. Wisniewski SJ, Hurdle M, Erickson JM, Finnoff JT, Smith J. Ultrasound-guided ischial bursa injection: Technique and positioning considerations. PMR. 2014;6(1):56–60.

10 31

Facet Pain: Pathogenesis, Chapter Title to Go Here Diagnosis, and Treatment CHAPTER AUTHOR

STEVEN P. COHEN, JAVIER DE ANDRÉS ARES

Introduction (Importance of the Problem) Low back pain (LBP) and neck pain represent two of the five leading causes of medical disability worldwide. More than 75% of patients reporting spine pain are between 18 and 65 years old, thereby adding to the burden through lost productivity and wages.1 Although the prevalence of LBP varies greatly throughout the literature, some lifetime prevalence estimates are as high as 84%–90%.2,3 The five year recurrence rate of LBP may be as high as 69%.4 The lifetime prevalence rate of neck pain has been estimated to be approximately 67%.5,6 In 2016, LBP and neck pain expenditures were estimated at $134.5 billion, an increase of 44.4% from 2013.7

Anatomy and Function The spine is usually composed of seven cervical, 12 thoracic, and five lumbar vertebrae. The z-joints are paired structures situated posterolateral to the vertebral body. In conjunction with the intervertebral disk, they make up what is commonly known as “the three-joint complex.” Together, these joints support and stabilize the spine and prevent injury by limiting motion in all planes. The lumbar z-joints are diarthrodial synovial joints formed from the superior articular process of one vertebra and the inferior articular process of the vertebra above. The volume capacity of these joints is approximately 1–1.5 mL in the lumbar region and 0.5–1.0 mL in the cervical region.8 The articular surfaces are covered by hyaline cartilage and contain a fibrous capsule. The fibrous capsule is approximately 1 mm thick and forms mostly collagenous tissue arranged in a transverse fashion to provide resistance to forward flexion.9,10 The superior and inferior joint borders are formed by the fibrous capsule. There is also a small meniscoid structure inside the joint composed of connective tissue rim or adipose tissue.11 In the lumbar spine, the multifidus muscle serves as the posterior joint border, and the ligamentum flavum replaces the fibrous capsule at the anterior border.11,12 The position of the joint relative to the sagittal and coronal planes helps determine the role the joint plays in protecting the spine against excessive motion. Joints oriented parallel to the sagittal plane (e.g. upper lumbar spine) provide little resistance to backward and forward shearing forces, but limit excess rotation, flexion, and extension. Joints oriented closer to the coronal plane (e.g. thoracic spine and lower lumbar spine) will allow less rotation, flexion, and extension but protect against shearing 432

forces. The cervical z-joints are inclined at approximately 45° from the horizontal plane and angled 85° from the sagittal plane. This alignment prevents excessive anterior translation and assists the disks in weight bearing.12,13 The mamillo-accessory ligament (MAL) is a fibrous connective band that extends from the mammary process to the accessory process (Fig. 31.1).14 The importance of the MAL lies in the fact that they provide a fibrous tunnel through which the lumbar medial branch of the T12–L4 dorsal rami course.15 This protects the medial branch but may interfere with nerve anesthetization during medial branch blocks and neurotomy during radiofrequency ablation.16 The MAL can also become ossified, becoming a hypothetical source of medial branch entrapment, particularly at lower lumbar levels.17 The medial branch of the posterior rami supplies sensory and proprioceptive innervation to the facet joint. Each exiting spinal nerve splits into ventral and dorsal rami. The ventral ramus is the largest of the two branches and is the primary source of motor and sensory fibers. The posterior ramus divides into the lateral, intermediate, and medial branches. In the lumbar region, the lateral branch innervates the paraspinal muscles, thoracolumbar fascia, and sacroiliac joint, and supplies variable sensory fibers to the skin overlying the spinous processes. The small intermediate branch supplies the longissimus muscle. The medial branch is the largest branch of the posterior primary ramus and innervates the lumbar z-joint, multifidus muscle, interspinal muscle and ligament, and periosteum of the neural arch. Each medial branch gives rise to an ascending and a descending branch, innervating half of two adjacent z-joints.12 Therefore to block sensory input from a single z-joint, two adjacent medial branches must be anesthetized. Facet joints are imbued with rich innervation containing encapsulated (Ruffini-type endings, Pacinian corpuscles), unencapsulated, and free nerve endings.18 In addition to being a potential pain generator, the z-joint capsule is thought to serve in a proprioceptive capacity as well, as evidenced by the presence of low threshold, rapidly adapting mechanosensitive neurons. In addition to substance P and calcitonin gene-related peptide, a substantial percentage of nerve endings in the facet capsules contain neuropeptide Y, which is indicative of the presence of sympathetic efferent fibers.19 Nerve fibers have been found in subchondral bone and intraarticular inclusions of facet joints, thus signifying that facet-mediated pain may originate in structures besides the joint capsule.20 Inflammatory mediators, such as prostaglandins,21

 

CHAPTER 31

Facet Pain: Pathogenesis, Diagnosis, and Treatment

433

Primary ventral ramus

Primary dorsal ramus Lateral branch

Intermediate branch Inconsistent

MAL

Medial branch for L2-L3 ZAJ

Inferior articular branch for L3-L4 ZAJ

• Figure 31.1  L2 Schematic drawing of the branches of the L2 dorsal ramus. Note that the L2 medial branch participates in the innervation of L2-L3 z-joint and L3-L4 z-joints. MAL, Mamillo-accessory ligament; ZAJ, zygapophysial joint.

and the inflammatory cytokines interleukin-6 and tumor necrosis factor-α22 have been found in facet joint cartilage and synovial tissue in degenerative lumbar spinal disorders.23

Lumbar Facet Joints The lumbar facet joints are aligned laterally to the sagittal plane and vary in angle. In an anatomic study published in 1940 by Horwitz and Smith,24 the authors found that the L4–5 z-joints tended to be more coronally positioned (almost 70° with respect to the sagittal plane), whereas the L2–3 and L3–4 joints were likely to be oriented more parallel (3 months after MVA

Pts rec’d cervical MBB with 0.5 mL of either 2% lidocaine or 0.5% bupivacaine. Pts with positive block rec’d other agent. A (+) response required longer pain relief with bupivacaine.

27 pts had longer relief with bupivacaine than with lidocaine, for a 60% prevalence rate.

13 pts (27%) had a (+) response to both LAs but in excess of the expected duration. Average age, 41 years. Female-male ratio, 1:1. All but three pts involved in litigation.

Barnsley et al.123 1995

50 pts with chronic neck pain of >3 months duration after a whiplash injury from MVC

Pts rec’d cervical MBB with 0.5 mL of either 2% lidocaine or 0.5% bupivacaine at random. Pts with a (+) block rec’d the complementary anesthetic. A (+) response required longer pain relief with bupivacaine.

27 pts who completed the study met the criteria for a (+) painful joint, for a 54% prevalence rate.

Ten pts (20%) had longer pain relief with lidocaine than with bupivacaine or no pain relief with repeated blocks. Average age, 41 years. Female-male ratio, 1.5:1. C2-3 and C5-6 most frequently affected levels.

Lord et al.51 1996

68 pts with chronic neck pain of >3 months duration after a whiplash injury from MVA

Pts rec’d diagnostic C2-3 blocks to rule out those with third occipital headache. Placebo-controlled cervical facet blocks below C2-3 were done with 0.5 mL of either 2% lidocaine or 0.5% bupivacaine. If (−), other levels were then attempted. If (+), pts rec’d either NS or other LA at random and then had a third block with the remaining agent.

31 of 52 pts (60%) who completed the study had cervical facet pain at C2-3 or below, for a 60% prevalence rate. Among pts with HA as the dominant Sx, 50% prevalence of C2-3 facet joint pain. In pts without C2-3 facet pain, the prevalence of lower cervical facet pain was 49%.

Average age, 41 years. Female-male ratio, 2:1. C2-3 and C5-6 most commonly affected levels.

Manchikanti et al.124 2002

46 pts with chronic thoracic pain (>6 months) without neurologic Sxs

Pts rec’d MBB with 1% lidocaine followed by confirmatory blocks with 0.5% bupivacaine. A (+) response was ≥80% concordant pain relief.

22 of 36 pts with (+) lidocaine blocks had longer relief with confirmatory bupivacaine blocks, for a 48% prevalence rate.

FP rate, 58%. Average age, 46 years.

Manchikanti et al.125 2002

106 pts with chronic neck pain with or without HA or upper extremity pain

Pts rec’d diagnostic blocks with 0.5 mL of 1% lidocaine followed by 0.5 mL of 0.25% bupivacaine two weeks apart.

64 of 81 pts with (+) lidocaine blocks had longer relief with confirmatory bupivacaine blocks, for a 60% prevalence rate

40% FP rate. Mean age, 43 years. Female-male ratio, 2:1. 15% of pts had previous neck surgery.

Manchikanti et al.117 2004

500 pts with chronic neck, thoracic, and/or LBP without neurologic Sxs. 255 pts had cervical Sxs, and 72 pts had thoracic Sxs

Pts rec’d MBB with 1% lidocaine followed by confirmatory blocks with 0.25% bupivacaine. A (+) response was ≥80% relief lasting longer with bupivacaine. Minimum of two levels blocked based on pain patterns.

55% prevalence rate of cervical facet joints in pts with cervical spine pain. 42% prevalence rate of thoracic facet joints in pts with thoracic pain.

FP rate of 63% for cervical and 55% for thoracic MBB. Average age, 47 years. Female-male ratio, 2:1 for both cervical and thoracic.

Manchukondet al.119 2007

251 patients with chronic neck pain of at least six monthsduration. Nonspecific with no radicular component

1% lidocaine 0.25% bupivacaine 0.5 mL volume

Pain relief ≥80% with the ability to perform previously painful movements

Prevalence = 39% (32%–45%) FP rate= 45% (37%–52%)

Yin and Bogduk126 2008

84 patients with chronic neck pain of at least three months duration

4% lidocaine 0.75% bupivacaine 0.5 mL

100% pain relief with duration of response concordant with the anesthetic used

HA, headache; MVC, motor vehicle collision; MVA, motor vehicle accident; Sxs, symptoms.

 

CHAPTER 31

Facet Pain: Pathogenesis, Diagnosis, and Treatment

T4–T5

T6–T7

439

T3–T4 T5–T6 T7–T8

T8–T9 T9–T10

• Figure 31.4 

Pain referral patterns from the lumbar facet joints. The most common referral patterns extend from the darkest (low back) to the lightest regions (flank and foot) in descending order. The following key is listed in order of affected frequency (i.e. low back to foot). The facet levels next to each location represent the zygapophyseal joints most associated with pain in each region. Low back: L5-S1, L4-5, L3-4; buttock: L5-S1, L4-5, L3-4; lateral thigh area: L5-S1, L4-5, L3-4, L2-3; posterior thigh area: L5S1, L4-5, L3-4; greater trochanter: L5-S1, L4-5, L3-4, L2-3; groin: L5-S1, L4-5, L3-4, L2-3, L1-2; anterior thigh area: L5-S1, L4-5, L3-4; lateral lower leg area: L5-S1, L4-5, L3-4; upper back area: L3-4, L2-3, L1-2; flank: L1-2, L2-3; foot: L5-S1, L4-5. (Adapted from Cohen, SP, Raja SN. Pathogenesis, diagnosis, and treatment of lumbar zygapophysial facet joint pain. Anesthesiology. 2007;106:591–614.)

C2–C3

C3–C4

C2–C3

C3–C4 C5–C6

C5–C6

• Figure 31.5  Pain referral patterns from the cervical facet joints. (Adapted from Bogduk N, Marsland A. Cervical zygapophysial joints are a source of neck pain. Spine. 1988;13:615.)

tenderness on palpation is probably the only sign weakly indicative of facetogenic pain.157,158 This finding is likely because of sensitized musculature rather than actual strain on the facet joints. Despite the limited value of physical examination in diagnosing facet pain, many research studies and clinicians still rely on provocative maneuvers to select patients for facet interventions. A study showed that patients who responded to intraarticular injections were more likely to have back pain associated with groin or thigh pain, paraspinal tenderness, and reproduction of pain with

T10–T11 T12–L1

• Figure 31.6  Pain referral patterns from the thoracic facet joints. (Adapted from Dreyfuss P, Tibiletti C, Dreyer SJ. Thoracic zygapophysial joint pain patterns. A study in normal volunteers. Spine. 1994;19:809.)

extension rotation maneuvers.145 Pain radiating below the knee was a negative predictor. Larger and more methodologically sound studies have failed to validate “lumbar facet syndrome” or the provocative maneuver commonly known as “facet loading.” Prospective studies of patients with chronic LBP could not correlate any historical or physical findings associated with a positive response to facet injections.145,159 In both studies, only a small percentage (10% and 15%, respectively) of patients responded to diagnostic blocks. A randomized, placebo-controlled study of 80 patients with chronic LBP by Revel et al. found seven factors to be associated with response to facet joint anesthesia: age older than 65 years and pain not exacerbated by coughing, not worsened by hyperextension, not worsened by forward flexion, not worsened when rising from forward flexion, not worsened by extension rotation maneuvers, and well relieved by recumbency.112 However, subsequent investigations failed to corroborate these findings.160 Very few studies have investigated the history and physical findings most consistent with cervical and thoracic facet pain. One study found that a blinded therapist specializing in manipulation could correctly diagnose symptomatic cervical facet joint pain in patients with positive diagnostic cervical MBBs through the perceived passive displacement of the joint and its resistance to displacement.161 However, a subsequent study conducted using controlled blocks as the “gold standard” for cervical z-joint pain found that although manual examination had a sensitivity of 88%, low specificity (39%) precluded its use as a valid diagnostic tool.162 The majority of cervical facet prevalence studies have been conducted on whiplash victims, thereby making it difficult to draw conclusions in non-trauma patients. A Delphi study from an expert panel identified 12 indicators of lumbar joint pain. Those that reached the highest levels of consensus were a positive response to facet joint injection, localized unilateral LBP, positive medial branch block, paraspinal tenderness, absence of radicular

440

PA RT 4 Clinical Conditions: Evaluation and Treatment

features, pain eased by flexion, and pain, if referred, located above the knee.163 A study by Laslett found seven characteristics suitable for selecting patients for interventions involving the lumbar z-joints: 1) age 50 years or greater, 2) pain relieved when walking, 3) pain improved by sitting, 4) paraspinal pain predominance, 5) Modified Somatic Perception Questionnaire score exceeding 13, 6) positive extension rotation test, and 7) absence of centralization during repeated movement testing.53 Recently, a meta-analysis by Usunier et al. identified four clinical tests that predicted cervical facet joint pain: passive intersegmental motion testing; mechanical sensitivity; pain consistent with cervical zygapophyseal joint referral patterns; and, based on a single study, a positive extension rotation test.164 However, the sensitivity and specificity of these tests were poor.

Radiologic Findings The prevalence of facet joint disease observed on radiologic imaging is dependent on the age of patients, presence of symptoms, imaging modality, and threshold used for designating an examination as “abnormal.” In LBP patients, the prevalence of degenerative facet disease on computed tomography (CT) ranges from 40% in some studies165 to 85% in others.166,167 Studies comparing the sensitivity and specificity of MRI and CT in detecting facet degenerative changes are not uniform (Table 31.4).88,169,170 In a study of 14 patients with DDD, those younger than 40 years showed minimal osteoarthritic changes of the lumbar facets.88 The prevalence of facet pathology increased significantly in patients older than 60 years. In asymptomatic volunteers, the incidence of lumbar facet degeneration ranges from 8% to 14%.168,171,172 The use of radiologic imaging as a predictor of response to diagnostic facet blocks has been conflicting. Although some studies have found a positive association between CT, MRI, and other imaging modalities and response to facet blocks,165,173 an equal number have not.54,146,166,133,174 Recent studies have focused on newer imaging modalities.175,176,177 A study by Rosen showed a positive correlation between the severity of degenerative disk and facet disease on PET/ MRI using an 18-F FDG radiotracer.178 However, Lehman and Diehm more recently demonstrated poor concordance between peri-facet joint signal changes and facet joint pain.179 In a study by Yolcu and Lehman comparing hybrid imaging techniques (PET/ CT, PET/MRI, and single-photon emission computed tomography [SPECT]/CT) to evaluate back and neck pain because of suspected z-joint arthropathy, the authors concluded that while they are promising, increased radiation exposure and higher costs must be considered.180 In summary, the literature does not support the routine use of radiologic imaging as a means of diagnosing facet pain. The lack of an association between imaging findings and facet joint pain is consistent with other musculoskeletal pain disorders such as knee and hip osteoarthritis.181,182,183

Diagnostic Blocks The poor correlation between historical, radiologic, and physical examination findings and zygapophyseal pain has led to widespread acceptance of the use of diagnostic blocks to confirm facet joints as primary pain generators.184 Although MBB and intraarticular injections are widely touted to be equally effective diagnostic tools,185 the evidence for this claim is based on two studies, neither of which used a crossover design, controlled blocks, or prescreened patients for

z-joint pain.148,186 Several factors undermine the diagnostic validity of MBB. In a cadaveric study done in the late 1930s, Kellegren showed that injection of 0.5 mL of fluid spread into an area encompassing 6 cm2 of tissue.187 Cohen and colleagues demonstrated that reduction in LA volume in cervical MBBs from 0.5 to 0.25 mL decreased aberrant spread to other potential pain generators, including spread to the intervertebral foramen, by over 50%.188 Because of the short distance between branches of the dorsal rami, even low-volume medial branch blocks are likely to block the lateral and intermediate branches. Since these nerves supply afferent innervation to multiple potential pain-generating structures, including the paraspinal muscles, ligaments, sacroiliac joints, and skin, MBB can relieve pain even in the presence of non-pain-generating z-joints. False positive rates have been reported to be as high as 63% in the cervical region, 53% in the thoracic region, and 27% in the lumbar facet region.117 However, the higher prevalence (true positive) rates in the neck and midback should theoretically result in a lower false-positive rate. False negative responses are also a concern as they can limit access to care and result from intravascular uptake of the LA, procedure-related pain, and failure of patients to distinguish between pain from the procedure and their baseline pain. Considering the low sensitivity of aspiration and intermittent fluoroscopy, some advocate using “realtime” fluoroscopy to detect intravascular uptake during MBB.189 Although intraarticular facet injections may be more theoretically accurate in diagnosing facet pain, these blocks can be technically challenging and fraught with limitations. Injection of >2 mL of fluid can rupture the joint capsule and lead to extravasation of LA onto other pain-generating structures, leading to false positive blocks. Depending on the point of extravasation, these structures can include the epidural space, intervertebral foramen, ligamentum flavum, and paraspinal musculature.68,149

Medial Branch Block Versus Intraarticular Injection The argument supporting a prognostic procedure that targets the nerves rather than the joints themselves is supported by a multicenter case-control study demonstrating better radiofrequency ablation outcomes in patients who undergo medial branch blocks rather than intraarticular injections.190 A study by Ackerman and Ahmad randomized 46 patients with axial LBP and a positive SPECT scan to receive either intraarticular injections or MBB using 0.7 mL of LA and steroid. Twelve weeks after treatment, 61% of the intraarticular injection group experienced a positive outcome, which favorably compared with 26% in the MBB group.191 It is difficult to draw conclusions based on these comparative studies because of the multitude of design flaws. The most prominent ones are the lack of a definitive diagnosis in the study populations and that only one study186 evaluated immediate post-procedure pain relief. Studies investigating the prevalence and false positive rates in chronic LBP patients (Table 31.2) have generally found comparable diagnostic values for MBB and intraarticular injection. None of the three placebo-controlled studies evaluating the outcome of lumbar RF denervation after intraarticular injections to “confirm” the presence of facetogenic pain demonstrated definitively positive outcomes.192,–194 In contrast, most studies that screened patients with lumbar MBB demonstrated a primary positive outcome.195 In a prospective, randomized study comparing lumbar facet cryodenervation success rates between patients who underwent medial branch and pericapsular lumbar facet screening blocks, Birkenmaier and associates196 found superior outcomes up to six months after the procedure in the MBB group. However, the excessive volumes used during both diagnostic procedures, the absence of

 

CHAPTER 31

Facet Pain: Pathogenesis, Diagnosis, and Treatment

441

TABLE Prospective Clinical Trials Evaluating Intraarticular Steroid Injections for Lumbar and Cervical Facet 31.4 Joint Pain

Authors, Year, Methodology Score

Patients and Interventions

Results

Comments

97 pts with chronic LBP who reported immediate relief after injections of 2 mL of steroid and saline (n = 49) or saline ( n = 48) into the L4-5 and L5-S1 lumbar z-joints.

42% of pts who received steroids and 33% who rec’d placebo reported marked improvement for up to three months (not significant). At six months, the steroid group reported less pain and disability. Only 22% of pts in the steroid group and 10% in the placebo group had improvement through six months.

Differences between groups at six months reduced when co-interventions were taken into account. NS is known to provide pain relief greater than that expected from a placebo.

Marks et al.149 1992; MQ score = three

86 pts with chronic LBP were randomized to receive either 1.5 mL of steroid and LA MBB or intraarticular injections (2 mL at the lowest level).

Pts who rec’d facet joint injections had better pain relief than did those who underwent MBB at all follow ups, but this was significant only at one month.

Flaws include no true control group, failure to identify pts based on diagnostic injections, no monitoring of co-interventions, and lack of a blinded observer.

Barnsley et al.221 1994; MQ score = five

41 pts with chronic neck pain following MVA were randomized and received an injection of either 1 mL of 0.5% bupivacaine or 5.7 mg of betamethasone into painful cervical z-joints diagnosed by comparative LA MBB.

Less than half the pts reported relief for more than one week, and fewer than one in five reported relief for more than one month. The median time to return of 50% of the preprocedure pain was three days in the steroid group and 3.5 days in the LA group.

All pts had neck pain following a whiplash injury. Some pts with long-lasting benefit in both groups.

Fuchs et al.218 2005; MQ score = one

60 pts with chronic LBP were randomized to either 1 mL of HA or steroid into the three lowest facet joints at weekly intervals for six weeks.

Pts who rec’d HA injections experienced a 40% decrease in pain scores vs. a 56% reduction in those who rec’d steroid (not significant). The greatest pain reduction was observed after three months in the HA group and after one week in the steroid group.

Inclusion criteria included at least moderate facet degeneration on radiologic imaging. Flaws include lack of a control group, failure to identify pts based on diagnostic injections, no monitoring of cointerventions, and multiple injections.

Pneumaticos et al.222 2006; MQ score = three

47 pts with chronic LBP and radiologic evidence of lumbar z-joint abnormalities were randomized in a 2:1 ratio to undergo intraarticular LA and steroid injections (3 mL) based on SPECT scans or physical examination.

One month after injection, 87% of pts with (+) SPECT had significant pain improvement vs. 12.5% of pts with (−) SPECT and 31% of pts who underwent injections based on physical examination.

Differences remained significant at three months but not six months. No functional assessment was done. The use of SPECT was cost effective.

Kennedy et al.225 2018; MQ score = three

28 subjects with confirmed z-joint pain via dual comparative medial branch blocks were randomized to receive either intraarticular corticosteroid (triamcinolone 20 mg) or saline via fluoroscopic guidance.

There was no statistically significant difference in the need for radiofrequency ablation between groups, with 75% of the saline group and 91% of the corticosteroid group receiving neurotomy. No difference was observed in the mean time to radiofrequency neurotomy between saline (6.1 weeks) and corticosteroid (6.5 weeks) groups.

Corticosteroid injections into the lumbar z-joints were not effective in reducing the need for radiofrequency neurotomy in those with z-joint pain confirmed by medial branch blocks.

Cohen, et al.1052018; MQ score four

229 patients were randomized in a 2:2:1 ratio to receive intraarticular facet injections with LA and steroid, medial branch blocks with LA and steroid, or saline.

Mean reduction in average numeric rating scale pain score at one month was 0.7 ± 1.6 in the intraarticular group, 0.7 ± 1.8 in the medial branch block group, and 0.7 ± 1.5 in the placebo group; P = 0.993. The proportion of patients with positive blocks was higher in the intraarticular (54%) and medial branch (55%) groups than in the placebo group (30%; P = 0.01). Radiofrequency ablation was performed on 135 patients (45, 48, and 42 patients from the intraarticular, medial branch, and saline groups, respectively). The mean reduction in average pain score at three months was 1.8 ± 2.3 in the intraarticular, 1.8 ± 2.4 in the medial branch, and 0.7 ± 1.5 in the control group (P = 0.025). At three months, the proportions of positive responders in the intraarticular, medial branch block, and placebo groups were 51%, 56%, and 24%, respectively (P = 0.005).

This study establishes that facet blocks are not therapeutic. The higher responder rates in the treatment groups suggest that facet blocks might provide prognostic value before radiofrequency ablation.

Carette et al. score = five

220

1991; MQ

The methodologic quality (MQ) score is based on the five point Jadad scale.223 A score of three or higher indicates high methodologic quality. HA, Hyaluronic acid; LA, local anesthesia; LBP, low back pain; MBB, medial branch block; MVA, motor vehicle accident; NS, normal saline; pts, patients; rec’d, received; SPECT, single-photon emission computed tomography; z-joint, zygapophyseal (facet) joint.

442

PA RT 4 Clinical Conditions: Evaluation and Treatment

controlled blocks, and the lack of proven validity for pericapsular injections detract from the authors’ conclusions. The most recent randomized study published in 2018 by Cohen et al.105 compared the therapeutic and prognostic value of intraarticular blocks and medial branch blocks performed with bupivacaine and steroids and sham injections. Among patients in the intraarticular and medial branch block groups who experienced a positive block but failed to derive long-term (≥3 months) relief, radiofrequency ablation was performed. In the sham group, radiofrequency ablation was performed in all non-responders. The authors determined that the strongest factor associated with a positive radiofrequency ablation outcome was a positive outcome from a true diagnostic block, with medial branch and intraarticular injections having comparable prognostic value. The difference in radiofrequency ablation outcomes between the treatment groups and the control group was small but statistically and clinically meaningful. Finally, the authors found no meaningful benefit at one month or subsequent time points between either of the true injections and the placebo. Intraarticular injections can be technically challenging, especially in the steep, frontally oriented thoracic facet joints.197 In addition, MBB involves anesthetization of the nerves to be lesioned and hence may serve as a “dry run” before definitive treatment, similar to performing a selective nerve root block before surgical decompression. Multiple guidelines, including those by the 14 participating federal and international organizations,185 have endorsed lumbar medial branch blocks but not intraarticular injections based on face validity,107 target-specificity,24 and construct validity,198 as a selection tool for medial branch neurotomy.150 Given the lack of evidence for intraarticular injections as a superior diagnostic tool and the technical ease of performing MBB, MBB is recommended as the prognostic tool of choice for subsequent medial branch denervation.

False Positive Blocks Numerous studies have found a high false positive rate for diagnostic facet blocks that appear unaffected by the type of block used (i.e. intraarticular or MBB). Published rates have ranged from 25% – 40% in the lumbar spine,114,117,185,198 58% in the thoracic spine,124 and 27%–63% in the cervical spine.47,117,125,161,199 A study showed high specificity and marginal sensitivity of serial local anesthetic cervical MBBs with lidocaine and bupivacaine.200 Although high specificity will result in a low false positive rate, the low sensitivity predisposes patients to false negative diagnoses, thereby reducing access to care. Reasons for false positive facet blocks are multifactorial and include a placebo response (18%–32%) to diagnostic interventions, use of sedation, liberal use of superficial LA, and spread of injectate to other pain-generating structures.201 The International Facet Joint Guidelines Committee,185 the American Society of Anesthesiologists,202 and the Spine Intervention Society203 all recommend against the routine use of sedation. Dreyfuss et al. used postprocedural CT scans following 120 fluoroscopically guided lumbar MBBs to assess the specificity and spread of contrast material.31 Two target points were chosen: one at the superomedial border of the transverse process and a second lower site midway between the upper border of the transverse process and the MAL. In 16% of injections, contrast material was noted to spread into the intervertebral foramen or epidural space, which was more common at the upper target point. In all cases, distal spread into the cleavage plane between the multifidus and longissimus muscles was noted. The injectate volume (0.5 mL) bathed the target

in every case, leading the authors to conclude that lower volumes may be adequate. In a study of 24 patients undergoing cervical MBB, Cohen et al. investigated the spread of LA (0.5 mL versus 0.25 mL) mixed with contrast agent.188 MBBs were performed in either the prone or lateral position. CT scans were conducted following MBBs to assess aberrant spread. Blocks performed in the 0.25 mL group resulted in aberrant spread to untargeted adjacent levels and into the intervertebral foramina less than half as often as those in the 0.5 group. There were six “missed” medial branches in the 86 blocks performed, which were evenly distributed between the groups. These findings indicate that lower volumes may enhance specificity without affecting sensitivity. To reduce the amount of superficial anesthetic used for MBB, Stojanovic et al. introduced a single-needle technique whereby multiple medial branches are blocked via a single skin entry point.204 In a prospective crossover study comparing the single-needle and conventional multiple-needle techniques, the authors found that the single-needle technique required significantly less superficial LA, resulted in less procedure-related pain, and was faster to perform than the multiple-needle approach.205 With regard to the final needle position, spread of contrast material, and postprocedural pain relief, no differences were noted between the two techniques.

False Negative Blocks Similar to false positive blocks, false negative blocks may result from many factors. The prevalence of false negative blocks can never be known for certain in the absence of a pathognomonic reference standard, but in a retrospective study by Derby et al.,206 the false negative rate (determined by a subsequent positive block using 70% pain relief as the cutoff) was 47% in individuals who obtained 75% success rate) than those with no SPECT findings (50% relief after two MBBs to continuous RF or pRF. Although no significant differences between groups were found at the three month follow up, a comparison of within-group differences revealed greater improvements in pain and disability in conventional RF patients. This study was underpowered to detect between-group differences. In the second study, Tekin et al.252 randomized 60 patients with a positive response to a single MBB to either sham RF (LA only), pRF, or continuous RF. All groups, including the LA only group, showed improvements in pain and disability. However, the magnitude of improvement and duration of benefit was significantly greater in the continuous RF group. A randomized, double blind study was conducted by Çetin et al.253 comparing continuous radiofrequency neurotomy to pRF in 118 patients with injection-confirmed lumbar facet joint pain. The authors found that continuous radiofrequency was superior to pRF in both the short and long term for pain reduction and satisfaction. In summary, the current state of evidence does not support pRF in the treatment of facet joint pain.

Radiofrequency Denervation (see also Chapter 66 Radiofrequency Treatment) Although percutaneous rhizotomy was first described by Rees in 1971,255 the technique of percutaneous RF lesioning is generally credited to the neurosurgeon Norman Shealy.256,257 For lumbar facet RF denervation, most studies report sustained relief in 50%–80% of patients without previous back surgery,158,258 whereas 35%–50% of subjects with failed back surgery syndrome obtain prolonged relief.158,259–261 In the only study comparing outcomes of cervical z-joint denervation in operated and non-operated spines, Cohen et al. found no difference in success rates between patients with failed neck surgery syndrome and those who had never undergone surgery.157 Reasons by which prior surgery might predispose patients to treatment failure include altered anatomy, greater baseline disease burden including opioid use, and a higher incidence of false positive diagnostic blocks.185

Lumbar Radiofrequency Neurotomy Several randomized and numerous uncontrolled studies have evaluated the effectiveness of lumbar and cervical radiofrequency neurotomy and reported variable results. These studies are summarized in Table 31.5. A key flaw in many studies is the failure to select patients based on placebo-controlled or even comparative LA blocks, which are now acknowledged to be inferior to placebo controls. Although double blocks are often impractical and will inevitably result in a lower overall success rate with a higher total cost, elimination of “false positive” responders is ideal for studies that seek to establish

Facet Pain: Pathogenesis, Diagnosis, and Treatment

445

efficacy. Because the anatomy of the lumbar spine makes it more difficult to position electrodes to create large lesions that enhance the likelihood of capturing the target nerve, practitioners should ideally insert the cannulas at a sharp cephalad-medial angle so that they are situated near parallel to the medial branches. In most randomized trials evaluating lumbar facet RFA, electrode positioning was suboptimal, including the Leclaire,193 Gallagher,192 van Kleef,195 van Wijk194, and MINT studies.262 However, some may construe these findings as evidence that RF denervation is a fundamentally flawed treatment. A more plausible interpretation is that they indicate a strong need to optimize RF denervation techniques and better identify candidates likely to obtain positive outcomes. Among randomized studies, those that have employed more stringent selection criteria (i.e. lower enrollment rates) and utilized optimal lesioning strategies are more likely to report positive outcomes.

Thoracic Radiofrequency Neurotomy As noted above, an older observational study performed in 40 patients reported an 83% success rate for thoracic medial branch RFA at a mean follow up of 31 months.263 Other small, retrospective studies have reported success rates of 40% and 68% at variable follow ups. The main challenge with thoracic facet RFA is the highly variable locations of the thoracic medial branches.41 This is one reason aggressive lesioning strategies such as bipolar RFA, cooled RFA, and creating multiple lesions have been advocated.264,265 Cervical Radiofrequency Neurotomy Only three randomized, double blind trials have evaluated percutaneous RF denervation for cervical facet pain (Fig. 31.7). Lord et al. randomized 24 patients with whiplash injury following an MVA and a positive response to diagnostic, placebo-controlled cervical MBB to receive either cervical medial branch denervation or a sham procedure.129 Patients with pain stemming solely from the C2-3 z-joint were excluded. A series of three blocks were performed to diagnose cervical facet pain, including a placebo block. A block was deemed positive if the patient had complete, concordant relief each time an LA was used but no relief with saline. At each level, two to three lesions were created. The mean time for a return to 50% of baseline pain was 263 days in the RF group and eight days in the placebo group. At 27 weeks, seven patients in the RF group and one patient in the control group remained pain free. Five of the patients in the RF group had numbness in the territory of the treated nerves, but none considered it troublesome. In a 2004 study, Stovner et al.266 randomized 12 patients in whom cervicogenic headache was diagnosed based on clinical symptoms to receive either cervical facet RF denervation or a sham procedure. Although the authors performed medial branch and greater occipital nerve blocks, the results were not used to select patients. The study was halted early secondary to the failure to enroll the subjects. At the three month follow up, four of six patients in the RF denervation group obtained a meaningful clinical response versus two of six patients in the sham group. At six months, no differences were noted between the groups. The results of sham denervation in this study are comparable to those of a previous uncontrolled study that evaluated RF for cervicogenic headache in which patients reported a 34% reduction in symptoms.267 In 2021, van Eeerd et al. randomized 76 patients to cervical MBB with bupivacaine and sham RFA or medial branch RFA. Patients were selected based on clinical presentation and radiographic findings, without prognostic blocks. Through 6-month follow-up, the benefits favoring the RFA group for pain and patient global impression of change did not significantly differ from the MBB

446

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE Outcomes Studies Assessing Medial Branch Radiofrequency Denervation for Lumbar, Thoracic, and Cervical 31.5 Facet Joint Pain

Study, Year

Number and Type of Patients

Gallagher et al.192 1994

41 pts with chronic LBP who obtained “clear-cut or equivocal” relief from single intraarticular facet joint injections with LA and steroid. 18 pts with a good response and six pts with an equivocal response underwent RF denervation. 12 pts with a good response and five with an equivocal response underwent sham denervation.

Lord et al.51 1996

Follow Up Period and Methodologic Scores

Results

Comments

• Six months • MQ = 2 • CR = 6

Significant differences in pain scores were noted only between patients with a good response to LA blocks who underwent true RF denervation (n = 18) and those with a good response who underwent sham treatment (n = 12) through six months.

Did not define “good” or “equivocal” response. Anatomic landmarks were not well described. Observers were not blinded. Electrode not placed parallel to the nerve. In “Methods” stated that only LA was used, but in abstract stated that LA and steroids were used

24 pts (12 per group) with chronic neck pain after MVA. Included pts with a (+) response to placebo-controlled diagnostic blocks. Randomized to undergo true RF at 80°C for 90 s or 37°C (placebo treatment) between C3 and C7 according to response to diagnostic blocks.

• Three months (12 months in pts with persistent relief) • MQ = 5 • CR = 8

The mean time to return 50% of preoperative to pain was 263 days in the RF group and eight days in the placebo group. At 27 weeks, seven points in the RF group and one in the control group remained pain free.

Excluded pts with solely C2-3 facet pain. Five pts in the RF group reported numbness in the territory of treated nerves.

van Kleef et al.195 1999

Subjects were 31 pts with chronic LBP who obtained ≥50% pain relief after a single MBB (one dropout). Compared true denervation with sham.

• 12 months • MQ = 5 • CR = 8

After three months, nine of 15 pts in the lesion group vs. four of 16 in the sham group had ≥50% pain relief. At one year f/u, seven of 15 in the lesion group and two of 16 in the sham group had ≥50% relief.

Used 0.75 mL of injectate for diagnostic blocks. Electrode not placed perpendicular to the target nerve. Used multifidus rather than sensory stimulation to identify the medial branch. Used 60 s lesions.

Leclaire et al.193 2001

Subjects were 70 pts with chronic LBP who obtained “significant” pain relief lasting >24 h after a single intraarticular facet injection of lidocaine and steroid (four dropouts). Compared true denervation with sham.

• 12 weeks • MQ = 4 • CR = 8

At four weeks, there were modest improvements in Roland-Morris (P = 0.05) and VAS (P = NS) pain scores, but not the Oswestry score. No difference in any outcome measure at 12 weeks.

Did not define “significant pain relief” with diagnostic injection. Inclusion criterion of >24 h pain relief is inconsistent with the pharmacology of lidocaine. Performed two lesions, each for 90 s. Anatomic landmarks not noted. Electrode not placed parallel to the nerve.

Stovner et al.266 2004

12 pts with unilateral cervicogenic HA received comparative LA blocks and a greater occipital nerve block. Randomized to cervical facet RF or sham procedure.

• 24 months • MQ = 4 • CR = 7

At three months, four of six RF pts had a meaningful clinical response (≥30% improvement), as did two of the six in the sham group. Six months after the procedure, no differences were noted between groups.

The RF group had a better response to diagnostic blocks. Able to recruit only 12 pts in 2.9 years. Excluded pts with ongoing litigation. Diagnostic blocks were not used to select RF patients.

Van Wijk et al.194 2005

81 pts with chronic LBP who obtained ≥50% pain relief after two-level intraarticular facet injection of LA (no dropouts). Compared true denervation with sham.

• 12 months • MQ = 5 • CR = 7

No significant difference at three months for combined outcome measure (pain score, physical activity, and analgesic intake). The global perceived effect was greater in the treatment group at three months.

Improvement in pain scores persisted throughout the 12 month f/u. Used 60 s lesions.

 

CHAPTER 31

Facet Pain: Pathogenesis, Diagnosis, and Treatment

447

TABLE Outcomes Studies Assessing Medial Branch Radiofrequency Denervation for Lumbar, Thoracic, and Cervical 31.5 Facet Joint Pain­—cont’d

Study, Year Tekin et al.

Number and Type of Patients

Results

Comments

60 chronic LBP pts with ≥50% relief from a single MBB at either L1-3 or L3-5 received either sham, pulsed RF, or RF denervation.

• 12 months • MQ = 4 • CR = 8

Continuous RF was better than pulsed RF and sham for pain. No significant difference between sham and pulsed RF. Regarding improvement in disability, continuous RF and pulsed RF were better than sham.

Used 0.3 mL diagnostic MBBs. The proper technique was used for MBB and RF.

Nath et al.243 2008

40 pts with chronic LBP with ≥80% relief from three LA facet blocks.

• Six months • MQ = 4 • CR = 6

RF group fared better than the control group for all outcome measures, though benefits were modest.

40 of the 376 screened were randomized. Created six empirical lesions without stimulation.

Civelek et al.271 2012

100 patients with LBP were randomized to receive a medial branch block or radiofrequency neurotomy.

• 12 months • MQ = 2 • CR = 4

Medial Branch block was more effective at one month than radiofrequency, but at six and 12 months, RFA pts had better results.

Myriad methodologic flaws including lack of blinding, suboptimal RF technique, and lack of prescreening with diagnostic MBB.

Lakemeier et al.242 2013

56 patients with axial LBP were randomized in a double blind fashion to intraarticular steroids with sham RFA or medial Branch RFA.

• Six months • MQ = 1 • CR = 4

Both intraarticular and RFA groups improved with no significant differences between them.

Methodologic flaws in the study included intraarticular block rather than MBB screening; suboptimal RFA technique; permitted analgesic cointerventions.

Moussa et al.272 2016

A prospective randomized controlled trial where 120 patients with injectionconfirmed lumbar facet joint pain were randomly divided into three groups: radiofrequency coagulation of the facet joint capsule, radiofrequency denervation of the medial branches, and sham radiofrequency lesioning.

• Three years • MQ = 4 • CR = 8

Both RF groups > control group. RF of the facet joint capsule = RF of the medial branches through 1-year, but superior to RF of the medial branches after one year.

Use of RFA not validated for capsular denervation. All groups also received a local anesthetic and steroid injection. Two lesions were created in the capsule, three along the medial branches. Used small electrodes with a short heating time.

Van Tilburg e al.273 2016

A randomized placebocontrolled double blind multicenter trial was performed in 60 patients with chronic LBP. The active group was treated with radiofrequency and the sham with lidocaine and placebo RFA.

• Three months • MQ = 4 • CR = 6

No difference between groups.

Required less than 50% pain relief for a positive block; 79% of blocks positive. Suboptimal technique (perpendicular electrode orientation, short heating time). Permitted co-interventions.

Juch et al.262 2017

The MINT study consisted of three pragmatic multi-center, nonblinded randomized clinical trials that evaluated the effectiveness of RFA treatments for participants with chronic LBP. The facet joint trial contained 251 participants.

• 12 months • MQ = 3 • CR = 6

Radiofrequency denervation combined with a standardized exercise program resulted in no clinically important improvement in chronic LBP compared with a standardized exercise program alone.

Myriad flaws included >70% positive rate for diagnostic blocks, that patients with a negative block in one study proceeded to blocks for another study, permitted psychological and exercise co-interventions, and suboptimal technique.

252

2007

Follow Up Period and Methodologic Scores

Continued

448

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE Outcomes Studies Assessing Medial Branch Radiofrequency Denervation for Lumbar, Thoracic, and Cervical 31.5 Facet Joint Pain­—cont’d

Study, Year

Number and Type of Patients

Kennedy et al.225 2018

This double blind, controlled trial randomized 24 patients to receive intraarticular corticosteroid (triamcinolone 20 mg) or saline via fluoroscopic guided injection.

Cohen et al.105 2018

This multi-center randomized study randomized 229 patients in a 2:2:1 ratio to receive intraarticular facet injections with bupivacaine and steroid, medial branch blocks, or saline.

Follow Up Period and Methodologic Scores

Results

Comments

• Six weeks • MQ = 4 • CR = 8

Corticosteroid injections into the lumbar facet joints were ineffective in reducing the need for radiofrequency neurotomy of the medial branches in those with facet joint pain confirmed by comparative medial branch blocks.

Pain scores and function were not recorded. Diagnostic MBB was performed with 0.2 mL.

• Three months • MQ = 5 • CR = 9

No long-term benefit for intraarticular steroids or MBB. Individuals who received MBB or IA injections had a greater reduction in pain after RFA.

This study confirmed the lack of long-term efficacy for intraarticular and medial branch facet blocks but supports their use as prognostic tools.

The methodologic quality (MQ) score was based on the five point Jadad scale.223 A score of three or greater indicates high methodologic quality. The clinical relevance (CR) score was based on patient selection parameters and description of the RF technique (zero to nine scale) as described by Geurts and colleagues. 319 f/u, Follow up; HA, headache; LA, local anesthetic; LBP, low back pain; MBB, medial branch block; MVA, motor vehicle accident; NS, not significant; pts, patients; rec’d, received; RF, radiofrequency; VAS, visual analog scale.

• Figure 31.7  Lateral

view of obliquely-placed electrodes targeting the cervical medial branches. Note that the electrodes are inserted in a cephalad direction in the center of the articular pillar, after which they may be adjusted based on stimulation parameters. MB, Medial branch.

group, but the benefits lasted longer (median duration of benefit 42 vs. 12 months).268 In an open-label prospective study comparing cervical z-joint RF results between litigant and non-litigant patients with whiplash injuries, Sapir and Gorup found no significant differences between groups in one year outcomes.269 Potential reasons for limited RF success rates for chronic neck pain and cervicogenic headache include technical difficulty denervating the frequently affected C2–3 facet joint, concomitant sources of head pain, and lack of specificity for diagnostic injections. As noted above, the higher pre-test probability of neck pain arising from the

facet joints (i.e. lower false positive rate and higher false negative rate) and a greater likelihood of nerve capture during RFA (electrodes can be placed parallel to the nerve in a smaller area) have led some investigators to forego any diagnostic blocks. As a prelude to their randomized, controlled trial that did not utilize prognostic blocks, van Eerd et al.270 performed a retrospective review of 65 patients who underwent a modified posterolateral RFA procedure based solely on clinical findings. The rationale for performing RFA without a diagnostic block is based on 1) the lower false positive rate in the cervical spine because of a higher prevalence rate of facetogenic pain in individuals with neck pain than in those with LBP; 2) the lower variability in location for the cervical than the lumbar medial branches; and 3) the greater ease in targeting them with electrodes oriented parallel. The authors reported a 55% success rate at the two month follow up. However, in their follow up sham-controlled trial using the same approach, the authors found no significant differences between the group that received RFA and those who received medial branch blocks and placebo RFA, through with both groups achieving >50% success rates.268 Outcome studies on cervical radiofrequency denervation are summarized in Table 31.5.271–273

Use of Neurostimulation Generally, a threshold of 0.5 V or less is deemed sufficient to create a lesion that encompasses the target nerve, although the margin of error can be increased using techniques that enhance lesion size. Although sensory stimulation may indicate close proximity to the target nerve at this voltage, many patients perceive concordant stimulation at 0.5 V or less even when the electrode is purposefully placed in muscle, as during a sham procedure. In a prospective study involving 61 patients, Cohen and colleagues274 found no correlation between the mean sensory threshold and lumbar RF denervation outcomes. Although one might construe this to mean that sensory stimulation is not necessary, it should be emphasized

 

CHAPTER 31

that sensory thresholds in these patients were recorded only after repeated electrode adjustments. In addition to nerve proximity, other factors that can affect sensory stimulation include age, sex, inherent pain perception, analgesic therapy, the use of sedation, and the presence of comorbidities such as diabetes. An alternative or complement to sensory stimulation in the lumbar and cervical spine regions is to elicit multifidus or other paraspinal muscle contraction since the medial branch that innervates the lumbar facet joint also supplies this paraspinal muscle. The 2020 International Lumbar Facet Joint guidelines185 provided a grade C recommendation for sensory stimulation and a grade B recommendation for motor stimulation. In the cervical spine, there is a reported case of permanent head drop in a patient who underwent bilateral cervical medial branch RFA without the use of motor stimulation.275

Meta-analysis on Radiofrequency Denervation Several meta-analyses of radiofrequency denervation have reached different conclusions. A meta-analysis published in 2014 by Poetscher et al.276 concluded that RFA of lumbar facet joints was more effective than placebo and possibly more effective than steroid injections. A 2015 Cochrane systematic review by Maas et al.277 concluded that there was no high quality evidence suggesting that RF denervation provides pain relief or functional improvement in patients with chronic LBP. They also found that the quality of evidence for RF denervation in chronic LBP ranged from very low to moderate. In 2017, a meta-analysis by Lee et al.278 concluded that conventional radiofrequency denervation resulted in significant reductions in LBP originating from the facet joints in patients with a positive response to diagnostic blocks over 12 months when compared with sham procedures or epidural nerve blocks. Manchikanti et al. performed several systematic reviews evaluating cervical279 and lumbar280 facet radiofrequency denervation. In the cervical spine, the authors concluded that there was level II for the long-term effectiveness of radiofrequency neurotomy. In the lumbar area, they found moderate evidence supporting radiofrequency neurotomy for chronic LBP. Another comprehensive systematic review published by Schneider281 in 2019 sought to determine the effectiveness of lumbar medial branch thermal radiofrequency neurotomy based on different selection criteria and procedural techniques. The authors found that the best outcomes were achieved when patients were selected based on high degrees of pain relief from dual medial branch blocks, using a technique employing parallel electrode placement.

Factors Associated With Outcome In a multi-center study, Cohen et al. identified factors associated with successful RF treatment in 192 patients who underwent lumbar facet denervation after a single positive MBB.158 Among the 15 variables analyzed, only paraspinal tenderness was found to predict successful treatment. Factors associated with failed treatment included increased pain with hyperextension and axial rotation (i.e. facet loading), duration of pain, and previous back surgery. The latter two variables have been associated with treatment failure for RF denervation and a host of other LBP interventions including epidural steroid injections and surgery.282–284 A study performed on the cervical spine by the same group of investigators found similar results. The only variable associated with a positive outcome was paraspinal tenderness. Factors associated with a negative outcome included opioid use, radiation to the occiput, and pain worsened by extension rotation maneuvers.157 Streitberger et al.285 performed a prospective study in 275 individuals and found that depression was associated with a shorter duration of benefit after lumbar medial

Facet Pain: Pathogenesis, Diagnosis, and Treatment

449

branch RFA. In a retrospective study involving 111 people by Conger et al.,286 the authors found that a larger Cobb angle and older age foretold lumbar medial branch RFA treatment success. More recently, Cohen et al.287 performed a prospective observational study in 318 patients to determine predictors of treatment results for minimally invasive low back interventions in general, including medial branch RFA. They found that older age, shorter duration of pain, lower baseline pain scores and functional disability, absence of secondary gain, absence of concomitant pain and psychiatric conditions, and having less non-organic (Waddell) signs were associated with treatment success. A negative correlation between Waddell signs and facet treatment outcomes was previously reported by Lilius et al.219 for lumbar facet intraarticular steroid injections.

Repeating Radiofrequency Denervation When pain returns following RF denervation, which typically occurs between six months and one year, neurotomy can be repeated with similar efficacy.288,289 In the cervical spine, the success rate for repeated RF denervation may be slightly higher than that in the lumbar spine. One systematic review reported a 59% success rate for repeat lumbar medial branch RFA based on two studies and an 88% repeat success rate for cervical medial branch RFA based on five studies.290 The international lumbar facet guidelines186 recommend repeating lumbar facet RFA in individuals who obtain at least three months of meaningful relief, up to twice per year, without repeating the prognostic block if the recurrence is similar to the pre-RFA pain pattern.185

High Intensity Focused Ultrasound Ablation and Other Novel Forms of Denervation An alternative approach to RFA is high intensity focused ultrasound (HIFU) ablation, guided by magnetic resonance.291,292 HIFU is a novel non-invasive technique whose target point is the entire facet surface, whereby nerve endings terminate to innervate the joint. Advantages of this technique include its non-invasive nature and that it does not entail radiation exposure.293 Several other non-radiofrequency mediated forms of denervation have been described, including laser irradiation,294 cryoablation,295 and phenol, and alcohol injection,296 some of which are limited by their lack of precision, which can theoretically result in extravasation of neurolytic substances into the intervertebral foramen, which can lead to numbness and/or weakness. However, there have been no randomized trials evaluating efficacy.

Surgery Surgery is occasionally performed to treat facet arthropathy despite a lack of evidence supporting fusion for degenerative spinal disorders.297,298 Not surprisingly, the results of studies evaluating the use of lumbar z-joint blocks to predict outcomes of lumbar arthrodesis are discouraging. The three studies that compared surgical outcomes between facet block responders and non-responders failed to show a difference between groups.299–301 Bough and associates131 conducted a retrospective review of 127 facet joints surgically removed from 84 patients in an attempt to correlate histologic evidence of facet degeneration with a provocative response to preoperative facet arthrography. Although the authors found the positive predictive value of concordant pain reproduction to be 85%, the negative predictive value was only 43%, which led them to conclude that provocative facet arthrography was of little value as a presurgical screening tool. In a prospective case series,

450

PA RT 4 Clinical Conditions: Evaluation and Treatment

Lovely and Rastogi302 found that 83% of 23 patients who responded to bracing and three facet blocks achieved 90% or greater pain relief after fusion surgery at the latest follow up. However, the large volumes used per block, the failure to exclude placebo responders, and the lack of a comparison group undermine the conclusions that can be drawn. Patients with lumbar z-joint pain might respond to arthrodesis because some surgeons, either purposefully or inadvertently, perform medial branch rhizotomies during pedicle screw placement. More recently, percutaneous fusion and open facet arthroplasty303 have recently been used to treat facet joint pain, but there are no prospective outcome data for either procedure. In summary, there is no convincing evidence to support any surgical intervention for lumbar z-joint pain other than that resulting from a traumatic dislocation.

Complications Serious complications are uncommon after facet interventions.304 The metabolic and endocrine sequelae of intraarticular facet joint steroids have not been studied. However, based on extrapolation from epidural steroid injections, one would expect suppression of the hypothalamicpituitary-adrenal axis for up to four weeks depending on the steroid used and elevated glucose levels for less than one week.305,306 Although infrequent, a host of infections has been associated with intraarticular injections, including septic arthritis, epidural abscess, and meningitis, but these infections are rare following RF denervation.307,308,309 Reports of spinal anesthesia and post-dural puncture headache have been published but are preventable using imaging in multiple views.310,311 A prospective study described complications associated with more than 7400 patient encounters and more than 43,000 individual facet injections in the cervical, thoracic, and lumbar spine,312 with no serious complications reported. Intravascular injection was detected in 11.4% of patients overall, with the highest incidence in the cervical region (20%). In less than 1% of cases, patients experienced vasovagal reactions, bruising, and nerve root irritation. Catastrophic injuries have been reported, including a posterior circulation stroke during a C1–2 intraarticular steroid injection that was thought to be because of microvascular injury from accidental injection into the vertebral artery, and a case of head drop after bilateral cervical medial branch RFA.275,313 Numbness and dysesthesia have been reported after RF denervation but tend to be transient and self-limited. Burns are rare with RFA and may result from electrical faults, breaks in the insulation of electrodes, generator malfunction, and theoretically from the creation of large lesions in a thin individual with little soft tissue overlying the target nerve.314 The most common complication following facet joint RF is neuritis, with a reported incidence of less than 10% in the lumbar spine but higher in the upper cervical spine.315 In one study, the post-administration of corticosteroids or pentoxifylline was found to reduce the incidence of postprocedural pain following RF denervation.316 However, a subsequent large retrospective study failed to find a reduction in neuritis in individuals administered post-RFA steroids vs. those who did not. Notably, one study found that steroids administered pre-RF lesioning reduced lesion size.317,318

Guidelines or Recommendations of Best Practice Many pain societies have tried to establish guidelines to promote the best way to select patients and perform radiofrequency denervation. Below is a brief summary of the international working group guidelines for lumbar facet joint pain.185

1- Consensus Practice Guidelines on Interventions for Lumbar Facet Joint Pain From a Multispecialty, International Working Group Authors: Cohen et al. Societies: 12 international societies and the United States Depts. of Defense and Veterans Affairs Designs: A modified Delphi method was used to answer 17 questions for guideline development. The USPSTF was utilized to grade the level of evidence and strength of recommendations. Year: 2020 Recommendations: 1. There are no pathognomonic physical examinations or historical signs that can reliably predict the response to facet joint blocks in individuals with mechanical chronic LBP, although paraspinal tenderness may be weakly associated with a positive block. 2. There is weak or no evidence supporting the use of image tests for identifying painful lumbar facet joints prior to lumbar MBB or IA facet joint injections. 3. A three month trial of different conservative treatments is recommended before facet joint interventions. 4. CT or fluoroscopy (lower costs, faster time, and less radiation exposure than CT) is recommended for lumbar MBB. However, ultrasound may be helpful in patients in whom radiation exposure may be associated with potential harm (e.g. pregnancy) or in patients without obesity when radiographic or radiologic imaging is unavailable. 5. MBBs have limitations as a diagnostic tool related to aberrant lumbar facet joint innervation. They provide better predictive information for medial branch RF denervation than intraarticular injections. 6. MBB should be a prognostic screening test of choice before lumbar facet RFA. Intraarticular injections of corticosteroids may be of therapeutic value for certain populations in whom there is acute inflammation and in whom denervation may be relatively contraindicated but are unlikely to provide longterm benefit in most people. 7. Sedation should not be routinely administered for diagnostic or prognostic facet injections without reasonable indications. 8. Lumbar MBBs should be performed with ≤0.5 mL (total volume) to reduce spread to adjacent structures. 9. The routine use of therapeutic facet injections should be discouraged. However, in patients who are at risk of adverse consequences from RF denervation (e.g. young athletes, older individuals on anticoagulation therapy or with implantable cardiac devices) or in whom there is a strong likelihood of success (e.g. individuals who obtained prolonged relief from previous diagnostic injections with or without steroids), it may be reasonable to add steroids to a block to derive intermediate-term relief. 10. A ≥50% reduction in pain relief should be considered as a positive prognostic block to maximize access to care. 11. A single block is recommended as a prognostic block before RF denervation because of the significant false negative rate of blocks. 12. Creating larger lesions with reduced lesion variability may increase the likelihood of capturing the medial branch. 13. Near parallel placement of traditional electrodes (non-cooled electrodes) is recommended to maximize nerve capture. 14. Sensory stimulation is recommended when single lesions are anticipated; when multiple lesions are planned, the evidence for sensory stimulation is inconclusive. Motor stimulation should always be performed.

 

CHAPTER 31

15. Recommendations for Avoiding Complications: a. Vascular penetration: Aspirating and visualizing the spread of contrast on real-time fluoroscopy while performing MBB can reduce false negative results. Non-heparin anticoagulants should be continued in the peri-procedural period for patients undergoing lumbar MBB or RF denervation. b.  Procedural pain and numbness: Injection of steroids through the cannula after ablation may reduce pain and discomfort following RF denervation. c. Injury to the spinal cord or nerves: Adequate visualization of needles in true anteroposterior, oblique, and lateral views and absence of sensorimotor responses in a radicular distribution in response to test stimulation prior to RF may also reduce the probability of injury to the spinal cord and spinal nerve roots. d. Degeneration of spinal anatomy and musculature: Physical therapy regimens aimed at restoring the function of paraspinal muscles before and after RF denervation are recommended.

Facet Pain: Pathogenesis, Diagnosis, and Treatment

451

e. Impact on implanted devices: Use of bipolar RF mode is preferable, along with consulting the device manufacturer and the specialist team that implanted the device. f.  Tissue burns: Positioning large monopolar ground pads in an optimal location and orientation may prevent tissue burns. g. Impact on spinal instrumentation: Ensure that the RF cannula is not in contact with a pedicle screw to avoid thermal injury to tissues surrounding the implanted spinal hardware. Previous spine surgery is associated with a higher rate of false positive blocks and lower RFA success rate. 16. There should be different standards in selecting patients for radiofrequency ablation in clinical trials and clinical practice. 17. The lumbar medial branch RFA can be repeated on recurrence of baseline pain in patients who experience a minimum of three months of improvement (preferably six months improvement for multiple procedures) following a previous RF denervation.

Conclusions Pain originating from the facet joints has long been recognized as a potential source of back and neck pain. The three most caudal lumbar facet joints, L3–4, L4–5, and L5–S1, are exposed to the greatest strain and are thus more prone to pathology. In patients with chronic neck pain, the C2–3 and C5–6 facet joints are most commonly affected clinically, while radiologic studies have shown that C3–4, C4–5, and C2–3 undergo the most degeneration. The exact prevalence of facet disease is unclear but maybe as high as 10%–15% in patients with axial LBP, 49%–60% in patients with chronic neck pain, and 42%–48% in patients with axial mid-back pain. By the age of 60 years, more than half of all symptomatic individuals will experience significant lumbar facet joint degeneration, with similar proportions in other spine regions. No discrete historical data for physical findings are pathognomonic for facet arthropathy in any region. Paraspinous muscle tenderness appears to be the only physical examination finding reliably associated with a positive response to diagnostic blocks and

RF of the medial branches; however, its specificity is unknown. The referral patterns for pain arising from the facet joints at different levels and different structures (e.g. facet joints and disks) overlap considerably. Reports on the correlation between CT and MRI evidence of facet arthropathy and the response to diagnostic lumbar facet blocks are conflicting. Since the facet joint is innervated by medial branches arising from the posterior rami of the spinal nerve at the same level and a level above the joint, LA blocks of these nerves have been advocated for diagnostic and prognostic purposes. Intraarticular facet injections with LA have been proposed as an alternative method for diagnosing facet joint pain, although the existing data suggest that MBB is a better predictive tool for RF denervation outcomes. Similar to other blocks, the potential for false positive and false negative results needs to be considered, and steps should be implemented to reduce their incidence. Studies evaluating the long-term outcomes of RF denervation have demonstrated efficacy in well-selected patients.

Key Points • Facet joints are an important source of axial spinal pain and are more common in individuals with neck and mid-back pain than in those with LBP. • Facetogenic pain is often referred into the head, shoulder, and scapula in the cervical region, laterally in the thoracic region, and into the upper legs and sometimes groin in the lumbar region. There is a significant overlap between cervical facet levels and other spinal structures, such as the intervertebral discs. • Facetogenic pain is more prevalent in elderly patients; in the cervical spine, whiplash is a common cause of facet joint pain. • Facetogenic pain cannot be reliably identified using imaging modalities. Paraspinal tenderness is weakly predictive of response to facet interventions but has low specificity. • Both medial branch blocks and intraarticular injections can be used to identify painful joints and select patients for radiofrequency ablation.  There is some evidence that medial branch

blocks are a better prognostic tool before radiofrequency ablation. Although intraarticular injections may theoretically confer greater diagnostic value than medial branch blocks, the high technical failure rate limits their utility. • Steps that may reduce the false positive rate include limiting the volume of superficial anesthetic, avoiding procedural sedation, reducing block volumes, using a single-needle technique, and avoiding patients with poorly controlled psychopathology. • Neither intraarticular injections nor medial branch blocks are likely to confer long-term benefits in a significant percentage of the population. • To optimize access to care in light of the potential for false negative injections, more liberal selection criteria, such as using a single block and a 50% cutoff threshold, are recommended in clinical practice. In clinical trials, more rigorous criteria may be employed.

Suggested Readings

Bogduk N. The innervation of the lumbar spine. Spine (Phila Pa 1976). 1983;8:286–293. Bogduk N. On the rational use of diagnostic blocks for spinal pain. Neurosurg Q. 2009;19:88–100.

Bogduk N (ed). Practice guidelines for spinal diagnostic and treatment procedures. 2nd ed. San Francisco: International Spine Intervention Society 2013:514–522.

452

PA RT 4 Clinical Conditions: Evaluation and Treatment

Bajwa ZH, Cohen SP, Kraemer JJ, et al. Factors predicting success and failure for cervical facet radiofrequency denervation: a multi-center analysis. Reg Anesth Pain Med. 2007;32:495–503. Bhaskar A, Cohen SP, Bhatia A, et al. Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group. Reg Anesth Pain Med. 2020;45:424–467. DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does age play a role? Pain Med. 2011;12:224–233. Doshi TL, Cohen SP, Constantinescu OC, et al. Effectiveness of lumbar facet joint blocks and predictive value before radiofrequency denervation: the facet treatment study (FACTS), a randomized, controlled clinical trial. Anesthesiology. 2018;129:517–535. Dreyfuss P, Halbrook B, Pauza K, et al. Efficacy and validity of radiofrequency neurotomy for chronic lumbar zygapophysial joint pain. Spine. 2000;25:1270–1277. Juch JNS, Maas ET, Ostelo RW, et al. Effect of radiofrequency denervation on pain intensity among patients with chronic low back pain: the MINT randomized clinical trials. JAMA. 2017;318:68–81. Kennedy DJ, Mattie R, Scott Hamilton A, et al. Detection of intravascular injection during lumbar medial branch blocks: a comparison of aspiration, live fluoroscopy, and digital subtraction technology. Pain Med. 2016;17:1031–1036. Laslett M, McDonald B, Aprill CN, et al. Clinical predictors of screening lumbar zygapophyseal joint blocks: development of clinical prediction rules. Spine J. 2006;6:370–379. Lord SM, Barnsley L, Wallis BJ, et al. Percutaneous radio-frequency neurotomy for chronic cervical zygapophyseal-joint pain. N Engl J Med. 1996;335:1721–1726.

Maas ET, Ostelo RWJG, Niemisto L, et al. Radiofrequency denervation of chronic low back pain. Cochrane Database Syst Rev. 2015;10: CD008572. Manchikanti L, Pampati V, Fellows B, et al. The inability of the clinical picture to characterize pain from facet joints. Pain Phys. 2000;3: 158–166. Moon JY, Cohen SP, Brummett CM. Medial branch blocks or intraarticular injections as a prognostic tool before lumbar facet radiofrequency denervation: a multicenter, case-control study. Reg Anesth Pain Med. 2015;40:376–383. Raja SN, Cohen SP. Pathogenesis, diagnosis, and treatment of lumbar zygapophysial (facet) joint pain. Anesthesiology. 2007;106:591–614. Spine Intervention Society. Conscious sedation. Available at: https:// www.spineintervention.org/news/386491/NewFactFinderonConsciousSedation.HTM. Stojanovic MP, Sethee J, Mohiuddin M, et al. MRI analysis of the lumbar spine: can it predict response to diagnostic and therapeutic facet procedures? Clin J Pain. 2010;26:110–115. Tekin I, Mirzai H, Ok G, et al. A comparison of conventional and pulsed radiofrequency denervation in the treatment of chronic facet joint pain. Clin J Pain. 2007;23:524–529. Williams KA, Cohen SP, Kurihara C, et al. Multicenter, randomized, comparative cost-effectiveness study comparing 0, 1, and 2 diagnostic medial branch (facet joint nerve) block treatment paradigms before lumbar facet radiofrequency denervation. Anesthesiology. 2010;113:395–405. The references for this chapter can be found at ExpertConsult.com.

References 1. American Academy of Orthopaedic Surgeons. Health care utilization and economic cost of musculoskeletal diseases. In: American Academy of Orthopaedic Surgeons (eds). The Burden of Musculoskeletal Disease in the United States. Rosemont: Illinois; 2008. 2. Levin KH, Covington EC, Devereaux MW. Neck and Low Back Pain, Volume 7. Continuum: New York; 2001:1-205. 3. Walker BF. The prevalence of low back pain: a systematic review of the literature from 1966 to 1998. J Spinal Disord. 2000;13:205–217. 4. American Academy of Orthopaedic Surgeons. Spine: low back and neck pain. In: American Academy of Orthopaedic Surgeons (eds). The Burden of Musculoskeletal Disease in the United States. Rosemont: Illinois; American Academy of Orthopaedic Surgeons; 2008. 5. Côté P, Cassidy DJ, Carroll LJ, et  al. The annual incidence and course of neck pain in the general population: a population-based cohort study. Pain. 2004;112:267–273. 6. Andersson G. The burden of musculoskeletal diseases in the United States: prevalence, societal and economic cost. Am Acad Orthopaedic. 2008. 7. Dieleman JL, Cao J, Chapin A, et al. US Health care spending by payer and health condition, 1996-2016. JAMA. 2020;323:863–884. 8. Glover JR. Arthrography of the joints of the lumbar vertebral arches. Orthop Clin North Am. 1977;8:37–42. 9. Cyron BM, Hutton WC. The tensile strength of the capsular ligaments of the apophyseal joints. J Anat. 1981;132:145–150. 10. Yahia LH, Garzon S. Structure on the capsular ligaments of the facet joints. Ann Anat. 1993;175:185–188. 11. Bogduk N, Engel R. The menisci of the lumbar zygapophyseal joints. A review of their anatomy and clinical significance. Spine. 1984;9:454–460. 12. Bogduk N. Clinical Anatomy of the Lumbar Spine and Sacrum. Edinburgh: Churchill Livingstone; 1997. 13. Masharawi Y, Rothschild B, Dar G, et al. Facet orientation in the thoracolumbar spine: three-dimensional anatomic and biomechanical analysis. Spine. 2004;29:1755–1763. 14. Bogduk N. The lumbar mamillo-accessory ligament. Its anatomical and neurosurgical significance. Spine. 1981;6:162–167. 15. Bogduk N. The innervation of the lumbar spine. Spine (Phila Pa 1976). 1983;8:286–293. 16. Dupont G, et al. Ossification of the mamillo-accessory ligament: a review of the literature and clinical considerations. Anat Cell Biol. 2019;52:115–119. 17. Trescot A. Peripheral Nerve Entrapments: Clinical Diagnosis and Management. Springer; 2016. 18. Cavanaugh JM, Ozaktay AC, Yamashita HT, et  al. Lumbar facet pain: biomechanics, neuroanatomy and neurophysiology. J Biomech. 1996;29:1117–1129. 19. Kallakuri S, Singh A, Chen C, et al. Demonstration of substance P, calcitonin gene-related peptide, and protein gene product 9.5 containing nerve fibers in human cervical facet joint capsules. Spine. 2004;29:1182–1186. 20. Ashton IK, Ashton BA, Gibson SJ, et  al. Morphological basis for back pain: the demonstration of nerve fibers and neuropeptides in the lumbar facet joint capsule but not in ligamentum flavum. J Orthop Res. 1992;10:72–78. 21. El-Bohy A, Cavanaugh JM, Getchell ML, et al. Localization of substance P and neurofilament immunoreactive fibers in the lumbar facet joint capsule and supraspinous ligament of the rabbit. Brain Res. 1988;460:379–382. 22. Beaman DN, Graziano GP, Glover RA, et al. Substance P innervation of lumbar spine facet joints. Spine. 1993;18:1044–1049. 23. Igarashi A, Kikuchi S, Konno S, et  al. Inflammatory cytokines released from the facet joint tissue in degenerative lumbar spinal disorders. Spine. 2004;29:2091–2095. 24. Horwitz T, Smith RM. An anatomical pathological and roentgenological study of the intervertebral joints of the lumbar spine and of the sacroiliac joints. AJR Am J Roentgenol. 1940;43:173–186.

25. Panjabi MM, Oxland T, Takata K, et  al. Articular facets of the human spine. Quantitative three-dimensional anatomy. Spine. 1993;18:1298–1310. 26. Grobler LJ, Robertson PA, Novotny JE, et al. Etiology of spondylolisthesis. Assessment of the role played by lumbar facet joint morphology. Spine. 1993;18:80–91. 27. Boden SD, Riew KD, Yamaguchi K, et al. Orientation of the lumbar facet joints: association with degenerative disc disease. J Bone Joint Surg Am. 1996;78:403–411. 28. Pedersen HE, Blunck CF, Gardner E. The anatomy of lumbosacral posterior rami and meningeal branches of spinal nerve (sinu-vertebral nerves); with an experimental study of their functions. J Bone Joint Surg Am. 1956;38-A:377–391. 29. Maigne JY, Maigne R, Guerin-Surville H. The lumbar mamilloaccessory foramen: a study of 203 lumbosacral spines. Surg Radiol Anat. 1991;13:29–32. 30. Bogduk N, Wilson AS, Tynan W. The human lumbar dorsal rami. J Anat. 1982;134:383–397. 31. Dreyfuss P, Schwarzer AC, Lau P, et al. Specificity of lumbar medial branch and L5 dorsal ramus blocks. A computed tomography study. Spine. 1997;22:895–902. 32. Jerosch J, Castro WH, Liljenqvist U. Percutaneous facet coagulation: indication, technique, results, and complications. Neurosurg Clin N Am. 1996;7:119–134. 33. Paris SV. Anatomy as related to function and pain. Orthop Clin North Am. 1983;14:475–489. 34. Shuang F, Hou SX, Zhu JL, et al. Clinical anatomy and measurement of the medial branch of the spinal dorsal ramus. Medicine. 2015;94:e2367. 35. Ebraheim NA, Xu R, Ahmad M, et al. The quantitative anatomy of the thoracic facet and the posterior projection of its inferior facet. Spine. 1997;22:1811–1817 discussion 1818. 36. Malmivaara A, Videman T, Kuosma E, et al. Facet joint orientation, facet and costovertebral joint osteoarthrosis, disc degeneration, vertebral body osteophytosis, and Schmorl’s nodes in the thoracolumbar junctional region of cadaveric spines. Spine. 1987;12:458–463. 37. Murtagh FR, Paulsen RD, Rechtine GR. The role and incidence of facet tropism in lumbar spine degenerative disc disease. J Spinal Disord. 1991;4:86–89. 38. Liebsch C, Wilke H-J. Basic biomechanics of the thoracic spine and rib cage. Biomechanics of the Spine: Acad Press; 2018:35–50. 39. Fukui S, Ohseto K, Shiotani M. Patterns of pain induced by distending the thoracic zygapophyseal joints. Reg Anesth. 1997;22:332–336. 40. Chua WH, Bogduk N. The surgical anatomy of thoracic facet denervation. Acta Neurochir Wien. 1995;136:140–144. 41. Joshi A, Amrhein TJ, Holmes MA, et al. The source and the course of the articular branches to the T4-T8 zygapophysial joints. Pain Med. 2019;20:2371–2376. 42. Ishizuka K, Sakai H, Tsuzuki N, et al. Topographic anatomy of the posterior ramus of thoracic spinal nerve and surrounding structures. Spine. 2012;37:E817–E822. 43. Milne N. The role of zygapophysial joint orientation and uncinate processes in controlling motion in the cervical spine. J Anat. 1991;178:189–201. 44. Pal GP, Routal RV, Saggu SK. The orientation of the articular facets of the zygapophyseal joints at the cervical and upper thoracic region. J Anat. 2001;198:431–441. 45. Bogduk N, Marsland A. The cervical zygapophysial joints as a source of neck pain. Spine. 1988;13:610–617. 46. Kweon TD, et al. Anatomical analysis of medial branches of dorsal rami of cervical nerves for radiofrequency thermocoagulation. Reg Anesth Pain Med. 2014;39:465–471. 47. Barnsley L, Lord S, Bogduk N. Comparative local anaesthetic blocks in the diagnosis of cervical zygapophysial joint pain. Pain. 1993;55:99–106. 48. Santavirta S, Hopfner-Hallikainen D, Paukku P, et al. Atlantoaxial facet joint arthritis in the rheumatoid cervical spine. A panoramic zonography study. J Rheumatol. 1988;15:217–223. 452.e1

452.e2

References

49. Bovim G, Berg R, Dale LG. Cervicogenic headache: anesthetic blockades of cervical nerves (C2-C5) and facet joint (C2/C3). Pain. 1992;49:315–320. 50. Lord SM, Barnsley L, Wallis BJ, et al. Third occipital nerve headache: a prevalence study. J Neurol Neurosurg Psychiatry. 1994;57: 1187–1190. 51. Lord SM, Barnsley L, Wallis BJ, et al. Chronic cervical zygapophysial joint pain after whiplash. A placebo-controlled prevalence study. Spine. 1996;21:1737–1744 discussion 1744. 52. Laplante BL, Ketchum JM, Saullo TR, et al. Multivariable analysis of the relationship between pain referral patterns and the source of chronic low back pain. Pain Phys. 2012;15:171–178. 53. Laslett M, McDonald B, Aprill CN, et  al. Clinical predictors of screening lumbar zygapophyseal joint blocks: development of clinical prediction rules. Spine J. 2006;6:370–379. 54. Manchikanti L, Manchikanti KN, Cash KA, et al. Age-related prevalence of facet-joint involvement in chronic neck and low back pain. Pain Phys. 2008;11:67–75. 55. Schwarzer AC, Wang SC, Bogduk N, et  al. Prevalence and clinical features of lumbar zygapophysial joint pain: a study in an Australian population with chronic low back pain. Ann Rheum Dis. 1995;54:100–106. 56. Suri P, Miyakoshi A, Hunter DJ, et al. Does lumbar spinal degeneration begin with the anterior structures? A study of the observed epidemiology in a community-based population. BMC Musculoskelet Disord. 2011;12:202. 57. Odonkor CA, Chen Y, Adekoya P, et al. Inciting events associated with lumbar facet joint pain. Anesth Analg. 2018;126:280–288. 58. Barnsley L. Percutaneous radiofrequency neurotomy for chronic neck pain: outcomes in a series of consecutive patients. Pain Med. 2005;6:282–286. 59. Wolf A, Levi L, Mirvis S, et al. Operative management of bilateral facet dislocation. J Neurosurg. 1991;75:883–890. 60. Nabeshima Y, Iguchi T, Matsubara N, et al. Extension injury of the thoracolumbar spine. Spine. 1997;22:1522–1525 discussion 1525. 61. Song KJ, Lee KB. Bilateral facet dislocation on L4-L5 without neurologic deficit. J Spinal Disord Tech. 2005;18:462–464. 62. Ianuzzi A, Little JS, Chiu JB, et  al. Human lumbar facet joint capsule strains: I. During physiological motions. Spine J. 2004;4: 141–152. 63. Chow DH, Luk KD, Evans JH, et al. Effects of short anterior lumbar interbody fusion on biomechanics of neighboring unfused segments. Spine. 1996;21:549–555. 64. Esses SI, Doherty BJ, Crawford MJ, et al. Kinematic evaluation of lumbar fusion techniques. Spine. 1996;21:676–684. 65. Lee CK. Accelerated degeneration of the segment adjacent to a lumbar fusion. Spine. 1988;13:375–377. 66. Lee CK, Langrana NA. Lumbosacral spinal fusion. A biomechanical study. Spine. 1984;9:574–581. 67. Little JS, Ianuzzi A, Chiu JB, et al. Human lumbar facet joint capsule strains: II. Alteration of strains subsequent to anterior interbody fixation. Spine J. 2004;4:153–162. 68. Dory MA. Arthrography of the lumbar facet joints. Radiology. 1981;140:23–27. 69. Gray DP, Bajwa ZH, Warfield CA. Facet block and neurolysis. In: Waldman SD (ed). Interventional Pain Management. 2nd ed. Philadelphia: Saunders; 2001:446–483. 70. Oudenhoven RC. Lumbar monoradiculopathy due to unilateral facet hypertrophy. Neurosurgery. 1982;11:726–727. 71. Pape E, Eldevik P, Vandvik B. Diagnostic validity of somatosensory evoked potentials in subgroups of patients with sciatica. Eur Spine J. 2002;11:38–46. 72. Wilde GP, Szypryt EP, Mulholland RC. Unilateral lumbar facet joint hypertrophy causing nerve root irritation. Ann R Coll Surg Engl. 1988;70:307–310. 73. Igarashi A, Kikuchi S, Konno S. Correlation between inflammatory cytokines released from the lumbar facet joint tissue and symptoms in degenerative lumbar spinal disorders. J Orthop Sci. 2007;12:154–160.

74. Stojanovic MP, Sethee J, Mohiuddin M, et al. MRI analysis of the lumbar spine: can it predict response to diagnostic and therapeutic facet procedures? Clin J Pain. 2010;26:110–115. 75. Kang YM, Choi WS, Pickar JG. Electrophysiologic evidence for an intersegmental reflex pathway between lumbar paraspinal tissues. Spine. 2002;27:E56–E63. 76. Cavanaugh JM, Ozaktay AC, Yamashita T, et  al. Mechanisms of low back pain: a neurophysiologic and neuroanatomic study. Clin Orthop Relat Res. 1997;335:166–180. 77. Ozaktay AC, Cavanaugh JM, Blagoev DC, et al. Effects of a carrageenan-induced inflammation in rabbit lumbar facet joint capsule and adjacent tissues. Neurosci Res. 1994;20:355–364. 78. Ozaktay AC, Cavanaugh JM, Blagoev DC, et  al. Phospholipase A2-induced electrophysiologic and histologic changes in rabbit dorsal lumbar spine tissues. Spine. 1995;20:2659–2668. 79. Yamashita T, Cavanaugh JM, Ozaktay AC, et al. Effect of substance P on mechanosensitive units of tissues around and in the lumbar facet joint. J Orthop Res. 1993;11:205–214. 80. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769. 81. Chen C, Lu Y, Kallakuri S, et al. Distribution of A-delta and C-fiber receptors in the cervical facet joint capsule and their response to stretch. J Bone Joint Surg Am. 2006;88:1807–1816. 82. Gotfried Y, Bradford DS, Oegema TR. Facet joint changes after chemonucleolysis-induced disc space narrowing. Spine. 1986;11:944–950. 83. Kirkaldy-Willis WH, Wedge JH, Yong-Hing K, et  al. Pathol ogy and pathogenesis of lumbar spondylosis and stenosis. Spine. 1978;3:319–328. 84. Panjabi MM, Krag MH, Chung TQ. Effects of disc injury on mechanical behavior of the human spine. Spine. 1984;9:707–713. 85. Adams MA, Freeman BJ, Morrison HP, et al. Mechanical initiation of intervertebral disc degeneration. Spine. 2000;25:1625–1636. 86. Adams MA, Hutton WC. The effect of posture on the role of the apophysial joints in resisting intervertebral compressive forces. J Bone Joint Surg Br. 1980;62:358–362. 87. Haher TR, O’Brien M, Dryer JW, et al. The role of the lumbar facet joints in spinal stability. Identification of alternative paths of loading. Spine. 1994;19:2667–2670 discussion 2671. 88. Fujiwara A, Tamai K, Yamato M, et  al. The relationship between facet joint osteoarthritis and disc degeneration of the lumbar spine: an MRI study. Eur Spine J. 1999;8:396–401. 89. Li W, Wang S, Xia Q, et al. Lumbar facet joint motion in patients with degenerative disc disease at affected and adjacent levels: an in vivo biomechanical study. Spine. 2011;36:E629–E637. 90. Crisco JJ, Panjabi MM. The intersegmental and multisegmental muscles of the lumbar spine. A biomechanical model comparing lateral stabilizing potential. Spine (Phila Pa 1976). 1991;16:793–799. 91. Boyd-Clark LC, Briggs CA, Galea MP. Muscle spindle distribution, morphology, and density in longus colli and multifidus muscles of the cervical spine. Spine (Phila Pa 1976). 2002;27:694–701. 92. Leinonen V, et al. Lumbar paraspinal muscle function, perception of lumbar position, and postural control in disc herniation-related back pain. Spine (Phila Pa 1976). 2003;28:842–848. 93. Kalichman L, Hodges P, Li L, et al. Changes in paraspinal muscles and their association with low back pain and spinal degeneration: CT study. Eur Spine J. 2010;19:1136–1144. 94. Brumagne S, Cordo P, Lysens R, et al. The role of paraspinal muscle spindles in lumbosacral position sense in individuals with and without low back pain. Spine (Phila Pa 1976). 2000;25:989–994. 95. Danneels LA, Vanderstraeten GG, Cambier DC, et  al. CT imaging of trunk muscles in chronic low back pain patients and healthy control subjects. Eur Spine J. 2000;9:266–272. 96. Aebi M. The adult scoliosis. Eur Spine J. 2005;14:925–948. 97. Jacobsen S, Sonne-Holm S, Rovsing H, et al. Degenerative lumbar spondylolisthesis: an epidemiological perspective: the Copenhagen osteoarthritis study. Spine (Phila Pa 1976). 2007;32:120–125. 98. Das De S, McCreath SW. Lumbosacral fracture-dislocations. A report of four cases. J Bone Joint Surg Br. 1981;63-B:58–60.

References

99. Fabris D, Costantini S, Nena U, et  al. Traumatic L5-S1 spondylolisthesis: report of three cases and a review of the literature. Eur Spine J. 1999;8:290–295. 100. Kaplan SS, Wright NM, Yundt KD, et  al. Adjacent fracture dislocations of the lumbosacral spine: case report. Neurosurgery. 1999;44:1134–1137. 101. Verlaan JJ, Oner FC, Dhert WJ, et al. Traumatic lumbosacral dislocation: case report. Spine. 2001;26:1942–1944. 102. Levine AM, Bosse M, Edwards CC. Bilateral facet dislocations in the thoracolumbar spine. Spine. 1988;13:630–640. 103. Twomey LT, Taylor JR, Taylor MM. Unsuspected damage to lumbar zygapophyseal (facet) joints after motor-vehicle accidents. Med J Aust. 1989;151:215–217 210-212. 104. Aprill C, Bogduk N. The prevalence of cervical zygapophyseal joint pain. A first approximation. Spine. 1992;17:744–747. 105. Cohen SP, Doshi TL, Constantinescu OC, et al. Effectiveness of lumbar facet joint blocks and predictive value before radiofrequency denervation: the facet treatment study (FACTS), a randomized, controlled clinical trial. Anesthesiology. 2018;129:517–535. 106. Engel A, MacVicar J, Bogduk N. A philosophical foundation for diagnostic blocks, with criteria for their validation. Pain Med. 2014;15:998–1006. 107. Kim JH, Sharan A, Cho W, et al. The prevalence of asymptomatic cervical and lumbar facet arthropathy: a computed tomography study. Asian Spine J. 2019;13:417–422. 108. Derby R, Melnik I, Choi J, et al. Indications for repeat diagnostic medial branch nerve blocks following a failed first medial branch nerve block. Pain Phys. 2013;16:479–488. 109. Manchikanti L, Singh V, Pampati V, et  al. Evaluation of the prevalence of facet joint pain in chronic thoracic pain. Pain Phys. 2002;5:354–359. 110. Schwarzer AC, Aprill CN, Derby R, et al. The relative contributions of the disc and zygapophyseal joint in chronic low back pain. Spine. 1994;19:801–806. 111. Schwarzer AC, Aprill CN, Derby R, et al. The false-positive rate of uncontrolled diagnostic blocks of the lumbar zygapophysial joints. Pain. 1994;58:195–200. 112. Revel M, Poiraudeau S, Auleley GR, et al. Capacity of the clinical picture to characterize low back pain relieved by facet joint anesthesia. Proposed criteria to identify patients with painful facet joints. Spine. 1998;23:1972–1976. discussion 1977. 113. Manchikanti L, Pampati V, Fellows B, et al. Prevalence of lumbar facet joint pain in chronic low back pain. Pain Phys. 1999;2:59–64. 114. Manchikanti L, Pampati V, Fellows B, et al. The diagnostic validity and therapeutic value of lumbar facet joint nerve blocks with or without adjuvant agents. Curr Rev Pain. 2000;4:337–344. 115. Dreyfuss P, Halbrook B, Pauza K, et  al. Efficacy and validity of radiofrequency neurotomy for chronic lumbar zygapophysial joint pain. Spine. 2000;25:1270–1277. 116. Manchikanti L, Pampati V, Fellows B, et  al. The inability of the clinical picture to characterize pain from facet joints. Pain Phys. 2000;3:158–166. 117. Manchikanti L, Boswell MV, Singh V, et  al. Prevalence of facet joint pain in chronic spinal pain of cervical, thoracic, and lumbar regions. BMC Musculoskelet Disord. 2004;5:15. 118. Manchikanti L, Manchukonda R, Pampati V. Prevalence of facet joint pain in chronic low back pain in postsurgical patients by controlled comparative local anesthetic blocks. Arch Phys Med Rehabil. 2007;88:449–455. 119. Manchukonda R, Manchikanti KN, Cash KA. Facet joint pain in chronic spinal pain: an evaluation of prevalence and falsepositive rate of diagnostic blocks. J Spinal Disord Tech. 2007;20: 539–545. 120. Manchikanti L, Manchikanti KN, Cash KA. Age-related prevalence of facet-joint involvement in chronic neck and low back pain. Pain Phys. 2008;11:67–75. 121. Manchikanti L, Pampati S, Cash KA. Making sense of the accuracy of diagnostic lumbar facet joint nerve blocks: an assessment of the

452.e3

implications of 50% relief, 80% relief, single block, or controlled diagnostic blocks. Pain Phys. 2010;13:133–143. 122. DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does age play a role? Pain Med. 2011;12:224–233. 123. Barnsley L, Lord SM, Wallis BJ, et al. The prevalence of chronic cervical zygapophysial joint pain after whiplash. Spine. 1995;20: 20–25. discussion 26. 124. Manchikanti L, Singh V, Pampati V, et  al. Evaluation of the prevalence of facet joint pain in chronic thoracic pain. Pain Phys. 2002;5:354–359. 125. Manchikanti L, Singh V, Rivera J, et al. Prevalence of cervical facet joint pain in chronic neck pain. Pain Phys. 2002;5:243–249. 126. Yin W, Bogduk N. The nature of neck pain in a private pain clinic in the United States. Pain Med. 2008;9:196–203. 127. Cohen SP, Raja SN. Pathogenesis, diagnosis, and treatment of lumbar zygapophysial (facet) joint pain. Anesthesiology. 2007;106:591–614. 128. Rydman E, et  al. Association between cervical degeneration and self-perceived nonrecovery after whiplash injury. Spine J. 2019; 19:1986–1994. 129. Lord SM, Barnsley L, Wallis BJ, et al. Percutaneous radio-frequency neurotomy for chronic cervical zygapophyseal-joint pain. N Engl J Med. 1996;335:1721–1726. 130. Brummett CM, et al. Aberrant analgesic response to medial branch blocks in patients with characteristics of fibromyalgia. Reg Anesth Pain Med. 2015;40:249–254. 131. Bough B, Thakore J, Davies M, et  al. Degeneration of the lumbar facet joints. Arthrography and pathology. J Bone Joint Surg Br. 1990;72:275–276. 132. Schwarzer AC, Derby R, Aprill CN, et al. The value of the provocation response in lumbar zygapophyseal joint injections. Clin J Pain. 1994;10:309–313. 133. Schwarzer AC, Wang SC, O’Driscoll D, et al. The ability of computed tomography to identify a painful zygapophysial joint in patients with chronic low back pain. Spine. 1995;20:907–912. 134. Slipman CW, Plastaras CT, Palmitier RA, et  al. Symptom provocation of fluoroscopically guided cervical nerve root stimulation. Are dynatomal maps identical to dermatomal maps? Spine. 1998;23:2235–2242. 135. Strong EK, Davila JC. The cluneal nerve syndrome; a distinct type of low back pain. Ind Med Surg. 1957;26:417–429. 136. Isu T, et  al. Superior and middle cluneal nerve entrapment as a cause of low back pain. Neurospine. 2018;15:25–32. 137. Young S, Aprill C, Laslett M. Correlation of clinical examination characteristics with three sources of chronic low back pain. Spine J. 2003;3:460–465. 138. Hirsch C, Ingelmark BE, Miller M. The anatomical basis for low back pain. Studies on the presence of sensory nerve endings in ligamentous, capsular and intervertebral disc structures in the human lumbar spine. Acta Orthop Scand. 1963;33:1–17. 139. Mooney V, Robertson J. The facet syndrome. Clin Orthop Relat Res. 1976;115:149–156. 140. McCall IW, Park WM, O’Brien JP. Induced pain referral from posterior lumbar elements in normal subjects. Spine. 1979;4:441–446. 141. Fairbank JC, Park WM, McCall IW, et  al. Apophyseal injection of local anesthetic as a diagnostic aid in primary low-back pain syndromes. Spine. 1981;6:598–605. 142. Lippitt AB. The facet joint and its role in spine pain. Management with facet joint injections. Spine. 1984;9:746–750. 143. Lynch MC, Taylor JF. Facet joint injection for low back pain. A clinical study. J Bone Joint Surg Br. 1986;68:138–141. 144. Helbig T, Lee CK. The lumbar facet syndrome. Spine. 1988;13: 61–64. 145. Jackson RP, Jacobs RR, Montesano PX. 1988 Volvo award in clinical sciences. Facet joint injection in low-back pain. A prospective statistical study. Spine. 1988;13:966–971. 146. Marks R. Distribution of pain provoked from lumbar facet joints and related structures during diagnostic spinal infiltration. Pain. 1989;39:37–40.

452.e4

References

147. Kuslich SD, Ulstrom CL, Michael CJ. The tissue origin of low back pain and sciatica: a report of pain response to tissue stimulation during operations on the lumbar spine using local anesthesia. Orthop Clin North Am. 1991;22:181–187. 148. Marks RC, Houston T, Thulbourne T. Facet joint injection and facet nerve block: a randomised comparison in 86 patients with chronic low back pain. Pain. 1992;49:325–328. 149. Kaplan M, Dreyfuss P, Halbrook B, et  al. The ability of lumbar medial branch blocks to anesthetize the zygapophysial joint. A physiologic challenge. Spine. 1998;23:1847–1852. 150. DePalma MJ, Ketchum JM, Trussell BS, et al. Does the location of low back pain predict its source? PMR. 2011;3:33–39. 151. Aprill C, Dwyer A, Bogduk N. Cervical zygapophyseal joint pain patterns, II. A clinical evaluation. Spine. 1990;15:458–461. 152. Dwyer A, Aprill C, Bogduk N. Cervical zygapophyseal joint pain patterns, I. A study in normal volunteers. Spine. 1990;15:453–457. 153. Fukui S, Ohseto K, Shiotani M, et al. Referred pain distribution of the cervical zygapophyseal joints and cervical dorsal rami. Pain. 1996;68:79–83. 154. Windsor RE, Nagula D, Storm S, et  al. Electrical stimula tion induced cervical medial branch referral patterns. Pain Phys. 2003;6:411–418. 155. Dreyfuss P, Michaelsen M, Fletcher D. Atlanto-occipital and lateral atlanto-axial joint pain patterns. Spine. 1994;19:1125–1131. 156. Dreyfuss P, Tibiletti C, Dreyer SJ. Thoracic zygapophyseal joint pain patterns. A study in normal volunteers. Spine. 1994;19: 807–811. 157. Cohen SP, Bajwa ZH, Kraemer JJ, et al. Factors predicting success and failure for cervical facet radiofrequency denervation: a multicenter analysis. Reg Anesth Pain Med. 2007;32:495–503. 158. Cohen SP, Hurley RW, Christo PJ, et al. Clinical predictors of success and failure for lumbar facet radiofrequency denervation. Clin J Pain. 2007;23:45–52. 159. Schwarzer AC, Aprill CN, Derby R, et  al. Clinical features of patients with pain stemming from the lumbar zygapophysial joints. Is the lumbar facet syndrome a clinical entity? Spine. 1994;19:1132–1137. 160. Laslett M, Öberg B, Aprill CN, et al. Zygapophysial joint blocks in chronic low back pain: a test of Revel’s model as a screening test. BMC Musculoskelet Disord. 2004;5:43. 161. Jull G, Bogduk N, Marsland A. The accuracy of manual diagnosis for cervical zygapophysial joint pain syndromes. Med J Aust. 1988;148:233–236. 162. King W, Lau P, Lees R, et al. The validity of manual examination in assessing patients with neck pain. Spine J. 2007;7:22–26. 163. Wilde VE, Ford JJ, McMeeken JM. Indicators of lumbar zygapophyseal joint pain: survey of an expert panel with the Delphi technique. Phys Ther. 2007;87:1348–1361. 164. Usunier K, Hynes M, Schuster JM, et al. Clinical diagnostic tests versus medial branch blocks for adults with persisting cervical zygapophyseal joint pain: a systematic review and meta-analysis. Physiother Can. 2018;70:179–187. 165. Carrera GF, Williams AL. Current concepts in evaluation of the lumbar facet joints. Crit Rev Diagn Imaging. 1984;21:85–104. 166. Murtagh FR. Computed tomography and fluoroscopy guided anesthesia and steroid injection in facet syndrome. Spine. 1988; 13:686–689. 167. Leone A, Aulisa L, Tamburrelli F, et al. The role of computed tomography and magnetic resonance in assessing degenerative arthropathy of the lumbar articular facets. Radiol Med. 1994;88:547–552. 168. Weishaupt D, Zanetti M, Hodler J, et al. MR imaging of the lumbar spine: prevalence of intervertebral disk extrusion and sequestration, nerve root compression, end plate abnormalities, and osteoarthritis of the facet joints in asymptomatic volunteers. Radiology. 1998;209:661–666. 169. Weishaupt D, Zanetti M, Boos N, et  al. MR imaging and CT in osteoarthritis of the lumbar facet joints. Skelet Radiol. 1999;28:215–219.

170. Berg L, Thoresen H, Neckelmann G, et al. Facet arthropathy evaluation: CT or MRI? Eur Radiol. 2019;29:4990–4998. 171. Jensen MC, Brant-Zawadzki MN, Obuchowski N, et al. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med. 1994;331:69–73. 172. Wiesel SW, Tsourmas N, Feffer HL, et al. A study of computerassisted tomography, I. The incidence of positive CAT scans in an asymptomatic group of patients. Spine. 1984;9:549–551. 173. Dolan AL, Ryan PJ, Arden NK, et al. The value of SPECT scans in identifying back pain likely to benefit from facet joint injection. Br J Rheumatol. 1996;35:1269–1273. 174. Raymond J, Dumas JM, Lisbona R. Nuclear imaging as a screening test for patients referred for intraarticular facet block. J Can Assoc Radiol. 1984;35:291–292. 175. Lee SH, Yun SJ, Jo HH, et  al. Diagnostic accuracy of low-dose versus ultra-low-dose CT for lumbar disc disease and facet joint osteoarthritis in patients with low back pain with MRI correlation. Skelet Rad. 2018;47:491–504. 176. Russo VM, Dhawan RT, Baudracco I, et al. Hybrid bone SPECT/ CT imaging in evaluation of chronic low back pain: correlation with facet joint arthropathy. World Neurosurg. 2017;107:732–738. 177. Ravindra VM, Mazur MD, Bisson EF, et  al. The usefulness of single-photon emission computed tomography in defining painful upper cervical facet arthropathy. World Neurosurg. 2016;96: 390–395. 178. Rosen RS, Fayad L, et al. Increased 18F-FDG uptake in degenerative disease of the spine: characterization with 18F-FDG PET/CT. J Nucl Med. 2006;7:1274–1280. 179. Lehman VT, Diehn FE, Broski SM, et  al. Comparison of [18F] FDG-PET/MRI and clinical findings for assessment of suspected lumbar facet joint pain: a prospective study to characterize candidate nonanatomic imaging biomarkers and potential impact on management. AJNR Am J Neuroradiol. 2019;40:1779–1785. 180. Yolcu YU, Lehman VT, Bhatti AUR, et  al. Use of hybrid imaging techniques in diagnosis of facet joint arthropathy: a narrative review of three modalities. World Neurosurg. 2020;134:201–210. 181. Creamer P, Keen M, Zananiri F, et al. Quantitative magnetic resonance imaging of the knee: a method of measuring response to intra-articular treatments. Ann Rheum Dis. 1997;56:378–381. 182. Hannan MT, Felson DT, Pincus T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J Rheumatol. 2000;27:1513–1517. 183. Creamer P, Lethbridge-Cejku M, Costa P, et al. The relationship of anxiety and depression with self-reported knee pain in the community: data from the Baltimore longitudinal study of aging. Arthritis Care Res. 1999;12:3–7. 184. Bogduk N. On the rational use of diagnostic blocks for spinal pain. Neurosurg Q. 2009;19:88–100. 185. Cohen SP, Bhaskar A, Bhatia A, et al. Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group. Reg Anesth Pain Med. 2020;45: 424–467. 186. Nash TP. Facet joints-intra-articular steroids or nerve block? Pain Clin. 1990;3:77–82. 187. Kellegren JH. On the distribution of pain arising from deep somatic structures with charts of segmental pain areas. Clin Sci. 1939;4:35–46. 188. Cohen SP, Strassels SA, Kurihara C, et al. Randomized study assessing the accuracy of cervical facet joint nerve (medial branch) blocks using different injectate volumes. Anesthesiology. 2010;112:144–152. 189. Kennedy DJ, Mattie R, Scott Hamilton A, et  al. Detection of intravascular injection during lumbar medial branch blocks: a comparison of aspiration, live fluoroscopy, and digital subtraction technology. Pain Med. 2016;17:1031–1036. 190. Cohen SP, Moon JY, Brummett CM, et al. Medial branch blocks or intra-articular injections as a prognostic tool before lumbar facet radiofrequency denervation: a multicenter, case-control study. Reg Anesth Pain Med. 2015;40:376–383.

References

191. Ackerman WE, Ahmad M. Pain relief with intraarticular or medial branch nerve blocks in patients with positive lumbar facet joint SPECT imaging: a 12-week outcome study. South Med J. 2008;101:931–934. 192. Gallagher J. Radio frequency facet joint denervation in the treatment of low back pain: a prospective controlled double-blind study to assess its efficacy. Pain Clin. 1994;7:193–198. 193. Leclaire R, Fortin L, Lambert R, et al. Radiofrequency facet joint denervation in the treatment of low back pain: a placebo-controlled clinical trial to assess efficacy. Spine. 2001;26:1411–1416 discussion 1417. 194. Van Wijk RM, Geurts JW, Wynne HJ, et  al. Radiofrequency denervation of lumbar facet joints in the treatment of chronic low back pain: a randomized, double-blind, sham lesion-controlled trial. Clin J Pain. 2005;21:335–344. 195. Van Kleef M, Barendse GA, Kessels A, et  al. Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain. Spine. 1999;24:1937–1942. 196. Birkenmaier C, Veihelmann A, Trouillier HH, et al. Medial branch blocks versus pericapsular blocks in selecting patients for percutaneous cryodenervation of lumbar facet joints. Reg Anesth Pain Med. 2007;32:27–33. 197. Lee DG, et  al. Comparison of intra-articular thoracic facet joint steroid injection and thoracic medial branch block for the management of thoracic facet joint pain. Spine. 2018;43:76–80. 198. Schwarzer AC, Aprill CN, Derby R, et al. The false-positive rate of uncontrolled diagnostic blocks of the lumbar zygapophysial joints. Pain. 1994;58:195–200. 199. Barnsley L, Lord S, Wallis B, et al. False-positive rates of cervical zygapophysial joint blocks. Clin J Pain. 1993;9:124–130. 200. Lord SM, Barnsley L, Bogduk N. The utility of comparative local anesthetic blocks versus placebo-controlled blocks for the diagnosis of cervical zygapophysial joint pain. Clin J Pain. 1995;11:208–213. 201. Hogan QH, Abram SE. Neural blockade for diagnosis and prognosis. A review. Anesthesiology. 1997;86:216–241. 202. American Society of Anesthesiologists. Statement on anesthetic care during interventional pain procedures for adults. Available at: https://www.asahq.org/StandardsandGuidelines/StatementonAnestheticCareDuringInterventionalPainproceduresforAdults. 203. Spine Intervention Society. Conscious sedation. Available at: https://www.Spineintervention.org/news/386491/New-FactFinderonConsciousSedation.htm. 204. Stojanovic MP, Zhou Y, Hord ED, et al. Single needle approach for multiple medial branch blocks: a new technique. Clin J Pain. 2003;19:134–137. 205. Stojanovic MP, Dey D, Hord ED, et  al. A prospective crossover comparison study of the single-needle and multiple-needle techniques for facet-joint medial branch block. Reg Anesth Pain Med. 2005;30:484–490. 206. Derby R, Melnik I, Choi J, et al. Indications for repeat diagnostic medial branch nerve blocks following a failed first medial branch nerve block. Pain Phys. 2013;16:479–488. 207. Lee CJ, Kim YC, Shin JH, et al. Intravascular injection in lumbar medial branch block: a prospective evaluation of 1433 injections. Anesth Analg. 2008;106:1274–1278 table of contents. 208. Bogduk N, ed. Practice Guidelines for Spinal Diagnostic and Treatment Procedures. 2nd ed. San Francisco: International Spine Intervention Society; 2013:514–522. 209. Bogduk N. Evidence-informed management of chronic low back pain with facet injections and radiofrequency neurotomy. Spine J. 2008;8:56–64. 210. Datta S, Lee M, Falco FJ, et al. Systematic assessment of diagnostic accuracy and therapeutic utility of lumbar facet joint interventions. Pain Phys. 2009;12:437–460. 211. Manchikanti L, Singh V, Falco FJ, et al. Comparative outcomes of a 2-year follow up of cervical medial branch blocks in management of chronic neck pain: a randomized, double-blind controlled trial. Pain Phys. 2010;13:437–450.

452.e5

212. Manchikanti L, Singh V, Falco FJ, et al. Lumbar facet joint nerve blocks in managing chronic facet joint pain: one-year follow up of a randomized, double-blind controlled trial: clinical trial NCT00355914. Pain Phys. 2008;11:121–132. 213. Manchikanti L, Singh V, Falco FJ, et  al. Comparative effectiveness of a one-year follow up of thoracic medial branch blocks in management of chronic thoracic pain: a randomized, double-blind active controlled trial. Pain Phys. 2010;13:535–548. 214. Koshi EB, Short CA. Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Pract. 2007;7:4–20. 215. Cohen SP, Williams KA, Kurihara C, et al. Multicenter, randomized, comparative cost-effectiveness study comparing 0, 1, and 2 diagnostic medial branch (facet joint nerve) block treatment paradigms before lumbar facet radiofrequency denervation. Anesthesiology. 2010;113:395–405. 216. Bogduk N, Holmes S. Controlled zygapophysial joint blocks: the travesty of cost-effectiveness. Pain Med. 2000;1:24–34. 217. Van Eerd M, Patijn J, Lataster A, et al. 5. Cervical facet pain. Pain Pract. 2010;10:113–123. 218. Fuchs S, Erbe T, Fischer HL, et al. Intraarticular hyaluronic acid versus glucocorticoid injections for nonradicular pain in the lumbar spine. J Vasc Interv Radiol. 2005;16:1493–1498. 219. Lilius G, Laasonen EM, Myllynen P, et al. Lumbar facet joint syndrome. Significance of non-organic signs. A randomized placebocontrolled clinical study. Rev Chir Orthop Réparatrice Appar Mot. 1989;75:493–500. 220. Carette S, Marcoux S, Truchon R, et al. A controlled trial of corticosteroid injections into facet joints for chronic low back pain. N Engl J Med. 1991;325:1002–1007. 221. Barnsley L, Lord SM, Wallis BJ, et al. Lack of effect of intraarticular corticosteroids for chronic pain in the cervical zygapophyseal joints. N Engl J Med. 1994;330:1047–1050. 222. Pneumaticos SG, Chatziioannou SN, Hipp JA, et  al. Low back pain: prediction of short-term outcome of facet joint injection with bone scintigraphy. Radiology. 2006;238:693–698. 223. Jadad AR, Moore RA, Carroll D, et  al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. 224. Schütz U, Cakir B, Dreinhöfer K, et al. Diagnostic value of lumbar facet joint injection: a prospective triple cross-over study. PLoS One. 2011;6:e27991. 225. Kennedy DJ, Huynh L, Wong J, et  al. Corticosteroid injections into lumbar facet joints: a prospective, randomized, double-blind placebo-controlled trial. Am J Phys Med Rehabil. 2018;97:741–746. 226. Davis VL, Abukabda AB, Radio NM, et al. Platelet-rich preparations to improve healing. Part I: workable options for every size practice. J Oral Implantol. 2014;40:500–510. 227. DeLong JM, Russell RP, Mazzocca AD. Platelet-rich plasma: the PAW classification system. Arthroscopy. 2012;28:998–1009. 228. Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009;23:177–189. 229. Aufiero D, Vincent H, Sampson S, et  al. Regenerative injection treatment in the spine: review and case series with platelet rich plasma. J Stem Cells Res Rev Reprod. 2015;2:1019. 230. Wu J, et al. A new technique for the treatment of lumbar facet joint syndrome using intra-articular injection with autologous platelet rich plasma. Pain Phys. 2016;19:617–625. 231. Wu J, Zhou J, Liu C, Zhang J, et al. A prospective study comparing platelet-rich plasma and local anesthetic (LA)/corticosteroid in intra-articular injection for the treatment of lumbar facet joint syndrome. Pain Pract. 2017;17:914–924. 232. Djouad F, Bouffi C, Ghannam S, et al. Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases. Nat Rev Rheumatol. 2009;5:392–399. 233. Freitag J, Bates D, Boyd R, et al. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy-a review. BMC Musculoskelet Disord. 2016;17:230.

452.e6

References

234. Ha CW, Park YB, Kim SH, et al. Intra-articular mesenchymal stem cells in osteoarthritis of the knee: a systematic review of clinical outcomes and evidence of cartilage repair. Arthroscopy. 2019;35: 277–288 e2. 235. Navani A, Manchikanti L, Albers SL, et al. Responsible, safe, and effective use of biologics in the management of low back pain: American Society of Interventional Pain Physicians (ASIPP) guidelines. Pain Phys. 2019;22:S1–S74. 236. O’Leary SA, Paschos NK, Link JM, et al. Facet joints of the spine: structure-function relationships, problems and treatments, and the potential for regeneration. Annu Rev Biomed Eng. 2018;20: 145–170. 237. Butscher A, Bohner M, Hofmann S, et  al. Structural and material approaches to bone tissue engineering in powder-based threedimensional printing. Acta Biomater. 2011;7:907–920. 238. Manchikanti L, Pampati V, Bakhit CE, et al. Effectiveness of lumbar facet joint nerve blocks in chronic low back pain: a randomized clinical trial. Pain Phys. 2001;4:101–117. 239. Manchikanti L, Manchikanti KN, Manchukonda R, et al. Evaluation of therapeutic thoracic medial branch block effectiveness in chronic thoracic pain: a prospective outcome study with minimum 1-year follow up. Pain Phys. 2006;9:97–105. 240. Manchikanti L, Manchikanti KN, Damron KS, et al. Effectiveness of cervical medial branch blocks in chronic neck pain: a prospective outcome study. Pain Phys. 2004;7:195–201. 241. Rocha IDD, Cristante AF, Marcon RM, et al. Controlled medial branch anesthetic block in the diagnosis of chronic lumbar facet joint pain: the value of a three-month follow up. Clin (Sao Paulo). 2014;69:529–534. 242. Lakemeier S, Lind M, Schultz W, et al. A comparison of intraarticular lumbar facet joint steroid injections and lumbar facet joint radiofrequency denervation in the treatment of low back pain: a randomized, controlled, double-blind trial. Anesth Analg. 2013;117:228–235. 243. Nath S, Nath CA, Pettersson K. Percutaneous lumbar zygapophysial (facet) joint neurotomy using radiofrequency current, in the management of chronic low back pain: a randomized double-blind trial. Spine. 2008;33:1291–1297 discussion 1298. 244. Cahana A, Van Zundert J, Macrea L, et al. Pulsed radiofrequency: current clinical and biological literature available. Pain Med. 2006;7:411–423. 245. Malik K, Benzon HT. Radiofrequency applications to dorsal root ganglia: a literature review. Anesthesiology. 2008;109:527–542. 246. Perret DM, Kim DS, Li KW, et al. Application of pulsed radiofrequency currents to rat dorsal root ganglia modulates nerve injuryinduced tactile allodynia. Anesth Analg. 2011;113:610–616. 247. Van Zundert J, de Louw AJ, Joosten EA, et  al. Pulsed and continuous radiofrequency current adjacent to the cervical dorsal root ganglion of the rat induces late cellular activity in the dorsal horn. Anesthesiology. 2005;102:125–131. 248. Makharita MY, El Bendary HM, Sonbul ZM, et al. Ultrasoundguided pulsed radiofrequency in the management of thoracic postherpetic neuralgia: a randomized, double-blinded, controlled trial. Clin J Pain. 2018;34:1017–1024. 249. Cohen SP, Peterlin BL, Fulton L, et al. Randomized, double-blind, comparative-effectiveness study comparing pulsed radiofrequency to steroid injections for occipital neuralgia or migraine with occipital nerve tenderness. Pain. 2015;156:2585–2594. 250. Koh W, Choi SS, Karm MH, et al. Treatment of chronic lumbosacral radicular pain using adjuvant pulsed radio frequency: a randomized controlled study. Pain Med. 2015;16:432–441. 251. Kroll HR, Kim D, Danic MJ, et al. A randomized, double-blind, prospective study comparing the efficacy of continuous versus pulsed radiofrequency in the treatment of lumbar facet syndrome. J Clin Anesth. 2008;20:534–537. 252. Tekin I, Mirzai H, Ok G, et al. A comparison of conventional and pulsed radiofrequency denervation in the treatment of chronic facet joint pain. Clin J Pain. 2007;23:524–529.

253. Çetin A, Yektaş A. Evaluation of the short- and long-term effectiveness of pulsed radiofrequency and conventional radiofrequency performed for medial branch block in patients with lumbar facet joint pain. Pain Res Manag. 2018;2018:1–8. 254. Rees WE. Multiple bilateral subcutaneous rhizolysis of segmental nerves in the treatment of the intervertebral disc syndrome. Ann Gen Pract. 1971;26:126–127. 255. King JS, Lagger R. Sciatica viewed as a referred pain syndrome. Surg Neurol. 1976;5:46–50. 256. Shealy CN. Percutaneous radiofrequency denervation of spinal facets. Treatment for chronic back pain and sciatica. J Neurosurg. 1975;43:448–451. 257. Shealy CN. Facet denervation in the management of back and sciatic pain. Clin Orthop Relat Res. 1976;115:157–164. 258. Niemistö L, Kalso E, Malmivaara A, et al. Radiofrequency denervation for neck and back pain: a systematic review within the framework of the Cochrane collaboration back review group. Spine. 2003;28:1877–1888. 259. McCulloch JA, Organ LW. Percutaneous radiofrequency lumbar rhizolysis (rhizotomy). Can Med Assoc J. 1977;116:30–32. 260. North RB, Han M, Zahurak M, et  al. Radiofrequency lumbar facet denervation: analysis of prognostic factors. Pain. 1994; 57:77–83. 261. Schaerer JP. Radiofrequency facet rhizotomy in the treatment of chronic neck and low back pain. Int Surg. 1978;63:53–59. 262. Juch JNS, Maas ET, Ostelo RWJG, et al. Effect of radiofrequency denervation on pain intensity among patients with chronic low back pain: the MINT randomized clinical trials. JAMA. 2017;318:68–81. 263. Stolker RJ, Vervest ACM, Groen GJ. Percutaneous facet denervation in chronic thoracic spinal pain. Acta Neurochir. 1993;122: 82–90. 264. Rohof O, Chen CK. The response to radiofrequency neurotomy of medial branches including a bipolar system for thoracic facet joints. Scand J Pain. 2018;18:747–753. 265. Kim D. Bipolar intra-articular radiofrequency thermocoagulation of the thoracic facet joints: a case series of a new technique. Korean J Pain. 2014;27:43–48. 266. Stovner LJ, Kolstad F, Helde G. Radiofrequency denervation of facet joints C2-C6 in cervicogenic headache: a randomized, double-blind, sham-controlled study. Cephalalgia. 2004;24: 821–830. 267. Van Suijlekom HA, van Kleef M, Barendse GA, et  al. Radiofrequency cervical zygapophyseal joint neurotomy for cervicogenic headache: a prospective study of 15 patients. Funct Neurol. 1998;13:297–303. 268. van Eerd M, de Meij N, Kessels A, et al. Efficacy and long-term Effect of Radiofrequency Denervation in Patients with Clinically diagnosed cervical facet joint pain: a double-blind tandomized controlled trial. Spine (Phila Pa 1976). 2021 Mar 1;46(5):285–293. doi: 10.1097/ BRS.0000000000003799. PMID: 33534439. 269. Sapir DA, Gorup JM. Radiofrequency medial branch neurotomy in litigant and nonlitigant patients with cervical whiplash: a prospective study. Spine. 2001;26:E268–E273. 270. van Eerd M, Lataster A, Sommer M, et al. A modified posterolateral approach for radiofrequency denervation of the medial branch of the cervical segmental nerve in cervical facet joint pain based on anatomical considerations. Pain Pract. 2017;17:596–603. 271. Civelek E, Cansever T, Kabatas S, et al. Comparison of effectiveness of facet joint injection and radiofrequency denervation in chronic low back pain. Turk Neurosurg. 2012;22:200–206. 272. Moussa WMM, Khedr W. Percutaneous radiofrequency facet capsule denervation as an alternative target in lumbar facet syndrome. Clin Neurol Neurosurg. 2016;150:96–104. 273. Van Tilburg CWJ, Stronks DL, Groeneweg JG, et al. Randomised sham-controlled double-blind multicentre clinical trial to ascertain the effect of percutaneous radiofrequency treatment for lumbar facet joint pain. Bone Joint J. 2016;98-B:1526–1533.

References

274. Cohen SP, Strassels SA, Kurihara C, et al. Does sensory stimulation threshold affect lumbar facet radiofrequency denervation outcomes? A prospective clinical correlational study. Anesth Analg. 2011;113:1233–1241. 275. Stoker GE, Buchowski JM, Kelly MP, et  al. Dropped head syndrome after multilevel cervical radiofrequency ablation: a case report. J Spinal Disord Tech. 2013;26:444–448. 276. Poetscher AW, Gentil AF, Lenza M, et al. Radiofrequency denervation for facet joint low back pain: a systematic review. Spine. 2014;39:E842–E849. 277. Maas ET, Ostelo RWJG, Niemisto L, et al. Radiofrequency denervation for chronic low back pain. Cochrane Database Syst Rev. 2015;10 CD008572. 278. Lee CH, Chung CK, Kim CH. The efficacy of conventional radiofrequency denervation in patients with chronic low back pain originating from the facet joints: a meta-analysis of randomized controlled trials. Spine J. 2017;17:1770–1780. 279. Manchikanti L, Hirsch JA, Kaye AD, et al. Cervical zygapophysial (facet) joint pain: effectiveness of interventional management strategies. Postgrad Med. 2016;128:54–68. 280. Manchikanti L, Hirsch JA, Falco FJ, et al. Management of lumbar zygapophysial (facet) joint pain. World J Orthop. 2016;7:315–337. 281. Schneider BJ, Doan L, Maes MK, et al. Systematic review of the effectiveness of lumbar medial branch thermal radiofrequency neurotomy, stratified for diagnostic methods and procedural technique. Pain Med. 2020;21:1122–1141 6. 282. Benzon HT. Epidural steroid injections for low back pain and lumbosacral radiculopathy. Pain. 1986;24:277–295. 283. North RB, Campbell JN, James CS, et  al. Failed back surgery syndrome: 5-year follow up in 102 patients undergoing repeated operation. Neurosurgery. 1991;28:685–690. discussion 690. 284. Quigley MR, Bost J, Maroon JC, et  al. Outcome after microdiscectomy: results of a prospective single institutional study. Surg Neurol. 1998;49:263–267. discussion 267. 285. Streitberger K, Müller T, Eichenberger U, et al. Factors determining the success of radiofrequency denervation in lumbar facet joint pain: a prospective study. Eur Spine J. 2011;20:2160–2165 12. 286. Conger A, Burnham T, Salazar F, et  al. The effectiveness of radiofrequency ablation of medial branch nerves for chronic lumbar facet joint syndrome in patients selected by guidelineconcordant dual comparative medial branch blocks. Pain Med. 2020;21:902–909. 287. Cohen SP, Doshi TL, Kurihara C, et al. Waddell (nonorganic) signs and their association with interventional treatment outcomes for low back pain. Anesth Analg. 2021;132:639–651. 288. Schofferman J, Kine G. Effectiveness of repeated radiofrequency neurotomy for lumbar facet pain. Spine. 2004;29:2471–2473. 289. Husted DS, Orton D, Schofferman J, et  al. Effectiveness of repeated radiofrequency neurotomy for cervical facet joint pain. J Spinal Disord Tech. 2008;21:406–408. 290. Smuck M, Crisostomo RA, Trivedi K, et al. Success of initial and repeated medial branch neurotomy for zygapophysial joint pain: a systematic review. PMR. 2012;4:686–692. 291. Tiegs-Heiden CA, Lehman VT, Gorny KR, et al. Improved treatment response following magnetic resonance imaging-guided focused ultrasound for lumbar facet joint pain. Mayo Clin Proc Innov Qual Outcomes. 2020;4:109–113. 292. Krug R, Do L, Rieke V, et al. Evaluation of MRI protocols for the assessment of lumbar facet joints after MR-guided focused ultrasound treatment. J Ther Ultrasound. 2016;4:14. 293. Harnof S, Zibly Z, Shay L, et  al. Magnetic resonance-guided focused ultrasound treatment of facet joint pain: summary of preclinical phase. J Ther Ultrasound. 2014;2:9. 294. Iwatsuki K, Yoshimine T, Awazu K. Alternative denervation using laser irradiation in lumbar facet syndrome. Lasers Surg Med. 2007;39:225–229. 295. Trescot AM. Cryoanalgesia in interventional pain management. Pain Phys. 2003;6:345–360.

452.e7

296. Perolat R, Kastler A, Nicot B, et  al. Facet joint syndrome: from diagnosis to interventional management. Insights Imaging. 2018; 9:773–789. 297. Deyo RA, Nachemson A, Mirza SK. Spinal-fusion surgery-the case for restraint. N Engl J Med. 2004;350:722–726. 298. Gibson JN, Waddell G, Grant IC. Surgery for degenerative lumbar spondylosis. Cochrane Database Syst Rev. 2003;4 CD001352. 299. Esses SI, Botsford DJ, Kostuik JP. The role of external spinal skeletal fixation in the assessment of low-back disorders. Spine. 1989;14:594–601. 300. Jackson RP. The facet syndrome. Myth or reality? Clin Orthop Relat Res. 1992;279:110–121. 301. Esses SI, Moro JK. The value of facet joint blocks in patient selection for lumbar fusion. Spine. 1993;18:185–190. 302. Lovely TJ, Rastogi P. The value of provocative facet blocking as a predictor of success in lumbar spine fusion. J Spinal Disord. 1997;10:512–517. 303. Zhu Q, Larson CR, Sjovold SG, et al. Biomechanical evaluation of the total facet arthroplasty system: 3-dimensional kinematics. Spine. 2007;32:55–62. 304. Kornick C, Kramarich SS, Lamer TJ, et al. Complications of lumbar facet radiofrequency denervation. Spine. 2004;29:1352–1354. 305. Kay J, Findling JW, Raff H. Epidural triamcinolone suppresses the pituitary-adrenal axis in human subjects. Anesth Analg. 1994;79:501–505. 306. Ward A, Watson J, Wood P, et al. Glucocorticoid epidural for sciatica: metabolic and endocrine sequelae. Rheumatol (Oxf Engl). 2002;1:68–71. 307. Alcock E, Regaard A, Browne J. Facet joint injection: a rare form cause of epidural abscess formation. Pain. 2003;103:209–210. 308. Gaul C, Neundörfer B, Winterholler M. Iatrogenic (para-) spinal abscesses and meningitis following injection therapy for low back pain. Pain. 2005;116:407–410. 309. Orpen NM, Birch NC. Delayed presentation of septic arthritis of a lumbar facet joint after diagnostic facet joint injection. J Spinal Disord Tech. 2003;16:285–287. 310. Cohen SP. Postdural puncture headache and treatment following successful lumbar facet block. Pain Dig. 1994;4:283–284. 311. Goldstone JC, Pennant JH. Spinal anaesthesia following facet joint injection. A report of two cases. Anaesthesia. 1987;42:754–756. 312. Manchikanti L, Malla Y, Wargo BW, et  al. Complications of fluoroscopically directed facet joint nerve blocks: a prospective evaluation of 7,500 episodes with 43,000 nerve blocks. Pain Phys. 2012;15:E143–E150. 313. Edlow BL, Wainger BJ, Frosch MP, et al. Posterior circulation stroke after C1-C2 intraarticular facet steroid injection: evidence for diffuse microvascular injury. Anesthesiology. 2010;112:1532–1535. 314. Youn HJ, Shim JC. Burn wound along the guide needle trajectory as a complication of radiofrequency neurotomy of the lumbar medial branch-A case report. Korean J Pain. 2006;19:257–260. 315. Tzaan WC, Tasker RR. Percutaneous radiofrequency facet rhizotomy– experience with 118 procedures and reappraisal of its value. Can J Neurol Sci. 2000;27:125–130. 316. Dobrogowski J, Wrzosek A, Wordliczek J. Radiofrequency denervation with or without addition of pentoxifylline or methylprednisolone for chronic lumbar zygapophysial joint pain. Pharmacol Rep. 2005;57:475–480. 317. Tiyaprasertkul W, Perez J. Injection of steroids before radiofrequency ablation has a negative impact on lesion size. Reg Anesth Pain Med. 2014;39:189–191. 318. Singh JR, Miccio VF, Modi DJ, et al. The impact of local steroid administration on the incidence of neuritis following lumbar facet radiofrequency neurotomy. Pain Physician. 2019;22:69–74. 319. Geurts JW, van Wijk RM, Stolker RJ, Groen GJ. Efficacy of radiofrequency procedures for the treatment of spinal pain: a systematic review of randomized clinical trials. Reg Anesth Pain Med. 2001 Sep-Oct;26(5):394–400. doi: 10.1053/rapm.2001.23673. PMID: 11561257.

32

Neurosurgical Approaches to Pain Management

MARSHALL T. HOLLAND, AHMED M. RASLAN, KIM J. BURCHIEL

Neurosurgeons have a long history of surgical treatment for pain, particularly cancer pain. The notion that sectioning pain pathways could achieve pain control was first introduced by Spiller and Martin1 in 1912, and was followed by the development of a whole array of surgical procedures aimed at interrupting ascending pain signals throughout different parts of the central nervous system. Two major approaches are used when targeting the brain or the spinal cord to treat pain. The first is a nondestructive approach that uses either electrical stimulation of brain targets, which is thought to modulate the process of pain perception, or pharmacologic agents, which are introduced into the ventricular or intrathecal spaces to target pain-modulating receptors. Targets for electrical stimulation include the peripheral nerves, spinal cord, thalamic nuclei, periventricular gray (PVG) matter, periaqueductal gray (PAG) matter, and motor cortex. Currently, the pharmacologic agent of choice for intrathecal or intracerebroventricular (ICV) injection is morphine or other opiates. In general, nondestructive procedures are used for non-malignant pain. However, intrathecal opioids are also used for the treatment of cancer pain. The second approach is a destructive approach, which is used with the goal of interrupting signals that lead to the perception of pain at various levels. Neuroablation can be performed on cellular complexes, such as nuclei or gyri, or on tracts to either disrupt the ascending sensory signals or destroy the limbic pathways involved in the emotional processes associated with pain. This chapter discusses several approaches within the two broad categories of neurosurgical procedures for pain: (1) neuroablation and (2) neuromodulation, which is further subdivided into electrical and pharmacologic neuromodulation. Each broad category is further discussed based on the level of the nervous system that is being intervened.

wide involvement of many thalamic nuclei in pain processing, it has been considered a part of the pain surgery armamentarium.2 The first structure targeted for neuroablation was the ventral caudal (Vc) nucleus, as defined by Hassler.3 However, it was soon recognized that neuroablation of the Vc nucleus was associated with significant deafferentation pain phenomena. The work of Mark and colleagues led to the belief that targeting the medial thalamic nuclei was more effective in managing pain.4 Nuclear targets for neuroablative medial thalamotomy are (1) the centralis lateralis, (2) the centrum medianum, and (3) the parafascicularis. Several pain syndromes, including cancer pain, central and peripheral deafferentation pain, spinal cord injury, malignancy, arthritis, and neurogenic pain associated with Parkinson’s disease, have been successfully treated by medial thalamotomy. Frank et al. reported the overall success rate of medial thalamotomy to be 52%,5 with cancer pain being the main condition treated. Jeanmonod et al.6 and Young et al.7 used radiofrequency and gamma knife treatment, respectively, and reported a 60% success rate in achieving pain control. The ideal target lying between the three main medial thalamic nuclei (listed above) has yet to be determined, although the centrum medianum nucleus is the most frequently targeted. Deep brain stimulation (DBS) of the medial nuclei does not usually produce a conscious sensory response, and lesioning does not induce sensory loss. The published literature on medial thalamotomy is inconsistent regarding the target, guidance technique, patient population, and lesioning method used. Therefore the actual success rate of medial thalamotomy is challenging to assess. However, in general, the procedure is considered to be effective in treating nociceptive pain, with recent data pointing to some success in relieving neuropathic pain.

Neuroablation

Cingulotomy refers to stereotactic lesioning of the anterior cingulate gyrus. Le Beau performed the first open cingulotomy to treat intractable pain in 1954,8 which is believed to cause relief by altering a patient’s emotional reaction to painful stimuli by interrupting the Papez circuit9 and increasing tolerance to the subjective and emotional feelings of pain.10,11 Cingulotomy is performed with standard stereotactic protocols, usually under general anesthesia. Bilateral lesions are made in the anterior aspect of the cingulate gyrus, and the success of the procedure is directly related to the extent of ablation of the cingulum (Fig. 32.1).1 A suitable stereotactic cingulotomy candidate is a terminally ill patient with widespread metastatic disease that has extended to

Cerebral Neuroablation Historically, many procedures fall into this category, including mesencephalotomy, pontine tractotomy, and hypophysectomy. We focus on procedures that we believe have more than what could be considered purely historical significance.

Medial Thalamotomy Stereotactic thalamic neuroablative surgery for pain is relatively safe with respect to deep brainstem structures, and because of the

Stereotactic Cingulotomy

453

454

PA RT 4 Clinical Conditions: Evaluation and Treatment

Cerebral Neuromodulation

Cerebral Neuroablation

Deep brain stimulation

Medial thalamotomy

Spinal Neuroablation Myelotomy

Trigeminal nucleotomy-tractotomy

Motor cortex stimulation

Cingulotomy

Cordotomy

Intraventricular opioids

DREZ

Caudalis DREZ

Not illustrated: Hypophysectomy mesencephalotomy

Hypothalamotomy pontine tractotomy

• Figure 32.1  Diagrammatic representation of cerebral neuromodulation and neuroablation procedures and spinal neuroablation procedures. DREZ, Dorsal root entry zone. (Adapted with permission from Raslan AM, McCartney S, Burchiel KJ. Management of chronic severe pain: spinal neuromodulatory and neuroablative approaches. Acta Neurochir Suppl. 2007;97:33-41. With kind permission from Springer Science and Business Media.)

the musculoskeletal system, where intrathecal or intraventricular administration of opiates is difficult. Emotional factors associated with pain would favor the selection of a stereotactic cingulotomy procedure. Stereotactic cingulotomy has been used to treat nonmalignant pain with a success rate of approximately 25%.12 Stereotactic cingulotomy involves the ablation of sufficient anterior cingulate gyrus volume, which is usually achieved by producing at least two lesions with a wide surface area and non-insulated tip electrode. The procedure is generally safe, with few minor side effects. Pillay and Hassenbusch reported on a series of 12 patients in whom seven had satisfactory pain relief.13 Cingulotomy is rarely used today, mainly because of its narrow indication, advances in the medical management of terminal cancer patients, and the widespread use of neuroaugmentive procedures.

Caudalis Dorsal Root Entry Zone (Brainstem Level) Following the introduction of stereotaxis in the 1960s, the use of open ablative brain and brainstem surgery was almost abandoned. Siqueira first reported the performance of the caudalis dorsal root entry zone (DREZ) procedure in two patients.14 Gorecki et al. at Duke University15,16 later adopted the technique and expanded its indications. In the caudalis DREZ procedure, the caudal portion of the spinal trigeminal nucleus, along with the overlying trigeminal tract, is destroyed. Similar to spinal DREZ surgery, the objective is to destroy the cells of second-order neurons thought to be hyperactive in trigeminal deafferentation pain, thereby achieving pain relief (Fig. 32.1). The main indications for the caudalis

DREZ procedure are ophthalmic postherpetic neuralgia and trigeminal anesthesia dolorosa. In cases of neuropathic facial pain in which all other medical and surgical modalities are ineffective, the caudalis DREZ procedure may represent a last resort. The procedure is rarely performed, and potential risks include ipsilateral limb ataxia and weakness.

Spinal Neuroablation The first report of surgical disruption of spinal pain pathways was presented by Spiller and Martin in 1912. They sectioned the anterolateral quadrant of the spinal cord to interrupt the transmission of pain signals via the spinothalamic tract (anterolateral system) and to relieve pain on the contralateral side of the body caudal to the lesion.1 Several decades ago, open surgical sectioning of the spinothalamic tract (anterolateral cordotomy) to control pain was a common procedure in many neurosurgical centers. The procedure is mainly used to treat somatic nociceptive pain, usually from cancer. However, factors such as the debilitated state of cancer patients resulting in poor tolerance of open spinal cord surgery, together with high complication rates, meant that the procedure was not an ideal solution to the problem of cancer pain. Currently, spinal cord targets for destructive procedures to treat pain include (1) the spinothalamic tract (anterolateral column), where destruction can alleviate somatic nociceptive pain below the level of the neck (e.g. anterolateral cordotomy), (2) the trigeminal

 

CHAPTER 32

spinal nucleus, which is disrupted to treat trigeminal neuropathic pain (e.g. trigeminal tractotomy-nucleotomy [“caudalis DREZ”]), (3) the midline ascending polysynaptic visceral pain pathway, which is used to treat visceral pain, particularly pelvic pain (i.e. midline myelotomy), and (4) the DREZ, primarily to treat deafferentation pain in the upper extremity (i.e. DREZ procedure; Fig. 32.1). The role of each of these procedures in contemporary surgical pain management is reviewed.

Anterolateral Cordotomy Anterolateral cordotomy refers to lesioning, sectioning, or other disruption of the lateral spinothalamic tract (LST), which is located in the anterolateral quadrant of the spinal cord. The procedure was historically performed in the upper thoracic spine via an open posterior approach and, less commonly, high in the cervical spine.17 The spinal cord anterolateral ascending pain transmission system carries information about pain and temperature from one side of the body. The tract is formed by the central processes of nociceptive neurons in the dorsal horn that cross the spinal cord in the anterior commissure, ascend in the anterolateral column to the brainstem, and relay in the thalamus. Lesions of the anterolateral tract produce a contralateral deficit in pain and temperature sensation in two to five segments below the level of the cordotomy. Fibers in the LST have a somatotopic arrangement, with the sacral segments arranged posterolaterally and the cervical segments anteromedially.18 The corticospinal (pyramidal) tract lies posterior to the LST with the white matter in between. The ventral spinocerebellar tract overlies the LST, and a lesion that damages the spinocerebellar tract may cause ipsilateral ataxia of the arm. Autonomic pathways for vasomotor and genitourinary control and reticulospinal fibers that subserve ipsilateral automatic respiration are also part of the anterolateral quadrant of the spinal cord. A patient with hemibody somatic cancer pain localized caudal to the cervical and upper thoracic areas represents the best candidate for a cordotomy procedure.19 From the beginning of the 20th century until the late 1960s to early 1970s, cordotomy was an open procedure undertaken at the mid to high thoracic levels since these sites largely avoided the complications of upper limb ataxia and sleep apnea.20 Introduction of the minimally invasive percutaneous approach for cordotomy by Mullan et al. mitigated some of the neurologic risks and made it possible for the procedure to be performed on patients in poor general health.21,22 In the mid-1980s and early 1990s, advances in opioid pharmacology, as well as the introduction of reversible and testable neuroaugmentive techniques, reduced the perceived need for spinal destructive procedures for pain control and led to a major reduction in the number of cordotomies performed by neurosurgeons worldwide. These neuroaugmentive procedures are expensive, particularly given the short life expectancy of many of the candidates, and are not uniformly effective. Kanpolat et al. first introduced the concept of computed tomography (CT)-guided cordotomy, which allowed for a safer, selective, and more effective procedure.23–25 In 1995, Fenstermaker and associates26 performed anterior CT-guided lower cervical cordotomy through the disk space to avoid sleep apnea (a modification of Gildenberg et al.’s anterior low cervical percutaneous cordotomy).27 CT-guided cordotomy is typically performed as a percutaneous procedure via a lateral approach to the spinal cord at the level of C2. However, the anterior cervical transdiscal approach can also be used; in a clinical study, this approach was used to control cancer pain in six of eight patients with ­pulmonary-pleural malignancy while avoiding sleep apnea.28

Neurosurgical Approaches to Pain Management

455

Currently, the CT-guided cordotomy procedure involves lumbar puncture and injection of a water-soluble dye into the patient’s intrathecal space. After 30 min, a cervical CT scan was performed. These and subsequent scans were used to direct the cordotomy electrode into the anterolateral quadrant of the ipsilateral spinal cord. The electrode is insulated throughout the entire shaft except for the tip (2 mm in length and 0.3 to 0.4 mm in diameter). After measurement of the skin-dura distance and local anesthesia of the lateral cervical region, an electrode was introduced from the lateral side of the neck opposite the C2 foramen into the anterolateral quadrant of the spinal cord. Electrophysiologic testing is essential to ensure complete entry into the spinothalamic tract while avoiding the corticospinal tract. Radiofrequency lesions are performed until adequate hypoesthesia is achieved in the contralateral hemibody, or at least in the region of pain. CT-guided cordotomy has a higher success rate and fewer complications than traditional approaches. Control of cancer pain has been reported in more than 95% of the cases. Procedural complications may include weakness, hypotension, dysesthesia, mirror-image pain, ataxia, incontinence, and sleep apnea. Contemporary CT-guided cordotomy complications tend to be both minor and transient.29 An evidence-based review concluded that the case for cordotomy is somewhat unique among all cancer pain procedures in that it has the most supportive evidence.30 The review used the ­Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system, and a recommendation for cordotomy was given. The GRADE system produces recommendations that are independent of the level of evidence.31

Trigeminal Tractotomy-Nucleotomy (Spinal Level) Sensory information from the 5th, 7th, 9th, and 10th cranial nerves is carried by the trigeminal tract and branches into the trigeminal tract spinal nucleus. It extends caudally into the spinal cord to C2.32 The trigeminal tract is considered a target for surgical treatment of facial pain,33 and the history of procedures with this target is similar to cordotomy in that initial open procedures evolved toward less invasive stereotactic operations. Crue et al. and Hitchcock developed a stereotactic technique to lesion the trigeminal tract and nucleus via radiofrequency, named trigeminal nucleotomy.34,35 As with CT-guided cordotomy, CT is used when performing the trigeminal tractotomy-nucleotomy (TR-NC) procedure today. Indications include anesthesia dolorosa, postherpetic neuralgia, neuropathic facial pain, facial cancer pain, and either glossopharyngeal or geniculate neuralgia.25,36 The procedure can be considered, in some ways, a mini-caudalis DREZ procedure. The nucleus caudalis DREZ operation involves the same concept as the TR-NC procedure but includes the destruction of the substantia gelatinosa (Rexed laminae II and III) of the nucleus caudalis. Pain relief from TR-NC is reported to be complete or satisfactory in 80% of cases. Complications include ataxia from injury to the spinocerebellar tract (usually temporary) and contralateral hypoalgesia if the spinothalamic tract is included in the lesion.25,34,36,37

Extralemniscal Myelotomy The extralemniscal myelotomy (ELM) procedure was first described by Hitchcock, who initially aimed to destroy the decussating fibers of the spinothalamic tract in the anterior commissure of the spinal cord to control pain in the neck and both arms.38 ELM was achieved by creating a lesion in the central medullary region at the cervicomedullary junction. Unexpectedly, the ELM procedure also seemed to control pain caudal to the level of the

456

PA RT 4 Clinical Conditions: Evaluation and Treatment

lesion. Schvarcz added the term “extralemniscal” to “myelotomy” because of the contention that the lesion incorporated an ascending polysynaptic nociceptive pathway.39 Subsequently, the presence of such a tract has been confirmed anatomically. Several authors have presented reports of midline “punctuate” ELM via open procedures to interrupt this pathway at various spinal cord levels. The polysynaptic ascending pathway is thought to carry visceral nociceptive information and lies deep to the midline dorsal column.40–42 The concept of CT guidance, previously applied to cordotomy and TR-NC procedures, has also been applied to ELM by Kanpolat et al., thus developing the image-guided ELM procedure used today.36 ELM is currently conceived as a pain control procedure for pain of visceral origin, including pelvic malignancy or cancer pain in the lower part of the trunk and lower extremities with a predominant visceral pain component. The procedure appears to be safe. However, pain relief results are not as good as those achieved with cordotomy and TR-NC procedures.17

Dorsal Root Entry Zone Lesions With the introduction of the gate control theory in the 1960s, attention was drawn to the spinal dorsal horn as the initial physiologic substrate for pain modulation.43 The dorsal horn and DREZ were then reconsidered as targets for neuromodulation (spinal cord stimulation) and neuroablation. In 1972, Sindou first attempted cervical DREZ destruction for neuropathic deafferentation pain in the upper extremity secondary to brachial plexus avulsion.44 Nashold et al. soon followed and introduced the use of radiofrequency lesions to perform DREZ disruption.45 Laser and ultrasound have also been used to damage the DREZ.46,47 When large-fiber afferents (touch, position sense) in peripheral nerves or dorsal roots are altered, there is a reduction in the inhibitory control of the dorsal horn.48 This situation is presumed to result in the excessive firing of the dorsal horn neurons, which is thought to be the cause of deafferentation pain and can be controlled by DREZ lesioning.49 The technical details of the procedure and its variants are beyond the scope of this chapter, but DREZ lesioning is performed as an open surgical procedure under general anesthesia and often accompanied by intraoperative neurophysiologic monitoring. Surgical candidates include patients with brachial plexus avulsion, Pancoast’s tumor with brachial plexus invasion combined with a good general condition and reasonable life expectancy, pain caused by spinal cord or cauda equina lesions, and pain accompanying spasticity after plexus or cord injury.44 A general prerequisite for the DREZ procedure is a lack of functional use of the limb where the DREZ procedure is performed because complete sensory denervation of the limb will render it functional even if there is residual motor power. When patients are carefully selected, and the lesions are accurately performed, the success rate can be as high as 90% (with follow up success rates reported for up to four years). Complications and side effects include cerebrospinal fluid fistula, meningitis, ataxia, increased neurologic deficits, and dysesthesias.50

Neuromodulation Electrical Neuromodulation Central Electrical Neuromodulation Deep Brain Stimulation

Pool first observed and reported on the analgesic effects of septal stimulation in the frontal and lateral forniceal columns while performing psychosurgery in the 1950s.51 Heath and Mickle and Pool

et al. subsequently reported the pain-relieving effect of septal and near-septal stimulation in nonpsychiatric patients.52,53 Mazars and coauthors and Reynolds first reported pain relief from thalamic stimulation in 1960.54,55 Neurostimulation of the brain to relieve pain was thus introduced decades before what has become the main contemporary indication for DBS, that is, the treatment of movement disorders.56 However, these early reports only set the stage for the eventual application of DBS for pain relief. In the mid-1960s, Melzack and Wall’s gate theory43 provided a logical rationale for DBS of the sensory thalamus to control pain. Shortly afterward, Reynolds reported on the analgesic effect of focal brain stimulation in rats (stimulation produced analgesia).55 In the early 1970s, Hosobuchi and associates57,58 and Richardson and Akil59,60 were the first to report on stimulation of the human thalamus and PVG and PAG matter for pain control. Although stimulation of the thalamic sensory nuclei produced paresthesia in painful areas, consistent pain relief was not achieved. Similar results were produced by stimulation of the internal capsule.61,62 Stimulation of the PVG and PAG typically did not produce paresthesia but did induce a sense of “warmth.” High-intensity PVG/PAG stimulation produced unpleasant and sometimes overwhelming sensations, such as those of impending doom or terror. The centromedian-parafascicular complex was also targeted by Andy63 as a stimulation site to treat pain, and this stimulation likewise did not produce paresthesia. Despite reports describing the use of DBS to treat chronic pain in the 1970s and the early 1980s, data to support the technique never reached contemporary evidentiary standards. The use of DBS for pain control has failed to gain much acceptance in the neurosurgical community, and the use of DBS electrodes as pain control implants has never achieved United States Federal Drug Administration (FDA) approval. The lack of data to support the procedure is due, in part, to the small number of patients treated, inconsistent target localization, heterogeneity of the pain diagnoses treated, and failure to mount a prospective randomized trial that was sufficiently powered to answer the question of efficacy. The mechanism of pain relief by DBS is poorly understood but appears to be dependent on the site. The thalamus and PVG/PAG are the most commonly64 targeted sites for DBS implants for pain. Hosobuchi et al.58 suggested that the pain-relieving effect of PVG and PAG stimulation might involve endogenous opioid receptors based on their studies that found that the pain-relieving effect of DBS could be reversed by naloxone. Evidence supporting this mechanism of action of PAG/PVG DBS is inconsistent. Some investigators supported this concept, whereas others disagreed. Currently, it is postulated that the pain-relieving effect of PAG/PVG DBS is because of activation of multiple supraspinal descending pain modulatory systems, both opioid and nonopioid.64 Pain relief resulting from stimulation of the ventral posterolateral (VPL) nucleus and ventral posteromedial (VPM) nucleus (Vc nucleus in the European Hassler terminology), the major sensory nuclei of the thalamus, is poorly understood. Inhibition of spinothalamic tract neurons65 and activation of dopaminergic mechanisms have both been proposed.66 The most accepted hypothesis is that thalamic stimulation activates the nucleus raphe magnus of the rostroventral medulla, which results in activation of a suprasegmental descending endogenous pain inhibition system.64 Meticulous patient selection, with classification of pain (i.e. nociceptive or neuropathic) and informed DBS target selection, should help improve the outcome of DBS for pain. Clinical case series (class III evidence) observations suggest that PVG/PAG

 

CHAPTER 32

stimulation seems more effective in treating somatic nociceptive pain. This is consistent with the opioid-mediated effects of PAG/PVG stimulation. It has also been suggested that VPL and VPM (Vc) stimulation is more effective in treating neuropathic pain, a gate theory-based concept.67 In the absence of controlled trials to prove efficacy, definitive conclusions regarding the ideal target for any particular pain syndrome remain elusive. Furthermore, many patients have mixed neuropathic/nociceptive pain, which suggests that the DBS target to control pain should be individualized according to the patient. Some authors have suggested placing two electrodes simultaneously in the sensory thalamic nucleus (Vc) and the PVG.68 Another target, the anterior cingulate nucleus, has been tested and may produce better overall results.69,70 For some pain syndromes (e.g. thalamic infarction-induced pain), target selection is simpler, given that thalamic stimulation is impossible.70 Chronic neuropathic pain conditions treated by DBS include anesthesia dolorosa, post-stroke pain, thalamic pain, brachial plexus avulsion, postherpetic neuralgia, postcordotomy dysesthesia, spinal cord injuries, and peripheral neuropathy pain. Nociceptive pain conditions treated by but not limited to DBS include failed back surgery syndrome, osteoarthritis, and cancer pain.71 Another target of interest for patients with post-stroke pain is the ventral striatum/anterior limb of the internal capsule.71 Unfortunately, a recent randomized study failed to achieve a >50% decrease in pain compared to the control (sham) population. However, upon further analysis, the researchers showed significant improvement in the affective sphere of pain.72 DBS for chronic pain is similar to DBS for other indications (movement disorders) in that surgeons have several targets that are applicable to the general problem (Fig. 32.1). DBS target locations are often indirectly derived from the Schaltenbrand and Bailey atlas or measured directly from the patient’s CT or magnetic resonance imaging scans. The location of these targets can be confirmed intraoperatively by macrostimulation, microelectrode mapping, or intraoperative imaging. To best judge the benefits of stimulation and help fine-tune stimulation parameters following final electrode implantation, a trial period of approximately one week is often a prerequisite. The complications of DBS for pain relief are similar to those of movement disorders. Typically, they are related to (1) brain injury from bleeding or inadvertent trauma as a result of electrode insertion, (2) infection, (3) hardware failure, or (4) transient site-specific side effects related to overstimulation or unintentional stimulation of neighboring areas. The latter might produce diplopia, seizures, nausea, paresthesia, or headaches. Overall, DBS surgery is a safe procedure with a relatively low risk of complications or unintended neurologic sequelae. However, data supporting its efficacy are limited. Currently, DBS for pain control is an extraordinary treatment that may be applicable to only a few chronic pain conditions. DBS implantable hardware is not approved by the FDA for pain control procedures, and many insurance carriers do not authorize implantation. Given the tremendous interest in and application of DBS for movement disorders, whether DBS for pain will be substantially resurrected at some point remains to be seen. Motor Cortex Stimulation

In 1954, Penfield and Jasper observed that stimulation of the precentral (motor) gyrus elicited sensory responses when the

Neurosurgical Approaches to Pain Management

457

corresponding portion of the adjacent postcentral gyrus had previously been resected.73 They treated burning pain on one side of the body by postcentral gyrectomy, and when the pain recurred, they performed precentral gyrectomy, which then controlled the pain. In 1955 White and Sweet attempted surgical resection of the postcentral gyrus for relief of central pain and reported 13% pain relief.74 It was not until 1971, after the publication of the gate theory in 1965, that Lende et al. re-explored the motor cortex as a potential site for pain control. In an attempt to treat central neuropathic facial pain,75 they performed two cases of precentral and postcentral gyrectomy of the facial cortex. These reports formed the basis for establishing a link between the precentral and postcentral areas and pain control surgery. By the 1980s the cumulative failure of other procedures, both modulatory and destructive, to fundamentally alter neuropathic pain made it clear that the development of an innovative methodology to surgically treat pain was critically needed. Exploration of the motor area as a target site is under way. Hardy et al. stimulated the rat medial prefrontal cortex with a resultant significant elevation in nociceptive response latency.76,77 Hosobushi implanted electrodes in subcortical somatosensory areas for control of dysesthetic pain, and from this study, it was concluded that somatosensory stimulation could be effective in the treatment of leg pain.78 In 1991 Tsubokawa et al. first introduced epidural stimulation of the motor cortex as an option to treat central deafferentation pain. His group had tried postcentral gyrus (sensory) stimulation and found that it was either ineffective or exacerbated the pain. They demonstrated that epidural MCS inhibited abnormal thalamic neuronal burst activity and increased regional blood flow to the cortex and thalamus.79 Primarily, Tsubokawa et  al. used MCS for central deafferentation pain syndromes, such as poststroke pain.79,80 The mechanism of action of MCS is still poorly understood. However, the work of Garcia-Larrea, P ­ eyron, and coworkers81–83 has shed some light on its mechanism of action. Positron emission tomography and electrophysiologic studies have ­demonstrated that MCS increases blood flow to the ipsilateral thalamus, cingulate gyrus, orbitofrontal cortex, insula, and brainstem, with some correlation between increased thalamic and brainstem blood flow and efficacy of pain relief. The increased blood flow to the ipsilateral sensory thalamus was greater than that to the motor (ventrolateral) thalamus. It does not appear that an intact somatosensory system is absolutely necessary for the clinical benefits to be realized, an important discovery allowing the use of this technology for stroke and other deafferentation states.81–83 As with many forms of chronic stimulation, habituation seems to occur, which is more likely with the use of high frequency stimulation. The patient selection process for MCS is of paramount importance (as it is for all pain-relieving surgeries), and in this case, the debate continues. Neuropathic pain is more responsive to this form of therapy than nociceptive pain. Attempting to predict the best candidates for MCS can be challenging, and Yamamoto et al. introduced a pharmacologic classification of post-stroke patients based on their pain relief response to escalating doses of intravenous thiamylal and morphine. They concluded that patients with a good response to thiamylal or ketamine and a poor response to morphine were the best candidates for MCS.84 Several neurogenic pain syndromes have been treated by MCS, including thalamic pain, bulbar post-stroke pain (which typically occurs with “Wallenberg’s syndrome”), facial neuropathic and deafferentation pain, and phantom and brachial plexus avulsion pain.85,86 Treatment of central post-stroke pain following thalamic infarction or thalamic or putaminal bleeding

458

PA RT 4 Clinical Conditions: Evaluation and Treatment

by MCS was reported by Tsubokawa et al. to achieve good to excellent pain control in 65% of cases (follow up >12 months), with no seizures observed.79,80 Katayama and associates extended the indications to include bulbar pain secondary to “Wallenberg’s syndrome” and reported on four patients initially treated by VPL thalamic stimulation that resulted in increased pain. Three other patients were later treated by MCS, with a greater than 60% reduction in pain in two patients and greater than 40% in one patient.87 Treatment of neuropathic facial pain appears to be one of the most promising indications for MCS, which may be related to the breadth of facial representation over the motor cortex. Several reports have described neuropathic facial pain treatment using MCS. Raslan et al. all treated trigeminal neuropathic pain with MCS and reported pain relief in approximately 60% of patients for up to 12 months.86,88–93 Peripheral deafferentation pain and brachial plexus avulsion pain have also been treated by MCS, with variable results. Movement disorders are an active area of ongoing MCS research.85 MCS has been shown to improve the symptoms of thalamic hand syndrome, action tremors, intention myoclonus, and Parkinson’s disease. MCS involves the implantation of epidural electrodes over the motor cortex (Fig. 32.1), which can be localized by (1) radiologic landmarks of the central sulcus, (2) intraoperative somatosensory evoked potentials with an observation of “phase reversal” over the central sulcus, (3) intraoperative stimulation of the cortex with concurrent electromyographic monitoring of the relevant muscle groups contralaterally, and, more recently, (4) the use of neuronavigation systems to localize either the central sulcus or the precentral gyrus. Some authors even recommend the use of functional magnetic resonance imaging for targeting, especially with infarctions involving the motor cortex.94 A trial period of MCS is usually required, followed by implantation of a permanent system if the trial produces adequate relief. Complications of MCS include intraoperative seizures, stimulator pocket infection, epidural bleeding, subdural effusion, and “tolerance” to stimulation with diminished analgesia over time. Unfortunately, long-term studies with extended follow up have shown poor chances of meaningful and sustained pain relief outcomes.86,95 Therefore the procedure is rarely covered by insurance and is not commonly performed in the United States. Spinal Cord Stimulation (SCS)

Approved by the FDA in 1989 as part of the treatment paradigm for chronic pain, SCS represents a safe and effective therapy, particularly for neuropathic pain. Indications include neuropathic pain with a spinal origin, CRPS, peripheral neuropathic pain, and anginal pain. Evidence for this has been borne out via randomized controlled trials and systematic reviews.96–98 Patients undergo a trial period of stimulation in which a percutaneous lead is placed into the extradural space. Stimulation was performed using an external generator. Typically, following a trial period of three to seven days, it is determined whether the trial is deemed successful based on the patient’s perception of satisfactory pain relief. The trial lead is then removed, and the patient may undergo permanent implantation surgery. Most commonly, these systems focus on the stimulation delivery of paresthesia-inducing frequencies. More recent research has focused on the investigation of novel waveforms including 10,000 Hz high frequency stimulation and “burst stimulation.”99–102 Randomized control trials have shown mixed results of the superiority of these novel waveforms.102,103 Most recently, the concept of “closed loop” SCS has come to the forefront. This treatment

paradigm uses feedback via a sensing arm to extract an actionable biomarker signal (evoked compound action potentials) that allows the device to self-adjust with the potential to maximize therapeutic efficacy.104 This technology will need to be evaluated over time with well-designed outcome studies. Dorsal Root Ganglion (DRG) Stimulation

Stimulation of the DRG is an alternative form of neuromodulation that is most effective for the treatment of CRPS type 2. This was evidenced by the pivotal FDA trial revealing DRG stimulation to be superior to SCS.104 The procedure involves the placement of the epidural stimulator into the neuroforamen adjacent to the DRG. Similar to most neuromodulatory interventions, a trial period of stimulation is utilized as a confirmatory test prior to permanent implantation.

Peripheral Nerve Stimulation (PNS)

There is sparse evidence for the use of the peripheral nervous system, dependent on the nerve of interest that is being stimulated. In general, this intervention involves the placement of a stimulating electrode near the nerve. Similar to other neuromodulation procedures, a successful stimulation trial must precede permanent implantation. Recent recommendations have been produced by the Congress of Neurological Surgeons surrounding the deployment of occipital nerve stimulation (ONS).105 Additionally, studies have explored the use of occipital nerve stimulation for trigeminal neuropathic pain.106,107 Presently, nerve stimulators are being placed in the femoral and sciatic nerves for post-amputation pain and in the tibial nerve for foot pain. The topics of SCS, DRG stimulation, and PNS are discussed in detail in Chapter 71.

Pharmacologic Neuromodulation Intraventricular Opioids Studies showing the direct analgesic effects of opioids applied in the ventricular region and around the medulla of the central nervous system108,109 led to the work of Leavens et al. in 1982, in which human ICV use of morphine was first reported.110 The profound analgesic response to intrathecal morphine coupled with its widespread clinical use for lower body pain suggested the need for more rostral injection sites to control pain in the head, neck, and upper extremity regions. Although cervical intrathecal opioid injection sometimes results in respiratory depression, it is possible to deliver a small amount of ICV morphine without respiratory dysfunction or dysautonomia. Opioid receptors are abundant around the wall of the third ventricle and aqueduct, as well as in the PVG and PAG. In Leavens et al.’s 1982 report, 1 mg of morphine was used to treat patients with intractable cancer pain, resulting in profound analgesia and no respiratory depression or neurologic changes.110 In a report on 82 patients, Lazorthes and associates recommended nine specific guidelines for the ICV use of morphine: (1) chronic pain secondary to inoperable malignant tumors in patients with terminal cancer, (2) pain not relieved by medical treatment and, in particular, the development of serious side effects from using oral or systemic morphine, (3) intractable bilateral, midline, or diffuse pain not appropriate for percutaneous or open surgical interruption of nociceptive pathways, (4) chronic pain of somatic nociceptive origin (neurogenic pain was a contraindication), (5) upper body pain secondary to cervicothoracic cancer, (6) chronic pain of the lower half of

 

CHAPTER 32

the body (­subdiaphragmatic) only after failure of or contraindication to conventional intrathecal spinal opioid administration, (7) absence of general risks for complications, such as coagulation disturbances, cutaneous infection, and septicemia, (8) informed consent from the patient and family, and (9)  the presence of a favorable domestic environment (e.g. physician, nurse, or family) for ambulatory surveillance and chronic ICV morphine treatment. The authors recommended that when the topography of the pain involved a transitional area (e.g. lower thoracic, diaphragmatic, or upper abdominal region), ICV morphine could be indicated if the patient fails a more standard intrathecal morphine trial.111 Surgically, the implantation of a chronic ICV morphine infusion system involves placement of a catheter into the lateral ventricle near the foramen of Monro to deliver drugs near target receptors in the periaqueductal parenchyma of the midbrain (Fig. 32.1). The analgesic latency of ICV morphine administration was between 15 and 30 min, and the effect lasted for a mean of 28 h. Excellent or good pain relief rates range from greater than 50% to 97%, and side effects include somnolence, nausea, confusion, and respiratory depression, which are usually transient. Finally, Lazorthes et al. reported tolerance in three of 82 patients.111 The increased effectiveness of oral opioids has diminished the need for ICV morphine administration. However, the technique remains relatively simple and effective and is a viable option for

Neurosurgical Approaches to Pain Management

459

patients with intractable pain of malignant etiology, following oral opioid failure and when pain is diffuse or cephalic in topography.112 Intrathecal Opioids

The main advantage of intrathecal opioid administration is the ability to achieve therapeutic efficacy via a smaller dose without the side effects induced by peripheral administration.113,114 Similar to neuromodulation, patients undergo a trial prior to proceeding with a permanent implant. This approach involves accessing the intrathecal space via the lumbar cistern and advancing an intrathecal catheter up to the mid-thoracic spine. The catheter is then connected to a programmable pump with a reservoir that was placed in the abdominal adipose layer. The reservoir requires scheduled refills of medication, the frequency of which is determined by the patient’s infusion rate, medication concentration, and reservoir capacity.115 Beyond opioids, multiple medications have been used by providers to treat chronic pain via the intrathecal route. These medications include clonidine, ziconotide, benzodiazepines, and tricyclic anti-depressants, among others.116 The most commonly used drugs are clonidine and ziconotide. The potential advantage of nonopioid medications is the decrease in the potential for unwanted side effects, development of dependency, and risk of medication withdrawal in the event of a pump failure.117 Intrathecal therapies are further discussed in Chapter 72.

Summary Neurosurgical procedures to treat intractable pain have gone through an evolutionary process, dictated in part by technologic advances, scientific discovery, and changes in the survival rates of patients with chronic pain, especially those with cancer pain. Irreversible ablative procedures are used much less frequently today, yet they remain the

procedures of choice on occasion. Depending on the physiologic substrate and pain topography, multiple brain and spinal cord regions can be targeted to treat chronic pain. Neuromodulation by either electrical stimulation or pharmacologic manipulation is generally the preferred approach to treat chronic pain.

Key Points • Neurosurgical treatments for intractable pain are usually reserved as the last option for the treatment of intractable pain. • These interventions can be either ablative or neuromodulatory, which can be divided into pharmacologic and electrical. • Neurosurgical procedures can be performed at either the spinal or cerebral level. Spinal spinothalamic ablation (cordotomy) is the most studied and performed neurosurgical ablative procedure, and it is very effective in treating unilateral somatic cancer pain. • Opioid use has limited the indications for ablative procedures, but there are still defined but limited indications for spinal ablative procedures that are confined to cancer-related pain. • Spinal neuromodulation (i.e. SCS and intrathecal opioid devices) is widely used to treat chronic spinal pain.

• Advances in spinal cord stimulation include high frequency and burst stimulation and “closed loop” SCS. • PNS involves the placement of the electrode near the nerve. Studies have shown a beneficial effect of occipital nerve stimulation. Clinically, electrodes are placed in the femoral and sciatic nerves for post-amputation pain and in the tibial nerve for foot pain. • Clinical intrathecal therapies involve mainly opioids, ziconotide, and baclofen. • Cerebral ablation of pain pathways or centers is rarely performed. However, cerebral neuromodulation procedures, such as deep brain stimulation and motor cortex stimulation, may have limited indications and utility that are usually related to central pain and neuropathic pain.

Acknowledgment The authors thank Shirley McCartney, Ph.D., for her editorial assistance.

460

PA RT 4 Clinical Conditions: Evaluation and Treatment

Suggested Readings Deer T, Slavin KV, Amirdelfan K, et al. Success using neuromodulation with BURST (SUNBURST) study: Results from a prospective, randomized controlled trial using a novel burst waveform. Neuromodulation. 2018;21(1):56–66. Grider JS, Manchikanti L, Carayannopoulos A, et al. Effectiveness of spinal cord stimulation in chronic spinal pain: A systematic review. Pain Physician. 2016;19(1):E33–54. Hosobuchi Y. Combined electrical stimulation of the periaqueductal gray matter and sensory thalamus. Appl Neurophysiol. 1983;46(1–4): 112–115. Kanpolat Y. Percutaneous cordotomy, tractotomy, and midline myelotomy: minimally invasive stereotactic pain procedures. In: W Fisher, K Burchiel (eds). Seminars in Neurosurgery: Pain Management for the Neurosurgeon. Vol. 2/3. New York: Thieme Medical; 2004:203–219. Kapural L, Yu C, Doust MW, et al. Comparison of 10-kHz highfrequency and traditional low-frequency spinal cord stimulation

for the treatment of chronic back and leg pain: 24-month results from a multicenter, randomized, controlled pivotal trial. Neurosurgery. 2016;79(5):667–677. Lazorthes YR, Sallerin BA, Verdié JC. Intracerebroventricular administration of morphine to control irreducible cancer pain. Neurosurgery. 1995;37(3):422–428, discussion 428. Raslan AM, Cetas JS, McCartney, Burchiel KJ. Destructive procedures for control of cancer pain: the case for cordotomy. J Neurol Surg. 2011;114(1):155–170. Slavin KV. Peripheral nerve stimulation for neuropathic pain. Neurotherapeutics. 2008;5(1):100–106. Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir Suppl (Wein). 1991;52:137–139. The references for this chapter can be found at ExpertConsult.com.

References 1. Spiller WM. The treatment of persistent pain of organic origin in the lower part of the body by division of the anterolateral column of the spinal cord. JAMA. 1912;58:1489–1490. 2. Hariz MI, Bergenheim AT. Thalamic stereotaxis for chronic pain: Ablative lesion or stimulation? Stereotact Funct Neurosurg. 1995;64(1):47–55. 3. Hassler R, Riechert T. Clinical and anatomical findings in stereotactic pain operations on the thalamus. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr. 1959;200:93–122. 4. Mark VH, Ervin FR, Yakovlev PI. Correlation of pain relief, sensory loss, and anatomical lesion sites in pain patients treated with stereotactic thalamotomy. Trans Am Neurol Assoc. 1961;86:86–90. 5. Frank F, Fabrizi AP, Gaist G, Weigel K, Mundinger F. Stereotactic mesencephalotomy versus multiple thalamotomies in the treatment of chronic cancer pain syndromes. Appl Neurophysiol. 1987;50(16):314–318. 6. Jeanmonod D, Magnin M, Morel A. Thalamus and neurogenic pain: Physiological, anatomical and clinical data. NeuroReport. 1993;4(5):475–478. 7. Young RF, Jacques DS, Rand RW, Copcutt BC, Vermeulen SS, Posewitz AE. Technique of stereotactic medial thalamotomy with the Leksell gamma knife for treatment of chronic pain. Neurol Res. 1995;17(1):59–65. 8. Le Beau J. Anterior cingulectomy in man. J Neurosurg. 1954;11(3):268–276. 9. Hassenbusch S, ed. Intracranial Ablative Procedures for Pain. 4th ed. Philadelphia: Saunders; 1996. 10. Foltz EL, White Jr LE. Pain “relief ” by frontal cingulumotomy. J Neurosurg. 1962;19:89–100. 11. Siegfried J. Therapeutical neurostimulation—indications reconsidered. Acta Neurochir Suppl (Wien). 1991;52:112–117. 12. Hurt RW, Ballantine Jr HT. Stereotactic anterior cingulate lesions for persistent pain: A report on 68 cases. Clin Neurosurg. 1974;21:334–351. 13. Pillay PK, Hassenbusch SJ. Bilateral MRI-guided stereotactic cingulotomy for intractable pain. Stereotact Funct Neurosurg. 1992;59(1-4):33–38. 14. Siqueira JM. A method for bulbospinal trigeminal nucleotomy in the treatment of facial deafferentation pain. Appl Neurophysiol. 1985;48(1-6):277–280. 15. Gorecki JP, Nashold BS. The Duke experience with the nucleus caudalis DREZ operation. Acta Neurochir Suppl. 1995;64:128–131. 16. Gorecki JP, Nashold Jr BS, Rubin L, Ovelmen-Levitt J. The Duke experience with nucleus caudalis DREZ coagulation. Stereotact Funct Neurosurg. 1995;65(1-4):111–116. 17. Kanpolat Y, ed. Percutaneous Cordotomy, Tractotomy, and Midline Myelotomy: Minimally Invasive Stereotactic Pain Procedures. New York: Thieme Medical; 2004. 18. Walker AE. The spinothalamic tract in man. Arch NeuroPsych. 1940;43(2):284. 19. Kanpolat Y, Savas A, Ucar T, Torun F. CT-guided percutaneous selective cordotomy for treatment of intractable pain in patients with malignant pleural mesothelioma. Acta Neurochir (Wien). 2002;144(6):595–599 discussion 99. 20. Hodge C, Christen M (eds). Anterolateral Cordotomy. New York: Thieme Medical; 2002. 21. Mullan S, Harper PV, Hekmatpanah J, Torres H, Dobbin G. Percutaneous interruption of spinal-pain tracts by means of a strontium 90 needle. J Neurosurg. 1963;20:931–939. 22. Rosomoff HL, Brown CJ, Sheptak P. Percutaneous radiofrequency cervical cordotomy: Technique. J Neurosurg. 1965;23(6):639–644. 23. Kanpolat Y, Akyar S, Cağlar S, Unlü A, Bilgiç S. CT-guided percutaneous selective cordotomy. Acta Neurochir (Wien). 1993;123(1-2):92–96.

24. Kanpolat Y, Akyar S, Cağlar S. Diametral measurements of the upper spinal cord for stereotactic pain procedures: Experimental and clinical study. Surg Neurol. 1995;43(5):478–482 discussion 82-83. 25. Kanpolat Y, Savas A, Batay F, Sinav A. Computed tomographyguided trigeminal tractotomy-nucleotomy in the management of vagoglossopharyngeal and geniculate neuralgias. Neurosurgery. 1998;43(3):484–489 discussion 90. 26. Fenstermaker RA, Sternau LL, Takaoka Y. CT-assisted percutaneous anterior cordotomy: Technical note. Surg Neurol. 1995;43(2):147– 149 discussion 49-50. 27. Gildenberg PL, Lin PM, Polakoff 2nd PP, Flitter MA. Anterior percutaneous cervical cordotomy: Determination of target point and calculation of angle of insertion. Technical note. J Neurosurg. 1968;28(2):173–177. 28. Raslan AM. Percutaneous computed tomography-guided transdiscal low cervical cordotomy for cancer pain as a method to avoid sleep apnea. Stereotact Funct Neurosurg. 2005;83(4):159–164. 29. Kanpolat Y, Savas A, Akyar S, et al. Percutaneous computed tomography-guided spinal destructive procedures for pain control. Neurosurg Q. 2004;14(4):229–238. 30. Raslan AM, Cetas JS, McCartney S, Burchiel KJ. Destructive procedures for control of cancer pain: The case for cordotomy. J Neurosurg. 2011;114(1):155–170. 31. Guyatt G, Gutterman D, Baumann MH, et  al. Grading strength of recommendations and quality of evidence in clinical guidelines: Report from an American College of Chest Physicians task force. Chest. 2006;129(1):174–181. 32. Taren JA, Kahn EA. Anatomic pathways related to pain in face and neck. J Neurosurg. 1962;19:116–121. 33. Sjogvist O. Studies on pain conduction in the trigeminal nerve: A contribution to the surgical treatment of facial pain. Acta Psychiatr Neurol Scand Suppl. 1938;17:93–122. 34. Hitchcock E. Stereotactic trigeminal tractotomy. Ann Clin Res. 1970;2(2):131–135. 35. Crue BL, Carregal EJA, Felsoory A. Percutaneous stereotactic radio frequency trigeminal tractotomy with neurophysiological recording. Confinia Neurologica. 1972;34(6):389–397. 36. Kanpolat Y, Atalağ M, Deda H, Siva A. CT guided extralemniscal myelotomy. Acta Neurochir (Wien). 1988;91(3-4):151–152. 37. Teixeira M, ed. Various Functional Procedures for Pain. Part II: Facial Pain. New York: McGraw-Hill; 1998. 38. Hitchcock E. Stereotactic cervical myelotomy. J Neurol Neurosurg Psychiatry. 1970;33(2):224–230. 39. Schvarcz JR. Stereotactic extralemniscal myelotomy. J Neurol Neurosurg Psychiatry. 1976;39(1):53–57. 40. Al-Chaer ED, Lawand NB, Westlund KN, Willis WD. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway. J Neurophysiol. 1996;76(4):2675–2690. 41. Al-Chaer ED, Lawand NB, Westlund KN, Willis WD. Visceral nociceptive input into the ventral posterolateral nucleus of the thalamus: A new function for the dorsal column pathway. J Neurophysiol. 1996;76(4):2661–2674. 42. Nauta HJ, Hewitt E, Westlund KN, Willis Jr WD. Surgical interruption of a midline dorsal column visceral pain pathway. Case report and review of the literature. J Neurosurg. 1997;86(3):538–542. 43. Melzack R, Wall PD. Pain mechanisms: A new theory. Science. 1965;150(3699):971–979. 44. Sindou M, Mertens P (eds). Surgery in the Dorsal Root Entry Zone for Pain. New York: Thieme Medical; 2005. 45. Nashold BSJ, Wilson WI, Slaughter O. The midbrain and pain. Adv Neurol. 1974;4:191–196. 46. Powers SK, Adams JE, Edwards MS, Boggan JE, Hosobuchi Y. Pain relief from dorsal root entry zone lesions made with argon and carbon dioxide microsurgical lasers. J Neurosurg. 1984;61(5):841–847. 47. Dreval ON. Ultrasonic DREZ-operations for treatment of pain due to brachial plexus avulsion. Acta Neurochir (Wien). 1993;122(1-2):76–81.

460.e1

460.e2

References

48. Wall PD (ed). Presynaptic Control of Impulses at The First Central Synapse in The Cutaneous Pathway. Amsterdam: Elsevier; 1964. 49. Guenot M, Bullier J, Sindou M. Clinical and electrophysiological expression of deafferentation pain alleviated by dorsal root entry zone lesions in rats. J Neurosurg. 2002;97(6):1402–1409. 50. Emery E, Blondet E, Mertens P, Sindou M. Microsurgical DREZotomy for pain due to brachial plexus avulsion: Long-term results in a series of 37 patients. Stereotact Funct Neurosurg. 1997;68(1-4 Pt 1):155–160. 51. Pool JL. Psychosurgery in older people. J Am Geriatr Soc. 1954;2(7):456–466. 52. Heath R, Mickle W (eds). Evaluation of 7 Years’ Experience With Depth Electrode Studies in Human Patients. New York: Harper & Brothers; 1960. 53. Pool J, Clark W, Hudson P, et al. Hypothalamic-Hypophyseal Interrelationships. Springfield, IL: Charles C Thomas; 1956. 54. Mazars G, Roge R, Mazars Y. Results of the stimulation of the spinothalamic fasciculus and their bearing on the physiopathology of pain. Rev Neurol (Paris). 1960;103:136–138. 55. Reynolds DV. Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science. 1969;164(3878):444–445. 56. Tasker R (ed). Stereotactic Medial Thalamotomy for Chronic Pain: Is it an Effective Procedure. New York: Thieme Medical; 2002. 57. Hosobuchi Y, Adams JE, Rutkin B. Chronic thalamic stimulation for the control of facial anesthesia dolorosa. Arch Neurol. 1973;29(3):158–161. 58. Hosobuchi Y, Adams JE, Linchitz R. Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. Science. 1977;197(4299):183–186. 59. Richardson DE, Akil H. Pain reduction by electrical brain stimulation in man. Part 1: Acute administration in periaqueductal and periventricular sites. J Neurosurg. 1977;47(2):178–183. 60. Richardson DE, Akil H. Pain reduction by electrical brain stimulation in man. Part 2: Chronic self-administration in the periventricular gray matter. J Neurosurg. 1977;47(2):184–194. 61. Adams JE, Hosobuchi Y, Fields HL. Stimulation of internal capsule for relief of chronic pain. J Neurosurg. 1974;41(6):740–744. 62. Fields HL, Adams JE. Pain after cortical injury relieved by electrical stimulation of the internal capsule. Brain. 1974;97(1):169–178. 63. Andy OJ. Parafascicular-center median nuclei stimulation for intractable pain and dyskinesia (painful-dyskinesia). Appl Neurophysiol. 1980;43(3-5):133–144. 64. Rezai A, Lozano A (eds). Deep Brain Stimulation for Chronic Pain. New York: Thieme Medical; 2006. 65. Gerhart KD, Yezierski RP, Fang ZR, Willis WD. Inhibition of primate spinothalamic tract neurons by stimulation in ventral posterior lateral (VPLc) thalamic nucleus: Possible mechanisms. J Neurophysiol. 1983;49(2):406–423. 66. Tsubokawa T, Yamamoto T, Katayama Y, Moriyasu N. Clinical results and physiological basis of thalamic relay nucleus stimulation for relief of intractable pain with morphine tolerance. Appl Neurophysiol. 1982;45(1-2):143–155. 67. Whitworth L, Fernandez J (eds). Deep Brain Stimulation for Chronic Pain. New York: Thieme Medical; 2005. 68. Hosobuchi Y. Combined electrical stimulation of the periaq ueductal gray matter and sensory thalamus. Appl Neurophysiol. 1983;46(1-4):112–115. 69. Boccard SG, Fitzgerald JJ, Pereira EA, et al. Targeting the affective component of chronic pain: A case series of deep brain stimulation of the anterior cingulate cortex. Neurosurgery. 2014;74(6):628–635 discussion 35–37. 70. Boccard SGJ, Prangnell SJ, Pycroft L, et  al. Long-term results of deep brain stimulation of the anterior cingulate cortex for neuropathic pain. World Neurosurg. 2017;106:625–637. 71. Holland MT, Zanaty M, Li L, et al. Successful deep brain stimulation for central post-stroke pain and dystonia in a single operation. J Clin Neurosci. 2018;50:190–193.

72. Lempka SF, Malone Jr DA, Hu B, et  al. Randomized clinical trial of deep brain stimulation for poststroke pain. Ann Neurol. 2017;81(5):653–663. 73. Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown & Co; 1954. 74. White J, Sweet W. Pain: Its Mechanisms and Neurosurgical Control. Springfield, IL: Charles C Thomas; 1955. 75. Lende RA, Kirsch WM, Druckman R. Relief of facial pain after combined removal of precentral and postcentral cortex. J Neurosurg. 1971;34(4):537–543. 76. Hardy SG. Analgesia elicited by prefrontal stimulation. Brain Res. 1985;339(2):281–284. 77. Hardy SG, Haigler HJ. Prefrontal influences upon the midbrain: A possible route for pain modulation. Brain Res. 1985;339(2):285–293. 78. Hosobuchi Y. Subcortical electrical stimulation for control of intractable pain in humans. Report of 122 cases (1970-1984). J Neurosurg. 1986;64(4):543–553. 79. Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir Suppl (Wien). 1991;52:137–139. 80. Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex stimulation in patients with thalamic pain. J Neurosurg. 1993;78(3):393–401. 81. Peyron R, Garcia-Larrea L, Deiber MP, et al. Electrical stimulation of precentral cortical area in the treatment of central pain: Electrophysiological and PET study. Pain. 1995;62(3):275–286. 82. García-Larrea L, Peyron R, Mertens P, et  al. Positron emission tomography during motor cortex stimulation for pain control. Stereotact Funct Neurosurg. 1997;68(1-4 Pt 1):141–148. 83. García-Larrea L, Peyron R, Mertens P, et al. Electrical stimulation of motor cortex for pain control: A combined PET-scan and electrophysiological study. Pain. 1999;83(2):259–273. 84. Yamamoto T, Katayama Y, Hirayama T, Tsubokawa T. Pharmacological classification of central post-stroke pain: Comparison with the results of chronic motor cortex stimulation therapy. Pain. 1997;72(1-2):5–12. 85. Brown JA, Barbaro NM. Motor cortex stimulation for central and neuropathic pain: Current status. Pain. 2003;104(3):431–435. 86. Raslan AM, Nasseri M, Bahgat D, Abdu E, Burchiel KJ. Motor cortex stimulation for trigeminal neuropathic or deafferentation pain: An institutional case series experience. Stereotact Funct Neurosurg. 2011;89(2):83–88. 87. Katayama Y, Tsubokawa T, Yamamoto T. Chronic motor cortex stimulation for central deafferentation pain: Experience with bulbar pain secondary to Wallenberg syndrome. Stereotact Funct Neurosurg. 1994;62(1-4):295–299. 88. Meyerson BA, Lindblom U, Linderoth B, Lind G, Herregodts P. Motor cortex stimulation as treatment of trigeminal neuropathic pain. Acta Neurochir Suppl (Wien). 1993;58:150–153. 89. Herregodts P, Stadnik T, De Ridder F, D’Haens J. Cortical stimulation for central neuropathic pain: 3-D surface MRI for easy determination of the motor cortex. Acta Neurochir Suppl. 1995;64:132–135. 90. Ebel H, Rust D, Tronnier V, Böker D, Kunze S. Chronic precentral stimulation in trigeminal neuropathic pain. Acta Neurochir (Wien). 1996;138(11):1300–1306. 91. Nguyen JP, Keravel Y, Feve A, et  al. Treatment of deafferentation pain by chronic stimulation of the motor cortex: Report of a series of 20 cases. Acta Neurochir Suppl. 1997;68:54–60. 92. Rainov NG, Fels C, Heidecke V, Burkert W. Epidural electrical stimulation of the motor cortex in patients with facial neuralgia. Clin Neurol Neurosurg. 1997;99(3):205–209. 93. Nguyen JP, Lefaucheur JP, Le Guerinel C, et al. Treatment of central and neuropathic facial pain by chronic stimulation of the motor cortex: Value of neuronavigation guidance systems for the localization of the motor cortex. Neurochirurgie. 2000;46(5):483–491.

References

94. Roux FE, Ibarrola D, Tremoulet M, et  al. Methodological and technical issues for integrating functional magnetic resonance imaging data in a neuronavigational system. Neurosurgery. 2001;49(5):1145–1156 discussion 56-57. 95. Sachs AJ, Babu H, Su YF, Miller KJ, Henderson JM. Lack of efficacy of motor cortex stimulation for the treatment of neuropathic pain in 14 patients. Neuromodulation. 2014;17(4):303–310 discussion 10-11. 96. Kemler MA, Barendse GA, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med. 2000;343(9):618–624. 97. North RB, Kidd DH, Farrokhi F, Piantadosi SA. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: A randomized controlled trial. Neurosurgery. 2005;56(1):98–106 discussion 6-7. 98. Grider JS, Manchikanti L, Carayannopoulos A, et  al. Effectiveness of spinal cord stimulation in chronic spinal pain: A systematic review. Pain Phys. 2016;19(1):E33–E54. 99. De Ridder D, Plazier M, Kamerling N, Menovsky T, Vanneste S. Burst spinal cord stimulation for limb and back pain. World Neurosurg. 2013;80(5):642–649 e1. 100. Kapural L, Yu C, Doust MW, et al. Novel 10-kHz high-frequency therapy (HF10 therapy) is superior to traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: The SENZA-RCT randomized controlled trial. Anesthesiology. 2015;123(4):851–860. 101. Kapural L, Yu C, Doust MW, et al. Comparison of 10-kHz highfrequency and traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: 24-month results from a multicenter, randomized, controlled pivotal trial. Neurosurgery. 2016;79(5):667–677. 102. Deer T, Slavin KV, Amirdelfan K, et al. Success using neuromodulation with BURST (SUNBURST) study: Results from a prospective, randomized controlled trial using a novel burst waveform. Neuromodulation. 2018;21(1):56–66. 103. De Andres J, Monsalve-Dolz V, Fabregat-Cid G, et  al. Prospective, randomized blind effect-on-outcome study of conventional vs high-frequency spinal cord stimulation in patients with pain and disability due to failed back surgery syndrome. Pain Med. 2017;18(12):2401–2421.

460.e3

104. Russo M, Cousins MJ, Brooker C, et  al. Effective relief of pain and associated symptoms with closed-loop spinal cord stimulation system: Preliminary results of the Avalon study. Neuromodulation. 2018;21(1):38–47. 105. Sweet JA, Mitchell LS, Narouze S, et  al. Occipital nerve stimulation for the treatment of patients with medically refractory occipital neuralgia: Congress of Neurological Surgeons systematic review and evidence-based guideline. Neurosurgery. 2015;77(3):332–341. 106. Slavin KV. Peripheral nerve stimulation for neuropathic pain. Neurotherapeutics. 2008;5(1):100–106. 107. Stidd DA, Wuollet AL, Bowden K, et al. Peripheral nerve stimulation for trigeminal neuropathic pain. Pain Phys. 2012;15(1):27–33. 108. Atweh SF, Kuhar MJ. Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res. 1977;129(1):1–12. 109. Dickenson AH, Le Bars D. Supraspinal morphine and descending inhibitions acting on the dorsal horn of the rat. J Physiol. 1987;384:81–107. 110. Leavens ME, Hill Jr CS, Cech DA, Weyland JB, Weston JS. Intrathecal and intraventricular morphine for pain in cancer patients: Initial study. J Neurosurg. 1982;56(2):241–245. 111. Lazorthes YR, Sallerin BA, Verdié JC. Intracerebroventricular administration of morphine for control of irreducible cancer pain. Neurosurgery. 1995;37(3):422–428 discussion 28-29. 112. Lazorthes Y, Sallerin B, Verdie J, et al (eds). Intrathecal and Intracerebroventricular Opiods: Past and Current Indications. New York: Thieme Medical; 2016. 113. Textor LH. CE: Intrathecal pumps for managing cancer pain. Am J Nurs. 2016;116(5):36–44. 114. Kleinmann B, Wolter T. Intrathecal opioid therapy for non-malignant chronic pain: A long-term perspective. Neuromodulation. 2017;20(7):719–726. 115. Raslan AM, McCartney S, Burchiel KJ. Management of chronic severe pain: Spinal neuromodulatory and neuroablative approaches. Acta Neurochir Suppl. 2007;97(Pt 1):33–41. 116. Garber JE, Hassenbusch SJ (eds). Innovative Intrathecal Analgesics. New York: Thieme; 2002. 117. Anderson VC, Burchiel KJ. A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain. Neurosurgery. 1999;44(2):289–300 discussion 00-1.

33

Evaluation and Treatment of Cancer-Related Pain

DERMOT FITZGIBBON, MARGARET HSU

Introduction Cancer is a disease process that results when cellular changes cause uncontrolled growth and division of cells. It continues to be a major health problem and is the second leading cause of death in the United States.1 The three most prevalent cancers in 2019 were prostate, colon, and rectum, and melanoma of the skin among males, and breast, uterine corpus, and colon and rectum among females.2 Common side effects of cancer and its treatment are pain, fatigue, and emotional distress,3,4 all of which can affect functional status. Pain can be problematic at different phases of cancer treatment. Van den Beuken‐van Everdingen et al.5 reported pain prevalence rates of 39% after curative treatment; 55% during anticancer treatment; 66% in advanced, metastatic, or terminal disease; and 51% in all cancer stages. There was a prevalence rate of 38% of moderate to severe pain in studies reporting pain intensity. Hematologic patients also have high prevalence rates of pain at diagnosis, during therapy, and in the last month of life.6 Despite the availability of opioids and other treatment strategies, undertreatment of cancer pain remains problematic,7,8 with some authors estimating that one in three patients does not receive an analgesic prescription to match the reported level of pain.9 Despite increased attention to cancer pain, pain prevalence in cancer patients has not significantly changed over the last decade compared to the prior four decades.10 This continues into survivorship, where the prevalence of pain also is high.11 At initial diagnosis, oncology patients face a continuum of care that may progress from disease-oriented, curative, life-prolonging treatment through symptom-oriented, supportive, and palliative care extending to terminal-phase hospice care (Fig. 33.1). Treatments are usually multifaceted and often include surgery, radiation therapy, and systemic treatment, which includes the use of chemotherapeutic cytostatic drugs, targeted therapy with small molecule inhibitors, monoclonal antibodies that involved targeted immunotherapy, and inhibition of tumor-associated angiogenesis or immune regulation by checkpoint inhibitors (Fig. 33.2, Table 33.1). Once treatment is completed, patients frequently require an extended interval of surveillance, resulting in additional treatments for recurrences or the appearance of new diseases or problems. Advances in cancer prevention and treatment with an improved understanding of the biology of cancer have resulted in improved patient survival and quality of life.12 Cancer survival has improved since the mid‐1970s for all of the most common

cancers except uterine cervix and uterine corpus,13 and there has been an overall drop of 29% in the mortality rate since 1991.1 Even after completion of care, pain can be a persistent problem, and the ability to address this is an increasing issue because of advances in cancer treatment with a record number of survivors in the United States.12 Pain management should be an integral component of the cancer care continuum. For oncology patients, the ultimate goal is to cure disease and pain, often an undesirable consequence of disease or treatment. Although pain management should be integrated into oncology care, it should not be the focus of care in contrast to many chronic pain models. Interdisciplinary collaboration is essential for the comprehensive care of cancer patients with pain. Aggressive therapy of both cancer and pain is mutually beneficial and is best done by skilled, interdisciplinary teams that understand and respond to the changing demands of oncology care that include pain management. The most successful strategy for managing tumor-related pain is identifying the source and directing appropriate anti-tumor measures (which may include all care options in oncology) toward the source. Symptomatic management of the pain may be appropriate while implementing these measures. However, such measures may not be appropriate for patients with pre-existing chronic non-cancer-related pain who present for oncology care. These issues can usually be differentiated by a comprehensive pain assessment with a clear understanding of the current tumor location(s) and correlation with the patient’s pain complaint. The goal of any pain management strategy is to manage pain that allows for the optimization of function and enable an acceptable quality of life. Although a reduction in pain intensity is ideal, the guiding principle for pain management should be an improvement in function. Adequate management of cancer pain depends on making an accurate diagnosis of the underlying cause(s) of pain and contributing factors. In every situation, this requires a comprehensive assessment of these issues. The diagnosis will include a reason for the pain complaint, a summary of the current disease status, the appropriateness and efficacy of the current pain medication regimen, and an assessment of functional and social status. It is important to recognize that the source of pain in the cancer patient is usually not a single entity but often has multiple sources that may result from different issues such as tumor staging, treatment phase, preexisting conditions causing chronic pain, and posttreatment complications. Tumor-related pain may be classified according to the tissue source as nociceptive (somatic or visceral) or neuropathic. Once a treatment plan is implemented, 461

462

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Figure 33.1  Cancer Care Continuum.

appropriate, interfering with nociceptive transmission outside of and within the central nervous system, for example, with anesthetic techniques (e.g. neurolytic celiac plexus block, neuraxial analgesia, and spinal neurolysis), or neurosurgery procedures (e.g. cordotomy, dorsal root entry zone lesioning). Options for disease modification should always be foremost.

World Health Organization Analgesic Ladder

• Figure 33.2  Major modalities of cancer therapy. assessment and re-assessment at regular intervals are key to ensuring that treatment is appropriate and safe, as well as minimizing and addressing side effects related to treatment throughout care. The concurrent use of adjunctive, specialized, or complementary therapies should be considered, and referral for specialized surgical, anesthetic, or psychological intervention benefits selective patients. However, most patients can attain adequate management of pain (and improvement in function) using appropriate oral pharmacotherapy. Cancer (tumor-related) pain management guidelines typically incorporate pharmacologic, anesthetic, neurosurgical, and behavioral approaches. The mainstay of cancer pain therapy is pharmacologic, but radiotherapeutic, anesthetic, neurosurgical, psychological, physiotherapeutic, spiritual, and social interventions all play roles in adequate cancer pain management (Table 33.2). The basic principles of tumor-directed pain control include modifying the source of pain by treating cancer, altering the central perception of pain (for example, by the use of analgesics, anti-depressants, anxiolytics, and psychotherapy), and, when

In 1986, the World Health Organization (WHO) developed a simple model for the introduction and upward titration of analgesics, which became known as the WHO analgesic ladder.14 In 2018, WHO updated its guidelines for pharmacologic and radiotherapeutic management of cancer pain (WHO 2018). Pharmacologic options should be used by following the WHO analgesic ladder (Fig. 33.3). Implementation of the three-step ladder, in combination with appropriate dosage guidelines, should result in adequate pain relief for 70%–90% of patients.15–17 Successful implementation of the ladder requires adherence to basic principles of medication use (Table 33.3). The ladder advocates for the use of analgesics (non-opioids including automatic positive airway pressure [APAP] and nonsteroidal anti-inflammatory drugs [NSAIDs], adjuvant analgesics such as anti-depressants and anticonvulsants, and opioids) should be used incrementally according to pain intensity with the focus on the use of opioids for moderate to severe intensity pain. Opioids are commonly used to treat moderate or severe cancer pain, and the most commonly used opioid drugs are buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, tramadol, and tapentadol.18 For initiation and maintenance of pain relief, NSAIDs, APAP, and opioids either alone or in combination may be used with a strength appropriate for patient-reported pain severity. The use of steroids for the shortest time possible is recommended if deemed appropriate for care, but evidence for the efficacy of steroids in cancer pain is weak, and the side effect profile of prolonged use needs to be defined.19 Optimal dosing of steroids likely depends on location and type of pain, presence of or risk of infection, stage of illness, presence of diabetes mellitus, and goals of care. In patients with pain related to bone metastases, bisphosphonates or monoclonal antibodies (denosumab) should be considered to prevent and treat bone pain. Regarding the use of anti-depressants and

 

CHAPTER 33

TABLE 33.1

Evaluation and Treatment of Cancer-Related Pain

463

Types of Cancer Treatment

Surgery

Open versus minimally invasive Primary tumor resection Resection of metastases Cytoreduction Palliative Reconstructive

Radiation Therapy

External beam (photon, proton, neutron)* Internal radiation therapy (brachytherapy) Systemic radiation therapy (radioactive iodine, radium, radiostrontium)

Chemotherapy

Cytotoxic (oral, IV, injection, intrathecal, intraperitoneal, intra-arterial)

Immunotherapy

Immune checkpoint inhibitors Cellular immunotherapy (CAR T-cell, TIL) Monoclonal antibodies (rituximab) Cancer treatment vaccines Immune system modulators (cytokines – interferons, interleukins; BCG; immunomodulatory drugs – thalidomide, lenalidomide, pomalidomide, which are also angiogenesis inhibitors)

Targeted Therapy

Tyrosine kinase inhibitors (e.g. erlotinib for EGFR, venetoclax for BCL2, imatinib for BCR-ABL mutations in CML, ibrutinib in CLL) Monoclonal antibody-drug conjugate (e.g. brentuximab-vedotin for lymphoma, obinutuzumab-ozogamicin for ALL) Angiogenesis inhibitors primarily target VEGF (e.g. bevacizumab, everolimus) Hormone therapy Gene therapy

Hormone Therapy

Oral Injection Surgery (oophorectomy, orchiectomy)

Stem Cell Transplant

Autologous Allogenic Syngeneic

Precision Medicine

Certain tumors, including melanoma, some leukemias, and breast, lung, colon, and rectal cancers, may be tested for certain genetic changes

*Types of external beam radiation therapy include 3-D conformal therapy, intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), stereotactic radiosurgery, and stereotactic body radiation therapy. ALL, Acute lymphoblastic leukemia; BCG, Bacillus Calmette- Guérin; BCL2, B-cell lymphoma 2; BCR-ABL, Breakpoint cluster region protein. The symbol ABL1 is derived from Abelson, the name of a leukemia virus. A fusion gene is created by juxtaposing the ABL1 gene on chromosome 9 (region q34) to a part of the BCR gene on chromosome 22 (region q11); CAR-T, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; EGFR, epidermal growth factor receptor; IV, intravenous; TIL, tumor-infiltrating lymphocytes; VEGF, vascular endothelial growth factor.

TABLE 33.2

Approaches to Oncology Pain Management

Drugs

Analgesics (opioids, NSAIDs, APAP) Adjuvant analgesics (anti-depressants, anti-convulsants) Steroids

Psychosocial

Cognitive behavioral Stress management, including biofeedback Social support

Integrative medicine

Acupuncture Massage Hypnotherapy

Physical therapy and Rehabilitation

Flexibility, strength, endurance, aerobic conditioning Lymphedema control

Modification of pathologic process

Radiation therapy Chemotherapy Surgery

Interruption of pain pathways

Local anesthetics Neurolytics (alcohol, phenol) Thermal ablation (radiofrequency, cryoablation) Neurosurgery (cordotomy, DREZ, anterior cingulotomy)

APAP, Automatic positive airway pressure; DREZ,**; NSAIDs, nonsteroidal anti-inflammatory drugs.

• Figure 33.3  World Health Organization analgesic ladder (2018).

464

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 33.3

Acetaminophen

Principles of Analgesic Use

Principle

Comment

By mouth

Oral intake is preferred. Transdermal/ transmucosal can also be considered.

By the clock

Give medications regularly. Anticipate pain problems, particularly breakthrough pain. For opioid use, schedule ATC opioids and use BTP opioids as needed.

For the individual

Patient responses vary by patient and by medication. Variations in drug metabolism may cause unpredictable pharmacokinetics.

With attention to detail

Regular assessment of response to a regimen is essential. Assume patients may not follow a new regimen accurately or as prescribed.

ATC, Around the clock; BTP, breakthrough pain.

anti-convulsants for cancer pain management, the WHO report did not make a recommendation for these classes of medications for the treatment of cancer-related neuropathic pain. Adequate data from clinical trials regarding the use of anti-depressants and anti-convulsants in oncology pain was not available. In the absence of clear evidence in favor of use, practitioners may consider an individual trial of therapy and prescribe for those patients without adequate pain relief or have severe/unmanageable side effects to standard analgesic regimens. Drugs or drug classes recommended for the management of neuropathic pain are listed in Table 33.4. TABLE 33.4

N-acetyl-p-aminophenol (APAP) is an antipyretic/analgesic drug that is discussed extensively in Chapter 49. Hepatotoxicity is the most well-known severe adverse effect of APAP. Particularly in cases of overdose, APAP characteristically shows direct hepatocellular injury.20 Hepatocellular injury may result in elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) blood levels, usually 24–48 h after ingestion. Elevated ALT level greater than three times the upper limit of normal was seen in 33%–44% of normal volunteers who were administered 4 g of APAP daily for 14 days.21 The maximum daily therapeutic dose of 3900–4000 mg was established in separate actions in 1977 and 1988, respectively, via the Food and Drug Administration (FDA) monograph process for nonprescription medications. The 3900 mg maximum daily dose, as recommended originally, was deemed to be safe and is five to seven times lower than the estimated median lethal dose (LD50) of 400 mg/kg.22 Some studies have indicated that daily APAP doses of 4000 mg for 6 to 12 months demonstrated that no patient exceeded liver function tests beyond two times the upper limit of normal.23 The FDA has conducted multiple advisory committee meetings to evaluate acetaminophen and its safety profile and has suggested (but not mandated) a reduction in the maximum daily dosage from 3900– 4000 mg to 3000–3250 mg, which appears based on the potential of an overdose occurring if a patient was not using acetaminophen properly or if, unknowingly, a patient was using multiple acetaminophen-containing products. The concern was not with therapeutic dosing (≤4000 mg/24 h) but with excessive dosing when two or more products containing acetaminophen are taken inadvertently and the potential for hepatotoxicity with chronic use at excessive doses. In a Cochrane review, there was no high quality evidence to support or refute the use of APAP alone or in

Drugs or Drug Classes With Strong or Weak Recommendations for the Management of Neuropathic Pain192 Total Daily Dose and Dose Regimen

Recommendations

Gabapentin

1200–3600 mg, in three divided doses

First line

Gabapentin extended release or enacarbil

1200–3600 mg, in two divided doses

First line

Pregabalin

300–600 mg, in two divided doses

First line

Serotonin noradrenaline reuptake inhibitors duloxetine or venlafaxinea

60–120 mg, once a day (duloxetine); 150–225 mg, once a day (venlafaxine extended release)

First line

Tricyclic anti-depressants

25–150 mg, once a day or in two divided doses

First lineb

Capsaicin 8% patches

One to four patches to the painful area for 30–60 min every three months

Second line (peripheral neuropathic pain)c

Lidocaine patches

One to three patches to the region of pain once a day for up to 12 h

Second line (peripheral neuropathic pain)

Strong Recommendations for Use

Weak Recommendations for Use

a

Duloxetine is the most studied, and therefore recommended, of the serotonin noradrenaline reuptake inhibitors.

Tricyclic anti-depressants generally have similar efficacy; tertiary amine tricyclic anti-depressants (amitriptyline, imipramine, and clomipramine) are not recommended at doses greater than 75 mg/day in adults aged 65 years and older because of major anticholinergic and sedative side effects and potential risk of falls; an increased risk of sudden cardiac death has been reported with tricyclic antidepressants at doses greater than 100 mg daily.

b

The long-term safety of repeated applications of high-concentration capsaicin patches in patients has not been clearly established, particularly with respect to degeneration of epidermal nerve fibers, which might be a cause for concern in progressive neuropathy.

c

Reprinted with permission from Elsevier. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M: Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–173.

 

CHAPTER 33

combination with opioids for the first two steps of the three-step WHO cancer pain ladder.24 It was not clear whether any additional analgesic benefit of acetaminophen could be detected in the available studies. In an era of concern for opioid prescribing, there is a tendency to prescribe regular and higher doses of APAP (up to 4 G/day) in cancer patients. Toxicity from high daily doses of APAP is of concern. Unintentional fever suppression in patients receiving chemotherapy is also an issue. APAP should be used cautiously and not for extended periods in oncology patients receiving active treatment.

Nonsteroidal Anti-inflammatory Medications NSAIDs exhibit their action by inhibiting the cyclooxygenase (COX) enzyme, which consists of two isoforms named as COX-1 and COX-2. Most NSAIDs are nonselective and inhibit both COX-1 and COX-2. Celecoxib is the only marketed drug belonging to the class of selective COX-2 inhibitors approved by the FDA. COX-2 overexpression is demonstrated throughout various steps of tumorigenesis to metastasis, and COX-2 expression directly co-related with increased prostaglandin levels in neoplastic tissues, particularly in the gastrointestinal tract,25 and possibly breast.26 Long-term use of (low dose) aspirin and non-selective NSAIDs are potential candidates for chemoprevention of gastrointestinal cancer.27 The anti-inflammatory activity of NSAIDs in descending order is indomethacin > diclofenac > piroxicam > ketoprofen > lornoxicam > ibuprofen > ketorolac > acetylsalicylic acid. The greater the degree of COX-1 block, the greater the tendency to cause gastrointestinal (GI) ulceration and the promotion of bleeding. From the first day of use, all NSAIDs increase the risk of GI bleeding, myocardial infarction, and stroke. The risk of bleeding is low for patients using NSAIDs intermittently. NSAIDs increase the risk of GI bleeding by inhibiting platelet aggregation, causing gastric mucosa lesions, ulceration, overt bleeding, enteropathy, and occult bleeding associated with a decrease in hemoglobin. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for three to six months and in about 2%–4% of patients treated for one year. Even short-term (zero to three days) treatment with NSAIDs was associated with increased risk of bleeding compared with no NSAID use in patients receiving antithrombotic therapy.28 Nonselective NSAIDs increase the risk of a GI bleed four fold, whereas COX-2 inhibitors increase this risk three fold. Co-prescription of NSAIDs with corticosteroids increases bleeding risk 12-fold, spironolactone 11-fold, and SSRIs 7-fold.29 Monotherapy with non-selective NSAIDs increased the risk of upper GI bleeding by an incidence rate ratio (IRR) of 4.3 to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of GI bleeding; concomitant NSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and produced the greatest excess risk relative excess risk because of an interaction (RERI of 5.5. Concomitant use of NSAIDs and aldosterone antagonists produced an IRR for upper GI bleeding of 11.0 (RERI 4.5). The excess risk from the concomitant use of NSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from the use of COX-2 inhibitors with SSRIs was 1.9, and that for the use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of NSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9.29 Concomitant

Evaluation and Treatment of Cancer-Related Pain

465

use of non-selective NSAIDs or low dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces a significant excess risk of upper GI bleeding. Castellsague et al. pooled relative risks (RRs) of upper GI complications associated with individual NSAID use.30 Agents such as celecoxib and ibuprofen have a low RR (1.5 and 1.8, respectively), while piroxicam and ketorolac have a higher RR (7.4 and 11.5, respectively). Approximately 10% of the total drug-induced hepatotoxicity is NSAID-related.31 Sulindac and diclofenac are the NSAIDs most associated with hepatotoxicity, but virtually all NSAIDs have been linked to at least rare cases of clinically apparent drug-induced liver injury. The most common adverse effects affect the gastric mucosa, renal system, cardiovascular system, hepatic system, and hematologic system. The mechanism of injury to the liver is usually hepatocellular, but cholestatic injury can also occur.32 COX-2 selective inhibitors and non-selective NSAIDs are associated with an increased risk of acute cardiovascular events.33 Even one week of NSAID use is associated with an elevated risk of myocardial infarction (MI), and this phenomenon may apply to those with no prior history of MI. While the risk increases with increasing dosage, the risk appears to plateau after a one-month duration of use.34 In older patients with arthritis and established coronary artery disease or risk factors who used chronic NSAID therapy (celecoxib 100–200 mg twice daily, ibuprofen 600–800 mg thrice daily, or naproxen 375–500 mg twice daily), naproxen and ibuprofen at moderate doses were associated with more cardiovascular events that with celecoxib.35 The vascular risks of high-dose diclofenac (150 mg/day) and possibly ibuprofen (2400 mg/day) are comparable to coxibs. In contrast, high-dose naproxen (1000 mg/day) is associated with less vascular risk than other NSAIDs.36 NSAIDs can cause serious renal adverse effects, which include sodium and water retention with edema, worsening of heart failure, hypertension, hyponatremia, hyperkalemia, acute kidney injury, renal papillary necrosis, and acute interstitial nephritis. Acute forms of kidney injuries are transient and often reversible upon drug withdrawal. Approximately 1%–8% of patients taking NSAIDs develop renal adverse effects such as a reduction in glomerular filtration rate, acute renal failure, renal papillary necrosis, nephrotic syndrome, acute interstitial nephritis, and chronic renal failure.37 NSAIDs, unlike aspirin, bind reversibly at the active site of COX-1, usually depressing platelet thromboxane formation to the degree that platelet function is impaired for only a portion of the dosing interval. Platelet function normalizes within 24 h of the last dose of ibuprofen in healthy volunteers who took 600 mg q 8 h for one week.38 Studies on the use of NSAIDs in cancer (including both aspirin and non-aspirin NSAIDs) show inconsistent and contradictory findings in terms of the role of these drugs in cancer, with some reporting an increased risk in certain types of cancer and others showing a reduction in cancer risk.39 Although many NSAIDs are available to treat various painful conditions, it is unclear which agent is most clinically efficacious for relieving cancer-related pain and if there are clinical differences between these agents that justify their cost differences. In a Cochrane review of the use of NSAIDs either alone or in combination with opioids, the quality of evidence supporting the use of NSAIDs was poor and suggested that moderate to severe cancer pain was reduced to no worse than mild pain after one to two weeks in approximately 1:3 patients. One in four patients stopped taking NSAIDs because the drug did not work, and 1:20 stopped because of side effects.40 In effect, there is no evidence to support or refute the use of NSAIDs alone

466

PA RT 4 Clinical Conditions: Evaluation and Treatment

or in combination with opioids for cancer pain.40,41 The long-term use of NSAIDs for pain management is not advisable in patients with cancer, particularly because of the additional bleeding risks in cancer patients undergoing active treatment with myelosuppressive regimens and the probability that a patient with cancer may be on a broad regimen of medications, some of which may increase NSAID-related toxicity (myocardial infarction, gastrointestinal bleeding, and renal failure).

Antiepileptic Drugs The pharmacologic mechanism of action responsible for therapeutic effects in pain management is unclear (Table 33.5) and may involve enhancement of GABAergic inhibition, decreased glutamatergic excitation, modulation of voltage-gated sodium and calcium channels, and effects on intracellular signaling pathways.42 Antiepileptic drugs (AEDs) are often administered as polytherapy or combined with other treatments. The pharmacokiTABLE 33.5

netics of carbamazepine is nonlinear because of autoinduction that completes within three weeks and can result in a threefold increase in elimination. It is extensively metabolized in the liver, primarily by CYP3A4. Because of this, it is readily inducible and potently inhibited. Therefore it is subject to many pharmacokinetic drug-drug interactions. As well as being an enzyme-inducing drug, carbamazepine is affected by the autoinduction of CYP3A4mediated metabolism. This mainly occurs at the beginning of treatment when clearance can increase up to three times during the first two to three weeks. Carbamazepine, oxcarbazepine, phenobarbital, and phenytoin may reduce the levels of cyclosporin, tacrolimus, and corticosteroids, delaying the immunosuppressant effect by up to ten days.43 Gabapentin, lacosamide, levetiracetam, pregabalin, and vigabatrin are essentially not associated with clinically significant pharmacokinetic interactions.44 Gabapentinoids include gabapentin and pregabalin. The α2δ-1, commonly known as a voltage-activated Ca2+ channel subunit, is a binding site of gabapentinoids.45 Gabapentinoids commonly

Antiepileptic Drugs

Medication

Mechanism of Action

Indication

IR

ER

Comment

Valproate

Influences GABAergic neurotransmission. It is also thought to block sodium and calcium channels.

Epilepsy, acute mania/ bipolar disorder, and migraine prophylaxis.

Yes

DR and ER tablets

ER formulation has lower bioavailability. Doses need to be increased by 12% (8%–20%) compared to the standard formulation. Effective for migraine prevention. Risk of fetal malformation. Adverse benefits include liver function test abnormalities, dizziness, drowsiness, and nausea. Maximum dose is 60 mg/kg/day.

Carbamazepine

Blocks voltage-gated sodium channels.

Epilepsy (especially partial seizures), bipolar disorder, and trigeminal neuralgia.

Yes

Carbatrol or Tegretol-XR

Side effects include hyponatremia, leukocytosis, thrombocytopenia, dizziness, drowsiness, ataxia, nausea/vomiting, and blurred vision. Dosing starts at 100–200 mg twice a day and is titrated up by 200 mg/day every three to five days until pain relief is achieved. The maximum dose is 1200 mg/day.

Partial and generalized seizures; monotherapy for trigeminal neuralgia.

Yes

ER

Non-linear pharmacokinetics.

Phenytoin

Oxcarbazepine

Blocks voltage-gated sodium channels.

Focal seizures with or without secondary generalization.

Yes

ER

ER peak concentrations are 19% lower than with OXC IR. It can be started at 300 mg twice a day and titrated up by 300 mg/day every three days for therapeutic effect. The maximum dose is 2400 mg/day.

Lamotrigine

Blocks Na+ channels, neuronal α-4-β2-nicotinic acetylcholine receptors may be a target.

Partial seizures, the generalized seizures of Lennox-Gastaut syndrome, primary generalized tonicclonic seizures. Mood stabilizer in bipolar.

Yes

XR

Risk of Stevens-Johnson. Start at low doses (25 mg/day) with weekly titration to target dose. Syndrome, blood dyscrasia.

 

CHAPTER 33

TABLE 33.5

Evaluation and Treatment of Cancer-Related Pain

467

Antiepileptic Drugs—cont’d

Medication

Mechanism of Action

Indication

IR

ER

Comment

Lacosamide

Selectively enhances the slow inactivation of voltagegated sodium channels and interacts with the collapsin-response mediator protein-2.

Primary generalized tonic-clonic seizures, partial onset seizures.

Dosing starts at 50 mg twice daily and can be increased to 400 mg/ day. Abrupt discontinuation can precipitate seizures. No convincing evidence of efficacy in neuropathic pain and fibromyalgia at doses of 200–400 mg daily.

Gabapentin

Binds to calcium channels and modulating calcium influx. Exert analgesic effect through high affinity binding and modulation of the calcium channel α2-δ proteins in the dorsal root ganglion.

Partial seizures, postherpetic neuralgia.

Yes

ER

Compared with other anti-convulsant drugs, the α2-δ ligands do not have significant drug interactions, predominantly because of their lack of hepatic metabolism or their modulation of cytochrome P450 activity. Nonlinear pharmacokinetics (absorbed in the proximal small bowel by the L-amino acid transporter, which is a saturable mechanism).

Pregabalin

Binds to calcium channels and modulating calcium influx. Exert analgesic effect through high affinity binding and modulation of the calcium channel α2-δ proteins in the dorsal root ganglion.

Painful diabetic peripheral neuropathy, postherpetic neuralgia, partial onset seizures, fibromyalgia, neuropathic pain associated with spinal cord injury.

Yes

ER

Compared with other anti-convulsant drugs, the α2-δ ligands do not have significant drug interactions, predominantly because of their lack of hepatic metabolism or their modulation of cytochrome P450 activity. Unlike gabapentin, it has linear pharmacokinetics over its recommended dose ranges. Start at low doses (50 mg daily), adding 50 mg each week on a twice a day basis to a max of 600 mg per day.

Topiramate

Blocks activity-dependent, voltage-gated sodium channels; enhance the action of GABA receptors; inhibit L-type voltagegated calcium channels; presynaptically reduce glutamate release, and postsynaptically block kainate/α-amino-3hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors.

Generalized tonicclonic seizures, partial seizures, migraine.

Yes

ER

Dosing starts at 50 mg/day and can be titrated up to 400 mg/day. No convincing evidence of efficacy in neuropathic pain. Serious adverse events thought to be related to topiramate included convulsion and bradycardia plus syncope. Additional adverse effects include sedation, nausea, diarrhea, and metabolic acidosis.

IR = Immediate release. ER/XR = Extended release. DR = Delayed release.

cause adverse effects such as sedation, confusion, dizziness, ataxia, visual disturbances, and altered cognition. Combined with opioids, this side effect profile can be potentiated. For first-time pregabalin users, dizziness and somnolence were reported by 25% and 14% of patients, respectively.45 Gabapentinoids have the potential to be abused with an estimated prevalence of 1.6% in the general population with ranges from 3% to 68% among opioid abusers,46 and are associated with euphoria, sedation, and dissociation. Gabapentin was misused primarily for recreational purposes, self-medication, or intentional self-harm and was misused alone or combined with other substances, especially opioids, benzodiazepines, and/or alcohol.47 Risk factors for abuse include a history of substance abuse,

particularly opioids, and psychiatric comorbidities. Sedation and dizziness are relatively common, and some patients experience cognitive difficulties while taking these drugs.48 In 2008, the FDA issued a warning on all AEDs that these drugs have an increased risk of suicidal thoughts and behaviors. The relative risk was higher in the epilepsy patient group when compared to the groups of patients receiving AEDs for psychiatric and other conditions. However, patients and clinicians should not avoid the use of AEDs because of the risk of suicidality.49 However, the high prevalence of comorbid behavioral health issues in patients treated with AEDs suggests that the association is confounded by indication, preexisting mental health conditions, and medications received. In a cohort analysis,

468

PA RT 4 Clinical Conditions: Evaluation and Treatment

Patorno et al.50 found an increased risk for these events in new users of gabapentin, lamotrigine, oxcarbazepine, and tiagabine compared with topiramate. A secondary analysis confirmed the increased risk and identified an excess of 5.6 cases of attempted or completed suicide per 1000 person-years among new users of gabapentin, 10.0 cases per 1000 person-years among new users of oxcarbazepine, and 14.1 cases per 1000 person-years among new users of tiagabine compared with topiramate. The risk remained increased for gabapentin in subgroups of younger and older patients, patients with a mood disorder, and patients with epilepsy or seizure disorders. Gabapentinoids are indicated for the treatment of epilepsy, peripheral and neuropathic pain, fibromyalgia, and generalized anxiety disorder in adults. Recommendations for use and doses in neuropathic pain are listed in Table 33.4. For gabapentin, the only pain related indication approved by the FDA is postherpetic neuralgia. For pregabalin, FDA-approved indications related to pain are limited to postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy or spinal cord injury, and fibromyalgia. Despite these limited indications, gabapentin and pregabalin are widely prescribed off-label for multiple different pain complaints.51 A common mistaken perception is that an effective drug for one type of neuropathic pain is beneficial for all neuropathic pain, regardless of underlying etiology or mechanism. Recommendations across guidelines consistently endorse gabapentinoids as first line agents for general neuropathic pain complaints but that the overall quality of these guidelines is poor.52 Similarly, the evidence does not support gabapentinoid therapy for low back pain or radiculopathy, suggesting that pregabalin was ineffective.53 A Cochrane review showed that some patients with neuropathic pain would benefit substantially from pregabalin, while more are having moderate benefit, and many are without any benefit.54 Gabapentin can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy, but evidence for other types of neuropathic pain is very limited.55,56 Similarly, there is little evidence to support the effectiveness of oxcarbazepine in painful diabetic neuropathy, neuropathic pain from radiculopathy, and a mixture of neuropathies.56 Overall, there is low quality evidence that gabapentinoids are effective in reducing pain intensity in patients with cancer pain.57

Anti-depressants Anti-depressants can be classified into different classes based on their mechanisms of action (Table 33.6). The two classic mechanisms are demonstrated by tricyclic antidepressants and monoamine oxidase inhibitors. The nonclassical anti-depressants, the most widely prescribed agents, are SSRIs and dual serotonin norepinephrine reuptake inhibition (SNRI). Anti-depressants have virtually no antinociceptive effects but are prescribed for neuropathic pain. Tricyclic anti-depressants and serotonin noradrenaline reuptake inhibitors are used to treat chronic pain, such as neuropathic pain and fibromyalgia. SSRIs are generally the first line anti-depressants for the treatment of depression in cancer patients because of their tolerability profile. SSRIs, which are frequently used to treat depression, are not effective against chronic pain.58 The inhibitory effects of antidepressants for neuropathic pain manifest more quickly than their anti-depressant effects, suggesting different modes of action. The analgesic effect on chronic pain may manifest in as little as a few days to one week, whereas the anti-depressant effects may take two to four weeks.59 Anti-depressants that inhibit the reuptake

of both noradrenaline and 5-HT have stronger analgesic effects than a drug that selectively inhibits the reuptake of only one of these neurotransmitters, and norepinephrine plays a greater role than 5-HT in the analgesic action. Anti-depressants have several other actions in addition to increasing monoamines that may contribute to the inhibition of neuropathic pain, such as sodium channel blockers, N-methyl-d-aspartate (NMDA) receptor antagonists, effects on α-1 receptors, calcium channel blockers, potassium channel activators, modulation of the adenosine system, and activation of GABA-B receptors.59 Serotonin and dopamine may reinforce the noradrenergic effects to inhibit neuropathic pain. Increasing norepinephrine in the spinal cord by reuptake inhibition directly inhibits neuropathic pain through α2-adrenergic receptors. Also, increasing norepinephrine acts on the locus coeruleus and is an essential element of both the ascending and descending pain modulator systems regulated by these anti-depressants.60 TCAs (amitriptyline, nortriptyline, and desipramine) have been the first line treatment for neuropathic pain for many years, but only a minority of people will achieve satisfactory pain relief.61–63 Finnerup et al.58 reviewed the pharmacotherapy for neuropathic pain in adults. Outcomes were generally modest even for effective drugs: in particular, NNTs were 3.6 (95% confidence interval [CI] 3.0-4.4) for TCAs and 6.4 (95% CI 5.2-8.4) for the SNRI anti-depressants duloxetine and venlafaxine. There was no evidence for a dose-response effect for amitriptyline. Combined NNH was 13.4 (9.3-24.4) for TCAs and 11.8 (9.5-15.2) for SNRIs. Low-dose amitriptyline (25 mg/day) for chronic low back pain did not improve outcomes at six months with no improvement in pain intensity, but there was a reduction in disability at three months.64 When anti-depressants are used for chronic pain, the most prevalent adverse effects from anti-depressants were dry mouth, dizziness, nausea, headache, and constipation.65 Risk for withdrawal because of adverse effects was highest for desipramine followed by venlafaxine and duloxetine. TCAs are associated with increased mortality in cases of intentional or accidental overdose, and their side effects profile and tolerability require careful dose titration and frequent monitoring, which substantially limits their wide use.66 Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily than 20 mg daily, but serious side effects are rare. Chemotherapy-induced peripheral neuropathy (CIPN) is common among cancer patients who undergo chemotherapy with platinum analogs, taxanes, vinca alkaloids, epothilone, bortezomib, and thalidomide. Chemotherapeutic agents can damage nervous system structures and, depending on the individual compound, can cause various neuropathies that affect different structures, including large and small fibers and autonomic function.67 The effects of chemotherapy on the nervous system vary among the different classes of drugs, depending on the specific physical and chemical properties of the drug used and its single or cumulative doses. The mechanism by which chemotherapeutics damages nervous system structures and causes CIPN is multifactorial and involves microtubule disruption, oxidative stress and mitochondrial damage, altered ion channel activity, myelin sheath damage, DNA damage, immunologic processes, and neuroinflammation.68 The mechanisms of injury are complex and interested readers are referred to the review by Carozzi et al.69 When patients experience drug-induced chronic neurotoxicity that necessitates intervention beyond dose reduction or discontinuation, the strongest evidence supports the use of duloxetine.70 However, other anti-depressants have not shown a similar benefit. Furthermore, the best available data support a moderate recommendation for

 

CHAPTER 33

TABLE 33.6

Evaluation and Treatment of Cancer-Related Pain

469

Classification of Anti-depressants

Drug Type

Example

Comment

Norepinephrine-dopamine reuptake inhibitors (NDRI)

Bupropion

Acts selectively to inhibit the noradrenergic and dopaminergic reuptake transporter pump systems. Side effects include anxiety, insomnia or sedation, weight loss, and may be excessively activating for some patients. Seizures may occur at dosages above 450 mg/day.

Serotonin noradrenaline reuptake inhibitors (SNRIs)

Mixed action on both NE and serotonin. Used in the treatment of pain disorders, including neuropathies and fibromyalgia. SNRIs are also used in the treatment of generalized anxiety disorder, stress urinary incontinence, and vasomotor symptoms of menopause. Pharmacologic properties are dose dependent. At low doses, behave essentially like an SSRI; while at medium doses, additional NE reuptake inhibition occurs, and at high-to-very high doses, weakly inhibit the reuptake of dopamine. Duloxetine

Side effects include nausea, dry mouth, constipation, dizziness, and insomnia.

Venlafaxine

Serotonin reuptake inhibition in dosages below 150 mg/day; mixed serotonin and noradrenergic reuptake inhibition in dosages above 150 mg/day Side effects may include headache, nausea, sweating, sedation, hypertension, and seizures.

Desvenlafaxine

Major active metabolite of venlafaxine. X10 times more potent inhibiting serotonin than norepinephrine uptake.

Selective serotonin reuptake inhibitors (SSRIs)

Proven efficacy in panic disorder, generalized anxiety disorders, obsessive-compulsive disorder, and bulimia, with encouraging findings in social phobia, post-traumatic stress disorder. Side effects of SSRIs may include nausea, sedation, decreased libido, sexual dysfunction, headache, and weight gain. Citalopram

QT prolongation.

Escitalopram

(S)-enantiomer of citalopram.

Fluoxetine

Can cause activation (take during daytime). Because of a long half-life and active metabolites, rare symptoms of discontinuation or withdrawal symptoms if abruptly stopped.

Paroxetine

Can be sedating and thus taken at bedtime. Its anticholinergic side effects can affect cognition, especially in the elderly. Discontinuation/ withdrawal symptoms could develop if abruptly discontinued.

Sertraline Serotonin receptors antagonist with serotonin reuptake inhibition (SARI)

Trazodone

Tricyclic anti-depressants (TCAs)

Moderate-to-strong serotonin receptor(s) antagonism with a weak serotonin reuptake transporter inhibition. Side effects include sedation and drowsiness, tachycardia, and priapism (rarely). “Gold standard” anti-depressants. Among the best studied and most commonly used are the first-generation TCAs, which are mixed reuptake inhibitors with both NE and serotonergic 5-HT effects such as amitriptyline, imipramine, and doxepin.

Amitriptyline

Most potent anticholinergic; cautious use in elderly.

Clomipramine Desipramine

As secondary amine, fewer anticholinergic effects.

Doxepin

Most potent antihistamine effects.

Imipramine Nortriptyline

Acts by inhibiting the reuptake of NE and serotonin 5-HT and possesses central anticholinergic activities. As secondary amine, fewer anticholinergic effects.

Desipramine Noradrenergic α2-receptor antagonist with specific serotonergic receptors-2 and -3 antagonism (NASSA)

Mirtazapine

Enhances release of NE and 5-HT1A-mediated serotonergic transmission. Side effects include drowsiness, dizziness, anxiety, confusion, increased appetite, and weight gain.

470

PA RT 4 Clinical Conditions: Evaluation and Treatment

treatment with duloxetine.71 CIPN trials were also inconclusive regarding tricyclic anti-depressants (such as nortriptyline) and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine.71 Anti-convulsants, such as gabapentinoids, have not been proven effective for patients with CIPN.70 Duloxetine, when used for diabetic peripheral neuropathy and fibromyalgia, has efficacy for pain associated with diabetic neuropathy at doses >60 mg/day (not at lower doses).72 The effect in fibromyalgia was likely achieved through a greater improvement in mental symptoms than in somatic physical pain.

Opioids Opioids are extensively discussed in Chapter 48. Although some suggest that opioids are relatively ineffective for the management of neuropathic in chronic pain,58,73 this has not been our experience and of others in cancer pain.74–76 Clinical pathways have emerged as one of the key approaches to minimize unwarranted variation in care and improve both the quality and efficiency of care. When appropriately designed and implemented, oncology pathways are detailed with evidence-based treatment protocols for delivering quality cancer care for particular patient presentations that include the type and stage of disease.77 Extrapolation from opioid prescribTABLE 33.7

ing recommendations, including the guideline for prescribing opioids for chronic pain from the Centers for Disease Control and Prevention,78 and applying these to the cancer population is problematic as most of the recommendations have not included opioid outcomes in this particular population. Consequently, some professional oncology organizations and societies have issued policy and position statements on opioid therapy emphasizing continued access for cancer-related pain.79–81 Continued use of opioids in oncology requires risk evaluation and strategies for continued monitoring in all patients, including those considered at high risk for opioid misuse or abuse or illicit substance use (Table 33.7). Opioids have been classified as weak and strong opioids, based upon their affinity for the µ-receptor.82,15 Distinct opioids may elicit very different intracellular responses and may ultimately have very different outcomes on behavior, including analgesic ability, addiction liability, and the risk for acute negative side effects such as respiratory depression.83 The wide-ranging drug-specific differences among opioids in their pharmacokinetics and pharmacodynamics include opioid receptor biases and ligand biases at the opioid receptors, as well as differential interactions with the non-opioid system. These result in differential coupling and activation of intracellular signaling and likely accounts for diverse interactions with various biologic systems, such as the immune

Risk Evaluation and Monitoring for Continued Opioid (All Doses) Therapy in Oncology Patients

All Patients Risk stratification

Screening tool such as ORT Personal history of substance abuse including prescription opioids, psychoactive medications, illicit substances, alcohol Family history of substance abuse including prescription opioids, psychoactive medications, illicit substances, alcohol Presence of adequate support system (family, friends, social)

Education on opioid use and safety

Risk versus benefit Informed consent for opioid therapy Safe medication keeping Adherence to prescription instructions Naloxone use

Regular ongoing screening and monitoring

Regular follow-up with pill counts/opioid reconciliation (telephone/telemedicine/clinic) or office visit Prescription monitoring program review at each refill Current opioid misuse measure at each clinic/office visit Review for the presence of aberrant drug behaviors Urine toxicology screening (to include alcohol, illicit drug, comprehensive panel for opioids) at minimum yearly or sooner as clinically indicated

Regular concomitant psychoactive medication review

Elimination of other psychoactive medications when possible Avoidance of concurrent long term use of benzodiazepines or Z drugs

High Risk Patients No evidence of current substance use

Regular review of medical indication for continued opioid use Referral for addiction specialist assessment (as indicated) Frequent (at least four times per year) random urine drug screening (to include alcohol, illicit drug, comprehensive panel for opioids) Consequences for unsanctioned substance/non-prescribed medication use, including alcohol

Evidence of current substance use

No initiation of controlled substance prescriptions with ongoing illicit substance use, including alcohol Referral for addiction assessment and management Frequent (at least four times per year or more frequently as clinically indicated) urine drug screening (to include alcohol, illicit drug, comprehensive panel for opioids) Elimination of other psychoactive medications when possible Consequences for unsanctioned substance/non-prescribed medication use, including alcohol

The use of an opioid contract is not considered mandatory in oncology care. High risk patients include patients with an opioid risk tool (ORT) score of ≥ eight; history of chemical coping or issues with prescription adherence; active problematic alcohol use, illicit drug or prescription drug abuse. Aberrant drug-related behavior is a behavior suggestive of a substance abuse and/or substance use disorder.

 

CHAPTER 33

system and the dopaminergic reward system.84 Three distinct opioid receptors have been cloned, mu (MOR), kappa (KOR), and delta (DOR), with different selectivity for individual endogenous peptides and the various opioids. The three opioid signaling systems have unique and counterbalancing roles as they relate to their regulation of pain, stress, and affect. Though the MOR is the main target for opioid analgesics, the DOR and KOR also regulate pain, and analgesia and the relative affinities of opioid analgesics for these receptors confer their unique properties. MOR agonists produce euphoria and promote stress coping. KOR agonists produce dysphoria and are associated with stress and negative affect. DOR is on the opposite end of the continuum describing mood, and DOR agonists have anxiolytic and anti-depressant activity.85 Opioids mimic endogenous opioids and act by binding to the opioid receptors, thereby activating them with individual differences in receptor binding and signal transduction.86 Additionally, G protein signaling can be selectively targeted.87 Opioids are the mainstay of pharmacotherapy for patients with moderate or more intense pain resulting from virtually any cancer-related etiology. The specific pathogenic mechanism that underlies a patient’s cancer pain should not be a factor in deciding which opioid to use, as the mechanism of pain does not reliably predict the response to opioid therapy. This particularly applies to situations in which tumor-associated neuropathic mechanisms dominate the pain complaint. Opioids should be used as first line therapy in such situations, particularly if the pain is considered moderate to severe in intensity. In oncology, opioids have demonstrable benefits for neuropathic pain.88–90 Factors influencing the selection of a particular opioid are listed in Table 33.8. All clinicians who prescribe opioids for the treatment of cancer pain should be familiar with at least three different agents appropriate for the management of moderate to severe pain.91 The regimen for opioid medications should generally provide around the clock analgesia with provision for rescue doses for the management of exacerbations of the pain not covered by the regular dosage. Predicting the effectiveness of extended release opioids requires knowledge of associated pharmacokinetics. The onset time and time to maximal concentration (Tmax) are particularly helpful. For the extended release opioids, the elimination half-life is not particularly useful because of altered absorption characteristics into the central compartment. Opioids are effective after peripheral (topical, intra-articular), neuraxial (intrathecal, epidural, intracerebroventricular), or systemic (intravenous, oral, subcutaneous, sublingual, intranasal, transdermal) administration, although the final effects are highly dependent on the particular pharmacokinetic and pharmacodynamic features of each drug.84 TABLE 33.8

Factors Influencing the Selection of Opioid Therapy

Previous opioid exposure and preference Severity, nature, and stage of disease Age of patient Extent of cancer, particularly hepatic and renal involvement altering normal opioid pharmacokinetics Concurrent disease Available formulations Risk assessment for problematic opioid use

TABLE 33.9

Evaluation and Treatment of Cancer-Related Pain

471

Opioid-Related Side Effects Transient Side Effects

Nausea/ vomiting

Direct effect on CTZ Sensitivity of vestibular apparatus (activation of MROs in vestibular epithelium) Delayed gastric emptying (central and peripheral)

Pruritus

? agonism at MOR

Sedation

Disordered level of consciousness in which both arousal mechanisms and content processing are functional but attenuated Symptoms include feeling drowsy, sleepy, groggy, dizzy, dreamy, cloudy, mentally foggy, or lethargic Signs may include cognitive impairment, lack of coordination, slowed reaction time, and performance deficits

Respiratory depression

Consider synergistic effects from concomitant other centrally acting drugs Rule out other contributors (e.g. pneumonia, sleep apnea)

Urinary retention

Spinal cord opioid receptor activation ® bladder wall relaxation Increased parasympathetic activity to detrusor muscle

Persistent Side Effects Opioid-induced constipation

Enteral activation of opioid receptors resulting in gastric emptying, sphincter tone, and peristalsis Consider peripherally acting MOR antagonist (PAMORA) agents

Endocrine effects

? direct effect on opioid receptors within hypothalamus, pituitary, and testes Hypothalamic effect, gonadotropin-releasing hormone

CTZ = Chemoreceptor trigger zone. MOR = Mu opioid receptor.

All clinicians involved in the treatment of cancer patients should be familiar with the most common types and dosages of opioids, as well as the management of the most common side effects (Table 33.9).18

Selected Opioids Tramadol Tramadol is a synthetic analog of morphine and codeine and was approved by the FDA to treat moderate to severe pain in adults. Formulations include immediate-release tablets, sustained-release tablets, and extended release capsules. It has a unique mechanism of action and pharmacologic effects that differ from those of other opioid drugs. It has opioidergic, noradrenergic, and serotonergic actions and also has modulatory effects on several mediators involved in pain signaling. Tramadol’s active metabolite (M1) contributes significantly to its analgesic effect. Cmax is achieved approximately 2 h after oral administration, t1/2 is 5–6 h, and bioavailability of 68%–84%. The kidneys are responsible for 90%

472

PA RT 4 Clinical Conditions: Evaluation and Treatment

excretion of tramadol and its metabolites; the remaining 10% is excreted through feces. Because of its hepatic metabolism and renal clearance, impairment in these systems may require dose modifications. Serotonin syndrome may occur with concomitant administration of serotonergic psychotropic agents within recommended dosing parameters for fluoxetine, paroxetine, sertraline, venlafaxine, mirtazapine, citalopram, bupropion, and olanzapine. Certain serotonergic anti-depressants (i.e. paroxetine, fluoxetine) inhibit cytochrome P-450 2D6, elevating plasma concentrations of tramadol and further increasing the risk for serotonin syndrome. Importantly, tramadol is specifically contraindicated with monoamine oxidase inhibitors or within 14 days of discontinuing a monoamine oxidase inhibitor.92 Tramadol side effects are varied. However, the most common events are nausea, followed by vertigo, dizziness, vomiting, tiredness, constipation, sweating, dry mouth, and sedation. The causes of seizures after tramadol exposure are unclear. There is limited, very low quality evidence from randomized controlled trials that tramadol produced pain relief in some adults with pain because of cancer.93

Tapentadol Tapentadol, a centrally acting analgesic, has been proposed as the first agent in a new class of drugs (MOR-NRI) combining the two mechanisms of action µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule.94 Because of its limited protein binding capacity, the absence of active metabolites, and significant microsomal enzyme induction or inhibition, tapentadol has a limited potential for drug-drug interactions.95 Bioavailability is approximately 32% with t½ of 4 h for immediate-release formulations and 5–6 h for extended release. It shows moderate MOR agonist activity, pronounced NA reuptake inhibition, and minimal 5‐HT effect. Clinical trials for chronic severe pain suggested that tapentadol provided equivalent or superior levels of pain relief for acute and chronic pain similar to oxycodone, hydromorphone, fentanyl, oxymorphone, and morphine and significantly less frequent gastrointestinal adverse events (nausea, vomiting, constipation) compared with fentanyl, morphine, hydromorphone, and oxymorphone.96 From the limited data available for oncology pain, pain relief, and adverse events were comparable to morphine and oxycodone, with the most common adverse events being gastrointestinal (nausea, vomiting, constipation).96 Hydrocodone Hydrocodone is a full opioid agonist with relative selectivity for the µ-opioid receptor, although it can interact with other opioid receptors (δ and κ) at higher doses.97 Human PK studies indicate that the conversion of hydrocodone to its primary metabolite, norhydrocodone, and lesser metabolite, hydromorphone, is mediated by the cytochrome P450 enzyme system. Some authors suggest that hydrocodone is a pro-drug and requires metabolism to hydromorphone for therapeutic benefit and that pain relief correlates with plasma hydromorphone concentrations rather than hydrocodone.98 Immediate-release hydrocodone is available as a combination product (acetaminophen, ibuprofen), and single entity hydrocodone only available as extended-release formulations. Hydrocodone is also an antitussive and indicated for cough in adults. The analgesic efficacy can be highly variable and devoid of therapeutic effect in some patients, likely because of CYP2D6 polymorphisms.99 Data regarding the use of hydrocodone in oncology is limited. When low-dose hydrocodone (25 mg/day)

was compared to tramadol (200 mg/day) in patients with chronic cancer pain, hydrocodone was not superior in terms of analgesic efficacy, and tramadol produced more mild side effects than hydrocodone.100

Methadone Methadone is available as a racemic mixture of two stereoisomers – L-methadone (pharmacologically active isomer) and D-methadone. L‐methadone is eight to 50 times more potent than D‐methadone in humans and is believed to be almost entirely responsible for its analgesic properties. Because of its large volume of distribution and its long half-life, methadone tends to accumulate in adipose tissues, especially after repeated doses. It is 60%–90% bound to plasma proteins, and its bioavailability after oral administration is 70%–90%. Tmax averages 2.5–4.4 h following oral administration. On average, the half-life of methadone is around 24 h, but it may vary as much as from 8 to 120 h depending on an individual patient’s adipose tissue composition. Because of its long, biphasic elimination half‐life, it may take up to ten days to reach steady‐state serum levels. Dosage adjustment is not required in renal or hepatic insufficiency or hemodialysis. Methadone is primarily metabolized by N-demethylation to an inactive metabolite. Cytochrome P450 enzymes are responsible for the conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine. One of the enzymes, CYP3A4, is also involved in the metabolism of other drugs: benzodiazepines, calcium antagonists, macrolide antibiotics, and anti-convulsants (carbamazepine). Its activity is strongly inhibited by ketoconazole, fluoxetine, and grapefruit juice (large amounts). Because CYP3A4 is inducible, it can result in drug interactions with other drugs that are also dependent on that enzyme for metabolism. This may directly affect plasma concentrations of methadone with CYP3A4 inducers decreasing plasma levels and inhibitors increasing blood levels (Table 33.10).

Managing the Cardiac Effects of Methadone The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. While the ability of methadone to block the NMDA receptor has been demonstrated in animal models,101 it is unclear if this has clinical relevance at normal doses. Studies for this indication are limited with very low quality evidence of efficacy and safety.102 In cancer pain, the analgesic benefits of methadone appear similar to morphine.103 Our experience is that this is an excellent opioid for pain management but should be avoided in situations of rapidly changing pain complaints where frequent changes in opioid dosing are anticipated (e.g. uncontrolled tumor pain). Further, many drugs used in oncology (e.g. tyrosine kinase inhibitors, 5-HT inhibitor antiemetics, monoclonal antibodies) can also prolong QTc.

Buprenorphine Buprenorphine is a semi-synthetic high affinity partial agonist at µ-opioid receptors and an antagonist at κ receptors with a ceiling effect on sedation and respiratory depression without a clinically relevant ceiling on pain relief.104 The high receptor affinity results in a slow dissociation from the receptor and prolonged activity. Precipitated withdrawal can result if buprenorphine is introduced in the presence of other opiates with lesser binding affinities. Unlike other opioids, buprenorphine exhibits a ceiling effect for respiratory depression (acts as a partial agonist) but not for pain relief.105 Data in opioid-naive volunteers indicate that buprenorphine

 

CHAPTER 33

TABLE 33.10

Drug Effects on Methadone Levels and QTc Interval Effect on Methadone Levels

Drug

Effect on QTc Interval

Antibiotic/antifungal Ciprofloxacin

□

Clarithromycin

□

□

Erythromycin

□

□

Ketoconazole

□

Fluconazole

□

Rifampin

□

Anti-convulsants Carbamazepine

□

Phenytoin

□

Antipsychotics Quetiapine

□

□

Benzodiazepines/Z–Drugs Alprazolam

□

Diazepam

□

Lorazepam

□

Midazolam

□

Triazolam

□

Zopiclone

□

Serotonin Noradrenaline Reuptake Inhibitors Fluoxetine

□

Fluvoxamine

□

Nefazodone

□

Paroxetine

□

Sertraline

□

Evaluation and Treatment of Cancer-Related Pain

473

of effect is 30–60 min with Tmax at about 90–100 min). Oral formulations of buprenorphine have low bioavailability with only 10% of the intravenous route if swallowed and only between 30% and 50% bioavailability with the sublingual administration. The bioavailability of buccal buprenorphine is 46%–65%. In low doses, buprenorphine can only partially activate the μ-opioid receptor. In moderate doses, the buprenorphine’s opioid agonist effect reaches a plateau (ceiling) such that any further dose increase is unlikely to enhance analgesia. In high doses, buprenorphine functions as an opioid antagonist to further limit its analgesic effect.107 The role of buprenorphine in the management of chronic pain is questionable, with few high quality, unbiased studies performed in this area.108 Two buprenorphine formulations are approved by the FDA for the management of pain—buprenorphine buccal film (BelbucaR) and buprenorphine transdermal (ButransR). The transdermal is intended for use for patients requiring a MED 10 years) in Norway with persistent or highdose opioid use may also be prescribed benzodiazepines or benzodiazepine-like hypnotics.140 The use of benzodiazepines may be particularly problematic with concurrent opioid use. Co-prescribing was associated may be associated with a significantly higher risk of death,120 emergency room (ER) visits, or inpatient admission141 than with the use of opioids alone. The FDA released a black box caution warning patients and providers about the potential risks of combined use.

The Opioid Epidemic and Cancer Pain The opioid epidemic is discussed in Chapters 50 and 51. The widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids have contributed to this problem.142 Over and inappropriate medical prescribing, diversion and misuse of prescription opioids, a resurgence in heroin use, an increase in the abuse of illicit, and the availability of illicitly manufactured high-potency synthetic opioids such as fentanyl are likely major contributors to this problem. Overdose deaths related to opioids have dramatically increased. Identifiable characteristics associated with an elevated risk of opioid overdose include a history of overdose, a history of addiction to any substance (but particularly alcohol, benzodiazepines, or opioids), and health problems associated with respiratory depression or concurrent prescription of any medication that has a depressive effect on the respiratory system, such as benzodiazepines and sedative-hypnotics.143 Abuse of opioids is a complex issue that is not solely related to the opioid used. Mental health disorders, genetic, environmental, and lifestyle factors are important contributors. Opioid abuse and misuse also occur for various reasons, including self-medication, use for reward, compulsive use because of addiction, and diversion for profit.144 In a meta-analysis of 568,640 patients who had not used opioids in the six months prior and with a new diagnosis of any type of chronic non-cancer pain, the odds ratio for developing an opioid use disorder (OUD) was 14.9 for patients on chronic (> three months of use) low-dose (1–36 mg MED) opioids and 122.45 for patients on chronic high-dose (120 mg + MED) opioids, respectively, with the duration of opioid therapy more important than the daily dose in developing OUD.145 Policy changes, including recommendations contained in Pain Management Best Practices Inter-Agency report,146 and CDC guidelines78 inform prescribers on best practices for using opioids in chronic pain. For chronic non-cancer pain, most recommendations caution against the use of opioids for chronic pain complaints.

Evaluation and Treatment of Cancer-Related Pain

475

Public and healthcare information has emphasized that addiction in the context of cancer pain and the use of opioids is rare or non-existent. The prevalence of opioid abuse in patients with cancer on opioid therapy is unknown, and most of the published data relate to non-cancer pain issues. Data about substance abuse in cancer patients and those seen in palliative care clinics have been scarce. Barclay et al.147 found that more than 40% of cancer patients seen were moderate to high risk for opioid abuse as measured by the opioid risk tool; 62% of these at risk patients with a urine drug screen ordered had at least one abnormal result. However, most hospice and palliative care programs do not have substance abuse and diversion policies or report screening all patients.148 In the complex milieu of complications of cancer and metastasis, including heterogeneous cancer biology, multiple drugs being used, pain, opioid analgesic use, and psychosocial factors, delineating the specific contribution of individual factors on survival is challenging. It is important to recognize that cancer patients are not immune to developing aberrant opioid and drug use behaviors. Patients who have ongoing anxiety, financial distress, and a prior history of alcoholism/illicit drug abuse are at increased risk.149 Solutions for the opioid epidemic are complex and appear to have largely been focused on physician prescribing habits and regulating patient access to opioids.150 Although well-intentioned, these regulations could inadvertently create an atmosphere that inhibits access to opioid pain treatment for cancer patients and cancer survivors. Withholding opioids from patients with advanced cancer pain has significant ethical implications. Clinicians should be concerned about problematic opioid use even in patients with advanced disease. Without screening or testing for opioid misuse or abuse, it is impossible to address and manage these issues. Standard precautions should include a risk assessment of opioid abuse in all patients, considering whether there is a risk of diversion or abuse, monitoring of adherence, the management of any known psychological or psychiatric conditions, and the monitoring of drug-related behaviors.151 If problems are identified, these should be managed appropriately according to standard clinical guidelines with accommodation for continued oncologic care. The dynamic and frequently changing nature of oncology pain makes this particularly challenging.149

Prevention of Opioid Overdose The opioid overdose epidemic in the United States has been closely associated with a parallel increase in opioid prescribing and with widespread misuse of these medications.152 Long-term opioid therapy carries clinically significant risks, including motor vehicle collisions, sleep-disordered breathing, and accidental overdose.153 All patients treated with opioids are at risk for overdose. Factors increasing that risk include end-organ (liver, kidney) dysfunction resulting in impaired clearance, pulmonary disease, sleep-disordered breathing, and concomitant use of psychoactive medications. Strategies to improve patient safety include patient screening and risk stratification, patient and community education and outreach concerning appropriate pain management, medication reviews/medication therapy management, education on safe storage and disposal, and distribution of naloxone/ opioid rescue kits and training on their proper use. Prescription monitoring programs (PMPs) allow the assessment of a patient’s prescription history (scheduled II and III medications). However, not all psychoactive medications are included in this monitoring program. Also, the program does not identify the prescription of

476

PA RT 4 Clinical Conditions: Evaluation and Treatment

methadone for substance use disorder. PMPs can identify doctor shopping, concomitant benzodiazepine prescriptions, and evidence of undisclosed opioid prescriptions from other providers. Medication disposal boxes and community-based drug take-back events offer alternatives to storing unused opioids (or other controlled substances) at home. Hallmarks of OUD include emotional volatility and signs of problematic medication use, such as taking more medication than prescribed, using opioids for reasons other than pain, and frequent loss of medication or early refills. Several instruments are used clinically to screen for problematic opioid use (see Chapter 51). Prescribers must carefully weigh potential benefits against the risks of opioid-related adverse events and overdose for all encounters involving prescription opioids, and if patients are to be continued on long-term opioids, informed consent should be obtained. Patients with or who are subsequently identified as having an OUD require specialized treatment with professional addiction care. With ongoing oncology care issues, a co-management model for pain and substance use disorder is likely ideal. Ideally, a carefully planned structure of care should be in place for patients receiving chronic opioid therapy. Opioids should be primarily prescribed for improvement of function (defined on an individual basis) and not for reductions in pain intensity scores. Opioid dose escalation among patients with chronic pain is not associated with improvements in Numeric Rating Scale pain scores.154 Before medication refills, an assessment of pain, functional status, safety, and other pertinent information should be conducted. Patients should provide pill counts and are given specific use dates for each prescription. PMP should be routinely checked along with the utilization of mass spectrometry urine drug tests based on opioid morphine milligram equivalent per day. This comprehensive based structure is labor-intensive and understandably may not be easily replicable in every practice. However, we consider this approach as it is essential for the continued and safe prescribing of opioid doses in this patient population who may benefit from continued use.

Intravenous Infusions for Cancer Pain Lidocaine, an amide local anesthetic, inhibits voltage-gated sodium channels resulting in a reversible block of action potential propagation, but its exact analgesic mechanism is unknown. Preclinical and clinical evidence, particularly for acute and chronic pain, indicates that IV lidocaine has antihyperalgesic effects and by infusion for chronic neuropathic pain may reduce spontaneous pain, allodynia, and hyperalgesia.155 Most studies advocate an initial bolus of 1–2 mg/kg followed by continuous infusion of 2–4 mg/kg/h, resulting in plasma concentrations of 1–3 mcg/mL.156 Lidocaine and oral analogs (mexiletine, tocainide) were considered safe and better than placebo in clinical trials for non-cancer neuropathic pain.157 Evidence for cancer-related pain is more limited, and there is wide variation in recommendations for use. Sharma et al.158 demonstrated in 50 opioid-refractory cancer patients that a 2 mg/kg bolus and 2 mg/kg infusion over 1 h resulted in pain relief lasting a mean of 9.34 ± 2.58 days after the single infusion. Side effects observed were tinnitus, perioral numbness, sedation, lightheadedness, and headache. These were self-limited and did not require any intervention except for one patient. However, the role of systemic lidocaine in the management of tumor-associated pain is not defined. For cancer-related pain, the frequency of administration needed for the benefit and sustainability of analgesic efficacy is unknown.

Ketamine, an NMDA receptor antagonist, at subanesthetic doses may alleviate various chronic and neuropathic pain complaints.159 A Cochrane review in 2017 concluded that there was insufficient evidence for the use of ketamine (administered intrathecally, by intravenous bolus, and subcutaneously) as an opioid adjunct in cancer pain.160 In this review, the study using intravenous bolus administration, ketamine caused hallucinations in four of ten participants. In the rapid dose escalation/high-dose (500 mg) subcutaneous ketamine study, there was almost twice the incidence of adverse events in the ketamine group. Adverse events are most commonly somnolence, feelings of insobriety, nausea/vomiting, hallucinations, depersonalization/derealization, and drowsiness.161 In a randomized, double-blind study of subcutaneous ketamine (at three dose levels of 100 mg/24 h, 300 mg/24 h, 500 mg/24 h for a five day schedule) for cancer pain, Hardy et al.162 reported that the number needed to treat was 20 and the number needed to harm was six, suggesting no clinical benefit from ketamine as an adjunct. To date, subcutaneous or intravenously administered ketamine has not been shown to be effective in cancer pain.163

Intrathecal Therapies for Cancer Pain Intrathecal therapies are discussed in Chapter 72. Intrathecal therapy involves the administration of drugs directly into CSF and to CNS receptor sites. Therapy may be delivered by bolus injection or by infusion. Options for drug delivery include an externalized catheter system (percutaneous or tunneled), a fully implanted pump (subcutaneous electronic pump with a tunneled catheter into the intrathecal space), or into the intraventricular system via an intracerebroventricular (ICV) device such as Ommaya reservoir. Administration of drugs via an Ommaya reservoir is typically for anti-neoplastic therapy, and most of the experience of ICV infusion of morphine has been from the 1980s and 1990s.164 This route is not commonly used for oncology pain management. Drugs most commonly infused for spinal administration include opioids and bupivacaine. Compared to epidural administration, intrathecal drug delivery has higher analgesic efficacy and lower rates of treatment failure.165 Although implanted drug delivery systems have been advocated for the management of cancer pain,166 we advise against such systems in the management of patients undergoing active oncologic care. The complexity of programming, organizational challenges related to dose changes and pump refills, and potential safety issues in immunocompromised patients with low platelet counts are problematic. The use of tunneled externalized infusions systems such as those advocated by Nitescu, Sjoberg, et al. has potential for the management of intractable pain that require the administration of intrathecal bupivacaine.167–173 Such systems allow for easy adjustment and titration of intrathecal bupivacaine doses. However, the administration of bupivacaine in such systems is usually significantly functionally limiting and again is not usually indicated in patients with active oncologic treatment.

Vertebral Augmentation (Vertebroplasty, Kyphoplasty) Metastatic tumors to the spine or primary diseases such as multiple myeloma can cause painful vertebral compression fractures. Pain associated with these processes may require surgical treatment or anti-neoplastic therapy such as radiation treatment. Patients with

 

CHAPTER 33

intractable pain who are not responsive to conservative therapy, including analgesics, or who are not surgical or radiation therapy candidates, may benefit from vertebral augmentation techniques assuming no other contraindications to this technique. In an extensive review involving 3,391 citations, of which 111 clinical reports (4,235 patients) evaluated the effectiveness of vertebroplasty (78 reports, 2,545 patients) or kyphoplasty (33 reports, 1,690 patients) for patients with mixed primary spinal metastatic cancers, multiple myeloma, or hemangiomas, the authors concluded that vertebral augmentation could significantly reduce pain intensity, decrease opioid needs, and improve functional disabilities.174 In oncology, the procedure is most often considered for fractures related to multiple myeloma or those induced by steroid therapy. A consensus statement from the International Myeloma Working group recommended that myeloma patients with significant pain at a fracture site and without neurologic compromise should be offered augmentation, and the procedure should be performed within four to eight weeks unless there are medical contraindications. As patients with myeloma are susceptible to multilevel fractures, the total number of fractures should be limited to three at a time.175 Long term (>six months) steroid use may cause osteoporosis which is associated with an increased fracture (vertebral and non-vertebral) risk.176 There is also an increased fracture risk in patients exposed to intermittent high-dose oral steroid therapy.177 The role of vertebral augmentation in treating acute or subacute osteoporotic vertebral fractures in routine practice is controversial and has not been validated consistently.178,179

Evaluation and Treatment of Cancer-Related Pain

477

Neurolytic Autonomic Plexus Blocks These blocks typically include neurolysis of the celiac plexus and superior hypogastric plexus. The role of neurolytic celiac plexus blocks versus systemic analgesic therapy alone in the management of intractable tumor-associated intra-abdominal visceral pain is well established, particularly for the management of pain associated with pancreatic cancer.180,181 Different techniques have been described to denervate the celiac plexus. Extensive tumor involvement of the celiac axis may not result in adequate denervation of the plexus with approaches specifically targeting the celiac plexus because of tumor infiltration of the plexus.182 In this situation, our preferred denervation technique is bilateral retrocrural neurolysis of the thoracic splanchnic nerves.183–185 Plancarte186 introduced the option of superior hypogastric plexus block for the management of chronic cancer-­related pelvic visceral pain. Although the block is considered relatively safe for pelvic associated pain, there is a need for large prospective studies to determine efficacy in cancer pain management.187,188 It is important to remember that both of these blocks modify only nociceptive visceral pain and will not affect other potential sources of pain that are somatic or neuropathic in origin. For example, patients with pelvic disease that extends to the pelvic side wall (somatic) or involve neural plexuses (sacral) will not benefit from a superior hypogastric plexus block.

Summary The optimal method of managing cancer-related pain is to diagnose the factor(s) contributing to the pain complaint. This disease-based (in contrast to symptom management) model of pain management focuses on the source of pain, and in patients with tumor-associated pain, therapy (not exclusively pharmacologic) should be directed to modify the source of that pain. These options typically include surgical, chemotherapeutic, and radiation oncologic options. Management of pain in cancer survivors is also complex, and models for the management of chronic non-cancer pain do not apply. Inadequate treatment of cancer pain continues to be an issue over the last three decades.9,189,190 The humanitarian impact of cancer pain management should not be forgotten. Cancer pain profoundly impacts a patient’s quality of life with physical, psychological, and social consequences. It is incumbent on healthcare professionals involved in the care of cancer patients to educate

themselves on the complexities of pain and methods of management that focus on improving function and overall quality of life. Commonly cited barriers to effective cancer pain management among healthcare providers were fear of drug addiction, tolerance of medication, and side effects of opioids continue to be an issue.191 These issues are even more problematic in an era of concerns for opioid overprescribing. The overall approach for oncology pain management should focus on a disease-based model of pain that focuses on routine pain assessments, uses both pharmacologic and nonpharmacologic interventions, and requires ongoing reevaluation of the patient and the effectiveness of the treatment strategy. The emergence of new pain problems must be assessed, and the treatment plan modified appropriately. Oncology healthcare systems require a supportive pain management infrastructure to allow for longitudinal care of the course of a patient’s treatment.

Key Points • Undertreatment of cancer pain remains problematic, with the prevalence of pain remaining high in survivorship. • The guiding principle for pain management should be focused on improvement in function with a reduction in pain intensity as an ideal. • Adequate management of cancer pain depends on identifying the source and making an accurate diagnosis of the underlying cause(s) of pain and contributing factors. • Pharmacologic therapy is the primary treatment for cancer pain, but radiotherapeutic, anesthetic, neurosurgical, psychological, physiotherapeutic, spiritual, and social interventions all play roles in adequate cancer pain management.

• Opioids are commonly used to treat moderate or severe cancer pain, but there is substantial interpatient variability in opioid responsiveness. Therefore clinicians should be familiar with different opioid options for the appropriate management of cancer-related pain. • Multiple psychoactive medications can be hazardous. Frequent efforts should be made to eliminate all unnecessary or ineffective medications that detract from the primary goal of opioid use and improved function. • Responsible opioid prescribing practices are paramount in managing oncology pain.

478

PA RT 4 Clinical Conditions: Evaluation and Treatment

Suggested Readings American Society of Clinical Oncology. Policy statement on opioid therapy: Protecting access to treatment for cancer-related pain. Alexandria, VA: ASCO;2016. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain- United States, 2016. MMWR Recomm Rep. 2016;65:1–49. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:162–73. Fitzgibbon DR, Loeser JD. Cancer pain: Assessment, diagnosis, and management. Philadephia: Lippincott, Williams & Wilkins; 2010. Goodman CW, Brett AS. A clinical overview of off-label use of gabapentinoid drugs. JAMA Intern Med. 2019;179:695–701.

Hershman DL, Lacchetti C, Loprinzi CL. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline summary. J Oncol Pract. 2014;10:e421–e424. Magee DJ, Jhanji S, Poulogiannis G, Farquhar-Smith P, Brown MRD. Nonsteroidal anti-inflammatory drugs and pain in cancer patients: A systematic review and reappraisal of the evidence. Br J Anaesth. 2019;123:e412–e423. Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA. Opioids for cancer pain- an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017;7:Cd012592. The references for this chapter can be found at ExpertConsult.com.

References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30. 2. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69:363–385. 3. van Leeuwen M, Husson O, Alberti P, et al. Understanding the quality of life (QOL) issues in survivors of cancer: Towards the development of an EORTC QOL cancer survivorship questionnaire. Health Qual Life Outcomes. 2018;16:114. 4. Stanton AL, Rowland JH, Ganz PA. Life after diagnosis and treatment of cancer in adulthood: Contributions from psychosocial oncology research. Am Psychol. 2015;70:159–174. 5. van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, Tjan-Heijnen VC, Janssen DJ. Update on prevalence of pain in patients with cancer: Systematic review and meta-analysis. J Pain Symptom Manage. 2016;51:1070–1090. 6. Bandieri E, Sichetti D, Luppi M, et al. Is pain in patients with haematological malignancies under-recognised? The results from Italian ECAD-O survey. Leuk Res. 2010;34:e334–e335. 7. Reis-Pina P, Lawlor PG, Barbosa A. Adequacy of cancer-related pain management and predictors of undertreatment at referral to a pain clinic. J Pain Res. 2017;10:2097–2107. 8. Müller-Schwefe G, Ahlbeck K, Aldington D, et al. Pain in the cancer patient: Different pain characteristics CHANGE pharmacological treatment requirements. Curr Med Res Opin. 2014;30:1895–1908. 9. Greco MT, Roberto A, Corli O, et al. Quality of cancer pain management: An update of a systematic review of undertreatment of patients with cancer. J Clin Oncol. 2014;32:4149–4154. 10. van den Beuken-van Everdingen MHJ, van Kuijk SMJ, Janssen DJA, Joosten EAJ. Treatment of pain in cancer: Towards personalised medicine. Cancers (Basel). 2018:10. 11. Sanford NN, Sher DJ, Butler SS, et al. Prevalence of chronic pain among cancer survivors in the United States, 2010-2017. Cancer. 2019;125:4310–4318. 12. Markham MJ, Wachter K, Agarwal N, Bertagnolli MM, et al. Clinical cancer advances 2020: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2020:JCO1903141. 13. Jemal A, Ward EM, Johnson CJ, et al. Annual report to the nation on the status of cancer, 1975-2014, featuring survival. J Natl Cancer Inst. 2017;109. 14. World Health Organization. Cancer Pain Relief. Geneva, Switzerland: World Health Organization; 1986. 15. Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA. Validation of World Health Organization guidelines for cancer pain relief: A 10-year prospective study. Pain. 1995;63:65–76. 16. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management. Stepping up the quality of its evaluation. JAMA. 1995;274:1870–1873. 17. Azevedo São Leão Ferreira K, Kimura M, Jacobsen Teixeira M. The WHO analgesic ladder for cancer pain control, twenty years of use. How much pain relief does one get from using it? Support Care Cancer. 2006;14:1086–1093. 18. Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA. Opioids for cancer pain- an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017;7:Cd012592. 19. Haywood A, Good P, Khan S, et al. Corticosteroids for the management of cancer-related pain in adults. Cochrane Database Syst Rev. 2015:CD010756. 20. Ni HM, Williams JA, Jaeschke H, Ding WX. Zonated induction of autophagy and mitochondrial spheroids limits acetaminopheninduced necrosis in the liver. Redox Biol. 2013;1:427–432. 21. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: A randomized controlled trial. JAMA. 2006;296:87–93. 22. Krenzelok EP, Royal MA. Confusion: Acetaminophen dosing changes based on NO evidence in adults. Drugs RD. 2012;12:45–48.

23. Temple AR, Benson GD, Zinsenheim JR, Schweinle JE. Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6-12 months) safety of acetaminophen in adult patients with osteoarthritis. Clin Ther. 2006;28:222–235. 24. Wiffen PJ, Derry S, Moore RA, et al. Oral paracetamol (acetaminophen) for cancer pain. Cochrane Database Syst Rev. 2017;7:Cd012637. 25. Nagaraju GP, El-Rayes BF. Cyclooxygenase-2 in gastrointestinal malignancies. Cancer. 2019;125:1221–1227. 26. Hawk E, Maresso KC, Brown P. NSAIDs to prevent breast cancer recurrence? An unanswered question. J Natl Cancer Inst. 2018;110: 927–928. 27. Brusselaers N, Lagergren J. Maintenance use of non-steroidal anti-inflammatory drugs and risk of gastrointestinal cancer in a nationwide population-based cohort study in Sweden. BMJ Open. 2018;8:e021869. 28. Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA. 2015;313:805–814. 29. Masclee GM, Valkhoff VE, Coloma PM, et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterol. 2014;147:784–792 e9quiz e13-4. 30. Castellsague J, Riera-Guardia N, Calingaert B, et  al. Individual NSAIDs and upper gastrointestinal complications: A systematic review and meta-analysis of observational studies (the SOS project). Drug Saf. 2012;35:1127–1146. 31. Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol. 2010;16:5651–5661. 32. Agúndez JA, Lucena MI, Martínez C, et al. Assessment of nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol. 2011;7:817–828. 33. Strand V. Are COX-2 inhibitors preferable to non-selective nonsteroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet. 2007;370:2138–2151. 34. Khan S, Andrews KL, Chin-Dusting JPF. Cyclo-oxygenase (COX) inhibitors and cardiovascular risk: Are non-steroidal anti-inflammatory drugs really anti-inflammatory? Int J Mol Sci. 2019:20. 35. Solomon DH, Husni ME, Libby PA, et al. The risk of major NSAID toxicity with celecoxib, ibuprofen, or naproxen: A secondary analysis of the PRECISION trial. Am J Med. 2017;130:1415–1422 e4. 36. Bhala N, Emberson J, Merhi A, et  al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Metaanalyses of individual participant data from randomised trials. Lancet. 2013;382:769–779. 37. Harirforoosh S, Jamali F. Renal adverse effects of nonsteroidal antiinflammatory drugs. Expert Opin Drug Saf. 2009;8:669–681. 38. Goldenberg NA, Jacobson L, MJ Manco-Johnson. Brief communication: Duration of platelet dysfunction after a 7-day course of Ibuprofen. Ann Intern Med. 2005;142:506–509. 39. Wong RSY. Role of nonsteroidal anti-inflammatory drugs (NSAIDs) in cancer prevention and cancer promotion. Adv Pharmacol Sci. 2019;2019:3418975. 40. Derry S, Wiffen PJ, Moore RA, et  al. Oral nonsteroidal anti inflammatory drugs (NSAIDs) for cancer pain in adults. Cochrane Database Syst Rev. 2017;7:Cd012638. 41. Magee DJ, Jhanji S, Poulogiannis G, Farquhar-Smith P, Brown MRD. Nonsteroidal Anti-inflammatory drugs and pain in cancer patients: A systematic review and reappraisal of the evidence. Br J Anaesth. 2019;123:e412–e423. 42. Bialer M. Why are antiepileptic drugs used for nonepileptic conditions? Epilepsia. 2012;53(Suppl 7):26–33. 43. Mignat C. Clinically significant drug interactions with new immunosuppressive agents. Drug Saf. 1997;16:267–278. 44. Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother. 2010;10:119–140. 45. Härmark L, van Puijenbroek E, Straus S, van Grootheest K. Intensive monitoring of pregabalin: Results from an observational, 478.e1

478.e2

References

web-based, prospective cohort study in the Netherlands using patients as a source of information. Drug Sa.f. 2011;34:221–231. 46. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs. 2017;77:403–426. 47. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: A systematic review. Addiction. 2016;111:1160–1174. 48. Grant BF, Saha TD, Ruan WJ, et al. Epidemiology of DSM-5 drug use disorder: Results from the national epidemiologic survey on alcohol and related conditions-III. JAMA Psychiatry. 2016;73:39–47. 49. Shneker BF, Cios JS, Elliott JO. Suicidality, depression screen ing, and antiepileptic drugs: Reaction to the FDA alert. Neurol. 2009;72:987–991. 50. Patorno E, Bohn RL, Wahl PM, et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA. 2010;303:1401–1409. 51. Goodman CW, Brett AS. A clinical overview of off-label use of gabapentinoid drugs. JAMA Intern Med. 2019;179:695–701. 52. Deng Y, Luo L, Hu Y, Fang K, Liu J. Clinical practice guidelines for the management of neuropathic pain: A systematic review. BMC Anesthesiol. 2016;16:12. 53. Mathieson S, Maher CG, McLachlan AJ, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med. 2017;376:1111–1120. 54. Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 2019;1:CD007076. 55. Zhou M, Chen N, He L, Yang M, Zhu C, Wu F. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev. 2017;12:CD007963. 56. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD007938. 57. van den Beuken-van Everdingen MH, de Graeff A, Jongen JL, Dijkstra D, Mostovaya I, Vissers KC. Pharmacological treatment of pain in cancer patients: The role of adjuvant analgesics, a systematic review. Pain Pract. 2017;17:409–419. 58. Finnerup NB, Attal N, Haroutounian S, McNicol E, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:162–173. 59. Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017;18. 60. Alba-Delgado C, Mico JA, Sánchez-Blázquez P, Berrocoso E. Analgesic antidepressants promote the responsiveness of locus coeruleus neurons to noxious stimulation: Implications for neuropathic pain. Pain. 2012;153:1438–1449. 61. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015:CD008242. 62. Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1:CD011209. 63. Hearn L, Moore RA, Derry S, Wiffen PJ, Phillips T. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014: CD011003. 64. Urquhart DM, Wluka AE, van Tulder M, et al. Efficacy of low-dose amitriptyline for chronic low back pain: A randomized clinical trial. JAMA Intern Med. 2018;178:1474–1481. 65. Riediger C, Schuster T, Barlinn K, Maier S, Weitz J, Siepmann T. Adverse effects of antidepressants for chronic pain: A systematic review and meta-analysis. Front Neurol. 2017;8:307. 66. Miura N, Saito T, Taira T, Umebachi R, Inokuchi S. Risk factors for QT prolongation associated with acute psychotropic drug overdose. Am J Emerg Med. 2015;33:142–149. 67. Cioroiu C, Weimer LH. Update on chemotherapy-induced peripheral neuropathy. Curr Neurol Neurosci Rep. 2017;17:47. 68. Areti A, Yerra VG, Naidu V, Kumar A. Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy. Redox Biol. 2014;2:289–295. 69. Carozzi VA, Canta A, Chiorazzi A. Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci Lett. 2015;596:90–107.

70. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapyinduced painful peripheral neuropathy: A randomized clinical trial. JAMA. 2013;309:1359–1367. 71. Hershman DL, Lacchetti C, Loprinzi CL. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline summary. J Oncol Pract. 2014;10:e421–e424. 72. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014:CD007115. 73. Alles SRA, Smith PA. Etiology and pharmacology of neuropathic pain. Pharmacol Rev. 2018;70:315–347. 74. Fallon MT. Neuropathic pain in cancer. Br J Anaesth. 2013;111: 105–111. 75. Kane CM, Mulvey MR, Wright S, Craigs C, Wright JM, Bennett MI. Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis. Palliat Med. 2018;32:276–286. 76. Majithia N, Loprinzi CL, Smith TJ. New practical approaches to chemotherapy-induced neuropathic pain: Prevention, assessment, and treatment. Oncol. 2016;30:1020–1029. 77. Malin JL. Charting the course: Use of clinical pathways to improve value in cancer care. J Clin Oncol. 2020;38:367–371. 78. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain- United States, 2016. MMWR Recomm Rep. 2016;65:1–49. 79. American Society of Clinic Oncology. Policy statement on opioid therapy: Protecting access to treatment for cancer-related pain. Alexandria, VA: ASCO; 2016. 80. Lefkowits C, Duska L. Opioid use in gynecologic oncology; balancing efficacy, accessibility and safety: An SGO clinical practice statement. Gynecol Oncol. 2017;144:232–234. 81. American College of Surgeons. Statement on the opioid abuse epidemic. Chicago, IL: American College of Surgeons; 2017. 82. Prommer EE. Pharmacological management of cancer-related pain. Cancer Control. 2015;22:412–425. 83. Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: From simple switches to allosteric microprocessors. Nat Rev Drug Discov. 2018;17:243–260. 84. Emery MA, Eitan S. Members of the same pharmacological family are not alike: Different opioids, different consequences, hope for the opioid crisis? Prog Neuropsychopharmacol Biol Psychiatry. 2019;92:428–449. 85. Valentino RJ, Volkow ND. Untangling the complexity of opioid receptor function. Neuropsychopharmacol. 2018;43:2514–2520. 86. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest. 2010;120:3779–3787. 87. Pergolizzi JV, LeQuang JA, Berger GK, Raffa RB. The basic pharmacology of opioids informs the opioid discourse about misuse and abuse: A review. Pain Ther. 2017;6:1–16. 88. De Santis S, Borghesi C, Ricciardi S, et al. Analgesic effectiveness and tolerability of oral oxycodone/naloxone and pregabalin in patients with lung cancer and neuropathic pain: An observational analysis. Onco Targets Ther. 2016;9:4043–4052. 89. Haumann J, Geurts JW, van Kuijk SM, et al. Methadone is superior to fentanyl in treating neuropathic pain in patients with head-andneck cancer. Eur J Cancer. 2016;65:121–129. 90. Cartoni C, Brunetti GA, Federico V, et  al. Controlled-release oxycodone for the treatment of bortezomib-induced neuropathic pain in patients with multiple myeloma. Support Care Cancer. 2012;20:2621–2626. 91. Cherny NJ, Chang V, Frager G, et al. Opioid pharmacotherapy in the management of cancer pain: A survey of strategies used by pain physicians for the selection of analgesic drugs and routes of administration. Cancer. 1995;76:1283–1293. 92. Hassamal S, Miotto K, Dale W, Danovitch I. Tramadol: Understanding the risk of serotonin syndrome and seizures. Am J Med. 2018;131:1382 .e1–1382.e6.

References

93. Wiffen PJ, Derry S, Moore RA. Tramadol with or without paracetamol (acetaminophen) for cancer pain. Cochrane Database Syst Rev. 2017;5:CD012508. 94. Tzschentke TM, Christoph T, Kögel BY. The mu-opioid receptor agonist/noradrenaline reuptake inhibition (MOR-NRI) concept in analgesia: The case of tapentadol. CNS Drugs. 2014;28:319–329. 95. Wiffen PJ, Derry S, Naessens K, Bell RF. Oral tapentadol for cancer pain. Cochrane Database Syst Rev. 2015:Cd011460. 96. Riemsma R, Forbes C, Harker J, et  al. Systematic review of tapentadol in chronic severe pain. Curr Med Res Opin. 2011;27: 1907–1930. 97. Cardia L, Calapai G, Quattrone D, et al. Preclinical and clinical pharmacology of hydrocodone for chronic pain: A mini review. Front Pharmacol. 2018;9:1122. 98. Stauble ME, Moore AW, Langman LJ, et al. Hydrocodone in postoperative personalized pain management: Pro-drug or drug? Clin Chim Acta. 2014;429:26–29. 99. VanderVaart S, Berger H, Sistonen J, et  al. CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: A pilot study. Ther Drug Monit. 2011;33:425–432. 100. Rodriguez RF, Castillo JM, Castillo MP, et al. Hydrocodone/acetaminophen and tramadol chlorhydrate combination tablets for the management of chronic cancer pain: A double-blind comparative trial. Clin J Pain. 2008;24:1–4. 101. Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE. Cooperative N-methyl-d-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009;60:284–290. 102. McNicol ED, Ferguson MC, Schumann R. Methadone for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;5: Cd012499. 103. Nicholson AB, Watson GR, Derry S, Wiffen PJ. Methadone for cancer pain. Cochrane Database Syst Rev. 2017;2:CD003971. 104. Aiyer R, Gulati A, Gungor S, Bhatia A, Mehta N. Treatment of chronic pain with various buprenorphine formulations: A systematic review of clinical studies. Anesth Analg. 2018;127:529–538. 105. Pergolizzi J, Aloisi AM, Dahan A, et  al. Current knowledge of buprenorphine and its unique pharmacological profile. Pain Pract. 2010;10:428–450. 106. Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth. 2005;94:825–834. 107. Chen KY, Chen L, Mao J. Buprenorphine-naloxone therapy in pain management. Anesthesiol. 2014;120:1262–1274. 108. Sun EC, Mao J, Anderson TA. Treating chronic pain: Is buprenorphine the (or even an) answer? Anesth Analg. 2018;127:336–337. 109. Schmidt-Hansen M, Bromham N, Taubert M, Arnold S, Hilgart JS. Buprenorphine for treating cancer pain. Cochrane Database Syst Rev. 2015:CD009596. 110. Naing C, Yeoh PN, Aung K. A meta-analysis of efficacy and tolerability of buprenorphine for the relief of cancer pain. Springerplus. 2014;3:87. 111. Anderson TA, Quaye ANA, Ward EN, Wilens TE, Hilliard PE, Brummett CM. To stop or not, that is the question: Acute pain management for the patient on chronic buprenorphine. Anesthesiol. 2017;126:1180–1186. 112. White LD, Hodge A, Vlok R, Hurtado G, Eastern K, Melhuish TM. Efficacy and adverse effects of buprenorphine in acute pain management: Systematic review and meta-analysis of randomised controlled trials. Br J Anaesth. 2018;120:668–678. 113. Mégarbane B, Hreiche R, Pirnay S, Marie N, Baud FJ. Does highdose buprenorphine cause respiratory depression?: Possible mechanisms and therapeutic consequences. Toxicol Rev. 2006;25:79–85. 114. World Health Organization. Psychoactive medications. Available at: https://www.who.int/substance_abuse/terminology/psychoactive_substances/en/.

478.e3

115. Weng MC, Tsai CF, Sheu KL, et  al. The impact of number of drugs prescribed on the risk of potentially inappropriate medication among outpatient older adults with chronic diseases. QJM. 2013;106:1009–1015. 116. Steinman MA, Hanlon JT. Managing medications in clinically complex elders: “there’s got to be a happy medium.” JAMA. 2010;304:1592–1601. 117. Lees J, Chan A. Polypharmacy in elderly patients with cancer: Clinical implications and management. Lancet Oncol. 2011;12: 1249–1257. 118. Kotlinska-Lemieszek A, Paulsen O, Kaasa S, Klepstad P. Polypharmacy in patients with advanced cancer and pain: A European cross-sectional study of 2282 patients. J Pain Symptom. Manage. 2014;48:1145–1159. 119. Kotlinska-Lemieszek A, Klepstad P, Haugen DF. Clinically significant drug-drug interactions involving opioid analgesics used for pain treatment in patients with cancer: A systematic review. Drug Des Devel Ther. 2015;9:5255–5267. 120. Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: Case-cohort study. BMJ. 2015;350:h2698. 121. Garg RK, Fulton-Kehoe D, Franklin GM. Patterns of opioid use and risk of opioid overdose death among Medicaid patients. Med Care. 2017;55:661–668. 122. Gralow JR, Biermann JS, Farooki A, et  al. NCCN task force report: Bone health in cancer care. J Natl Compr Canc Netw. 2009; 7(Suppl 3):S1–32. 123. Landi F, Onder G, Cesari M, et  al. Psychotropic medications and risk for falls among community-dwelling frail older people: An observational study. J Gerontol A Biol Sci Med Sci. 2005;60: 622–626. 124. Hartikainen S, Mäntyselkä P, Louhivuori-Laako K, Enlund H, Sulkava R. Concomitant use of analgesics and psychotropics in homedwelling elderly people-Kuopio 75 + study. Br J Clin Pharmacol. 2005;60:306–310. 125. Caruso R, Breitbart W. Mental health care in oncology. Contemporary perspective on the psychosocial burden of cancer and evidence-based interventions. Epidemiol Psychiatr Sci. 2020;29:e86. 126. Wigmore P. The effect of systemic chemotherapy on neurogenesis, plasticity and memory. Curr Top Behav Neurosci. 2013;15: 211–240. 127. Ng CG, Boks MP, Smeets HM, Zainal NZ, de Wit NJ. Prescription patterns for psychotropic drugs in cancer patients; a large population study in the Netherlands. Psychooncol. 2013;22: 762–767. 128. van Laar MW, Volkerts ER, Verbaten MN, Trooster S, van Megen HJ, Kenemans JL. Differential effects of amitriptyline, nefazodone and paroxetine on performance and brain indices of visual selective attention and working memory. Psychopharmacol. 2002;162: 351–363. 129. Amado-Boccara I, Gougoulis N, Poirier Littré MF, Galinowski A, Lôo H. Effects of antidepressants on cognitive functions: A review. Neurosci Biobehav Rev. 1995;19:479–493. 130. Schmitt JA, Kruizinga MJ, Riedel WJ. Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors. J Psychopharmacol. 2001;15:173–179. 131. Meador KJ, Loring DW, Hulihan JF, Kamin M, Karim R, Group C-S. Differential cognitive and behavioral effects of topiramate and valproate. Neurol. 2003;60:1483–1488. 132. Loring DW, Williamson DJ, Meador KJ, Wiegand F, Hulihan J. Topiramate dose effects on cognition: A randomized double-blind study. Neurol. 2011;76:131–137. 133. Brinkman TM, Zhang N, Ullrich NJ, et al. Psychoactive medication use and neurocognitive function in adult survivors of childhood cancer: A report from the childhood cancer survivor study. Pediatr Blood Cancer. 2013;60:486–493.

478.e4

References

134. Ostuzzi G, Matcham F, Dauchy S, Barbui C, Hotopf M. Antidepressants for the treatment of depression in people with cancer. Cochrane Database Syst Rev. 2018;4:CD011006. 135. Syrowatka A, Chang SL, Tamblyn R, Mayo NE, Meguerditchian AN. Psychotropic and opioid medication use in older patients with breast cancer across the care trajectory: A population-based cohort study. J Natl Compr Canc Netw. 2016;14:1412–1419. 136. LeBlanc TW, McNeil MJ, Kamal AH, Currow DC, Abernethy AP. Polypharmacy in patients with advanced cancer and the role of medication discontinuation. Lancet Oncol. 2015;16:e333–e341. 137. Barry DT, Sofuoglu M, Kerns RD, Wiechers IR, Rosenheck RA. Prevalence and correlates of coprescribing anxiolytic medications with extensive prescription opioid use in Veterans Health Administration patients with metastatic cancer. J Opioid Manag. 2016;12:259–268. 138. Turner JP, Jamsen KM, Shakib S, Singhal N, Prowse R, Bell JS. Polypharmacy cut-points in older people with cancer: How many medications are too many? Support Care Cancer. 2016;24:1831–1840. 139. American Geriatrics Society. 2019 updated AGS beers criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67:674–694. 140. Fredheim OM, Skurtveit S, Handal M, Hjellvik V. A complete national cohort study of prescriptions of analgesics and benzodiazepines to cancer survivors in Norway 10 years after diagnosis. Pain. 2019;160:852–859. 141. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association between concurrent use of prescription opioids and benzodiazepines and overdose: Retrospective analysis. BMJ. 2017;356:j760. 142. Skolnick P. The opioid epidemic: Crisis and solutions. Annu Rev Pharmacol Toxicol. 2018;58:143–159. 143. Volkow ND, McLellan AT. Opioid abuse in chronic pain- misconceptions and mitigation strategies. N Engl J Med. 2016;374: 1253–1263. 144. Kaye AD, Jones MR, Kaye AM, et  al. Prescription opioid abuse in chronic pain: An updated review of opioid abuse predictors and strategies to curb opioid abuse: Part 1. Pain Physician. 2017;20:S93–S109. 145. Edlund MJ, Martin BC, Russo JE, DeVries A, Braden JB, Sullivan MD. The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: The role of opioid prescription. Clin J Pain. 2014;30:557–564. 146. United States Department of Health and Human Services. Pain Management Best Practices Inter-Agency Task Force Report: Updates, Gaps, Inconsistencies, and Recommendations. Washington, D.C.: United States Department of Health and Human Services; 2019. 147. Barclay JS, Owens JE, Blackhall LJ. Screening for substance abuse risk in cancer patients using the opioid risk tool and urine drug screen. Support Care Cancer. 2014;22:1883–1888. 148. Tan PD, Barclay JS, Blackhall LJ. Do palliative care clinics screen for substance abuse and diversion? Results of a national survey. J Palliat Med. 2015;18:752–757. 149. Yennurajalingam S, Edwards T, Arthur JA, et al. Predicting the risk for aberrant opioid use behavior in patients receiving outpatient supportive care consultation at a comprehensive cancer center. Cancer. 2018;124:3942–3949. 150. Page R, Blanchard E. Opioids and cancer pain: Patients’ needs and access challenges. J Oncol Pract. 2019;15:229–231. 151. Pinkerton R, Hardy JR. Opioid addiction and misuse in adult and adolescent patients with cancer. Intern Med J. 2017;47:632–636. 152. Strickler GK, Kreiner PW, Halpin JF, Doyle E, Paulozzi LJ. Opioid prescribing behaviors- prescription behavior surveillance system, 11 States, 2010-2016. MMWR Surveill Summ. 2020;69:1–14. 153. Babu KM, Brent J, Juurlink DN. Prevention of opioid overdose. N Engl J Med. 2019;380:2246–2255. 154. Hayes CJ, Krebs EE, Hudson T, Brown J, Li C, Martin BC. Impact of opioid dose escalation on pain intensity: A retrospective cohort study. Pain. 2020;161:979–988.

155. Hermanns H, Hollmann MW, Stevens MF, et al. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: A narrative review. Br J Anaesth. 2019;123:335–349. 156. Wallace MS, Ridgeway BM, Leung AY, Gerayli A, Yaksh TL. Concentration-effect relationship of intravenous lidocaine on the allodynia of complex regional pain syndrome types I and II. Anesthesiol. 2000;92:75–83. 157. Couto JE, Romney MC, Leider HL, Sharma S, Goldfarb NI. High rates of inappropriate drug use in the chronic pain population. Popul Health Manag. 2009;12:185–190. 158. Sharma S, Rajagopal MR, Palat G, Singh C, Haji AG, Jain D. A phase II pilot study to evaluate use of intravenous lidocaine for opioid-refractory pain in cancer patients. J Pain. Symptom Manage. 2009;37:85–93. 159. Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-Daspartate receptor for chronic pain management. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage. 2000;20:358–373. 160. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2017;6:Cd003351. 161. Bredlau AL, Thakur R, Korones DN, Dworkin RH. Ketamine for pain in adults and children with cancer: A systematic review and synthesis of the literature. Pain Med. 2013;14:1505–1517. 162. Hardy J, Quinn S, Fazekas B, et  al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol. 2012;30:3611–3617. 163. Jonkman K, van de Donk T, Dahan A. Ketamine for cancer pain: What is the evidence? Curr Opin Support Palliat Care. 2017;11:88–92. 164. Cramond T, Stuart G. Intraventricular morphine for intractable pain of advanced cancer. J Pain Symptom Manage. 1993;8:465–473. 165. Dahm P, Nitescu P, Appelgren L, Curelaru I. Efficacy and technical complications of long-term continuous intraspinal infusions of opioid and/or bupivacaine in refractory nonmalignant pain: A comparison between the epidural and the intrathecal approach with externalized or implanted catheters and infusion pumps. Clin J Pain. 1998;14:4–16. 166. Deer TR, Hayek SM, Pope JE, et al. The polyanalgesic consensus conference (PACC): Recommendations for trialing of intrathecal drug delivery infusion therapy. Neuromodulation. 2017;20:133–154. 167. Nitescu P, Appelgren L, Hultman E, Linder LE, Sjoberg M, Curelaru I. Long-term, open catheterization of the spinal subarachnoid space for continuous infusion of narcotic and bupivacaine in patients with “refractory” cancer pain. A technique of catheterization and its problems and complications. Clin J Pain. 1991;7:143–161. 168. Nitescu P, Dahm P, Appelgren L, Curelaru I. Continuous infusion of opioid and bupivacaine by externalized intrathecal catheters in long-term treatment of “refractory” nonmalignant pain. Clin J Pain. 1998;14:17–28. 169. Nitescu P, Hultman E, Appelgren L, Linder LE, Curelaru I. Bacteriology, drug stability and exchange of percutaneous delivery systems and antibacterial filters in long-term intrathecal infusion of opioid drugs and bupivacaine in “refractory” pain. Clin J Pain. 1992;8:324–337. 170. Nitescu P, Sjoberg M, Appelgren L, Curelaru I. Complications of intrathecal opioids and bupivacaine in the treatment of “refractory” cancer pain. Clin J Pain. 1995;11:45–62. 171. Sjoberg M, Appelgren L, Einarsson S, et al. Long-term intrathecal morphine and bupivacaine in “refractory” cancer pain. I. Results from the first series of 52 patients. Acta Anaesthesiol Scand. 1991;35:30–43. 172. Sjoberg M, Karlsson PA, Nordborg C, et  al. Neuropathologic findings after long-term intrathecal infusion of morphine and bupivacaine for pain treatment in cancer patients. Anesthesiol. 1992;76:173–186. 173. Sjoberg M, Nitescu P, Appelgren L, Curelaru I. Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain. Results from a morphine: Bupivacaine dose regimen of 0.5:4.75 mg/ml. Anesthesiol. 1994;80:284–297.

References

174. Ontario Health Quality. Vertebral augmentation involving vertebroplasty or kyphoplasty for cancer-related vertebral compression fractures: A systematic review. Ont Health Technol Assess Ser. 2016;16:1–202. 175. Kyriakou C, Molloy S, Vrionis F, et al. The role of cement augmentation with percutaneous vertebroplasty and balloon kyphoplasty for the treatment of vertebral compression fractures in multiple myeloma: A consensus statement from the international myeloma working group (IMWG). Blood Cancer J. 2019;9:27. 176. Gudbjornsson B, Juliusson UI, Gudjonsson FV. Prevalence of long term steroid treatment and the frequency of decision making to prevent steroid induced osteoporosis in daily clinical practice. Ann Rheum Dis. 2002;61:32–36. 177. De Vries F, Bracke M, Leufkens HG, Lammers JW, Cooper C, Van Staa TP. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum. 2007;56:208–214. 178. Buchbinder R, Johnston RV, Rischin KJ, et al. Percutaneous vertebroplasty for osteoporotic vertebral compression fracture. Cochrane Database Syst Rev. 2018;11:CD006349. 179. Buchbinder R, Ebeling PR, Akesson K, et al. Response to: Some questions about the article “the efficacy and safety of vertebral augmentation: A second ASBMR task force report.” J Bone Miner Res. 2020;35:212–213. 180. Wong GY, Schroeder DR, Carns PE, et  al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: A randomized controlled trial. JAMA. 2004;291:1092–1099. 181. Arcidiacono PG, Calori G, Carrara S, McNicol ED, Testoni PA. Celiac plexus block for pancreatic cancer pain in adults. Cochrane Database Syst Rev. 2011:Cd007519. 182. Rykowski JJ, Hilgier M. Efficacy of neurolytic celiac plexus block in varying locations of pancreatic cancer: Influence on pain relief. Anesthesiol. 2000;92:347–354.

478.e5

183. Loukas M, Klaassen Z, Merbs W, Tubbs RS, Gielecki J, Zurada A. A review of the thoracic splanchnic nerves and celiac ganglia. Clin Anat. 2010;23:512–522. 184. Rahman A, Rahman R, Macrinici G, Li S. Low volume neurolytic retrocrural celiac plexus block for visceral cancer pain: Retrospective review of 507 patients with severe malignancy related pain due to primary abdominal cancer or metastatic disease. Pain Physician. 2018;21:497–504. 185. Ischia S, Ischia A, Polati E, Finco G. Three posterior percutaneous celiac plexus block techniques. A prospective, randomized study in 61 patients with pancreatic cancer pain. Anesthesiol. 1992;76:534–540. 186. Plancarte R, Amescua C, Patt RB, Aldrete JA. Superior hypogastric plexus block for pelvic cancer pain. Anesthesiol. 1990;73:236–239. 187. Hou S, Novy D, Felice F, Koyyalagunta D. Efficacy of superior hypogastric plexus neurolysis for the treatment of cancer-related pelvic pain. Pain Med. 2020;21:1255–1262. 188. Mercadante S, Klepstad P, Kurita GP, Sjogren P, Giarratano A. European Palliative Care Research C. Sympathetic blocks for visceral cancer pain management: A systematic review and EAPC recommendations. Crit Rev Oncol Hematol. 2015;96:577–583. 189. Deandrea S, Montanari M, Moja L, Apolone G. Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol. 2008;19:1985–1991. 190. Vuong S, Pulenzas N, DeAngelis C, et al. Inadequate pain management in cancer patients attending an outpatient palliative radiotherapy clinic. Support Care Cancer. 2016;24:887–892. 191. Makhlouf SM, Pini S, Ahmed S, Bennett MI. Managing pain in people with cancer- a systematic review of the attitudes and knowledge of professionals, patients, caregivers and public. J Cancer Educ. 2020;35:214–240. 192. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and metaanalysis. Lancet Neurol. 2015;14:162–173.

34

Evaluation and Treatment of Neuropathic Pain Syndromes

CHRISTOPHER M. LAM, ANDREA L. CHADWICK, ROBERT W. HURLEY

Introduction Neuropathic pain comprises a wide range of heterogeneous conditions. Various types of neuropathic pain may have distinct pathophysiologic causes and different clinical signs and symptoms. Despite the diversity of conditions classified as “neuropathic pain,” many potentially share common underlying mechanisms of nociception, including neuronal hyperexcitability, but others may not. This may, in part, explain why certain analgesic agents are relatively effective for a wide range of neuropathic pain states but why notable exceptions exist that appear to be resistant to conventional “neuropathic” pain therapy. A group has been assembled to address the inconclusive research on “neuropathic” pain and to operationalize and specify definitions and criteria for conditions to be referred to as neuropathic pain (Box 34.1).1 This work should lead to a more reductionist approach to the study of neuropathic pain and effective therapies for specific disease processes. This chapter focuses on some of the more common states of “neuropathic” pain as defined by the sensitive but non-specific definition of the International Association for the Study of Pain (IASP). These conditions include postherpetic neuralgia (PHN), painful diabetic peripheral neuropathy (DPN), human immunodeficiency virus (HIV) painful sensory neuropathy, and chemotherapy induced peripheral neuropathy (CIPN). While complex regional pain syndrome (CRPS) is considered nocicplastic in nature, it is also discussed in this chapter.

Complex Regional Pain Syndrome The term CRPS, which denotes both types one and two, originated from a history of different names appointed by individuals who made particular observations. In 1864 Silas Weir Mitchell • BOX 34.1

Updated Definition of Neuropathic Pain

IASP Definition:323 2017 “Pain caused by a lesion or disease of the somatosensory nervous system”

Revised Research and Clinical Definition:1 2007 “Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” IASP, International Association for the Study of Pain.

made an important observation of Civil War soldiers when he noticed that they suffered from burning pain and muscle atrophy at the sites of their injuries caused by gunshot wounds.2 He called this “causalgia,” which is derived from the Greek words kausis (burning) and algos (pain). In 1900 at a lecture in Germany, Paul Sudeck stated that this syndrome could not only extend from the initial insult but also had an inflammatory component.2 The name Sudeck’s dystrophy was applied in his honor. Half a century passed before the discovery that invasive procedures that block the sympathetic nervous system provide further relief of pain symptoms. Because of the success of these methods, Evans renamed the syndrome “reflex sympathetic dystrophy.”3 Over the years, cases arose in which patients lacked a trophic component, sympathetic involvement was absent, or there was no evidence of reflex involvement. These exceptions led to a meeting in 1993 by the IASP at which the term “complex regional pain syndrome” was formulated and subsequently published the following year.4 The most commonly used clinical diagnostic criteria for CRPS types one and two are low in specificity but high in sensitivity, which has led to overdiagnosis of the pain syndrome.5 This has made it difficult to obtain accurate epidemiologic data for CRPS or to perform rigorous studies of the pathologic state. In 2007, research criteria (also known as the Budapest criteria) were published that included objective signs of pathology characteristic of patients with CRPS (Box 34.2).6 These criteria had good specificity and sensitivity. Although they were initially intended for research use, this was later revised to include both a clinical and research set of criteria commonly used for diagnosis.

Pathophysiology There are two types of CRPS, known as type one and type two (Box 34.3). They differ because type two has evident nerve injury, whereas type one assumes an injury to the nerve or nerves. A consistent finding in both types of CRPS is the discrepancy between the severity of the symptoms and the severity of the inciting injury. In addition, symptoms have the propensity to spread in the affected limb in a pattern not restricted to the specific nerve’s area of innervation. CRPS is characterized by intense burning pain with resultant hyperalgesia or allodynia. It may be associated with local edema and autonomic involvement, such as changes in skin color and sweating and increased or decreased skin temperature in the affected area. There may also be trophic changes in the skin, hair, and nails in the affected site (see Box 34.3). Although many 479

480

PA RT 4 Clinical Conditions: Evaluation and Treatment

• BOX 34.2

Difference Between the IASP Criteria and the Budapest Criteria for the Diagnosis of CRPS

IASP Criteria for the Diagnosis of CRPS* 1. 2. 3. 4.

Presence of an initiating noxious event or reason for immobilization Disproportional pain, allodynia, or hyperalgesia from a known inciting event Sign or symptom of any evidence showing edema, skin changes, blood flow, or abnormal sudomotor activity in the region of the pain No other condition that would otherwise explain the degree of pain or dysfunction

Budapest Criteria for Diagnosis of CRPS 1. Presence of continued disproportional pain from the known inciting event 2. Must report at least one symptom in three of these four categories: • Sensory: hyperesthesia, allodynia • Vasomotor: temperature asymmetry, changes in skin color • Sudomotor/edema: edema, changes in sweating, sweating asymmetry • Motor/trophic: decreased range of motion, motor dysfunction (tremor, weakness, dystonia), trophic changes (hair, nail, skin) 3. Must report at least one sign in two or more of these categories at the time of evaluation: • Sensory: hyperalgesia to pinprick, allodynia to touch, or joint movement • Vasomotor: temperature asymmetry, color asymmetry • Sudomotor/edema: edema, asymmetric sweating, sweating changes • Motor/trophic: decreased range of motion, motor dysfunction, trophic changes 4. No other condition that would otherwise explain the degree of pain or dysfunction

Budapest Clinical Criteria6,42 At least one symptom in three or four symptom categories At least one sign in two or more sign categories

Budapest Research Criteria At least one symptom in all four symptom categories At least one sign in two or more sign categories *If seen without any major nerve damage, the diagnosis is CRPS type one; if seen with evidence of nerve damage, the diagnosis is CRPS type two. CRPS, Complex regional pain syndrome; IASP, International Association for the Study of Pain.

• BOX 34.3

Difference Between CRPS Type One and Two

CRPS Type One (Reflex Sympathetic Dystrophy)* 1. 2. 3. 4.

The presence of an initiating noxious event or a cause of immobilization Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain This diagnosis is excluded by conditions that would otherwise account for the degree of pain and dysfunction

CRPS Type Two (Causalgia)† 1. The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve 2. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain 3. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction CRPS, Complex regional pain syndrome. Criteria two to four must be satisfied. † All three criteria must be satisfied. *

questions about the pathophysiology of this syndrome are still unanswered, three main principles remain at the core of CRPS: abnormalities in both somatosensory and sensory pathways and sympathetic nervous system involvement.

Somatosensory Abnormalities Inciting injury to either the upper or lower extremity is an important trigger of CRPS. Studies have shown that changes in cutaneous innervation of the injured extremities occur even when no nerve injury is found. Albrecht et al. performed a study where skin

biopsy samples were obtained from the affected limbs of patients with CRPS type one. A lower density of C and A fibers were found in the affected limbs than in the unaffected limbs, which led to sensory deficits in the affected limbs.7 Brain plasticity is another important factor found to be associated with somatosensory abnormalities. Data suggest that patients with CRPS have decreased activity in the somatosensory cortex of the affected side.8 These patients also tend to have tactile mislocation because of somatotopic reorganization, which was found to be directly correlated with hyperalgesia.9 Changes occurring within the primary somato-

 

CHAPTER 34

sensory (SI) cortex are dependent on pain and have been shown to be reversible after recovery from the pain.10 Recently, a study published by Azqueta-Gavaldon et al. where 20 patients with sensory and motor deficits attributed to chronic CRPS (> six months of pain) underwent a battery of tests including functional magnetic resonance imaging, showed that patients with sensory and motor deficits had bilateral decreases in gray matter in the putamen. They theorize that putamen alterations may explain the pain and motor impairment seen in patients with chronic CRPS.11

Sensory Pathways (Central Nervous System Sensitization, Peripheral Sensitization) Central sensitization occurs when pain perception increases because of the constant firing of painful stimuli to the central nervous system. Neuropeptides such as substance P and bradykinin are released in response to nociceptive stimuli and activate N-methyl-d-aspartate (NMDA) receptors, leading to hyperalgesia and allodynia.12 Chronic exposure to these neuropeptides may influence and remodel normal neuroanatomy. Glial cells (namely microglia and astrocytes) are immunocompetent CNS cells that are activated after tissue injury. In a cadaveric study of an individual with CRPS comparing spinal cord anatomy to four control cadavers, significant posterior horn cell loss along with microglial and astrocyte activation was found at the level of the original injury and entire spinal cord.13 Peripheral sensitization is the counterpart of central sensitization. When a nerve injury occurs, multiple pro-inflammatory factors such as glial cell activation, substance P, bradykinin, tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), prostaglandin E2, and nerve growth factor are activated, which results in increased nociceptive sensitivity and a decreased threshold for the firing of nociceptive stimuli.14 A study where immunoglobulin G (IgG) from patients with chronic CRPS was injected into mice showed increased edema and paw hyperalgesia with concomitant sustained microglial and astrocyte activation in the spinal cord dorsal horn and pain-related regions of the brain. Furthermore, this was found to be IL-1β mediated as IL-1 receptor antagonists, and IL-1β floxed mice prevented these changes when exposed to IgG of CRPS patients.15 Together, central and peripheral sensitization results in the allodynia and hyperesthesia seen in patients with CRPS. There are other important factors in the inflammatory pathway, such as the role of nuclear factor kappa B (NFκB) upstream in the proinflammatory pathway observed in animal studies.16 To date, anatomic, biomolecular, and immunohistologic studies such as those mentioned above illustrated the multifactorial influences in the development of central and peripheral sensitization of this disease along with their effect on neuroanatomy. Neuroinflammation An emerging hypothesis for the mechanism for CRPS development is neurogenic inflammation. As mentioned previously, many pro-inflammatory factors are released during nerve injury, evidenced in patients and animal models. This early stage of CRPS (“warm phase”) results in vascular symptoms, trophic changes, and pain mediated by neuropeptides with resultant production of high levels of cytokines, nerve growth factors, and mast cells.17 Studies on IL-6 and TNFα levels in patients with CRPS have shown elevated levels in blisters and skin that decrease once the patient’s condition has become chronic.18–20 Dendritic cells whose roles include activating helper T cells have been hypothesized as the primary mediator for neuroinflammation. 21 A study by Russo et al. utilizing mass cytometry immunophenotyping found that

Evaluation and Treatment of Neuropathic Pain Syndromes

481

in 14 patients with Budapest criteria supported clinically diagnosed CRPS showed an increased level of central memory CD4 and CD8 T cells implicating a possible role of antigen mediated T-lymphocyte response in the development of CRPS.22 Although further studies are needed to further validate this pathway, it is possible that neuroinflammation itself plays a role in the evolution of this condition.

Altered Sympathetic Nervous System Function Involvement of the sympathetic nervous system is thought to be responsible for the limbs in patients with CRPS becoming cool, blue, and painful secondary to vasoconstriction because of excessive outflow from the sympathetic nervous system. In an animal study, rats with chronic post ischemic pain that had norepinephrine injected into their hind paws experienced increased nociceptive firing, supporting the notion that pain can be sympathetically maintained.23 Interestingly, norepinephrine levels were found to be lower in the affected extremity than the normal contralateral extremity in patients with chronic CRPS. Several studies evaluating the effect of adrenergic receptor stimulation on the vasculature in patients with CRPS have indicated an increased response to an adrenergic stimulus.24 However, this provides little evidence in support of sympathetic maintenance of CRPS pain. Coupling of sympathetic neurons may occur not only to nociceptive afferents but also to non-nociceptive mechanosensitive or cold-sensitive neurons. Sympathetic afferent coupling, considered the cause of sympathetically maintained pain, occurs in cutaneous and deep somatic tissues, but during the acute event of CRPS, the deep somatic tissues are of greater importance.25 Although coupling occurs in some patients with CRPS, a subset of patients with clinically identical CRPS have sympathetically independent pain. These patients exhibit little to no response to sympathetic blockade either pharmacologically with phentolamine or via interventional blockade of the sympathetic ganglia.

Epidemiology Multiple studies of CRPS type one have shown that the maleto-female ratio ranges between 1:2 and 1:4, thus suggesting that females are at higher risk for the development of the syndrome.26,27 However, the male-to-female ratio for most other pain syndromes is similar. A retrospective, cross-sectional analysis study showed that the male-to-female ratio was 1:4 and that the most common initiating events were bone fractures, sprains, and trauma.27 In a prospective study, it was found that CRPS incidence four months after a wrist fracture was 3.8%. This group generated a prediction rule to identify high risk patients based on a 25 min assessment evaluating pain, response time, dysynchiria, and swelling one week after wrist fracture. This study found that a pain score of ≥ five within the first week of injury was nearly as accurate as performing the 25 min assessment in identifying wrist fracture patients at high risk for developing CRPS.28 Outcomes of the disease tended to be worse in patients with upper extremity injuries than in those with lower extremity injuries, injuries other than fractures, and “cold” (commonly chronic) CRPS rather than “warm” (acute) CRPS.16 Other risk factors that contribute to the development of CRPS are age, workplace, concomitant use of angiotensin-converting enzyme (ACE) inhibitors, history of migraines, history of asthma, and type of injury.29 The average age of patients ranges between 16 and 79 (median range, 41.6), with a higher incidence in the older population. Patients with motor nerve damage were found to be at higher risk for CRPS

482

PA RT 4 Clinical Conditions: Evaluation and Treatment

than those with sensory nerve damage. Fracture has been reported to be the most common initiating injury.30 The incidence of jobrelated injuries leading to CRPS was as high as 76%,31 which may indicate a psychosocial or secondary gain component in reporting of this pain. Studies report that CRPS develops in patients with a family history of CRPS at a higher incidence and younger age, suggesting that CRPS may have a genetic component.32 Another study showed that siblings of patients in whom CRPS developed before 50 years of age had a three-fold increased risk for development of the syndrome.33 Psychological factors such as depression, personality disorders, and anxiety have no correlation with CRPS patients, suggesting no specific type of CRPS personality.34

Over time, symptom severity changes reflecting stability or progression of disease. In 2010 Harden et al. developed a CRPS symptom severity score (CSS) to help categorize the degree of CRPS for aiding in clinical decision making, which was validated by an international prospective multi-site study.35,39 In the study, they found that changes in CSS correlated with greater changes in fatigue, pain intensity, social functioning, ability to take physical roles, and overall wellbeing, indicating the possible role of this score in clinical monitoring and research.39 Eventually, approximately three-quarters of all CRPS cases resolve even without treatment, with the resolution of microvascular signs and symptoms resolving before resolution of pain.40

Clinical Features

Diagnosis

The pain must be greater in proportion to the inciting event. There must be at least one symptom in three of the following four categories: sensory (hyperesthesia/allodynia), vasomotor (changes in temperature or sweating in the affected limb than the normal limb), sudomotor/edema, and motor/trophic (demonstration of weakness, decreased range of motion, or trophic changes in hair, nails, or skin). At least one sign must be present at the time of evaluation in two or more of these four categories: sensory, vasomotor, sudomotor/edema, and motor/trophic. There must be no other diagnosis that better explains the patient’s signs and symptoms.29 This differs from the criteria proposed in 1993 by the IASP (see Box 34.3). A recent study in which the validity of CRPS was evaluated by comparing the Budapest criteria in patients with CRPS and those with neuropathy showed that the IASP criteria had a sensitivity of 1.0 and a specificity of 0.4, and the Budapest criteria had a clinical sensitivity of 0.99 and a specificity of 0.68.35 The newly revised criteria are also divided into clinical and research. The research criteria contain more inclusions, which allows a specificity of 0.96.36 The current IASP taxonomy also divides CRPS into CRPS one (formerly known as reflex sympathetic dystrophy) and CRPS two (formerly known as causalgia).29 The distinction between CRPS one and two is the presence of a definable nerve lesion in patients with CRPS two.37 The signs and symptoms for both conditions are clinically indistinguishable and include sensory changes (allodynia, hyperalgesia, and hypoalgesia), edema, temperature abnormalities, and changes in sweating (see Box 34.3). Pain is the principal feature in both CRPS one and CRPS two. In patients with CRPS, the associated clinical signs are typically out of proportion to the inciting injury. Patients describe a burning, deep-seated ache that may be shooting in nature and associated with allodynia or hyperalgesia.38 Pain occurs in 81.1% of patients meeting the CRPS criteria.5 Patients also frequently complain of sensory abnormalities such as hyperesthesia in response to the typical mechanical stimuli encountered in day-to-day activities (such as dressing) involving the affected limb. In CRPS two (i.e. CRPS with associated major nerve injury), patients often report hyperesthesia around the injured nerve in addition to electric shock-like sensations, shooting pain, and allodynia. Symptoms indicative of vasomotor autonomic abnormalities (including color changes) occurred in 86.9% of patients; temperature instability occurred in 78.7%. Sudomotor symptoms of hyperhidrosis and hypohidrosis were reported in 52.9%. Trophic changes in skin, nail, or hair patterns were reported in 24.4%, 21.1%, and 18%, respectively. Edema was reported in 79.7%, with decreased range of motion in 80.3% and motor weakness in 74.6%.5

There is currently no “gold standard” test for the diagnosis of CRPS. A very thorough history and physical examination are essential for evaluation and diagnosis. Patients with this condition will have the signs and symptoms mentioned. Many clinicians utilize the Budapest criteria (Box 34.2) to help diagnose this condition. In 2018, a European Pain Federation Task Force developed standards for diagnosis and treatment of CRPS where they recommended the utilization of the Budapest criteria as the main tool to diagnosis the condition with further diagnostic tests only to exclude other diagnoses.41 A physical examination must be performed to establish the sensory, motor, trophic, sudomotor/edema, and autonomic changes. Sensory changes such as allodynia may be evaluated by light touch and the application of warm/cold temperature to the affected area. Autonomic dysfunction may be confirmed by the presence of asymmetry in temperature and color. Trophic changes may be manifested as changes in skin, nails, and hair in the affected limb. Motor activity may be evaluated by examining motor strength and range of motion. Sudomotor/edema changes may be assessed by dragging a smooth object over the affected and unaffected limb, with the wetter limb allowing a smoother drag than the drier limb.42 Common diagnostic tools used for diagnosis, characterizing, and monitoring of CRPS include quantitative sensory testing, tests of autonomic function, and imaging for trophic changes.

Quantitative Sensory Testing (QST) QST is a noninvasive means to evaluate sensory and pain perception to classify pain but cannot be used as the sole method to diagnose a particular pain pathology. There is variability in the ability to reproduce results, and as such, the precision and accuracy of this modality are still up for debate.43 Such testing includes the use of standardized psychophysical tests of the sensory and motor systems, thermal sensation, thermal pain, and vibratory thresholds to assess the function of myelinated small fiber and unmyelinated small fiber afferents. Patients with CRPS may have impaired paradoxical heat sensations, mechanical detection thresholds, mechanical pain thresholds to pinprick stimuli and blunt pressure, allodynia, and pain summation with the use of continuous pinprick stimuli.44 There is currently no definitive diagnostic sensory pattern in patients with CRPS, but this test can aid in distinguishing other neuropathies from CRPS.45,46 Tests of Autonomic Function Thermoregulation and sudomotor regulation are the main systems tested in patients with CRPS for disorders in autonomic function. Thermoregulation is tested by using the thermoregulatory sweat test (TST) and infrared thermography or thermometry. The TST

 

CHAPTER 34

assesses calorimetric precipitation from a specific region of the body by adding a solution that changes color when enough heat is generated to produce sweat.47 Infrared thermography is direct visualization of the change in temperature of the affected site, and in infrared thermometry, a device is used to measure temperature through the detection of infrared energy. Changes in temperature in patients with CRPS versus those with other types of pain had a sensitivity of 76% and a specificity of 94%.48 Sudomotor regulation is tested by using the quantitative sudomotor axon reflex test (QSART), which measures sweat output from various regions of the skin. However, a recent retrospective review of patients who underwent QSART was found to have a sensitivity of 67.6% and specificity of 40.6%, with a not statistically significant odds ratio of 1.43.49

Trophic Changes Three-phase bone scintigraphy (TPBS) is a very valuable test for the detection of CRPS. Although joint and bone alterations are not part of the IASP inclusion criteria, they are very important in the outcome of the syndrome.25 TPBS detects alterations in periarticular bone metabolism, particularly increased bone metabolism, by detecting increase uptake of a periarticular tracer, which occurs predominantly within the first year. TPBS is low in sensitivity but high in specificity.50 Furthermore, TPBS may have a role in monitoring treatment effectiveness for CRPS as well, possibly predicting disease response to ketamine treatment.51,52 Magnetic resonance imaging of the affected limb has also been used for detection of CRPS but has high sensitivity (97%) and low specificity (17%).53

Treatment Management of CRPS has been complicated by scant knowledge of the cause of the disease, which has resulted in few targeted therapies. Most of the medications initiated as first line therapy have been investigated for other non-CRPS neuropathic pain conditions and then applied to the treatment of CRPS, with mixed success. The historical approach to therapy for CRPS remains a multimodal, multi-disciplinary methodology. The predominant therapeutic modalities for the care of CRPS patients include physical therapy, pharmacologic agents, and interventional procedures.

Physical and Occupational Therapy Physical and occupational therapy for restoration of function and improvement of limbs affected by CRPS has been studied widely. Physical exercises such as isometric strengthening, active range of motion, myofascial release, and stress loading are all tools that aid in restoring the functional capacity of the affected limb.54 A 2019 multi-disciplinary study utilizing physical therapy modalities (graded motor imagery and physiotherapy exercises) along with psychological treatment, memantine, and morphine treatment was successful in reducing some of the CRPS symptoms.55 Other methods of therapy are currently under study. In a large controlled study in which tactile acuity and pain on the application of a tactile stimulus were measured in patients with CRPS, and mirror images were used to show the reflection of the unaffected limb during the stimulus, a decreased two-point discrimination threshold and decreased pain acuity were observed.56 This suggests that therapies that improve functional restoration of the affected limb (including mirror therapy) may improve the outcome of CRPS.57 However, evidence for other forms of physiotherapy for the management of CRPS I and II is unclear.58 Despite

Evaluation and Treatment of Neuropathic Pain Syndromes

483

ongoing studies and modeling, an optimal clinical physiotherapy algorithm to treat this condition has yet to be validated.59

Pharmacologic Therapy Membrane Stabilizers

Medications such as gabapentin and pregabalin have been shown to be effective in relieving neuropathic pain.60,61 CRPS is considered neuropathic pain, and gabapentin is presumed to be effective in treating it, yet there are very limited studies showing its specific efficacy for CRPS. In a randomized, double blind, placebo controlled crossover study in which patients were treated for two three week periods with two weeks in between, gabapentin had minimal effect on pain, but it significantly reduced patients’ sensory deficits.62 In a case report of a 15-year-old female with left arm CRPS one, pregabalin was successful in the management of her pain after she failed treatment with gabapentin, selective serotonin anti-depressants, and stellate ganglion block.63 Although there is no clear evidence of efficacy for gabapentin, these neuroleptic medications are the first line therapy for neuropathic pain and are thus considered first line therapy for CRPS. Corticosteroids

A large part of the pathophysiology in CRPS is the acute inflammatory process that occurs after an inciting event (see “Pathophysiology”). Because of this inflammatory course, corticosteroids have been used for treatment. In a 2006 randomized controlled trial comparing prednisolone with piroxicam, patients were given either medication for one month, and their shoulder-hand syndrome scores (measuring pain, distal edema, passive humeral abduction, and external rotation) were determined. In the prednisolone group, 83.3% showed improvement, and in the piroxicam group, only 16.7% improved. The shoulder-hand syndrome score in the steroid group was significantly lower than that in the piroxicam group.64 Other studies have shown that continuation of prednisolone treatment (two months) after an initial one month high-dose (40 mg) taper was successful in reducing post stroke CRPS one patients.65 Short term steroid use was further found to normalize microcirculation in response to remote ischemic conditioning (RIC, a non-damaging method to induce ischemia to an extremity) in CRPS patients (typically RIC causes an increased O2 extraction and decreased blood flow) implicating the antiinflammatory role of steroids in CRPS.66 Anti-depressants

These drugs have not been studied for use specifically with CRPS, but they have been widely studied for the control of neuropathic pain, and because CRPS is considered neuropathic pain, they are used in pain management. Anti-depressants such as tricyclic antidepressants (TCAs) and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) have been used to control neuropathic pain effectively. In a recent Cochrane review, TCAs were found to be effective in treating neuropathy, with a number needed to treat (NNT) of 3.6 and a relative risk (RR) of 2.1. Venlafaxine, an SSNRI, was also found to be effective, with an NNT of 3.1 and RR of 2.2.67 Further studies to investigate the drugs’ ability to specifically target CRPS are warranted. A recent study showed that the combination of gabapentin and nortriptyline was a more effective therapy than either medication alone for neuropathic pain (including CRPS).68 In children with CRPS, a randomized controlled trial comparing amitriptyline to gabapentin revealed no statistical difference between the efficacy of both medications in successfully decreasing pain intensity scores.69

484

PA RT 4 Clinical Conditions: Evaluation and Treatment

Opioids

Studies on the effects of opioids directly on CRPS are lacking, although some have shown opioids to improve neuropathic pain when used in high doses.70 However, a double blind, placebo controlled trial studying the efficacy of sustained-release morphine in CRPS patients for a total treatment of eight days showed that it was ineffective in decreasing pain, but the study had many limitations.71 In 2016, a Cochrane review evaluating fentanyl use for the treatment of neuropathic pain including CRPS and PHN showed that there was insufficient evidence to support or refute the use of the medication in those conditions.72 Substantial challenges to using opioid therapy for nonmalignant pain include nausea, constipation, cognitive impairment, tolerance, and hyperalgesia.73,74 Therefore it should be used only until other therapies can be initiated. Studies of these medications in the CRPS population are lacking, and more is needed to demonstrate the efficacy of opioids. Ketamine

Ketamine is an NMDA receptor antagonist. The NMDA receptor is a major part of the central sensitization that occurs in patients with CRPS (see “Pathophysiology”). Ketamine can be administered topically, orally, intranasally, or parentally in subanesthetic (analgesic) doses or in high doses to produce ketamine coma. Its role in medicine has expanded from anesthetic uses to include treatment of pain (acute and chronic), headaches, seizures, and depression.75 A double blind, randomized, placebo controlled, parallel-group trial studying the effects of subanesthetic intravenous dosing of ketamine for four days in CRPS patients showed decreased pain levels, but the pain progressively increased from the first week after infusion to the 12th week. In patients undergoing ketamine infusion, minor and rare side effects such as nausea, vomiting, and psychomimetic effects developed.76 In another nonrandomized open-label trial in which chronic CRPS patients refractory to standard therapies were treated with anesthetic doses of ketamine for five days, the pain improved significantly for six months, but 79.3% relapsed back to baseline after the six months.77 A 2018 meta-analysis of 15 studies where ketamine was used for the treatment of CRPS included 15 randomized controlled or cohort studies revealing an immediate pain relief rate of 69% with a 58% pain relief rate at one to three months follow up.78 The topical form of ketamine has also been shown to decrease allodynia and hyperalgesia in response to pinprick stimuli,79 but this has not been well validated.

Bisphosphonates

Bone resorption at the site of inflammation in the affected limb contributes to the pain in CRPS. The use of bisphosphonates to decrease osteoclast overactivity has shown promise in its painreducing effects. In an eight week randomized, double blind, placebo controlled study, alendronate was used in patients with posttraumatic CRPS type one. This drug improved spontaneous pain, tolerance to pressure, and extremity range of motion.80 However, other trials have shown no reduction in CRPS-related pain. A 2013 Cochrane review evaluating interventions for pain treatment of CRPS patients from six Cochrane reviews and 13 nonCochrane reviews showed low quality evidence that bisphosphonates may be beneficial for pain management.81 A later review in 2018 of four moderate to good quality trials were analyzed, which revealed significantly lower short term (30–40 days) and medium term (two to three months) visual analog scale (VAS) reduction in patients on bisphosphonates for the treatment of CRPS one.82 However, a

higher percentage (35.5% vs. 16.4%) of adverse events occurred compared to placebo with a RR of 2.1, and the number needed to harm of 4.6 was reported, although no serious side effects were observed.83 Because of the success of bisphosphonates in the management of acute phase CRPS type one, it was theorized that bone tissue involvement (through the release of inflammatory cytokines and effects on microvascular remodeling) plays an integral role in the early stages of CRPS one development.84

Interventional Treatment Sympathetic Nerve Block

The most common sympathetic nerve blocks are the stellate ganglion and lumbar sympathetic blocks for the treatment of CRPS of the upper and lower extremities, respectively. Multiple modalities have been studied for their ability to disrupt the sympathetic pathway through these nerve plexuses, including local anesthetics, chemical neurolysis, and radiofrequency ablation. In a study in which both stellate ganglion and lumbar sympathetic blocks were performed with local anesthetic and normal saline on each subject, it was observed that the decreased pain that each experienced was almost identical, but the duration of decreased pain was longer when patients received the local anesthetic block.85 In a small randomized study in which radiofrequency neurolysis was compared to chemical neurolysis, the pain decreased from baseline, but no significant difference was seen between the two methods.86 A retrospective review of 287 stellate ganglion blocks for upper extremity CRPS treatment showed an average reduction of > three numeric rating scale from baseline or provoked pain.87 Although sympathetic blocks may provide a significant reduction in pain by blocking the sympathetic pathway of the pathophysiologic stages in CRPS, their greatest limitation is that they provide only short term relief in the vast majority of treated patients. This means that patients must continue to frequently undergo sympathetic blocks, which most often places them on maintenance therapy. A 32 question survey evaluating the use of sympathetic blocks for CRPS treatment was distributed nationally with a response from 248 pain physicians. In this group, 44% of providers schedule a sympathetic block at the first clinic visit, with 73% of providers performing one to three consecutive blocks with over 50% of respondents performing repeat injections for patients with at least 50% response from the prior injection.88 This form of therapy should be performed to provide enough pain relief so that patients are able to perform physical therapy exercises for functional restoration and multi-disciplinary therapy, but not as a sole therapeutic modality.

Neuromodulation

Neuromodulation has implemented itself in the treatment algorithm of patients with chronic pain, including CRPS, utilizing percutaneous or surgically placed leads in the epidural space implementing electrical dosing via an implantable pulse generator (IPG). Currently, modalities for the treatment of CRPS include dorsal column neuromodulation and dorsal root ganglion (DRG) neuromodulation. In a randomized trial, patients with CRPS were separated into two groups: spinal cord stimulation (SCS) with physical therapy and physical therapy only.89 This study showed that SCS provided significant improvement in pain for the first two years.90 Unfortunately, there was no amelioration in quality of life or functionality in the group undergoing SCS with physical therapy, although this study was seriously flawed because of excessive patient dropout.91 Several studies since have been performed evaluating the efficacy of these techniques in managing CRPS. A systematic review of 19 manuscripts evaluating SCS in

 

CHAPTER 34

the treatment of CRPS revealed improvement of perceived pain, pain score, and quality of life in patients. However, the results from this review were inconclusive for the role of SCS in improving functional status, psychological status, sleep hygiene, or resolution of the signs of CRPS.92 DRG neuromodulation was first evaluated in a multicenter prospective trial for management of chronic pain, including nine patients with CRPS of the lower extremity. Six months after implant, participants had an overall reduction of 58% from baseline.93 The ACCURATE study was a prospective multicenter randomized controlled trial evaluating the efficacy and safety of DRG neuromodulation in the treatment of CRPS of the lower extremities than tonic dorsal column neuromodulation. The 152 patient study showed that there was a greater percentage (81.2% vs. 55.7%) of patients with >50% pain relief at three months post implant without difference in the incidence of device related or serious adverse events.94 This finding was further emphasized by the Neuromodulation Appropriateness Consensus Committee (NACC) guidelines for DRG best practices.95 Though the role of neuromodulation for management of upper extremity CRPS requires further investigation, neuromodulation may be an effective therapy of management of lower extremity CRPS. Intrathecal Treatments

Baclofen and ziconotide administered intrathecally have been examined for the treatment of CRPS. Baclofen is a γ-aminobutyric acid receptor agonist. It is used as a muscle relaxant and has been indicated for muscle spasticity and dystonia. A single-blind, placebo run-in, dose escalation study of CRPS patients with dystonia showed that intrathecal baclofen was very effective in decreasing dystonia and pain, as well as in improving quality of life, as indicated in a 12-month follow up.96 Ziconotide is a very potent drug made from the toxin of sea snail venom and works by blocking chemicals that transmit pain signals. Intrathecal administration of this drug has great potential in reducing edema, trophic changes, and pain in these patients.97 However, it is associated with a nearly 100% side effect profile. Incidentally, a four-year retrospective evaluation of 26 patients with intrathecal pumps for CRPS management revealed that intrathecal narcotics did not reduce the dose of oral narcotics while intrathecal ziconotide may.98 Other medications trialed with success include clonidine99 and morphine with bupivacaine.100 The majority of the literature surrounding the use of intrathecal treatments for CRPS are case reports, and formalized trials are needed to verify the efficacy of these modalities.

Postherpetic Neuralgia Postherpetic neuralgia is neuropathic pain that arises from herpes zoster (HZ- shingles) in a dermatome distribution. This form of pain is very debilitating and leads to poor quality of life and poor functional status at home and in society. Control of pain is difficult, with multiple interventions being required. There are multiple risk factors for the development of HZ and subsequent PHN. It is essential to understand the risk factors, pathophysiology, and diagnostic approach to PHN to delve into the various pharmacologic and interventional treatments available.

Epidemiology and Risk Factors Varicella is a viral infection that may lead to varicella zoster (chicken pox) on first exposure and remains in a latent phase for the majority of lifetimes. HZ develops secondary to the reactivation of

Evaluation and Treatment of Neuropathic Pain Syndromes

485

the varicella virus from its latent state. Varicella virus is kept in a latent state by the body’s cell-mediated immunity. When there is a decrease in cell-mediated immunity, the risk for reactivation and subsequent HZ increases. Cell-mediated immunity may decrease with age, HIV infection, cancer, and immunosuppressive therapy as used for transplant patients.101 The annual incidence of acute herpes zoster is estimated to be 3.4 cases per 1,000 patients with significant increases after the age of 50 years, with an approximate incidence of 11 cases per 1,000 patients by the age of 90 years.102 A separate study found the incidence as 3.6 cases per 1,000 personyears that was low for patients between age 20–29 years old but increased to 7.1 cases per 1,000 person-years by seventy and 12.0 cases per 1,000 person-years by eight years old.102 PHN pain is pain that persists three months after the acute phase of the disease. It is seen in approximately 10%–20% of patients infected with HZ.103 The incidence of PHN developing from HZ also increases with age, with 80% of cases occurring in patients 50 years or older.103 Patients older than 70 years with HZ have a 50% risk for the development of PHN; approximately 13% of all patients over 50 years old will develop this condition.104 PHN rarely develops in patients younger than 40 years. There are many risk factors for the development of PHN, and among them are increased age, greater severity of the rash during the acute phase, female gender, and greater acute pain severity.105 In an epidemiologic study of patients with PHN in the Ferrara University Dermatology Unit, Italy, from 2000–2008, males had an earlier age at onset than females did, and 72% of the patients were older than 45 years. The most commonly observed sites were ophthalmic in 32%, thoracic in 16.5%, and facial in 16%.106 The correlation of PHN developing after the first episode of HZ was reviewed in a prospective study in which patients were monitored for 12 months. It was concluded that three months after the appearance of the HZ rash, the risk for the development of PHN was 1.8%. In patients older than 60 years, the risk for the development of PHN and the severity of the pain was higher.107 In recent years, the administration of the varicella vaccine has become very popular as PHN cannot be prevented once a patient has developed HZ.108 Some data suggest that these vaccines may lead to an increase in the incidence of HZ secondary to a reduced opportunity for subclinical boosting, which results in an extreme reduction in the incidence of varicella from the immunizations.109 However, the administration of the zoster vaccine has been proven to decrease the incidence of HZ and PHN. In a randomized, double blind, placebo controlled trial of the zoster vaccine, the incidence of PHN decreased by 66.5% (P < 0.001), and the incidence of HZ decreased by 51.3% (P < 0.001).110 In a population-based database review of post-vaccination incidence of HZ after starting a varicella vaccination program in Ontario the rate of HZ increased, incidence decreased by 29% in children, and hospitalization visits decreased because of HZ by 53%.111 Original versions of the vaccine contained live attenuated varicella zoster virus. The efficacy waned over time (six to eight years), but an immune boost can be provided with revaccination ten years after the initial vaccination. In 2017, a new recombinant glycoprotein E adjuvant vaccine was approved and available for use in the United States with increased efficacy and less decline over time than the live attenuated virus.108 The recombinant vaccine was found to be significantly more efficacious in reducing HZ and PHN incidence in adults ≥60 years old than the live attenuated vaccine.112

486

PA RT 4 Clinical Conditions: Evaluation and Treatment

Pathophysiology

Diagnosis

Varicella zoster is the primary infection that leads to chicken pox. After the primary infection, the virus remains dormant within one of the sensory nerve ganglia, the most common of which are the trigeminal and thoracic ganglia; these are also the sites where most of the cutaneous dermatomes are involved. The cellmediated immune system keeps the virus dormant in the latent phase. Progression from the latent phase to reactivation of the virus leads to the development of HZ and subsequently PHN in some patients.113 During the reactivation phase of varicella zoster virus (VZV), destruction of neurons and satellite cells occurs because this is the site of replication for the virus.114 VZV traveling along the affected sensory nerves leads to evasion of the host immune system and spreads from cell to cell until its characteristic unilateral dermatome rash is produced. The spread of the virus and its destruction of neurons occurs before the development of the rash.115 Studies in postmortem patients have led to the conclusion that reactivation and replication of VZV result in inflammatory changes within the sensory neurons that it disturbs, which causes pain. This mechanism may help explain the findings of loss of cells, myelin, and axons, fibrosis of the affected ganglion, and atrophy of the dorsal horn in postmortem patients.116 The previously mentioned mechanism contributes to the two primary pathophysiologic mechanisms of PHN pain: sensitization (hyperexcitability) and deafferentation.117 These mechanisms describe not only peripheral nerve pain but also central nerve pain.118 Following nerve injury, nociceptive receptors in the peripheral and central nervous systems become sensitized, so the threshold for the firing of action potentials after a certain stimulus is lowered. This causes the nerve to become hyperexcitable and leads to allodynia without sensory loss.117 Deafferentation pain arises from the neuronal destruction and loss of afferent neurons that occur after the virus reactivates and subsequently produces the inflammatory response within the affected nerve. The loss of afferent neurons leads to spontaneous activity centrally, which results in pain in areas where there is sensory loss. Neural sprouting is initiated in an attempt to reconnect the former C-fiber receptors, a process that leads to hyperalgesia with allodynia.117 The sympathetic nervous system is also thought to play a role in PHN by stimulating a vasoconstrictive response during the inflammatory process that results in decreased intraneural blood flow, hypoxia, and endoneurial edema.119 Typically, patients will report three types of pain, including constant pain without stimulus, intermittent pain without stimulus, and pain with a stimulus that is disproportionate to the stimulus.118

Postherpetic neuropathy is principally a clinical diagnosis. The typical clinical scenario involves a patient complaining of persistent pain that is within a certain dermatome and affects the region that the dermatome innervates in a unilateral fashion.120 The acute phase of HZ is characterized as a maculopapular vesicular rash that crusts over after one to two weeks and results in a burning sensation, hyperesthesia, itching, and severe pain. Prodromal symptoms that may occur one to five days before the rash include headache, fever, malaise, abnormal skin sensation, and photophobia. PHN may occur two weeks after the presence of HZ and is the chronic form of the disease. This is a very debilitating pain that consists of burning, dysesthesia, pruritus, and allodynia or paresthesia of the affected dermatomal region. The pain usually decreases or resolves within six months after exposure, but in some cases, it may last years.121 A detailed physical exam is often helpful in the diagnosis as patients will have sensory abnormalities in the area involved, including allodynia, hyperalgesia, or dysesthesia to touch. Furthermore, thermal stimulus and vibrational stimulus may elicit these sensory abnormalities as well.118 Furthermore, QST may be a useful tool in helping further assess the functional status of the somatosensory system.122

TABLE 34.1

Treatment Therapy for HZ can be separated into the acute phase (shingles) and the chronic phase (PHN). In the acute phase of the disease process, the first line medications that have proved to significantly decrease the length of disease are antiviral medications such as famciclovir and valacyclovir. Three randomized controlled trials that measured the efficacy of these agents when initiated within the first 72 hours of disease onset concluded that they were all effective in increasing the rate of healing and decreasing pain.123–125 Another study showed that valacyclovir resulted in faster complete resolution than acyclovir did (44 vs. 51 days, respectively).126 In addition, a study comparing famciclovir with valacyclovir showed no statistically significant difference.123 A Cochrane review of antivirals in the prevention of PHN showed high quality evidence that oral acyclovir does not reduce the incidence of PHN significantly. Unfortunately, data on the administration of antiviral medications aside from acyclovir for the prevention of PHN are inconsistent.127 When deciding which agent to use, it is important to consider the amount of administration and cost (Table 34.1). Other medications that may be used to control the pain of acute HZ are acetaminophen, nonsteroidal anti-inflammatory agents, tramadol, and opioids.101 Studies and randomized trials comparing

Antiviral Medications for Acute Herpes Zoster

Medications

Recommended Dosages

Side Effects

Prices

Acyclovir

800 mg five times a day for seven to ten days

Nausea, vomiting, diarrhea, constipation, decreased appetite, headache, joint pain

$24.95 for 30 400-mg tablets

Valacyclovir

1000 mg three times a day for seven days

Nausea, vomiting, diarrhea, constipation, abdominal pain and cramping, headache, tremors

$173.92 for 30 1-g tablets

Famciclovir

500 mg three times a day for seven days

Headache, nausea, vomiting, fatigue, pruritus

$166.38 for 21 500-mg tablets

 

CHAPTER 34

opioids, TCAs, and membrane stabilizers for treatment of acute pain from HZ are lacking, but they are still recommended as adjunctive therapy for refractory severe pain.101 The addition of corticosteroids with antiviral medications has proved effective in relieving the intensity of the pain of shingles, but not the duration of the disease process.128 Furthermore, corticosteroid administration did not aid in preventing the development of PHN, as shown in a Cochrane review study.129 Interventional therapy for the treatment of acute HZ has proved effective in relieving the pain but not consistent in preventing the development of PHN. A randomized trial in which patients older than 50 years with HZ were given standard therapy versus standard therapy and one epidural injection of methylprednisolone, 80 mg, with bupivacaine, 10 mg, showed that in one month, patients in the epidural injection group experienced a significant reduction in pain.130 A randomized prospective study was performed comparing interlaminar and transforaminal steroid injections for management of acute phase HZ found similar VAS, Short Form (36) Health Survey Physical Component Summary (SF 36 PCS), and Short Form (36) Health Survey Mental Component Summary (SF 36 MCS) scores with no difference in analgesic effects one or three months between the two groups.131 An alternative method for acute HZ treatment with subcutaneous injection of triamcinolone with lidocaine was reported with improvement in pain at three months post infection than standard antiviral therapy with analgesics.132 Further studies are needed to validate this modality of acute HZ treatment.

Analgesic Therapy PHN is a neuropathic pain historically refractory to many forms of therapy. PHN therapies have been separated into analgesic medications (e.g. topical, membrane stabilizers, opioids), interventional procedures (such as sympathetic blocks, intrathecal injections, or surgical interventions), and preventative therapy with the zoster vaccine. Nontraditional PHN therapies such as cognitive and physical therapy have also proved beneficial. As with most other chronic pain disorders, a multimodal therapeutic plan leads to an optimal chance of success. Medications such as gabapentin, pregabalin, tramadol, and topical lidocaine are considered first line treatments because they TABLE 34.2

Evaluation and Treatment of Neuropathic Pain Syndromes

have been shown to be most well tolerated by the (commonly elderly) patient population. Other medications shown to help patients with PHN are TCAs and SSNRIs, opioids, and topical capsaicin cream (Table 34.2). The therapeutic modality chosen is patient specific and depends on a thorough history and physical examination. Topical Medication

A 5% lidocaine patch and 4%–10% lidocaine cream are widely used topical forms. A randomized, two-treatment period, vehiclecontrolled, crossover study showed that a lidocaine patch is effective in controlling PHN pain from allodynia. At the end of the study, 78.1% of subjects enjoyed the lidocaine patch treatment phase, and only 9% liked the placebo patch treatment phase.133,134 The lidocaine patch is also very safe because of minimal systemic absorption. It is also used safely with other medications based on studies showing no significant drug-drug interaction. The most common side effect reported has been mild skin irritation.135 The NNT has been quoted as 2.0 with 95% confidence intervals (CI) 1.4–3.3.136 Topical capsaicin in cream or high-concentration patch form has shown promise in treating PHN pain. The first application of the cream leads to exacerbation of the burning sensation, but with time, application leads to desensitization of the nerve root endings and decreases the hyperalgesia. In a four week, double blind study, patients were randomized to receive a high-concentration topical capsaicin patch or placebo. The study showed that the highstrength capsaicin patch relieved pain in 64% of patients at the six week mark than 25% taking placebo.137 The NNT has been quoted as 3.3 with 95% CI 2.3–5.8 for the cream and NNT 11.0 with 95% CI 6.1–62.0 for the patch.136 Anti-convulsants

Gabapentin has been used widely as a first line therapeutic agent for PHN. A quantitative systematic review of randomized controlled trials indicated that the pooled NNT for gabapentin was approximately 4.4.138 Another study, a randomized, double blind, parallelgroup trial of nine weeks’ duration, showed that gabapentin was

Efficacy and Side Effects of Analgesic Medications for Post-herpetic Neuropathy Number Needed to Treat (NNT)

Side Effects

Gabapentin

4.3

Diarrhea, dizziness, drowsiness, dry mouth, tiredness, somnolence

Pregabalin

4.9

Blurred vision, changes in sexual function, constipation, dizziness, drowsiness, dry mouth

Lidocaine

2

Mild skin irritation

Capsaicin

3.6

Major skin irritation and burning

Tricyclic antidepressants

2.64

Dizziness, drowsiness, dry mouth, headache, impotence, nausea, nightmares, pupil dilation, sensitivity to sunlight, sweating, tiredness

Tramadol

4.76

Constipation, dependence, dizziness, drowsiness, increased sweating, loss of appetite, nausea

Oxycodone

2.64

Constipation, dependence, dizziness, drowsiness, increased sweating, loss of appetite, nausea

Morphine

2.64

Constipation, dependence, dizziness, drowsiness, increased sweating, loss of appetite, nausea

Medications

487

Anti-convulsants

Topical

Opioids

488

PA RT 4 Clinical Conditions: Evaluation and Treatment

just as effective as nortriptyline but was tolerated better. After nine weeks of gabapentin treatment, the pain score declined by 43%, and sleeping improved by 52%.139 The dosage may be titrated up to effect to 1800 mg/day to a maximum of 3600 mg/day.140 Pregabalin has an identical site of action as gabapentin and is as efficacious in the treatment of PHN. It has the drawback of being on patent (and therefore more expensive) but can be better tolerated by patients because of its greater bioavailability, which results in twice a day dosing compared to the three times daily dosing required for gabapentin.141 Pregabalin has a similar NNT of 4.2 with 95% CI 3.4–5.4 with a similar side effect profile as gabapentin, including sedation, dizziness, and peripheral edema.136 Anti-depressants

TCA medications have been the first line therapy for neuropathic pain. In a 2006 randomized, double blind, parallel-group trial of nine weeks’ duration, patients with PHN who received nortriptyline had a 47.6% reduction in pain with sleeping scores improved from baseline.139 A quantitative systematic review of analgesic therapy for PHN noted a significant analgesic benefit with TCAs for the treatment of PHN pain, with the pooled data showing an NNT of 2.6 (95% CI 2.1–3.5).138 The efficacy of amitriptyline in providing relief of pain in patients with PHN was studied by comparing nortriptyline with amitriptyline. The results showed that both these drugs provided adequate pain relief in 67% of patients. Although they are both equally effective, patients tolerated nortriptyline better because of its fewer side effects.142 Venlafaxine is another anti-depressant medication with the potential for the management of neuropathic pain, including PHN. It is classified as an SSNRI and provides relief of neuropathic pain by increasing the amount of serotonin and norepinephrine and inhibiting their reuptake. This drug has been shown to have fewer side effects than TCAs.143 Venlafaxine must be used in doses exceeding a total daily dose of 200 mg/day to inhibit norepinephrine reuptake; doses below this level will only inhibit serotonin reuptake and have no analgesic benefit. A 2015 Cochrane review evaluated six double-blinded randomized controlled trials that revealed little compelling evidence to support the use of venlafaxine for neuropathic pain. However, there was some lower quality studies that implicated benefit, and the authors of the review do not recommend revising prescribing guidelines to promote venlafaxine use, given the number of effective medications available to treat neuropathic pain.144 This may be because of venlafaxine’s side effects, including hypertension, exacerbation of seizures, and mania.

Opioid Medications

Although opioids are considered effective in overall pain management, their efficacy in controlling neuropathic pain is still controversial. In a double blind, crossover, four week study of sustained-release oxycodone, 20–60 mg, for moderate to severe pain in patients with PHN, the response rate for pain relief was 58% versus 18% for placebo.145 Another study reported that the administration of 10 mg oxycodone to a patient already taking pregabalin did not enhance the pain relief obtained,145 demonstrating that oxycodone at low doses is not as effective as the administration at higher doses. Morphine was also found to be beneficial in managing the pain of PHN. It was shown that a combination of morphine and gabapentin improved neuropathic pain in patients with PHN more than did either of them alone.146 These data suggest that opioids at high doses are of therapeutic value in relieving pain in patients with PHN. The NNT for morphine was quoted

as 2.8 with 95% CI 2.0–4.6, while the NNT for oxycodone was 2.5 with 95% CI 1.7–4.4.136 Tramadol

Tramadol is a weak µ-receptor agonist medication with properties that increase the release of serotonin and inhibition of norepinephrine reuptake. This medication has been effective in treating neuropathic pain with an NNT of 4.8.147 In a multicenter, randomized, double blind, parallel-group study involving 127 outpatients treated with tramadol or placebo for six weeks, the tramadol group showed significantly reduced pain than the placebo group. Quality of life in the tramadol group was also improved.147

Combination Therapy

Many studies have combined medications to achieve the greatest efficacy with the least dosage and increased tolerability of the medications. In a double blind, double-dummy, crossover trial in which patients with neuropathic pain took gabapentin or nortriptyline as monotherapy or combination therapy, combination therapy was shown to be better than monotherapy. However, each medication was effective in relieving neuropathic pain.68 The combination of gabapentin and morphine has also been widely researched. Gabapentin combined with morphine was more effective than either medication alone.146

Interventional Therapy Interventional therapy for the pain of PHN includes nerve blocks, intrathecal injections, and SCS. Interventional therapies are not considered a first line choice, but they should be considered in a multimodal management approach for PHN treatment. Sympathetic Nerve Blocks

The role of sympathetic nerve blocks is to provide relief of pain during the development of HZ, provide relief of PHN pain, and prevent the development of PHN from HZ. Unfortunately, most of the data attempting to prove the efficacy of sympathetic nerve blocks in these three main roles come from retrospective studies and are limited. Thus the use of sympathetic nerve blocks remains controversial. In a small, randomized study based on retrospective data in which bupivacaine was compared to the saline solution, there was evidence of the reduced duration of acute HZ pain in patients with sympathetic nerve blocks.119 Another retrospective study concluded that sympathetic nerve blocks provided temporary short term pain relief in 41%–50% of patients with PHN.148 A study comparing sympathetic nerve blocks and lidocaine patches for the treatment of PHN revealed similar rates of failure (18.9% vs. 27.1%, respectively) with similar average Numerical Rating Scale (NRS) change (5.88 vs. 5.01) but a significant proportion of patients remaining pain free eight weeks after treatment in those treated with sympathetic blocks than those with lidocaine patches (34.4% vs. 13.5%).149

Neuraxial Blocks

Epidural injections, paravertebral injections, and intrathecal steroid injections have all been used for temporary relief of pain from PHN, with successful short term results. Epidural steroid injections have been proved to effectively reduce pain in the acute phase of PHN, but most research has focused on its effects in preventing the progression of HZ to PHN. In a study performed in Italy, 600 patients older than 55 years with HZ were administered bupivacaine and methylprednisolone through an epidural catheter versus intravenous administration of prednisolone and

 

CHAPTER 34

acyclovir until they were pain free. After one year, the incidence of PHN was 22% in patients receiving intravenous prednisolone and acyclovir instead of 1.6% in those receiving bupivacaine and methylprednisolone through an epidural catheter.150 A retrospective review of PHN patients receiving epidural steroid injections to determine variables to predict the efficacy of injection revealed no demographic characteristics, concurrent medication use, or type of epidural steroid injection were associated with efficacy at two or 12 weeks after the injection.151 The efficacy of paravertebral blocks in preventing PHN was assessed in a single-center randomized study of patients with HZ given either the standard therapy of oral antivirals and pain medications or a series of four paravertebral injections with bupivacaine and methylprednisolone besides standard therapy. The study concluded that after 12 months, the incidence of PHN with standard therapy alone was 16% compared to 2% in the paravertebral block group. Although it seems that paravertebral blocks are effective in preventing PHN, larger multicenter trials are still required.152 Another promising procedure for the relief of PHN pain is intrathecal methylprednisolone. A study in which 279 patients with intractable PHN pain for more than one year were given either intrathecal methylprednisolone with lidocaine, lidocaine alone, or no therapy concluded that the group receiving methylprednisolone with lidocaine experienced a significant reduction in pain than the groups receiving lidocaine alone or no therapy.153 Unfortunately, these data have never been replicated, and clinical experience has not corresponded to the positive results that the authors obtained. Further, a planned randomized study was terminated prematurely after the six patients who had intrathecal methylprednisolone had increased pain and four of the six patients had the area of allodynia increased.154 Although this method of management of intractable PHN may have been effective in this single study, its association with adhesive arachnoiditis has and should limit its application. In a systematic review interventional treatments of PHN including transcutaneous electrical nerve stimulation (TENS), botulinum toxin A local injection, cobalamin injection, triamcinolone injection, stellate ganglion block, DRG destruction, pulsed radiofrequency ablation, and intrathecal methylprednisolone and midazolam injection were evaluated. All interventions to treat PHN except for intrathecal methylprednisolone injection was deemed level 2 evidence, substantiating a grade B recommendations. Subcutaneous injections of botulinum toxin A, subcutaneous injections of triamcinolone, TENS, stellate ganglion block, and peripheral nerve stimulation were recommended as treatments to try first given the invasiveness, price, and safety of these techniques. If pain persists, these authors recommended paravertebral blocks or pulsed radiofrequency therapy. With patients in refractory pain, SCS was recommended for consideration while DRG destruction and intrathecal methylprednisolone was reserved for select scenarios requiring comprehensive discussion given the risks associated.155 Neuromodulation

With the increase in evidence with concurrent development of neuromodulation technologies, neuromodulation has expanded its role in pain management to addressing PHN as well. The 2014 NACC guidelines reviewed the literature for PHN management with dorsal column SCS and peripheral nerve stimulation (PNS).156 Since then, several retrospective studies evaluating the role of neuromodulation were performed. In one retrospective study evaluating short term (7–14 days) dorsal column SCS in 46

Evaluation and Treatment of Neuropathic Pain Syndromes

489

patients with acute HZ that failed conventional therapies, 69.6% of patients achieved minimally clinically important difference, with 39.1% reporting complete pain relief. The study was limited as no comparative group was available.157 Another retrospective study of 99 patients with various stages of HZ (acute, subacute) along with PHN who received short term dorsal column SCS treatment were evaluated at one, three, five, and 12 months follow up. The study showed that 97.5% of acute HZ and 84% of subacute HZ patients had pain expressed as VAS scores of two or less at 12 months than 37.5% in patients with PHN. Although no control group was available for comparison, the authors implied that short term dorsal column SCS might decrease the incidence of PHN after an HZ infection.158 PNS is another potential modality for the management of PHN. Though most of the literature on this technique are case reports or nestled within a larger neuromodulation cohort, several reviews of this technique discuss the applicability of this procedure in treating PHN. In a case report of two patients with a ten month and 2.5 year follow up, PNS provided an average pain relief of 90%. A review of various neurosurgical techniques for the management of PHN included a review of three PNS studies encompassing ten patients. The procedure was performed after six months of HZ onset with a successful trial before PNS implant. Patients were evaluated at followed up with a mean follow up time of >20 months after IPG implant, where 80% of patients reported satisfactory reduction (>50%) of their pre-procedural pain.159 Further well controlled trials are needed to validate PNS in the treatment of PHN. However, it may be a promising technique to help patients in the future.

Diabetic Neuropathy Epidemiology and Risk Factors The definition of diabetic neuropathy as proposed by the San Antonio Consensus Statement is “demonstrable disorder, either clinically evident or subclinical in the setting of diabetes without other causes of peripheral neuropathy.”160 The diabetic neuropathies are collectively considered a diverse, complex disease that affects many components of the nervous system and exhibits varied clinical manifestations. The condition is a unique neurodegenerative process that preferentially targets sensory axons, autonomic axons, and eventually motor axons to a lesser extent.161 They can be classified into two main categories: generalized neuropathies versus focal or multifocal neuropathies. Generalized neuropathies include acute sensory neuropathy, chronic sensorimotor distal polyneuropathy, and autonomic neuropathy. Focal and multifocal neuropathies include cranial, truncal, focal limb, and proximal motor neuropathy (amyotrophy), as well as chronic inflammatory demyelinating polyneuropathy.162 The prevalence and incidence of DPN have been very difficult to verify given the inconsistencies in clinical diagnostic criteria, variability in patient populations, and wide range of physiologic techniques. The World Health Organization estimated that 150 million people had diabetes in the year 2000, and this number was expected to increase to 366 million by the year 2030.163 It has been estimated that approximately 56% of patients with DPN will complain of pain that affects their quality of life.164 In earlier studies, the prevalence of lower limb pain ranged from 6% to 27%, and DPN affected men and women equally.165 A study conducted in the United Kingdom involved 356 diabetic patients, most of whom had type two diabetes mellitus (T2DM),

490

PA RT 4 Clinical Conditions: Evaluation and Treatment

and included a structured questionnaire with a physical examination. Chronic sensorineural DPN (CSDPN) was diagnosed in almost half the patients, but only a third of them complained of pain that had been present for at least one year. The prevalence rate for DPN in this study was 16% compared to 5% for chronic neuropathic pain in a similar population without diabetes. It is also important to note that in this study, 12.5% of patients with DPN did not report symptoms to their physicians, and the 39% who reported pain did not obtain treatment of their pain, which suggests that DPN is undertreated.166 A cross-sectional descriptive study reported the prevalence of DPN in patients with diabetes mellitus type two to be 26%. The prevalence of diabetic patients suffering from CSDPN was found to be 44%.167 A 2009 multicenter study conducted in Belgium included 1111 diabetic patients, types 1 and 2, and estimated the prevalence of CSDPN and DPN.168 The study was performed with the NeuroPEN device, which tests for pain and monofilament perception and, based on studies, is able to identify CSDPN with confidence.169 The duration of diabetes in this population was greater in patients with type one than in those with type two, 16 versus 11 years, respectively. The study concluded that the prevalence of CSDPN was 43% and was higher with type two (51%) than with type one (26%) diabetes. The prevalence of lower limb neuropathic pain was 14%, again higher with type two (18%) than with type one (6%).168 The prevalence of peripheral neuropathy in type one diabetic patients was quoted as 34% in the Pittsburgh Epidemiology of Diabetes Complications Study, while the SEARCH for Diabetes in Youth Study quoted the prevalence of DPN in youths (average age 15.7) with type one diabetes mellitus (T1DM) as 8.2%.170, 171 In the SEARCH study, the prevalence of DPN was quoted as 26% while the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial found that 42% of adults with type two diabetes had peripheral neuropathy.171,172 The prevalence of diabetic neuropathy increases with increased T2DM duration as the prevalence increased from 8% to 42% when T2DM were monitored over ten years in a 1995 Finnish study.173 Similar findings were seen in the 2013 Bypass Angioplasty Revascularization Investigation Two Diabetes trial where patients with advanced T2DM in the cohort with 50% confirmed diabetic neuropathy at baseline had a four year cumulative incidence of diabetic neuropathy of 66%–72% in patients who had no neuropathy at baseline.174 According to these and other studies, the incidence of diabetic neuropathy in patients with T2DM is approximately 6,100 per 100,000 person-years, while it is 2,800 per 100,000 person-years in those with T1DM. The prevalence of diabetic neuropathy in patients with T2DM may be 8%–51%, while the prevalence in patients with T1DM may be 11%–50%.161 Risk factors for DPN have been widely studied to prevent its development. The most commonly reported risk factors are age, duration of diabetes, and hemoglobin A1C levels.161,175 Other risk factors associated with DPN are arterial hypertension,165 impaired glucose tolerance (IGT),176 smoking history, alcohol abuse history, and increased height.177 In a study examining patients with neuropathy of unknown origin, 36% of patients had IGT, 77% of whom had painful neuropathy.178 Other risk factors shown to have a relationship with the presence of DPN are obesity with low high-density lipoprotein cholesterol and high plasma triglyceride levels.168 Genetic factors are also considered risk factors based on a study by Galer and colleagues;164 56% of patients with DPN also had first- or second-degree relatives suffering from DPN. Specific

genes have also been implicated with this condition, including the ACE and MTHFR polymorphisms.161

Pathophysiology Diabetic neuropathy is theorized to occur by three mechanisms: the polyol pathway, microvascular damage, and glycosylation end-product theories. These three models most likely act simultaneously, but there may also be some overlap between them.179 Neurotrophic factors, neuronal membrane ion channel dysfunction, mitochondrial dysfunction, and lipid toxicity may likewise play a role in DPN.180 The polyol pathway theory proposes that increased blood glucose leads to elevated glucose concentrations within nerve endings. Through a series of reactions, the glucose is converted into sorbitol via the polyol pathway involving aldose reductase and elevation of the fructose level. The high sorbitol and fructose levels subsequently lead to a decrease in sodium-potassium adenosine triphosphatase (Na+, K+-ATPase) activity. Activation of the aldose reductase-depleting cofactor NADPH (reduced nicotinamide adenine dinucleotide phosphate) leads to decreased nitric oxide and glutathione, which inhibits the buffer against oxidative injury and vasodilation and results in chronic ischemia.179 In the microvascular damage theory, thickening of the capillary basement membrane along with endothelial cell hyperplasia leads to neuronal ischemia and infarction.179 The glycosylation end-product theory proposes that interference in axonal transport results in decreased nerve conduction velocity because of chronic hyperglycemia, which results in the deposition of advanced glycosylation end products around peripheral nerves. These end products may also produce NADPH (which activates NADPH oxidase) and contribute to the formation of hydrogen peroxide and increased oxidative stress. These reactive species may have an increased effect in the face of mitochondrial dysfunction resulting in further nerve injury.180 Regardless of the mechanism, diabetic neuropathy ultimately develops when the peripheral terminal sensory axons are retracted with the preservation of perikarya (cell bodies). Ultimately the entire neuron, including the perikarya, is affected by diabetes. Schwann cells are targeted by chronic hyperglycemia resulting in damage furthering axonal dysfunction.161 This progressive axonal damage results in loss of mRNA expressing needed for neurofilament production, promoting oxidative damage and loss of peripheral nerve function.161 Nerve growth factors are important in the repair of nerve structure and function after an injury. Low levels of these neurotrophic factors correlate with diabetic neuropathy in animal models. Other factors associated with diabetic neuropathy are abnormal calcium channel activity contributing to cellular injury and death and sodium channel dysfunction playing a role in the genesis of painful neuropathy.181

Clinical Features Acute sensorimotor neuropathy often occurs in association with periods of poor metabolic control, such as uncontrolled glycemic levels or the development of ketoacidosis. This form of neuropathy is very rare.162 The most common form of peripheral neuropathy is CSDPN, as seen in over 80% of patients with DPN. Patients with CSDPN typically complain of distal, symmetric burning pain that usually involves the feet initially and gradually moves upward in a symmetric fashion. This is because of damage to longer nerves, a

491

systems. Some clinical manifestations include resting tachycardia, orthostatic hypotension, distal anhidrosis, bladder dysfunction, erectile dysfunction, female sexual dysfunction, severe constipation, diarrhea, and dysmotility syndrome.194 In addition, because of the loss of sympathetic tone, vasodilation occurs and leads to the pooling of blood in the lower extremities. This has been proposed to cause osteopenia and is related to the development of Charcot’s neuroarthropathy.195 Multifocal neuropathies comprise a wide spectrum of neuropathies, including diabetic amyotrophy, truncal neuropathies, cranial neuropathies, and mononeuropathies. Diabetic amyotrophy most often occurs in type two diabetics and is characterized by subacute pain and asymmetrical weakness and atrophy of the proximal lower limb muscles. There may also be involvement of the upper limb muscles and distal end of the lower extremity, but this is rare.196 Mononeuropathies most commonly involve the ulnar, median, and common peroneal nerves secondary to nerve ischemia because these nerves are more susceptible to injury from compression. Cranial nerve involvement may be present but is extremely rare.196

Treatment Options Treatment of DPN has been widely studied and includes the use of TCAs and SSNRIs, anti-convulsants, opioids, and other modalities. Treatment options can be viewed as approaches to prevent the development of DPN or alleviate its symptoms. As is true for all chronic pain syndromes, a multimodal approach is the most effective therapy for DPN, with the primary aim often focusing on protecting the lower limbs from damage caused by sensory loss or on relieving pain to enhance the quality of life and functionality of each patient.

Lifestyle Modification Hyperglycemia and insulin deficiency are associated with the pathogenesis of DPN. It appears that glycemic control is one of the most effective treatments to slow the progression of the disease and delay its onset.1 In a study conducted by the Diabetes Control and Complications Trial Research Group, a total of 1441 patients with insulin-dependent diabetes mellitus (726 of whom had no retinopathy and 715 had mild retinopathy) were monitored for 6.5 years after random assignment to intensive external insulin pump therapy or three or more daily insulin injections. The study concluded that in the group without retinopathy, intensive therapy reduced the risk for development of DPN by 76% compared to conventional therapy. In the retinopathy group, intensive therapy decreased progression by 54%. The study also showed that the progression of microalbuminuria in both groups was reduced by 39%, albuminuria by 54%, and clinical neuropathy by 60% with intensive insulin therapy.197 Thus tight glycemic control contributes to a delayed onset and slowed progression of DPN. Recent focus has also emphasized the role of dyslipidemia in the development of DPN. Obesity has been associated as a comorbid risk factor for the development of DPN, and having elevated lipids and triglycerides may contribute to the nerve injury seen in DPN. Non-esterified fatty acids from elevated triglycerides undergo -oxidation in the cytosol of all peripheral nervous system cells. The byproduct of this process is acetyl Co-A, which is converted into acylcarnitine when accumulated, leading to worsening nerve injury.198 Reactive oxygen species are also byproducts of -oxidation, which may stress the endoplasmic reticulum, produce mitochondrial dysfunction, impair axonal transport, and b

phenomenon known as length-dependent diabetic polyneuropathy.182 DPN causes neuropathic pain because of the involvement of small nerve fibers,183 and diagnosis is achieved through a diligent history and physical examination. One study showed that clinical neurologic examination, including questionnaires, was 23% sensitive and 93% specific in diagnosing DPN.184 A 2007 study concluded that the development of the DN4 questionnaire has improved diagnostic performance, with a sensitivity of 83% and specificity of 90% in patients with a neuropathic pain score greater than four out of 10.185 However, such assessment tools, including the Michigan Neuropathy Screening Instrument, the Toronto Clinical Neuropathy Score, and the United Kingdom Screening test, are subjective and rely on examiner familiarity to interpret the results.186 The initial symptoms in up to 50% of patients with DPN are highly nociceptive and include burning pain, electric or stabbing sensations, paresthesia, hyperesthesia, and deep aching pain, which are typically worse at night. Upper extremity involvement is rare.187 Physical examination of the lower limbs typically shows sensory loss of vibration, pressure, pain, temperature perception, and absent ankle reflexes. Loss of touch and pin sensation typically occurs before a loss of proprioception and vibration and is caused by the involvement of large-diameter fibers.182 This is evaluated with 10 gauge monofilament and tuning fork tests.169 Gait ataxia may occur with severe neuropathy. In addition, signs of peripheral autonomic dysfunction can be observed, including a warm or cold foot, distended dorsal foot veins, dry skin, and calluses under pressure-bearing areas.162 It is important to note that the diagnosis of DPN is a diagnosis of exclusion and that multiple pathologies may mimic this form of neuropathy. The gold standard for diagnosing DPN is with nerve conduction studies that may aid in verifying small and/or large fiber disease and ruling out other mimicking conditions.186 The differential diagnosis should include peripheral vascular disease, restless legs syndrome, Morton’s neuroma, vitamin B12 deficiency, hypothyroidism, and uremia.162,182 Several devices may be helpful in diagnosing DPN. DPNCheck, a handheld point of care device that performs a sural nerve conduction test that may serve as a proxy for a full nerve conduction test. It has a reported 95% sensitivity and 71% specificity compared against a reference standard nerve conduction test.188,189 Neuropad is a device that measures plantar foot sweat production with relatively high sensitivity for detection of small fiber neuropathy. Compared to other tests for detecting DPN, it has a higher sensitivity than the 10 g monofilament test or the biothesiometer test.190 Sudoscan is a device that quantifies electrochemical reaction between electrodes and chloride ions when sweat glands are stimulated with a sensitivity of 87.5% and specificity of 76.2% in classifying DPN.191 Although primarily in the validation stage, these instruments may potentially allow for bedside use for confirming the diagnosis of DPN. Autonomic neuropathy is a common pathology that may occur in patients with chronic diabetes types 1 and 2. This form of neuropathy may be present at any stage of the disease, but it most often affects patients who have had the disease for over 20 years.192 The parasympathetic, sympathetic, and enteric nerves are affected, and myelinated and unmyelinated nerves are affected and damaged. The condition is considered irreversible, but cardiac sympathetic dysinnervation has been shown to revert with tight glucose control.193 It affects multiple organ systems, including the cardiovascular, genitourinary, sudomotor, gastrointestinal, and endocrine

Evaluation and Treatment of Neuropathic Pain Syndromes

b

 

CHAPTER 34

492

PA RT 4 Clinical Conditions: Evaluation and Treatment

decrease available ATP.199 Although dyslipidemia may be associated with the development of DPN, initiation of statins for dyslipidemia has had mixed results. In many mouse models, statins were able to reduce neuropathic pain from oxidative, physical, and chemotherapeutic induced neuropathies.200,201 Interestingly, statins were once thought of as a medication class capable of causing neuropathy. A small study in 2002 has implicated statins in causing peripheral neuropathy. However, reanalysis of this study by the same investigators found no association between the two.202 Further well-controlled studies in humans are needed to establish statins as a preventative means of managing DPN. Regardless, exercise has benefits for lipid and glucose control that may have a role in preventing DPN.161,203

Anti-convulsants Gabapentin has been used as first line therapy for neuropathic pain and has been shown to provide mild relief of pain in patients with DPN. In a randomized, double blind, placebo controlled, eight week trial comparing gabapentin and placebo, it was concluded that daily pain in the gabapentin-treated patients decreased from 6.4 to 3.9 versus a decrease in the placebo group from 6.5 to 5.1. Patients in the gabapentin treatment group also had improved sleep.204 Another trial comparing the efficacy of gabapentin for DPN used three different forms of recording pain, including the VAS, present pain intensity, and McGill pain questionnaire (MPQ) completed before and after therapy. Only the MPQ showed statistical improvement in pain with gabapentin treatment versus placebo.205 A 2019 prospective double blind randomized controlled study evaluated the effectiveness of duloxetine and gabapentin in treating DPN over eight weeks. The study found that both medications were effective in lowering VAS scores (64–39 for gabapentin and 62–36 for duloxetine) and improved sleep in both groups. Furthermore, gabapentin was found to be more effective earlier in treatment, while duloxetine had better medication compliance because of fewer side effects.206 A clinical synopsis of updated findings from the Cochrane review found that patients on gabapentin with DPN had a higher substantial benefit (38% vs. 21%) and moderate benefit (52% vs. 37%) than placebo.207 Gabapentin has an NNT of three for overall neuropathic pain. The use of gabapentin for DPN had no effect on the quality of life, but it did yield improvements in sleep and mental health.205 A systematic review of the literature on the treatment of DPN from 1960 to 2008 recommended that pregabalin be used if medically appropriate before gabapentin. Gabapentin and valproic acid should be considered as alternative therapies for DPN.208 A randomized controlled trial comparing pregabalin with placebo in patients with DPN for one to five years showed that 46% of the patients taking a dosage of 300 mg/day, 48% taking 600 mg/ day, and 18% taking placebo had greater than a 50% reduction in pain.209 In a 12 week randomized, double blind, multicenter, placebo controlled trial using a fixed dose of 100 mg/day for one week and 600 mg/day for 11 weeks in one group and flexible doses of 150, 300, 450, and 600 mg/day in the other group concluded that both treatments were superior in reducing neuropathic pain than the group receiving placebo.210 A 2019 Cochrane review evaluated the efficacy of pregabalin in treating neuropathic pain across 22 studies found the number needed to benefit (NNTB) for 300 mg of pregabalin was 14 while the NNTB for 600 mg pregabalin was 6.1. Meanwhile, the patient global impression of change NNTB was 4.9 for 300 mg pregabalin and 3.7 for 600 mg pregabalin.211 Thus pregabalin has been shown to be effective in providing relief of neuropathic pain in patients with DPN.

Anti-depressants Multiple anti-depressant medications, including TCAs and SSNRIs, have been used for general neuropathic pain with positive results. In one study in which nortriptyline and fluphenazine were given in combination and compared with placebo, the group receiving combination therapy had 63% more patients with greater than a 50% reduction in VAS scores for pain.212 The NNT for TCAs in patients with DPN was 1.3, as recorded by five randomized trials that established its effectiveness in treating neuropathic pain in those with DPN.67 In addition, combination therapy with gabapentin has increased the effectiveness of treating PHN and DPN pain.68 In a multicenter, double blind, randomized, placebo controlled study in which patients were treated with venlafaxine, those patients taking low dose venlafaxine (75 mg) had a 32% reduction from their baseline VAS scores after six weeks, and those taking high dose venlafaxine (150–225 mg) had 50% reduction after six weeks with an NNT of 4.5.213 Duloxetine is another SSNRI that has shown promise in relieving neuropathic pain from DPN. Multiple studies have demonstrated duloxetine to be more effective than placebo.214,206,215 In a randomized, double blind, crossover clinical trial comparing duloxetine with amitriptyline after a six-week treatment concluded that both were effective in treating DPN. The duloxetine group had a 59% reduction in VAS scores with good pain relief, a 21% reduction with moderate pain relief, and a 9% reduction with mild pain relief. Duloxetine was also better tolerated than amitriptyline.216 When utilizing TCA’s and gabapentinoids for management of DPN, care should be taken when prescribing to geriatric populations as both medication classes were associated with increased risk of fall but not necessarily fracture risk.217 Opioids and Tramadol Many studies have shown that opioid medications decrease pain in patients with DPN. The fear of dependency on and addiction to these drugs warrants close observation; opioid medication should be administered only if the patient’s condition is unresponsive to non-opioid therapy (Fig. 34.1). Of these agents, tramadol, morphine sulfate, and oxycodone consistently decrease pain from DPN. An open, randomized comparative study of gabapentin versus tramadol and acetaminophen showed that the combination of tramadol and acetaminophen was just as effective in relieving DPN pain as gabapentin.218 In a randomized, double blind, placebo controlled crossover study using tramadol, the group receiving tramadol experienced relief from polyneuropathy symptoms such as pain, allodynia, and paresthesia (NNT 4.3).219 However, a 2017 Cochrane review of six randomized controlled trials of tramadol use in neuropathic pain including DPN, PHN, and CIPN showed substantial bias in the studies reviewed, implying the data behind the medication was not a reliable indication of its likely effect.220 Oxycodone has also been shown to be effective in treating neuropathic pain in patients with DPN. In a multicenter, randomized, double blind, placebo controlled study comparing controlledrelease oxycodone with placebo, it was concluded that pain scores in the groups receiving oxycodone and placebo were 4.1 and 5.3, respectively.221 This suggests that oxycodone is mildly effective in relieving neuropathic pain in patients with DPN. Another study that added oxycodone to the regimen of diabetic patients already taking gabapentin for neuropathic pain concluded that the use of the combination of these drugs relieved pain more than when gabapentin was used alone.222 A 2016 Cochrane review of

 

CHAPTER 34

Evaluation and Treatment of Neuropathic Pain Syndromes

493

Painful Diabetic Peripheral Neuropathy Gabapentin/Pregabalin

TCA

SNRIs

Poor pain control

Poor pain control

Poor pain control

TCA or SNRIs

Gabapentin/Pregabalin or SNRIs

Gabapentin/Pregabalin or TCAs

Poor pain control

Poor pain control

Poor pain control

Opioids

Opioids

Opioids

• Figure 34.1  Treatment algorithm for painful diabetic peripheral neuropathy. SNRI, Serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic anti-depressant.

oxycodone use for neuropathic pain showed low quality evidence that oxycodone may have value in treating PHN and DPN but no other neuropathic pain conditions.223 There are limited data on the use of morphine monotherapy in diabetic patients with neuropathy. A crossover study investigating morphine and gabapentin used as either monotherapy or combination therapy showed that the addition of morphine to gabapentin was more effective with lower doses of each medication.146 Furthermore, Cochrane reviews of morphine and hydromorphone utilization for treatment of chronic neuropathic pain, including DPN, showed there was insufficient evidence for the use of either medication for chronic neuropathic pain.224,225

NMDA Receptor Antagonists The NMDA receptor plays an important role in processing nociceptive and chronic pain. Thus antagonizing its actions may reduce neuropathic pain. One of the most common NMDA receptor antagonists is dextromethorphan. This drug has been examined in past studies, and it was shown to be efficacious in providing relief of pain in diabetic patients suffering from neuropathy. One study demonstrated that the pain in DPN patients had been reduced by 33% and that 68% of patients receiving dextromethorphan had more than moderate pain relief.226 A study comparing dextromethorphan with placebo showed a 27% reduction in neuropathic pain in diabetic patients, with higher efficacy achieved with increased doses.227 Also, it is worth noting that both these studies showed the efficacy of dextromethorphan for DPN but not for PHN. Despite certain studies demonstrating the efficacy of dextromethorphan in addressing DPN, other studies reported varying results because of the variability of response to a wide range of doses. Furthermore, because of the amount of metabolism that it undergoes, it was argued that it would not have sufficient bioavailability to treat DPN as a monotherapy agent.228 However, other formulations of dextromethorphan exist in conjunction with subtherapeutic (for cardiac use) dosing of quinidine to inhibit CYP 2D6 activity allows for dextromethorphan to be used as a single agent. A 13-week phase three randomized controlled trial evaluating the efficacy of dextromethorphan-quinidine (45 mg/30 mg or 30 mg/30 mg) in the treatment of DPN was successful at reducing patient reported pain and pain intensity while increasing sleep quality and activity.228

Topicals Topical anesthetics have been deemed safe to use because of their lack of drug interactions, decreased side effects, and lack of titration required. Capsaicin cream (0.075%) has been shown to decrease neuropathic pain with an NNT of 6.6.229 In addition, 5% lidocaine-medicated plaster has been demonstrated to be as effective as capsaicin, amitriptyline, gabapentin, and pregabalin, as shown in a systemic review study comparing the efficacy of each of these drugs in patients with DPN.230 Complementary and Alternative Medicine Because oxidative stress may play an important role in the pathogenic mechanisms of diabetic neuropathy, the use of antioxidants such as α-lipoic acid may have some beneficial effect in the treatment of diabetic neuropathy. A meta-analysis showed that treatment with α-lipoic acid, 600 mg intravenously for a three-week course, provided effective relief of neuropathic pain and improved neuropathic deficits.231 A more current study reported significant improvement in neuropathic pain with a 600 mg daily intravenous dose for five weeks (NTT 2.7).232 Other treatment forms have been suggested for DPN based on its pathophysiology, such as glycation inhibitors, aldose reductase inhibitors, and growth factors, but further research in these areas is necessary.233 Acupuncture has been trialed for the management of DPN. In a randomized controlled trial involving 45 patients with DPN, where patients were assigned to either real or sham acupuncture, a 15 point drop in VAS was observed in patients receiving acupuncture.234 A 2017 meta-analysis of four randomized controlled trials where acupuncture or electroacupuncture was used to treat patients with DPN showed that either form of acupuncture was successful in treating DPN. However, the majority of the studies had methodologic problems, and further well-controlled trials were needed.235

Neuromodulation Growing interest has developed in utilizing neuromodulation for the treatment of DPN. Several studies in mice have shown that SCS may alleviate or attenuate mechanical hypersensitivity in DPN models utilizing various wave forms.236–238 A case series have been published implicating a possible role for certain waveforms in the successful management of DPN.239 Traditional targets of dorsal column and DRG neuromodulation are being investigated.

494

PA RT 4 Clinical Conditions: Evaluation and Treatment

A study investigating the role of high-frequency dorsal column SCS in the management of painful DPN has recently been published on a cohort of 216 randomized patients in the SENZAPDN study for a 6 month period.240 Patients with greater than a 1 year history of PDN refractory to 2 analgesics including a gabapentinoid with a VAS for lower extremity pain of 5 or more, a BMI of 45 or less, oral morphine equivalents less than 120 mg a day, and a hemoglobbin A1c of 10 or less were eligible for enrollment in the study. These patients were trialed and, if found to have improved pain, implanted with the study device. Results of the study showed that patients treated with SCS had a statistically significant improvement of pain superior to conservative medical management (CMM) with a mean decrease in VAS of 5.9 compared to a mean decrease of 0.1 at 6 months. Further, SCS patients were noted have an improved sensory exam at 6 months compared to patients managed with CMM. Additional studies are needed to evaluate and verify the durable efficacy of this modality and other wave forms in managing DPN.

HIV-Related Pain Syndromes Epidemiology It is estimated that there are roughly 37.9 million people living with Human Immunodeficiency Virus (HIV)/acquired immunodeficiency syndrome (AIDS) worldwide as of 2018.241 With the development and widespread use of highly active antiretroviral therapy (HAART) and the resultant decrease in opportunistic infections of the central nervous system, polyneuropathy has become the most prevalent neurologic complication associated with HIV infection.242 This disease affects the patient’s immune and nervous systems. As the patient progresses through different stages of the disease, a variety of neurologic complications arise that are directly or indirectly related to HIV infection.243 Although symptomatic neuropathy occurs in 10%–35% of individuals seropositive for HIV, pathologic abnormalities exist in almost all those with end-stage AIDS.244 A systematic review in which multiple studies were compiled in the hope of determining the incidence and prevalence of neuropathy in HIV-infected patients found a high level of variation across all the studies. The prevalence of neuropathy ranged from 1.2% to 69.4%. The rate of development of neuropathy per 100 person-years in HIV patients ranged from 0.7 to 39.7, with a greater risk for neuropathy in older patients and those with more advanced disease.245 Multiple neurologic deficits occur with HIV infection, but the two most common forms of HIV-related sensory neuropathy (HIV-SN) are distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathy (ATN). DSP is because of the viral infection itself, whereas ATN is because of medical treatment of the viral disease.242 The more common of the two disorders is DSP. The most common risk factors for the development of HIV-SN before the introduction of HAART were older age and advanced disease states (such as high plasma viral load and low CD4+ cell count).246 After initiation of HAART, risk factors for the development of neuropathy became more ambiguous and included older age, CD4+ count lower than 50 cells/mm, nutritional deficit, use of dideoxynucleoside reverse transcriptase inhibitors, and exposure to protease and alcohol.247 Medications associated with causing ATN include stavudine (d4T), didanosine (ddI), and zalcitabine (ddC), collectively known as dideoxynucleoside reverse transcriptase inhibitors or “D-drugs.”242

Clinical Features Although these HIV-SN disorders may represent two distinct entities,248 the clinical syndrome and pathophysiologic manifestation of the two disorders are almost indistinguishable. In the case of ATN, the time course of the illness and the temporal relationship to commencement of antiretroviral therapy represent the primary differentiating characteristic. The onset of DSP can occur in either the subacute or chronic phase or following the development of an AIDS-defining illness. The clinical manifestations of ATN can appear within the first week to six months after the initiation of antiretroviral therapy and may subside after its cessation. The clinical features of HIV-SN are dominated by painful dysesthesia, allodynia, and hyperalgesia. Its onset is often gradual, and it most commonly begins with bilateral lower extremity involvement. The neuropathy progresses in a lengthdependent fashion with a worsening gradient of disease from distal structures to those more proximal. The dysesthesia commonly involves the soles of the feet first and progresses proximally; when the symptoms encompass the dermatomes of the knee, the patient will frequently report finger involvement. Though patients with DSP may be asymptomatic, most present with neurologic deficits. A 2014 study found that neuropathy was detected in 35% of participates 3.5 months after initial HIV transmission.249 The first symptoms noted are often numbness or burning sensations following a diurnal cycle, with the pain being worse at night. Shortly after that, patients will report allodynia (a stimulus previously not found to be noxious is perceived as painful) and hyperalgesia (a lower pain threshold) of the involved structures. Therefore wearing shoes and walking become painful, and the patient’s gait becomes antalgic. There is minimal subjective or objective motor involvement, and pain is typically limited to the intrinsic muscles of the foot. Besides the sensory findings, physical examination reveals a diminution or loss of ankle reflexes.250

Diagnostic Studies There is currently no gold standard for the diagnosis of DSP. In addition, the optimal combination of diagnostic studies has yet to be defined. The disease process remains primarily a clinical diagnosis.251 The neuropathy may be secondary to many other physiologic processes for which blood work must be obtained for exclusion, such as vitamin B12 deficiency, diabetes mellitus, hypothyroidism, IGT, and syphilis.250 In a nonrandomized, crosssectional study, HIV patients with axonal peripheral neuropathy who were taking neurotoxic nucleoside analogs had their acetylcarnitine serum levels measured. Patients suffering from neuropathy while taking nucleoside analog medications had a deficiency in acetylcarnitine and were nutritionally deficient.252 Although the level of acetylcarnitine may be used for the diagnosis of ATN, more studies are necessary. Nerve conduction studies are not necessary for the diagnosis of DSP and will show an axonal, length-dependent, sensory polyneuropathy. Needle electromyograms are of no significant benefit because the findings are usually normal, but they may show chronic denervation and reinnervation.253 Punch skin biopsy specimens from the distal end of the calf and proximal part of the thigh may be used to detect small fiber neuropathy by measuring intraepidermal nerve fiber density.248 The lower the intraepidermal density, the greater the likelihood of DSP symptoms developing

 

CHAPTER 34

and the greater the neuropathic pain level. Epidermal nerve fiber density may be used as a quantitative marker in clinical trials of neurodegenerative agents and predict the likelihood of symptoms developing in an asymptomatic patient.254 DRG neuronal loss has been reported, although the reduction is more modest than distal axon loss.255

Pathophysiology DSP and ATN are clinically similar but have distinct pathophysiology. The exact mechanism of the disease process is not fully understood, but it is hypothesized that there are multiple mechanisms at work that eventually cause axonal injury. The peripheral and central nerve toxicity related to HIV infection may be because of cytokine-mediated effects because HIV does not infect axons or Schwann cells. The gp120 protein is an HIVassociated protein thought to play a key role in pathogenesis through the ligation of chemokine receptors located on glial cells and neurons.256 It may also play a role on chemokine receptors related to Schwann cell-to-neuron interaction.257 Damage to axons occurs secondary to the inflammatory reaction in the nerve and surrounding tissues, which eventually leads to the characteristic pain seen in DSP. This hypothesis has been supported by animal studies in which gp120 was found to produce pain in rats when administered epineurally into the sciatic nerve258 and intradermally into the paw.259 The indirect causes of DSP pain are thought to be mediated by inflammatory injury. They can be divided into peripheral and central mechanisms. The peripheral hypothesis proposes that the pain results from the spontaneous activity of uninjured pain-transmitting or C fibers after injury to adjacent fibers. Inflammatory mediators released by macrophages may further sensitize these fibers. The central hypothesis involves an alteration in ion channels in the DRG combined with changes in the spinal cord dorsal horn that result in “central sensitization.”260 ATN primarily occurs because of the use of nucleoside reverse transcriptase inhibitors and typically ensues within a year of beginning treatment or in patients with preexisting peripheral neuropathy.261 The mechanism for ATN is currently unknown, but mitochondrial dysfunction as a result of abnormal mitochondria in Schwann cells and axons has been shown to play a role.262 Data have also shown that the depletion of mitochondrial Deoxyribonucleic Acid (DNA) seen in AIDS patients treated with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) leads to increased serum lactate levels and increased cell death.263 In recent years, some of the protease inhibitor medications, more specifically, indinavir, ritonavir, and saquinavir, have led to an increased risk for mitochondrial toxicity that is partly because of their enhanced ability to penetrate within the neural compartments.264

Treatment No medication is currently approved by the Food and Drug Administration for the treatment of HIV-SN. Most of the therapeutic modalities available have been tested and approved for other neuropathic pain (PHN and DPN). The therapeutic approach for HIV-SN first involves removing or reducing the dosage of the antiretroviral medication whenever possible.265 Also, the patient’s metabolic and nutritional status must be optimized to exclude alternative explanations for the neurologic symptoms

Evaluation and Treatment of Neuropathic Pain Syndromes

495

(see “Diagnostic Studies”) before initiating any other forms of therapy. Greater placebo response was attributed to the difficulty in evaluating analgesic efficacy in treating patients with HIV-SN. However, a systematic meta-analysis comparing placebo responses between HIV-SN and DPN found no statistical difference.265,266 Many different medications have been studied for the treatment of this form of neuropathic pain with no great success. Intranasal peptide T did not show any effectiveness in a randomized, double blind multicenter study in which patients with HIV-SN received either placebo or 6 mg/day of peptide T.267 One medication that has been proved to be effective in relieving pain is recombinant human nerve growth factor, but it does not provide any evidence of neuroregeneration.268 Acetyl-l-carnitine (ALCAR) increases neurotrophic support of sensory neurons, as demonstrated in a double blind, parallelgroup, placebo controlled, multicenter study. The groups were divided into those receiving placebo and those receiving ALCAR intramuscularly for 14 days, followed by ALCAR orally for 42 days. The group receiving ALCAR had significant improvement in pain.269 Erythropoietin, a hematopoietic growth factor, was shown to prevent axonal degeneration in cells that had been exposed to HIV gp120 protein, but further studies are needed.270 Amitriptyline and mexiletine have proved effective in relieving neuropathic pain in patients with DPN and PHN. Unfortunately, they did not prove to be more beneficial for HIV-SN than placebo in a randomized, double blind study.271 Other medications such as duloxetine and venlafaxine, both SSNRIs, have been approved for the treatment of DPN, but further research is required to demonstrate their efficacy in relieving pain in patients with HIV-SN. Acetaminophen and nonsteroidal anti-inflammatory drugs have limited efficacy in the management of DSP. In cases of severe/ refractory cases, opioids may be considered as an additive agent.250 Gabapentin has been shown to be effective in treating all types of neuropathy, including HIV-SN pain. In a placebo controlled trial in which patients were treated with gabapentin (1200 to 3600 mg/day) or placebo for four weeks and then an open trial for two weeks, the group receiving gabapentin experienced improvement in pain by 44% and improvement in sleep by 49% when compared with the placebo group, with the most statistically significant side effect being somnolence.272 Pregabalin is also very effective in relieving neuropathic pain. A recent randomized, double blind, placebo controlled, 14-week parallel-group trial testing the efficacy of pregabalin showed that there was no benefit in taking pregabalin over placebo.273 Lamotrigine, 300 mg/day, was found to significantly reduce pain in patients with DSP and ATN in a randomized controlled trial.274 Topical medication has also been studied for HIV-SN, including 5% lidocaine and high dose capsaicin cream. In a randomized controlled trial, 5% lidocaine cream was shown to be ineffective in treating HIV-SN pain.275 A double blind, multicenter, randomized trial using high dose capsaicin cream demonstrated pain relief in patients with HIV-SN.276 Cannabis may have a role in treating HIV-SN. A randomized placebo controlled trial evaluated the use of cannabis (3.56% tetrahydrocannabinol [THC]) to placebo cigarettes in 50 patients with HIV-SN. Patients using cannabis reported a 34% reduction in daily pain than placebo (17%). A phase II, double blind placebo controlled crossover study of 28 patients with HIV-SN who failed two prior analgesic agents was performed comparing 1%-8% THC use to placebo in the management of their HIVSN. Forty-six percent of patients who used cannabis reported >30% pain relief than the placebo group (18%). However, the

496

PA RT 4 Clinical Conditions: Evaluation and Treatment

duration of treatment and primary end point of both studies was only five days.277,278 Further studies are needed to verify long term outcomes.

Chemotherapy Induced Peripheral Neuropathy In 2018 the World Health Organization attributed one in six deaths to cancer. The incidence of cancer in 2018 was estimated to be 18.1 million new cases with a cumulative lifetime risk of one in eight for men and one in ten for women.279 Chemotherapy and surgery are the mainstays for the management of cancer. As cancer treatment algorithms evolve with increased efficacy, the number of cancer survivors are increasing. The fiveyear survival rate of cancer has increased dramatically since the 1960s from 39% to 70% among white and 27% to 63% among black patients.280 Chemotherapy induced peripheral neuropathy (CIPN) is a neuropathic pain condition that results from chemotherapy exposure. Many cancer patients develop CIPN that continues long after their disease is in remission, and CIPN is developing into one of the most burdensome long term side effects from cancer.281

Epidemiology Early studies have reported that CIPN occurred in roughly 90% of all patients who received neurotoxic chemotherapy.282 Subsequent studies have found that CIPN more accurately had a prevalence of 68.1% within the first month of chemotherapy, 60.0% at three months, and 30.0% at six months or more.283 Overall, it seems that the prevalence was found to be between 36% and 58% in patients actively on cancer treatment and patients 12 years after treatment.284–286 CIPN presents a unique scenario as dose reductions of chemotherapy may help address the pain and concurrently increase the risk of morbidity and mortality from undertreatment of cancer. With increased survivorship from cancer diagnosis, CIPN has long-lasting consequences as it often continues beyond the period of treatment and once the cancer is in remission. Agents that may cause CIPN include platinum containing compounds (cisplatin, carboplatin, oxaliplatin), taxanes (paclitaxel and docetaxel), vinca alkaloids (vincristine and vinblastine), proteasome inhibitors (bortezomib), epothilones (ixabepilone), immune checkpoint inhibitors, antibody drug conjugates, and other chemotherapeutics (eribulin, thalidomide, lenalidomide).287 The main risk factors for CIPN include cancer type (because of the chemotherapeutics required to treat specific cancers) and the cumulative dose of the chemotherapeutic agent. Solid tumors (colorectal, breast, gynecologic, testicular, lung) and hematologic cancers are the most common cancers requiring neurotoxic chemotherapy.287 Other risk factors include baseline neuropathy, age, concurrent chemotherapy treatment, smoking, early cancer diagnosis, and cancer treatment protocols utilizing drugs that can cause CIPN.287,288 Genetic markers have been implicated to be associated with CIPN. A Genome Wide Association Study (GWAS) on patients with multiple myeloma found 13 single nucleotide peptide polymorphisms associated with CIPN development.289 A similar approach was performed in breast cancer patients with CIPN from taxane exposure where the GWAS revealed an association with an allele gene variant that may decrease the risk of developing CIPN when exposed to taxane.290 However, current efforts have

been unsuccessful in identifying genes that serve to reliably predict susceptibility to this condition.291

Clinical Features Similar to DPN, CIPN manifests in a glove and stocking distribution with a proximal spread in more severe cases. Though largely a sensory neuropathy, patients may develop autonomic dysfunction, fine motor dysfunction, and decreased proprioception.292 Patients can report either negative (impaired touch, pinprick vibration perception, imbalance) or positive (paresthesia, dysesthesia, neuropathic pain) symptoms in a distal to proximal fashion. Unique to exposure to platinum containing compounds, patients may report worsening symptoms months after cessation of chemotherapy, presenting the “coasting” phenomenon.281 Aside from pain and sensory loss, CIPN also negatively impacts the functionality and quality of life of afflicted patients. In a comparative cross-sectional descriptive study comparing cancer patients with all cause neuropathic pain to those without neuropathic pain on hospice found that 40% of all patients had neuropathic symptoms, of which 76.7% reported pain.286 These patients are noted to be at high risk for falls, and the majority have decreased sleep quality.293 In a prospective study evaluating SPADE symptoms in a cohort of 65 cancer patients with CIPN, 69.5% of patients reported sleep impairment.294

Diagnostic Studies The diagnosis of CIPN is largely a clinical diagnosis. Care to obtain a detailed history and physical focusing on the natural history of other causes for neuropathy, including alcohol use, diabetes, nutritional deficiencies, and other exposures, should be exercised to rule out other causes of peripheral neuropathy. Although no gold standard exists for diagnosing CIPN, clinical tools including MPQ, brief pain inventory, Leeds assessment of neuropathic symptoms and signs, and Douleur neuropathique 4 may be helpful to characterize and trend the patient’s pain. Specific tools for assessment of CIPN exist, including the Ajani scale, the functional assessment of cancer therapy-taxane, CIPN20, and the NCI common toxicity criteria, but may not truly reflect the incidence of neuropathy and suffer from inter-observer variations.288,292

Pathophysiology Several theories regard the mechanism by which CIPN develops, as varying classifications of chemotherapeutics have different mechanisms of action and end targets. Overall, these theories fall within three main categories, including mitochondrial dysfunction with oxidative stress, neuroinflammation, and ion channel dysfunction although each associated chemotherapeutic has a target that is most likely affected.288 Many chemotherapeutics target nuclear DNA. However, mitochondrial DNA may be affected as well. Unlike nuclear DNA, mitochondrial DNA does not have a robust repair mechanism, and damage may result in mitochondrial dysfunction. Studies in rats exposed to paclitaxel producing painful peripheral neuropathy revealed intact myelin and DRG structure but swollen, atypical mitochondria in myelinated and unmyelinated neurons that correlated with the pain behavior displayed by the rats.295 Another rat study with cisplatin induced peripheral neuropathy showed that DRG cell cultures from affected rats displayed dysfunctional mitochondrial transport that was reversible over time.296 Among

 

CHAPTER 34

the many roles of mitochondria, regulation of reactive oxygen species (ROS) plays a particularly important role, especially in light of chemotherapeutics, which inherently increases the amount of ROS. In a study of breast cancer patients, blood was evaluated in those with and without CIPN (from paclitaxel), which showed mitochondrial dysfunction pathways including those related to oxidative stress in patients with CIPN but not those without.297 Neuroinflammation plays a role in the development of chronic pain states. Certain cell types, including glial cells, are activated and play a role in inflammation and injury in chronic pain. In recent studies, the focus has shifted to astrocyte activation from chemotherapeutics as playing a role in maintaining the chronic pain state from CIPN. In rat models with oxaliplatin and bortezomib induced peripheral neuropathy, astrocyte but not microglial activation correlated to chemotherapeutic treatment.298 These astrocytes contain adenosine kinase, which removes extracellular adenosine, a neuroprotective agent released to counter neuropathologic changes. A study in rodents with overexpression of adenosine kinase resulted in pro-inflammatory IL1ß expression indicating a possible mechanism by which dysfunctional astrocytes may result in CIPN.299 Chemotherapies have also been associated with increased pro-inflammatory chemokine release, including TNF-α, bradykinin, and nerve growth factors, while downregulating anti-inflammatory chemokines.300 Further studies are needed to elucidate the cellular mechanisms by which CIPN occurs. It has been noted that certain chemotherapeutics (namely taxanes, platinum containing compounds, and vinca alkaloids) may modulate primary afferent neuron ion channel expression.301 Channels reportedly affected include sodium channels, potassium channels, and to some extent, calcium channels. Sodium channel and potassium channel dysfunction have been found in acute oxaliplatin toxicity resulting in cold hypersensitivity by causing delayed sodium channel inactivation and decreased potassium receptor expression, respectively.302,303 Studies in rats exposed to paclitaxel have shown an increase in calcium channel currents in the DRG by increased channel expression.304 Despite these findings, targeting specific ion channels has had mixed results.

Treatment Prevention and Physical Therapy There is great emphasis on prevention in the management of CIPN, as many neuropathic treatments are ineffective for this condition. A 2014 review of 48 randomized clinical trials by the American Society of Clinical Oncology to provide guidance for the prevention of CIPN revealed that no agent is recommended given the lack of high quality evidence.305 Similarly, a 2014 Cochrane review for agents to prevent CIPN from platinum containing chemotherapeutics concluded that there was insufficient evidence to recommend chemoprotective agents.306 As such, a careful balance between chemotherapeutic dose reduction to achieve efficacious cancer treatment while minimizing the risk or severity of CIPN development needs to be weighed by oncologists. Aside from neuropathic pain and numbness, patients consequently have difficulties with gait, balance, and falls. Although physical therapy has not been successful in reducing pain, work with physical therapists has been effective in addressing functional deficits as a result of CIPN. In a prospective study, 29 cancer survivors with CIPN underwent an eight-week exercise interven-

Evaluation and Treatment of Neuropathic Pain Syndromes

497

tion under the guidance of physical therapists. There was a statistically significant improvement in objective and patient reported measures of dynamic balance, standing balance, mobility, and quality of life compared to pre-exercise intervention.307

Anti-convulsants Gabapentin and pregabalin are effective in managing many neuropathic pain conditions. However, their use has not been as effective in managing patients with CIPN. In a study evaluating 61 ovarian cancer patients who developed CIPN, eligible patients were trialed on gabapentin with observed improvement in pain and neurologic deficits, but no improvement in quality of life was observed.308 Gabapentin was further evaluated in a randomized, double blind placebo controlled crossover controlled trial of 115 patients with CIPN that revealed statistically similarly symptom severity despite the use of gabapentin.309 Comparatively, pregabalin may be more effective than gabapentin for symptom improvement. In a study of 120 cancer patients with CIPN, patients were trialed on either amitriptyline, gabapentin, pregabalin, or placebo with oral morphine for breakthrough pain for four weeks.310 At the end of the trial, there was a statistically significant difference in morphine sparing pain score improvement in the pregabalin group than gabapentin and amitriptyline. One study evaluated the concurrent use of oxycodone/ naloxone with either gabapentin or pregabalin in 72 patients with CIPN who had previously had inadequate symptom control alone with gabapentinoids. Over the course of four weeks, patients reported an NRS reduction of 1.29.311

Anti-depressants Of the various classes of anti-depressants, the class of norepinephrine and serotonin reuptake inhibitors have shown the most promise in treating CIPN. In particular, duloxetine has been shown to be most effective in treating CIPN. A multicenter, randomized, double blinded, placebo controlled, crossover study of 231 patients with CIPN evaluated the efficacy of 60 mg daily duloxetine in pain management. The observed mean difference in pain score between duloxetine and placebo was 0.73, with 59% of patients on duloxetine reporting decreased pain than 38% of placebo.312 Compared to venlafaxine in a randomized controlled trial with placebo, duloxetine was found to significantly reduce neuropathic pain grade by week two than venlafaxine or placebo. Reduction in cranial, motor, and sensory neuropathy was also found to be greater in patients treated with duloxetine than venlafaxine or placebo.313

Topicals Useful adjuncts in treating other forms of neuropathic pain, there may be a role of topical anesthetics in this patient population. Like other neuropathic pain types, lidocaine patches have had anecdotal success, but evidence from studies to support their use is lacking.314 Topical 1% menthol cream was utilized for the treatment of cancer associated neuropathic pain in a proof of concept study where 51 patients (35/51 with CIPN) were followed for four to six weeks. At the study conclusion, 82% of all patients reported an improvement in their Brief Pain Inventory (BPI) score, mood, catastrophizing, walking ability, and sensation.315 Capsaicin (8%) has also been reported to provide pain relief and sensory improvement in patients with CIPN.316 Other studies utilizing multi-component creams including baclofen, amitriptyline, and ketamine in pluronic lecithin organogel (BAK-PLO) were tried on patients with CIPN in a double blinded placebo controlled trial over four

498

PA RT 4 Clinical Conditions: Evaluation and Treatment

weeks. Patients utilizing BAK-PLO experienced greater sensory and motor improvement than placebo.317 However, further larger studies are needed to fully evaluate traditional and nontraditional topical analgesics for CIPN treatment.

Cannabinoids Cannabinoids have been found to provide beneficial treatment for several other neuropathic pain conditions, but their use may be limited by the effects on the CNS.318 Activation of the cannabinoid receptors (CB1 and CB2) have been found to have beneficial effects on CIPN in animals studies. A peripherally acting CB1 agonist (PrNMI) was found to successfully suppress allodynic effects in cisplatin induced CIPN rat models.319 In a study in rats, a CB2 agonist was successful in suppressing mechani-

cal and cold allodynia in cisplatin and paclitaxel induced CIPN models.320 Further animal studies have shown that CB2 specific agonist MDA7 attenuated the behavior and molecular changes in rats associated with microglial dysregulation and CIPN. Despite these successes in animal models, large well-controlled studies are needed to verify use in humans for the management of CIPN.

Neuromodulation Much of the literature on CIPN treatment with neuromodulation is limited to case reports of DRG or dorsal column stimulation.321,322 There may be a role for neuromodulation in the treatment of CIPN, but randomized controlled trials are needed to fully assess their efficacy and role in this disease.

Summary Despite the diversity of conditions and pathophysiology characterized by neuropathic pain, many of the underlying treatment options are comparable but not identical. Traditional systemic analgesic agents, such as anti-depressants, anti-convulsants, local anesthetics, and opioids, are typically the mainstay of treatment of neuropathic

pain, although the efficacy of individual classes of agents varies with the specific type of neuropathic pain. Few high quality trials are available as interventional options for the treatment of neuropathic pain. Clinicians should be aware of the paucity and support the use of traditional interventional options in some cases.

Key Points • The most commonly used clinical diagnostic criteria for CRPS types one and two have low specificity and high sensitivity, leading to overdiagnosis of this pain syndrome. • In 2007, research criteria (also known as the Budapest criteria) were published that included objective signs of pathology characteristic of patients with CRPS6 (see Box 34.2). • Psychological factors such as depression, personality disorders, and anxiety have no correlation with CRPS patients, suggesting no specific type of CRPS personality. • A double blind, randomized, placebo controlled, parallel-group trial studying the effects of subanesthetic intravenous dosing for four days in patients with CRPS showed decreased levels of pain but a progressive increase in pain from the first week after infusion to the 12th week. Minor and rare side effects such as nausea, vomiting, and psychomimetic effects developed in patients treated with ketamine infusion. • In a randomized trial, patients with CRPS were separated into two groups: SCS with physical therapy and physical therapy only. This study showed that SCS provided significant improvement in pain for the first two years. • The acute phase of herpes zoster is characterized by a maculopapular vesicular rash that crusts over after one to two weeks and leads to a burning sensation, hyperesthesia, itching, and severe pain. Prodromal symptoms that may occur one to five days before the rash include headache, fever, malaise, abnormal skin sensation, and photophobia. PHN may occur two weeks

Suggested Readings Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA. 1998;280:1831–1836. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: A randomized, double-blind, placebo-controlled trial. Pain. 2003;104:323–331.

•

•

•

• •

after the presence of herpes zoster and is the chronic form of the disease. Medications such as gabapentin, pregabalin, tramadol, and topical lidocaine are considered first line treatments because they have been shown to be most well tolerated by the (commonly elderly) patient population. Other medications shown to help in relieving the pain associated with PHN are tricyclic and serotonin-norepinephrine reuptake inhibitor anti-depressants, opioids, and topical capsaicin cream (see Table 34.2). The initial symptoms in up to 50% of patients with painful DPN are highly nociceptive and include burning pain, electric or stabbing sensations, paresthesia, hyperesthesia, and deep aching pain, which are typically worse at night. Upper extremity involvement is rare.187 The rate of development of neuropathy per 100 person-years in patients infected with HIV ranged from 0.7 to 39.7, with a greater risk for neuropathy in older patients and those with more advanced disease.245 Lamotrigine, gabapentin, and topical capsaicin are effective in the treatment of HIV-associated neuropathic pain, but amitriptyline, topical lidocaine, and pregabalin are ineffective. The current evidence for the management of CIPN is lacking. Emphasis should be placed on prevention by balancing the duration and dose of the chemotherapeutic. In situations where a patient has developed CIPN, pregabalin and duloxetine have shown the most promise for managing neuropathic symptoms.

Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiol. 2010;113:713–725. Cherry CL, Wadley AL, Kamerman PR. Diagnosing and treating HIVassociated sensory neuropathy: A global perspective. Pain Manag. 2016;6(2):191–199. Deer TR, Pope JE, Lamer TJ, et al. The neuromodulation appropriateness consensus committee on best practices for dorsal root ganglion stimulation. Neuromodulation. 2019;22(1):1–35.

 

CHAPTER 34

Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis. 2017;44(Suppl 1): S1-S26. Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–1334. Gilron I, Bailey JM, Tu D, et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial. Lancet. 2009;374:1252–1261. Harden RN, Bruehl S, Perez RS, et al. Validation of proposed diagnostic criteria (the “Budapest criteria”) for complex regional pain syndrome. Pain. 2010;150:268–274. Kemler MA, Barendse GA, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med. 2000;343:618–624. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS clinical trial group 242 protocol team. Neurol. 1998;51: 1682–1688. Majdinasab N, Kaveyani H, Azizi M. A comparative double-blind randomized study on the effectiveness of duloxetine and gabapentin on painful diabetic peripheral polyneuropathy. Drug Des Devel Ther. 2019;13:1985–1992. Moseley GL, Wiech K. The effect of tactile discrimination training is enhanced when patients watch the reflected image of their unaffected limb during training. Pain. 2009;144:314–319.

Evaluation and Treatment of Neuropathic Pain Syndromes

499

Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer. 2007;110(9):2110–2118 Smith EM, Pang H, Cirrincione C, et al. (2013). Effect of duloxetine on pain, function, and quality of life among patients with chemotherapyinduced painful peripheral neuropathy: A randomized clinical trial. JAMA. 2013;309(13):1359–1367 Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurol. 2008;70:1630–1635. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: Effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative famciclovir herpes zoster study group. Ann Intern Med. 1995;123:89–96. van Rijn M, Munts AG, Marinus J, et al. Intrathecal baclofen for dystonia of complex regional pain syndrome. Pain. 2009;143: 41–47. The references for this chapter can be found at ExpertConsult.com.

References 1. Treede RD, Jensen TS, Campbell JN, et  al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurol. 2008;70(18):1630–1635. 2. Iolascon G, de Sire A, Moretti A, et al. Complex regional pain syndrome (CRPS) type I: Historical perspective and critical issues. Clin Cases Miner Bone Metab. 2015;12(Suppl 1):4–10. 3. Coderre TJ. Complex regional pain syndrome: What’s in a name? J Pain. 2011;12(1):2–12. 4. Merskey H, Bogduk N. Part III: Pain Terms, A Current List with Definitions and Notes on Usage for the IASP Task Force on Taxonomy. Seattle: IASP Press; 1994. 5. Harden RN, Bruehl S, Galer BS, et al. Complex regional pain syndrome: Are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain. 1999;83(2):211–219. 6. Harden RN, Bruehl S, Stanton-Hicks M, et  al. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8(4):326–331. 7. Albrecht PJ, Hines S, Eisenberg E, et  al. Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain. 2006;120(3):244–266. 8. Moisset X, Bouhassira D. Brain imaging of neuropathic pain. Neuroimage. 2007;37(Suppl 1):S80–S88. 9. Maihofner C, Neundorfer B, Birklein F, et  al. Mislocalization of tactile stimulation in patients with complex regional pain syndrome. J Neurol. 2006;253(6):772–779. 10. Maihofner C, Handwerker HO, Neundorfer B, et al. Cortical reorganization during recovery from complex regional pain syndrome. Neurol. 2004;63(4):693–701. 11. Azqueta-Gavaldon M, Youssef AM, Storz C, et al. Implications of the putamen in pain and motor deficits in complex regional pain syndrome. Pain. 2020;161(3):595–608. 12. Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiol. 2010;113(3):713–725. 13. Del Valle L, Schwartzman RJ, Alexander G. Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav Immun. 2009;23(1):85–91. 14. Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res. 2008;33(10):1970–1978. 15. Helyes Z, Tekus V, Szentes N, et  al. Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms. Proc Natl Acad Sci U S A. 2019;116(26):13067–13076. 16. de Mos M, Laferriere A, Millecamps M, et al. Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPSI). J Pain. 2009;10(11):1161–1169. 17. Tajerian M, Clark JD. New concepts in complex regional pain syndrome. Hand Clin. 2016;32(1):41–49. 18. Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ, et al. Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1. Mediators Inflamm. 2006(1):28398. 19. Huygen FJ, De Bruijn AG, De Bruin MT, et al. Evidence for local inflammation in complex regional pain syndrome type 1. Mediators Inflamm. 2002;11(1):47–51. 20. Pepper A, Li W, Kingery WS, et al. Changes resembling complex regional pain syndrome following surgery and immobilization. J Pain. 2013;14(5):516–524. 21. Russo M, Georgius P, Santarelli DM. A new hypothesis for the pathophysiology of complex regional pain syndrome. Med Hypotheses. 2018;119:41–53. 22. Russo MA, Fiore NT, van Vreden C, et al. Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome. J Neuroinflammation. 2019;16(1):63. 23. Xanthos DN, Bennett GJ, Coderre TJ. Norepinephrine-induced nociception and vasoconstrictor hypersensitivity in rats with chronic post-ischemia pain. Pain. 2008;137(3):640–651.

24. Schlereth T, Drummond PD, Birklein F. Inflammation in CRPS: Role of the sympathetic supply. Auton Neurosci. 2014;182:102–107. 25. Schattschneider J, Binder A, Siebrecht D, et al. Complex regional pain syndromes: The influence of cutaneous and deep somatic sympathetic innervation on pain. Clin J Pain. 2006;22(3):240–244. 26. Maihofner C, Seifert F, Markovic K. Complex regional pain syndromes: New pathophysiological concepts and therapies. Eur J Neurol. 2010;17(5):649–660. 27. Schwartzman RJ, Erwin KL, Alexander GM. The natural history of complex regional pain syndrome. Clin J Pain. 2009;25(4):273–280. 28. Moseley GL, Herbert RD, Parsons T, et al. Intense pain soon after wrist fracture strongly predicts who will develop complex regional pain syndrome: Prospective cohort study. J Pain. 2014;15(1):16–23. 29. Stanton-Hicks MD. CRPS: What’s in a name? Taxonomy, epidemiology, neurologic, immune and autoimmune considerations. Reg Anesth Pain Med. 2019;44(3):376–387. 30. Demir SE, Ozaras N, Karamehmetoglu SS, et  al. Risk factors for complex regional pain syndrome in patients with traumatic extremity injury. Ulus Travma Acil Cerrahi Derg. 2010;16(2):144–148. 31. Duman I, Dincer U, Taskaynatan MA, et al. Reflex sympathetic dystrophy: A retrospective epidemiological study of 168 patients. Clin Rheumatol. 2007;26(9):1433–1437. 32. Shirani P, Jawaid A, Moretti P, et al. Familial occurrence of complex regional pain syndrome. Can J Neurol Sci. 2010;37(3):389–394. 33. de Rooij AM, de Mos M, van Hilten JJ, et  al. Increased risk of complex regional pain syndrome in siblings of patients? J Pain. 2009;10(12):1250–1255. 34. Lesky J. Sudeck syndrome (CRPS) caused by unique personality traits: Myth and fiction. Z Orthop Unfall. 2010;148(6):716–722. 35. Harden RN, Bruehl S, Perez RS, et al. Validation of proposed diagnostic criteria (the “Budapest criteria”) for complex regional pain syndrome. Pain. 2010;150(2):268–274. 36. Baron R, Janig W. Complex regional pain syndromes- how do we escape the diagnostic trap? Lancet. 2004;364(9447):1739–1741. 37. Misidou C, Papagoras C. Complex regional pain syndrome: An update. Mediterr J Rheumatol. 2019;30(1):16–25. 38. Alam OH, Zaidi B, Pierce J, et al. Phenotypic features of patients with complex regional pain syndrome compared with those with neuropathic pain. Reg Anesth Pain Med. 2019;44(9):881–885. 39. Harden RN, Maihofner C, Abousaad E, et al. A prospective, multisite, international validation of the complex regional pain syndrome severity score. Pain. 2017;158(8):1430–1436. 40. Oaklander AL, Horowitz SH. The complex regional pain syndrome. Handb Clin Neurol. 2015;131:481–503. 41. Goebel A, Barker C, Birklein F, et al. Standards for the diagnosis and management of complex regional pain syndrome: Results of a European Pain Federation task force. Eur J Pain. 2019;23(4):641–651. 42. Harden RN, Bruehl SP. Diagnosis of complex regional pain syndrome: Signs, symptoms, and new empirically derived diagnostic criteria. Clin J Pain. 2006;22(5):415–419. 43. Roldan CJ, Abdi S. Quantitative sensory testing in pain management. Pain Manag. 2015;5(6):483–491. 44. Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values. Pain. 2006;123(3):231–243. 45. Palmer S, Bailey J, Brown C, et al. Sensory function and pain experience in arthritis, complex regional pain syndrome, fibromyalgia syndrome, and pain-free volunteers: A cross-sectional study. Clin J Pain. 2019;35(11):894–900. 46. Meyer-Friessem CH, Attal N, Baron R, et al. Pain thresholds and intensities of CRPS type I and neuropathic pain in respect to sex. Eur J Pain. 2020. 47. Longmire DR. An electrophysiological approach to the evaluation of regional sympathetic dysfunction: A proposed classification. Pain Physician. 2006;9(1):69–82. 48. Krumova EK, Frettloh J, Klauenberg S, et al. Long-term skin temperature measurements – a practical diagnostic tool in complex regional pain syndrome. Pain. 2008;140(1):8–22. 499.e1

499.e2

References

49. Lee HJ, Kim SE, Moon JY, et al. Analysis of quantitative sudomotor axon reflex test patterns in patients with complex regional pain syndrome diagnosed using the Budapest criteria. Reg Anesth Pain Med. 2019;44(11):1026–1032. 50. Wuppenhorst N, Maier C, Frettloh J, et al. Sensitivity and specificity of 3-phase bone scintigraphy in the diagnosis of complex regional pain syndrome of the upper extremity. Clin J Pain. 2010;26(3):182– 189. 51. Howard BA, Roy L, Kaye AD, et al. Utility of radionuclide bone scintigraphy in complex regional pain syndrome. Curr Pain Headache Rep. 2018;22(1):7. 52. Sorel M, Beatrix JC, Locko B, et al. Three-phase bone scintigraphy can predict the analgesic efficacy of ketamine therapy in CRPS. Clin J Pain. 2018;34(9):831–837. 53. Graif M, Schweitzer ME, Marks B, et al. Synovial effusion in reflex sympathetic dystrophy: An additional sign for diagnosis and staging. Skeletal Radiol. 1998;27(5):262–265. 54. Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: Report of an expert panel. Pain Pract. 2002;2(1):1–16. 55. Elomaa M, Hotta J, de CWAC, et  al. Symptom reduction and improved function in chronic CRPS type 1 after 12-week integrated, interdisciplinary therapy. Scand J Pain. 2019;19(2):257–270. 56. Moseley GL, Wiech K. The effect of tactile discrimination training is enhanced when patients watch the reflected image of their unaffected limb during training. Pain. 2009;144(3):314–319. 57. Sayegh SA, Filen T, Johansson M, et al. Mirror therapy for complex regional pain syndrome (CRPS)- a literature review and an illustrative case report. Scand J Pain. 2013;4(4):200–207. 58. Smart KM, Wand BM, NE O’Connell. Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II. Cochrane Database Syst Rev. 2016;2:CD010853. 59. Pons T, Shipton EA, Williman J, et al. A proposed clinical conceptual model for the physiotherapy management of complex regional pain syndrome (CRPS). Musculoskelet Sci Pract. 2018;38:15–22. 60. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;4:CD007938. 61. Moisset X, Bouhassira D, Avez Couturier J, et  al. Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev Neurol (Paris). 2020;176(5):325–352. 62. van de Vusse AC, Stomp-van den Berg SG, Kessels AH, et al. Randomised controlled trial of gabapentin in complex regional pain syndrome type 1 [ISRCTN84121379]. BMC Neurol. 2004;4:13. 63. Saltik S, Sozen HG, Basgul S, et al. Pregabalin treatment of a patient with complex regional pain syndrome. Pediatr Neurol. 2016;54: 88–90. 64. Kalita J, Vajpayee A, Misra UK. Comparison of prednisolone with piroxicam in complex regional pain syndrome following stroke: A randomized controlled trial. QJM. 2006;99(2):89–95. 65. Kalita J, Misra U, Kumar A, et al. Long-term prednisolone in poststroke complex regional pain syndrome. Pain Physician. 2016;19(8): 565–574. 66. Kumowski N, Hegelmaier T, Kolbenschlag J, et al. Short-term glucocorticoid treatment normalizes the microcirculatory response to remote ischemic conditioning in early complex regional pain syndrome. Pain Pract. 2019;19(2):168–175. 67. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;4:CD005454. 68. Gilron I, Bailey JM, Tu D, et  al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial. Lancet. 2009;374(9697): 1252–1261. 69. Brown S, Johnston B, Amaria K, et  al. A randomized controlled trial of amitriptyline versus gabapentin for complex regional pain syndrome type I and neuropathic pain in children. Scand J Pain. 2016;13:156–163.

70. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release oxycodone relieves neuropathic pain: A randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105(1-2):71–78. 71. Harke H, Gretenkort P, Ladleif HU, et al. The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: A double-blinded randomized study. Anesth Analg. 2001;92(2):488–495. 72. Derry S, Stannard C, Cole P, et al. Fentanyl for neuropathic pain in adults. Cochrane Database Syst Rev. 2016;10:CD011605. 73. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study. J Pain. 2006;7(1):43–48. 74. Yi P, Pryzbylkowski P. Opioid induced hyperalgesia. Pain Med. 2015;16(Suppl 1):S32–S36. 75. Pribish A, Wood N, Kalava A. A review of nonanesthetic uses of ketamine. Anesthesiol Res Pract. 2020:5798285. 76. Sigtermans MJ, van Hilten JJ, Bauer MC, et al. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. Pain. 2009;145(3):304–311. 77. Kiefer RT, Rohr P, Ploppa A, et al. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: An open-label phase II study. Pain Med. 2008;9(8):1173–1201. 78. Zhao J, Wang Y, Wang D. The effect of ketamine infusion in the treatment of complex regional pain syndrome: A systemic review and meta-analysis. Curr Pain Headache Rep. 2018;22(2):12. 79. Finch PM, Knudsen L, Drummond PD. Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine. Pain. 2009;146(1-2):18–25. 80. Manicourt DH, Brasseur JP, Boutsen Y, et al. Role of alendronate in therapy for posttraumatic complex regional pain syndrome type I of the lower extremity. Arthritis Rheum. 2004;50(11):3690–3697. 81. O’Connell NE, Wand BM, McAuley J, et al. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev. 2013(4):CD009416. 82. Nicol AL, Hurley RW, Benzon HT. Alternatives to opioids in the pharmacologic management of chronic pain syndromes: A narrative review of randomized, controlled, and blinded clinical trials. Anesth Analg. 2017;125(5):1682–1703. 83. Chevreau M, Romand X, Gaudin P, et al. Bisphosphonates for treatment of complex regional pain syndrome type 1: A systematic literature review and meta-analysis of randomized controlled trials versus placebo. Joint Bone Spine. 2017;84(4):393–399. 84. Varenna M, Crotti C. Bisphosphonates in the treatment of complex regional pain syndrome: Is bone the main player at early stage of the disease? Rheumatol Int. 2018;38(11):1959–1962. 85. Price DD, Long S, Wilsey B, et al. Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain. 1998;14(3):216–226. 86. Manjunath PS, Jayalakshmi TS, Dureja GP, et al. Management of lower limb complex regional pain syndrome type 1: An evaluation of percutaneous radiofrequency thermal lumbar sympathectomy versus phenol lumbar sympathetic neurolysis- a pilot study. Anesth Analg. 2008;106(2):647–649 table of contents. 87. Datta R, Agrawal J, Sharma A, et al. A study of the efficacy of stellate ganglion blocks in complex regional pain syndromes of the upper body. J Anaesthesiol Clin Pharmacol. 2017;33(4):534–540. 88. Zhu X, Kohan LR, Morris JD, et al. Sympathetic blocks for complex regional pain syndrome: A survey of pain physicians. Reg Anesth Pain Med. 2019 rapm-2019-100418. 89. Kemler MA, Barendse GA, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med. 2000;343(9):618–624. 90. Kemler MA, De Vet HC, Barendse GA, et al. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: Two years’ follow-up of the randomized controlled trial. Ann Neurol. 2004;55(1):13–18.

References

91. Kemler MA, de Vet HC, Barendse GA, et al. Effect of spinal cord stimulation for chronic complex regional pain syndrome type I: Five-year final follow-up of patients in a randomized controlled trial. J Neurosurg. 2008;108(2):292–298. 92. Visnjevac O, Costandi S, Patel BA, et  al. A comprehensive outcome-specific review of the use of spinal cord stimulation for complex regional pain syndrome. Pain Pract. 2017;17(4):533–545. 93. Liem L, Russo M, Huygen FJ, et  al. A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain. Neuromodulation. 2013;16(5):471–482 discussion 482. 94. Deer TR, Levy RM, Kramer J, et al. Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: A randomized comparative trial. Pain. 2017;158(4):669–681. 95. Deer TR, Pope JE, Lamer TJ, et al. The neuromodulation appropriateness consensus committee on best practices for dorsal root ganglion stimulation. Neuromodulation. 2019;22(1):1–35. 96. van Rijn MA, Munts AG, Marinus J, et al. Intrathecal baclofen for dystonia of complex regional pain syndrome. Pain. 2009;143(12):41–47. 97. Kapural L, Lokey K, Leong MS, et al. Intrathecal ziconotide for complex regional pain syndrome: Seven case reports. Pain Pract. 2009;9(4):296–303. 98. Herring EZ, Frizon LA, Hogue O, et  al. Long-term outcomes using intrathecal drug delivery systems in complex regional pain syndrome. Pain Med. 2019;20(3):515–520. 99. Rauck RL, North J, Eisenach JC. Intrathecal clonidine and adenosine: Effects on pain and sensory processing in patients with chronic regional pain syndrome. Pain. 2015;156(1):88–95. 100. Hagedorn JM, Atallah G. Intrathecal management of complex regional pain syndrome: A case report and literature. Scand J Pain. 2017;14:110–112. 101. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis. 2007;44(Suppl 1):S1–26. 102. Hadley GR, Gayle JA, Ripoll J, et  al. Post-herpetic neuralgia: A review. Curr Pain Headache Rep. 2016;20(3):17. 103. Saguil A, Kane S, Mercado M, et al. Herpes zoster and postherpetic neuralgia: Prevention and management. Am Fam Physician. 2017;96(10):656–663. 104. Gruver C, Guthmiller KB. Postherpetic Neuralgia. Treasure Island, FL: StatPearls; 2020. 105. Jung BF, Johnson RW, Griffin DR, et al. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurol. 2004;62(9):1545– 1551. 106. Gabutti G, Serenelli C, Sarno O, et  al. Epidemiologic fea tures of patients affected by herpes zoster: Database analysis of the Ferrara University dermatology unit, Italy. Med Mal Infect. 2010;40(5):268–272. 107. Helgason S, Petursson G, Gudmundsson S, et  al. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: Prospective study with long term follow up. BMJ. 2000;321(7264):794– 796. 108. Johnson RW, Levin MJ. Herpes zoster and its prevention by vaccination. Interdiscip Top Gerontol Geriatr. 2020;43:131–145. 109. Edmunds WJ, Brisson M. The effect of vaccination on the epidemiology of varicella zoster virus. J Infect. 2002;44(4):211–219. 110. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271–2284. 111. Tanuseputro P, Zagorski B, Chan KJ, et al. Population-based incidence of herpes zoster after introduction of a publicly funded varicella vaccination program. Vaccine. 2011;29(47):8580–8584. 112. McGirr A, Widenmaier R, Curran D, et al. The comparative efficacy and safety of herpes zoster vaccines: A network meta-analysis. Vaccine. 2019;37(22):2896–2909.

499.e3

113. Kilgore PE, Kruszon-Moran D, Seward JF, et al. Varicella in Americans from NHANES III: Implications for control through routine immunization. J Med Virol. 2003;70(Suppl 1):S111–S118. 114. Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med. 2005;352(22):2266–2267. 115. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et  al. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med. 2000;342(9):635–645. 116. Watson CP, Deck JH, Morshead C, et al. Post-herpetic neuralgia: Further post-mortem studies of cases with and without pain. Pain. 1991;44(2):105–117. 117. Opstelten W, van Wijck AJ, Stolker RJ. Interventions to prevent postherpetic neuralgia: Cutaneous and percutaneous techniques. Pain. 2004;107(3):202–206. 118. Mallick-Searle T, Snodgrass B, Brant JM. Postherpetic neuralgia: Epidemiology, pathophysiology, and pain management pharmacology. J Multidiscip Healthc. 2016;9:447–454. 119. Wu CL, Marsh A, Dworkin RH. The role of sympathetic nerve blocks in herpes zoster and postherpetic neuralgia. Pain. 2000;87(2):121–129. 120. High KP. Preventing herpes zoster and postherpetic neuralgia through vaccination. J Fam Pract. 2007;56(10 Suppl A):51A–57A quiz 58A. 121. Creed R, Satyaprakash A, Ravanfar P. Varicella zoster vaccines. Dermatol Ther. 2009;22(2):143–149. 122. Backonja MM, Attal N, Baron R, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain. 2013;154(9):1807–1819. 123. Tyring SK, Beutner KR, Tucker BA, et  al. Antiviral therapy for herpes zoster: Randomized, controlled clinical trial of valacyclovir and famciclovir Therapy in immunocompetent patients 50 years and older. Arch Fam Med. 2000;9(9):863–869. 124. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: Effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative famciclovir herpes zoster study group. Ann Intern Med. 1995;123(2):89–96. 125. Wood MJ, Kay R, Dworkin RH, et al. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo-controlled trials. Clin Infect Dis. 1996;22(2):341–347. 126. Beutner KR, Friedman DJ, Forszpaniak C, et  al. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother. 1995;39(7):1546–1553. 127. Chen N, Li Q, Yang J, et  al. Antiviral treatment for pre venting postherpetic neuralgia. Cochrane Database Syst Rev. 2014(2):CD006866. 128. Whitley RJ, Weiss H, Jr Gnann JW, et  al. Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med. 1996;125(5):376–383. 129. Chen N, Yang M, He L, et al. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev. 2010(12):CD005582. 130. van Wijck AJ, Opstelten W, Moons KG, et  al. The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: A randomised controlled trial. Lancet. 2006;367(9506): 219–224. 131. Fujiwara A, Watanabe K, Hashizume K, et  al. Transforaminal vs interlaminar epidural steroid injection for acute-phase shingles: A randomized, prospective trial. Pain Physician. 2018;21(4):373–382. 132. Ni J, Wang X, Tang Y, et al. Subcutaneous injection of triamcinolone and lidocaine to prevent postherpetic neuralgia. Pain Physician. 2017;20(5):397–403. 133. Galer BS, Rowbotham MC, Perander J, et  al. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: Results of an enriched enrollment study. Pain. 1999;80(3):533–538.

499.e4

References

134. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64(9):937–947. 135. Gammaitoni AR, Alvarez NA, Galer BS. Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: A review of the literature. J Clin Pharmacol. 2003;43(2):111–117. 136. Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med. 2014;371(16):1526–1533. 137. Backonja MM, Malan TP, Vanhove GF, et al. NGX-4010, a highconcentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomized, double-blind, controlled study with an open-label extension. Pain Med. 2010;11(4):600–608. 138. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: A quantitative systematic review. PLoS Med. 2005;2(7):e164. 139. Chandra K, Shafiq N, Pandhi P, et al. Gabapentin versus nortriptyline in post-herpetic neuralgia patients: A randomized, doubleblind clinical trial- the GONIP Trial. Int J Clin Pharmacol Ther. 2006;44(8):358–363. 140. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: Evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003;25(1):81–104. 141. Tarride JE, Gordon A, Vera-Llonch M, et  al. Cost-effectiveness of pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia: A Canadian perspective. Clin Ther. 2006;28(11):1922–1934. 142. Watson CP, Vernich L, Chipman M, et  al. Nortriptyline versus amitriptyline in postherpetic neuralgia: A randomized trial. Neurol. 1998;51(4):1166–1171. 143. Khalifa M, Daleau P, Turgeon AJ. Mechanism of sodium channel block by venlafaxine in guinea pig ventricular myocytes. J Pharmacol Exp Ther. 1999;291(1):280–284. 144. Gallagher HC, Gallagher RM, Butler M, et  al. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015(8):CD011091. 145. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: A randomized trial in postherpetic neuralgia. Neurol. 1998;50(6): 1837–1841. 146. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352(13): 1324–1334. 147. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in postherpetic neuralgia: A randomized, double-blind, placebo-controlled trial. Pain. 2003;104(1-2):323–331. 148. Kumar V, Krone K, Mathieu A. Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: An appraisal of current evidence. Reg Anesth Pain Med. 2004;29(5):454–461. 149. Malec-Milewska M, Horosz B, Sekowska A, et  al. 5% lidocaine medicated plasters vs. sympathetic nerve blocks as a part of multimodal treatment strategy for the management of postherpetic neuralgia: A retrospective, consecutive, case-series study. Neurol. Neurochir Pol. 2015;49(1):24–28. 150. Pasqualucci A, Pasqualucci V, Galla F, et  al. Prevention of postherpetic neuralgia: Acyclovir and prednisolone versus epidural local anesthetic and methylprednisolone. Acta Anaesthesiol Scand. 2000;44(8):910–918. 151. Ghanavatian S, Wie CS, Low RS, et  al. Parameters associated with efficacy of epidural steroid injections in the management of postherpetic neuralgia: The Mayo Clinic experience. J Pain Res. 2019;12:1279–1286. 152. van Wijck AJ, Wallace M, Mekhail N, et al. Evidence-based interventional pain medicine according to clinical diagnoses. 17. Herpes zoster and post-herpetic neuralgia. Pain Pract. 2011;11(1):88–97. 153. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med. 2000;343(21):1514–1519. 154. Rijsdijk M, van Wijck AJ, Meulenhoff PC, et  al. No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain. 2013;17(5):714–723.

155. Lin CS, Lin YC, Lao HC, et  al. Interventional treatments for postherpetic neuralgia: A systematic review. Pain Physician. 2019;22(3):209–228. 156. Deer TR, Mekhail N, Provenzano D, et al. The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: The neuromodulation appropriateness consensus committee. Neuromodulation. 2014;17(6):515–550 discussion 550. 157. Dong DS, Yu X, Wan CF, et al. Efficacy of short-term spinal cord stimulation in acute/subacute zoster-related pain: A retrospective study. Pain Physician. 2017;20(5):E633–E645. 158. Huang J, Yang S, Yang J, et al. Early Treatment with temporary spinal cord stimulation effectively prevents development of postherpetic neuralgia. Pain Physician. 2020;23(2):E219–E230. 159. Texakalidis P, Tora MS, Boulis NM. Neurosurgeons’ armamentarium for the management of refractory postherpetic neuralgia: A systematic literature review. Stereotact Funct Neurosurg. 2019;97(1):55–65. 160. Assal JP, Lindblom U. San Antonio conference on diabetic neuropathy. Ann Neurol. 1988;24(5):695. 161. Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41. 162. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care. 2005;28(4):956–962. 163. Rathur HM, Boulton AJ. Recent advances in the diagnosis and management of diabetic neuropathy. J Bone Joint Surg Br. 2005;87(12):1605–1610. 164. Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: Epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. 2000;47(2):123–128. 165. Harris M, Eastman R, Cowie C. Symptoms of sensory neuropathy in adults with NIDDM in the U.S. population. Diabetes Care. 1993;16(11):1446–1452. 166. Daousi C, MacFarlane IA, Woodward A, et  al. Chronic painful peripheral neuropathy in an urban community: A controlled comparison of people with and without diabetes. Diabet Med. 2004;21(9):976–982. 167. Davies M, Brophy S, Williams R, et al. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29(7):1518–1522. 168. Van Acker K, Bouhassira D, De Bacquer D, et al. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab. 2009;35(3):206–213. 169. Paisley A, Abbott C, van Schie C, et al. A comparison of the Neuropen against standard quantitative sensory-threshold measures for assessing peripheral nerve function. Diabet Med. 2002;19(5): 400–405. 170. Maser RE, Steenkiste AR, Dorman JS, et  al. Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh epidemiology of diabetes complications study. Diabetes. 1989;38(11): 1456–1461. 171. Jaiswal M, Lauer A, Martin CL, et  al. Peripheral neuropathy in adolescents and young adults with type 1 and type 2 diabetes from the SEARCH for diabetes in youth follow-up cohort: A pilot study. Diabetes Care. 2013;36(12):3903–3908. 172. Ismail-Beigi F, Craven T, Banerji MA, et  al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: An analysis of the ACCORD randomised trial. Lancet. 2010;376(9739):419–430. 173. Partanen J, Niskanen L, Lehtinen J, et al. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(2):89–94. 174. Pop-Busui R, Lu J, Brooks MM, et al. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the bypass angioplasty revascularization investigation 2 diabetes (BARI 2D) cohort. Diabetes Care. 2013;36(10):3208–3215.

References

175. Ziegler D, Rathmann W, Dickhaus T, et al. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: The MONICA/KORA Augsburg Surveys S2 and S3. Pain Med. 2009;10(2): 393–400. 176. Franklin GM, Kahn LB, Baxter J, et  al. Sensory neuropathy in non-insulin-dependent diabetes mellitus. The San Luis Valley diabetes study. Am J Epidemiol. 1990;131(4):633–643. 177. Callaghan BC, Price RS, Feldman EL. Distal symmetric polyneuropathy: A review. JAMA. 2015;314(20):2172–2181. 178. Sumner CJ, Sheth S, Griffin JW, et  al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurol. 2003;60(1):108–111. 179. Shakher J, Stevens MJ. Update on the management of diabetic polyneuropathies. Diabetes Metab Syndr Obes. 2011;4:289–305. 180. Zochodne DW. The challenges of diabetic polyneuropathy: A brief update. Curr Opin Neurol. 2019;32(5):666–675. 181. Waxman SG. Neurobiology: A channel sets the gain on pain. Nature. 2006;444(7121):831–832. 182. Hartemann A, Attal N, Bouhassira D, et  al. Painful diabetic neuropathy: Diagnosis and management. Diabetes Metab. 2011; 37(5):377–388. 183. Devigili G, Tugnoli V, Penza P, et  al. The diagnostic criteria for small fibre neuropathy: From symptoms to neuropathology. Brain. 2008;131((Pt 7):1912–1925. 184. Franse LV, Valk GD, Dekker JH, et al. Numbness of the feet’ is a poor indicator for polyneuropathy in Type 2 diabetic patients. Diabet Med. 2000;17(2):105–110. 185. Bennett MI, Attal N, Backonja MM, et al. Using screening tools to identify neuropathic pain. Pain. 2007;127(3):199–203. 186. Selvarajah D, Kar D, Khunti K, et al. Diabetic peripheral neuropathy: Advances in diagnosis and strategies for screening and early intervention. Lancet Diabetes. Endocrinol. 2019;7(12):938–948. 187. Harke H, Gretenkort P, Ladleif HU, et al. Spinal cord stimulation in postherpetic neuralgia and in acute herpes zoster pain. Anesth Analg. 2002;94(3):694–700 table of contents. 188. Bordier L, Dolz M, Monteiro L, et  al. Accuracy of a rapid and non-invasive method for the assessment of small fiber neuropathy based on measurement of electrochemical skin conductances. Front Endocrinol (Lausanne). 2016;7:18. 189. Chatzikosma G, Pafili K, Demetriou M, et al. Evaluation of sural nerve automated nerve conduction study in the diagnosis of peripheral neuropathy in patients with type 2 diabetes mellitus. Arch Med Sci. 2016;12(2):390–393. 190. Zografou I, Iliadis F, Sambanis C, et al. Validation of neuropad in the assessment of peripheral diabetic neuropathy in patients with diabetes mellitus versus the Michigan neuropathy screening instrument, 10 g Monofilament application and biothesiometer measurement. Curr Vasc Pharmacol. 2019;18(5):517–522. 191. Mao F, Liu S, Qiao X, et  al. Sudoscan is an effective screening method for asymptomatic diabetic neuropathy in Chinese type 2 diabetes mellitus patients. J Diabetes Investig. 2017;8(3):363–368. 192. Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve. 2001;24(9):1229–1231. 193. Stevens MJ, Raffel DM, Allman KC, et al. Regression and progression of cardiac sympathetic dysinnervation complicating diabetes: An assessment by C-11 hydroxyephedrine and positron emission tomography. Metabolism. 1999;48(1):92–101. 194. Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy. Am Fam Physician. 2005;71(11):2123–2128. 195. Gorson KC, Herrmann DN, Thiagarajan R, et  al. Non-length dependent small fibre neuropathy/ganglionopathy. J Neurol Neurosurg Psychiatry. 2008;79(2):163–169. 196. Kelkar P. Diabetic neuropathy. Semin Neurol. 2005;25(2): 168–173. 197. Nathan DM, Genuth S, Lachin J, et  al. The effect of intensive treatment of diabetes on the development and progression of

499.e5

long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–986. 198. Callaghan BC, Gallagher G, Fridman V, et al. Diabetic neuropathy: What does the future hold? Diabetologia. 2020;63(5):891–897. 199. Rumora AE, LoGrasso G, Hayes JM, et al. The divergent roles of dietary saturated and monounsaturated fatty acids on nerve function in murine models of obesity. J Neurosci. 2019;39(19):3770–3781. 200. Miranda HF, Sierralta F, Aranda N, et al. Antinociception induced by rosuvastatin in murine neuropathic pain. Pharmacol Rep. 2018;70(3):503–508. 201. Hasanvand A, Ahmadizar F, Abbaszadeh A, et al. The antinociceptive effects of rosuvastatin in chronic constriction injury model of male rats. Basic Clin Neurosci. 2018;9(4):251–260. 202. Pergolizzi Jr JV, Magnusson P, LeQuang JA, et al. Statins and neuropathic pain: A narrative review. Pain Ther. 2020;9(1):97–111. 203. Baute V, Zelnik D, Curtis J, et  al. Complementary and alternative medicine for painful peripheral neuropathy. Curr Treat Options Neurol. 2019;21(9):44. 204. Backonja M, Beydoun A, Edwards KR, et  al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA. 1998;280(21):1831–1836. 205. Gorson KC, Schott C, Herman R, et al. Gabapentin in the treatment of painful diabetic neuropathy: A placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry. 1999;66(2):251–252. 206. Majdinasab N, Kaveyani H, Azizi M. A comparative double-blind randomized study on the effectiveness of duloxetine and gabapentin on painful diabetic peripheral polyneuropathy. Drug Des Devel Ther. 2019;13:1985–1992. 207. Moore A, Derry S, Wiffen P. Gabapentin for chronic neuropathic pain. JAMA. 2018;319(8):818–819. 208. Bril V, England JD, Franklin GM, et  al. Evidence-based guideline: Treatment of painful diabetic neuropathy- report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation. Muscle Nerve. 2011;43(6):910–917. 209. Lesser H, Sharma U, LaMoreaux L, et al. Pregabalin relieves symptoms of painful diabetic neuropathy: A randomized controlled trial. Neurol. 2004;63(11):2104–2110. 210. Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, doubleblind, multicentre, placebo-controlled trial of flexible- and fixeddose regimens. Pain. 2005;115(3):254–263. 211. Derry S, Bell RF, Straube S, et al. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 2019;1:CD007076. 212. Gomez-Perez FJ, Rull JA, Dies H, et  al. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study. Pain. 1985;23(4):395–400. 213. Rowbotham MC, Goli V, Kunz NR, et  al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: A doubleblind, placebo-controlled study. Pain. 2004;110(3):697–706. 214. Goldstein DJ, Lu Y, Detke MJ, et  al. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116(1-2): 109–118. 215. Raskin J, Pritchett YL, Wang F, et  al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6(5):346–356. 216. Kaur H, Hota D, Bhansali A, et al. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: A randomized, double-blind, cross-over clinical trial. Diabetes Care. 2011;34(4):818–822. 217. Randolph AC, Lin YL, Volpi E, et  al. Tricyclic antidepressant and/or gamma-aminobutyric acid-analog use is associated with fall risk in diabetic peripheral neuropathy. J Am Geriatr Soc. 2019;67(6):1174–1181.

499.e6

References

218. Ko SH, Kwon HS, Yu JM, et al. Comparison of the efficacy and safety of tramadol/acetaminophen combination therapy and gabapentin in the treatment of painful diabetic neuropathy. Diabet Med. 2010;27(9):1033–1040. 219. Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: A randomised, double-blind, controlled trial. Pain. 1999;83(1):85–90. 220. Duehmke RM, Derry S, Wiffen PJ, et al. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD003726. 221. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial. Neurol. 2003;60(6):927–934. 222. Hanna M, O’Brien C, MC Wilson. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008;12(6):804–813. 223. Gaskell H, Derry S, Stannard C, et al. Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016;7:CD010692. 224. Cooper TE, Chen J, Wiffen PJ, et  al. Morphine for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;5: CD011669. 225. Stannard C, Gaskell H, Derry S, et al. Hydromorphone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016(5): CD011604. 226. Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: Efficacy and dose-response trials. Anesthesiol. 2002;96(5):1053–1061. 227. Nelson KA, Park KM, Robinovitz E, et  al. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurol. 1997;48(5):1212–1218. 228. Shaibani AI, Pope LE, Thisted R, et al. Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: A double-blind, placebo-controlled, multicenter study. Pain Med. 2012;13(2):243–254. 229. Derry S, Lloyd R, Moore RA, et  al. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009(4):CD007393. 230. Wolff RF, Bala MM, Westwood M, et al. 5% lidocaine medicated plaster in painful diabetic peripheral neuropathy (DPN): A systematic review. Swiss Med Wkly. 2010;140(21-22):297–306. 231. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: A meta-analysis. Diabet Med. 2004;21(2):114–121. 232. Tang J, Wingerchuk DM, Crum BA, et  al. Alpha-lipoic acid may improve symptomatic diabetic polyneuropathy. Neurologist. 2007;13(3):164–167. 233. Boulton AJ, Malik RA, Arezzo JC, et al. Diabetic somatic neuropathies. Diabetes Care. 2004;27(6):1458–1486. 234. Garrow AP, Xing M, Vere J, et al. Role of acupuncture in the management of diabetic painful neuropathy (DPN): A pilot RCT. Acupunct Med. 2014;32(3):242–249. 235. Dimitrova A, Murchison C, Oken B. Acupuncture for the treatment of peripheral neuropathy: A systematic review and metaanalysis. J Altern Complement Med. 2017;23(3):164–179. 236. Pluijms WA, van Kleef M, Honig WM, et al. The effect of spinal cord stimulation frequency in experimental painful diabetic polyneuropathy. Eur J Pain. 2013;17(9):1338–1346. 237. van Beek M, van Kleef M, Linderoth B, et  al. Spinal cord stimulation in experimental chronic painful diabetic polyneuropathy: Delayed effect of high-frequency stimulation. Eur J Pain. 2017;21(5):795–803. 238. van Beek M, Hermes D, Honig WM, et al. Long-term spinal cord stimulation alleviates mechanical hypersensitivity and increases peripheral cutaneous blood perfusion in experimental painful diabetic polyneuropathy. Neuromodulation. 2018;21(5):472–479. 239. Sills S. Treatment of painful polyneuropathies of diabetic and other origins with 10 kHz SCS: A case series. Postgrad Med. 2020:1–6. 240. Petersen EA, Stauss TG, Scowcroft, JA, et al. Effect of high-frequency (10-kHz) spinal cord stimulation in patients with painful

diabetic neuropathy: A randomized clinical trial. JAMA Neurol, 2021;78(6):687–698. 241. World Health Organization. Global health observation data: HIV/ AIDS. Available at: https://www.who.int/gho/hiv/en/. 242. Kaku M, Simpson DM. HIV neuropathy. Curr Opin HIV AIDS. 2014;9(6):521–526. 243. Portegies P, Solod L, Cinque P, et al. Guidelines for the diagnosis and management of neurological complications of HIV infection. Eur J Neurol. 2004;11(5):297–304. 244. Verma A. Epidemiology and clinical features of HIV-1 associated neuropathies. J Peripher Nerv Syst. 2001;6(1):8–13. 245. Ghosh S, Chandran A, Jansen JP. Epidemiology of HIV-related neuropathy: A systematic literature review. AIDS Res Hum Retroviruses. 2012;28(1):36–48. 246. Childs EA, Lyles RH, Selnes OA, et al. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurol. 1999;52(3):607–613. 247. Smyth K, Affandi JS, McArthur JC, et al. Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993-2006. HIV Med. 2007;8(6):367–373. 248. Luciano CA, Pardo CA, McArthur JC. Recent developments in the HIV neuropathies. Curr Opin Neurol. 2003;16(3):403–409. 249. Wang SX, Ho EL, Grill M, et al. Peripheral neuropathy in primary HIV infection associates with systemic and central nervous system immune activation. J Acquir Immune Defic Syndr. 2014;66(3): 303–310. 250. Stavros K, Simpson DM. Understanding the etiology and management of HIV-associated peripheral neuropathy. Curr HIV/AIDS Rep. 2014;11(3):195–201. 251. Simpson DM, Kitch D, Evans SR, et al. HIV neuropathy natural history cohort study: Assessment measures and risk factors. Neurol. 2006;66(11):1679–1687. 252. Famularo G, Moretti S, Marcellini S, et al. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS. 1997;11(2):185–190. 253. Gonzalez-Duarte A, Robinson-Papp J, Simpson DM. Diagnosis and management of HIV-associated neuropathy. Neurol Clin. 2008;26(3):821–832 x. 254. Polydefkis M, Yiannoutsos CT, Cohen BA, et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurol. 2002;58(1):115–119. 255. Bradley WG, Shapshak P, Delgado S, et  al. Morphometric analysis of the peripheral neuropathy of AIDS. Muscle Nerve. 1998;21(9):1188–1195. 256. Ferrari S, Vento S, Monaco S, et  al. Human immunodefi ciency virus-associated peripheral neuropathies. Mayo Clin Proc. 2006;81(2):213–219. 257. Keswani SC, Polley M, Pardo CA, et al. Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons. Ann Neurol. 2003;54(3):287–296. 258. Herzberg U, Sagen J. Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis. J Neuroimmunol. 2001;116(1):29–39. 259. Oh SB, Tran PB, Gillard SE, et  al. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci. 2001;21(14):5027–5035. 260. Keswani SC, Pardo CA, Cherry CL, et al. HIV-associated sensory neuropathies. AIDS. 2002;16(16):2105–2117. 261. Lichtenstein KA, Armon C, Baron A, et  al. Modification of the incidence of drug-associated symmetrical peripheral neuropathy by host and disease factors in the HIV outpatient study cohort. Clin Infect Dis. 2005;40(1):148–157. 262. Roda RH, Hoke A. Mitochondrial dysfunction in HIV-induced peripheral neuropathy. Int Rev Neurobiol. 2019;145:67–82. 263. Dalakas MC, Semino-Mora C, Leon-Monzon M. Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2′3′-dideoxycytidine (ddC). Lab Invest. 2001;81(11):1537–1544.

References

264. Pettersen JA, Jones G, Worthington C, et al. Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: Protease inhibitor-mediated neurotoxicity. Ann Neurol. 2006;59(5):816–824. 265. Cherry CL, Wadley AL, Kamerman PR. Diagnosing and treating HIV-associated sensory neuropathy: A global perspective. Pain Manag. 2016;6(2):191–199. 266. Kemp HI, Eliahoo J, Vase L, et al. Meta-analysis comparing placebo responses in clinical trials of painful HIV-associated sensory neuropathy and diabetic polyneuropathy. Scand J Pain. 2020;20(3):439–449. 267. Simpson DM, Dorfman D, Olney RK, et al. Peptide T in the treatment of painful distal neuropathy associated with AIDS: Results of a placebo-controlled trial. The peptide T neuropathy study group. Neurol. 1996;47(5):1254–1259. 268. McArthur JC, Yiannoutsos C, Simpson DM, et  al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS clinical trials group team 291. Neurol. 2000;54(5):1080–1088. 269. Youle M, Osio M, Group AS. A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Med. 2007;8(4):241–250. 270. Keswani SC, Leitz GJ, Hoke A. Erythropoietin is neuroprotective in models of HIV sensory neuropathy. Neurosci Lett. 2004;371(23):102–105. 271. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS clinical trial group 242 protocol team. Neurol. 1998;51(6):1682–1688. 272. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004;251(10):1260–1266. 273. Simpson DM, Schifitto G, Clifford DB, et al. Pregabalin for painful HIV neuropathy: A randomized, double-blind, placebo-controlled trial. Neurol. 2010;74(5):413–420. 274. Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIVassociated painful sensory neuropathies: A placebo-controlled trial. Neurol. 2003;60(9):1508–1514. 275. Estanislao L, Carter K, McArthur J, et  al. A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr. 2004;37(5): 1584–1586. 276. Simpson DM, Brown S, Tobias J, et al. Controlled trial of highconcentration capsaicin patch for treatment of painful HIV neuropathy. Neurol. 2008;70(24):2305–2313. 277. Abrams DI, Jay CA, Shade SB, et  al. Cannabis in painful HIVassociated sensory neuropathy: A randomized placebo-controlled trial. Neurol. 2007;68(7):515–521. 278. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: A randomized, crossover clinical trial. Neuropsychopharmacol. 2009;34(3):672–680. 279. Bray F, Ferlay J, Soerjomataram I, et  al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. 280. American Cancer Society Cancer facts & figures 2019. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancerfacts-and-statistics/annual-cancer-facts-and-figures/2019/cancerfacts-and-figures-2019;pdf. 281. Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in cancer survivors: An underdiagnosed clinical entity? Am Soc Clin Oncol Educ Book. 2015:e553–e560. 282. Fallon MT. Neuropathic pain in cancer. Br J Anaesth. 2013;111(1): 105–111. 283. Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014;155(12):2461–2470.

499.e7

284. Bao T, Basal C, Seluzicki C, et  al. Long-term chemotherapyinduced peripheral neuropathy among breast cancer survivors: Prevalence, risk factors, and fall risk. Breast Cancer Res Treat. 2016;159(2):327–333. 285. Ezendam NP, Pijlman B, Bhugwandass C, et  al. Chemother apy-induced peripheral neuropathy and its impact on healthrelated quality of life among ovarian cancer survivors: Results from the population-based PROFILES registry. Gynecol Oncol. 2014;135(3):510–517. 286. Tofthagen C, Visovsky C, Dominic S, et  al. Neuropathic symptoms, physical and emotional well-being, and quality of life at the end of life. Support Care Cancer. 2019;27(9):3357–3364. 287. Cavaletti G, Alberti P, Argyriou AA, et al. Chemotherapy-induced peripheral neurotoxicity: A multifaceted, still unsolved issue. J Peripher Nerv Syst. 2019;24(Suppl 2):S6–S12. 288. Gordon-Williams R, Farquhar-Smith P. Recent advances in understanding chemotherapy-induced peripheral neuropathy. F1000Res. 2020;9. 289. Mahmoudpour SH, Bandapalli OR, da Silva Filho MI, et  al. Chemotherapy-induced peripheral neuropathy: Evidence from genome-wide association studies and replication within multiple myeloma patients. BMC Cancer. 2018;18(1):820. 290. Sucheston-Campbell LE, Clay-Gilmour AI, Barlow WE, et  al. Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci. Pharmacogenet Genom. 2018;28(2): 49–55. 291. Argyriou AA, Bruna J, Genazzani AA, et  al. Chemotherapy induced peripheral neurotoxicity: Management informed by pharmacogenetics. Nat Rev Neurol. 2017;13(8):492–504. 292. Colvin LA. Chemotherapy-induced peripheral neuropathy: Where are we now? Pain. 2019;160(Suppl 1):S1–S10. 293. Tofthagen CS, Cheville AL, Loprinzi CL. The physical consequences of chemotherapy-induced peripheral neuropathy. Curr Oncol Rep. 2020;22(5):50. 294. Knoerl R, Chornoby Z, Smith EML. Estimating the frequency, severity, and clustering of SPADE symptoms in chronic painful chemotherapy-induced peripheral neuropathy. Pain Manag Nurs. 2018;19(4):354–365. 295. Flatters SJ, Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: Evidence for mitochondrial dysfunction. Pain. 2006;122(3):245–257. 296. Krukowski K, Ma J, Golonzhka O, et al. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. Pain. 2017;158(6):1126–1137. 297. Kober KM, Olshen A, Conley YP, et al. Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors. Mol Pain. 2018;14:1744806918816462. 298. Robinson CR, Zhang H, Dougherty PM. Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neurosci. 2014;274:308–317. 299. Wahlman C, Doyle TM, Little JW, et  al. Chemotherapy induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain. 2018;159(6): 1025–1034. 300. Brandolini L, d’Angelo M, Antonosante A, et al. Chemokine signaling in chemotherapy-induced neuropathic pain. Int J Mol Sci. 2019;20(12). 301. Aromolaran KA, Goldstein PA. Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy; cause and effect? Mol Pain. 2017;13:1744806917714693. 302. Heide R, Bostock H, Ventzel L, et al. Axonal excitability changes and acute symptoms of oxaliplatin treatment: In vivo evidence for slowed sodium channel inactivation. Clin Neurophysiol. 2018;129(3):694–706. 303. Descoeur J, Pereira V, Pizzoccaro A, et al. Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol Med. 2011;3(5):266–278.

499.e8

References

304. Kawakami K, Chiba T, Katagiri N, et al. Paclitaxel increases high voltage-dependent calcium channel current in dorsal root ganglion neurons of the rat. J Pharmacol Sci. 2012;120(3):187–195. 305. Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(18):1941–1967. 306. Albers JW, Chaudhry V, Cavaletti G, et al. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014(3):CD005228. 307. McCrary JM, Goldstein D, Sandler CX, et al. Exercise-based rehabilitation for cancer survivors with chemotherapy-induced peripheral neuropathy. Support Care Cancer. 2019;27(10):3849–3857. 308. Magnowska M, Izycka N, Kapola-Czyz J, et  al. Effectiveness of gabapentin pharmacotherapy in chemotherapy-induced peripheral neuropathy. Ginekol Pol. 2018;89(4):200–204. 309. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer. 2007;110(9):2110–2118. 310. Mishra S, Bhatnagar S, Goyal GN, et  al. A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: A prospective randomized double-blind placebo-controlled study. Am J Hosp Palliat Care. 2012;29(3):177–182. 311. Kim BS, Jin JY, Kwon JH, et al. Efficacy and safety of oxycodone/ naloxone as add-on therapy to gabapentin or pregabalin for the management of chemotherapy-induced peripheral neuropathy in Korea. Asia Pac J Clin Oncol. 2018;14(5):e448–e454. 312. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA. 2013;309(13):1359–1367. 313. Farshchian N, Alavi A, Heydarheydari S, et al. Comparative study of the effects of venlafaxine and duloxetine on chemotherapyinduced peripheral neuropathy. Cancer Chemother Pharmacol. 2018;82(5):787–793.

314. Derry S, Wiffen PJ, Moore RA, et  al. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014(7): CD010958. 315. Fallon MT, Storey DJ, Krishan A, et al. Cancer treatment-related neuropathic pain: proof of concept study with menthol- A TRPM8 agonist. Support Care Cancer. 2015;23(9):2769–2777. 316. Anand P, Elsafa E, Privitera R, et  al. Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: From pain relief towards disease modification. J Pain Res. 2019;12:2039–2052. 317. Barton DL, Wos EJ, Qin R, et  al. A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer. 2011;19(6):833–841. 318. Blanton HL, Brelsfoard J, DeTurk N, et al. Cannabinoids: Current and future options to treat chronic and chemotherapy-induced neuropathic pain. Drugs. 2019;79(9):969–995. 319. Mulpuri Y, Marty VN, Munier JJ, et  al. Synthetic peripherallyrestricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. Neuropharmacol. 2018;139:85–97. 320. Deng L, Guindon J, Vemuri VK, et al. The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB(2) receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy. Mol Pain. 2012;8:71. 321. Groenen PS, van Helmond N, Chapman KB. Chemotherapyinduced peripheral neuropathy treated with dorsal root ganglion stimulation. Pain Med. 2019;20(4):857–859. 322. Abd-Elsayed A, Schiavoni N, Sachdeva H. Efficacy of spinal cord stimulators in treating peripheral neuropathy: A case series. J Clin Anesth. 2016;28:74–77. 323. IASP. IASP terminology. Available at: https://www.iasp-pain.org/ Education/Content.aspx?ItemNumber=1698#Neuropathy.

10 35

Evaluation and Chapter Title toTreatment Go Here of Complex Regional Pain Syndrome CHAPTER AUTHOR

FRANK J.P.M. HUYGEN

Introduction

Pathophysiology

As defined by the International Association for the Study of Pain (IASP), complex regional pain syndrome (CRPS) is a collection of locally painful conditions following trauma, usually manifesting distally and exceeding the clinical course of the original trauma in severity and duration, often resulting in a significant impairment of motor skills, and is characterized by a variable progression over time. CRPS can develop as a complication after surgery or trauma. The spontaneous occurrence has been described, but the question is whether there was no unnoticed trauma in these cases.1 In the literature, the syndrome has been given more than 72 different names, including well-known names such as Sudeck dystrophy, posttraumatic dystrophy, and sympathetic reflex dystrophy. At a meeting of the IASP in Orlando in 1992, it was agreed that only the term “complex regional pain syndrome” would henceforth be used. A distinction has been made between type 1 without and type 2 with demonstrable nerve damage.2 Over time, it was proposed to add a third type, namely CRPS not otherwise specified, for conditions that meet the diagnostic criteria only to a limited extent but where no other diagnosis can be made. In clinical practice, “warm” CRPS (in which the skin is red, strongly perfused, and warm) is distinguished from “cold” CRPS (in which the skin is bluish, poorly perfused, and cold).3 CRPS has long been seen as a curious disease in which perception and behavior played a major role, which was self-limiting and did not last too long. Recent research has pointed out the opposite. CRPS is a complex condition based on an interaction between the immune system and the nervous system that severely damages various tissues and leads to severe limitations and ultimately disability. Genetic and immunologic factors can also play a role; the unraveling of pathophysiology has only just begun. The disease has serious consequences for functionality and quality of life and leads to high direct and indirect health costs. This chapter will discuss the pathophysiology, epidemiology, clinical features, and treatment of CRPS. A review of the pharmacologic management will be brief since there is an expanded discussion of the topic in Chapter 34. Neuromodulatory treatments are also successful, as there is a detailed discussion of spinal cord stimulation, stimulation of the dorsal root ganglion (DRG), and peripheral nerve stimulation in Chapter 71.

During the last two decades, important discoveries have resulted in a better understanding of the pathophysiology.4 Several mechanisms seem to play a role next to each other. A distinction can be made between afferent mechanisms, such as inflammation and endothelial dysfunction, efferent mechanisms, such as changes in the somatosensory and autonomic nervous system, and central mechanisms, including cortical reorganization and psychological factors.

500

Afferent Mechanisms Some of the symptoms of CRPS are similar to those of inflammation, such as pain, redness, warmth, and swelling. Sudeck suggested more than 100 years ago that CRPS could be a form of bone inflammation, but this idea could not be confirmed because CRPS is not associated with fever, increased blood sedimentation rate, increased C-reactive protein (CRP), and leukocytosis. However, over the past 20 years, several studies have shown that inflammation is an important mechanism in the development and maintenance of CRPS.5 Increased levels of two neuropeptides, C-gene related peptide and substance-P, have been demonstrated in the serum of CRPS patients. Levels of the pro-inflammatory cytokines, interleukin-6 (IL-6), and tumor necrosis factor (TNF)-α, measured in artificial blisters on the skin of CRPS patients, were found to be elevated in the affected extremity.6 TNF-α and IL-6 levels in skin biopsies from fracture patients with and without CRPS were higher in patients with CRPS.7 Serum levels of soluble TNF receptors, and the proinflammatory cytokines TNF-α, IL-1, and IL-8 are increased in patients with early CRPS. In contrast, the levels of anti-infla­ mmatory cytokines such as IL- 4, IL-10, and transforming growth factor β-1 are reduced.8 Artificial blisters on the skin of CRPS patients have also been found to contain more tryptase in the affected extremity. Tryptase is a marker of mast cell activity. Therefore it seems likely that mast cells are involved in the release of pro-inflammatory cytokines in CRPS. The involvement of T lymphocytes in CRPS has recently been demonstrated in a study in which levels of the soluble interleukin two receptor (sIL-2R) were higher in serum from CRPS patients. The level of sIl-2R is a biomarker of inflammatory activity. However,

 

CHAPTER 35

Evaluation and Treatment of Complex Regional Pain Syndrome

it is important to realize that it is not a disease-specific biomarker; sIL-2R may also be increased in other syndromes. It is a specific measure of inflammatory activity. Signs and symptoms remain the cornerstone for the diagnosis of CRPS.9 In patients with CRPS, signs of hypoxia, such as increased lactate levels, muscle acidosis, and specific histopathologic features, have been found in local tissue. A decrease in the capillary oxygenation of the skin was observed with micro-light-guided spectroscopy. In other studies, an imbalance between the vasodilating nitric oxide (NO) and the vasoconstricting endothelin-1 (ET-1) has been shown, in artificial blisters on the skin of patients with cold CRPS, the NO level is lower, and the ET-1 level is higher in the affected extremity.10 This is probably a direct consequence of persistent inflammation. Skin biopsies showed an increase in α receptors.11 It was previously believed to be because of an autonomic nervous system disorder. Recent research has also shown a direct influence of persistent inflammation on the increase in α receptors. In the affected extremities of CRPS-1 patients, histopathologic examination of skin biopsies revealed a loss of C and Aδ fibers and abnormal branching nerve endings. In one study, axonal density was found to be 29% lower in CRPS patients.12 This is probably the result of ongoing inflammation. According to the IASP definition, CRPS-1 does not show nerve damage in classic neurophysiologic research. The fact that CRPS1 may have an unrecognized small fiber neuropathy makes the distinction between CRPS-1 and CRPS-2 somewhat artificial.13

Efferent Mechanisms Chronic stimulation of nociceptors can lead to central sensitization, pain, and sensory disturbances. Previously, these signs and symptoms have been termed neuropathic. Today, we use the term nociplastic pain, which is a pain that arises from altered nociception despite the absence of clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence of a disease or lesion of the somatosensory system causing pain.14 The sensory disturbances in CRPS are related not only to the pathology at the affected site but also to disturbances at the spinal or supraspinal level. Changes in the central nervous system, central sensitization, and neuroplasticity can lead to hypersensitivity to normal stimuli (allodynia) and painful stimuli (hyperalgesia). The exact mechanisms have not yet been fully elucidated. The action of neurotransmitters on postsynaptic receptors for N-methyl-d-aspartate, aminomethylphosphonic acid (AMPA), and neurokinin-1 (NK1) are involved. CRPS is also referred to as sympathetic reflex dystrophy because of the signs and symptoms of autonomic dysfunction. In the acute phase of CRPS, both phasic and tonic sympathetic reflexes in the affected extremity are disturbed.15 Noradrenaline levels in the affected extremity are lower. Changes in the spinal cord or higher centers of the central nervous system are likely to play a role in the dysregulation of the autonomic nervous system. In the past, dysfunction of the sympathetic nervous system has been used to explain the increased blood flow in warm CRPS. With today’s knowledge, it makes more sense to relate this increased blood flow to inflammation. Cold CRPS was thought to be caused by an increase in α-adrenergic receptors because of the depletion of local catecholamines. As previously described, the upregulation of α-adrenergic receptors can also be explained by continuing inflammation. The motor system may also be affected.16 A decrease in the range of motion is common and cannot always be explained by pain alone but is also

501

likely to be of spinal or supraspinal origin. Severe dystonia may occur, characterized by flexion of the fingers, wrist, elbow, and sometimes shoulder, and plantar flexion or extension of the foot. This is typical of a more chronic phase. Since dystonia responds to intrathecal administration of baclofen, spinal g-aminobutyric acid (GABA) receptors are likely to play a role in its development.

Central Mechanisms Functional MRI has shown that in CRPS patients, a reorganization can occur in the cerebral cortex.17 Possibly altering blood flow to the thalamus plays a role, resulting in changes in activation patterns and sensory mapping. It has been frequently suggested in the past that CRPS is an imaginary disease that typically occurs in women who somatize and have secondary gains because of chronic disabilities. In a systematic review of the literature, Beerthuizen et al. refuted this view and demonstrated that a link between psychological and/ or psychiatric determinants and the development of CRPS could only be found in poorly conducted research and not in methodologically sound research.18 A potentially important explanation for this misconception is that CRPS is regularly used as an embarrassment diagnosis. Another reason is that the natural course of a chronic pain syndrome such as CRPS easily gives rise to anxiety, depression, and catastrophizing. Therefore patients with chronic CRPS can also develop such symptoms. The cause and effect should not be confused. Certain experiences and/or behaviors can influence the course of CRPS. Extreme fear of pain can lead to kinesiophobia and disuse. Therefore immobilization of the affected extremity takes longer than necessary, the blood flow decreases, and the final result is increased rigidity and muscle atrophy. This was confirmed in a study in which the forearm of healthy volunteers was immobilized with a plaster splint.19 This immobilization has been shown to cause various symptoms of CRPS, such as temperature changes and changes in mechanical and thermal sensitivity. It is striking that the participants had no pain. The symptoms disappeared after the cast was removed. Several activation mobilization treatments have been developed for this mechanism that can play a role in CRPS, varying from regular physiotherapy to graded exposure.

Interactions Between the Different Mechanisms CRPS appears to be the result of a complex cascade. The trigger is usually tissue or nerve damage. This leads to sterile inflammation, which is initially physiologic. For unclear reasons, this inflammation runs out of control and does not normally stop after healing. Continuing inflammation leads to spinal and supraspinal changes in sensory and motor skills. Continuing inflammation can also lead to endothelial dysfunction, an increase in α receptors, and small fiber neuropathy. In many patients, inflammatory symptoms are prominent in the early stages. Often, but not always, these symptoms disappear over time, and neuropathic/nociplastic, vasomotor, and/or motor dysregulation become more prominent. However, there are also patients in whom the affected extremity is cold from the start. In this respect, patients with CRPS can be divided into subtypes, although this is difficult because there is a lot of overlap. Such a classification is relevant because it makes the treatment more mechanically oriented and better tailored to the individual patient. Bruehl distinguished several subtypes in a cluster analysis:20

502

PA RT 4 Clinical Conditions: Evaluation and Treatment

• a relatively limited syndrome in which vasomotor symptoms are prominent • a relatively limited syndrome in which neuropathic/nociplastic pain and/or sensory disturbances are prominent • a profuse CRPS syndrome in accordance with the classic description An important question remains as to why some develop and others do not get CRPS and, even more remarkably, how someone who has experienced major trauma does not advance to the pain syndrome while others progress into a thunderous CRPS after minor trauma. The process is likely determined by a combination of intrinsic factors, such as genetic susceptibility or an autoimmune disease that is acquired or not, extrinsic factors such as the type of trauma and treatment, and environmental factors.

Epidemiology Various studies have reported different incidence rates for the general population in different studies. A North American study found an incidence of 5.5/100,000 person-years.21 A Dutch study noted, depending on the diagnostic evaluation strategy used, an incidence of 20 to 26.2/100,000 person-years.22 This discrepancy may result from differences in population characteristics (ethnicity, rural versus urban), in social, no-life, or health insurance, and in how the diagnosis is defined and classified. The Dutch data show that CRPS occurs more often in the upper extremity and that a fracture is the most common cause. There was no relationship between the severity of initiating trauma and the risk of developing CRPS. CRPS can develop at any age; the peak is between 50 and 70 years of age. The incidence in women is 3.4 times higher than that in men. Several case reports have described the frequent co-occurrence of CRPS and chronic inflammatory diseases such as amyotrophic lateral sclerosis and Ehlers-Danlos disease. There is some evidence that autoimmunity plays a role in the pathophysiology of CRPS. Several case reports and small observational studies suggest an association between CRPS and previous exposure to certain viruses and bacteria, such as parvovirus B19.23 About 35% of CRPS patients have autoantibodies against sympathetic neurons, mesenteric plexus neurons, and differentiated cholinergic neuroblastoma lines. There are indications of a possible genetic predisposition to CRPS. Associations have been found with different polymorphisms of human leukocyte antigen (HLA) and with a TNF-α polymorphism.24 The findings regarding the role of an ACE gene are contradictory. CRPS is more common in certain families. The prognosis of this condition remains unclear. In a Dutch study of patients with an average disease duration of 5.8 years, three-quarters of the participants still reported sensory and motor trophic disturbances, and some people still had vasomotor and sudomotor complaints.25

Clinical Features The clinical presentation of CRPS is heterogeneous and may vary over time in the same patient.

Medical History The condition often develops distally in one extremity. The affected area was often more extensive than the ​​ original damage. The complaints are characterized by a combination of pain, sensory, vasomotor, sudomotor, motor, and trophic symptoms. The pain is continuous.

TABLE 35.1

New IASP Criteria26

1. Continuous persistent pain that is disproportionate to the severity of an injury 2. From at least three of the following four categories, one symptom must be reported by the patient: • sensory: hyperesthesia and/or allodynia • vasomotor: temperature asymmetry, skin color changes, and/or skin color asymmetry • sudomotor/edema: edema and/or sweating changes and/or sweating asymmetry • motor/trophic: reduced range of motion and/or motor dysfunction (weakness, tremor, dystonia) 3. From at least two of the following categories, one symptom must be demonstrated at the time of evaluation: • sensory: evidence of hyperalgesia (pinprick) and/or allodynia (light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement) • vasomotor: evidence of temperature asymmetry (>1°C) and/or skin color changes and/or skin color asymmetry • sudomotor/edema: evidence of edema and/or changes in perspiration and/or perspiration asymmetry • motor/trophic: evidence of a reduced range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin) 4. There is no other diagnosis that better explains the symptoms The criteria in Table 35.1 apply for clinical purposes. For research purposes, the diagnostic decision rule is that it is anamnestic in each of the four at least one symptom is identified, and at the physical examination, at least one symptom in two or more categories.

The skin is hypersensitive to touch. Asymmetry can occur in temperature, color, edema, and/or sweating. Sometimes the range of motion is decreased, and sometimes there are motor impairments such as weakness, tremor, or dystonia. Changes in hair and/or nail growth may also occur. Often, the symptoms are not constant over time. CRPS can worsen with the exertion of the affected extremities. The diagnosis of CRPS is based on these criteria. The criteria most commonly used today were originally initiated by Harden and Bruehl.26 These were later called the Budapest criteria. After acceptance by the IASP, they are referred to as the new IASP criteria for CRPS. (See Table 35.1.)

Physical Examination Vasomotor, sudomotor, and trophic signs may be present on inspection. There may be a difference in skin color, edema, hair, and nail growth between the affected and unaffected extremities. Sensory and vasomotor symptoms may be present on palpation. There may be allodynia, hyperalgesia, and skin temperature differences between the affected and contralateral extremities. Motor abnormalities such as loss of function, loss of strength, stiffness, and pain, involuntary movements, tremor, and dystonia may occur during motor function tests. There are no specific clinical tests for the diagnosis of CRPS. Additional neurologic examination of sensitivity, strength, and reflexes did not reveal any other abnormalities besides the abnormalities previously mentioned.

Additional Research Several additional studies are possible, but none are pathognomonic.27 Sometimes supplemental testing is necessary to rule out other diagnoses. Several methods have been developed to classify

 

CHAPTER 35

Evaluation and Treatment of Complex Regional Pain Syndrome

and quantify the clinical signs and symptoms of CRPS. These can be used in the context of research or to assess whether a patient meets the CRPS criteria. However, they have no additional value for clinical diagnosis. Examples are: • infrared temperature measurements

Quantitative Sensory Tests Volumetry and finger diameter in edema of the extremities

Differential Diagnosis Many symptoms that can occur with CRPS also occur under other conditions. Therefore CRPS has an extensive differential diagnosis (see Table 35.2).28 In addition to inflammation, neuropathic, myofascial pain syndromes, degenerative disorders, vascular disease, and psychogenic disorders can be distinguished.

Treatment Many different therapies are used in CRPS, but most have not been proven to be effective. One problem is that treatment targeting one of the mechanisms involved usually treats only part of the pathophysiology. Treatment outcomes can be improved if patients are divided into subgroups. The choice of therapy should be guided by the symptoms most prominent in a particular patient. A common assumption is that the sooner the therapy starts, the better the result will be. This has never been demonstrated, but it seems likely that persistent inflammation will lead to damage: the sooner treatment starts, the less damage the disease can cause. Also widely accepted is the idea that CRPS patients, especially if they have had the disease for a long time, benefit most from multidisciplinary treatment combining pharmacotherapy, invasive techniques, physiotherapy, occupational therapy, and psychotherapy. The individual treatments can be divided into anti-inflammatory, activation of mobilization, analgesic, vasodilating, spasmolytic, and psychological treatments. Generally, one will start with more conservative treatments and move to invasive treatments only after conservative treatment has failed.

TABLE 35.2

503

Differential Diagnosis of CRPS4

Neuropathic pain syndromes Peripheral polyneuropathy Nerve entrapment Radiculopathy Postherpetic neuralgia Post-CVA deafferentation pain

Myofascial pain syndromes Overload CANS Disuse Fibromyalgia Non-specific myofascial pain

Degenerative disorders (Pseudo) osteoarthritis Chronic tendinopathy Malposition or pseudoarthrosis after fracture

Inflammation Epicondylitis Bursitis Tendonitis Erysipelas Seronegative arthritis

Rheumatoid arthritis Vascular disease Thrombosis Atherosclerosis

Anti-Inflammatory Treatment Dimethyl Sulfoxide and N-Acetyl-L-cysteine Oxygen radical scavengers, such as dimethyl sulfoxide (DMSO) and N-acetyl-L-cysteine ​​(NAC), appear to have a positive effect. Intravenous mannitol did not have any effect. DMSO and NAC are excellent therapies in European countries, especially the Netherlands. However, the use of these drugs is much less in other parts of the world.29 Immune Modulating Drugs21

Acrocyanosis Raynaud’s phenomenon Erythromelalgia Charcot’s disease

Psychogenic disorders Somatoform disorder Munchhausen syndrome CANS, Complaints of arm, neck, and/or shoulder; CVA, cerebrovascular accident.

Corticosteroids

Corticosteroids have been shown to be effective in small studies, but their efficacy in practice remains limited. Side effects, in particular, require great restraint.30

TNF-α Inhibitors

TNF-α is a pro-inflammatory cytokine. Thus the effect of antiTNF probably relies on the inhibition of the inflammatory cytokine cascade. The literature contains two case reports and one report of a prematurely terminated randomized control trial

(RCT).31–33 The case reports show a favorable effect. The provisionally terminated RCT did not provide a clear conclusion regarding the place of this therapy. Thalidomide inhibits monocyte TNF-α production thalidomide had a favorable outcome in two case reports and open-label studies.34–36 Lenalidomide is a third-generation thalidomide. An RCT did not show any beneficial effects.37 The adverse effects were serious.

504

PA RT 4 Clinical Conditions: Evaluation and Treatment

Bisphosphonates

Bisphosphonates influence the production of pro- and antiinflammatory cytokines. The literature contains four double-blind RCTs.38–41 The RCTs examined the effects of oral or intravenous alendronate, clodronate, and pamidronate and found a significant reduction in pain. Immunoglobulins

The mechanism of action of immunoglobulins is based on complex interference with the immune system. The literature contains a double-blind RCT, which compared intravenous immunoglobulin with placebo, the pain intensity in the treatment group decreased 1.55 units more on an 11 point numeric scale than in the placebo group.42

Activation and Mobilization Fear of pain can lead to kinesiophobia (fear of physical movement and activity), disuse, prolonged immobilization of the affected extremity, and eventually rigidity and muscle atrophy.43 Physiotherapy has a positive effect on the patient’s activity level, reduces edema, improves blood flow, prevents muscle atrophy, contractures, and fear of movement, and promotes functional recovery. It is recommended to prescribe activation and mobilization therapy in all patients with CRPS. Analgesia Pain in CRPS can be the result of several underlying mechanisms. Inflammation causes nociceptive pain, and vasomotor disorder causes ischemic pain, which is mixed nociceptive and neuropathic; central sensitization causes nociplastic pain. Additionally, thin fiber neuropathy and, the underlying lesion of the somatosensory system in CRPS 2 will cause neuropathic pain. Dystonia and contractures cause nociceptive pain. Based on the underlying and predominant pain category (nociceptive, nociplastic, neuropathic), a choice can be made from one or a combination of painkillers. The efficacy of individual analgesics in patients with CRPS has also been studied. Only a minor effect of gabapentin and S-ketamine has been demonstrated.44,45 No effect has been shown for other drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, other anti-epileptics, and anti-depressants. It is conceivable that there is a place for these drugs, but especially when prescribing NSAIDs and opioids, care must be taken with close monitoring for side effects and preferably only for the short term. Vasodilation

There is evidence that local application of NO via an isosorbide dinitrate ointment 1% or 2% and/or a phosphodiesterase inhibitor is effective in patients with endothelial dysfunction with NO and endothelin-1 imbalance.46 Autonomic dysfunction and/or ongoing inflammation increase the number of α receptors. Calcium blockers, such as verapamil, can be effective.47,48 Ketanserin intravenously appears to be effective.49 Based on this, it is also prescribed orally, but the effectiveness of this route has not been proven.

Spasmolytic Therapy

Based on the observation that intrathecal baclofen can be effective in the treatment of dystonia in CRPS, the GABA system is believed to play a role. From the recommendation that we first start as conservatively as possible, oral antispasmodic therapy with benzodiazepines (diazepam or clonazepam) or baclofen is prescribed, but unlike the intrathecal administration of baclofen,

there is insufficient evidence supporting the effectiveness of this route.50 Although widely used, there is also no evidence of the efficacy of botulinum toxin A for the treatment of dystonia in CRPS patients.51 Psychological Counseling, Pain Management, and Rehabilitation Therapy

If components of perception or behavior perpetuate the clinical picture or cause much suffering, psychological treatment or a pain management program can be valuable. Disability in CRPS is the sum of the damage and disability.

Invasive Treatments

Several invasive treatments are available. In general, it is advisable to start with more conservative methods and start with more invasive therapies if the patients are refractory. The efficacy of invasive pain therapies has recently been summarized in an update of the evidence-based guidelines on invasive pain treatment.52

Sympathetic blocks

The application of sympathetic blocks is based on the idea that autonomic nervous system dysfunction and an increase in α receptors play a central role in CRPS. It is also believed that a pathologic connection may arise between the somatosensory system and the sympathetic system, causing sympathetic mediated pain.

Intravenous Block With Guanethidine Intravenous sympathetic blockade with guanethidine has been widely used in the past, based on the idea that guanethidine depletes norepinephrine in nerve endings. There is moderate evidence that intravenous regional blocks with guanethidine for the treatment of CRPS do not provide better pain relief than placebo at one, three, and six months.53 Blocks of the Sympathetic Chain There are several ways to block the sympathetic ganglion: with a local anesthetic (repeated or not), with a neurolytic agent such as alcohol or phenol, botulinum toxin, or radiofrequency lesion. While it has been widely advocated and practiced in the past, the evidence is disappointing. Sympathetic Blocks With Local Anesthetics There is conflicting evidence that sympathetic blocks are effective. A Cochrane review showed moderate evidence that sympathetic blocks with a local anesthetic at the cervical and lumbar levels are ineffective for the treatment of complex regional pain.54 However, there is low quality evidence showing that thoracic sympathetic blocks (T2-3) with ropivacaine and triamcinolone reduce pain significantly better in patients with upper extremity CRPS than a subcutaneous injection 12 months after treatment.55 A more recent retrospective study showed very low quality evidence that sympathetic blocks with local anesthetics (with or without corticosteroids) to be effective (greater than 50% relief) in 61% of patients (155 of 255), with relief las­ ting one to four weeks or longer. In this study, the Budapest criteria were used, and the sympathetic blocks consisted of either stellate ganglion blocks, T1-T3 sympathetic blocks, or L2-L4 for lumbar sympathetic blocks.56 They also noted that the effects of sympathetic blocks did not predict the success of spinal cord stimulation. There seems to be a place for sympathetic blockades, especially because of the minimal invasiveness of the treatment, the low cost, and the lack of more conservative alternatives. Further research is necessary, especially focusing on predictors of outcomes.

 

CHAPTER 35

Evaluation and Treatment of Complex Regional Pain Syndrome

505

Neurostimulation

DRG Stimulation

Neurostimulation is a direct clinical application of the gate-control. Primarily, it is used to treat neuropathic pain, but with stimulation of the spinal cord and stimulation of the DRG, there are additional effects on the vasomotor disturbance and possibly inflammation, as well as stimulation of the DRG on motor dysfunction. This is probably why spinal cord stimulation and spinal ganglion stimulation are among the most effective treatments for CRPS. Neurostimulation has simultaneous effects on the multiple mechanism which can play a role in the pathophysiology of CRPS.

A randomized controlled trial (ACCURATE study)59 demonstrated the superiority of DRG stimulation over conventional SCS stimulation at three and 12 months of follow up in patients with lower extremity CRPS.

Transcutaneous Electrical Nerve Stimulation (TENS) TENS is widely used. However, there is no evidence to suggest that TENS is effective. Spinal Cord Stimulation (SCS) There is moderate evidence that SCS reduces pain in patients with complex regional pain syndrome.57 A randomized placebo-controlled study with 29 CRPS patients was found to have a statistically and clinically significant effect on pain for different stimulation modes than a placebo after a two week test period.58

Peripheral Nerve Stimulation There is evidence of very low quality that in CRPS, peripheral nerve stimulation effectively reduces pain during long term follow up and reduces pain-related disability.60

Intrathecal Baclofen If conventional spasmolytic treatments are ineffective, baclofen can be considered intrathecally. It is a technically complex treatment with many potential side effects.61

Prophylaxis In an RCT, it has been shown that vitamin C has a protective effect against the development of CRPS-1 after wrist fractures.62 If a person with a history of CRPS has new trauma or requires surgery on an extremity, prophylactic therapy with vitamin C may be considered. Vitamin C can be administered during the perioperative period.

Summary CRPS is a complication of tissue and/or nerve damage. Multiple pathophysiologic mechanisms, including autoinflammation, sensory, vasomotor and sudomotor, and motor/trophic disorders, may play a role simultaneously. Depending on the

most prominent mechanism, different phenotypes can be distinguished. Treatment appears to be the most effective when it is mechanism oriented.

Key Points • Several mechanisms contribute to the development of the CRPS. These include afferent mechanisms such as inflammation and endothelial dysfunction, efferent mechanisms such as changes in the somatosensory and autonomic nervous system, and central mechanisms, including cortical reorganization and psychological factors. • Subtypes of CRPS include a relatively limited syndrome in which vasomotor symptoms are prominent, a relatively limited syndrome in which neuropathic/nociplastic pain and/or sensory disturbances are prominent, and a profuse CRPS syndrome in accordance with the classic description. • The commonly used criteria for CRPS are the Budapest criteria, now referred to as the new IASP criteria for CRPS. • Many therapies have been used in CRPS, but their effectiveness has not been proven. This is because the treatment targets one of the mechanisms involved, treating only a part of the pathophysiology. The choice of therapy should be guided by the symptoms most prominent in a particular patient. • The individual treatments can be divided into anti-inflammatory, activation of mobilization, analgesic, vasodilating, spasmolytic, and psychological treatments.

• One usually starts with more conservative treatments and move to invasive treatments after conservative approaches have failed. • Of the anti-inflammatory pharmacologic medications, biphosphonates appear to be effective. • Physiotherapy has a positive effect on the patient’s activity level, reduces edema, improves blood flow, prevents muscle atrophy, contractures, fear of movement, and promotes functional recovery. • Oral antispasmodic therapy with benzodiazepines (diazepam or clonazepam) or baclofen was attempted. Unlike the intrathecal administration of baclofen, there is insufficient evidence regarding the effectiveness of the oral route. Intrathecal baclofen is technically complex and has many potential side effects. • Sympathetic blocks with local anesthetics have not been uniformly effective. • There is moderate evidence that SCS reduces pain in patients with CRPS. • There is initial evidence of the superiority of DRG stimulation over conventional SCS in patients with lower extremity CRPS. • There is very low quality evidence that peripheral nerve stimulation effectively reduces CRPS pain and diminishes painrelated disability.

506

PA RT 4 Clinical Conditions: Evaluation and Treatment

Suggested Readings Bharwani KD, Dirckx M, Huygen FJ. Complex regional pain syndrome: Diagnosis and treatment. BJA Educ. 2017;17(8):262–268. Cheng J, Salmasi V, You J, et al. Outcomes of sympathetic blocks in the management of complex regional pain syndrome: A retrospective cohort study. Anesthesiol. 2019;131(4):883–893. Deer TR, Levy RM, Kramer J, et al. Dorsal root ganglion stimulation yielded a higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months in a randomized comparative trial. Pain. 2017;158(4):669–681. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC. The incidence of complex regional pain syndrome: A population-based study. Pain. 2007;129(1-2):12–20. Dirckx M, Stronks DL, Groeneweg G, Huygen FJ. Effect of immunomodulating medications in complex regional pain syndrome: A systematic review. Clin J Pain. 2012;28(4):355–363. Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8(4):326–331.

Huygen F, Kallewaard JW, van Tulder M, et al. “Evidence-based interventional pain medicine according to clinical diagnoses”: Update. Pain Pract. 2018;19(6):664–675. Kemler MA, Barendse GA, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med. 2000;343(9):618–624. Rocha Rde O, Teixeira MJ, Yeng LT, et al. Thoracic sympathetic block for the treatment of complex regional pain syndrome type I: A doubleblind randomized controlled study. Pain. 2014;155(11):2274–2281. van Rijn MA, Munts AG, Marinus J, et al. Intrathecal baclofen for dystonia in complex regional pain syndrome. Pain. 2009;143(1-2):41–47. Stanton TR, Wand BM, Carr DB, Birklein F, Wasner GL, O’Connell NE. Local anesthetic sympathetic blockade for complex regional pain syndrome. Cochrane Database Syst Rev. 2013;8(8):CD004598. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on the frequency of reflex sympathetic dystrophy in wrist fractures: a randomized trial. Lancet. 1999;354(9195):2025–2028. The references for this chapter can be found at ExpertConsult.com.

References 1. Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: Prospective study of 829 patients. Lancet. 1993;342(8878):1012–1016. 2. Stanton-Hicks M, Jänig W, Hassenbusch S, Haddox JD, Boas R, Wilson P. Reflex sympathetic dystrophy: Changing concepts and taxonomy. Pain. 1995;63(1):127–133. 3. Bruehl S, Maihöfner C, Stanton-Hicks M, et al. Complex regional pain syndrome: Evidence for warm and cold subtypes in a large prospective clinical sample. Pain. 2016;157(8):1674–1681. 4. Bharwani KD, Dirckx M, Huygen FJ. Complex regional pain syndrome: Diagnosis and treatment. BJA Educ. 2017;17(8):262–268. 5. Bharwani KD, Dik WA, Dirckx M, Huygen FJPM. Highlighting the role of biomarkers of inflammation in the diagnosis and management of complex regional pain syndrome. Mol Diagn Ther. 2019;23(5):615–626. 6. Huygen FJ, De Bruijn AG, De Bruin MT, Groeneweg JG, Klein J, Zijlstra FJ. Evidence for local inflammation in complex regional pain syndrome type 1. Mediators Inflamm. 2002;11(1):47–51. 7. Uçeyler N, Eberle T, Rolke R, Birklein F, Sommer C. Differential expression patterns of cytokines in complex regional pain syndrome. Pain. 2007;132(1-2):195–205. 8. Krämer HH, Eberle T, Üçeyler N, et al. TNF-α in CRPS and ‘normal’ trauma - significant differences between tissue and serum. Pain. 2011;152(2):285–290. 9. Bharwani KD, Dirckx M, Stronks DL, Dik WA, Huygen FJPM, Dozio E. Serum soluble interleukin-2 receptor does not differentiate complex regional pain syndrome from other pain conditions in a tertiary referral setting. Mediators Inflam. 2020:1–10 Sep6259064. 10. Groeneweg JG, Huygen FJ, Heijmans-Antonissen C, Niehof S, Zijlstra FJ. Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1. BMC Musculoskelet Disord. 2006;7:91. 11. Finch PM, Drummond ES, Dawson LF, Phillips JK, Drummond PD. Up-regulation of cutaneous α1 -adrenoceptors in complex regional pain syndrome type I. Pain Med. 2014;15(11):1945–1956. 12. Albrecht PJ, Hines S, Eisenberg E, et  al. Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain. 2006;120(3):244–266. 13. Oaklander AL, Rissmiller JG, Gelman LB, Zheng L, Chang Y, Gott R. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain. 2006;120(3):235–243. 14. Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain. 2016;157(7):1382–1386. 15. Wasner G, Heckmann K, Maier C, Baron R. Vascular abnormalities in acute reflex sympathetic dystrophy (CRPS I): Complete inhibition of sympathetic nerve activity with recovery. Arch Neurol. 1999;56(5):613–620. 16. van Hilten JJ, van de Beek WJ, Vein AA, van Dijk JG, Middelkoop HA. Clinical aspects of multifocal or generalized tonic dystonia in reflex sympathetic dystrophy. Neurol. 2001;56(12):1762–1765. 17. Pleger B, Ragert P, Schwenkreis P, et al. Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome. Neuroimage. 2006;32(2):503–510. 18. Beerthuizen A, van’t Spijker A, Huygen FJ, Klein J, de Wit R. Is there an association between psychological factors and the complex regional pain syndrome type 1 (CRPS1) in adults? A systematic review. Pain. 2009;145(1-2):52–59. 19. Terkelsen AJ, Bach FW, Jensen TS. Experimental forearm immobilization in humans induces cold and mechanical hyperalgesia. Anesthesiol. 2008;109(2):297–307. 20. Bruehl S, Harden RN, Galer BS, Saltz S, Backonja M, StantonHicks M. Complex regional pain syndrome: Are there distinct subtypes and sequential stages of the syndrome? Pain. 2002;95(12):119–124.

21. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type I: Incidence and prevalence in Olmsted county, a population-based study. Pain. 2003;103(1-2):199–207. 22. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC. The incidence of complex regional pain syndrome: A population-based study. Pain. 2007;129(1-2):12–20. 23. van de Vusse AC, Goossens VJ, Kemler MA, Weber WE. Screening of patients with complex regional pain syndrome for antecedent infections. Clin J Pain. 2001;17(2):110–114. 24. van Rooijen DE, Roelen DL, Verduijn W, et al. Genetic HLA associations in complex regional pain syndrome with and without dystonia. J Pain. 2012;13:784–789. 25. de Mos M, Huygen FJ, van der Hoeven-Borgman M, Dieleman JP, Ch Stricker BH, Sturkenboom MC. Outcome of the complex regional pain syndrome. Clin J Pain. 2009;25(7):590–597. 26. Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8(4):326–331. 27. Geertzen JHB, Perez RSGM, Dijkstra PU, et al. Guideline Complex Regional Pain Syndrome Type I. Utrecht: Quality Institute for Healthcare Cbo/Dutch Association of Rehabilitation Physicians. Netherlands: Dutch Association of Anesthesiology; 2006. 28. van Eijs F, Stanton-Hicks M, Van Zundert J, et al. Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome. Pain Pract. 2011;11(1):70–87. 29. Perez MRSG, Zuurmond AWW, Bezemer DP, et al. The treatment of complex regional pain syndrome type I with free radical scavengers: A randomized controlled study. Pain. 2003;102(3):297–307. 30. Dirckx M, Stronks DL, Groeneweg G, Huygen FJ. Effect of immunomodulating medications in complex regional pain syndrome: A systematic review. Clin J Pain. 2012;28(4):355–363. 31. Huygen FJ, Niehof S, Zijlstra FJ, van Hagen PM, van Daele PL. Successful treatment of CRPS 1 with anti-TNF. J Pain Symptom Manage. 2004;27(2):101–103. 32. Bernateck M, Rolke R, Birklein F, Treede RD, Fink M, Karst M. Successful intravenous regional block with low-dose tumor necrosis factor-alpha antibody infliximab for treatment of complex regional pain syndrome 1. Anesth Analg. 2007;105(4):1148–1151 table of contents. 33. Dirckx M, Groeneweg G, Wesseldijk F, Stronks DL, Huygen FJ. Report of a preliminary discontinued double-blind, randomized, placebo-controlled trial of the anti-TNF-alpha chimeric monoclonal antibody infliximab in complex regional pain syndrome. Pain Pract. 2013;13(8):633–640. 34. Rajkumar SV, Fonseca R, Witzig TE. Complete resolution of reflex sympathetic dystrophy with thalidomide treatment. Arch Intern Med. 2001;161(20):2502–2503. 35. Ching DW, McClintock A, Beswick F. Successful treatment with low-dose thalidomide in a patient with both Bechet’s disease and complex regional pain syndrome type I: Case report. J Clin Rheumatol. 2003;9(2):96–98. 36. Schwartzman RJ, Chevlen E, Bengtson K. Thalidomide has activity in treating complex regional pain syndrome. Arch Intern Med. 2003;163(12):1487–1488 author reply 1488. 37. Manning DC, Alexander G, Arezzo JC, et  al. Lenalidomide for complex regional pain syndrome type 1: Lack of efficacy in a phase II randomized study. J Pain. 2014;15(12):1366–1376. 38. Manicourt DH, Brasseur JP, Boutsen Y, Depreseux G, Devogelaer JP. Role of alendronate in therapy for post-traumatic complex regional pain syndrome type I of the lower extremity. Arthritis Rheum. 2004;50(11):3690–3697. 39. Adami S, Fossaluzza V, Gatti D, Fracassi E, Braga V. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis. 1997;56(3):201–204. 40. Varenna M, Zucchi F, Ghiringhelli D, et  al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study. J Rheumatol. 2000;27(6):1477–1483. 506.e1

506.e2

References

41. Robinson JN, Sandom J, Chapman PT. Efficacy of pamidronate in complex regional pain syndrome type I. Pain Med. 2004;5(3): 276–280. 42. Goebel A, Baranowski A, Maurer K, Ghiai A, McCabe C, Ambler G. Intravenous immunoglobulin treatment of the complex regional pain syndrome: A randomized trial. Ann Intern Med. 2010;152(3):152–158. 43. Marinus J, Perez RS, van Eijs F, et al. The role of pain coping and kinesiophobia in patients with complex regional pain syndrome type 1 of the legs. Clin J Pain. 2013;29(7):563–569. 44. van de Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE. Randomised controlled trial of gabapentin in complex regional pain syndrome type 1 [ISRCTN84121379]. BMC Neurol. 2004;4:13. 45. Sigtermans MJ, van Hilten JJ, Bauer MCR, et  al. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome Type 1. Pain. 2009;145(3):304–311. 46. Groeneweg G, Huygen FJ, Niehof SP, et  al. Effect of tadalafil on blood flow, pain, and function in chronic cold complex regional pain syndrome: A randomized controlled trial. BMC Musculoskelet Disord. 2008;9:143. 47. Muizelaar JP, Kleyer M, Hertogs IA, DeLange DC. Complex regional pain syndrome (reflex sympathetic dystrophy and causalgia): Management with the calcium channel blocker nifedipine and/ or the alpha-sympathetic blocker phenoxybenzamine in 59 patients. Clin Neurol Neurosurg. 1997;99(1):26–30. 48. Prough DS, McLeskey CH, Poehling GG, et al. Efficacy of oral nifedipine in the treatment of reflex sympathetic dystrophy. Anesthesiol. 1985;62(6):796–799. 49. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain. 1997;73(2):123–139. 50. Marsden CD, Obeso JA, Traub MM, Rothwell JC, Kranz H, La Cruz F. Muscle spasms associated with Sudeck’s atrophy after injury. Br Med J (Clin Res Ed). 1984;288(6412):173–176. 51. Cordivari C, Misra VP, Catania S, Lees AJ. Treatment of dystonic clenched fist with botulinum toxin. Mov Disord. 2001;16(5):907–913.

52. Huygen F, Kallewaard JW, van Tulder M, et  al. “Evidence-based interventional pain medicine according to clinical diagnoses”: Update. Pain Pract. 2018;19(6):664–675. 53. Jadad AR, Carroll D, Glynn CJ, McQuay HJ. Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: A systematic review and a randomized, double-blind crossover study. J Pain Symptom Manage. 1995;10(1):13–20. 54. Stanton TR, Wand BM, Carr DB, Birklein F, Wasner GL, O’Connell NE. Local anaesthetic sympathetic blockade for complex regional pain syndrome. Cochrane Database Syst Rev. 2013;8(8):CD004598. 55. Rocha Rde O, Teixeira MJ, Yeng LT, et al. Thoracic sympathetic block for the treatment of complex regional pain syndrome type I: A doubleblind randomized controlled study. Pain. 2014;155(11):2274–2281. 56. Cheng J, Salmasi V, You J, et al. Outcomes of sympathetic blocks in the management of complex regional pain syndrome: A retrospective cohort study. Anesthesiol. 2019;131(4):883–893. 57. Kemler MA, Barendse GA, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med. 2000;343(9):618–624. 58. Kriek N, Groeneweg JG, Stronks DL, de Ridder D, Huygen FJ. Preferred frequencies and waveforms for spinal cord stimulation in patients with complex regional pain syndrome: A multicentre, double-blind, randomized and placebo-controlled crossover trial. Eur J Pain. 2017;21(3):507–519. 59. Deer TR, Levy RM, Kramer J, et al. Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: A randomized comparative trial. Pain. 2017;158(4):669–681. 60. Buschmann D, Oppel F. Peripheral nerve stimulation for pain relief in CRPS II and phantom-limb pain. Schmerz. 1999;13(2):113–120. 61. van Rijn MA, Munts AG, Marinus J, et al. Intrathecal baclofen for dystonia of complex regional pain syndrome. Pain. 2009;143(1-2): 41–47. 62. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: A randomised trial. Lancet. 1999;354(9195):2025–2028.

36

Evaluation and Treatment of Pain in Selected Neurologic Disorders AMIR HADANNY, ANNA BLANCHFIELD, OLGA KHAZEN, CHARLES E. ARGOFF, JULIE G. PILITSIS

Pain in Selected Neurologic Disorders Although chronic pain may be the defining feature of certain neurologic disorders, physicians often focus on treatments aimed at addressing the primary neurologic condition. As most comorbidities may come from pain associated with the condition, it should be addressed early during treatment. Chronic pain is a three-dimensional process consisting of biologic, psychological, and social components. All three interact dynamically and affect the states of the others. Here, we provide a basic pathophysiologic explanation of pain that accompanies these conditions and treatment strategies to complement disease-based treatments and improve the quality of life of affected individuals. Although it is not possible to include every disorder in which pain is a feature, this chapter discusses the pertinent features of diseases that pain specialists are likely to encounter with some frequency (see the reference list for detailed reviews of each disorder in the literature, when available). We focused on the evaluation, diagnosis, and treatment of neuropathies due to peripheral nerve, spinal cord, and brain pathologies (Table 36.1). Chapter 34 discusses complex regional pain syndrome (CRPS); postherpetic neuralgia and diabetic peripheral neuropathy are addressed in Chapter 33. More details on neuroanatomy and pathophysiology can be found in Chapters 8 and 9.

Peripheral Neuropathies Most instances of painful peripheral neuropathies are acquired and can be divided into metabolic, autoimmune, infectious, traumatic, iatrogenic, and idiopathic etiologies (Table 36.2). Evaluation begins with a medical history, physical and neurologic examinations, and laboratory tests. Nerve conduction studies (NCS), electromyography (EMG), autonomic function assessment, cerebrospinal fluid analysis (CSF), magnetic resonance imaging (MRI), and biopsy may be included.

The Workup To differentiate among the different types of neuropathies, a detailed history must be obtained. Specifically, the time course, presence and characteristics of sensory, motor, and autonomic symptoms, the distribution of symptoms (proximal and/or distal, hands and/or feet, symmetric/asymmetric), and intensity must be assessed. Medical history, social history, family history, medications,

and exposure to toxins must be considered. The duration of symptoms is important in categorizing neuropathy into acute (12 weeks). Acute inflammatory demyelinating polyradiculoneuropathy (GuillainBarre syndrome [GBS]) peaks at four weeks of onset, and progression beyond eight weeks suggests chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Based on their distribution, neuropathies can be categorized as mononeuropathy (single peripheral nerve involvement, usually due to trauma, compression, or entrapment), mononeuropathy multiplex (multiple, separate noncontiguous peripheral nerves either simultaneously or sequentially, commonly due to systemic vasculitis), and polyneuropathy (toes and soles are affected first and hands later, usually due to metabolic, toxic, or systemic disorders). Sensory symptoms include positive (burning, pain, walking on cotton wool, band-like sensation on the feet or trunk, stumbling, tingling, pins and needles) and negative symptoms (numbness, loss of sensation) in the hands and feet. Motor symptoms include weakness and fine motor difficulties (e.g. unfastening a button and opening bottles). Autonomic symptoms, such as postural hypotension, impotence, sphincter disturbance, diarrhea, constipation, dryness, and excessive sweating, point to the involvement of small myelinated or unmyelinated nerve fibers.1 Medical history should look for systemic diseases that can be associated with neuropathy, such as diabetes, hypothyroidism, chronic infections, and/or autoimmune diseases. Aside from chemotherapeutic agents that may cause polyneuropathy, commonly used medications associated with polyneuropathy include pyridoxine (vitamin B6), phenytoin, linezolid, metronidazole, nitrofurantoin, isoniazid, chloramphenicol, dapsone, reverse transcriptase inhibitors, amiodarone, colchicine, and disulfiram.1 Family history should include ethnic background, consanguinity, and details about parents and siblings, such as the presence of high-arched feet, flatfeet, hammertoes, gait dysfunction, bilateral carpal tunnel syndrome, and other signs of possible inherited neuropathies.2 Social history includes the patient’s country of origin, potential occupational exposure, potential exposure to people with transmittable illness, alcohol and drug use, and travel history.3 Psychosocial assessment should be performed for depression, anxiety, personality disorders, substance use, and cognitive deficit comorbidities.4 Neurologic examination should include examination of cranial nerves, muscle power, tone, and reflexes, detailed evaluation 507

508

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 36.1

Pain Syndromes in Neurologic Disorders

Primary Disorder

Pain Location

Pain Classification and Descriptors

Etiologies

Peripheral neuropathy

Stocking-glove distribution

Neuropathic Burning, tingling, stabbing, dysesthesias

• • • • • • •

Metabolic (diabetes) Autoimmune (vasculitis) Idiopathic (trigeminal neuralgia, small fiber) Infectious (postherpetic) Trauma Iatrogenic (chemotherapy) Other

Spinal cord disorders

Radicular, transitional zone pain, deafferentation pain, musculoskeletal pain (shoulders), spasticity related pain (lower limbs), abdomen (visceral)

Neuropathic Constant burning, tingling, aching, evoked shooting pain Nociceptive Aching, dull Visceral Dull, cramping,dysreflexia, autonomic dysfunction

• • • • • •

Infectious Trauma (SCI) Tumor Demyelination (MS) Vascular (stroke, malformations) Other

Brain and brainstem lesions

Contralateral extremities, ipsilateral face (brainstem)

Neuropathic Aching, burning, dysesthesias, sharp Spasticity related Musculoskeletal

• • • • •

Vascular (stroke, malformations) Neurodegenerative Demyelination Trauma (TBI) Other

TABLE 36.2

Painful Peripheral Neuropathies

Classification by Cause

Examples

Metabolic disorders

Diabetes mellitus, vitamin deficiency (thiamine, vitamin B12), uremia

Toxins

Ethanol, heavy metals (arsenic, lead), industrial solvents

Drug induced

Chemotherapy, isoniazid, antiretroviral therapy

Trauma

Complex regional pain syndrome type 2, neuromas, postamputation pain, peripheral nerve trauma

Entrapment

Peroneal, ulnar, median (carpal tunnel syndrome), posterior tibial (tarsal tunnel syndrome)

Autoimmune

Connective tissue disorders, vasculitis, paraneoplastic disorders, GuillainBarré syndrome, chronic inflammatory demyelinating polyneuropathy

Infectious

Lyme disease, spirochetal infection, herpes zoster, cytomegalovirus infection

Hereditary

Familial amyloid polyneuropathy, Fabry’s disease

of all sensory modalities (pinprick, pain, temperature, vibration, and joint position), and an observation of the patient’s gait and the ability to stand up from a chair. Specific findings include anosmia (as in B12 deficiency), impaired pupillary light reflex (diabetes, GBS), ophthalmoplegia (GBS), and widespread reflex loss, including muscles that are not particularly weak or wasted,

favoring demyelinating neuropathy. In contrast, selective loss of ankle reflex in the presence of distal wasting and weakness is characteristic of axonopathy.2 Meticulous general physical examination can identify several clues for diagnosis, nail changes (Mee’s lines) in toxin poisoning (such as arsenic and thallium), musculoskeletal abnormalities, such as pes cavus, high-arched feet, and mutilation (usually hereditary neuropathy), skin changes, or nerve thickened nerves in rare diseases. Following history and examination, chronic, distal, slowly progressive, symmetric, predominantly sensory polyneuropathy can be diagnosed clinically without further testing. If any atypical feature is noted in the initial or subsequent evaluation, including asymmetry, severe early sensory complaints such as ataxia and loss of proprioception, early or severe pain, the predominance of or early motor involvement, proximal symptoms, and fast progre­ ssion, neurophysiologic testing should be pursued. Similarly, other than a classic presentation of acute GBS, all other acute neuropathies should be further evaluated. The clinical evaluation includes evaluation of complete blood count (CBC), erythrocyte sedimentation rate (ESR), fasting glucose or glucose tolerance test, liver and renal function tests, serum vitamin B12 and folate levels, thyroid function tests, serum protein electrophoresis, and immunofixation electrophoresis. The vasculitis profile (antinuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, extractable nuclear antigen, anti-Ro, anti-La) is added when patients suffer from related complaints, such as joint pain or Sicca syndrome. Human immunodeficiency virus (HIV), hepatitis B and C, and Lyme tests should be added based on risk factors or previous exposure. In case of alcohol abuse, malnutrition, absorption abnormalities, or vitamin toxicity, methylmalonic acid (especially when borderline B12), homocysteine (especially when borderline B12), pyridoxine (vitamin B6), thiamine (vitamin B1), and vitamin E should be evaluated. Heavy metals, including copper and zinc, can also be checked for patients with an exposure history. Sarcoidosis can be evaluated using serum or CSF angiotensin-converting enzyme, although the specificity

 

CHAPTER 36

Evaluation and Treatment of Pain in Selected Neurologic Disorders

is limited. Paraneoplastic markers, such as anti-Hu, can be added based on clinical suspicion and previous workup. For acute neuropathy, laboratory work should mainly include infections (West Nile virus, Hepatitis B, C, Rabies, HIV, CMV, Lyme, ESR, and CRP), heavy metal levels (arsenic, thallium, and lead), inflammatory panel (antinuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, cryoglobulins), serum and urine paraproteins, urine porphobilinogen, and urine porphyrin excretion for porphyria evaluation.5 In many cases, NCS of sensory and motor nerves, late responses (F response and H reflex), and needle EMG are performed. These tests do not provide information regarding the cause of neuropathy but enable the determination of the type (demyelinating vs. axonal) and localize the lesion more precisely than on clinical examination alone. This is valuable mainly in acute neuropathies,6 asymmetric neuropathies, and mononeuropathies. The classic demyelinating neuropathy findings include slowing of nerve conduction velocity, prolongation of terminal latency (F latencies), temporal dispersion, and prolonged compound muscle action potential (CMAP) or conduction block (decline in the compound muscle action potential exceeding 20% on proximal stimulation compared to that on distal stimulation). Axonal neuropathy usually shows mild slowing of nerve conduction (due to sparing of remaining axons), reduced CMAP amplitude, and fibrillations on EMG. Sensory nerve action potentials and sensory conduction velocities are reduced in both axonal and demyelinating neuropathies. However, sensory conduction studies evaluate only fast-conducting fibers, which may be normal in selective small fiber and autonomic neuropathies.3 Thus NCS and EMG tests are mainly useful for large fiber peripheral neuropathies rather than small fiber neuropathies. CSF analysis is indicated in acute neuropathies for GBS evaluation, and it is useful in chronic inflammatory demyelinating polyneuropathy and chronic immune-mediated axonal neuropathies where the levels of CSF protein are elevated. Significant pleocytosis can suggest other acute inflammatory neuropathies, such as Borrelia, sarcoidosis, and HIV. Nerve biopsy, usually taken from the sural nerve, remains the primary method of establishing vasculitis neuropathy when histology is unavailable elsewhere. Combined nerve and muscle biopsies are recommended to improve the diagnostic yield. The yield of biopsy in the diagnosis of chronic axonal neuropathies is very small and not justified when vasculitis is unlikely.3 Skin biopsy allows for the quantification of somatic and autonomic small nerve fibers. Small fiber neuropathy is diagnosed when intraepidermal nerve fiber density falls below age- and sex-adjusted normative reference values.7 Fine-needle aspiration biopsy of the abdominal fat pad with Congo red staining is a minimally invasive procedure used to demonstrate tissue deposits of amyloid in patients with neuropathy related to amyloidosis. In the case of autonomic neuropathy, bedside autonomic tests include blood pressure response to standing or vertical tilt (normal fall, 50% pain relief ) before permanent implant,53 which is difficult to treat with SCS. Dorsal root ganglion stimulation and intrathecal drug therapy (IDT) have shown higher efficacy.54 IDT involves the delivery of medications directly to their site of action at the dorsal horn of the spinal cord, bypassing the first pass effect and the blood–brain

 

CHAPTER 36

Evaluation and Treatment of Pain in Selected Neurologic Disorders

barrier. This significantly increases the potency of the medication, allowing much smaller doses to be used. For effective therapy, patient selection is crucial and should undergo a successful trial before implantation.

Pain Associated With Spinal Cord Disorders The differential diagnosis of spinal cord disorders that result in pain can be divided into infectious, demyelinating, vascular, trauma, and neoplastic etiologies. The evaluation includes specific history, physical/neurologic examination, and MRI imaging in most cases. The causes and locations of spinal cord disorders typically determine the need for surgical or medical management of the primary condition. Pain may be a prominent element in the manifestation of certain spinal cord disorders (e.g. spinal cord injury) or may occur as a late effect of the disease or therapy (e.g. radiation treatment or tumor resection). The characteristics of the pain experience, variable findings, and secondary pain generators are common to all spinal cord disorders.

The Workup To differentiate between the different types of spinal cord disorders, specific history should assess the speed of symptom onset (acute or chronic), disease course (monophasic, relapsing, progressive, complete or partial), additional clinical features (pain, visual symptoms in multiple sclerosis (MS), systemic symptoms in autoimmune disorders, and lung/eye/skin involvement in sarcoidosis. MRI can distinguish between lesions according to position, size, and enhancing pattern.55 Hyperacute onset (minutes to hours) includes vascular etiologies (spinal infarction and/or, more rarely, hemorrhage). Infarction phenotypes are classified according to the vascular supply involved. The most frequently encountered clinical presentation is symmetric motor dysfunction, bilateral spinothalamic sensory deficit below the level of the lesion, autonomic sphincter dysfunction, and flaccid weakness associated with areflexia. Weakness is due to anterior and lateral column dysfunction as a result of anterior spinal artery territory infarction. Posterior spinal artery infarcts are rare and involve proprioception and vibration loss below the level of the injury besides complete anesthesia at the level of the lesion.56 Acute/subacute onset (days to weeks) can suggest trauma, infectious, inflammatory, autoimmune, demyelinating, neoplastic, paraneoplastic, and metabolic etiologies. Etiologies of chronic onset (months to years) may include infectious, neoplastic, paraneoplastic, autoimmune, metabolic, and vascular causes.55 Tumors comprise a small percentage of cases. Here, the pain that slowly starts initially fluctuates prior to becoming more constant, gradually increases and worsens at night when the patient is recumbent, and eventually disturbs the patient even at rest and is considered the most typical sign for spinal tumors. Additional information should include medical, surgical, family, and detailed social histories. If a suspected infectious etiology occurs, patients should be further asked about any recent infection, an immunocompromised or autoimmune condition, spaceoccupying lesion, travel, vaccination, trauma, sexual exposure, and/or animal/insect bites. The assessment of pain as the chief complaint begins with medical history concerning pain descriptors, including pain onset, time course, pain location, intensity, quality, quantity, alleviating and aggravating factors, clonus and/ or spasticity, medications, and medications, previous evaluations,

513

and treatments. Associated cord symptoms, including bladder and bowel control, weakness, and altered sensations, should be investigated. Functional capacity history, including both occupational and recreational history, should be obtained for functional impact as well as possible pain promoters (such as wheelchair, crutch, or cane use).57 Psychosocial comorbidity assessment is required to assess depression, anxiety, personality disorders, substance use, personality disorders, and cognitive deficits.58 Physical examination should be broadly systemic and should focus on neurologic findings such as motor weakness, changes in sensation such as allodynia, hyperalgesia, and hyperpathia (pinprick, light touch, vibration, position sense, or temperature), tone, muscle stretch reflexes, coordination, muscle overactivity (clonus, spasticity, spasms), focal examination of specific pain regions, and bowel and bladder function. Local back tenderness may suggest trauma, osteoporotic fractures, or a tumor. Gait (if possible), how the walking aids are used, and functional capacity should all be observed. Following the history and physical examination, either computed tomography (CT) (in case of bony lesions) or MRI (preferred in most cases) is required for diagnosis.59 Short lesions (80%.

7, 8

Supraspinatus—origins above the scapular spine, near the medial border

9, 10

Second rib—upper lateral surface of the second costochondral joint

11, 12

Lateral epicondyle—2 cm distal to the epicondyles

13, 14

Gluteal—upper outer aspect of the buttock, anterior fold of the muscle

15, 16

Greater trochanter—posterior to the trochanteric prominence

17, 18

Knees—medial fat pad, just proximal to the medial condyle

Description Chronic, widespread (four quadrants) soft tissue pain for three months.

Adapted from Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia report of the multicenter criteria committee. Arthritis Rheum. 1990;33:160–172. FMS, Fibromyalgia syndrome.

The ACR used these categorical scales to develop a severity scale. Finally, they combined the severity scale with the WPI to stratify disease severity in patients with FM (Box 37.1). The diagnostic criteria for fibromyalgia were initially designed by unblinded rheumatologists for research purposes. With the evolution of diagnostics to extend to clinical space, a large proportion of clinically diagnosed fibromyalgia does not meet the research diagnostic criteria.6 A critical advance in our understanding of fibromyalgia is the evolution to symptom-based diagnosis and elimination of the tender point criteria, reflecting a shift in thinking about the spectrum of FM symptoms.3

Prevalence Estimates FM has been found in all ethnic groups studied to date; it is not limited to affluent or industrialized nations. With prevalence estimates ranging from 2% to almost 12% in the general population, it must be viewed as a common medical condition.7,8 Its prevalence increases with age, most dramatically in women, with a peak in the fifth to seventh decade (7.4% to 10%). Using the original 1990 criteria, including tender points, women were four to seven times more likely to be affected than men of similar age.8 This was another unintended consequence of the 1990 ACR criteria, by using the same tenderness threshold in men and women, even though we now understand that women are substantially more tender than men, which overestimates the prevalence of FM in men. Using the newer criteria, the ratio was closer to a 2:1 female:male ratio. In contrast, the sex distribution of childhood FM is almost equal (until puberty, girls have similar levels of tenderness relative to boys). Many children outgrow their symptoms.9 Fibromyalgia the incidence of fibromyalgia is poorly characterized, but risk factors for its development may include obesity, lack of physical activity, poor life/job satisfaction, physical trauma, a febrile illness, or a family history of FM; these factors may not be mutually exclusive.

Clinical Features The proposed clinical flow would stratify these patients for improved management (Box 37.2). The clinical manifestations of FM typically involve much more than pain, and in fact, these non-pain symptoms are often the key to differentiating the nociplastic pain of FM from nociceptive or neuropathic pain.

521

Adapted from Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia report of the multicenter criteria committee. Arthritis Rheum. 1990;33:160–172.

The most important manifestation in FM and nociplastic pain is that pain is more widespread and more severe than expected. In the new FM criteria, the widespread nature of pain is assessed by asking individuals if they have pain in 19 different bodily regions; this is scored from zero to 19 depending on how man sites are involved. The comorbid symptoms that are most commonly seen and thus are scored from zero (not present) to three (severe) within the Symptom Severity Index in the new FM criteria are difficulty with sleep, memory, and fatigue, and headaches, irritable bowel syndrome symptoms, and depression are also assessed in this measure and are given one point each toward the total score on this measure. Another set of symptoms that are becoming increasingly understood with a better understanding of the pathophysiology of these conditions is sensory hyper-responsiveness. Individuals with FM are just as sensitive to the loudness of noises or brightness of lights as they are to painful stimuli, and these symptoms of sensory hyper-responsiveness throughout the body (leading to symptoms such as urinary frequency, dry eyes) can be very helpful in identifying this type of pain.

Cognitive Dysfunction Ranging from difficulty concentrating when reading a book to short-term memory deficits, people with FM frequently complain of diminished cognitive function. Research has suggested that FM patients perform poorly on a range of cognitive tasks10 and exhibit premature cognitive aging, with the main evidence of abnormality being derived from distraction or multitasking experiments.

Insomnia Most patients with FM experience chronic insomnia. Some have difficulty falling asleep (initial insomnia), but most awaken feeling distressingly alert after only a few hours of sleep (mid-insomnia)

522



PA RT 4 Clinical Conditions: Evaluation and Treatment

• Box 37.1

American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity

1. Criteria A patient satisfies the diagnostic criteria for fibromyalgia if the following three conditions are met: 1. Widespread pain index (WPI) score >7 and symptom severity (SS) scale score >5 or WPI score of 3 to 6 and SS scale score >9. 2. Symptoms present at a similar level for at least three months. 3. No disorder present that would otherwise explain the pain.

2. Ascertainment 1. WPI: note the number of areas in which the patient experienced pain over the last week. In how many areas has the patient had pain? The score will be between zero and 19. Shoulder girdle, left hip (buttock, trochanter), left jaw, left upper part of the back Shoulder girdle, right hip (buttock, trochanter), right jaw, right lower part of the back Upper part of the arm, left upper part of the leg, left side of the chest, or neck Upper part of the arm, right upper part of the leg, right side of the abdomen

Left lower part of the arm, left lower part of the leg Right lower part of the arm, right lower part of the leg 2. SS scale score: Fatigue Waking unrefreshed Cognitive symptoms 3. For each of the three symptoms above, indicate the level of severity over the past week according to the following scale: 0= No problem 1= Slight or mild problems, generally mild or intermittent 2= Moderate: considerable problems, often present and/or at a moderate level 3= Severe: pervasive, continuous, life-disturbing problems 4. Considering somatic symptoms in general, indicate whether the patient has the following*: 0= No symptoms 1= Few symptoms 2= Moderate number of symptoms 3= Great deal of symptoms

The SS scale score is the sum of the severity of the symptoms (fatigue, waking unrefreshed, cognitive symptoms) and the extent (severity) of somatic symptoms in general. The final score ranged from 0 to 12. *Somatic symptoms that might be considered are muscle pain, irritable bowel syndrome, fatigue or tiredness, difficulty thinking or remembering, muscle weakness, headache, pain or cramps in the abdomen, numbness or tingling, dizziness, insomnia, depression, constipation, pain in the upper part of the abdomen, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud’s phenomenon, hives or welts, ringing in the ears, vomiting, heartburn, oral ulcers, loss of or change in taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing difficulty, easy bruising, hair loss, frequent urination, painful urination, and bladder spasms.



• Box 37.2

Proposed Plan for Screening and Comprehensive Care of Patients With Fibromyalgia

1. Phase 1: Pain Screening and Primary Care Phase 1 involves a simple screening questionnaire in which the receptionist for a primary care health professional (primary care physician [PCP], chiropractor, nurse practitioner, physician assistant, general practitioner, general internist) would give every patient entering the waiting room until all the primary care professionals’ regular patients had been assessed (Fig. 37.2). After that, it may be administered only to new patients. When the PCP reviews the form of a patient with pain (question 1 answered “yes”), a decision about the symptom’s distribution would be made (localized pain, regional pain, widespread pain). A second decision would be to initiate care for the patient’s symptoms or refer the patient for further care of this problem.

2. Phase 2: Comorbidity Screening and Secondary Care Based on the findings on the screening material, a patient identified as having widespread pain would be examined by the PCP or referral physician to make the diagnosis (fibromyalgia [FM] if it applies). The next stage would be screening for comorbid conditions by a well informed and willing PCP or consultant (rheumatologist, neurologist, pain specialist, internist, physiatrist). The patient began an exercise program and counseling with a professional specifically trained to

and are then unable to sleep soundly again until it is almost morning (terminal insomnia). People with FM typically awaken in the morning feel painfully stiff, cognitively sluggish, and unrefreshed by their sleep.11

provide advanced care for FM. Problems found in counseling (e.g. marital, financial, and psychiatric) would spin off to an experienced specialist (e.g. counselor, psychologist, psychiatrist, disability advisor, financial counselor).

3. Phase 3: Comorbidity Screening and Tertiary Care Based on the second line screening for comorbid conditions, care would begin for additional diagnoses. This phase may invoke referral to tertiary subspecialty care (e.g. cardiologists, gastroenterologists, neurologists, neurosurgeons, physical therapists, psychiatrists, physiatrists, obstetrician-gynecologists, urologists). This care should be integrated with follow up by primary care resources.

4. Phase 4: Long-Term Primary Care and Follow Up Assessment Primary or secondary healthcare professionals will continue to monitor the patient over time and assess the status of care for pain and comorbid conditions. There would be monitoring for side effects to medications and new problems intruding on the continuity of the FM that might or might not be related to it. In this phase, it is important not to assume that every new symptom in a patient with FM is a component of FM. Healthcare providers need to know what is and is not expected with FM.

Stiffness The morning stiffness experienced by most FM patients is lengthy and severe compared with other mechanisms for morning stiffness. The typical stiffness of osteoarthritis usually lasts 5 to

15 min, whereas that of patients with inflammatory rheumatoid arthritis is 30 min to 2 h. By comparison, the stiffness of FM patients typically lasts from 45 min to 4 h. The best clinical correlate with morning stiffness in FM is pain; therefore patients have challenges distinguishing these constructs from their experiences.

Fatigue Approximately 80% of FM patients complain of fatigue. Consequently, a large proportion of individuals who meet the criteria for FM also meet the criteria for chronic fatigue syndrome.12 The differential diagnosis of fatigue is difficult because it must include various sleep disorders, chronic infections, autoimmune disorders, psychiatric comorbidities, and neoplasia. Fatigue may also result from residual levels of prescribed medication, such as tricyclic anti-depressant drugs or other neuropathic medications often used to treat insomnia associated with FM.

Constellations of Previously Diagnosed Comorbid Pain Conditions There are two sets of comorbid conditions typically seen in association with FM or nociplastic pain: other Chronic Overlapping Pain Conditions (COPCs),13 that are also predominantly nociplastic pain (e.g. irritable bowel syndrome or tension headache); and other pain conditions that have a different primary pain mechanism (nociceptive or neuropathic pain) wherein nociplastic pain is superimposed. The former category had previously been called primary FM, and the latter category secondary FM or central sensitization. It may be very important to differentiate primary from secondary FM because, in secondary FM or central sensitization, ongoing nociceptive input or neuropathic damage may be partially driving or maintaining the central sensitization. In these individuals, more aggressively treating the underlying problem might help improve the FM or nociplastic pain, whereas that would not be expected in primary FM, which seems to be more of a top-down brain disorder that typically begins early in life. Chronic Overlapping Pain Conditions COPCs appear to be system-based expressions of central sensitization,14,15 reflecting a range of severities and present on functional neuroimaging and quantitative sensory testing.16,17 An alternate term previously used was sensory sensitivity symptoms. The spectrum of centrally mediated painful conditions includes headache, facial pain, temporomandibular disorders (TMD), irritable bowel syndrome, dyspepsia, interstitial cystitis, painful bladder syndrome, vulvodynia, endometriosis, and female urethral syndrome. These disorders may have specialist involvement of neurology, dentistry, gastroenterology, urology, or gynecology with a primary diagnosis of one of these centrally sensitizing spectrum conditions.

Neurologic/Dental Sensitization People with coexisting headaches, facial pain, and TMD may cycle between specialist providers in neurology, dentistry, and pain, but the shared sensitization appears to be consistent across the diagnoses.18–20 Headache demonstrates overlapping sensitization through shared pathways and treatment responses.21,22

Gastrointestinal Sensitization Irritable bowel syndrome (IBS) and benign dyspepsia are common gastrointestinal conditions that occur in 30% to 50% of patients with FM. A feature common to both FM and IBS may be central sensitization and underlying neuroplastic alterations. These

 

CHAPTER 37

Chronic Widespread Pain

523

conditions may be synergistic with respect to patients’ perceptions of their illness and have a modulating effect on clinical outcomes.

Gynecologic Sensitization Pelvic pain syndromes may first present to gynecologists, including vulvodynia, dysmenorrhea, and endometriosis. Nevertheless, these disorders are associated with sensitization findings and have a complicated association with stress.23–25 Urological Sensitization Approximately 60% of FM patients experience urinary urgency and nocturia regularly, and there is a high rate of bidirectional comorbidity between interstitial cystitis/painful bladder syndrome and FM. Up to 12% of FM patients also fulfill the diagnostic criteria for female urethral syndrome,26 which is defined as the presence of urinary frequency, dysuria, suprapubic discomfort, and urethral pain despite sterile urine. Many patients are frequently treated with antibiotics for culture-negative urinary tract infections. Intensive investigations often fail to identify specific causes. Self-report questionnaire instruments were developed to facilitate screening for this condition in patients with FM (Fig. 37.1).27

Secondary Fibromyalgia Diagnoses Conversely, FM can develop in patients with other chronic diseases during the course of their symptoms. In the setting of another painful condition or inflammatory disorder, the FM condition has been referred to as secondary FM. This terminology is not intended to imply that the FM is always caused by the other condition, but the terminology is entrenched and serves a purpose. Secondary FM may not be clinically distinguishable from primary FM,28 but increasingly, laboratory findings can be used to distinguish these FM subgroups.29 As examples of secondary FM, almost 30% of patients with rheumatoid arthritis, 40% of patients with systemic lupus erythematosus, and 50% of those with Sjögren’s syndrome have concomitant FM. Patients with rheumatic disease and FM seem to experience articular pain disproportionate to synovitis. This must be considered when treating rheumatic conditions because increasing the dosage of antirheumatic medications in the absence of active inflammation may have little effect on the pain amplified by FM. The best results are obtained by treating each condition separately. Patients with rheumatic disease and concomitant FM should be warned that a transient increase in FM symptoms may occur with each decrease in glucocorticoid dosage (steroid withdrawal FM). Therefore usual FM therapy may need to be increased transiently. This is a surprising phenomenon because glucocorticoids do not help treat primary FM. To avoid interference with a steroid taper by emergent FM, it is best to decrease the dosage of the glucocorticoid used to treat rheumatic disease in graduated steps at approximately two week intervals. The rate of tapering depends on the current dosage. Infectious and inflammatory conditions that seem to be associated with FM include hepatitis C, tuberculosis, syphilis, and Lyme disease. The prevalence of overlap may depend on the prevalence of infectious diseases in the community. An academic practice in a Lyme-endemic area evaluated 788 patients with apparent infection for a mean of 2.5 years.30 Of those with Lyme disease, 20% met the criteria for FM. The symptoms of FM developed one to four months after infection, often associated with Lyme arthritis. The signs of Lyme disease generally resolved with antibiotic

524

PA RT 4 Clinical Conditions: Evaluation and Treatment

PREVALENCE OF PAIN: GENERAL POPULATION

DISTRIBUTION OF PAIN: INTERNAL MEDICINE CLINIC

8%

10%

6%

13% 30%

60% 73%

A

No pain Acute or regional pain Chronic widespread pain

MPS FM

Other MSK Not MSK

B

• Figure 37.1  Prevalence of Pain in the General Population (A) and an Academic Internal Medicine Clinic (B). FM, Fibromyalgia; MPS, myopathic pain syndrome; MSK, musculoskeletal.

therapy, but FM symptoms often persisted. The largest subgroup of the 788 patients did not have Lyme disease, but they met the criteria for FM or chronic fatigue syndrome.

Pathogenesis Patients with FM have a constellation of symptoms, but the most common symptom is pain. Before the advent of research techniques such as quantitative sensory testing and functional neuroimaging, many believed that FM and chronic widespread pain had primarily a psychosocial origin with little “organic” basis. However, patients with FM demonstrate reliably augmented sensory processing that was initially thought to be confined to the sensation of pain (i.e. hyperalgesia or allodynia) but is now known to include hypersensitivity to other sensory stimuli such as auditory stimulation.31,32 Functional magnetic resonance imaging (fMRI) studies have corroborated this finding of hyperalgesia or allodynia in that multiple studies have now shown that FM patients display increased neuronal activation in comparison to controls when the same low-intensity stimulus is applied to both groups.33 fMRI studies have demonstrated the impact of comorbid psychological factors influencing FM.34 People with central sensitization conditions, such as FM, appear to have lower thresholds to generate pain responses than in normal controls.35-37 These imaging studies also provide a theoretical basis for globally augmented sensory processing in FM since the area of the brain that most consistently exhibits increased activity in FM and most other chronic pain states is the insula, a region involved in polysensory integration.38 Even though multiple mechanisms to assess alterations in pain perception are used, the pressure pain threshold (rather than heat or electrical stimuli) response has the closest relationship with the clinical features of FM and other chronic pain states. Patients with FM have also been found to have altered levels of biomarkers associated with pain, specifically glutamate and

substance P (SP).39 Harris and colleagues’ recent work using proton spectroscopy to evaluate insular glutamate elevations in patients with FM demonstrated higher mean levels than in controls.40,41 Although such techniques do not allow simple patient testing, the findings support the distinct biologic identity of FM. Endogenous opioid levels are elevated relative to controls, thereby providing a potential mechanism for the lack of responsiveness to opioid therapy in patients with FM, laying the foundation for using low dose naltrexone as a treatment option.42 Objectively, this has been demonstrated through positron emission tomography (PET)-derived µ-receptor occupancy.43,44 Abnormalities in neurochemical mediators of central nervous system (CNS) nociceptive function are present in ways consistent with the patterns of symptoms. The role of neurochemicals as neurotransmitters and modulators of the nociceptive process has been studied extensively in animals.45 It is believed that these agents participate in the descending inhibition of nociception. This line of reasoning has led to the measurement of neurotransmitter levels in biological fluids obtained from patients with FM. Several major classes of biochemical participants in the nociceptive process are biogenic amines (e.g. serotonin, norepinephrine, and dopamine), excitatory amino acids (e.g. glutamic acid, glutamine, aspartic acid, asparagine, glycine, arginine), neurokinins (e.g. SP, calcitonin gene-related protein, arginine vasopressin, neuropeptide Y), nerve growth factor (NGF), and nitric oxide. Biogenic amines are generally considered antinociceptive, whereas the excitatory amino acids, SP, NGF, and perhaps even nitric oxide are more likely to be pronociceptive. Another approach to understanding the cause of FM has been through genetic studies. While this is a promising approach to developing personalized treatment paradigms, this is an area of active research. Genetic studies have not yet identified reproducible and strong candidate polymorphisms or haplotypes despite familial associations in people with fibromyalgia. Candidate

 

CHAPTER 37

Chronic Widespread Pain

525

Phase 1: Screening Questionnaire Instructions: Answer yes or no to each of the following questions. If you answer no to question 1, you are done. You do not need to read any of the other questions. When you are done, please return the completed questionnaire to the office clerk. Yes No 1. Have you had body pain for at least three months? 2. Was your body pain one of your reasons for coming to the doctor today? Instructions: If you answered Yes to question 1, mark a slanted line across the line below to indicate how severe your pain has been over the past two weeks.

No pain

Severe pain

Instructions: If you answered yes to question 1, use a pencil or pen to mark darkly on the body diagrams the locations of your pain during the last week.

Below this line is for office use only. Please do not mark below this line. • Physician interpretation [check one]: Localized Regional • Optional examination findings [indicate values]: • Referral:

Widespread Soft Tissue Pain

Total Tender Point Count Yes No To

TPI

APT

• Figure 37.2  Screening Questionnaire for Chronic Widespread Pain as Seen in Fibromyalgia Syndrome (FM). The findings supportive of FM would be chronic pain from question 1, the relative severity of the pain from question 3, and widespread pain from question 4. Each question could also be applied to other categories of soft tissue pain, and patients with localized or regional musculoskeletal pain, if present, would be identified by the body pain diagram. APT, Average pain threshold; TPI, tender point index. polymorphisms for fibromyalgia have been inconsistent in studies, including serotonin 5-HT2A receptor polymorphism T/T phenotype, serotonin transporter, dopamine four receptor, and catecholamine o-methyl transferase (COMT).46,47 Epigenetic theories are emerging in mechanistic fibromyalgia research because of their strong association with environmental factors such as stressful experiences.48 Published studies have documented familial patterns. Some have predicted an autosomal dominant mode of inheritance for FM,49,50 and evidence for this has increased. In a study by Yunus et al.51 a linkage of FM with the histocompatibility locus was examined using the sibship method. A complete genome scan of families with two or more FM-affected members has been undertaken by using samples of DNA from a large num-

ber of multi-case FM families for comparison of clinical and laboratory genotypic features.52 Meanwhile, several candidate genes have been proposed to directly explain the specific metabolic abnormalities that have been consistently observed in FM.53 No evidence for linkage was found in the HTTLPR gene region. Families with an older age of onset were linked to the human leukocyte antigen (HLA) region (logarithm of the odds [LOD] = 3.02, P = 0.00057), thus suggesting an immune-mediated pathogenesis. Bioinformatics mining and further sequencing of genes in the HTR2A region will help identify specific polymorphisms for further clinical association testing. Subsets of patients with FM exhibit functional abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, sympathoadrenal  

526

PA RT 4 Clinical Conditions: Evaluation and Treatment

(autonomic nervous) system, hypothalamic-pituitary-thyroid axis, hypothalamic-pituitary-gonadal axis, or hypothalamic-pituitarygrowth hormone axis.54 In FM patients, the HPA axis exhibits an exaggerated adrenocorticotropic hormone (ACTH) response to insulin-induced hypoglycemia or stressful exercise. Despite this dramatic rise in serum ACTH levels in FM, the level of cortisol did not increase commensurately. Mediators that regulate the HPA axis include corticotropin-releasing factor, serotonin, norepinephrine, SP, and interleukin (IL)-6.55,56 The reasons why these endocrinopathies are associated with chronic pain syndrome are not entirely clear.54,56 It may be that CNS abnormalities in the availability of biogenic amines such as serotonin, norepinephrine, and/or dopamine are responsible for the abnormal regulation of the neuroendocrine system.57 These systems interact and are interdependent, so in susceptible individuals, a partial failure of one system may lead to subtle malfunctions in others. Moreover, immune function abnormalities have been identified as early as the 1980s.58 This foundation has been expanded to include additional markers. Research on fibromyalgia has spanned the search for serum antinuclear antibodies,59-61 lymphocyte immune abnormalities,58 and critically evaluating the role of cytokines such as IL-6 and IL-8.55,62,63 In summary, the pathogenesis of FM was shaped by the recognition of allodynia as a manifestation of abnormal central nociceptive processing. This has redirected the collective view of the FM. This revised perspective pointed out research on this condition in a new direction, specifically toward the study of central sensitization. Some abnormalities found in FM are logically consistent with the pain amplification syndrome. The extent to which these mechanisms are unique to FM is critical in determining the direction of future research.

Management Approaches The objectives of FM treatment are to reduce pain, improve sleep, restore physical function, maintain social interaction, and re-establish emotional balance. A reasonable community objective might be to reduce the need for expensive healthcare resources. To achieve these goals, patients will need a combination of social support, education, physical modalities, and medication. A six-step outline of therapy has been developed; ADEPT living stands for attitude, diagnosis, education, physical modalities, treatment with medication, and living.

Attitude Attitude refers to the preparation or frame of mind that each participant brings to the therapeutic interaction. For clinicians, viewing FM as a neuroinflammatory disorder that creates central sensitization provides a framework for understanding the tremendous impact on the patient’s life. From the patient’s perspective, it is important to realize that FM is a constellation of symptoms with treatments that require biopsychosocial efforts and participation by the patient. Recognizing and sharing updates and limitations in knowledge regarding FM can help set up a more positive treatment dynamic for clinicians and patients. Diagnosis The correct diagnosis should be made to identify FM and disclose any comorbid medical conditions. The management approach will also need to accommodate these other conditions if the patient has concomitant hypothyroidism, diabetes mellitus, or renal insufficiency. For example, when rheumatoid arthritis and FM are evident in the same patient, treatment is more successful when both conditions are treated as though the other is not

present. Fibromyalgia is not a diagnosis of exclusion, and patients can have comorbid pain conditions that may benefit from tailored treatment (e.g. low back pain).

Education Education is crucial for the management of FM. Understanding is crucial for playing an active role in therapeutic programs. Several studies have examined the effects of cognitive behavior therapy (CBT) on outcomes in FM and demonstrated positive effects on pain scores, pain coping, pain behavior, depression, and physical functioning.64 Such gains are often maintained for several months after completion of the therapy, and periodic booster sessions may prolong the benefits. Joining a resource-oriented support group can help FM patients come to terms with a complicated illness. Physical Modalities A variety of physical modalities have been proposed as interventions for FM and can logically be segregated into two categories: those that patients can accomplish for themselves and those that require active participation by a trained therapist. At home, patients can pace their usual activities by setting a clock to time the necessary work activity and then balance the work time with an equal period of rest. Progressive exercise, heat applied as a shower or bath, and Jacobson relaxation techniques can all be used as self-directed therapies with minimal cost.64 Aerobic exercise was among the first nonpharmacologic strategies advocated for FM patients, with convincing evidence of benefit.64 Its goals are to maintain function for everyday activities and to prolong life through cardiovascular fitness. Low-impact exercise, with an intensity sufficient to challenge aerobic capacity, can also reduce pain, improve sleep, balance mood, improve stamina, instill new perspectives, restore cognition, and facilitate a sense of wellbeing.65 Patients who can exercise sustain a less negative impact of FM in their lives.66,67 Other recent studies have shown benefits in terms of quality of life and pain in patients involved in exercise programs alone.68 However, one should be aware that high levels of exertion can temporarily worsen the pain and result in fear of movement (kinesophobia), especially in this patient population. When FM is first diagnosed, the patient is usually deconditioned and has already learned to fear the pain induced by exercise. When prescribing exercise for FM patients, the clinician should begin with low-intensity exercise, such as walking in place in a swimming pool and minimize eccentric muscle contractions.69 the continuation of the exercise program. Other physical therapies, including yoga,70 pilates,71 and tai chi,72 have been found to be effective in reducing the pain associated with FM. However, other alternative and complementary methods, including Reiki, provided no benefits.73 Most patients report benefits from heat in the form of dry or moist heat. Many studies have found that a hot bath or shower can be more effective than analgesic medication for headaches, body pain, and stiffness. The application of heat can relax muscles, facilitate exercise, and improve the sense of wellbeing. Cold applications are preferred by some researchers. Light massage that gradually progresses to deep sedative palpation of large body surfaces can reduce muscle tension, but its influence on body pain usually lasts only one or two days. Treatments Cognitive Behavior Therapies

Numerous psychological therapies have been found to be beneficial for pain relief in patients with chronic widespread pain, including

FM. In a recent randomized controlled trial (RCT),74 telephonebased CBT was found to be beneficial for healthcare related quality outcomes. In this study, 442 patients with chronic widespread pain were randomized to receive six months of telephone CBT, graded exercise, combined intervention, or treatment as usual. Patients receiving CBT with or without exercise performed better than those who underwent standard medical treatment. Those who combined CBT with exercise showed the greatest improvement. These improvements in quality of life were long lasting, and the interventions were cost-effective by using telephone instead of face-to-face CBT. Attention modification has also been very successful in altering the perception of pain in patients with chronic widespread pain. Attention bias refers to the phenomenon whereby patients identify with information that reinforces their focus on their painful condition. The goal of attention modification is to interrupt this negative and self-reinforcing cognitive cycle. In a recent RCT, the Attentional Modification Paradigm (AMP), in which patients completed two 15 min AMP sessions per week for four weeks, was used to facilitate such changes in attentional pain biases.75 Those in the AMP program reported statistically significant and substantial reductions in several individual difference variables relative to those in the control condition, and a greater proportion experienced clinically significant reductions in pain. Pharmacotherapies

Recent developments regarding FM therapy relate to new medications being developed and tested specifically for this condition. Three medications, including amine reuptake inhibitors duloxetine and milnacipran, and the membrane stabilizer pregabalin, are currently approved by the Food and Drug Administration (FDA) for the treatment of pain related to FM. Many medications have been used with varying success in an off-label fashion. The theoretical background relating these agents to FM has been based on various biochemical or physiologic abnormalities found in FM,76-78 and is known to be an important contributor to the pathogenesis of pain. One approach to the therapeutic goals of pharmaceutical therapy would be to say that FM has three main domains (or symptoms) that represent targets for therapeutic intervention, which include pain, insomnia, and depression, but others could be substituted as well.

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are not effective as a monotherapy for this condition. Perhaps the more important role of such agents is to contribute to synergy with other medications because it is very likely that some of the central sensitization seen in conditions such as FM is probably driven by peripheral nociceptive input.

Local Anesthetics

Lidocaine infusions have not generally been found to provide supplemental benefit in addition to oral amitriptyline intake for pain outcomes.79 However, a recent study of 68 FM patients with MPS and 56 FM patients with regional joint pain showed that peripheral TrP injections and hydroelectrophoresis ameliorated FM pain and increased pain thresholds at sites distant from the therapeutic interventions, thus providing further evidence that painful peripheral stimuli contribute to the perpetuation of central augmentation.80

Opioids

Although opioids are prescribed for the treatment of FM, clinical experience and empirical evidence indicate that they are not

 

CHAPTER 37

Chronic Widespread Pain

527

effective in ameliorating this condition.81,82 Thus the risk of tolerance, opioid-induced hyperalgesia, addiction, and prescription drug diversion is not justified by the insignificant therapeutic benefit. Opioids can disrupt the sleep architecture of people with fibromyalgia, increasing lighter sleep and decreasing slow wave sleep. Sleep disruption can negatively impact symptoms associated with fibromyalgia. The higher the opioid dose, the greater is the sleep quality disruption.83 The aim of opioids in severe cases and those refractory to all conservative medical and psychological therapies should not be merely pain relief but rather a clear improvement in physical function. If improvement in function is not achieved, these agents must be discontinued and not restarted. A therapeutic trial with a defined endpoint and defined target dose must be discussed with the patient before starting opioid-based therapy. If the physician and patient engage in opioid therapy, a clear behavioral contract needs to be signed by both parties. Amine Reuptake Inhibitors

Tricyclic anti-depressant (TCA) drugs are effective at low doses (10–150 mg) and improve sleep and enhance the effects of analgesics. Two TCAs that have been extensively studied in FM are amitriptyline (typically administered in doses from 10 to 50 mg) and cyclobenzaprine (typically given in doses from 2.5 to 20 mg) administered at night to improve sleep. Selective serotonin reuptake inhibitor (SSRI) drugs were developed for the treatment of depression. However, in the usual antidepressant dosages, these agents are effective as monotherapy for depression, and at higher dosages (fluoxetine, 40–50 mg/day), to relieve FM pain.84 This analgesic effect may be non-serotonin selective at these high doses. The analgesic effects of the tricyclic drugs, not apparent with normal dosages of SSRIs, have suggested that the small contribution from inhibition of the norepinephrine transporter might be critical to their pain-relieving effect. In the tricyclic class, there is a large up to a 900-fold difference between norepinephrine reuptake inhibition activity and that of serotonin. Another class of amine reuptake inhibitors includes serotoninnorepinephrine reuptake inhibitors (SNRIs), which have been developed to achieve a better balance between the inhibition of the reuptake of serotonin and norepinephrine. One class (exemplified by duloxetine) exhibits almost equivalent activity to SNRI, whereas the other class (norepinephrine selective reuptake inhibitor [NSRI] exemplified by milnacipran) exhibited potent inhibition of norepinephrine reuptake. At dosages of 60 to 120 mg once daily in the morning, duloxetine can be effective in controlling FM body pain, regardless of whether the patient is depressed.85-87 It is well tolerated by most FM patients. Nausea, dry mouth, constipation, diarrhea, and anorexia are reported more frequently with active drugs than with placebo. The adverse effects can be lessened by starting the drug at a low dosage (30 mg in the morning) and gradually increasing it as tolerated, such as increasing the morning dosage by 30 mg every week. The most common target dose is 60 mg in the evening. However, some studies have noted efficacy at higher doses. Milnacipran is typically administered at doses of 100 to 200 mg daily.88 Because it is more noradrenergic than duloxetine, it might be helpful in individuals with more prominent fatigue or memory problems, although many individuals have trouble tolerating noradrenergic side effects. N-Methyl-d-Aspartate Antagonists

The pain amplification of central sensitization can be inhibited or attenuated by N-methyl-d-aspartate (NMDA) receptor antagonists. Several NMDA receptor antagonists, including ketamine,

528

PA RT 4 Clinical Conditions: Evaluation and Treatment

memantine, and dextromethorphan, have been studied in patients with FM and have been shown to have some beneficial effects.89,90 In the case of ketamine, about 50% of FM patients benefited from an open trial. The concept of FM subgroups was advanced by these findings because ketamine clearly identified responsive and unresponsive subjects from among otherwise comparable FM patients. The usefulness of ketamine as a therapeutic agent for FM has been limited by the fear of adverse effects, such as psychological disturbances (e.g. feelings of unreality, altered body image perception, modulation of hearing and vision), dizziness, anxiety, aggression, and nausea.91 Furthermore, a more recent trial that examined the long-term analgesic benefit of intravenous ketamine infusions found no benefit of discontinuation of ketamine or at eight weeks following discontinuation.92 Therefore the benefit of intravenous ketamine infusion may be restricted to its predictive value for dextromethorphan or oral ketamine therapy.93 α2δ Ligands

Some drugs initially developed as anti-convulsants can raise the threshold for pain fiber depolarization, as they do for central neurons to reduce seizure activity. Pregabalin and gabapentin are ligands for the α2δ subunit of voltage-gated calcium channels.94,95 These compounds have been shown to have anti-hyperalgesic/ anti-allodynic, anxiolytic, and anti-convulsant activities in animal models. They reduce the release of several neurochemicals, including glutamate, norepinephrine, and SP. Pregabalin was found to be effective in reducing the severity of body pain, improving quality of sleep, and reducing fatigue in FM patients.96 Pregabalin is available in the United States but is scheduled as a controlled substance because of its mild anti-anxiolytic activity. At therapeutic dosages (300 to 600 mg/day in two or three divided doses), it was well tolerated. Adverse effects can include dose-related dizziness and somnolence, which resolve despite continuous therapy with the drug. This observation suggests that it is helpful to start at a low dosage and increase it gradually (perhaps weekly) to help the patient adapt. One approach is to start with 100 to 150 mg at bedtime and increase the nighttime dosage weekly to 300 to 450 mg before adding a smaller morning dosage to achieve 450 to 600 mg/ day. Weight gain (5–10 lb) and peripheral edema occur in 6% to 12% of patients without any evidence of an effect on the heart or kidneys. Gabapentin has been shown to be effective in FM patients.97

Low Dose Naltrexone and Combination Therapies

Low dose naltrexone (LDN), an opioid antagonist, has emerged as a treatment option for fibromyalgia.42 The mechanistic theory supporting the use of LDN reflects its role as a central antiinflammatory agent. LDN is used in the range of 1–4.5 mg for these indications.98,99 The use of specific combinations of newer

therapeutic agents, or strategic polypharmacy, has been proposed for the management of FM.100 It should be noted that there are no published data on the consequences of combining drugs that are effective as monotherapy. The critical principles of this concept for FM are that complementary medications should be from different drug classes, have different mechanisms of action, and not be synergistic for any serious adverse effects. Procedural Interventions

Surgical interventions for FM pain are not indicated or recommended, and the search for a surgical panacea has resulted in unnecessary or potentially harmful surgical care for patients with chronic widespread pain, including FM. Other non-invasive procedures have been examined for their efficacy in populations with chronic widespread pain.

Other Comorbid Conditions Dysfunctional Sleep and Fatigue The bidirectional relationship between sleep and FM is a critical component in identifying strategies to improve pain and function. Focusing on sleep as a goal for improvement may be the first step in targeted therapy. People with fibromyalgia can demonstrate abnormal sleep rhythms, and abnormal sleep rhythms in people without fibromyalgia can cause symptoms that mimic tenderness, myalgia, and fatigue. Poor sleep quality can influence the development of chronic widespread pain states.101 The management of insomnia in patients with FM remains non-specific and empirical. CBT for insomnia may provide benefits for sleep initiation, maintenance, and perceived quality.102 The sedating of tricyclic biogenic amine reuptake drugs, such as amitriptyline and cyclobenzaprine, has been the most commonly prescribed medication for FM insomnia. They are not ideal for this role because they cause several adverse effects and are subject to tachyphylaxis, but a one month holiday from all biogenic amine reuptake inhibitors can restore effectiveness.82 Because SSRIs, SNRIs, and NSRIs are sometimes so stimulatory that they can interfere with sleep, they should be taken in the morning. Two medications used for FM, pregabalin and oxybate, are effective for pain and sleep disturbances.95,103,104 In addition, both correct the non-rapid eye movement sleep pattern abnormalities seen with FM. Fatigue in FM is probably a direct result of chronic insomnia. Exercise can be an important component in shifting the fatigue cycle.67 Depression and comorbid conditions, such as sleep apnea, hypothyroidism, diabetes, chronic infection, or anemia, can also drain energy and should therefore be included in the differential diagnosis. Mild exercise can reduce fatigue in patients with FM.

Summary Despite our evolving understanding of the disease process and increased therapeutic options, patients with chronic widespread pain continue to present diagnostic and management challenges. The disparate range of symptoms found in patients with chronic widespread pain and the multitude of associated comorbid conditions in the patient population contribute to the diagnostic difficulties in an increasingly overburdened healthcare system. Moreover, the most successful treatment modalities require significant personal changes in the behavior and lifestyle of patients, which creates a substantial barrier to implementation. Even the diagnostic criteria for FM are controversial, with researchers and

clinicians working to develop a working definition to help identify these patients. The most recent collaboration has resulted in the development of preliminary diagnostic criteria that address symptom severity (Box 37.1). The clinical manifestations of FM include cognitive dysfunction, affective distress, insomnia, stiffness, musculoskeletal pain, and fatigue. These non-specific symptoms contribute to both the diagnostic and therapeutic challenges of managing FM. Associated comorbid conditions include chronic fatigue syndrome, IBS, interstitial cystitis, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome. This diverse clinical

picture complicates both the diagnostic specification and burden of individual patient suffering. The evolution of the pathogenesis of FM is being clarified through molecular studies, sensory testing, and other testing modalities, including functional MRI and PET. Abnormalities in neurochemical biomarkers are being recognized as being associated with FM. Immunologic changes have also been identified through work with ILs and cytokines. Genetic markers (COMT gene) and sex may also play a role in the development of these chronic widespread pain syndromes. The composite result of these novel investigative approaches is an emerging spectrum of identifiable biochemical and functional changes that contribute to chronic widespread pain.

 

CHAPTER 37

Chronic Widespread Pain

529

Treatment modalities align with a multi-disciplinary paradigm that includes multiple recent drug developments, cognitive behavior modalities, physical therapy, and exercise programs. Recent changes in FDA-approved pharmacotherapies include the use of pregabalin, as well as the amine reuptake inhibitors duloxetine and milnacipran. The implementation of therapeutic agents is frequently tailored to the patient’s symptoms and comorbid conditions (e.g. osteoarthritis vs. insomnia). Ultimately, the most successful treatment outcomes result from multimodal therapy, which relies heavily on patient involvement and investment (physical therapy, exercise regimens, CBT).

Key Points • The objectives of treatment of fibromyalgia (FM) include reducing pain, improving sleep, restoring physical function, maintaining social interaction, and reestablishing emotional balance. To achieve these goals, patients will need a combination of social support, education, physical modalities, and medication. • Patients with FM demonstrate reliably augmented sensory processing, which was initially thought to be confined to the

sensation of pain (i.e. hyperalgesia and allodynia) but is now known to include hypersensitivity to other sensory stimuli. • Patients with FM have also been found to have altered levels of biomarkers associated with pain, specifically glutamate and substance P. • The FDA currently approves three medications for the treatment of pain related to FM: the amine reuptake inhibitors duloxetine and milnacipran, and the membrane stabilizer pregabalin.

Acknowledgments Portions of this chapter were transcribed or modified from the chapter “Chronic Widespread Pain” by the same authors from the fifth edition of Practical Management of Pain.

Suggested Readings Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain? Pain. 2016;157(7):1382–1386. Maixner W, Fillingim RB, Williams DA, Smith SB, Slade GD. Overlapping chronic pain conditions: Implications for diagnosis and classification. J Pain. 2016;17(9 Suppl):T93-T107. Nebel MB, Gracely RH. Neuroimaging of fibromyalgia. Rheum Dis Clin North Am. 2009;35(2):313–327. Patten DK, Schultz BG, Berlau DJ. The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn’s disease, and other chronic pain disorders. Pharmacotherapy. 2018;38(3):382–389.

Walitt B, Katz RS, Bergman MJ, Wolfe F. Three-quarters of persons in the US population reporting a clinical diagnosis of fibromyalgia do not satisfy fibromyalgia criteria: The 2012 national health interview survey. PLoS One. 2016;11(6):e0157235. Walitt B, Nahin RL, Katz RS, Bergman MJ, Wolfe F. The prevalence and characteristics of fibromyalgia in the 2012 national health interview survey. PLoS One. 2015;10(9):e0138024. Wolfe F, Clauw DJ, Fitzcharles MA, et al. Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016;46(3):319–329. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62(5):600–610. The references for this chapter can be found at ExpertConsult.com.

References 1. Phillips K, Clauw DJ. Central pain mechanisms in chronic pain states—Maybe it is all in their head. Best Pract Res Clin Rheumatol. 2011;25(2):141–154. 2. Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain. 2016;157(7):1382–1386. 3. Wolfe F, Clauw DJ, Fitzcharles MA, et  al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Sem Arthritis Rheum. 2016;46(3):319–329. 4. Wolfe F, Clauw DJ, Fitzcharles MA, et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR preliminary diagnostic criteria for fibromyalgia. J Rheumatol. 2011;38(6):1113–1122. 5. Wolfe F, Clauw DJ, Fitzcharles MA, et  al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62(5):600–610. 6. Walitt B, Katz RS, Bergman MJ, Wolfe F. Three-quarters of persons in the US population reporting a clinical diagnosis of fibromyalgia do not satisfy fibromyalgia criteria: The 2012 national health interview survey. PLoS One. 2016;11(6):e0157235. 7. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38(1):19–28. 8. Walitt B, Nahin RL, Katz RS, Bergman MJ, Wolfe F. The prevalence and characteristics of fibromyalgia in the 2012 national health interview survey. PLoS One. 2015;10(9):e0138024. 9. Buskila D. Fibromyalgia in children—Lessons from assessing nonarticular tenderness. J Rheumatol. 1996;23(12):2017–2019. 10. Park DC, Glass JM, Minear M, Crofford LJ. Cognitive function in fibromyalgia patients. Arthritis Rheum. 2001;44(9):2125–2133. 11. Vitiello MV, McCurry SM, Shortreed SM, et  al. Short-term improvement in insomnia symptoms predicts long-term improvements in sleep, pain, and fatigue in older adults with comorbid osteoarthritis and insomnia. Pain. 2014;155(8):1547–1554. 12. Hudson JI, Pope HG. The concept of affective spectrum disorder: Relationship to fibromyalgia and other syndromes of chronic fatigue and chronic muscle pain. Baillieres Clin Rheumatol. 1994;8(4): 839–856. 13. Maixner W, Fillingim RB, Williams DA, Smith SB, Slade GD. Overlapping chronic pain conditions: Implications for diagnosis and classification. J Pain. 2016;17(9 Suppl):T93–T107. 14. Barsky AJ, Borus JF. Functional somatic syndromes. Ann Int Med. 1999;130(11):910–921. 15. Fukuda K, Nisenbaum R, Stewart G, et  al. Chronic multisymptom illness affecting air force veterans of the Gulf War. JAMA. 1998;280(11):981–988.

16. López-Solà M, Pujol J, Wager TD, et al. Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients. Arthritis Rheumatol. 2014;66(11):3200–3209. 17. López-Solà M, Woo CW, Pujol J, et al. Towards a neurophysiological signature for fibromyalgia. Pain. 2017;158(1):34–47. 18. Bair E, Ohrbach R, Fillingim RB, et al. Multivariable modeling of phenotypic risk factors for first-onset TMD: The OPPERA prospective cohort study. J Pain. 2013;14(12 Suppl):T102–T115. 19. Greenspan JD, Slade GD, Bair E, et  al. Pain sensitivity and autonomic factors associated with development of TMD: The OPPERA prospective cohort study. J Pain. 2013;14(12 Suppl):T63-74.e1. 20. Greenspan JD, Slade GD, Bair E, et  al. Pain sensitivity risk factors for chronic TMD: Descriptive data and empirically identified domains from the OPPERA case control study. J Pain. 2011;12 (11 Suppl):T61–T74. 21. Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Int Med. 2001;134(9 Pt 2): 868–881. 22. Adelman LC, Adelman JU, Von Seggern R, Mannix LK. Venlafaxine extended release (XR) for the prophylaxis of migraine and tension-type headache: A retrospective study in a clinical setting. Headache. 2000;40(7):572–580. 23. Giesecke J, Reed BD, Haefner HK, Giesecke T, Clauw DJ, Gracely RH. Quantitative sensory testing in vulvodynia patients and increased peripheral pressure pain sensitivity. Obstet Gynecol. 2004;104(1):126–133. 24. Hampson JP, Reed BD, Clauw DJ, et al. Augmented central pain processing in vulvodynia. J Pain. 2013;14(6):579–589. 25. Pierce AN, Christianson JA. Stress and chronic pelvic pain. Prog Mol Biol Transl Sci. 2015;131:509–535. 26. Wallace DJ. Genitourinary manifestations of fibrositis: An increased association with the female urethral syndrome. J Rheumatol. 1990;17(2):238–239. 27. Brand K, Littlejohn G, Kristjanson L, Wisniewski S, Hassard T. The fibromyalgia bladder index. Clin Rheumatol. 2007;26(12):2097– 2103. 28. Wolfe F, Smythe HA, Yunus MB, et  al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: Report of the multicenter criteria committee. Arthritis Rheum. 1990;33(2):160–172. 29. Giovengo SL, Russell IJ, Larson AA. Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol. 1999;26(7):1564–1569. 30. Steere AC, Taylor E, McHugh GL, Logigian EL. The overdiagnosis of Lyme disease. JAMA. 1993;269(14):1812–1816. 31. Geisser ME, Strader Donnell C, Petzke F, Gracely RH, Clauw DJ, Williams DA. Comorbid somatic symptoms and functional status in patients with fibromyalgia and chronic fatigue syndrome: Sensory amplification as a common mechanism. Psychosomatics. 2008;49(3):235–242. 32. Geisser ME, Glass JM, Rajcevska LD, et al. A psychophysical study of auditory and pressure sensitivity in patients with fibromyalgia and healthy controls. J Pain. 2008;9(5):417–422. 33. Nebel MB, Gracely RH. Neuroimaging of fibromyalgia. Rheum Dis Clin North Am. 2009;35(2):313–327. 34. Berna C, Leknes S, Holmes EA, Edwards RR, Goodwin GM, Tracey I. Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness. Biol Psychiatry. 2010;67(11):1083–1090. 35. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46(5):1333–1343. 36. Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH. Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol. 2004;31(2):364–378.

529.e1

529.e2

References

37. Jensen KB, Loitoile R, Kosek E, et  al. Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol Pain. 2012;8:32. 38. Harte SE, Ichesco E, Hampson JP, et  al. Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula. Pain. 2016;157(9):1933–1945. 39. Dadabhoy D, Crofford LJ, Spaeth M, Russell IJ, Clauw DJ. Biology and therapy of fibromyalgia. Evidence-based biomarkers for fibromyalgia syndrome. Arthritis Res Ther. 2008;10(4):211. 40. Harris RE, Sundgren PC, Craig AD, et al. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 2009;60(10):3146–3152. 41. Harris RE, Sundgren PC, Pang Y, et al. Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia. Arthritis Rheum. 2008;58(3):903–907. 42. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65(2):529–538. 43. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27(37):10000–10006. 44. Baraniuk JN, Whalen G, Cunningham J, Clauw DJ. Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain. BMC Musculoskelet Disord. 2004;5(1):48. 45. Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science. 1992;257(5074):1276–1279. 46. Buskila D, Sarzi-Puttini P, Ablin JN. The genetics of fibromyalgia syndrome. Pharmacogenomics. 2007;8(1):67–74. 47. Diatchenko L, Fillingim RB, Smith SB, Maixner W. The phenotypic and genetic signatures of common musculoskeletal pain conditions. Nat Rev Rheumatol. 2013;9(6):340–350. 48. Ciampi de Andrade D, Maschietto M, Galhardoni R, et  al. Epigenetics insights into chronic pain: DNA hypomethylation in fibromyalgia-a controlled pilot-study. Pain. 2017;158(8):1473–1480. 49. Buskila D, Neumann L, Hazanov I, Carmi R. Familial aggregation in the fibromyalgia syndrome. Sem Arthritis Rheum. 1996;26(3): 605–611. 50. Pellegrino MJ, Waylonis GW, Sommer A. Familial occurrence of primary fibromyalgia. Arch Phys Med Rehab. 1989;70(1):61–63. 51. Yunus MB, Khan MA, Rawlings KK, Green JR, Olson JM, Shah S. Genetic linkage analysis of multicase families with fibromyalgia syndrome. J Rheumatol. 1999;26(2):408–412. 52. Arnold L, Iyengar S, Khan M, et al. Genetic linkage of fibromyalgia to the serotonin receptor 2A region on chromosome 13 and the HLA region on chromosome 6. Paper presented at. Arthritis and Rheumatism. 2003. 53. Arnold LM, Hudson JI, Hess EV, et al. Family study of fibromyalgia. Arthritis Rheum. 2004;50(3):944–952. 54. Crofford LJ. Neuroendocrine abnormalities in fibromyalgia and related disorders. Am J Med Sci. 1998;315(6):359–366. 55. Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: A pilot study in fibromyalgia. Arthritis Rheum. 2000;43(4):872–880. 56. Pillemer SR, Bradley LA, Crofford LJ, Moldofsky H, Chrousos GP. The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum. 1997;40(11):1928–1939. 57. Russell IJ, Vaeroy H, Javors M, Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992;35(5):550–556. 58. Caro XJ. Is there an immunologic component to the fibrositis syndrome? Rheum Dis Clin North Am. 1989;15(1):169–186. 59. Yunus MB, Hussey FX, Aldag JC. Antinuclear antibodies and connective tissue disease features in fibromyalgia syndrome: A controlled study. J Rheumatol. 1993;20(9):1557–1560.

60. Dinerman H, Goldenberg DL, Felson DT. A prospective evaluation of 118 patients with the fibromyalgia syndrome: Prevalence of Raynaud’s phenomenon, sicca symptoms, ANA, low complement, and Ig deposition at the dermal-epidermal junction. J Rheumatol. 1986;13(2):368–373. 61. Al-Allaf AW, Ottewell L, Pullar T. The prevalence and significance of positive antinuclear antibodies in patients with fibromyalgia syndrome: 2-4 years’ follow-up. Clin Rheumatol. 2002;21(6):472–477. 62. Gür A, Karakoç M, Nas K, et al. Cytokines and depression in cases with fibromyalgia. J Rheumatol. 2002;29(2):358–361. 63. Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH. Cytokines play an aetiopathogenetic role in fibromyalgia: A hypothesis and pilot study. Rheumatology. 2001;40(7):743–749. 64. Burckhardt CS. Nonpharmacologic management strategies in fibromyalgia. Rheum Dis Clin North Am. 2002;28(2):291–304. 65. Jones KD, Clark SR. Individualizing the exercise prescrip tion for persons with fibromyalgia. Rheum Dis Clin North Am. 2002;28(2):419–436, x. 66. Merriwether EN, Frey-Law LA, Rakel BA, et  al. Physical activity is related to function and fatigue but not pain in women with fibromyalgia: Baseline analyses from the fibromyalgia activity study with TENS (FAST). Arthritis Res Ther. 2018;20(1):199. 67. Ericsson A, Palstam A, Larsson A, et al. Resistance exercise improves physical fatigue in women with fibromyalgia: A randomized controlled trial. Arthritis Res Ther. 2016;18:176. 68. Sañudo B, Galiano D, Carrasco L, de Hoyo M, McVeigh JG. Effects of a prolonged exercise program on key health outcomes in women with fibromyalgia: A randomized controlled trial. J Rehab Med. 2011;43(6):521–526. 69. Jones KD, Clark SR, Bennett RM. Prescribing exercise for people with fibromyalgia. AACN Clin Issue. 2002;13(2):277–293. 70. Carson JW, Carson KM, Jones KD, Bennett RM, Wright CL, Mist SD. A pilot randomized controlled trial of the yoga of awareness program in the management of fibromyalgia. Pain. 2010;151(2): 530–539. 71. Altan L, Korkmaz N, Bingol U, Gunay B. Effect of pilates training on people with fibromyalgia syndrome: A pilot study. Arch Phys Med Rehab. 2009;90(12):1983–1988. 72. Wang C, Schmid CH, Rones R, et al. A randomized trial of tai chi for fibromyalgia. New Eng J Med. 2010;363(8):743–754. 73. Assefi N, Bogart A, Goldberg J, Buchwald D. Reiki for the treatment of fibromyalgia: A randomized controlled trial. J Altern Complement Med. 2008;14(9):1115–1122. 74. McBeth J, Prescott G, Scotland G, et al. Cognitive behavior therapy, exercise, or both for treating chronic widespread pain. Arch Int Med. 2012;172(1):48–57. 75. Carleton RN, Richter AA, Asmundson GJG. Attention modification in persons with fibromyalgia: A double blind, randomized clinical trial. Cogn Behav Ther. 2011;40(4):279–290. 76. Staud R. Evidence of involvement of central neural mechanisms in generating fibromyalgia pain. Curr Rheumatol Rep. 2002;4(4): 299–305. 77. Russell IJ. Advances in fibromyalgia: Possible role for central neurochemicals. Am J Med Sci. 1998;315(6):377–384. 78. Wheeler AH, Goolkasian P, Gretz SS. A randomized, doubleblind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal, myofascial pain syndrome. Spine (Phila Pa 1976). 1998;23(15):1662–1666 discussion 1667. 79. Vlainich R, Issy AM, Gerola LR, Sakata RK. Effect of intravenous lidocaine on manifestations of fibromyalgia. Pain Pract. 2010;10(4):301–305. 80. Affaitati G, Costantini R, Fabrizio A, Lapenna D, Tafuri E, Giamberardino MA. Effects of treatment of peripheral pain generators in fibromyalgia patients. Eur J Pain. 2011;15(1):61–69. 81. Sörensen J, Bengtsson A, Bäckman E, Henriksson KG, Bengtsson M. Pain analysis in patients with fibromyalgia. Effects of intra-

References

venous morphine, lidocaine, and ketamine. Scand J Rheumatol. 1995;24(6):360–365. 82. Curtis AF, Miller MB, Rathinakumar H, et  al. Opioid use, pain intensity, age, and sleep architecture in patients with fibromyalgia and insomnia. Pain. 2019;160(9):2086–2092. 83. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112(3):191–197. 84. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50(9):2974–2984. 85. Arnold LM, Rosen A, Pritchett YL, et  al. A randomized, doubleblind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119(1-3):5–15. 86. Arnold LM, Clauw D, Wang F, Ahl J, Gaynor PJ, Wohlreich MM. Flexible dosed duloxetine in the treatment of fibromyalgia: A randomized, double-blind, placebo-controlled trial. J Rheumatol. 2010;37(12):2578–2586. 87. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: A 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Therap. 2008;30(11):1988–2004. 88. Henriksson KG, Sörensen J. The promise of N-methyl-d-aspartate receptor antagonists in fibromyalgia. Rheum Dis Clin North Am. 2002;28(2):343–351. 89. Olivan-Blázquez B, Herrera-Mercadal P, Puebla-Guedea M, et  al. Efficacy of memantine in the treatment of fibromyalgia: A doubleblind, randomised, controlled trial with 6-month follow-up. Pain. 2014;155(12):2517–2525.

529.e3

90. Persson J, Axelsson G, Hallin RG, Gustafsson LL. Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to central sensitization. Pain. 1995;60(2):217–222. 91. Noppers I, Niesters M, Swartjes M, et al. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: A randomized, prospective, double blind, active placebocontrolled trial. Eur J Pain. 2011;15(9):942–949. 92. Cohen SP, Verdolin MH, Chang AS, Kurihara C, Morlando BJ, Mao J. The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients. J Pain. 2006;7(6):391–398. 93. Dooley DJ, Donovan CM, Meder WP, Whetzel SZ. Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium channels: Inhibition of K+-evoked [3H]-norepinephrine release from rat neocortical slices. Synapse. 2002;45(3):171–190. 94. Taylor CP. The biology and pharmacology of calcium channel α2-δ proteins Pfizer satellite symposium to the 2003 society for neuroscience meeting Sheraton New Orleans Hotel New Orleans, LA November 10, 2003. CNS Drug Rev. 2004;10(2):183–188. 95. Crofford LJ, Rowbotham MC, Mease PJ, et  al. Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52(4):1264–1273. 96. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: A randomized, double-blind, placebocontrolled, multicenter trial. Arthritis Rheum. 2007;56(4):1336–1344. 97. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33(4):451–459. 98. Patten DK, Schultz BG, Berlau DJ. The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in mul-

10 38

Chapter Title to Go Here Headache Management CHAPTER AUTHOR STEPHEN D. SILBERSTEIN

Introduction

Scales that Assess Quality of Life

Headache has plagued humans since the beginning of recorded time. It is one of the most common medical complaints and accounts for more than 18 million outpatient visits per year in the United States. More than 1% of physician’s office visits and emergency department visits are primarily for headaches.1,2 In 1988 the International Headache Society (IHS) published a formal classification system for the diagnosis of headache disorders,3 which has since been updated and improved (International Classification of Headache Disorders, third edition [ICHD-3]).4 The IHS classification system (Box 38.1) continues to divide headaches into primary and secondary disorders. In a primary headache disorder, headache itself is the illness, and no other etiology is diagnosed. In a secondary headache disorder, headache is attributed to an identifiable structural or metabolic abnormality.

QOL is influenced by environmental, economic, social healthrelated, spiritual, and political factors. The fundamental domains of instruments that measure QOL include physical, psychological, and social areas. Both generic and disease-specific measures have been used to measure QOL. The most commonly used generic scales are the Medical Outcomes Study (MOS) instrument, which includes the 20 item Short Form Health Survey (SF-20),10 the SF-36, and the SF-12.11 Other generic QOL scales used in headache studies include the Sickness Impact Profile,12 the Nottingham Health Profile,13 and the Psychological General Wellbeing Index.14 The specific QOL scales for migraine fall into two broadly defined categories: those that measure QOL in a single migraine attack (MQoLQ and MSQ version 2.1) and those that measure the QOL over a period of weeks or months (MSQOL).

Instruments and Scales in Headache Headaches can severely interfere with daily functioning and productivity.5,6 Research has demonstrated that improvement in symptoms and quality of life (QOL) are not perfectly correlated: symptoms may improve, but function may not.7 Consequently, it is important to embrace instruments that measure QOL. Instruments that assess migraine disability can improve headache care by facilitating physician-patient communication and guiding treatment decisions. Various headache scales are in use. The scales can be divided into two main groups: scales that measure the impact of a single migraine attack (with or without therapy) over a 24 h period and scales that measure the impact of migraine over a span of weeks or months. The first group of scales has been used in randomized, placebo-controlled trials; they are highly sensitive to acute treatment effects.8 The second group of scales has been chosen to compare results in randomized trials.9 Scales that measure the impact of an acute attack include (1) QOL (Migraine-Specific Quality of Life Questionnaire [MQoLQ] and Quality of Life Questionnaire [MSQ Version 2.1]) and (2) headache impact and disability (Headache Needs Assessment [HANA] Survey). Scales that measure long-term impact are (1) QOL (Migraine-Specific Quality of Life [MSQOL] Scale), (2) headache impact (Headache Impact Test [HIT], Headache Impact Questionnaire [HimQ], and Henry Ford Hospital Disability Inventory [HDI]), and (3) migraine disability (Migraine Disability Assessment [MIDAS]).

530

Migraine-Specific Quality-of-Life Questionnaire The MQoLQ is a questionnaire that assesses the short-term decrements in QOL associated with acute migraine headache attacks.15 This questionnaire evaluates QOL impairment in the 24 h period following the onset of a migraine headache. The questionnaire is self-administered and is completed quickly and easily. The MQoLQ consists of 15 items with five domains: (1) work functioning, (2) social functioning, (3) energy/vitality, (4) migraine headache symptoms, and (5) feelings and concerns. There are three items within each domain. The response option for each of the items is on a seven point scale, with one indicating maximum impairment of QOL and seven indicating no impairment. Each domain has a maximum score of 21 and a minimum score of three. The scores were compared between migraine-free and migraine periods. The construct validity of the questionnaire was established by showing that there are significant relationships between subjects’ 24 h MQoLQ scores and other indices of clinical migraine headache such as headache severity, limitation of activity, number of associated migraine symptoms, global change in migraine symptoms, and migraine duration.15 The ability of the MQoLQ to capture within-subject change in QOL was evaluated by comparing QOL scores during a “migraine-free” period with MQoLQ scores 24 h after migraine onset.8 The MQoLQ should be applicable to all adults suffering from episodic migraine headaches. It was designed primarily for use in clinical trials to assess migraine management and to be responsive to subject changes in QOL in the 24 h following the onset of a migraine headache. The

• Box 38.1

International Headache Society Criteria (ICHD-3)

Migraine Migraine without aura Migraine with aura Migraine with typical aura Migraine with brainstem aura Hemiplegic migraine Retinal migraine Chronic migraine Complications of migraine Status migrainosus Persistent aura without infarction Migrainous infarction Migraine aura triggered seizure Episodic syndromes that may be associated with migraine Tension-Type Headache Infrequent episodic tension-type headache Frequent episodic tension-type headache Chronic tension-type headache Cluster Headache and Other Trigeminal Autonomic Cephalalgias Cluster headache Paroxysmal hemicrania Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) Hemicrania continua Other Primary Headaches Primary cough headache Primary exercise headache Primary headache associated with sexual activity Primary thunderclap headache Cold stimulus headache External-pressure headache Primary stabbing headache Nummular headache Hypnic headache New Daily Persistent Headache (NDPH) Secondary Headaches Headache attributed to head and/or neck trauma Headache attributed to cranial or cervical vascular disorders Headache attributed to nonvascular intracranial disorders Headache attributed to a substance or its withdrawal Headache attributed to infection Headache attributed to a disorder of homeostasis Headache or facial pain attributed to a disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structure Headache attributed to a psychiatric disorder Cranial neuralgias and central causes of facial pain ICHD-3, International Classification of Headache Disorders, second edition.

MQoLQ assesses subjective wellbeing and daily ability to function, in addition to measuring the typical associated symptoms of migraine, such as nausea, photophobia/phonophobia, and head pain. The 24 h MQoLQ should not be used to measure global QOL between headache episodes.

Quality-of-Life Questionnaire (MSQ Version 2.1) The MSQ is a disease-specific QOL instrument with three hypothesized scales; it has been developed, tested, and revised.16 The MSQ (version 2.1) was structured similarly to older versions

 

CHAPTER 38

Headache Management

531

of the MSQ (versions 1.0 and 2.0). The revised 14 item MSQ (version 2.1) consists of seven items in the role-restrictive dimension that measure the degree to which performance of normal activities is limited by migraines, four items in the role-preventive dimension that measure the degree to which performance of normal activities is interrupted by migraines, and three items in the emotional function dimension that measure the emotional effects of migraine.16 The MSQ dimensions had low to modest correlations with the two component scores of the SF-36 and were modestly to moderately correlated with migraine symptoms. The validation was structured in three separate analyses applied to 267 subjects.17 The MSQ provides clinicians, researchers, and those who fund health care a measurement tool to assess health-related QOL. The questionnaire was designed to be completed quickly and easily in a self-administered form. This study suggested that the mean MSQ (version 2.1) scores six to 12 points higher (indicating better QOL).

Migraine-Specific Quality-of-Life Scale The MSQOL is used to assess a migraine patient’s QOL over a long period (average of three weeks). It is a valid and reliable self-administered measure and a useful tool in clinical migraine research.18 The information that MSQOL provides can add important information about migraine’s impact on QOL and the potential benefits of therapeutic interventions. This questionnaire has 25 items, with each question having four answers. The general format and scoring are one, very much; two, quite a lot; three, a little; and four, not at all. The total score is then transferred to a scale of zero to 100, with a higher number representing a better QOL. For the MSQOL, Cronbach’s alpha was 0.92, suggesting that the items are tapping into a single concept. The MSQOL can provide valuable information on a migraineur’s QOL and be a useful adjuvant measure when assessing long-term treatment outcomes.

Scales that Assess Headache Impact and Disability Headache impairs physical, social, and emotional functioning, but a diagnosis cannot always be made despite the availability of helpful tools. One reason for this is poor patient-physician communication. If the impact that headaches are having on a person’s life can be communicated adequately to the physician, the likelihood of appropriate management will increase.19 Impact and disability instruments are scored differently and have different interpretations. Generally, the impact is scaled in a positive direction, with higher scores reflecting better QOL (i.e. lower impact). For disability measures, higher scores reflect a greater limitation of activity (i.e. higher impact). Measurement of headache-related disability, together with assessments of pain intensity, headache frequency, tiredness, alterations in mood, and cognition, can be used to assess the impact of migraine on sufferers’ lives and on society.20 The tools currently used for assessing headache impact are the HIT and HIT-6, HimQ, HANA Survey, and HDI or Henry Ford Hospital Questionnaire. These scales, when used properly, can improve communication between patients and physicians, assess migraine severity, and act as outcome measures to monitor treatment efficacy. Impact tools are also used, along with other clinical assessments, to produce an individualized treatment plan.20 Disability measures assess impairment in role functioning (i.e. reduced ability to function in defined roles, such as

532

PA RT 4 Clinical Conditions: Evaluation and Treatment

paid work).6 The disability instruments used are the HDI and the MIDAS.

Headache Impact Test The HIT is a tool that measures headache’s impact on a person’s ability to function on the job, at home, and in social situations. The HIT was developed by the psychometricians who developed the SF-36 health assessment. HIT was designed for greater accessibility (on the Internet at www.headachetest.com and www. amlhealthy.com and as a paper-based form known as HIT-6). HIT-6 is a practical test that consists of six questions. A patient can complete the test in less than 2 min. HIT-6 assesses disability over a four week period. The range of scores is 36 to 78. Higher scores signify the greater impact of disability. A score of 60 or higher indicates a severe impact (the headache stops family, work, school, or social activities), a score between 56 and 59 indicates a substantial impact, a score between 50 and 55 signifies some impact, and a score below 49 denotes no impact.21 The availability of this test on the Internet, with feedback provided, makes it a useful tool to help headache sufferers understand the burden of their migraines and seek appropriate management.

Headache Impact Questionnaire The HimQ measures pain and limitations in activity over a three month period. This instrument was the precursor to the MIDAS instrument (see disability scales). The HimQ score is derived from four frequency-based questions (i.e. number of headaches, missed days of work, missed days of chores, or missed days of non-workrelated activity) and four summary measures of the average experience across headaches (i.e. average pain intensity and average reduced effectiveness when having a headache at work, during household chores, and in non-work-related activity).22,23 This scale was validated after assessing the pain and limitations in activity in a population-based sample of 132 migraine headache sufferers enrolled in a 90 day daily-diary study who completed the HimQ at the end of the study. Previous studies of the validity of retrospective pain and disability reporting were mixed.22,24–31 Study participants completed the HimQ in person and then completed daily diaries for 90 days. The HimQ was developed to identify headache sufferers who have the greatest need for medical care. Self-administered questionnaires can adequately capture information to rate pain severity.

Headache Needs Assessment Survey The HANA questionnaire was designed to assess two dimensions (frequency and bothersomeness) of migraine’s impact.32 Seven issues related to living with migraine were used as ratings of frequency and bothersomeness. Validation studies were performed in a Web-based survey, a clinical trial responsiveness population, and a retest reliability population. Headache characteristics (e.g. frequency, severity, and treatment), demographic information, and the HDI were used for external validation. The HANA can be used in medical practice groups (e.g. headache centers, managed care groups) as a screening tool to detect potential problems. Scores from the scale are compared before and after treatment to determine the headache’s impact. Primary care physicians could use the HANA to screen patients with a migraine for further evaluation. Once identified, those with severe migraines may be candidates for further evaluation and immediate treatment. The

HANA has several advantages in that it can (1) select who should be treated, (2) increase productivity by adequately treating headaches, and (3) identify the need for aggressive treatment without the usual slow advancement through stepped-care algorithms. This brief, self-applied questionnaire may be a useful screening tool to evaluate migraine’s impact. The two-dimensional approach to patient-reported QOL allows individuals to weigh the impact of both frequency and bothersomeness of chronic migraine (CM) on multiple aspects of daily life.

Henry Ford Hospital Disability Inventory The HDI is useful in assessing the impact of headaches and its treatment on daily living.33–36 It is a paper-and-pencil instrument that probes the functional and emotional effects of headaches on everyday life. The HDI is a 25 item headache disability inventory, with each item requiring a “yes” (four points), “sometimes” (two points), or “no” (zero points) response. Therefore a maximum score of 100 points reflects severe self-perceived headache disability. The scale is easy to complete and simple to score and interpret. The HDI has high internal consistency, reliability, and good content validity; the long-term (two month) test-retest stability of the HDI was robust.33,34 The test-retest reliability for the beta-HDI was acceptable for the total score and functional and emotional subscale scores.33 Scales of this nature help investigators understand headache’s impact on everyday life. Therefore the HDI can be used to (1) assess the impact of headache on the patient’s daily living, (2) monitor the effect of therapeutic intervention, and (3) plan for a global approach to coping with headache with the patient’s involvement.

Migraine Disability Assessment Questionnaire The MIDAS questionnaire (Fig. 38.1) was developed to measure headache-related disability and improve doctor–patient communication about the functional consequences of migraines. The questionnaire was based on five disability questions that focus on lost time in three domains: schoolwork or work for pay; household work or chores; and family, social, and leisure activities.37 This scale can be used by physicians, nurses, pharmacists, and alternative practitioners. It is easy to complete and takes only a few minutes. The MIDAS questionnaire has demonstrated reliability,38 as reported in two separate population-based studies, one in the United States and one in the United Kingdom, and validity by using a three month daily-diary study as the “gold standard.”39 Scores on the MIDAS are highly correlated with physician judgments about the severity of illness and the need for treatment.40 This instrument is scored as follows: a score of 5–10 indicates little or no disability, 10–20 indicates moderate disability, and higher than 20 indicates severe disability. The MIDAS questionnaire is an important part of a package of educational, investigative, and therapeutic measures and could play a major role in improving the care of patients with migraines and other types of headaches.20,41–48 A randomized, placebo-controlled trial showed that the MIDAS grade provides a basis for selecting initial treatment in stratified care.49

Migraine Migraine is a chronic neurologic disease characterized by episodic attacks of headache and associated symptoms. “Migraine” is derived from the Greek word “hemicrania” (Galen ≈200 A.D).50

Instructions: Please answer the following questions about ALL your headaches you have had over the last three months. Write your answer in the box next to each question. Write zero if you did not do the activity in the last three months. 1 On how many days in the last three months did you miss work or school because of your headache? 2 How many days in the last three months was your productivity at work or school reduced by half or more because of your headaches? (Do not include days you counted in question 1 where you missed work or school.) 3 On how many days in the last three months did you not do household work or go to school because of your headache? 4 How many days in the last three months was your productivity in household work reduced by half or more because of your headache? (Do not include days you counted in question three where you did not do household work.) 5 On how many days in the last three months did you have a headache? (If a headache lasted more than 1 day, count each day.)

533

Migraines decrease the sufferers’ QOL. The World Health Organization (WHO) ranks migraine among the world’s most disabling medical illnesses.59 Approximately 28 million Americans have severe, disabling migraine headaches.55 Migraine’s cost to employers is approximately $13 billion per year, and annual medical costs exceed $1 billion.6 Instruments to quantify migraine disability include the MIDAS39 and the HIT.21

The migraine attack can consist of premonitory, aura, headache, and resolution phases. Premonitory symptoms occur in 20% to 60% of migraineurs, hours to days before the onset of the headache. They may include psychological, neurologic, constitutional, or autonomic features, such as depression, cognitive dysfunction, and bouts of food craving.60

Aura

Total days

Grading system for the MIDAS questionnaire: Score Little or no disability Mild disability Moderate disability Severe disability

Headache Management

Description of the Migraine Attack

A On how many days in the last three months did you have a headache? (If a headache lasted more than one day, count each day.) B On a scale of 0-10, on average how painful were these headaches (where 0 = no pain at all and 10 = pain as bad as it can be). Once you have filled in the questionnaire, add up the total number of days from questions 1-5 (ignore A and B) .

Grade Definition I II III IV

 

CHAPTER 38

0-5 6-10 11-20 21+

• Figure 38.1  MIDAS questionnaire.37 The diagnosis is based on retrospective reporting of headache characteristics and associated symptoms.51 The revised IHS diagnostic criteria for headache disorders3 (ICHD-2) provide the criteria for a total of seven subtypes of migraine.4

Epidemiology The prevalence of migraines is similar and stable in Western countries and the United States.52 Three large-scale population-based studies have been conducted in the United States, one in 1989,53,54 one in 1999,55,56 and one in 2004.57,58 The first American Migraine Study53 found that the prevalence of migraine was 17.6% in women and 6% in men. Two follow-up studies, the American Migraine Study II and the American Migraine Prevalence and Prevention Study (AMPPS), provided results identical to the first, indicating that the prevalence of migraine has been stable in the United States, at least over the last 15 years.58 Before puberty, the prevalence of migraine is approximately 4%58; after puberty, it increases more rapidly in girls than in boys. It increases until approximately 40 years of age and then declines. Prevalence is lowest in Asian Americans, intermediate in African Americans, and highest in Caucasians.6 In the United States, the prevalence of migraines decreases as household income increases.6,53,56

The migraine aura consists of focal neurologic symptoms that precede, accompany, or (rarely) follow an attack. Aura usually develops over a period of 5 to 20 min and lasts less than 60 min. The aura can be visual, sensory, or motor and may involve language or brainstem disturbances.3 Headache usually follows within 60 min of the end of the aura. Patients can have multiple aura types: most patients with a sensory aura also have a visual aura.61 Simple auras include scotomata (loss of vision), simple flashes (phosphenes), specks, geometric forms, and shimmering in the visual field. More complicated visual auras include teichopsia or fortification spectra (the characteristic aura of migraine), metamorphopsia, micropsia, macropsia, zoom vision, and mosaic vision. Paresthesias are often cheiro-aural: numbness starts in the hand, migrates up the arm, and jumps to involve the face, lips, and tongue.51,62 Weakness is rare, occurs in association with sensory symptoms, and is unilateral.63 Apraxia, aphasia, agnosia, states of altered consciousness associated with déjà vu or jamais vu, and elaborate dreamy, nightmarish, trance-like, or delirious states can occur.60

Headache Phase The median migraine attack frequency is 1.5 per month.53 The typical headache is unilateral, of gradual onset, throbbing (85%),64 moderate to marked in severity, and aggravated by movement.3 Pain may be bilateral (40%) or start on one side and become generalized. It lasts 4 to 72 h in adults and 2 to 48 h in children.3 Anorexia is common. Nausea occurs in almost 90% of patients, whereas vomiting occurs in about a third.65 Sensory hypersensitivity results in patients seeking a dark, quiet room.51,65 Blurry vision, nasal stuffiness, anorexia, hunger, tenesmus, diarrhea, abdominal cramps, polyuria, facial pallor, sensations of heat or cold, and sweating may occur. Depression, fatigue, anxiety, nervousness, irritability, and impairment of concentration are common. Symptom complexes may be generated by linked neuronal modules.66

Formal Diagnostic Criteria The IHS subdivides migraine into migraine with aura (Box 38.2) and migraine without aura (Box 38.3).4 To diagnose migraines without aura, five attacks are needed. No single feature is mandatory, but recurrent episodic attacks must be documented.3 Migraine persisting for more than three days defines “status migrainosus.”3,4 Migraine occurring 15 or more days per month is called CM by the ICHD-3 (Box 38.4).67

534

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Box 38.2

Diagnostic Criteria for Migraine With Aura

A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. visual 2. sensory 3. speech and/or language 4. motor 5. brainstem 6. retinal C. At least three of the following six characteristics: 1. at least one aura symptom spreads gradually over ≥5 min 2. two or more aura symptoms occur in succession 3. each individual aura symptom lasts 5-60 min1 4. at least one aura symptom is unilateral2 5. at least one aura symptom is positive3 6. the aura is accompanied, or followed within 60 min, by headache D. Not better accounted for by another ICHD-3 diagnosis.

• Box 38.3

Diagnostic Criteria for Headache Without Aura

A. At least five attacks fulfilling criteria B to D B. Headache attacks lasting 4 to 72 h and occurring less than 15 days/ month (untreated or unsuccessfully treated) C. Headache with at least two of the following characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe intensity 4. aggravated by or causing avoidance of routine physical activity (i.e. walking or climbing stairs) D. During headaches, at least one of the following: 1. nausea and/or vomiting 2. photophobia and/or phonophobia E. Not attributed to another disorder

Migraine Variants Basilar-type migraine aura is characterized by brainstem symptoms: ataxia, vertigo, tinnitus, diplopia, nausea and vomiting, nystagmus, dysarthria, bilateral paresthesia, or a change in the level of consciousness and cognition.3 It should be considered when patients have paroxysmal brainstem disturbances. Some have suggested that hemiplegic migraines should be diagnosed if weakness is present.63 Ophthalmoplegic migraine is caused by idiopathic inflammatory neuritis.68 There is an enhancement of the cisternal segment of the oculomotor nerve, followed by resolution over several weeks as the symptoms resolve. Hemiplegic migraines can be sporadic or familial.51 Attacks are frequently precipitated by a minor head injury.63 Familial hemiplegic migraine (FHM) is an autosomal dominant, genetically heterogeneous disorder with variable penetration. FHM includes attacks of migraine without aura, migraine with typical aura, and episodes of prolonged aura, fever, meningismus, and impaired consciousness.69 Headache may precede the hemiparesis or be absent. The onset of hemiparesis may be abrupt and simulate a stroke. In 20% of unselected FHM families, patients have cerebellar symptoms and signs (nystagmus, progressive ataxia). All have mutations in the CACNA1A gene.70

Treatment

A. Headache on 15 or more days per month for at least three months and Fulfilling criteria B and C B. Patient has had at least five attacks fulfilling criteria B to D for migraine without aura (see Box 38.3) C. On eight or more days per month for at least three months, fulfilling any of the following: 1. criteria C and D for 1.1 Migraine without aura 2. criteria B and C for 1.2 Migraine with aura 3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative D. Not better accounted for by another ICHD-3 diagnosis

Migraine varies widely in its frequency, severity, and impact on patients’ QOL. A treatment plan should consider the patient’s diagnosis, symptoms, and any coexistent or comorbid conditions, and the patient’s expectations, needs, and goals.71 Migraine treatment begins with making a diagnosis,51 explaining it to the patient, and developing a treatment plan that considers any coincidental or comorbid conditions.72 Comorbidity indicates an association between two disorders that is more than coincidental.1 Conditions that occur in migraineurs with a higher prevalence than would be expected include stroke, myocardial infarction, angina, patent foramen ovale (aura), epilepsy, Raynaud’s syndrome, and affective disorders (depression, mania, anxiety, and panic disorder). Possible associations include essential tremor, mitral valve prolapse, and irritable bowel syndrome. Pharmacologic treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent, severe headaches often require both approaches. Acute treatment attempts to relieve or stop the progression of an attack or the pain and impairment once an attack has begun. It is appropriate for most attacks and should be used a maximum of two to three days per week. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability.

Migraine with aura is subdivided into typical aura, prolonged aura, hemiplegic migraine, basilar-type migraine, and migraine with acute-onset aura. The IHS classification now allows the association of aura with other headache types. Prolonged aura lasts from 1 h to one week, and persistent aura lasts for more than one week (but resolves); if neuroimaging demonstrates a stroke, a migrainous infarction has occurred.

Treatment for Acute Migraine Headache Acute treatment can be specific (ergots, triptans, gepants [small molecule calcitonin gene related peptide [CGRP] receptor antagonists], and lasmiditan [selective 5HT1F selective agonist]) or nonspecific (analgesics and opioids). Non-specific medications control the pain of migraines and other pain disorders, whereas specific medications are effective for migraine (and certain other) headache attacks but are not useful for non-headache-related pain disorders. Specific treatments are effective for mild, moderate, and

• Box 38.4

Revised International Headache Society Criteria for Chronic Migraine

severe migraine attacks.73 Devices approved for acute migraine treatment include vagal nerve stimulation (VNS), Nerivio (conditioned pain modulation), and Cefaly (transcutaneous stimulation of the area above the nose). The choice of treatment depends on attack severity and frequency, associated symptoms, coexistent disorders, previous treatment response, and the medication’s efficacy and potential for overuse and adverse events (AEs). A non-oral route of administration and an antiemetic should be considered when severe nausea or vomiting is present.74 Injections can provide rapid relief. Headaches can be stratified by severity and disability, using the MIDAS or the HIT. Analgesics are used for mild to moderate headaches.74 Triptans, gepants, lasmiditan, and dihydroergotamine (DHE) are first-line drugs for severe attacks and less severe attacks that do not adequately respond to analgesics.74 Patients with moderate or severe headaches and moderate or severe disability (based on the MIDAS) who were stratified to treatment with a triptan did better than patients given aspirin and metoclopramide.75 Early intervention prevents escalation and may increase efficacy.76 Triptans can prevent the development of cutaneous allodynia, and the presence of cutaneous allodynia predicts triptans’ effectiveness.77 Before deciding that a drug is ineffective, at least two attacks should be treated with that modality. It may be necessary to add an adjuvant or change the dose, formulation, or route of administration. If the response is inadequate, the headache recurs, or AEs are bothersome, a change in medication may be needed. Limiting acute treatment to two to three days a week can prevent medication overuse headache (MOH). When headaches are very frequent, early intervention may not be appropriate. All treatments occasionally fail. Therefore rescue medications (opioids, neuroleptics, and corticosteroids) are potentially needed. They provide reliable relief but often limit function because of sedation or other AEs.

Preventive Treatment Preventive therapy is given in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability. Preventive treatment may avert episodic migraine’s progression to CM and result in reductions in healthcare costs. Silberstein and colleagues retrospectively analyzed resource utilization information in a large claims database. The addition of migraine preventive drug therapy to therapy that consisted of only an acute medication was effective in reducing resource consumption. When the six months after the initial preventive medication was compared with the six months preceding preventive therapy, office and other outpatient visits with a migraine diagnosis decreased by 51.1%, emergency department visits with a migraine diagnosis decreased by 81.8%, computed tomography (CT) scans with a migraine diagnosis decreased by 75.0%, magnetic resonance imaging (MRI) with a migraine diagnosis decreased by 88.2%, and other migraine medication dispensing decreased by 14.1%.78 Preventive medications reduce attack frequency, duration, and severity.51,79 According to the United States Headache Consortium Guidelines,80 as recently revised,81 indications for preventive treatment include: • recurring migraine that significantly interferes with the patient’s QOL and daily routine despite acute treatment; • failure of, contraindication to, or troublesome AEs from acute medications; • acute medication overuse;

 

CHAPTER 38

Headache Management

535

• very frequent headaches (>1/week) (risk for CM or medication overuse); • patient preference; and • special circumstances such as hemiplegic migraine; frequent, very long, or uncomfortable auras; or attacks with a risk for permanent neurologic injury. Prevention is not being used to the extent that it should be. Results from the American Migraine Study I and II and the Philadelphia Phone Survey 2 demonstrated that migraine preventive therapy is underused: only 13% of all migraineurs currently use preventive therapy to control their attacks.58 In the American Migraine Study II, 25% of all people with migraine, or more than seven million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest.56 According to the AMPPS, 38.8% of patients with migraines should be considered for (13.1%) or offered (25.7%) migraine preventive therapy.82 Preventive medication groups include β-adrenergic blockers, anti-depressants, calcium channel antagonists, anti-convulsants, CGRP antagonists, and nonsteroidal anti-inflammatory drugs (NSAIDs). The choice is based on efficacy, AEs, and coexistent and comorbid conditions. The drug chosen is started at a low dose and increased slowly until therapeutic effects develop or the ceiling dose is reached. A full therapeutic trial may take two to six months. Acute headache medications should not be overused. Because of potential teratogenicity with some of these prophylactic medications, women of childbearing potential should be on adequate contraception. Preventive treatment is often recommended for only six to nine months, but until now, no randomized, placebo-controlled trials have been performed to investigate migraine frequency after preventive treatment has been discontinued. Diener and associates83 assessed 818 migraine patients who were treated with topiramate for six months to see the effects of discontinuation of topiramate. Patients received topiramate in a 26 week open-label phase. They were then randomly assigned to continue this dose or switch to a placebo for a 26 week, double-blind phase. The mean increase in the number of migraine days was greater in the placebo group (1.19 days in four weeks, 95% confidence interval [CI] = 0.71 to 1.66, P < 0.0001) than in the topiramate group (0.10, −0.36 to 0.56, P = 0.57). Patients in the placebo group had more days on acute medication than those in the topiramate group (mean difference between groups: −0.95, −1.49 to −0.41, P = 0.0007). Sustained benefit was reported after topiramate was discontinued, although the number of migraine days did increase. These findings suggest that patients should be treated for six months with the option to continue for 12 months. If headaches are well controlled, medication can be tapered and discontinued. Dose reduction may provide a better risk-to-benefit ratio. Behavioral and psychological interventions used for prevention include relaxation training, thermal biofeedback combined with relaxation training, electromyography biofeedback, and cognitive behavior therapy.84 Devices include gammaCore (non-invasive VNS), the Nerivio Migra device (non-invasive electronic device worn on the upper arm, which is operated through a mobile application and looks like a sports armband), and the Cefaly device (external trigeminal nerve stimulation device [e-TNS] placed on the forehead). Coexistent diseases have important implications for treatment. In some instances, two or more conditions may be treated with a single drug. If individuals have more than one disease, certain categories of treatment may be relatively contraindicated.

536

PA RT 4 Clinical Conditions: Evaluation and Treatment

The preventive medications with the best documented efficacy are divalproex, topiramate, and β-blockers, and the CGRP antagonists. The choice is based on a drug’s proven efficacy, the physician’s informed belief about medications not yet evaluated in controlled trials, the drug’s AEs, the patient’s preferences, the headache profile, and the presence or absence of coexisting disorders.51 The drug chosen should have the best risk-to-benefit ratio for the individual patient and take advantage of the drug’s side effect profile.85,86 An underweight patient would be a candidate for one of the medications that commonly lead to weight gain, such as a tricyclic anti-depressant (TCA); in contrast, one would try to avoid these drugs and consider topiramate if the patient is overweight. Tertiary TCAs that have a sedating effect would be useful at bedtime for patients with insomnia. Older patients with cardiac disease or patients with significant hypotension may not be able to use TCAs, calcium channel blockers, or β-blockers but could use divalproex or topiramate. Athletic patients should use β-blockers with caution. Medications that can impair cognitive functioning should be avoided when patients are dependent on their faculties.85,86 Comorbid and coexistent diseases have important implications for treatment. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. In some instances two or more conditions may be treated with a single drug. However, there are limitations to using a single medication to treat two illnesses. Giving a single medication may not treat two different conditions optimally: although one of the two conditions may be treated adequately, the second illness may require a higher or lower dose. Therefore the patient is at risk for the second illness not being treated adequately. Therapeutic independence may be needed should monotherapy fail. Avoiding drug interactions or increased AEs is a primary concern when using polypharmacy. For some patients, a single medication may adequately manage any comorbid conditions. However, this is likely to be the exception rather than the rule. Polytherapy may enable therapeutic adjustments based on the status of each illness. TCAs are often recommended for patients with migraines and depression.87 However, appropriate management of depression often requires higher doses of TCAs, which may be associated with more AEs. A better approach might be to treat the depression with a selective serotonin reuptake inhibitor or selective serotonin-norepinephrine reuptake inhibitor and treat the migraine with an anti-convulsant. Migraine and epilepsy88 may both be controlled with an antiepileptic drug, such as topiramate or divalproex sodium. Divalproex and topiramate are the drugs of choice for a patient with migraine and bipolar illness.89,90 When individuals have more than one disease, certain categories of treatment may be relatively contraindicated. For example, β-blockers should be used with caution in a depressed migraineur, whereas TCAs or neuroleptics may lower the seizure threshold and should be used with caution in an epileptic migraineur. Although monotherapy is preferred, it is sometimes necessary to combine preventive medications. Anti-depressants are often used with β-blockers or calcium channel blockers, and topiramate or divalproex sodium may be used in combination with any of these medications. Pascual and colleagues91 found that combining a β-blocker and sodium valproate could lead to increased benefit in patients with migraines previously resistant to either drug alone. Fifty-two patients (43 women) with a history of episodic migraine with or without aura and previously unresponsive to β-blockers or sodium valproate monotherapy were treated with a combination of propranolol (or nadolol) and sodium valproate

in an open-label fashion. Fifty-six percent had a greater than 50% reduction in migraine days. This open trial supports the practice of combination therapy. Controlled trials are needed to determine the true advantage of this combination treatment in patients with episodic migraine and CM. With the advent of monoclonal antibodies against CGRP and its receptor, we have a class of medications with good safety tolerability and efficacy. The four anti-CGRP monoclonal antibodies (eptinezumab, erenumab, fremanezumab, and galcanezumab) are safe, effective, and approved to prevent episodic migraine, CM, and MOH.92

Summary Migraine is an extremely common neurobiologic headache disorder that is caused by increased central nervous system excitability. It ranks among the world’s most disabling medical illnesses. Diagnosis is based on the headache’s characteristics and associated symptoms. The economic and societal impact of migraines is substantial. It affects the sufferers’ QOL and impairs work, social activities, and family life. There are many acute and preventive migraine treatments in the market. Acute treatment is either specific (triptans and ergots) or non-specific (analgesics). Disabling migraines should be treated with triptans. Increased headache frequency is an indication for preventive treatment. Preventive treatment decreases migraine frequency and improves QOL. More treatments are being developed, which provides hope to the many sufferers whose migraines are still uncontrolled.

Chronic Daily Headache Chronic daily headache (CDH) refers to headache disorders experienced very frequently (15 or more days per month), including those associated with medication overuse (MOH). CDH can be divided into primary and secondary varieties.93 Primary CDH is not related to a structural or systemic illness. Population-based studies in the United States, Europe, and Asia suggest that 4% to 5% of the general population has primary CDH,94–96 and that 0.5% has severe headaches daily.97,98 In population samples, chronic tension-type headache (CTTH) is the leading cause of primary CDH.99 CDH patients account for the greatest number of consultations in headache subspecialty practices.100 They often overuse medication, which may play a role in initiating or sustaining the pattern of pain. Anxiety, depression, and other psychological disturbances may accompany the headaches.100 Once secondary headache (including MOH) has been excluded, frequent headache sufferers are subdivided into two groups based on headache duration. When the headache duration is less than 4 h, the differential diagnosis includes cluster headache, paroxysmal hemicrania, idiopathic stabbing headache, hypnic headache, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome). When headache duration is longer than 4 h, the major primary disorders to consider are CM (see Box 38.4), hemicrania continua (HC), CTTH (Box 38.5), and new daily persistent headache (NDPH).100 CM, NDPH, and HC are primary CDH disorders that are now included in the second IHS classification.4 Transformed migraine (TM) is similar to CM.4 CM (see Box 38.4) has been called TM.101 Most patients with this disorder are women, 90% of whom have a history of migraines without aura. Patients often report a transformation process characterized by headaches that become more frequent

• Box 38.5

Diagnostic Criteria for Tension-Type Headache

Infrequent Episodic Tension-Type Headache (IHS Diagnostic Criteria) A. At least 10 episodes of headache occurring on 30) Snoring Stressful life events High caffeine consumption Acute medication overuse Depression Head trauma History of migraine Less than a high school education

trauma (OR = 3.3), analgesic use with every attack (OR = 2.8), and long duration of oral contraceptive use. Scher and coworkers125 described factors that predict CDH onset and remission in an adult population. CDH was more common in women (OR = 1.65 [1.3 to 2.0]), those previously married (OR = 1.5 [1.2 to 1.9]), those with obesity (body mass index >30) (OR = 1.27 [1.0 to 1.7]), and those with less education. Obesity, high baseline headache frequency, high caffeine consumption, habitual daily snoring, and stressful life events were significantly associated with new-onset CDH.126 Having less than a high school education was associated with a threefold increased risk for CDH (OR = 3.56 [2.3 to 5.6]). Bigal and colleagues,127 in a clinic-based study, looked for risk factors associated with CDH and its subtypes. TM without MOH (vs. episodic migraine) was associated with allergies, asthma, hypothyroidism, hypertension, and daily caffeine consumption. Zwart and associates128 examined the relationship between analgesic use at baseline and the subsequent risk for chronic pain (≥15 days/month) and analgesic overuse in a population-based study. In total, 32,067 adults reported the use of analgesics from 1984 to 1986 and at the follow up 11 years later (1995 to 1997). The risk ratios for chronic pain and analgesic overuse in the different diagnostic groups (i.e. migraine, nonmigrainous headache, and neck pain) were estimated in relation to analgesic consumption at baseline. Individuals who reported using analgesics daily or weekly at baseline had a significantly increased risk of having chronic pain at follow up. The risk was most evident for CM (relative risk [RR] = 13.3, 95% CI = 9.3 to 19.1), intermediate for chronic nonmigrainous headaches (RR = 6.2, 95% CI = 5.0 to 7.7), and lowest for chronic neck pain (RR = 2.4, 95% CI = 2.0 to 2.8). In subjects with chronic pain associated with analgesic overuse, the RR was 37.6 (95% CI = 21.3 to 66.4) for CM, 14.4 (95% CI = 10.4 to 19.9) for chronic nonmigrainous headaches, and 7.1 for chronic neck pain (95% CI = 5.5 to 9.2). The RR for chronic headache (migraine and nonmigrainous headache combined) associated with analgesic overuse was 19.6 (95% CI = 14.8 to 25.9) versus 3.1 (95% CI = 2.4 to 4.2) for those without overuse. Analgesic overuse strongly predicts chronic pain and chronic pain associated with analgesic overuse 11 years later, especially in those with CM. Although data on the natural history of patients with CM are not available (because of the 10 to 15 year time scale that would be required for a population-based study of this condition), information from the American migraine prevalence and prevention (AMPP) on the clinical evolution of this condition was published in 2011.129 Longitudinal data over a three year period were analyzed to determine rates of CM remission and to assess predictors

 

CHAPTER 38

Headache Management

539

of remission via logistic regression models. Three hundred and eighty-three individuals who had CM in 2005 were identified and evaluated in 2006 and 2007. Among individuals with CM at baseline, 52.7% continued to report this condition for at least one year of follow up. The study also found that 34% had persistent CM (defined as CM across all three years), whereas only 26% had remission of CM (defined as fewer than 10 headache days per month).129 Over a two year period, the individuals with persistent CM demonstrated increased disability, whereas those with remission showed decreased disability. Predictors of remission included a lower baseline headache frequency (15 to 19 headache days per month vs. 25 to 31 headache days per month; OR = 0.29, 95% CI = 0.11 to 0.75) and the absence of allodynia (OR = 0.45, 95% CI = 0.23 to 0.89).

Treatment Overview Patients with CDH can be challenging to treat, especially when the disorder is complicated by medication overuse, comorbid psychiatric disease, low tolerance of frustration, and physical and emotional dependency.95,130 We recommend the following steps. First, exclude secondary headache disorders. Second, diagnose the specific primary headache disorder (CM, CTTH, HC, or NDPH). Third, identify comorbid medical and psychiatric conditions and exacerbating factors, especially medication overuse. Limit acute medications (with the possible exception of longacting NSAIDs). Patients should start taking preventive medication (to decrease reliance on acute medication), with the explicit understanding that the drugs may not become fully effective until medication overuse has been eliminated.51 Some patients need to have their headache cycle terminated.51 Patients need education and continuous support during this process. Outpatient detoxification options, including outpatient infusion in an ambulatory infusion unit, are available. If outpatient treatment proves difficult or is dangerous, hospitalization may be required.93,131 Two separate studies in Europe and the United States showed that topiramate at a dose of 100 mg daily was effective as preventive therapy for CM.132,133 The key difference between the two studies was that patients were allowed to take acute rescue medication as usual in the European trial132 but not in the United States trial.133 Remarkably, the benefits of topiramate extended to the subgroup of patients who were overusing acute medications, as demonstrated by the significant reductions in mean monthly migraine days in this group versus the placebo group. The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT 1 and 2) multicenter randomized clinical trials were conducted to evaluate the efficacy and safety of botulinum toxin type A as prophylactic treatment in adults with CM. A total of 1384 patients with CM were enrolled across trials.134–136 Patients were stratified into groups according to whether they were overusing acute headache medications at baseline and were randomly assigned in a 1:1 ratio to treatment with either botulinum toxin type A or placebo injections. A total dose of 155 units of botulinum toxin type A was administered to 31 sites in seven head and neck muscles.134–136 The PREEMPT study results demonstrated significant improvement at the population level in multiple measures of headache symptoms and improvement in patients’ functioning, vitality, psychological distress, and overall health-related QOL in response to treatment with botulinum toxin type A. The four anti-CGRP monoclonal antibodies (eptinezumab, erenumab, fremanezumab, galcanezumab) are safe, effective, and

540

PA RT 4 Clinical Conditions: Evaluation and Treatment

approved for the prevention of episodic migraine and CM even in the presence of MOH without acute medication withdrawal. In some cases, CDH reverts to episodic headaches when preventive medication is initiated and acute medications are limited. In other cases, only moderate or no improvement may occur. Zeeberg and coworkers137 described the treatment outcomes of patients withdrawn from medication overuse. They studied 337 outpatients in whom MOH was diagnosed and who were treated and discharged from the Danish Headache Centre in 2002 and 2003. A 46% decrease in headache frequency from the first visit to dismissal was noted (P < 0.0001). Patients with no improvement two months after complete drug withdrawal (n = 88) subsequently responded to pharmacologic or nonpharmacologic prophylaxis (or both) with a 26% decrease in headache frequency as measured from the end of withdrawal to dismissal. At dismissal, 47% of patients were being maintained on prophylaxis. In this population, about half of the MOH patients benefited from drug withdrawal alone.137

cross-sectional headache study that included 549 persons. Among 146 subjects with frequent ETTH and 15 with CTTH at baseline, 45% experienced infrequent or no TTH (remission), 39% had frequent ETTH, and 16% experienced CTTH (poor outcome) at follow up. A poor outcome was associated with baseline CTTH, coexisting migraine, sleeping problems, and single state.147

Clinical Features and Associated Disorders (see Box 38.5)

The AMPPS was published in 2011.129 Among individuals with CM at baseline, 52.7% continued to report this condition for at least one year of follow up. The study also found that 34% had persistent CM (defined as CM across all three years), whereas only 26% had remission of CM (defined as fewer than 10 headache days per month).138 Over two years, the individuals with persistent CM demonstrated increased disability, whereas those with remission showed decreased disability. Predictors of remission included a lower baseline headache frequency (15 to 19 headache days per month vs. 25 to 31 headache days per month; OR = 0.29, 95% CI = 0.11 to 0.75) and the absence of allodynia (OR = 0.45, 95% CI = 0.23 to 0.89). In addition, retrospective analysis suggests that there may be periods of stable drug consumption and periods of accelerated medication use. Patients treated aggressively generally improve. There are no literature reports of spontaneous improvement of rebound headache, although this may happen. We performed follow-up evaluations on 50 hospitalized primary CDH drug overuse patients who were treated with repetitive intravenous DHE and became headache free.139 Once detoxified, treated, and discharged, most patients did not resume daily analgesic or ergotamine use. Seventy-two percent continued to show significant improvement at three months, and 87% continued to show significant improvement after two years. This would suggest at least 70% improvement at two years in the initial group (35 of 50) if allowance is made for patients lost to follow up. Our two year success rate of 87% is consistent with the longterm success rates reported in the literature.139 In a series of 22 papers published between 1975 and 1999, the success rate of withdrawal therapy (often accompanied by pharmacologic or behavioral intervention, or both) for patients overusing analgesics, ergotamine, or both was between 48% and 91%, with the rate being reported as 77% or higher in ten papers.103,104,107,124,140–145

ETTH is now classified as either infrequent (1 but 12 but 5 per day1 E. Prevented absolutely by therapeutic doses of indomethacin2 F. Not better accounted for by another ICHD-3 diagnosis.

Episodic Paroxysmal Hemicrania

Cluster Headache and Other Trigeminal Autonomic Cephalgia (Box 38.8)

A. Attacks fulfilling criteria A to F for Paroxysmal Hemicrania B. At least two attack periods lasting seven to 365 days and separated by pain-free remission periods of three months or longer

The short-lasting primary headache syndromes may be conveniently divided into those that exhibit marked autonomic activation and those without autonomic activation. This group includes cluster headache (episodic or chronic), paroxysmal hemicrania (episodic or chronic), and SUNCT syndrome.

A. Attacks fulfilling criteria A to F for Paroxysmal Hemicrania B. Attacks recurring more than one year without remission periods or with remission periods lasting less than three months

Pathogenesis and Pathophysiology The pathogenesis of cluster headache involves the trigeminovascular system, as demonstrated by a marked increase in the level of CGRP in the cranial venous circulation during attacks.156 Activation of the parasympathetic system has been corroborated by the finding of dramatically elevated levels of vasoactive intestinal polypeptide during attacks156 with robust ipsilateral autonomic features. Cluster events are probably related to alterations in the circadian pacemaker, which may be because of hypothalamic dysfunction. Attacks increase following the beginning and end of

Chronic Paroxysmal Hemicrania

daylight saving time, and there is a loss of the circadian rhythm for blood pressure, temperature, and hormones, including prolactin, melatonin, cortisol, and β-endorphins. Evidence for the role of the hypothalamus in the pathogenesis of cluster headaches has come from functional and morphometric neuroimaging. May and colleagues demonstrated marked activation in the ipsilateral ventral hypothalamic gray matter during nitroglycerin-induced acute cluster headache attacks using positron emission tomography.157 Neurogenic inflammation, dysfunction of the carotid body chemoreceptor, an imbalance in central parasympathetic and

542

PA RT 4 Clinical Conditions: Evaluation and Treatment

sympathetic tone, and increased responsiveness to histamine have been proposed as the cause of cluster headache.158

Epidemiology and Risk Factors With an incidence of 0.01% to 1.5% in various populations, the prevalence of cluster headaches is lower than that of migraine or TTH. Men have a higher prevalence than women, and African American patients have a higher prevalence than Caucasian patients. Recent evidence suggests a progressively decreasing male preponderance: the male-to-female ratio based on the year of onset in Manzoni’s study159 decreased from 6.2:1 in the 1960s to 2.1:1 in the 1990s.160 A family history of cluster headache is rare. The most common form of cluster headache is an episodic cluster. The rarest form is chronic cluster headache without remissions, with only about 1% of patients suffering from this variety of cluster. Cluster headaches can begin at any age but generally commence in the late twenties. Cluster headaches rarely begin in childhood and develop in only about 10% of patients when they are in their sixties.158,161

Clinical Features and Associated Disorders A. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 min if untreated B. Either or both of the following: Patients with cluster headaches have multiple episodes of shortlived but severe, unilateral orbital, supraorbital, or temporal pain lasting 15 to 180 min if untreated, with either or both of the following: 1) at least one of the following symptoms or signs, ipsilateral to the headache: conjunctival injection and/or lacrimation; nasal congestion and/or rhinorrhea; eyelid edema; forehead and facial sweating; miosis and/or ptosis or 2) a sense of restlessness or agitation. An episodic cluster consists of headache periods of one week to one year, with remission periods lasting at least 14 days, whereas a chronic cluster headache has either no remission periods or remissions that last less than 14 days.158,161 The pain of a cluster attack increases to excruciating levels rapidly (within 15 min). The attacks often occur at the same time each day and frequently awaken patients from sleep. If the condition is left untreated, the attacks usually last from 30 to 90 min, but they may last as long as 180 min. The pain is deep, constant, boring, piercing, or burning in nature and located in, behind, or around the eye. It may radiate to the forehead, temples, jaws, nostrils, ears, neck, or shoulders. During an attack, patients often feel agitated or restless and feel a need to isolate themselves and move around. Gastrointestinal symptoms are uncommon. A small subset of patients experience a typical migraine aura before a cluster headache attack.162 Attack frequency varies from one every other day to eight per day, with cluster periods lasting a week to a year. Remissions between cluster periods generally last from six months to two years. Most patients have one or two cluster periods per year that last two to three months, with one to two attacks per day.158 Peptic ulcer disease is the only known associated medical disorder. Secondary cluster-like headaches may be because of structural lesions near the cavernous sinuses.158,161

Differential Diagnosis The differential diagnosis of cluster headache includes chronic paroxysmal hemicrania, migraine, trigeminal neuralgia, temporal arteritis, pheochromocytoma, Raeder’s paratrigeminal syndrome,

Tolosa-Hunt syndrome, sinusitis, and glaucoma.158 Raeder’s syndrome has characteristics similar to cluster headaches. It may be associated with severe pain, unilateral and supraorbital distribution, and an associated partial Horner syndrome. It is distinct from cluster headache in that there are no distinct attacks, and the pain is constant.

Evaluation No studies have addressed the need for testing in patients with cluster-like headaches. In most cases, a careful history is all that is needed to make the diagnosis. MRI of the head is justified only for atypical cases or those with abnormal findings on neurologic examination (except when the abnormality is Horner’s syndrome).

Management Patients with cluster headaches should avoid alcohol and nitroglycerin, but other dietary and drug restrictions have little effect. Pharmacologic treatment of cluster headaches is divided into acute and preventive therapy, and recommendations are based mainly on uncontrolled trials.158,161 Because oral preparations are absorbed slowly, they are not recommended for acute attacks. Effective acute treatments that provide a rapid onset of action include oxygen, sumatriptan, DHE, and (perhaps) topical local anesthetics. Inhaled oxygen, 7 to 10 L/min for 10 min following the onset of the headache, is 70% effective and is often the first choice of treatment. Parenteral injections of sumatriptan or DHE provide significant relief to about 80% of patients. An intranasal local anesthetic provides relief for some patients.158,161 Most patients with cluster headaches require preventive treatment because each attack is too short in duration and too severe in intensity to treat with only acute medication. In addition, ergotamine, DHE, sumatriptan, and oxygen may just postpone rather than abort the attack. Preventive therapy for cluster headache includes ergotamine, calcium channel blockers, lithium, corticosteroids, divalproex, topiramate, melatonin, and galcanezumab for an episodic cluster. Occasionally, indomethacin is effective. If medical therapy fails, surgical intervention may be beneficial for psychologically stable patients with strictly unilateral chronic cluster headaches. The surgery consists of neuronal ablative procedures directed toward the sensory input of the trigeminal nerve and autonomic pathways and is effective in 75% of patients.163 Gamma knife radiosurgery was reported to be effective in six medically recalcitrant cluster headache patients, but delayed radiation necrosis can occur.164 Deep brain (hypothalamic) stimulation has been reported to be effective for intractable chronic cluster headaches.165 Since cluster headache is a chronic headache disorder that may last a patient’s lifetime, the prognosis is guarded. Drug therapy may help convert chronic headaches in some patients to episodic cluster headaches.158 Deep brain stimulation of the posterior hypothalamus (hDBS) and ONS along the greater occipital nerve have been introduced, and evidence is accumulating. Deep brain stimulation was developed based on findings of activation in the posterior part of the lateral portion of the hypothalamus.166 Both hDBS and ONS have so far resulted in positive outcomes in patients with drug-resistant chronic cluster headache (about a 50% reduction in attacks), but long-term studies have revealed that a positive outcome, especially with ONS, may take a week to months of stimulation to be reached, thus pointing at long-term brain alterations in pain processing as a mechanism.167–170 With both hDBS and ONS, the

pain and autonomic symptoms return to baseline levels when the stimulator is turned off.167–170 So far, no predictors of treatment response have been found, and greater occipital nerve block does not predict ONS response.171

Sphenopalatine Ganglion Stimulation In 2010 Ansarinia and coauthors described the acute effect of external electrical stimulation in eight patients with cluster headache, of whom four achieved complete freedom from pain, three achieved a reduction in pain, and one had no change.172 More sophisticated systems have been developed, and an ongoing European multicenter study is now testing the effect of an electrode implanted directly in the sphenopalatine fossa very close to the sphenopalatine ganglion (SPG). The preliminary results are very promising; there appears to be a significant preventive effect in addition to an acute abortive effect. The side effects have been limited; therefore the therapy looks promising for severely affected chronic cluster headache patients. However, long-term studies are needed. Furthermore, important insight into the pathophysiology of cluster headaches and the mechanisms of SPG stimulation can be achieved.

Chronic Paroxysmal Hemicrania (see Box 38.8) Chronic paroxysmal hemicrania resembles cluster headache in character but is distinguished by its dramatic responsiveness to indomethacin therapy. The pathophysiology of chronic paroxysmal hemicrania is unknown. The changes in intraocular pressure that occur during attacks suggest autonomic dysfunction, and the periodicity of this disorder suggests a central generator.173 In contrast to cluster headache, chronic paroxysmal hemicrania is a rare disorder that affects women more than men (ratio of approximately 7:1). Its prevalence is approximately 2% that of cluster headache.173 Like patients with cluster headaches, those with chronic paroxysmal hemicrania have severe unilateral headaches associated with unilateral nasal stuffiness, lacrimation, conjunctival eye tearing,

 

CHAPTER 38

Headache Management

543

ptosis, and eyelid edema. Headaches average 13 min in duration and occur an average of 11 times per day. Occasionally, patients experience a continuous dull ache between attacks. Ten percent of patients can trigger attacks by flexing, rotating, or pressing the upper portion of the neck.173 Typically, no remissions occur. Rarely, a patient has episodic paroxysmal hemicrania with remissions that last weeks or months. Patients may evolve from the episodic to the chronic form of the illness. By definition, chronic and episodic hemicranias are responsive to indomethacin. No other medical or psychiatric disorders have been associated with chronic paroxysmal hemicrania.173

Differential Diagnosis The differential diagnosis of chronic paroxysmal hemicrania is similar to that for cluster headaches. In addition, patients with “jabs and jolts syndrome” occasionally resemble those with chronic paroxysmal hemicrania. A rare headache disorder called SUNCT syndrome should be considered, although these headaches are much shorter in duration (15 to 30 s) and occur much more frequently (many times per hour) than those of chronic paroxysmal hemicrania.

Evaluation When evaluating a patient with chronic paroxysmal hemicrania, a trial of indomethacin is necessary to establish the diagnosis. Brain imaging with MRI or CT should be undertaken to exclude symptomatic causes of apparent chronic paroxysmal hemicrania. The treatment of choice is indomethacin (in a dose of up to 200 mg/day). Aspirin may also be beneficial, but it does not usually afford complete relief. Chronic paroxysmal hemicrania may last indefinitely, but the indomethacin requirement may be reduced over time. Temporary remissions and spontaneous cures have been described. Selective prostaglandin synthesis inhibitors, or indomethacin-like drugs without the gastrointestinal side effects of the current NSAIDs, are in development and may be beneficial.

Summary Headache is a problem that has plagued humans since the beginning of recorded time. Headaches can severely interfere with daily functioning and productivity. Migraine is a chronic neurologic disease characterized by episodic attacks of headache and associated symptoms. The migraine attack can consist of premonitory, aura, headache, and resolution phases. The IHS subdivides migraine into migraine with aura and migraine without aura. Migraine varies widely in its frequency, severity, and impact on patients’ QOL. Pharmacologic treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent, severe headaches often require both approaches. CDH refers to headache disorders experienced very frequently (15 or more days per month), including headaches associated with medication overuse. The major primary disorders to consider are CM, HC, CTTH, and NDPH. MOH was previously called rebound headache, drug-induced headache, and medication misuse headache. Patients with frequent headaches often overuse analgesics, opioids, ergotamine, and triptans. Patients with CDH can be difficult to treat. First, secondary headache disorders should be excluded; second, the specific primary headache disorder should be diagnosed; and third, comorbid medical and psychiatric conditions should be

identified. Acute medications should be limited. Patients should start taking preventive medication, with the explicit understanding that the drugs may not become fully effective until medication overuse has been eliminated. TTH is the most common type of headache, with a lifetime prevalence of 69% in men and 88% in women. ETTH is now classified as either infrequent (1 but 12 but 50 years, history of cancer, night pain leading to awakening, and weight loss. Special attention should be paid to high-risk patients, such as immunocompromised individuals, as they are more susceptible to more serious conditions, such as infections. The differential diagnosis includes: 545

546

PA RT 4



Clinical Conditions: Evaluation and Treatment

Tumor in the Posterior Fossa, Arnold Chiari Formation • The dura mater in the posterior cranial fossa is supplied by the sinuvertebral nerves C1–35.

Herniated Cervical Vertebral Disc • The C3 vertebral branch supplies the intervertebral discs of C2/C3. Discogenic pain may be an underlying cause.

Spinal Nerve Compression or Tumor, Intramedullary or Extramedullary Spinal Tumor • The dura mater of the upper cervical spinal cord is supplied by the sinuvertebral nerves C1–35.

Occipital Neuralgia • Greater occipital nerve entrapment. • The greater occipital nerve can be entrapped in its course between the obliquis capitis inferior and the semispinalis capitis. This is a commonly accepted cause of cervicogenic headaches resulting from occipital neuralgia.7

C2 Nerve Lesions • Figure 39.1  Nociceptive

afferents of the trigeminal and upper three cervical spinal nerves converge onto second-order neurons in the trigeminocervical nucleus in the upper cervical spinal cord. This convergence mediates the referral of pain signals from the neck to regions of the head innervated by cervical nerves or the trigeminal nerve. (Reprinted with permission from Elsevier. Bogduk N, Govind J. Cervicogenic headache: an assessment of the evidence on clinical diagnosis, invasive tests, and treatment. Lancet Neurol 2009;8:959–968.)

Internal Carotid or Vertebral Artery Dissection • The vertebral and internal carotid arteries are innervated by the cervical nerves, and dissection of these vessels can result in headaches.7 • May have stroke-like symptoms within one to three weeks.6 • Treatment with cervical manipulation can be fatal.6

• Nerve-vessel compression on the C2 nerve root. • This nerve runs across the capsule of the lateral atlantoaxial joint, and its roots are covered in the dura mater and a plexus of the epiradicular veins. Inflammatory lesions of the joint and lesions of the dura or surrounding vessels may result in compression of this nerve.5 C2 neuralgia is characterized by intermittent and lancinating pain, unlike cervicogenic headache, because of C2/C3 facet disease, which is a constant and dull ache in nature.

Migraines and Tension-Type Headaches • Cervicogenic headaches can be differentiated from migraine and tension-type headaches. These include: • Side-locked pain.

TABLE Cervicogenic Headache International Study Group (CHISG) criteria 39.1

Major Symptoms

Pain Characteristics

Other Important Criteria

Minor Symptoms and Signs

Unilateral pain

Non-clustering episodes

Female sex

Autonomic symptoms and signs

Symptoms and signs of neck involvement*

Varying duration

Head or neck trauma

Dizziness

Moderate, non-throbbing, non-excruciating

Pain abolished by C2 or major occipital nerve

Phonophobia and Photophobia

Starting in the neck and spreading to the oculo-frontotemporal region

Difficulty swallowing

*a) Provocation of attacks i) Pain triggered by neck movement; ii) pain elicited by external pressure over the ipsilateral upper, posterior neck, or occipital region. b) Reduced range of motion of the cervical spine c) Ipsilateral neck, shoulder, and arm pain of a rather vague, non-radicular nature Both major criteria must be present for diagnosis: unilateral pain with at least one sign or symptom of neck involvement. Other important criteria strongly support this diagnosis. Adapted from Sjaastad O, Fredriksen TA, Pfaffenrath V. Cervicogenic headache: diagnostic criteria. Headache. 1990;30(11):725–726.

 

CHAPTER 39

Cervicogenic Headache, Post-meningeal Puncture Headache, and Spontaneous Intracranial Hypotension

TABLE IHS International Classification of Headache 39.2 Disorders 3 Diagnostic Criteria A. Headache fulfilling criterion C. B. Clinical and/or imaging evidence of a disorder or lesion within the cervical spine or soft tissues of the neck. C. Evidence of causation demonstrated by at least two of the following: • Headache developed in a temporal relation to the onset of cervical disorder or appearance of the lesion • Headache significantly improved or resolved in parallel with improvement in or resolution of cervical disorders or lesions • Cervical range of motion is reduced • Headache is made significantly worse by provocative maneuvers • Headache was not explained by any other International Classification of Headache Disorders, 3rd edition (ICHD-3). D. Headache abolished following diagnostic blockade of a cervical structure or its nerve supply Adapted from the Headache Classification Committee of the International Headache Society. The international classification of headache disorders, third Edition. Cephalalgia. 2018;38(1):1–211.

• Can be elicited by digital pressure on neck muscles and by head movement. • Radiation of pain in a posterior-to-anterior radiation fashion. • Lesser degree of nausea, vomiting, photophobia, and phonophobia.9,11 • Not throbbing and no side shifts, unlike migraine headaches. • Lack of response to ergotamine and triptans, unlike migraine headaches.

Investigations A full history and physical examination are necessary for the diagnosis of cervicogenic headache. History should include: • History of trauma (e.g. whiplash injury) or cervical disease. • The presence of associated neurologic symptoms or stroke-like symptoms (may indicate more serious diagnoses). Physical examination should include the range of motion of the neck and attempt to produce a typical headache with head movement or head positioning. There should be a reasonable suspicion of cervicogenic headache prior to imaging studies. Imaging modalities, such as ultrasound, computed tomography (CT), and magnetic resonance imaging, may be helpful. Ultrasound may detect entrapment of the occipital nerve in occipital neuralgia. However, user variability affects reliability. CT imaging can be used to identify the bony pathology of the cervical spine. MRI is the modality of choice because it can visualize the bony pathology, soft tissue, and nerves of the cervical spine. Overall, it is important to remember that the imaging findings were not diagnostic. There should be a temporal relationship between positive findings and headaches to prove causation.

Treatment Non-pharmacologic Treatment Although there have been no controlled studies proving the efficacy of non-pharmacologic methods in the treatment of cervicogenic headaches, the potential benefits should still be considered.11

547

• Massage • Cold compress • Physical therapy, including manual therapy • Exercises to improve posture • Cranio-cervical exercises • Transcutaneous electrical nerve stimulation therapy • Biofeedback/relaxation therapy • Psychotherapy

Pharmacologic Treatment • Tricyclic anti-depressants (TCAs) • Antiepileptic drugs12 • Gabapentin • Carbamazepine • Divalproex sodium • Topiramate • Serotonin and norepinephrine re-uptake inhibitors (SNRIs) • Venlafaxine • Duloxetine • Muscle relaxants • Nonsteroidal anti-inflammatory drugs (can be topical or enteral)12 • Non-selective cyclo-oxygenase inhibitors • Cyclo-oxygenase-2 selective inhibitors • Topical local anesthetics

Interventional Minimally Invasive Procedures Cervical Facet MBB and Radiofrequency Ablation (RFA)12 Pain mediated by cervical facet joints can be diagnosed using a cervical MBB. Local anesthetics, with or without steroids, can be used. Patients who experience relief from this block tend to respond favorably to RFA. Once it has been proven that the headaches are relieved by diagnostic anesthetic blockade of a specific medial branch nerve, radiofrequency ablation can be performed to provide longerlasting relief. This is primarily used to treat cervicogenic headaches arising from the C2–C3 zygapophysial joint, whose nerve supply is via the third occipital nerve.5 RFA of C3 and C4 medial branches can also be performed in the same setting to help with concomitant neck pain. Technical Note for Cervical Facet MBB and RFA In the posterior approach, the patient was placed in the prone position, and the facet column was identified using anterior and posterior pillar views. The needle was aimed at the “waist” of the articular pillars. A lateral view can confirm optimal positioning. The target is the middle of the articular pillars of the target vertebra.13 The target for the third occipital nerve is the inferior aspect of C2–C3.14 This is because the nerve usually travels along the C2– C3 joint just opposite to the center of the superior articular process of C3.10 This is illustrated in Fig. 39.2, and the fluoroscopic images in Figs 39.3 and 39.4 highlight the needle placement targets. This procedure can also be performed when the patient is in a lateral position. Special precautions should be taken to ensure that the articular pillars are well superimposed, and fluoroscopy shows a true lateral image. This helps avoid faulty needle placement, which can result in spinal cord injury.

Other Interventions • Trigger point injections (TPIs)

548

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Figure 39.2 

“Posterior and lateral views of the upper cervical spine, showing the leading articular sources of cervicogenic headache, the related nerves, and where needles are placed for diagnostic blocks of these structures. The red labels and needles point to target sites for diagnostic blocks.” AOJ, Atlantooccipital joint; C3 DMB, C3 deep medial branch block; C4mb, medial branch of the C4 dorsal ramus; dmb, deep medial branch of the C3 dorsal ramus; LAA IAB, intra-articular block of the lateral atlantoaxial joint; LAAJ, lateral atlantoaxial joint; ton, third occipital nerve; TONB, third occipital nerve block; ZJ, zygapophysial joint. (Reprinted with permission from Elsevier. Bogduk N, Govind J. Cervicogenic headache: an assessment of the evidence on clinical diagnosis, invasive tests, and treatment. Lancet Neurol 2009;8:959–968.)

• Figure 39.3  Fluoroscopic image showing the lateral view used for needle placement for the third occipital nerve and medial branch of C3 and C4 RFA. Note that the needle target for the third occipital nerve is at the middle of the C2–C3 joint. For C3–C4, the needle target is at the middle of the articular pillars.

 

CHAPTER 39

Cervicogenic Headache, Post-meningeal Puncture Headache, and Spontaneous Intracranial Hypotension

549

Efficacy of Non-pharmacologic Treatment Generally, studies regarding the efficacy of non-pharmacologic treatment modalities have shown the greatest effect when the modes of treatment are combined. Further evidence suggests that control of cervicogenic headaches is considerable in those undergoing exercise and physical therapy programs.13,14 Furthermore, in a randomized control trial conducted by Jull et al., long term reduction in cervicogenic headache frequency and intensity was shown to be statistically significant in those who underwent manipulative therapy and specific exercise.15

Efficacy of Pharmacologic Treatment and Interventional Procedures At present, evidence of the efficacy of any pharmacologic treatment for cervicogenic headache is lacking. Therapeutic blocks of the occipital nerves have proven short term relief of symptoms, and repeated injections can lead to long term relief. Facet blocks were found to provide some acute pain relief but were less likely to have sustained benefits.11 Overall, there is a paucity of randomized control studies that support the efficacy of interventional procedures for the treatment of cervicogenic headache. • Figure 39.4  Fluoroscopic image showing the anterior-posterior view used for needle placement during the third occipital nerve and medial branch of C3, C4, and C5 RFA.

It is not uncommon to have underlying myofascial pain and muscle spasms over the trapezius and cervical paraspinal muscles. Trigger point injections cause relaxation of muscle spasms, which may lead to pain relief,11 and can help with the pain associated with myofascial pain triggers. • Occipital nerve block11 The block of the greater occipital nerve in the occipital nerve entrapment can be effective in treating occipital neuralgia. The block can be performed using anatomic landmarks or ultrasound guidance. Local anesthetics can be injected with or without steroids. It can provide transient benefits in most patients, although some patients experience relief for an extended period of up to several months. If the block provides short-term relief, radiofrequency ablation using a pulsed technique or other techniques such as cryoablation can be considered for prolonged pain relief. • Botulinum toxin12 Botulinum toxins can be injected into the pericranial and cervical muscles, which can potentially cause pain relief, although the Food and Drug Administration does not approve them. Further clinical studies are required to confirm its efficacy.

Summary Cervicogenic headache encompasses pain resulting from cervical spine disorders. This type of headache is more common in women and accounts for 25% of the headaches seen in chronic pain clinics. The pathogenesis of cervicogenic headaches can be explained by the overlap between the first three cervical nerves, the trigeminal nucleus, and the cervical plexus. Diagnosis can be made clinically using CHISG or HIS criteria or with relief of symptoms after a diagnostic block. History and physical examination are important for diagnosis, and more life-threatening causes should be ruled out. CT and MRI can be employed. However, this was not diagnostic. Imaging can be used to determine the presence of cervical disease. A temporal relationship is required to prove causation. Treatment can be non-pharmacologic, including massage, physical therapy, transcutaneous electrical nerve stimulation therapy, and psychotherapy. Interventional treatments such as radiofrequency ablation can be curative in patients who have complete pain relief after a diagnostic block. Surgical intervention, such as neurectomy and dorsal rhizotomy, requires weighing the risk of worsening pain post-intervention with the possible benefits of the procedure.

POST-MENINGEAL PUNCTURE HEADACHE Louise Hillen, Deepti Agarwal

Surgical Treatment

Post-Meningeal Puncture Headache

Surgical intervention requires weighing the risk of worsening pain post-intervention, with the possible benefits of the procedure. There must be strong evidence of a treatable pathology on imaging and a history of pain refractory to all other treatment modalities.12 Surgical procedures, such as neurectomy, dorsal rhizotomy, microvascular decompressing, nerve exploration and release, and joint fusion, can be considered a last resort, depending on the pathology suspected.

The first post-meningeal puncture headache (PMPH), also known as postdural puncture headache, was first described by August Bier in 1898 when he experienced a positional headache after undergoing a spinal anesthetic performed by his research assistant. He hypothesized that his headache was because of a loss of cerebrospinal fluid (CSF) during the spinal procedure.16 PMPH is most commonly seen in obstetric patients following neuraxial procedures but can also be seen following interventional pain and

550

PA RT 4 Clinical Conditions: Evaluation and Treatment

diagnostic lumbar puncture procedures. PMPH is a term used to describe an orthostatic bilateral headache following a meningeal puncture, and many argue that it should be termed as “meningeal puncture headache.” The headache is always bilateral and is typically frontal or occipital in location.17 Patients often present with neck stiffness, nausea, and vomiting. Other associated symptoms include vision changes (photophobia and diplopia) and auditory changes (tinnitus and hypoacusia). Headache most commonly presents 24–48 h following a dural puncture and within 72 h in 90% of cases. However, it can occur 5–12 days after the dural puncture.18,19 The headache generally resolves within seven days but, in rare cases, can persist for months after the initial complaint.20 If the postural component of the headache is absent, other etiologies should be considered.17 A PMPH can be severe and incapacitating and can greatly interfere with a parturient patient’s ability to care for and bond with her newborn.21 Among patients diagnosed with a PMPH, 39% experience at least one week of difficulty performing daily living activities.22 PMPH can cause an increased incidence of chronic headaches, cranial nerve palsies, permanent disability, and reversible cerebral vasoconstriction syndrome.17 Given the increase in healthcare costs and patient discomfort, prompt identification and treatment of PMPH is necessary.

Pathophysiology Although the exact mechanism of PMPH is not fully understood, the onset of a headache is thought to be bimodal, resulting from leakage of CSF from the intrathecal space causing mechanical traction and from a reflexive cerebral vasodilation in accordance with the Monro-Kellie doctrine.17 Both of which are caused by a disruption in the meninges that allows for leakage of CSF at a rate greater than CSF production. The average CSF volume in adults was 150 mL. It is constantly restored by the choroid plexus at a rate of 0.35 mL/min, creating 500 mL of CSF a day.20 The absolute amount of CSF leakage is not necessarily correlated with the onset of a headache.23 While some patients may develop a headache with small amounts of CSF leak, others may not develop a headache even with larger volumes of CSF loss. A loss of just 10% of CSF is thought to be sufficient to cause PMPH.24 The Monro-Kellie doctrine is a theory that the sum of the volumes of the brain, which includes CSF and intracranial blood, must remain constant. To maintain a constant intracranial volume, compensatory vasodilation of intracranial vessels occurs when CSF volume loss occurs. The increase in blood volume due to cerebral vasodilation activates the trigeminovascular system, leading to pain similar to that of migraine. The trigeminothalamic tract delivers signals to the thalamus and refers to pain to the ophthalmic branch and the first three cervical roots. Evidence of the Monro-Kellie doctrine is thickened meninges secondary to dural venous dilation observed on MRI in patients with PMPH.25 Secondary causes of PMPH are likely due to the relative CSF hypotension. CSF loss leads to a lower hydrostatic pressure, causing a loss of buoyant support and allowing the brain to sag while in the upright position.26 The higher the level of the meningeal puncture, the less hydrostatic pressure at the puncture site. This explains why cervical meningeal punctures are much less associated with PMPH than lumbar punctures. Uncompensated CSF loss leads to a decrease in the subarachnoid pressure. The normal CSF opening pressure in the horizontal position is 70–180 mmH20.12 An opening pressure of 60 mmH20, defined as CSF

hypotension, is often present in PMPH but is not consistently correlated with the presence of symptoms.27 Although the absolute volume of CSF loss does not correlate with a PMPH, a sudden loss of CSF volume and a change in pressure between the inside and outside of the intracranial venous structures are thought to result in venous dilation.28 Furthermore, a sudden loss of CSF results in a downward pull on pain-sensitive structures (dura, bridging veins, cranial nerves, venous sinus) when the patient is in an upright position.28 This is exacerbated by a redistribution of CSF downward toward the spinal dural sac, worsening the stretch and tension on the meninges, intracranial vessels, and nerves. This theory is supported by radiographic evidence of downward displacement of intracranial structures following a PMPH.25 Traction on the bridging veins can lead to a tear in the dura, potentially causing a subdural hemorrhage.29 A cohort study of over 26 million deliveries suggests a small but statistically significant increased risk of diagnosis of intracranial subdural hematoma in obstetric patients with PMPH.30 CSF hypotension and the resulting traction often result in cranial nerve palsies (Table 39.3). The abducens nerve (CN VI) is most frequently affected because of its acute angulation near the point of fixation of the cranium and the petrous bone, resulting in increased traction.31,32 Diplopia often occurs due to abducens nerve traction and subsequent paralysis of the lateral rectus muscle of the eye. Permanent vision damage is rare, and diplopia typically resolves within two weeks to eight months.33 The facial nerve (CN VII) is also frequently affected and can result in paralysis of facial muscles, disruption of lacrimal and salivary gland function, and loss of taste in the anterior two-thirds of the tongue.31 Changes in hearing can occur because of the effects on the vestibulocochlear nerve (CN VIII). A cochlear aqueduct connects the perilymphatic space to the CSF-filled subarachnoid space. CSF pressure changes are transmitted to the perilymphatic space (Fig. 39.5).34 A loss of CSF pressure through a patent cochlear aqueduct can lead to perilymphatic hypotonia and endolymphatic hydrops, resulting in low-frequency hearing loss and tinnitus.35 The ophthalmic branch TABLE Commonly Affected Cranial Nerves in Post39.3 meningeal Puncture Headaches

Cranial Nerve

Symptomatology

Trigeminal Nerve (CN V) • Ophthalmic Branch (V1) • Maxillary Branch (V2) • Mandibular Branch (V3)

• Frontal pain • Sensory changes to all three branches, without motor involvement • Tongue numbness

Abducens Nerve (CN VI)

• Ocular abnormalities • Double vision • Deviated gaze because of lateral rectus muscle weakness • Photophobia

Facial Nerve (CN VII)

• Paralysis of the facial nerve • Loss of taste to anterior 2/3 of tongue • Interruption of lacrimal and salivary gland function

Vestibulocochlear (CN VIII)

• Changes in hearing • Low frequency hearing loss • Tinnitus

Vagus Nerve (CN X)

• Nausea and vomiting because of chemoreceptor triggering in the medulla • Occipital and posterior fossa pain

 

CHAPTER 39

Cervicogenic Headache, Post-meningeal Puncture Headache, and Spontaneous Intracranial Hypotension

• Figure 39.5  Mechanism of hearing loss and tinnitus after meningeal puncture. (From Michel, Olaf, and Tilman Brusis. Hearing loss as a sequel of lumbar puncture. Ann Otol Rhinol Laryngol. 1992;101(5):390–394.)

(V1) of the trigeminal nerve (CN V) innervates the bridging veins and dura and refers to pain in the frontal region. Vagus nerve (CN X) traction can also be responsible for nausea and vomiting due to stimulation of the chemoreceptor regions in the medulla. The vagus nerve also refers to pain in the posterior fossa and occipital regions. Traction of the upper cervical nerves can also manifest as shoulder stiffness and occipital and cervical pain. Rare case reports have suggested optic nerve (CN II) and trochlear nerve (CN IV) involvement (please refer to Table 39.3 for a summary).31

The Role of Arachnoid Matter in the Pathogenesis of CSF Leak The dura mater is roughly 400 µm thick and comprises fibers distributed in a random organization of roughly 80 concentric layers called dural laminas.36 The dural layer is elastic in nature compared with the more structured arachnoid membrane, and has the primary purpose of acting as a barrier to limit the escape of CSF fluid. Electron microscopy has demonstrated that tight junctions are present in the outer layer of the arachnoid, similar to that of the capillary endothelium of the brain, whereas the dura does not contain tight junctions.37 This supports the concept that a puncture in the arachnoid mater, a typically impermeable layer that prevents the spread of CSF, rather than a puncture in the dura, is the primary cause of PMPH.

Dura Mater and Response to Trauma Following neurosurgery, dura mater closure and healing are vital to prevent CSF leakage and infection. If the dural gaps are small, conservative management can be the treatment of choice. However, larger dural gaps necessitate direct repair or via the application of synthetic or biologic graft materials. It was first thought that fibroblastic proliferation from the edge of the dural tear facilitated dural closure.38 In 1959 Keener showed that fibroblastic proliferation surrounding blood clots and tissue of the pia and arachnoid mater helped promote dural closure.38 Therefore only minimal trauma to the dural layers and adjacent tissue would likely not promote substantial dural healing.

Diagnosis The third edition of the International Classification of Headache Disorders defines a diagnosis of PMPH as a headache that occurs within five days of a dural puncture and resolves spontaneously within 14 days or with the closure of the epidural leak with an

551

autologous epidural lumbar patch.39 The period in which the headache develops is debatable and can occur within one–12 days of insult to the meninges. Headaches must fulfill the criteria that symptoms are attributed to low CSF pressure, which is an orthostatic headache accompanied by neck pain, changes in hearing, sunlight sensitivity, nausea, or vomiting.39 The orthostatic nature of the headache means that symptoms significantly worsen with standing or sitting and improve after moving in a supine position. Prior editions of the International Classification of Headache Disorder criteria included a postural headache occurring within 15 min in the upright position and resolving within 15 min in the supine position. The headache improved once the CSF pressure returned to normal. Brain imaging may show brain sagging or pachymeningeal enhancement. Spine MRI may be notable for extradural CSF.39 It is important to rule out other causes of headaches. Further evaluation is needed if the headache is constant, unilateral, or presents with new-onset nausea or vomiting. Neurologic consultation and further diagnostic imaging are warranted in patients with altered mental status, seizures, or sensory/motor deficits. The differential diagnosis of a headache that develops or does not meet the classic diagnostic criteria of PMPH includes intracerebral hemorrhage, cerebral venous thrombosis, infection, eclampsia, caffeine withdrawal, and subdural hematoma.40,41

Incidence and Risk Factors The incidence of PMPH ranges vastly from 1%–63%, and varies based on the patient characteristics, technique used, and needle size and design.42 A trial by Vandam and Dripps in 1956 followed 10,098 spinal anesthetics and found an 11% incidence of PMPH, of which 0.4% were associated with ocular difficulties and 0.4% with auditory difficulties.43 The greatest incidence of PMPH occurred in patients in the third and fourth decade of life and was twice as common in women (14%) than men (7%).43 In a study of 27,064 obstetric patients undergoing a neuraxial procedure, 142 developed a post-dural puncture headache.44 Eight of these were described as atypical, meaning the postural component of the headache did not exist despite other associated symptoms and improvement with an epidural blood patch (EBP).44 Choi et al. found that the highest risk group of patients is the obstetric population, in which 1.7% of parturients will experience PMPH following spinal anesthesia with a 27-gauge Whitacre needle.45 The incidence of accidental dural puncture with epidural placement is around 1.5%, with over half of these patients developing PMPH.45 Medicolegal analysis of outpatient procedures from 2009–2017 showed that interlaminar epidural injections at both the cervical and lumbar levels were most commonly associated with claims of unintentional dural puncture.46 Among 10,000 fluoroscopicguided interlaminar epidural injections, the incidence of inadvertent dural puncture was 0.5% overall, 1% in the cervical region, 1.3% in the thoracic region, and 0.8% in the lumbar region.47 The incidence of PMPH in these patients was not followed.47 The incidence of PMPH following intrathecal drug delivery systems is approximately 23%.48 While most of these patients’ symptoms were self-limited and resolved with conservative management, 21% of patients required an EBP or fibrin glue patch procedure.48 Patient risk factors for the development of PMPH include female sex, age (third to fourth decade of life), pregnancy, history of headaches, preexisting CSF hypotension, and low body mass index. Although the physiology resulting in the disparity among

552

PA RT 4 Clinical Conditions: Evaluation and Treatment

genders is not fully understood, a large meta-analysis concluded that compared to males, nonpregnant females have double the risk of developing a PMPH.49 Young age is also thought to be an independent risk factor for the development of a PMPH, possibly because the dura is more elastic and has a higher likelihood of maintaining a patent dural opening than the less elastic dura in older patients.50 A medical history of PMPH and headaches prior to the procedure is also associated with an increased risk of PMPH after dural puncture.51 Obesity is protective against the development of a PMPH because the increased epidural pressure decreases the gradient across the dural puncture, allowing less CSF to leak.52 An increased abdominal pressure may also help seal a defect in the dura and decrease CSF loss.52 Modifiable risk factors for PMPH include the number of attempts and needle design, size, shape, and bevel direction. Spinal needles can be designed with cutting bevels, such as the Quincke-type, or as a pencil point, such as the Whitacre-type and Sprotte.53 A systematic review of 25 randomized controlled trials comparing cutting and pencil point needles concluded that pencil point (non-cutting) needles had a much lower rate and incidence of PMPH and subsequent need for EBP.54 The risk of PMPH following a puncture with a 20 to 22- gauge cutting needle is ~36%, compared to ~2% with a 22-gauge non-cutting needle.55 The risk of PMPH is directly correlated to the diameter of the needle used, with smaller gauge needles having a lower incidence. Most unintentional dural punctures occur during epidural placement with a 17- or 18-gauge Tuohy cutting needle. Angle et al. found reduced CSF leakage with a 20-gauge Tuohy compared to a 17-gauge.56 similarly, a cadaver study showed a six-fold greater mean CSF leak when using a 22-gauge needle compared to a 25-gauge needle.57 Cutting needles have an increased rate of PMPH, likely because of its potential to cut dural fibers, whereas a pencil point blunt tip divides but does not disturb the continuity of the dural fibers.57 Electron microscopy revealed that a blunt tip could cause an irregular hole in the dura, whereas a clean hole is produced by a cutting needle.55 The irregular hole in the dura may promote an inflammatory reaction that promotes healing and hole closure. Electron microscopy studies have shown that dural fibers are collagen and lack a specific orientation, whereas the arachnoid mater cells are oriented parallel to the long axis of the spinal cord. The orientation in which the bevel is directed compared to the dural fibers has been proposed to affect the amount of CSF leakage and subsequent headache risk. In vitro studies by Cruickshank and Thompson showed that fluid loss was not reduced when the bevel of the needle was aligned parallel to the longitudinal direction of the fibers. However, 22-gauge Whitacre point needles produced less fluid loss than a 22-gauge Quincke point needle inserted across the fibers, suggesting that the leakage rate was related to needle design, not to the alignment of a bevel point.58 In contrast, a five study meta-analysis demonstrated that insertion of a beveled or cutting needle oriented parallel to the long axis of the spinal cord is associated with a statistically significant decrease in the incidence of PMPH than that inserted perpendicularly.59 Norris et al. compared epidural catheter placement in two groups: one in which the bevel of the Tuohy was parallel to the dural fibers and one in which the Touhy was perpendicular to the long axis of the spinal cord. There was a similar rate of unintentional dural puncture. However, the intensity of PMPH was much lower in the parallel orientation group, requiring fewer EBPs.60 Proceduralist characteristics may also play a role in the development of PMPHs. There is a higher incidence of PMPH after a diagnostic dural puncture performed by a neurologist or neu-

roradiologist, likely because of the higher gauge needles required and possibly because of less experience in performing the procedure.61 In a prospective study of 80 adult patients, the incidence of PMPH following a diagnostic lumbar puncture was 33%.62 Diagnostic lumbar punctures often require a 20- or 22-gauge needle to measure opening pressure and obtain CSF over a brief period. If needles are less than 22 gauge, the collection of just 2 mL of CSF can take at least 6 min, and measuring the opening pressure can be very challenging.

Prevention As mentioned before, PMPH prevention depends on needle characteristics and, probably, bevel orientation during dural puncture. Using the smallest pencil point needle parallel to the longitudinal access of the spinal cord will help decrease the incidence of PMPH. It is controversial whether the placement of an intrathecal catheter after an unintentional dural puncture during epidural placement can reduce the risk of PMPH. Many of the available studies are retrospective in design and cannot be randomized. Ayad et al. found a reduction in the incidence of PMPH from 81%–31% if an intrathecal catheter was placed but removed immediately after delivery, and an incidence of 3% if the catheter was left in for 24 h post accidental dural puncture.63 In 173 patients who had an accidental dural puncture, 73 had an intrathecal catheter placed that remained in situ for 36–48 h, resulting in a 36% incidence of PMPH. This is compared to a 59% incidence in 99 patients who had an epidural catheter placed at a different level or just a single shot spinal administered through the Tuohy needle itself.64 Furthermore, the severity of PMPH and requirement of analgesics was significantly less in the intrathecal catheter group.64 A 2017 meta-analysis of over 1,000 patients in 13 studies showed a decreased risk for PMPH and need for an EBP in patients receiving an intrathecal catheter than a replacement epidural catheter group.65 A survey of North American obstetric anesthesiologists suggested that 75% would replace the catheter epidurally after an accidental dural puncture and 25% would place it intrathecally, even though 76% believed that leaving the intrathecal catheter in place for 24 h would reduce the incidence of PMPH.66 The most important reason that an intrathecal catheter may not be placed following an inadvertent dural puncture is the safety of the intrathecal catheter. There is a high potential risk of misuse because of the lack of familiarity with intrathecal catheter dosage and usage. Although it may be beneficial to leave an intrathecal catheter in place for 24 h to reduce the incidence and severity of PMPH, it is often removed at most institutions because of safety concerns. The use of a prophylactic epidural blood patch (PEBP) following an accidental dural puncture (ADP) is controversial because of the lack of strong literature. Some retrospective studies have shown that PEBP can decrease the severity, duration, or need for a therapeutic blood patch. A randomized, controlled, doubleblinded study by Scavone et al. assessed the efficacy of PEBP in 64 parturients who had an unintentional dural puncture with a 17-gauge Tuohy.67 After delivery, all patients had 20 mL of autologous blood drawn, which was either administered or not via a sham procedure. There was no difference between the two groups in the rate of headache, peak pain scores, or the need for a therapeutic blood patch, although the median duration of the headache was shorter in the PEBP group.67 Other studies have shown that prophylactic epidural or intrathecal saline (typically 10cc) failed

 

CHAPTER 39

Cervicogenic Headache, Post-meningeal Puncture Headache, and Spontaneous Intracranial Hypotension

to show a decreased need for a therapeutic blood patch.68 An additional analysis of five studies involving 221 patients from the obstetric and surgical population showed insufficient evidence to recommend a PEBP.69 Overall, PEBP does not appear to decrease the incidence of PMPH or eventual need for a therapeutic blood patch after an unintentional dural puncture. Neuraxial morphine administration for prophylaxis following an unintentional dural puncture is controversial. In a randomized controlled trial by Al-Metwalli, a 3 mg dose of epidural morphine was administered immediately following an unintentional dural puncture and again at 24 h, demonstrating a decrease in PMPH from 48% to 12%.70 However, a randomized, doubleblind study by Peralta et al. showed that 150 µg of intrathecal morphine administered after delivery in patients with an ADP did not decrease the incidence or severity of PMPH discounting the prophylactic use of intrathecal morphine.21 Furthermore, Brinser et al. demonstrated that both epidural and intrathecal administration of morphine following inadvertent dural puncture did not decrease the risk of PMPH.71 It is important to recognize that neuraxial morphine is not without risks, including respiratory depression, nausea, vomiting, and itching. Caution must be taken when administering epidural morphine, especially after a dural puncture, since there may be translocation into the intrathecal space at unknown concentrations. Recent attention has been given to the administration of cosyntropin, an adrenocorticotropic analog, following ADP for prophylaxis against PMPH. The mechanism by which adrenocorticotropic hormone (ACTH) could improve PMPH is not fully understood but is thought to be due to ACTH stimulation of aldosterone, which enhances salt and water retention, expands blood volume, and favors the closure of a dural tear. ACTH may also increase CSF production because of the active transport of sodium ions into CSF and possibly an increase in β-endorphins that modulate pain perception.72 In a study of 95 patients who received 1 mg of cosyntropin following an ADP, the incidence of PMPH was halved from 69% with placebo to 33% with cosyntropin, and the need for an EBP was reduced from 30% to 11%.73 Aside from rare hypersensitivity reactions, the risk associated with administering cosyntropin is low.

Treatment Once the diagnosis of PMPH is established, treatment should be initiated. It is reasonable to start with conservative treatment options since 85% of PMPHs last less than five days and are rarely associated with significant morbidity.74 Though recumbent bed rest may improve the symptoms of PMPH, a meta-analysis by Thoennissen et al. failed to show that recumbent bed rest reduced the incidence of PMPH more than immediate mobilization.75 A survey of 1,024 anesthesiologists noted that aggressive hydration and bed rest were most commonly used as prophylactic measures to prevent PMPH following an inadvertent dural puncture. The same study concluded that the most frequently used treatment options were aggressive hydration, oral caffeine, oral non-opioid analgesics, and EBP procedures.76 Though aggressive hydration is commonly recommended, there is no evidence to support it. While many physicians would encourage a patient to use conservative management for 24–48 h prior to recommending an EBP, some would argue that this can be particularly disabling if that patient is postoperative or in the postpartum period. Many pharmacologic agents have been studied for the treatment of PMPH. These include methylxanthines (caffeine and theophylline),

553

serotonin agonists, anti-convulsant agents, adrenocorticotropic hormone, and corticosteroids. Caffeine is a potent methylxanthine central nervous system stimulant that causes cerebral vasoconstriction. It is the most widely used pharmacologic treatment for PMPH. Caffeine can be administered at an oral dose of 300 mg or an intravenous dose of 500 mg caffeine sodium, equating to 250 mg caffeine.77 While caffeine is considered safe in most patients, there have been reports of seizures associated with its use, and caution must be used in patients with a history of seizures. Careful use is also necessary for patients with hypertension, disorders of pregnancy-induced hypertension, anxiety, and arrhythmias. Sechzer showed that 75% of women receiving intravenous caffeine did have some temporary relief from their PMPH, supporting its use.78 Jarvis et al. revealed that over 70% of women had improvement in their pain scores four h after intravenous caffeine infusion.79 Additionally, 300 mg oral caffeine showed a decrease in pain scores at 4 h, but not at 24 h.77 These studies ultimately show that the effects of caffeine are transient, and administration may need to be repeated. Caffeine administration does not appear to decrease the need for an eventual blood patch. Theophylline, another cerebral vasoconstrictor, has not been widely studied or supported by the literature. Serotonin receptor agonists, such as sumatriptan, cause cerebral vasoconstriction and are often used to abort migraines. While there has been no evidence to support its use in the treatment of PMPH, a non-randomized study suggested that frovatriptan was useful in the prevention of PMPH in patients undergoing diagnostic lumbar punctures.80 More studies are needed to evaluate serotonin receptor agonists in other patient populations. Anti-convulsant agents such as gabapentin and pregabalin may be helpful in the treatment of PMPH. Pregabalin is a ligand of voltage-dependent calcium channels that reduces calcium influx at nerve terminals and attenuates the release of glutamate, substance P, and norepinephrine at the synapses. In a study of 40 patients experiencing a PMPH after spinal anesthesia or a lumbar puncture, half were assigned to receive 150 mg/day of oral pregabalin for three days, then 300 mg/day for two additional days, while the other half received placebo for the same length of time.80 The pregabalin group had significantly lower pain scores after the second day of treatment and required less diclofenac for additional pain control.81 An additional study of 42 patients showed that compared to the use of ergotamine and caffeine, patients taking gabapentin had significantly less pain, nausea, and vomiting following an ADP.82 While these studies looking at pregabalin and gabapentin are promising, more studies are needed to demonstrate its efficacy. Cortiosteroidogenic analogs (ACTH, cosyntropin, and tetracosactrin) have been studied for the treatment of PMPH. A prospective, randomized, double-blind study showed that a 1 mg single depot injection of the ACTH analog tetracosactrin did not decrease the severity of headache or the need for an EBP.83 Further studies have shown that patients receiving an EBP following the development of PMPH had significant improvement in pain and function scores in patients receiving cosyntropin on day one of symptoms. However, cosyntropin showed similar efficacy to the blood patch group immediately after treatment and at days three and seven.84 While these limited studies show some improvement with cosyntropin use, there is a question of its overall efficacy. Once a patient has failed medical and conservative management, it is reasonable to consider more invasive options. Epidural treatments for PMPH include the use of saline, colloids, fibrin glue, and blood. The gold standard treatment is EBP, which entails

554

PA RT 4 Clinical Conditions: Evaluation and Treatment

injecting a small amount of autologous blood into the epidural space. EBP offers a promising and immediate resolution of symptoms in approximately 61%–98% of patients.85 Contraindications to a blood patch are similar to those of any neuraxial procedure. The first contraindication was patient refusal. If a patient has religious concerns about blood transfusion, alternative patching materials can be offered. The coagulation status of the patient must be reviewed to minimize the risk of epidural hematoma. An EBP should not be performed on patients who are septic, āre bacteremic, or have a localized infection at the injection site to prevent the introduction of bacteria into the epidural space. It is safe to perform an EBP in patients who are HIV positive because HIV naturally crosses the blood–brain barrier; thus there is no increased risk of introduction centrally during the procedure.86 The technique of EBP was first described by Gormley in 1960 and is based on the placement of a single shot epidural.85 The procedure typically requires two people: one to locate the epidural space and the other to draw the blood. Sterility is of utmost importance during both epidural placement and blood collection. The patient can either be supine or in the lateral decubitus position, depending on the patient’s tolerance. It is wise to select a site that is caudal to the suspected dural tear since 15 cc of epidural blood will spread roughly six segments cephalad and three segments caudad.87 Additionally, more caudal levels are associated with less cord compression. After EBP, the patient remained supine with his legs slightly elevated. Martin et al. found that 2 h in the supine position after EBP provided the patient with 100% relief versus 60% in a group that remained supine for only 30 min.88 The mechanism of action of EBP is not fully understood, but appears to be due to two separate mechanisms. The first and initial effects can occur within minutes and are likely due to compression of the dura toward the spinal cord and the reduction of intradural volume. MRI analysis of five patients following EBP placement showed large extradural collectures with an anterior displacement of the thecal sac and a mean spread of 4.6 vertebral spaces.89 This epidural spread following an EBP is longitudinal and circumferential, helping to envelop the entire dural sac. The reduction in the intradural volume shifts the CSF more cephalad, re-suspending the brain, and reducing traction. In accordance with the MonroKellie rule, an increase in intracranial CSF helps to reduce cerebral vasodilation and intracranial blood volume. While patients often report instant relief in their symptoms because of these effects, post-blood patch MRI studies have shown that these compressive mass effects disappear by 7 h after the procedure.90 A second and more long-lasting effect is likely due to the sealing of the dural or arachnoid tear with a gelatinous plug, preventing further loss of CSF. The blood patch acts as a temporary plug until permanent repair of the meningeal puncture can occur. Failure of self-closure of the dural or arachnoid tear can result in EBP failure despite initial relief. Optic nerve sheet diameter (ONSD) is a surrogate marker of intracranial pressure and has been studied in patients undergoing EBP procedures. Dubost et al. found that the ONSD increased in patients who had a successful EBP but not in patients who had EBP failures.91 This suggests that a sustained increase in intracranial pressure is associated with a successful EBP. The ideal volume of blood to draw and inject during an EBP is ~20 mL, stopping on injection if the patient complains of back, buttocks, or neck pain. There appears to be no relation to the volume of blood injected and EBP success rate.92 In a multinational, multicenter, randomized, blinded trial to determine the optimum volume of autologous blood for an EBP, 121 patients experiencing

symptoms after an ADP were allocated to receive 15, 20, or 30 mL of blood.93 Only 54% of patients in the 30 mL group were able to receive the entire volume because of pain on injection, while 81% in the 20 mL and 98% in the 15 mL group were able to tolerate receiving the allocated volume.93 Interestingly, the 20 mL group had the highest incidence of permanent or partial relief, at 73%, while the 15 mL and 30 mL groups had an incidence of 61% and 67% relief, respectively.93 This study confirms that 20 mL of autologous blood appears to be the optimal volume for placement of an EBP. Chen et al. found that 7.5 mL of autologous blood was comparable to 15 mL of blood in its analgesic effect but with less nerve root irritation during injection.94 Further studies on optimal blood volume in the nonobstetric population are warranted. Alternative patching materials include epidural fibrin glue and epidural dextran-40. Although these materials have been successfully employed, they are not widely used owing to their cost and safety concerns. Dextran-40 appears to be a safe alternative for Jehovah’s Witnesses. Epidural saline blouses or infusions are ineffective alternatives and often result in more interventions with a lower success rate because saline is quickly absorbed from the epidural space. As a last resort, surgical repair of the dural tear may be considered and is typically reserved for severe cases of chronic PMPH that have failed management with an EBP. The optimal timing of EBP remains controversial. Placement of EBP too early in PMPH symptomatology is thought to be associated with an increased risk of EBP failure. In a 13-year retrospective review of 129 patients, the success rate for permanent relief of PMPH from an EBP was 86% in patients receiving it 48 h after a neuraxial procedure, 65% in patients receiving it at 24–28 h, and only 50% in patients receiving it within 24 h.95 This may be confounded because patients with worse symptoms and CSF leakage may require an EBP earlier, and subsequent patches may be necessary to help with closure of the dural puncture. EBP is typically considered a safe treatment option. The most common side effects of EBP are low back and radicular pain because of an inflammatory response and nerve root compression, which tends to resolve spontaneously or with nonsteroidal antiinflammatory drugs.96 Rare but possible complications include epidural hematoma, infection, and arachnoiditis because of unintentional subdural or subarachnoid injection of the blood. Two cases of facial nerve paralysis following EBP have been reported, both of which resolved spontaneously.97 While EBP is considered the gold standard for the treatment of PMPH, sphenopalatine ganglion block (SPGB) has been suggested as a simple and minimally invasive alternative to an epidural blood patch. The mechanism of SPGB, which was first described in 1909, is thought to be related to cerebral vasoconstriction.98 The sphenopalatine ganglion is a collection of parasympathetic fibers located bilaterally in each pterygopalatine fossa. With the loss of CSF, this ganglion is activated, releasing acetylcholine, nitric oxide, and vasoactive peptide, causing vasodilation of dural blood vessels.98 Blocking these ganglions with intranasal lidocaine decreases nociceptor signaling and blocks cerebral dural vasodilation, relieving the PMPH.99 The traditional approach to an SPGB involves introducing a cotton-tipped applicator soaked in a local anesthetic solution into the nares. The SPGB can be repeated at 20 min intervals, usually up to two times, if the resolution of headache symptoms is not achieved. In a 17-year retrospective chart review, more patients received relief from their headache symptoms at 30 min and 1 h in the SPGB group than in the EBP group with equal recovery at 24 h, 48 h, and one week.99 Patients who received an EBP required more return visits

 

CHAPTER 39

Cervicogenic Headache, Post-meningeal Puncture Headache, and Spontaneous Intracranial Hypotension

to the emergency department than the SPGB group.99 A clinical trial comparing the use of saline versus lidocaine for an SPGB did not show any significant difference in pain intensity at 30 min, with similar pain reduction and avoidance in an EBP, suggesting that the major effect of the SPGB may not necessarily be because of the local anesthetic used.100 SPGB appears to be a safe and useful alternative for patients who have contraindications or may be reluctant to undergo an EBP.

PMPH Summary PMPH and its management are well-known and widely accepted entities in anesthesia entities. With better awareness of the risk factors related to PMPH, clinicians need to be vigilant when performing neuraxial techniques. Although nonfatal, it can cause significant morbidity and should be treated seriously. In the setting of a dural puncture or inadvertent puncture with pathognomonic symptoms, the diagnosis of PMPH is straightforward. Treatment should start with conservative therapy as the headache is generally self-limiting within 7–10 days. EBP is the gold standard and the most effective treatment modality for PMPH. Surgical repair may be required in patients with chronic PMPH. Newer treatment modalities are available, but high-level evidence supporting their efficacy is still needed.

SPONTANEOUS INTRACRANIAL HYPOTENSION Dost Khan SIH was initially described by Schaltenbrand in 1938 and is characterized by symptoms similar to dural puncture headache, but in the absence of dural puncture. The incidence is approximately five per 100,000 person-years. Women are affected twice as often as men, and the peak incidence is in the fourth or fifth decade of life.101

Clinical Symptoms of SIH This syndrome is usually suspected in patients with postural headaches after a fall, trauma, whiplash, exercise, or violent coughing. Although classically postural, the headache can be nonpositional or even paradoxical (worse when lying down).102 The headache can be gradual or thunderclap in onset and has also been described as exertional, intermittent, or mainly occurring at the end of the day. Headache results from the downward displacement of the brain from the loss of buoyancy with traction on pain-sensitive structures, including the dura. Another mechanism is the compensatory dilation of the pain-sensitive intracranial venous structures. Additional symptoms include neck pain, stiffness, nausea, vomiting, blurred vision, tinnitus, vertigo, and photophobia. Tinnitus is secondary to the transmission of the abnormal CSF pressure to the perilymph,103 while vision and balance abnormalities are because of stretching of the optic and vestibulocochlear nerves. Cranial nerve (CN) palsies leading to ophthalmoplegia can involve the oculomotor (CN III), trochlear (CN IV), or abducens nerve (CN VI), with CN VI being the most commonly affected.104 Hyperprolactinemia and galactorrhea can result from distortion of the pituitary stalk.105 Symptoms referable to the spine include back pain and radiculopathy, presumably due to compression of the nerve roots or spinal cord by the leaked CSF. The International Classification of Headache Disorders has published diagnostic criteria for SIH (Table 39.4),106 although some experts consider

555

TABLE Diagnostic Criteria for Headache Attributed 39.4 to Low Cerebrospinal Fluid (CSF) Pressure A. Any headache fulfilling criterion C B. Either or both of the following: a. Low cerebrospinal fluid (CSF) pressure (10–13 mm (FPP). Perhaps unsurprisingly, alterations within structures neighboring the pelvis can also contribute to the development of pain. Dysfunction in the spine or the lower limbs (e.g. scoliosis, flat foot, hamstring tendon rupture) can also impact the transfer of load and have been looked at as potential causes of CPP.44 The abdominal wall frequently has an impact on pelvic pain, either via radiating/referred pain or by affecting the pelvic girdle mechanics.45 The hip joints, a common place for arthritis to develop, can also cause CPP via referred pain.5 The diagnostic approach should be focused on the history and physical examination (see subsection on H&P) as no single gold standard test exists for the diagnosis of musculoskeletal CPP. Along with the usual questions, history should include any previous history of trauma or symptoms such as pain with defecation, urination, or intercourse. Previous surgical interventions or childbirth instrumentation should also be noted. For the physical exam, it is important to assess the range of motion, posture, gait, lower limb strength and length, reflexes, and sensory examination. Assessment of internal and external pelvic musculoskeletal structures (e.g. ability to contract or relax, muscle tone, and tenderness) is also of great importance when assessing musculoskeletal causes of CPP. The pelvic floor muscle

• Figure 42.4  Posterior view of the coccygeus and levator ani. From Joseph E. Muscolino, The Muscle and Bone Palpation Manual, with Trigger Points, Referral Patterns, and Stretching, 2ed. Elsevier 2016.

604

PA RT 4 Clinical Conditions: Evaluation and Treatment

Endopelvic fascia lining superior aspect of the deep perineal space/pouch

Dorsal artery of the clitoris

Dorsal nerve of the clitoris

Perineal branches, posterior cutaneous nerve of the thigh

Posterior cutaneous nerve of the thigh

• Figure 42.5  Muscles of the pelvic floor (in a female) including the Levator Ani muscle group, which includes the puborectalis, iliococcygeus, and pubococcygeus muscles. A, Top (internal) view with organs, not pictured B, Bottom view, including nerves and vessels. (Part A, Reproduced with permission from: Gray’s Atlas of Anatomy. The Anatomical Basis of Clinical Practice. 41st Edition. Standring, Susan MBE, PhD, DSc, FKC, Hon FRCS. Elsevier Limited. Published January 1, 2016. Pages 1221-1236.e1. © 2016. Part B, Paulsen, Waschke, Sobotta Atlas of Human Anatomy, 16th Edition 2018 © Elsevier GmbH, Urban & Fischer, Munich) overactivity (firmness) manual examination is a pragmatic fourpoint scale of hypertonicity based on comparison of the PFMs to the thenar eminence. Fig. 42.6 illustrates how to quickly assess the tonicity of PFMs. An asymmetric Trendelenburg gait can be seen with hip dysfunction and myopathies impacting the gluteus medius. Heel or

toe walking should raise suspicion of neuropathic weakness. Pain with pubic diastasis will be elicited by bilateral pressure on the trochanters and hip flexion with the legs in extension. Osteitis pubis, which is found typically in young female athletes, leads to painful isometric adductor contraction. The Patrick (FABER: flexion, abduction, external rotation) test can diagnose sacroiliac joint

 

CHAPTER 42

Pelvic Pain

605

• Figure 42.6  The pelvic floor muscle overactivity (firmness) manual examination is a pragmatic four-

point scale of hypertonicity based on a comparison of the pelvic floor muscles to the thenar eminence. Normal (A), moderate (B), and severe (C) high tone. Hypotonicity would feel softer than the relaxed thenar muscle.

and iliopsoas pain. A positive FABER test suggests sacroiliac joint dysfunction or iliopsoas pain (see Chapter 30). Some diagnostics that have been of aid in diagnosis in the musculoskeletal cause of pelvic pain include pelvic radiographs, ultrasonography measured sacroiliac joint laxity, and bone mineral density, but in general, unless unstable bony or neurologic lesions are suspected, physical evaluation with a physical therapist certified in pelvic health will be the first (and often only) step.36 As with other causes of CPP, multimodal therapy might be needed to achieve the best outcome. Physical therapy techniques are the most important. Musculoskeletal pain can also be treated with a combination of medications and minimally invasive interventions.46 Tricyclic anti-depressants (TCA’s) have proven useful in the management of chronic pain and specifically myofascial pain. NSAIDs (i.e. ibuprofen, naproxen) have had success in musculoskeletal pain, as long as comorbidities allow empiric use (e.g. renal disease, peptic ulcer disease). Opioid use is reserved for severe or refractory cases by consensus among providers as they are limited by efficacy, side effects, and potential for tolerance/ dependence.7,46 Muscle relaxants can be used. However, a systematic review has shown that muscle relaxants increase adverse effects by 50% (relative risk of 1.50, 95% confidence interval, 1.14–1.98), including sedation, headaches, blurred vision, and dependence.47,48 Physical therapy is considered the cornerstone of treatment for musculoskeletal components of CPP because, as discussed above, muscle imbalances, bad posture, or alterations that affect load distribution in the pelvis are important sources of pain.49 Close follow up should be scheduled with orthopedics in the case of pelvic fractures as it can take up to a year to completely heal, and the risk for sequelae is high.5 Therapeutic injections (e.g. 1%–2% lidocaine) directed at trigger points or with botulinum toxin can be attempted if the previous interventions fail in improving pain.46,50 Targets include the obturator internus, piriformis, pubic symphysis, coccyx, the sacroiliac, or hip joint. In patients with concomitant neurogenic pain, lumbar or epidural injections can help in reducing the muscle spasm, in turn reducing the musculoskeletal source of pain. Therapeutic injections should be used along with other treatment modalities such as physical therapy.

Focal Neurologic Conditions Causing Pelvic Pain Neurologic causes of pelvic pain can arise anywhere in the nervous system. Conditions that affect the CNS or the peripheral nervous system, and systemic neuropathies, can manifest as CPP. This section will emphasize the focal neurologic etiologies of pelvic

pain while exploring the more systemic causes of neurologic CPP later. The pelvis is innervated by an array of nerve systems. The lumbar, hypogastric, and sacral plexuses are the main nerve groups innervating the pelvis.51 They contain somatic and autonomic fibers (both parasympathetic and sympathetic). The somatic component is found within the lumbosacral, femoral, sciatic, obturator, and pudendal (arising from the nerve roots S2–S4), while the parasympathetic and sympathetic components arise from T12–L2 and S2–S4, respectively.52 Fig. 42.7 illustrates the parasympathetic and sympathetic innervation of the abdomen, pelvis, and bladder. The parasympathetic fibers (mostly the pelvic splanchnic nerves, aka the pelvic nerve or nervi erigentes) regulate the contraction of the bladder and rectum and relaxation of the sphincters. The preganglionic neurons are located in the sacral parasympathetic nucleus. Axon fibers from these neurons travel through the ventral nerve roots to the peripheral ganglia. Postganglionic neuron cell bodies are located in the detrusor wall and pelvic plexus (inferior hypogastric plexus). Therefore cauda equina or pelvic plexus injury is decentralized but not necessarily denervated. Sexual functions such as erection are also regulated by the parasympathetic splanchnic nerves. Sympathetic fibers (mainly from the superior hypogastric plexus) are involved in ejaculation, inhibition of the detrusor muscle, and the involuntary closure of the bladder neck.53 Signaling is noradrenergic. The peripheral nerves involve the sympathetic chain ganglia, the inferior mesenteric ganglia, the hypogastric nerves, then the pelvic plexus (inferior hypogastric plexus) (Fig. 42.8). Voluntary sphincter control is somatic from the pudendal nerves, whose motor neurons are in Onuf ’s nucleus. Pelvic somatic fibers can be motor, sensory, or mixed; the main somatic nerves to consider are the obturator, pudendal, gluteal, genitofemoral, lateral femoral cutaneous, ilioinguinal, and femoral nerves. The interactions of these nerves are complex. For example, in urination, storage reflexes are maintained by parasympathetic low level firing and afferent firing from the pontine micturition center stimulating the spinal guarding reflex via sympathetic outflow, simultaneously inhibiting the detrusor and stimulating contraction of the bladder outlet, and pudendal outflow to the external urethral sphincter. Voiding reflexes are as follows: vesical afferent activity intensifies, activating the pontine micturition center. This inhibits the spinal guarding reflexes, stimulates high level parasympathetic outflow, and ascending afferents maintain the voiding reflex until the bladder is empty. Lesions can result from direct damage (e.g. childbirth, surgery) or compression of the nerves from adjacent structures.54

606

PA RT 4 Clinical Conditions: Evaluation and Treatment

Ascending fibers

Descending fibers

Spinal ganglion

Sympathetic fibers Preganglionic Postganglionic

Ventral root Gray ramus communicans

Renal ganglion

Aorticorenal ganglion

L1

Renal artery and plexus

L2

Lumbar part of spinal cord

Celiac ganglion

2nd lumbar spinal n. White ramus communicans Sympathetic trunk

1st and 2nd lumbar splanchnic nn.

Parasympathetic fibers Preganglionic Postganglionic Somatic motor fibers Afferent fibers

Intermesenteric plexus Inferior mesenteric ganglion

Ureter Superior hypogastric plexus (presacral n.)

Ascending fibers

Descending fibers

Hypogastric nn.

Gray rami communicantes

Inferior hypogastric (pelvic) plexus

S2

Urinary bladder

Sacral splanchnic nn.

S3

Vesical plexus Prostatic plexus

S4

Sacral part of spinal cord

Sacral plexus

Pelvic splanchnic nn. Pudendal n.

Sphincter urethrae in deep perineal space between layers of urogenital diaphragm

Bulbospongiosus muscle

• Figure 42.7  Autonomic innervation of the pelvic floor. From: Netter Images. Available at: https://www.

netterimages.com/innervation-of-the-urinary-bladder-and-lower-ureter-labeled-felten-2e-general-anatomy-frank-h-netter-29488.html.

• Figure 42.8  Photograph taken during laparoscopic abdominal sacro-

colpopexy. Structures are labeled as follows: IHP, Inferior hypogastric plexus, PSF, pelvic splanchnic fibers; HGN, hypogastric nerve; SHP, superior hypogastric plexus; SP, sacral promontory. Courtesy of Nucelio Lemos, MD PhD.

Neuropathies such as Small Fiber Neuropathies and infection (e.g. by herpes viruses) can also incur damage to the pelvic nerves.5 The sensory innervation of the pelvic structures is diffuse and demonstrates crosstalk, making it challenging to pinpoint a source of pain. Pain characteristics can help by suggesting whether it is visceral or somatic pain. Visceral pain arising from injury to visceral nerves is often described as dull, poorly localized, and is associated with autonomic symptoms (such as nausea).51,55,56 Somatic pain results from nociceptive signals associated with tissue damage, while neuropathic pain is associated with neural damage at the level of the nerve, plexus, nerve root, or central nervous system. Neuropathic pain is associated with symptoms such as paresthesia, hyperalgesia, allodynia, or abnormal thermal sensations. Muscle weakness in the myotome of the affected nerve may also be seen. Fig. 42.9 illustrates the nerve distribution in the pelvis. The most common causes of neuropathic pelvic pain because of peripheral nerve injury are discussed in Table 42.4. Pudendal neuralgia is the most commonly considered nerve entrapment in

 

CHAPTER 42

Pelvic Pain

607

Dorsal nerve of the penis (S3)

Perineal branch of the posterior femoral cutaneous nerve (S1–S3)

Dermatomes and cutaneous nerves of the perineum in women

• Figure 42.9  Distribution of select nerves of the pelvis that may contribute to chronic pain. Perineal der-

matomes showing the dermal distribution territories of the iliohypogastric, ilioinguinal, genitofemoral, femoral, pudendal, inferior cluneal, obturator, posterior femorocutaneous, lateral femorocutaneous, and the coccygeal plexus, which may present frequent anatomic variations and interconnections. Reproduced from Drake RL, Vogl A, Mitchell WA. Gray’s Atlas of Anatomy Elsevier. Churchill Livingstone, London. 3rd ed. Philadelpha, PA: Elsevier; 2021:213–292.

the differential of pelvic pain. Direct compression of the pudendal nerve can occur at several levels, and non-mechanical causes of pudendal neuralgia such as viral infections or diabetes can also occur.57 Location of a discrete lesion occurs at the sacrospinous/ sacrotuberous ligaments in 42% of cases, Alcock’s canal (medial to the obturator internus, within the fascia) in 26% of cases, and is at multiple levels in 17% of cases.58,59 It can occur at the level of the piriformis, although the frequency is not reported. The more distal the lesion along the pudendal nerve, the less likely the

anal region will be involved. Pudendal neuralgia presents with pain and dysfunction in the S2, S3, and S4 nerve distributions (including the rectum, genitalia, and urinary tract), sexual and sphincter dysfunction, and pain typically worse with sitting.60 Nantes Criteria is used as a diagnostic tool for pudendal nerve pain.61 Treatment is with neuromodulators, physical therapy, trigger point injection, botulinum toxin injection, neuromodulation, and in select cases, surgical release. Surgical release can be effective for decompression of discrete lesions. If pain has

608

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE Peripheral Nerve Injury Associated With Pelvic Pain and Dysfunction 42.4

Nerve Involved

Presentation

Ilioinguinal nerve (T12, L1)

Groin pain with radiation to the vagina, labia majora, root of the penis or upper scrotum, mons pubis, lateral waist.

Iliohypogastric nerve (T12, L1)

Lateral gluteal and suprapubic pain.

Obturator nerve (L2, 3, 4)

Pubic pain radiating to the inner thigh and knee. Weakness of adduction (adductors) and lateral rotation of the hip (gracilis muscle). Injury can occur during pelvic lymphadenectomy, deep endometriosis, dissection of the paravesical fossa, retzius space, or iliolumbar fossa.

Anterior abdominal cutaneous nerves

Abdominal pain usually lateral to the rectus sheath.

Lateral femoral cutaneous nerve (L2, L3)

Pain and numbness of the lateral thigh. Injury can occur secondary to obesity, tight pants or belts, or with impingement secondary to prolonged hip flexion.

S1 nerve root

Pain and numbness on the external aspect of the posterior thigh, calf, and leg and the exterior aspect of the foot. S1 nerve root entrapments can cause gait disturbances and loss of ankle stability.

S2 nerve root

Pain and numbness on the internal half of the posterior thigh, calf, and leg, internal surface of the foot, vulva, and clitoris (female), penis, and scrotum (male). Usually associated with urinary urgency and frequency. Genital arousal disorders, erectile dysfunction, and/or lack of vaginal lubrication may be present.

S3/4 nerve root (usually entrapped together because of proximity)

Pain and numbness on the buttock, anus, perineum, vulva, and clitoris (female), penis, and scrotum (male). Usually associated urinary and bowel urgency and frequency, pain on passing urine or stool. Often associated with vaginal and/or rectal foreign body sensation.

Sciatic nerve (L4, L5, S1, S2, S3)

Buttock, posterior thigh, calf, lateral leg, and foot pain. Impact on muscles of the posterior anterior and lateral compartments of the lower leg, foot drop. Lies 2 cm from the sacrospinous ligament and can be injured during sacrospinous ligament vault fixation. Hip replacement, and even improperly performed buttock injections.

Genitofemoral nerve (L1, L2)

Genital branch: Pain in the inguinal fold, mons pubis, base of the penis, labia majora, anterior vulva, clitoris, and urethra femoral branch: superomedial thigh. Injury can occur during, e.g. pelvic lymphadenectomy or psoas hitch.

Pudendal nerve (S2, 3, 4)

Pain and dysfunction in the S2, S3, and S4 nerve distributions (which includes the rectum, genitalia, and urinary tract, urethra), Urgency or pain associated with urination or bowel movement, sexual and sphincter dysfunction (erectile dysfunction, lack of lubrication), and pain that is typically worse with sitting. It can be an injured surgical leg. During sacrospinous ligament vault fixation, because of infection (e.g. herpes) or entrapped by a hypertonic muscle.

Posterior femoral cutaneous nerve and inferior cluneal nerves

Inferior gluteal (buttocks) pain.

Autonomic nerves Sympathetic: superior hypogastric plexus, hypogastric nerves, inferior hypogastric plexus Parasympathetic: pelvic splanchnic nerves, inferior hypogastric plexus, visceral nerve branches

Injury to the sympathetic nerves can lead to urinary incontinence and urgency. The hypogastric nerves can be encountered during sacral dissection. Injury to the parasympathetics can lead to atonic bladder, reduced bladder and rectal sensation, decreased vaginal blood flow, and lubrication. Abdominoperineal resection or application of mesh for prolapse can injure the inferior hypogastric plexus and rectal plexus visceral nerve branches, respectively.

Adapted from Facing Pelvic Pain.5

been present for fewer than six years, 66% of patients improve. If >6 years, 40% improve.59 Another pathologic condition, sacral radiculopathy, can present with similar symptoms and is often confused with pudendal neuralgia.62 Symptoms exclusive to sacral radiculopathy include the addition of back pain, gluteal pain, and sciatica. The most common causes include surgical damage, compression by varicose veins, endometriosis, sacral tumors, tethered cord, and Tarlov cysts.63 Pudendal neuralgia is but one of many peripheral nerve lesions that cause pelvic pain. Please refer to Table 42.4 for diagnostic guidance.

Figs. 42.10–42.12 illustrate the pelvic nerve, cutaneous nerves, and dermatomes. Lesions within the spinal cord can result in injury to the nerve fibers, which can present as pelvic pain (Table 42.5). CPP in patients with spinal cord pathologies can be especially prevalent. One study in the United States reviewed 1,295 patients with spinal cord injury and approximately 25% of the cohort presented with chronic pain throughout the pelvic girdle.62 Tumors, Tarlov cysts, disk herniations, and tethered spinal cord are causes of neurologic pelvic pain originating in the spinal cord (Fig. 42.13). Symptoms such as cauda

 

CHAPTER 42

Pelvic Pain

609

• Figure 42.10 

The lumbosacral plexus. These peripheral nerves (nerves that connect the spinal cord and brain to the limbs and organs) innervate many structures in the pelvis, although some of them originate outside of the pelvis. Reproduced from Standring S. Gray’s Atlas of Anatomy. The Anatomical Basis of Clinical Practice. 41st ed. Elsevier; USA, 2016:1083–1097.e2. Figure 62.14.

equina syndrome can present acutely, including bowel or bladder dysfunction, saddle anesthesia, bilateral sciatica, and leg weakness. This is most commonly caused by a tumor or midline disc and is considered a medical emergency. Other causes of cauda equina syndrome include abscess, arachnoiditis, tethered cord, chronic inflammatory demyelinating polyneuropathy, herpes simplex and zoster, Lyme disease, and tuberculosis.5 Pathology within the brain itself can also lead to pelvic pain, especially through central sensitization of pain. This concept is discussed further in the chapter. The diagnostic approach to the neurogenic cause of pelvic pain is via full genital and neurologic exam. History should focus on risk factors such as pelvic or abdominal surgeries, thrombosis, obstetric history, and pathologies of the CNS. It is important to note the characteristics of pain, timing, quality, intensity, and the presence of radiated or referred pain. The physical exam should assess for muscle strength, muscle tone, and range of motion. Sensation is assessed in all the dermatomes of the lumbosacral region. Proprioception, vibration, and reflex testing should also be performed. Focality or multifocality, upper versus lower motor neuron findings should be recorded. Some pathologies, e.g. pudendal, abdominal wall, or sacral neuropathies, can be diagnosed effectively with a selective nerve block.51 Additional tests such as ultrasound or urodynamic testing (bladder function), defecography (bowel function), and electromyography (EMG) can help in determining the cause. It is important to note that standard physical exams and EMG assess only the large nerve fibers. Small fiber neuropathy, discussed further below, requires quantitative sensory (mechanical and thermal) testing for diagnosis.

There are several treatment options in the management of neurogenic pelvic pain, ranging from conservative physical therapy to invasive procedures. Physical therapy alone remains controversial in the management of radicular pain, particularly in the acute setting, as some studies have noted no difference in outcome between physical therapy and rest.64,65 Medical treatment includes NSAIDs, acetaminophen, or serotonergic compounds. It is of note that their lack of selectivity for neurologic processes might limit their efficacy in the most severe cases. Opioids can be effective in the management of these patients; however, special attention should be made to avoid the development of tolerance and opioid-induced hyperalgesia, and most recommend their use primarily in the acute setting.66,67 The development of side effects and dependence also limit opioid use. Pregabalin has been proven effective in the management of pelvic pain of neurologic cause as it reduces neuronal hyperexcitability in the spinal cord and suppresses hypersensitivity in visceral pathways.68 It has been argued that if etiologic treatment is possible, it should take priority over solely medical symptomatic treatment.51 Targeted therapies such as therapeutic injections, either directed at a single nerve (e.g. local anesthetics, glucocorticoids, botulinum toxin) or as epidural injections (e.g. steroid injections), have proven very effective.66,69 Other therapies such as neurolysis, nerve decompression surgery, or neurosurgical or spinal procedures are also effective in management for specific indications. Neuromodulation has had considerable success in the treatment of refractory pelvic pain, with improvement seen in 50% up to around 90% of patients presenting with CPP, depending on

610

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Figure 42.11  Nerves of the pelvic viscera (male). Reproduced from Netter FH. Plate 392. Atlas of Human Anatomy. 2018: pp. 36.

the modality of neurostimulation performed.70 Examples include spinal cord stimulation, nerve root stimulation, and pudendal nerve stimulation. Motor cortex stimulation is also an approach that can be attempted in cases refractory to other neurostimulation modalities.71

Vascular Causes of Pelvic Pain Vascular causes of pelvic pain can stem from either venous or arterial disorders. Most of the arterial supply of the pelvis arises from the internal iliac artery and its numerous branches. The pudendal

artery supplies the perineum, the buttock region is supplied by the gluteal arteries, and the pelvic organs are supplied by the vesical, rectal, and uterine arteries (in the case of females).72 The veins that arise from the pelvis mostly drain into the internal iliac vein. The major exceptions are the gonadal arteries and veins, which arise from the abdominal aorta and drain into the inferior vena cava (IVC).73 It should be noted that the left gonadal vein drains into the left renal vein prior to the IVC. Figures 42.14 and 42.15 illustrate the vascular structures present in the pelvis. Although arterial etiologies are a rare cause of pelvic pain, these disorders should be ruled out if the context suggests their presence,

 

CHAPTER 42

Pelvic Pain

611

Posterior cutaneous of the arm

Medial cutaneous of the forearm Posterior divisions of the lumbar nerves

Branches of the posterior femoral cutaneous

Medial crural branches of the saphenous

• Figure 42.12

Cutaneous nerves and dermatomes. Submitted request for permission 8/1/20. Available at: https://www.dermnetnz.org/permission/image/42666, https://www.dermnetnz.org/topics/ dermatomes/Credit: https://www.grepmed.com/images/2963/dermatomal-dermatomes-diagnosis-cutaneous-anatomy-nerves-roots.  

TABLE Central Nervous System Causes of Pelvic Pain 42.5

Spine Diagnosis

Symptoms

Physical Exam Finding

Herniated disc: disc protrusion causes spinal cord or nerve root compression.

Back pain, shooting pain or numbness that follows a specific dermatomal pattern (e.g. a T10 through L1 disc herniation may radiate into the skin of the groin or abdomen), or sciatic symptoms in the leg; persistent genital arousal disorder has also been attributed to the spine.

Abnormal gait, pain with provocative maneuvers (e.g. pain with low back flexion, positive straight leg test that radiates pain with spine range of motion), possible increased or decreased reflexes.

Tarlov cysts: fluid-filled nerve root cysts found most often at the sacral level of the spine; small cysts may be a normal variant and are present in 5%–10% of people.

Symptoms vary but may present with pain over the buttocks and sacrum or with bowel, bladder, or sexual dysfunction.

Pain with sitting, standing, or walking; may have increased sensitivity or loss of sensitivity to touch over the sacrum and buttock; may present with lower extremity weakness.

Spina bifida occulta.

Typically asymptomatic but may cause lower extremity symptoms, including weakness, and urinary, sexual, or bowel symptoms, pelvic pain, and impaired sensation of the genitals, bladder, or bowels. Sometimes symptoms begin during growth spurts because of an associated tethered spinal cord.

May present with lower extremity weakness; the skin over the spine may present with an abnormal tuft of hair, dimple, or birthmark.

Continued

612

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE Central Nervous System Causes of Pelvic Pain—cont’d 42.5

Spine Diagnosis

Symptoms

Physical Exam Finding

Tethered spinal cord: caused by tissue attachments that limit the movement of the spinal cord within the spinal column; these attachments cause an abnormal stretching of the spinal cord, and therefore upper and lower motor neuron findings can be present; associated with spina bifida.

Back pain or shooting pain in the legs, weakness or numbness in the legs, lower extremity spasms, bowel or bladder dysfunction (over or underactive).

Lower extremity weakness, abnormally low or high reflexes, diminished lower extremity sensation. Gluteus or calf atrophy.

Cauda equina syndrome: caused by central spine nerve compression, such as stenosis in the lumbar region from a large herniated disc or tumor.

Symptoms may include severe lower extremity weakness and/or pain, decreased sensation in the legs and/or the lower pelvic region (“saddle anesthesia”), new-onset difficulty urinating or sudden urinary incontinence, and stool incontinence. If the above symptoms are acute, they require emergency evaluation.

Lower extremity weakness, reduced or absent reflexes in the legs, gluteus, or atrophy if chronic.

Sacral tumor: benign or malignant growths around the sacral nerve roots.

May present with symptoms similar to Tarlov cysts and herniated discs, such as back pain, lower extremity pain, lower extremity weakness, numbness or tingling, rectal dysfunction, urinary retention or incontinence, erectile dysfunction.

May present with tenderness over the sacrum or lower extremity weakness. A mass may be felt in the sacral area. Gluteal and calf atrophy may be present.

Adapted from Facing Pelvic Pain.5

• Figure 42.13  Sacral tumor affecting bladder function, gait, and muscle tone visually. Patient also reported radicular pain, fecal incontinence, and erectile dysfunction. Courtesy Elise De, MD.

namely because vasculitis and ischemic disease can have serious implications. Vasculitis is a rarely identified cause of pelvic pain and can be difficult to diagnose because of the non-specific signs and symptoms it presents, as it can affect any blood vessel in the body.

In these disorders, the vessel wall is infiltrated by white blood cells with resultant inflammatory reaction. Vasculitis can arise either as a primary disorder or secondary to another process and can occur because of a systemic disease or as single organ vasculitis. Both can cause CPP.74 Single organ vasculitis (SOV) can be either the first presentation of systemic vasculitis or a local inflammatory reaction to injury (e.g. tumors or pelvic surgery), with the latter being most common.75,76 The progression of true SOV to systemic vasculitis is uncommon (less than 1%) and often requires just symptomatic management beyond the treatment of the underlying diagnosis.77 Often, the precise cause of vasculitis remains unknown, but etiologies include autoimmune or rheumatic disorders, reaction to a medication, or infection. There is still an ongoing effort to develop a universal classification for vasculitis, but it is usually classified according to the size of the vessels involved (i.e. small, medium, and large sized vessels). Among the systemic vasculitides, giant cell arteritis (GCA; previously, temporal arteritis) is most prevalent in patients with pelvic pain. The classic symptoms of GCA include headaches, vision loss, jaw claudication, scalp tenderness, muscle stiffness, and pain.78 The high level of association between GCA and polymyalgia rheumatica (PMR) plays a role in the presentation of pelvic pain. Around 50% of patients with PMR have been documented to have concomitant GCA by biopsy. Pelvic girdle pain occurs bilaterally in these circumstances and is present in about 50%–70% of patients afflicted by PMR.79,80 It is important to have a high level of suspicion when diagnosing pelvic pain because of GCA, secondary to its potential to cause blindness. Other examples of systemic vasculitides which can cause pelvic pain include the following:

Large Sized Vessels • Takayasu’s arteritis, a large-vessel vasculitis that affects the aorta, with major branches to the extremities, and sometimes internal organs, usually occurring in females under 50 years • Giant/temporal cell arteritis, already discussed above

 

CHAPTER 42

Pelvic Pain

613

• Figure 42.14  Vessels of the posterior wall. From: Drake RL, Vogl A, Mitchell WA. Gray’s Atlas of Anatomy, 2021, pp. 133–212.

Small- and Medium-sized Vessels • Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s, which is a systemic disease that involves the lungs, kidneys, upper respiratory tract, and other organs associated with the autoantibody ANCA. • Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg Strauss, which is associated with asthma, nasal polyps, sinusitis, elevated eosinophil counts, and vasculitis and tends to involve the lungs, peripheral nerves, skin, kidneys, and heart.

• Microscopic polyangiitis: A systemic vasculitis affecting small and medium-sized blood vessels also associated with ANCA. • Polyarteritis nodosa: The prototype of systemic vasculitis involving many different organ systems such as the intestines and kidneys. The less common causes of vascular CPP, such as vasculitis, should be suspected in patients with systemic symptoms and evidence of organ dysfunction, while ischemic disease should be ruled out in patients with risk factors for peripheral artery disease.81

614

PA RT 4 Clinical Conditions: Evaluation and Treatment

Superficial dorsal vein of the penis Deep dorsal vein and left dorsal artery of the penis

Prostatic branches of the inferior vesical artery and vein

• Figure 42.15  Plate 385 arteries and veins of the pelvis: male. From: Netter FH. Plate 385. Atlas of Human Anatomy. 2018: 367–44D1.e11.

Laboratory studies such as C-reactive protein or erythrocyte sedimentation rate are of particular aid in diagnosing vasculitis. Doppler ultrasound has been found to have a sensitivity ranging from 70%–92% and a specificity of around 96% for the diagnosis of GCA.82,83 For the diagnosis of congestive pelvic venous disorders, venography (either by CT or MRI) is considered the gold standard, often demonstrating pelvic varicosities. Venous duplex/ Doppler ultrasound is also used. Treatment of vasculitides usually includes the administration of corticosteroids (dosing of 40–60 mg per day) with a more aggressive approach in the setting of visual symptoms such as in GCA (intravenous [IV] methylprednisolone, 1 g daily for the first three to five days).84 However, because of adverse effects of long-term

corticosteroid dosing (up to 85%), steroid-sparing agents such as tocilizumab or abatacept are under research and have shown promise in early trials.83 While rare in the context of CPP, ischemic disease can present as pain within the pelvic girdle. The abdominal aorta and the bifurcation of the common iliac arteries is a common place for atherosclerotic plaques to form, affecting pelvic blood flow.85 Chronic pelvic ischemia affects mainly the perfusion of the lower urinary tract. Ischemia in this region can precipitate the development of an overactive bladder, bladder pain syndrome, and associated sexual dysfunction can be present.86,87 Little has been written about the treatment of ischemic disease as a source of CPP, possibly because other manifestations of the disease are

 

CHAPTER 42

taking clinical precedence. Treatment should revolve around lifestyle changes such as smoking cessation. The addition of cardiovascular mortality-lowering medication, such as clopidogrel and aspirin, could be considered. Cilostazol is an effective medication for symptom control in intermittent claudication as it helps with vasodilation, but little information is available concerning chronic pelvic ischemia. Medications such as silodosin, tadalafil, mirabegron, and melatonin have been found to produce protective urodynamic parameters for bladder function in these patients, but further studies are needed. Pelvic venous disorders: Pelvic venous disorders have been cited as one of the most common causes of CPP, with figures as high as 31% of all CPP cases in females.7,88 They are more common in multiparous, premenopausal females. The complicated interplay of the pelvic venous vasculature and vague symptomatology has made it difficult to approach these disorders; it has been proposed to look at them as three interconnected systems: the renal and gonadal veins, the iliac veins, and lower extremity veins. Pain originating from venous disorders is most likely because of venous hypertension arising within these systems. The constellation of different signs and symptoms depend on what venous reservoir the venous pressure is being transmitted to (renal hilar, pelvic, or leg). The clinical manifestations include pelvic pain, pelvic varicosities, leg varices, and symptoms related to renal venous hypertension (e.g. hematuria, left flank pain). This increase in pressure usually is from primary or secondary insufficiency of the left gonadal vein, left renal vein (LRV), or the common iliac veins (CIV). Primary insufficiency of the pelvic veins can be congenital or acquired. In contrast, secondary insufficiency arises from pathologies such as nutcracker syndrome (compression of the LRV by the superior mesenteric artery) or May-Turner syndrome (usually compression of the left CIV by the left internal iliac artery).88 The diagnosis of a vascular cause of pelvic pain relies on a combination of the patient’s history, physical examination, and ultimately imaging studies. Questions should be directed at identifying the timing of pain onset and its characteristics. Pain arising from pelvic venous disorders is typically described as dull, throbbing, and achy. It arises or becomes worse when standing for long periods and is usually relieved when in a supine position. There can be a cyclic component. Low back pain, dyspareunia, and bladder and bowel symptoms may be present. The pain is often worse during menstruation, prolonged standing, or intercourse and is described as aching, throbbing pressure, or cramping. This condition is more common in females who have given birth, and the left side is more often affected because the left gonadal vein inserts into the LRV (or in the case of May-Turner, the configuration of the left common iliac vein with respect to the artery). The physical exam in females should assess for ovarian point tenderness or cervical motion tenderness: ovarian point tenderness on examination with a history of postcoital ache has been reported as 94% sensitive and 77% specific for pelvic congestion syndrome (PCS).89 The presence of varicosities in the lower extremities, the vulvoperineal region in the case of females, or varicoceles in the case of males should be documented. Moreover, 33% of those with PCS have vulvar varicosities (hemorrhoids or varicosities of perineum, vulva, buttocks), and 90% have lower extremity (LE) varicosities. However, of note, only 5% of those with LE varicosities have PCS. Imaging may show pelvic varicosities on ultrasound. MR Venography is considered diagnostic and will show dilation, most commonly of the left gonadal vein.90,91 Endovascular or surgical approaches are the best options for the management of pain stemming from pelvic venous congestion.

Pelvic Pain

615

Medication treatment with medroxyprogesterone or goserelin has been tried in females on the basis that pelvic venous vasculature is highly respondent to estrogens, but no sustained relief has been achieved, and the adverse effects are significant.92 Surgical management, including ovarian vein resection or hysterectomy, is practiced, but is invasive, carries a risk of hemorrhage given the dilated vasculature, and is associated with high relapse rates (up to 33% in hysterectomy). For venous valvular incompetence/reflux, endovascular procedures include simple coil embolization, glue embolization, or sclerotherapy to manage reflux in the primary ovarian and internal iliac veins. Endovascular stenting has also been found to be beneficial in compressive syndromes such as May-Turner and Nutcracker Syndromes.7 In May-Turner Syndrome, angioplasty followed by stenting may be considered as the first treatment option before embolization of dilated pelvic veins or formal surgical approaches. Following iliac venous stenting, pain relief and resolution of dyspareunia resolved in 80% one year after the procedure.93 In nutcracker syndrome, there is more robust data regarding formal surgical repair (LRV transposition) with the resolution of symptoms in 87% of patients at a mean follow up of 37 months.94,95 Endovascular stenting shows promise. However, data is lacking thus far, and stent migration, embolization to the right heart, and thrombosis have been described.

Systemic Causes of Pelvic Pain It can prove useful to evaluate systemic diseases, as sometimes CPP can manifest a larger process occurring within the body. A fundamental concept guiding evaluation is to determine whether pain is localized to the pelvic or whether the patient presents with multiple coexisting pain syndromes. Some of the established systemic causes of CPP are briefly discussed.

Neurologic As discussed, CPP can have a neurologic component involving direct or indirect injury to the central and peripheral nervous systems. However, some systemic neurologic diseases can present with widespread pain; the numbers range between 20% and 40% in patients afflicted by a primary neuronal disorder.96 Alterations within the structure and chemistry of the brain result in an aberrant communication among sensory, modulatory, cognitive, and emotional systems. These changes can precipitate pain in patients even when peripheral stimuli are no longer present. Complex regional pain syndrome is an example, as a small injury in a peripheral nerve induces changes at the thalamic and subthalamic level and can even include changes in the parietal lobe and basal ganglia. Other CNS disorders such as Parkinson’s disease, Alzheimer’s disease, stroke, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) can present with widespread pain, in some cases with high rates of prevalence. In MS, for example, widespread pain is reported in as many as 86% of patients.97 In Parkinson’s disease, pain is present in approximately 40% of patients, in some noted as the major complaint, even ranking above motor symptoms.98 Prevalence is also considerably high in Alzheimer’s disease (57%), stroke (particularly if the thalamus is affected) (8%–14%), and ALS (15%).99–101 Management can be attempted with pharmacologic treatment (e.g. anti-epilepsy drugs, anti-depressants, and membrane stabilizers), brain stimulation techniques, or even targeted delivery of medication to the CNS using CT or MR imaging.

616

PA RT 4 Clinical Conditions: Evaluation and Treatment

Peripheral neuropathy is essential to consider when evaluating patients with pelvic pain, particularly when CPP is refractory to intervention or occurring in concert with other pain syndromes. Peripheral neuropathy is experienced by approximately 40 million people in the United States. Many peripheral neuropathies are mixed neuropathies with both large fiber and small fiber involvement (Table 42.6). Increasingly recognized is the demonstration of specific involvement of small myelinated or unmyelinated fibers, e.g. small fiber neuropathies.102 In our population of complex pelvic pain patients (refractory or multisystem pain), 64% (25 of 39) had a skin biopsy positive for small fiber polyneuropathy. Comorbid conditions included gastroesophageal reflux disease in 46%, migraine in 38%, IBS in 33%, lower back pain in 33%, fibromyalgia in 38%, endometriosis in 15%, interstitial cystitis in 18%, vulvodynia in 5%, and other chronic pain syndromes in 36%.103 Of note, in separately published studies, approximately 50% of patients who have been diagnosed with fibromyalgia in several published studies have demonstrated findings consistent with small fiber polyneuropathy (SFPN) on diagnostic biopsies.104,105 Muscle cramps can be a symptom of SFPN. Small fiber neuropathies (SFN) occur when injury to the peripheral nerves predominantly or entirely affects the small myelinated (Aδ) or unmyelinated C fibers. The fibers affected include both small somatic pain fibers and autonomic fibers. Thermal perception and nociception, enteric function, cardiovascular, genitourinary, perspiratory, lacrimal, and salivary gland function are subserved by small fibers.106 Most SFNs occur in a length dependent fashion, first stocking distribution changes and later glove distribution. Less common but no longer rare, non-length dependent SFN can result in symptoms involving the face, trunk, proximal limbs, or other more localized areas such as the pelvis. The pathogenesis of injury to small fibers is not well understood and can progress to involve the myelinated and therefore better protected large fibers. Epidemiologic data from the Netherlands suggest a minimum incidence of SFPN of 12/100,000 people.107 Children can also experience SFN. Disorders associated with SFPN include diabetes, sarcoidosis, thyroid dysfunction, vitamin B12 deficiency, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, systemic lupus erythematosus, amyloidosis, Ehlers Danlos Syndrome, hereditary sensory and autonomic neuropathies, alcohol use, Lyme disease, metronidazole, statins, and celiac disease/gluten intolerance.

TABLE Large and Small Fiber Polyneuropathies 42.6

Large Fiber Neuropathy

Small Fiber Neuropathy

Symptoms

Numbness, pins and needles, tingling, poor balance

Pain: burning, electric shocks, stabbing pain, numbness

Exam findings

Reflexes, proprioception Vibration, +/– motor

Thermal, pinprick sensation, allodynia

Functional changes

Pressure, balance, fall risk

Nociception; protective sensation

Diagnostic test

EMG/NCV, sural nerve biopsy

QST, nerve biopsy, Intraepidermal nerve fiber density (skin biopsy)

Symptoms vary widely in severity. Often affected individuals describe a gradual onset of vague distal sensory disturbances, for example, feeling like there is sand in the person’s shoe, a sock feeling as if it has pebbles in it, pins and needle sensations, cold painful sensations or tingling, burning pain in the extremities, allodynia, and hyperesthesia. Socks or bedsheets on the feet may be painful. Symptoms are often worse at night. Autonomic and enteric dysfunction may be present, including dry eyes, dry mouth, lightheadedness with changes in posture, syncope, abnormalities of sweating, erectile dysfunction, gastrointestinal symptoms such as nausea and emesis, constipation, diarrhea, and changes in urinary frequency, including nocturia. Diagnosis is by history, quantitative sensory testing (QST), skin biopsy, and autonomic testing. The neurologic examination (which assesses large fibers) may be normal. However, possible findings include decreased pinprick, diminished thermal sensation, hyperalgesia, or dry skin. Autonomic (tilt-table) testing may show abnormal heart rate responses to deep breathing, heart rate and blood pressure responses during Valsalva maneuvers, heart rate and blood pressure response to a 70-degree tilt, and sudomotor responses (sweat production). The standard biopsy is a 3 mm skin punch biopsy that can be taken from anywhere over the body. Because of the need to compare to normal values, the LE 10 cm proximal to the lateral malleolus is most commonly assessed (of relevance, length dependent SFN is more common than non-length dependent). The results are expressed as the number of intraepidermal fibers per mm. The sensitivity (78%–92%) and specificity (65%–90%) are fairly high for this technique.106 Once diagnosed, workup depends on the suspected cause: metabolic, nutritional, infectious, autoimmune, allergic, paraneoplastic, neurotoxins, or hereditary. Lumbar puncture may be indicated if inflammatory, autoimmune, or paraneoplastic etiologies are suspected. If an underlying cause of SFN can be determined, optimal treatment of the causative condition may lessen the symptoms of SFN. Few studies and no guidelines have examined the pharmacologic treatment of the pain associated with SFN. In one such study, both gabapentin and tramadol were found to be effective for SFN. Tricyclics, IV lidocaine, serotoninnorepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and intravenous immunoglobulin have all been used.

Rheumatologic The most common cause of CPP because of a rheumatologic process is PMR, but it is important to note that rheumatologic disease is not as common a cause of CPP as other conditions. Nevertheless, if a rheumatologic condition affects the joints in the pelvic girdle (e.g. inflammatory arthritis), it can manifest as pelvic pain. Out of these, the sacroiliac joint is one of the most commonly affected. The most prevalent disorders associated with inflammatory arthritis are rheumatoid arthritis, ankylosing spondylitis, and gouty arthritis.108 Systemic lupus erythematosus, myopathy, and osteomalacia are other examples. Rheumatoid arthritis (RA) can cause pelvic pain if it directly affects joints in the pelvis or the bones that make up the pelvic girdle. Some cases of mutilating type of RA have been involved in the development of insufficiency fractures of the pelvic ring, manifesting as progressively worsening pelvic pain.109,110 RA has also been found to have an association with bladder pain syndrome/interstitial cystitis.111 Ankylosing spondylitis (AS) is characterized by inflammatory back pain (typically associated with improvement with exercise, insidious onset, nocturnal symptoms, no improvement with rest, and morning stiffness >30 min). Pelvic joint lesions have been reported to be present in about 25%–35% of all patients with AS,

 

CHAPTER 42

with the severity of hip involvement being correlating to the overall functional status.112 Gout, on the other hand, is an extremely rare cause of pelvic pain, as fewer than ten cases of gout affecting the pubic symphysis have been reported.113,114 Treatment of pelvic pain in rheumatologic diseases is directed at treating the underlying condition. NSAIDs, disease modifying anti-rheumatic drugs (DMARDs, e.g. methotrexate), and TNF-inhibitors are the mainstay of treatment in these diseases. Other medications such as colchicine or glucocorticoids in gout can also be considered. Last, there is a significant overlap of CPP and fibromyalgia to the extent that pelvic pain is part of the diagnostic criteria. The levator muscles may benefit from pelvic floor physical therapy and, because of potentiators of muscle tension and trigger points, training with a wand to self-treat at home.

Special Considerations Children and Adolescents Special considerations should be taken when evaluating pelvic pain in children and adolescents. As with adults, pelvic pain may stem from gastrointestinal, genitourinary, reproductive, orthopedic, neurologic, congenital, traumatic, or infectious sources, emphasizing the need to take a thorough history to include bowel function, athletic injury, fall, and menstruation. Sensitive questions must be addressed, including inquiry regarding inappropriate touching and other non-consensual physical exposures. This may require the clinician to ask parents and guardians to recuse themselves for part of the patient interview. A female escort must be present for this part of the interview and the physical exam. Examination of the genitals and perianal tissue may be indicated in addition to the neurologic exam, depending on the patient’s comfort level and the thoroughness of prior exams within other specialties. A urinalysis should be performed routinely, with cultures, labs, and imaging as indicated. Adolescent males typically only experience pelvic pain after puberty. It is most commonly because of urologic or injuries to the coccyx, genitals (e.g. straddle, zipper, or sexually transmitted disease), or hips. The most common causes of pelvic pain in adolescent females are painful menstruation and constipation, with symptoms often including bloating, nausea, and heartburn. A physician should evaluate significant menstrual pain, and when a young female misses a period three months in a row, periods occur fewer than three weeks apart, or there is frequent bleeding between periods at any point from the initiation of menstruation.115 A transabdominal pelvic ultrasound may be required, but internal vaginal exams are not typically necessary in children and adolescents. Occasionally a cotton swab may need to be placed into the vagina to test for obstruction or infection. About 70% of adolescent females with pelvic pain are diagnosed with endometriosis.116 Recommended treatment for endometriosis in adolescents is conservative surgical therapy for diagnosis and treatment, along with continuous suppressive hormonal therapy (i.e. an oral contraceptive) to prevent endometrial proliferation.117 Because endometriosis implants in adolescents can be difficult to identify as they typically appear clear or red, it is important to refer patients to gynecologists familiar with adolescent endometriosis. Both male and female adolescents may have myofascial pain from a primary injury or secondary to a known pelvic disorder. Muscles may spasm and become tender to touch, and pelvic floor dysfunction can cause pain with urination or bowel movement. Unlike adults, myofascial pelvic pain in adolescents is not usually associated with local nerve irritation or nerve entrapment, and

Pelvic Pain

617

though a diagnostic nerve block can help differentiate pain from the abdominal wall, spine, and pelvic muscles from other sources, about 95% of adolescent myofascial pelvic pain improves with physical therapy.118 In adults, pelvic floor physical therapy often involves the vaginal wall, but in adolescents, great benefit can still be derived from indirect stimulation from the external abdominal, hip, thigh, and lower back muscles. Treating chronic pain in adolescents is often easier than in adults because of neuroplasticity. It is often best to address pelvic pain in children and adolescents as a multi-disciplinary team, including pediatricians, adolescent gynecologists, urologists, gastrointestinal medicine doctors, pediatric pain physicians, physical and occupational therapists, and child and adolescent psychologists.

Pelvic Pain in Those With Disability Patients with intellectual disability (ID) might pose a challenge when managing chronic pain because of communication difficulties, unconstructive behavior, and preexisting conditions complicating diagnosis. Note should be taken of patients’ individual circumstances, as every patient with a disability may have different resources, coping skills, and mechanisms.119 Prevalence of chronic pain has been estimated to be close to 15% in patients suffering from ID. With the understanding that persons with a disability might not be able to communicate distress as effectively, this figure could potentially be higher.120 Self-reporting is considered the gold standard for assessing pain and should be considered whenever possible. Patients with ID have found some success when it comes to self-reporting and often need the aid of scales such as the visual analog scale. Behavioral observation methods with the aid of observational pain assessment tools have proven beneficial when the patient cannot self-report pain. Tools such as the noncommunicating children’s pain checklist or the faces, legs, activity, cry, and consolability scale consider several non-verbal cues that provide valuable information about whether pain is present. Management of these patients must include cognitive behavior therapy (CBT) or relaxation therapy in conjunction with medical treatment and teaching family members to identify when a patient is in pain. Coping strategies should be tailored and taught to the needs of each patient, all while giving preference to active coping methods (e.g. functioning despite pain) rather than passive ones (e.g. avoiding the development of pain).5,121 Pelvic pain in those with a physical and neurologic disability may best be served by a team including pain management, physical medicine and rehabilitation, neurology, physical therapy, and occupational therapy expertise. Sensory deficits can lead to prolongation of noxious stimulus, for example, prolonged sitting on the coccyx in a wheelchair. In ambulatory individuals, the provider should be cognizant of gait deviations, pain, and weaknesses that can lead to biomechanical compensation. Therapeutic exercise and adaptive equipment applied appropriately can reduce these strains.

Psychological Considerations People experiencing CPP should be assessed for psychological comorbidities and offered support. It is very important to emphasize that treating the impact of the pain on one’s life, psychological amplifiers of pain, and treating the whole person, is important to a good outcome, but that the pain is not thought to be because of a psychological disorder. Most female patients presenting to the clinic experience moderate to severe anxiety, and around 25% have reported moderate to severe depression.122 These comorbidities,

618

PA RT 4 Clinical Conditions: Evaluation and Treatment

along with the catastrophizing of pain, can complicate treatment if severe.5 Relationships and sexual function might also be affected by pelvic pain. Anticipatory anxiety or pain during intercourse can reduce sexual satisfaction and interest. This can lead to concerns about becoming less attractive to existing and new partners.123 Also of concern is the possibility of past trauma such as sexual abuse or other nonconsensual sexual activities. It has been documented that adolescent girls with a history of sexual abuse are almost twice as likely to report CPP development.124 A history of trauma is not uncommon in male patients. In all genders, including transgender individuals, a trauma informed approach making room for, but not requesting disclosure of past events while placing the locus of control in the patient’s hands usually leads to an easy clinical interaction for all parties involved. CBT and mindfulness-based therapy have both shown success in the treatment of CPP.

Chronification of Pain (Central and Peripheral Sensitization of Pain) We have discussed some of the central and peripheral neurologic causes of CPP, but it is important to understand that many patients with chronic pain have undergone changes in their neurophysiology. Chronification of pain refers to the transformation of acute pain into chronic pain. It involves the sensitization of peripheral and central nervous systems.124 The transmission of pain from a nociceptor to the cerebral cortex involves signal transduction, action potential generation, and its transmission to the thalamus and posteriorly to the parietal cortex.125 Changes within this pathway induce sensitization to pain stimuli (hyperalgesia). Nociceptors are chemoreceptors that react to inflammatory molecules (bradykinin, prostaglandins, and substance P). Repeated

stimulation in the peripheral nervous system results in the upregulation of nociceptors and an increase in neuronal excitability (e.g. by upregulating sodium channels). Second and third order neurons transmit the pain signals to the thalamus and the cerebral cortex, respectively. Central sensitization occurs when these neurons lower the threshold for their action potentials and end up reacting to subthreshold stimuli. The aforementioned sensitization occurs because of an upregulation of N-methyl-d-aspartate receptors, glutamate, and substance P interaction with membrane G-coupled-receptors, and a decrease in g-aminobutyric acid inhibitory signals.124 There are different etiologies of acute-to-chronic pain syndromes. The most common being chronic post-surgical pain (CPSP) and opioid-induced hyperalgesia, with individual patient factors playing a role in the potential for pain chronification. Preexisting conditions or genetic polymorphisms (e.g. mutations in the COMT gene) can render an individual more susceptible to developing chronic pain. Obesity, female sex, and young age are also risk factors.126 Patients at risk can be preemptively treated with perioperative ketamine, gabapentinoids, NSAIDs, and regional anesthesia. These interventions lower the risk of CPSP. For the treatment of chronic pain associated with central sensitization, brain-based treatments are centered on re-interpreting messages from the nerves. Interventions can be based on altering memories or fear of pain.127 TENS units, meditation, relaxation, mindfulness, mind-body medicine, CBT, and exercise can all be beneficial. The provider should focus on reducing any contributing physical pain promotors present (for example, a patient whose pain is complicated by chronic sitting, bladder irritant, and vulvar atrophy). Employing a multi-disciplinary approach can change how the patient responds to the stimuli, often helping cope with the chronic condition.128

Summary CPP improves or resolves in the majority of patients with a careful, informed, multifaceted approach. The care of these individuals can be very satisfying, and the more knowledge one has, the

more effective one will be. Usually, CPP responds to the more straightforward interventions, and the differential diagnosis can be expanded based on the content above where needed.

Key Points • Pelvic pain can arise from virtually any organ system in the body. • The approach to acute pelvic pain should rule out life threatening conditions. • Management of CPP requires a multi-disciplinary team.

• Some serious conditions, such as cancer, might manifest as progressive or refractory CPP. • Special considerations should be taken when dealing with pediatric patients and patients with disabilities. • History taking and physical examination should be performed with care because of the nature of the condition.

Acknowledgments We thank the authors of Facing Pelvic Pain for expanding our knowledge in the treatment of pelvic pain enough to write this chapter and to Kenneth Barron, MD, for his suggestions on the gynecologic pain section.

Suggested Readings European Association of Urology EAU Guideline. Available at: http:// www.uroweb.org/guidelines/online-guidelines/. International Pelvic Pain Society. Available at: https://www.pelvicpain. org/. ICS Institute. School of pelvic pain. Available at: https://www.ics.org/ institute/pelvicpain.

American Urological Association AUA Guideline. Available at: https:// www.auanet.org/guidelines/interstitial-cystitis-(ic/bps)-guideline. The International Continence Society ICS Standardization. Available at: https://www.ics.org/folder/standardisation/current-ics-standardisations. Levine T, Saperstein D, Argoff C, et al. Small nerves big problems: a comprehensive guide to small fiber neuropathy. Chicago, IL: Hilton Press, 2017.

 

CHAPTER 42

Patient Resources De EJB, Stern TA (eds). Facing pelvic pain: a guide for patients and their family members. Boston MA: Massachusetts General Hospital Psychiatry Academy; 2021. Available at: www.facingpelvicpain. org.

Pelvic Pain

619

Interstitial Cystitis Network. Available at: https://www.ic-network. com/. World Federation of Incontinent Patients. Available at: https://wfip. org/. The references for this chapter can be found at ExpertConsult.com.

References 1. Chronic pelvic pain. Obstet Gynecol. 2020;135(3):e98–e109. doi:10.1097/aog.0000000000003716. 2. Daniel S. Engeler, Andrew P. Baranowski, Paulo Dinis-Oliveira, et al. The 2013 EAU Guidelines on Chronic Pelvic Pain: Is Management of Chronic Pelvic Pain a Habit, a Philosophy, or a Science? 10 Years of Development, European Urology, Volume 64, Issue 3, 2013, Pages 431439, ISSN 0302-2838, https://doi.org/10.1016/j.eururo.2013.04.035. 3. Mathias SD, Kuppermann M, Liberman RF, et al. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol. 1996;87(3):321–327. 4. Deer TR, Leong MS. Treatment of chronic pain by interventional approaches. New York: Springer-Verlag. doi:10.1007/978-1-49391824-9. 5. De EJB, Stern TA. Facing Pelvic Pain: A Guide for Patients and Their Family Members. Boston MA: Massachusetts General Hospital Psychiatry Academy; 2021. Available at. www.facingpelvicpain.org. 6. The International Pelvic Pain Society. Pelvic pain assessment form. Available at: https://www.pelvicpain.org/. 7. Benzon HT, Raja SN, Liu SS, et al. Essentials of Pain Medicine. 4th ed. Elsevier; Philadelphia. 2018:262. 8. Ayorinde AA, Macfarlane GJ, Saraswat L, et  al. Chronic pelvic pain in women: an epidemiological perspective. Womens Health. 2015:851–864. 9. Meissner MH, Gloviczki P. Chapter 21 - pelvic venous disorders. In: Atlas of Endovascular Venous Surgery. 2nd ed. Elsevier; Philadelphia. Jose Almeida: 2019;567–599. doi:10.1016/B978-0-32351139-1.00021-8. 10. Zondervan KT, Yudkin PL, Vessey MP. Chronic pelvic pain in the community - symptoms, investigations, and diagnoses. Am J Obstet Gynecol. 2001;184(6):1149–1155. 11. Grace VM, Zondervan KR. Chronic pelvic pain in New Zealand: prevalence, pain severity, diagnoses and use of the health services. Aust NZ J Public Health. 2004;28(4):369–375. 12. Engeler DS, Baranowski AP, Dinis-Oliveira P, et al. The 2013 EAU guidelines on chronic pelvic pain: is management of chronic pelvic pain a habit, a philosophy, or a science? 10 years of development. Eur Urol. 2013;64(3):431–439. doi:10.1016/j.eururo.2013.04.035. 13. Crombie DL. Diagnostic process. J Coll Gen Pract. 1963;6:579–589. 14. Sandler G. The importance of the history in the medical clinic and the cost of unnecessary tests. Am Heart J. 1980;100(Pt 1):928–931. 15. Alice D, Domar MA. Psychological aspects of the pelvic exam. Women Health. 1986;10(4):75–90. doi:10.1300/J013v10n04_07. 16. Kruszka PS, Kruszka SJ. Evaluation of acute pelvic pain in women. Am Fam Physician. 2010;82(2):141–147. 17. Dewey K, Wittrock C. Acute pelvic pain. Emerg Med Clin N Am. 2019;37(2):207–218. doi:10.1016/j.emc.2019.01.012. 18. Siedentopf F, Wowro E, Möckel M, et al. Patients presenting to the emergency unit with gynaecological lower abdominal pain, with and without pathological clinical findings - service utilisation, pain history, implications. Geburtshilfe Frauenheilkd. 2016;76(9):952–959. doi:10.1055/s-0042-104929. 19. Rigor BM. Pelvic cancer pain. J Surg Oncol. 2000;75(4):280–300. 20. Chandler J, Wagner E, Riley K. Evaluation of female pelvic pain. Semin Reprod Med. 2018;36(2):99–106. doi:10.1055/s-0038-1676084. 21. Bishop LA. Management of chronic pelvic pain pain]. Clin Obstet Gynecol. 2017;60(3):524–530. doi:10.1097/GRF.0000000000000299. 22. Kuhn A. Chronischer Beckenschmerz [Chronic pelvic pain]. Ther Umsch. 2019;73(9):573–575. doi:10.1024/0040-5930/a001039. 23. Speer LM, Mushkbar S, Erbele T. Chronic pelvic pain in women. Am Fam Physician. 2016;93(5):380–387. 24. Wozniak S. Chronic pelvic pain. Ann Agric Environ Med. 2016;23(2): 223–226. doi:10.5604/12321966.1203880. 25. Bonnema R, McNamara M, Harsh J, et  al. Primary care management of chronic pelvic pain in women. Cleve Clin J Med. 2018;85(3):215–223. doi:10.3949/ccjm.85a.16038.

26. Tam T, Levine EM. Female sexual dysfunction in women with pelvic pain. Semin Reprod Med. 2018;36(2):152–158. doi:10.1055/s-0038-1676115. 27. Valentine LN, Deimling TA. Opioids and alternatives in female chronic pelvic pain. Semin Reprod Med. 2018;36(2):164–172. doi: 10.1055/s-0038-1676102. 28. Engeler DS, Baranowski AP, Dinis-Oliveira P, et al. European Association of Urology. The 2013 EUA guidelines on chronic pelvic pain: is management of chronic pelvic pain a habit, philosophy, or a science? 10 years of development. Eur Urol. 2013;64(3):431–439. 29. Greenwell TJ, Spilotros M. Urethral diverticula in women. Nat Rev Urol. 2015;12(12):671–680. doi:10.1038/nrurol.2015.230. 30. Hanno PM, Burks DA, Clemens JQ, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol. 2011;185(6):2162–2170. 31. Malde S, Solomon E, Spilotros M, et  al. Female bladder outlet obstruction: common symptoms masking and uncommon cause. Low Urin Tract Sympt. 2019;11(1):72–77. doi:10.1111/luts.12196. 32. Pedersen KV, Drewes AM, Frimodt-Møller PC, et al. Visceral pain originating from the upper urinary tract. Urol Res. 2010;38:345–355. 33. Davis R, Jones SJ, Barocas DA, et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults (2012, confirmed 2016). Available at: https://www.auanet.org/guidelines/asymptomatic-microhematuria-(amh)-guideline. 34. Flynn S, Eisenstein S. Inflammatory bowel disease presentation and diagnosis. Surg Clin North Am. 2019;99(6):1051–1062. doi:10.1016/j. suc.2019.08.001. 35. Guttenplan M. The evaluation and office management of hemorrhoids for the gastroenterologist. Curr Gastroenterol Rep. 2017;19(7):30. doi:10.1007/s11894-017-0574-9. 36. Tu FF, As-Sanie S, Steege JF. Musculoskeletal causes of chronic pelvic pain: a systematic review of diagnosis: part I*. Obstet Gynecol Surv. 2005;60(6):379–385. doi:10.1097/01.ogx.0000167831.83619.9f. 37. Tu FF, As-Sanie S, Steege J. Prevalence of pelvic musculoskeletal disorders in a female chronic pelvic pain clinic. J Reprod Med. 2006;51:185–189. 38. Reiter RC, Gambone JC. Nongynecologic somatic pathology in women with chronic pelvic pain and negative laparoscopy. J Reprod Med. 1991;36:253–259. 39. Prendergast SA, Weiss JM. Screening for musculoskeletal causes of pelvic pain. Clin Obstet Gynecol. 2003;46(4):773–782. doi:10.1097/00003081200312000-00006. 40. Gyang A, Hartman M, Lamvu G. Musculoskeletal causes of chronic pelvic pain: what a gynecologist should know. Obstet Gynecol. 2013;121(3):645–650. doi:10.1097/AOG.0b013e318283ffea 41. Rogalski MJ, Kellogg-Spadt S, Hoffmann AR, et  al. Retrospective chart review of vaginal diazepam suppository use in high-tone pelvic floor dysfunction. Int Urogynecol J Pelvic Floor Dysfunct. 2010;21(7):895–899. 42. Bedaiwy MA, Patterson B, Mahajan S. Prevalence of myofascial chronic pelvic pain and the effectiveness of pelvic floor physical therapy. J Reprod Med. 2013;58(11-12):504–510. 43. Sakamoto A, Gamada K. Altered musculoskeletal mechanics as risk factors for postpartum pelvic girdle pain: a literature review. J Phys Ther Sci. 2019;31(10):831–838. doi:10.1589/jpts.31.831. 44. Zhoolideh P. Are there any relations between posture and pelvic floor disorders? A literature review. Cres J Med Biol Sci. 2017;4(4):153–159. 45. Suleiman S. The abdominal wall: an overlooked source of pain. Am Fam Phys. 2001;64(3):431–439. 46. Prather H, Dugan S, Fitzgerald C, et al. Review of anatomy, evaluation, and treatment of musculoskeletal pelvic floor pain in women. PM&R. 2009;1(4):346–358. doi:10.1016/j.pmrj.2009.01.003. 47. Van Tulder MW, Touray T, Furlan A, et al. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane Collaboration. Spine. 2003;28(17):1978–1992. 48. Witenko C, Moorman-Li R, Motycka C, et al. Considerations for the appropriate use of skeletal muscle relaxants for the management of acute low back pain. Pharmacy and Therapeutics. 2014;39(6):427– 435. 619.e1

619.e2

References

49. Prather H, Spitznagle TM, Dugan SA. Recognizing and treating pelvic pain and pelvic floor dysfunction. Phys Med Rehabil Clin N Am. 2007;18:477–496 ix. 50. Purwar B, Khullar V. Use of botulinum toxin for chronic pelvic pain. Womens Health. 2016;12(3):293–296. doi:10.2217/whe-2016 -0007. 51. Possover M. Neuropelveological assessment of neuropathic pelvic pain. Gynecol Surg. 2014;11:139–144. 52. Kevin S. Anatomy, Bony Pelvis and Lower Limb, Nerves. NCBI: StatPearls Publishing, Florida, United States of America, 2019. 53. Watkins RG. Superior hypogastric sympathetic plexus. In: Surgical Approaches to the Spine. New York, NY: Springer; 2003. 54. Lemos N. Laparoscopic anatomy of the autonomic nerves of the pelvis and the concept of nerve-sparing surgery by direct visualization of autonomic nerve bundles. Fertil Steril. 2015;104(5):e11– e12. doi:10.1016/j.fertnstert.2015.07.1138. 55. Malykhina AP. Neural mechanisms of pelvic organ cross-sensitization. Neuroscience. 2007;14(9):660–672. 56. Sikandar S, Dickenson AH. Visceral pain: the ins and outs, the ups and downs. Curr Opin Support Palliat Care. 2012;6(1):17–26. doi:10.1097/SPC.0b013e32834f6ec9. 57. Kaur J. Pudendal Nerve Entrapment Syndrome: StatPearls Publishing, Treasure Island, Florida, 2019. Available at: https://www.ncbi.nlm.nih. gov/books/NBK544272/. 58. Rea W, Curran N. Abdominopelvic pain syndromes. Contin Edu Anaesth Crit Care Pain. 2015;15(1):38–43. 59. Robert R, Labat JJ, Bensignor M, et  al. Decompression and transposition of the pudendal nerve in pudendal neuralgia: a randomized controlled trial and long-term evaluation. Eur Urol. 2005;47(3): 403–408. 60. Labat JJ, Riant T, Robert R, et al. Diagnostic criteria for pudendal neuralgia by pudendal nerve entrapment (Nantes criteria). Neurourol Urodyn. 2008;27(4):306–310. doi:10.1002/nau.20505. 61. Ploteau S. Pudendal neuralgia due to pudendal nerve entrapment: warning signs observed in two cases and review of the literature. Pain Physician. 2016;19(3):E449–E454. 62. Possover M. Laparoscopic management of endopelvic etiologies of pudendal pain in 134 consecutive patients. J Urol. 2009;181:1732– 1736. 63. Possover M, Schneider T, Henle KP. Laparoscopic therapy of endometriosis and vascular entrapment of sacral plexus. Fertil Steril. 2011;95:756–758. 64. Ehsan M, Pirouzi P, Soroush MR, et al. Chronic pain after spinal cord injury: results of a long-term study. Pain Med. 2010;11(7):1037– 1043. 65. Hagen KB, Hilde G, Jamtvedt G, et al. Bed rest for acute low-back pain and sciatica. Cochrane Database Syst Rev. 2004(4):CD001254. 66. Sikandar S, Dickenson AH. Visceral pain: the ins and outs, the ups and downs. Curr Opin Support Palliat Care. 2012;6(1):17–26. doi:10.1097/SPC.0b013e32834f6ec9. 67. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain. 2008;24(6):479–496. 68. Bannister K, Sikandar S, Bauer CS, et  al. Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology. Anesthesiology. 2011;115(1):144–152. 69. Dydyk AM, M Das J. Radicular Back Pain. Treasure Island, FL: StatPearls Publishing; 2019. Available at: https://www.ncbi.nlm. nih.gov/books/NBK546593/. 70. Tam J, Loeb C, Grajower D, Kim J, Weissbart S. Neuromodulation for chronic pelvic pain. Curr Urol Rep. 2018;19(5). doi:10.1007/ s11934-018-0783-2. 71. Louppe JM, Nguyen JP, Robert R, et al. Motor cortex stimulation in refractory pelvic and perineal pain: report of two successful cases. Neurourol Urodyn. 2013;32(1):53–57. 72. Acland RD. Acland’s Video Atlas of Human Anatomy, Veins and Arteries of the Pelvis. 3.4.8: Wolter’s Kluver, Philadelphia 2003.

73. Chaudhry R, Chaudhry K. Anatomy, Abdomen and Pelvis, Uterine Arteries: StatPearls Publishing, Treasure Island, 2018. 74. Hernández-Rodríguez J, Hoffman GS. Updating single-organ vasculitis. Curr Opin Rheumatol. 2012;24(1):38–45. doi:10.1097/ BOR.0b013e32834d8482. 75. Roma AA, Amador-Ortiz C, Liapis H. Significance of isolated vasculitis in the gynecological tract: what clinicians do with the pathologic diagnosis of vasculitis? Ann Diag Pathol. 2014;18(4):199–202. doi:10.1016/j.anndiagpath.2014.03.008. 76. Hernández-Rodríguez J, Tan CD, Rodríguez ER, et  al. Gynecologic vasculitis: an analysis of 163 patients. Medicine (Baltimore). 2009;88:169–181. 77. Hoppé E, de Ybarlucéa LR, Collet J, et al. Isolated vasculitis of the female genital tract: a case series and review of literature. Virchows Arch. 2007;451(6):1083–1089. 78. Winkler A, True D. Giant cell arteritis: 2018 review. Mo Med. 2018;115(5):468–470. 79. Salvarani C, Cantini F, Boiardi L, et al. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002;347(4):261–271. 80. Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ, et al. Giant cell arteritis: disease patterns of clinical presentation in a series of 240 patients. Llorca J Med (Baltimore). 2005;84(5):269–276. 81. Knuttinen MG, Xie K, Jani A, et  al. Pelvic venous insufficiency: imaging diagnosis, treatment approaches, and therapeutic issues. Am J Roentgenol. 2015;204(2):448–458. 82. Schmidt WA. Ultrasound in the diagnosis and management of giant cell arteritis. Rheumatology (Oxford). 2018;57(Suppl 2):ii22–ii31. 83. Aranda-Valera IC, García Carazo S, Monjo Henry I, et al. Diagnostic validity of Doppler ultrasound in giant cell arteritis. Clin Exp Rheumatol. 2017;35(Suppl 103(1)):123–127. 84. Baig IF, Pascoe AR, Kini A, Lee AG. Giant cell arteritis: early diagnosis is key. Eye Brain. 2019;11:1–12. doi:10.2147/EB.S170388. 85. Günenç Beşer C, Karcaaltincaba M, Çelik HH, et al. The prevalence and distribution of the atherosclerotic plaques in the abdominal aorta and its branches. Folia Morphol (Warsz). 2016;75(3):364–375. doi:10.5603/FM.a2016.0005. 86. Andersson KE, Nomiya M, Sawada N, et al. Pharmacological treatment of chronic pelvic ischemia. Ther Adv Urol. 2014;6(3): 105–114. doi:10.1177/1756287214526768. 87. Kapoor H, Gupta E, Sood A. Chronic pelvic ischemia: etiology, pathogenesis, clinical presentation and management. Minerva Urol Nefrol. 2014;66(2):127–137. 88. Durham JD, Machan L. Pelvic congestion syndrome. Semin Intervent Radiol. 2013;30(4):372–380. doi:10.1055/s-0033-1359731. 89. Knuttinen MG, Xie K, Jani A, et  al. Pelvic venous insufficiency: imaging diagnosis, treatment approaches, and therapeutic issues. Am J Roentgenol. 2015;204(2):448–458. 90. Meissner MH, Gibson K. Clinical outcome after treatment of pelvic congestion syndrome: sense and nonsense. Phlebology. 2015;30(1 Suppl): 73–80. 91. Labropoulos N, Jasinski PT, Adrahtas D, et  al. A standardized ultrasound approach to pelvic congestion syndrome. Phlebology. 2017;32:608–619. 92. Soysal ME, Soysal S, Vicdan K, et al. A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion. Hum Reprod. 2001;16(5):931–939. 93. O’Brien MT, Gillespie DL. Diagnosis and treatment of the pelvic congestion syndrome. J Vasc Surg. 2015;3:96–106. 94. Velasquez CA, Saeyeldin A, Zafar MA, et al. A systematic review on management of nutcracker syndrome. J Vasc Surg. 2018;6: 271–278. 95. Erben Y, Gloviczki P, Kalra M, et al. Treatment of nutcracker syndrome with open and endovascular interventions. J Vasc Surg. 2015;3:389–396. 96. Borsook D. Neurological diseases and pain. Brain. 2012;135(Pt 2): 320–344. doi:10.1093/brain/awr271. 97. Bermejo PE, Oreja-Guevara C, Diez-Tejedor E. Pain in multiple sclerosis: prevalence, mechanisms, types and treatment. Rev Neurol. 2010;50:101–108.

References

98. Ford B. Pain in Parkinson’s disease. Mov Disord. 2010;25(Suppl 1): S98–103. 99. Bermejo PE, Oreja-Guevara C, Diez-Tejedor E. Pain in multiple sclerosis: prevalence, mechanisms, types and treatment. Rev Neurol. 2010;50:101–108. 100. Kumar B, Kalita J, Kumar G, et  al. Central poststroke pain: a review of pathophysiology and treatment. Anesth Analg. 2009;108: 1645–1657. 101. Franca Jr MC, D’Abreu A, Friedman JH, et al. Chronic pain in Machado-Joseph disease: a frequent and disabling symptom. Arch Neurol. 2007;64:1767–1770. 102. Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep. 2011;15:193–200. 103. Chen A, De E, Argoff C. Small fiber polyneuropathy is prevalent in patients experiencing complex chronic pelvic pain. Pain Med. 2019;20(3):521–527. doi:10.1093/pm/pny001. 104. Oaklander AL, Herzog ZD, Downs HM, et al. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310–2316. 105. Uceyler N, Sommer C. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136(Pt 6):1865–1867. 106. Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep. 2011;15: 193–200. 107. Peters MJ, Bakkers M, Merkies IS, et  al. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurol. 2013;81(15):1356–1360. doi:10.1212/WNL.0b013e3182a8236e. 108. Kim Y, Oh HC, Park JW, et  al. Diagnosis and treatment of inflammatory joint disease. Hip Pelvis. 2017;29(4):211–222. doi:10.5371/hp.2017.29.4.211. 109. Karim AA, Clayson AD, Jones AS. An unusual cause of apareunia. BMJ Case Rep. 2009. doi:10.1136/bcr.02.2009.1629 bcr02.2009.1629. 110. Fukunishi S, Fukui T, Nishio S, et al. Multiple pelvic insufficiency fractures in rheumatoid patients with mutilating changes. Orthop Rev (Pavia). 2009;1(2):e23. doi:10.4081/or.2009.e23. 111. Keller JJ, Liu SP, Lin HC. A case-control study on the association between rheumatoid arthritis and bladder pain syndrome/interstitial cystitis. Neurourol Urodyn. 2013;32(7):980–985. doi:10.1002/nau.22348. 112. Zhao J, Zheng W, Zhang C, et  al. Radiographic hip involvement in ankylosing spondylitis: factors associated with severe hip diseases. J Rheumatol. 2015;42(1):106–110. doi:10.3899/jrheum.140428. 113. van den Berge M, Vrugt B, Holt C, et al. Jicht als ongebruikelijke oorzaak van bekkenpijn [Gout as an unusual cause of pelvic pain]. Ned Tijdschr Geneeskd. 2006;150(3):151–154.

619.e3

114. Lin M, Thoelke M. Gout of the symphysis pubis, a rare pain in the pelvis. Abstract published at Hospital Medicine 2013, May 16-19, National Harbor, MD. Abstract 328. J Hosp Med. 2013;8(Suppl 2). 115. ACOG Committee. ACOG committee opinion no. 651. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2015;126(6):e143–e146. doi:10.1097/ AOG.0000000000001215. 116. Janssen EB, Rijkers AC, Hoppenbrouwers K, et al. Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review. Hum Reprod Update. 2013;19(5):570–582. doi:10.1093/humupd/dmt016. 117. Laufer MR. Helping “adult gynecologists” diagnose and treat adolescent endometriosis: reflections on my 20 years of personal experience. J Pediatr Adolesc Gynecol. 2011;24(5 Suppl):s13–s17. 118. Schroeder B, Sanfilippo JS, Hertweck SP. Musculoskeletal pelvic pain in a pediatric and adolescent gynecology practice. J Pediatr Adolesc Gynecol. 2000;13(2):90. doi:10.1016/s1083-3188(00)00019-x. 119. Breau LM, Burkitt C. Assessing pain in children with intellectual disabilities. Pain Res Manag. 2009;14(2):116–120. doi:10.1155/2009/642352. 120. McGuire BE, Kennedy S. Pain in people with an intellectual disability. Curr Opin Psychiatry. 2013;26(3):270–275. doi:10.1097/ YCO.0b013e32835fd74c. 121. Van Damme S, Crombez G, Eccleston C. Coping with pain: a motivational perspective. Pain. 2008;139:1–4. 122. Bryant C, Cockburn R, Plante AF, et al. The psychological profile of women presenting to a multidisciplinary clinic for chronic pelvic pain: high levels of psychological dysfunction and implications for practice. J Pain Res. 2016;9:1049–1056. 123. Maillé DL, Bergeron S, Lambert B. Body image in women with primary and secondary provoked vestibulodynia: a controlled study. J Sex Med. 2015;12(2):505–515. 124. Pak DJ, Yong RJ, Kaye AD, et al. Chronification of pain: mechanisms, current understanding, and clinical implications. Curr Pain Headache Rep. 2018;22(2). doi:10.1007/s11916-018-0666-8. 125. Voscopoulos C, Lema M. When does acute pain become chronic? Br J Anaesth. 2010;105(Suppl 1):i69–i85. doi:10.1093/bja/aeq323. 126. Diatchenko L, Nackley AG, Tchivileva IE, et al. Genetic architecture of human pain perception. Trend Genet. 2007;23(12):605– 613. doi:10.1016/j.tig.2007.09.004. 127. Sandkühler J, Lee J. How to erase memory traces of pain and fear. Trend Neurosci. 2013;36:343–352. 128. Hylands-White N, Duarte RV, Raphael JH. An overview of treatment approaches for chronic pain management. Rheumatol Int. 2016;37(1):29–42. doi:10.1007/s00296-016-3481-8.

10 43

Chapter to Go Here PediatricTitle Chronic Pain Management CHAPTER ANGELICAAUTHOR A. VARGAS, RAVI SHAH, BONNIE S. ESSNER, SANTHANAM SURESH

Chronic pain is a significant yet underreported problem in the pediatric population, with a prevalence of up to 25%–45%.1 It has psychological, emotional, and social implications for both the child and the family.2 Common pain related functional issues include sleep problems, inability to pursue hobbies, eating difficulties, school absence, and inability to interact with friends.1 The potential for such consequences to negatively impact a child’s quality of life has fostered the development of a multi-disciplinary approach to treat pediatric pain.3,4 A variety of behavioral, pharmacologic, and physical therapies are employed in pediatric chronic pain treatment regimens. Interventional procedures may be introduced after patients fail other treatment approaches.5 In this chapter, we discuss common chronic pain syndromes in children, along with their assessment, diagnosis, and management (Box 43.1). ~

Assessment of Chronic Pain in Children Assessment of children with chronic pain requires a biopsychosocial framework. Multidimensional models focus on various biologic, developmental, behavioral, affective, sociocultural, and situational factors that contribute to pain severity and the course to recovery.6,7 Each domain may become a target of assessment and intervention. Several developmentally sensitive validated instruments are now available to measure various aspects of children’s pain (Table 43.1). Two standardized interviews for school-age and adolescent children and their parents provided comprehensive yet practical evaluations of the child’s chronic pain: the Children’s Comprehensive Pain Questionnaire (CCPQ)8 and the Varni-Thompson Pediatric Pain Questionnaire. These interviews separately assess both the child’s and parents’ experiences of pain problems with open-ended questions, checklists, and quantitative pain rating scales. Some studies suggest potential limitations of these selfreport measures because of cultural or cognitive differences among children.9 Additionally, the Pain Behavior Observation Method is a 10 minute observational pain behavior measure that can be used in children with chronic pain who may have difficulty with selfreport measures because of age or cognitive limitations.10 Studies have supported the use of electronic versus paper pain diaries in children with chronic pain; electronic diary use was shown to be feasible and resulted in greater compliance and accuracy in diary recording than did traditional paper diaries in children with recurrent pain.11 The well documented comorbidity between pediatric chronic pain and psychiatric disorders,12 particularly internalizing disorders such as depression and anxiety,13 obligates the clinician to 620

screen for these disorders. The Children’s Depression Inventory (CDI)14 is a widely used self-report questionnaire for assessing depression in children aged seven to 17 years. It is important to assess anxiety symptoms because pain related disability is associated with anxiety sensitivity, a stable predisposition to fear of anxiety related sensations,15 and pain related avoidance behavior in children as well as adults with chronic pain.16 The Children’s Anxiety Sensitivity Index (CASI)15 is the only instrument developed to assess this characteristic in children. Several well validated self-report questionnaires assessed anxiety in children (see Table 43.1). Two instruments, the Self-Report for Child Anxiety Related Disorders (SCARED)17 and the Spence Children’s Anxiety Scale (SCAS),18 include subscales that distinguish among specific anxiety disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The Multidimensional Anxiety Scale for Children (MASC)19 and the Revised Children’s Manifest Anxiety Scale (RCMAS)20 include subscales that focus on other dimensions of anxiety. These subscales include physical symptoms, social and separation anxiety, and harm avoidance (the MASC) and physiologic symptoms, worry and oversensitivity, and concentration factors (the RCMAS), as well as social desirability items to detect inconsistency or randomness in reporting. The SCAS and SCARED provide both child and parent forms of the instrument, which allows examination of the convergence, or lack thereof, of the child’s and parents’ assessment of the child’s anxiety symptoms. Factors that are closely linked with a child’s ability to function with chronic pain, such as perceived stress21 and coping,22 can assist in planning behavioral interventions. The pain coping questionnaire (PCQ),23 pain response inventory (PRI),24 and pain catastrophizing scale for children (PCS-C)25 assess pain specific coping strategies. The identification and modification of maladaptive coping responses constitute the core elements of cognitive behavioral approaches for treating pediatric chronic pain. The ability to function in tasks of daily living is a critically important outcome measure to assess when treating children and adolescents with chronic pain. Frequently, pain cannot be completely relieved, and the child must learn to accept, cope, and adapt to the pain to enable participation in normal developmental activities and tasks, such as going to school, participating in extracurricular activities, and developing and sustaining social relationships. Several measures have been developed to assess a child’s functional abilities and quality of life. For example, the Pediatric Migraine Disability Scale (PedMIDAS) measures headache-related disability in children with chronic pain.26 This six-question tool assesses school, recreational, and social areas of participation and disability, domains relevant to all children with

• Box 43.1

Chronic Pain in Children: Common Diagnoses

• Neuropathic pain • Complex regional pain syndrome type 1 • Peripheral nerve injuries • Postamputation pain • Deafferentation pain • Headache • Chest pain • Chronic illness • Sickle cell crisis • Cystic fibrosis • Collagen vascular disease (e.g. juvenile rheumatoid arthritis, systemic lupus erythematosus) • Recurrent abdominal pain • Juvenile primary fibromyalgia • Pelvic pain • Back pain • Cancer-related pain

chronic pain. The Child Activity Limitations Interview (CALI)27 assesses the impact of recurrent pain on children’s daily activities as a way to identify appropriate targets for treatment. Additionally, the Functional Disability Inventory (FDI),28 developed to assess illness-related disability in children and adolescents, is a useful TABLE 43.1

 

CHAPTER 43

Pediatric Chronic Pain Management

621

tool for evaluating the functional status of pediatric patients with chronic pain, a particularly important concern in children with pain disorders associated with psychological factors and pain associated disability syndrome.29 Pain related disability increases with age, and sex differences emerge in adolescence, with more girls than boys reporting pain related functional disability.30 Quality of life can also be assessed in children and adolescents with chronic pain and as an index of treatment progress. One study found that the quality of life of children with recurrent headaches is similar to that of children with rheumatoid arthritis or cancer.31 The Child Health Questionnaire, including both children (CHQ-CF87) and parent reports (CHQ-50),32 and the PedsQL33 are measures that may be used to assess the general quality of life in children with chronic pain and have the advantage that the scores obtained on these instruments can be compared with standardized samples of scores obtained by children with other medical illnesses. Other instruments that may further elucidate the psychological factors contributing to a child’s behavioral adaptation to chronic pain include the Children’s Somatization Inventory (CSI),34 which measures a child’s propensity to somatization, and the Harter Scales of Perceived Competence,35 which assesses a child’s judgment about his or her capabilities in important domains such as school performance, peer relationships, and athletic abilities. The child’s own judgment of his or her competencies in these domains is useful in understanding other factors that may contribute to

Methods for Assessment of Chronic Pain in Children and Adolescents

Pain Measure

Disability or Quality of Life

Stress and Coping

Anxiety

Depression

Varni-Thompson Pediatric Pain Questionnaire (PPQ) Ages: 5–18

Functional Disability Inventory (FDI) Ages: 8–17 (plus parent form)

Children’s Hassles Scale (CHS) Ages: 8–17

Multidimensional Anxiety Scale for Children (MASC) Ages: 8–19

Children’s Depression Inventory (CDI) Ages: 7–17

Children’s Somatization Inventory (CSI) Ages: 8–18 (plus parent form)

Children’s Comprehensive Pain Questionnaire (CCPQ) Ages: 5–19

Child Health Questionnaire (CHQ) Ages: 5+ (plus parent form)

Pain Coping Questionnaire (PCQ) Ages: 8–18

Self-Report for Childhood Anxiety Related Disorders (SCARED) Ages: 9–18 (plus parent form)

Beck Depression Inventory-II Ages: 13+

Harter Scales of Perceived Competence for Children Ages: 4–12

Pain diary (written, electronic) Ages: 8+

Pediatric Quality of Life Inventory Generic Core Scales (PedsQL 4.0) Ages: 5–18 (plus parent report ages 2–18)

Pain Response Inventory (PRI) Ages: 8–19

Spence Children’s Anxiety Scale (SCAS) Ages: 8–12 (plus parent form)

Pain Behavior Observation Method Ages: 6–17

Pediatric Migraine Disability Assessment Scale (PedMIDAS) Ages: 6–18

Pain Catastrophizing Scale (PCS) Ages: 8-16

Revised Children’s Manifest Anxiety Scale (RCMAS) Ages: 6–19

Non-Communicating Children’s Pain Checklist (NCCPC-R) Ages: 2 years old to adult

Children’s Activity Limitations Scale (CALI) Ages: 8–16

State-Trait Anxiety Scale for Children (STAIC) Ages: 9–12 Childhood Anxiety Sensitivity Index (CASI) Ages: 7–12

Other Behavioral Measures

622

PA RT 4 Clinical Conditions: Evaluation and Treatment

the child’s functioning.36 For example, children with chronic pain who rate themselves as low on social and academic competency may have multiple reasons to avoid returning to school. A thorough assessment of a child’s baseline status and progress is essential to guide interventions for chronic pain and evaluate the response to treatment. The core elements of assessment include a comprehensive evaluation of the child’s pain problem and screening for psychiatric comorbidity and functional status (Box 43.2). More intensive screening of the child’s perceived stress and competencies and the parents’ and family’s functioning adds valuable information to treatment planning, especially in a child with long-standing pain problems who has not responded to previous treatment efforts.

Psychological Pain Management Methods A rehabilitative approach that emphasizes improving the child’s and family’s ability to cope with a chronic condition characterizes the course of most chronic pain treatment programs for children. The focus shifts from the narrow goal of pain reduction, which might be used in the treatment of acute pain, and broadens to decrease pain related emotional and behavioral disability, thereby increasing the child’s functional status.29,37 Research on the use of psychological therapies has focused mostly on clinical trials in children with headache.38,39 In a meta-analysis conducted to evaluate the efficacy of behavioral interventions for pediatric chronic pain, Eccleston et al.40 concluded “There is strong evidence that psychological treatment, primarily relaxation and cognitive behavioral therapy, are highly effective in reducing the severity and frequency of chronic pain in children and adolescents.” Additionally, findings by Logan et al. suggest that interdisciplinary pediatric pain rehabilitation may facilitate increased willingness to self-manage pain, which is associated with improvements in function and psychological wellbeing.39 Finally, promising psychological treatments have also been used for children with disease-related chronic pain, including sickle cell disease,41 recurrent abdominal pain,42 complex regional pain syndrome (CRPS) type 1,43 musculoskeletal pain,44 and juvenile primary fibromyalgia syndrome,45 and further support the probable efficacy of psychological approaches to pediatric pain management. These evidence-based psychological treatment programs are primarily rooted in cognitive behavior therapy (CBT) principles. Traditional CBT and more recent and emerging CBT variations, such as acceptance and commitment therapy, include a diverse array of standard intervention components that treat chronic pain by modifying children’s cognitive, affective, and sensory experiences of pain, their behavior in response to pain, and environmental and social factors that influence the pain experience. Education • Box 43.2

Pediatric Questionnaire Components

1. Developmental level 2. Understanding of pain 3. Pain and medical treatment history 4. Interactions with others in relation to pain 5. Affect and behavior 6. Impact of pain on functional abilities 7. Family environment and stress 8. Coping skills 9. History of psychiatric illness 10. Medical problems

about chronic pain and problem solving for improving the child’s functional status is central to the child and family, assuming an active role in managing chronic pain. Cognitive techniques are targeted at modifying the child’s thoughts about the pain, in particular, to increase a sense of predictability and control over the pain, to alter memories about painful experiences,46 and to reduce negative cognitions about pain, notably catastrophizing.47 Decreasing somatic preoccupation, pain related rumination,37 and passive coping and learning to accept that the pain may persist are also key interventional goals in the psychological management of pain.48 Please see Table 43.2 for sample components of CBT in the treatment of pediatric chronic pain. Techniques to alter the sensory aspects of chronic pain include relaxation training, biofeedback, imagery, and hypnosis. Interventions aimed at modifying situational factors that exacerbate chronic pain and disability include contingency or behavioral management methods, modification of activity and rest cycles to achieve a steady pace of activity, and a gradual, structured plan for exposing patients and families to situations previously avoided because of pain.37,48 Few analyses have been conducted to determine which components of psychological therapies may be essential in the management of pediatric chronic pain, but it is likely that for most chronic pain conditions, a combination of modalities will provide the best opportunity to affect the desired change. Changes in the emphasis of various behavioral components may present an opportunity to individualize treatment for a specific child by taking into account developmental, psychological, parental, and family factors, which may provide a way to tailor specific treatment to a child. There is growing acknowledgment of parents’ crucial role in the successful rehabilitation of children with chronic pain, and thus they are increasingly becoming included as active partners in their child’s treatment.49 Parental interactions with their child related to pain and the family characteristics of children with chronic pain that may be associated with the development of maladaptive coping with pain are areas of active research.50,51 Particular types of parental behaviors have been shown to influence a child’s ability to cope with pain. Walker et al.51 found that girls with functional abdominal pain are more vulnerable than boys to the symptom-reinforcing effects of parental attention. Interestingly, although the children with pain rated parental distraction as a helpful strategy, their parents rated distraction as having greater potential for a negative impact on their child than attention. Such findings help guide behavioral interventions for children with chronic pain and their families because parents’ beliefs in the most effective pain management strategies need to be targeted in any intervention designed to increase the functional abilities of children with chronic pain. Several methods for the delivery of psychological interventions for recurrent or chronic pain in children have been shown to be effective, including those that involve intensive inpatient or outpatient treatment; those that are self-administered,52 school-based,53 Internet-based,54,55 CD ROM-based56; and those that involve minimal clinic contact with home-based practice.55 The variety of methods for the delivery of these interventions offers opportunities to reach a broad population of children with chronic pain, thus increasing the potential to reach many more children than can be treated in specialized pediatric pain treatment centers. Optimally, the child’s school and other caretakers are included in the treatment team to ensure a consistent and comprehensive approach to the child’s pain and disability. The complex nature of chronic pain in children creates many challenges with regard to its assessment and treatment, but this

TABLE 43.2

 

CHAPTER 43

Pediatric Chronic Pain Management

623

Sample Components of Cognitive Behavioral Therapy for Pediatric Chronic Pain Treatment

Treatment Domain

Intervention Aims

Intervention Examples

Psychoeducation

• Enhance health literacy • Create positive treatment expectations and optimism for change

• Engaging didactic instruction on basic neuroscience of pain • Analogies describing how chronic pain operates as a faulty alarm and psychological treatments re-set pain signaling in the brain and body

Relaxation Practices

• Activate parasympathetic nervous system • Reduce emotional distress • Enhance self-efficacy

• Diaphragmatic breathing • Progressive muscle relaxation • Guided imagery

Cognitive Skills

• Increase awareness of cognitive patterns • Adopt adaptive thinking patterns • Neutralize affective response to thoughts

• Thought record and detective thinking for self-monitoring of thoughtemotion-pain-action patterns • Didactic instruction on cognitive distortions and thinking traps • Cognitive reframing and positive reappraisal practices • Cognitive defusion practices

Behavior Change Skills

• Promote adaptive physical activity • Increase daily developmentally adaptive daily activities • Enhance healthy behaviors

• Graduated exposure to experiences and environments associated with pain exacerbation and distress • Structured physical activity pacing and behavioral activation strategies • Graduated improvements to diet and eating behaviors • Graduated implementation of behavioral sleep medicine principles to decrease nighttime cognitive arousal

Family-focused Skills

• Enhance general family functioning • Promote adaptive parent responses to pain • Improve family communication patterns

• • • •

complexity can be exploited to provide the most efficacious methods for pain control and functional rehabilitation. Multidimensional assessment provides the foundation for optimal pain management and functional rehabilitation of chronic pain in children. Psychological interventions include a diverse array of techniques that treat chronic pain by modifying children’s cognitive, affective, and sensory experiences of pain, their behavior in response to pain, and environmental and interactional factors that influence the pain experience. Medical treatment of a child’s chronic pain may result in poorer outcomes without addressing the psychobehavioral factors that may contribute to pain and pain related disability. Research informed by multidimensional models of pediatric chronic pain can guide investigators in efforts to identify effective pain treatments, as well as the children for whom they work best.

Integrative Medicine Techniques It has been reported that nearly 75% of pediatric patients, particularly those with chronic health disorders, have used some form of complementary and alternative medicine.57 A few of the tenets of integrative medicine (IM) include an emphasis on preventative health and lifestyle as well as a consideration of all dimensions of health, including body, mind, and spirit. These concepts make this field a promising adjunct for the treatment of pediatric chronic pain. Data regarding the implementation of IM in pediatric pain practice are limited to headache management and irritable bowel syndrome/functional abdominal pain syndrome. Despite this, a recent study found that it was common for pediatric pain clinics to provide IM, including acupuncture, mind-body therapies, massage, aromatherapy, nutrition counseling, and/or art/music therapy.58 We frequently recommend these therapies to our patients, as well as other techniques such

Operant strategies for rewarding adaptive behavior changes Promote parent and family modeling of adaptive coping with pain and distress Communication strategies Structured problem solving skills training

as vitamin supplements/herbal remedies, chiropractic manipulation, and biofeedback.

Chronic Pain Syndromes We will briefly discuss the diagnosis and management of some common chronic pain syndromes diagnosed in pediatric patients referred to chronic pain clinics. The introduction of multidisciplinary pediatric pain clinics has allowed children to be seen in a single office visit by several consultants who can provide services for the child and develop a comprehensive pain management plan. An example of this model includes an anesthesiologist specializing in pain management, a pediatric pain psychologist, a physical therapist, a complementary medicine practitioner (including massage therapy and acupuncture therapy), and a specialist in biofeedback. This comprehensive approach reduces the need for multiple visits and exposes patients to a multimodal therapeutic approach. Common pain syndromes in children include CRPS type I, headache, abdominal pain, juvenile primary fibromyalgia, chest wall pain, back pain, pelvic pain, and cancer-related pain. We address each of these conditions with a specific emphasis on accepted current therapy.

Complex Regional Pain Syndrome CRPS type I or reflex sympathetic dystrophy (RSD), as originally named, is a complex syndrome consisting of neuropathic pain symptoms including allodynia and hyperalgesia, sudomotor dysfunction, and motor/trophic changes. In the pediatric population, it occurs more commonly in the lower extremity,59 with a female preponderance.60 Significant trauma is found with less frequency than in the adult population.60 Though there is a case report

624

PA RT 4 Clinical Conditions: Evaluation and Treatment

involving a two and half-year-old girl,61 it is generally seen in children older than nine years and more frequently in adolescents 11–13 years of age.62 Compared to adults, children are thought to better respond to non-invasive and treatment strategies and have a more favorable prognosis with treatment.43 However, early recognition and management are the major factors in improving outcomes and preventing resistant CRPS.63 Data regarding the epidemiology of CRPS type I is limited, though case reports exist describing pain in the sciatic distribution patients as young as three years old.64,65

TABLE 43.3

Symptoms and Changes in Stages of Chronic Regional Pain Syndrome Type 1

Characteristic

Acute

Dystrophic

Pain

Hyperpathic, burning

Chronic

Blood flow

Increased

Decreased

No change

Temperature

Increased

Decreased

No change

Evaluation of Complex Regional Pain Syndrome I

Hair and nail growth

Increased

Decreased

Chronic change

History

Sweating

Decreased

Increased

No change

Edema

None

Brawny edema

Wasted muscles, atrophic skin

Color

Red

Cyanotic

Atrophic

A detailed history of the nature of the injury, the type and duration of the pain, relieving and aggravating factors, and dependence on medications is mandatory before evaluation.

Physical Evaluation

Thorough and systematic neurologic examination should be performed. Complete evaluation of the motor, sensory, cerebellar, cranial nerve, reflex, cognitive, and emotional functioning should be conducted. A concerted effort must be made to rule out a rare but possible malignancy or central degenerative disorder that may include laboratory evaluation, imaging such as X-rays, magnetic resonance imaging (MRI), or computed tomography (CT), or electromyography of the affected limb. The strength of the extremities should be evaluated on several occasions. It is important to compare it with the strength in the contralateral extremity because CRPS I can occur in both extremities at the same time. Allodynia, pain to a stimulus that is not typically painful, is a common finding. Hyperalgesia, an increased painful response, is also common, particularly to cold sensation.66 Similarly, in adults, distribution is not generally restricted to particular dermatomes and commonly occurs along a glove-andstocking distribution. Although nerve conduction studies may provide insight into a specific nerve injury, sensory abnormalities appear in different combinations in patients despite similar clinical presentations pointing to a central origin of pathogenesis.67 Quantitative sensory testing (QST) with thermal and vibration sensations and thermal pain detection thresholds in the affected limbs can be compared with data from normal healthy children. Although this involves cumbersome equipment, bedside QST may play a greater role in the diagnosis of CRPS I in children and adolescents.68 Bone scans may be helpful in the diagnosis of CRPS. However, there is limited data on their diagnostic accuracy in children. A decrease in isotope uptake was observed with suspected CRPS I.

Diagnosis

The diagnosis of CRPS I in children was based on symptoms and signs (Table 43.3). The characteristics of pain and sensory, motor, and sudomotor changes may vary among patients. The 1994 International Association for the Study of Pain (IASP) criteria for CRPS I and the 2003 Budapest criteria can be applied to children and adolescents (see Box 43.3a and 43.3b). However, it should be noted that although the Budapest criteria have been found to have nearly 100% sensitivity and 70%–80% specificity in the adult population, these criteria have not been validated in the pediatric population. Treatment of CRPS I. Treatment of CRPS should be immediate and directed toward restoration of extremity function and rehabilitation.69 Management of CRPS (Box 43.4) can be frustrating

Atrophic

for the caregiver and the patient as no single therapy can uniformly provide relief to these patients. The treatment plan should be multidisciplinary in nature. Although medications can be prescribed and procedure-based treatments may be performed in children, rehabilitative treatments show the best evidence for positive outcomes. Logan et al. studied the effects of an intensive, multi-disciplinary model of daily cognitive behavioral and physical occupation therapies with medical and nursing services for pediatric CRPS over a three week timespan39 and found that patients experienced significantly decreased pain perception, improved functional ability and limb function, and improved emotional functioning. One of the primary goals is to return the child to a functional state and school, as a definitive resolution of the pain is not always possible. Most management techniques have been extrapolated from work done in adult patients.70 It is imperative to build trust with the patient and the parents. Family dynamics are important because the added burden of familial disharmony or parental abuse can worsen the symptoms. There seems to be a greater propensity for enmeshment in these families. Psychological and Behavioral Therapy

Psychologic therapies are a pillar in the treatment of pediatric CRPS and may require the expertise of a pain psychologist. Although no one therapy has been proven to be the “gold standard,” CBT is generally the accepted treatment strategy. Other • Box 43.3a

International Association for the Study of Pain Diagnostic Criteria for Complex Regional Pain Syndrome

1. Presence of an initiating noxious event or cause of immobilization 2. Continuous pain, allodynia, or hyperalgesia in which the pain is disproportionate to any known inciting event 3. Evidence at some time of edema, changes in blood flow, or abnormal sudomotor activity in the region of pain 4. Diagnosis excluded by the existence of other conditions that would otherwise account for the degree of pain and dysfunction Adapted from Bruehl S, Harden RN, Galer BS, et al. External validation of the IASP diagnostic criteria for complex regional pain syndrome and proposed research diagnostic criteria International Association for the Study of Pain. Pain. 1999;81:147–154.

• Box 43.3b

Budapest Criteria

Budapest Criteria for Complex Regional Pain Syndrome 1. Continuing pain, which is disproportionate to any inciting event 2. Must report at least one symptom in three of four of the following categories Sensory

Reports of hyperesthesia and/or allodynia

Vasomotor

Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry

Sudomotor/edema

Reports of edema and/or sweating changes and/or sweating asymmetry

Motor/trophic

Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

3. Must display at least one sign at time of evaluation in two or more of the following categories Sensory

Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)

Vasomotor

Vasomotor: evidence of temperature asymmetry (>0.6°C) and/or skin color changes and/or asymmetry

Sudomotor/edema

Sudomotor/edema: evidence of edema and/or sweating changes and/or sweating asymmetry

Motor/trophic

Evidence of a decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/ or trophic changes (hair, nail, skin)

4. There is no other diagnosis that better explains the signs and symptoms Reproduced with permission: Harden RN, Bruehl S, Perez RSGM, et al. Validation of proposed diagnostic criteria (the "Budapest criteria") for complex regional pain syndrome. Pain. 2010;150(2):268-74.

Physical Therapy

Physical therapy is geared toward the adequate functional ability of the child. Transcutaneous electrical nerve stimulation (TENS) is widely used, and its efficacy has been studied in adults and children. The therapeutic benefits of TENS in children with RSD have been reported by Kesler et al.,72 who used TENS regularly in their practice, along with physical therapy, which consists of both active and passive physical modalities. The physical therapy program is geared toward individual patients, with the primary goal of maximum participation. It may be necessary to have input from a specialized pediatric physical therapist or occupational therapist for adequate management. Commonly used treatment options for CRPS include desensitization, graduated weight bearing, exercise therapy, graded motor imagery, warm and cold baths, massage therapy, and water emersion therapy.

Pediatric Chronic Pain Management

625

Medical Therapy

Most medical treatment strategies for children have been extrapolated from adult data. These include pharmacotherapy, regional anesthetics, sympathetic blockade, and neuromodulation. Over counter medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are typically trialed by patients and families for initial pain treatment. However, there are mixed data regarding their efficacy.62 Anti-neuropathic pain medications can be trialed sequentially, although toxicities and side effects should be monitored closely in pediatric patients (see Box 43.4). Tricyclic Anti-depressants.  Adults are frequently prescribed tricyclic anti-depressants (TCAs) for the management of NP.73 Despite the lack of adequately controlled studies in pediatric patients, TCAs are widely prescribed for several forms of NP.74 Because amitriptyline may cause sedation, it is our practice to use nortriptyline, which appears to have less sedative and fewer anticholinergic side effects. A thorough examination of the cardiovascular system is necessary before instituting TCA treatment because of associated tachydysrhythmia and other conduction abnormalities of the heart, particularly prolonged QT syndrome.75,76 Anti-convulsants. Anti-convulsant medications have been used for several years to manage NP.77 Although carbamazepine and oxcarbazepine have been used extensively to treat NP, the introduction of gabapentin and pregabalin has revolutionized the world of pain medicine.78–80 Despite the lack of controlled trials in children to demonstrate the efficacy of either drug, both of these voltage-gated calcium channel blockers have been used in our clinic with promising results. More controlled trials are needed to better determine the dosing and efficacy of this class of drugs in children with CRPS 1.80 An important side effect that we have noted in our clinic setting is the potential for increased somnolence and the potential for weight gain. Similar to other anti-convulsant medications, there are concerns regarding mood changes and increased agitation and aggression in adolescents taking gabapentinoids. As such, the Food and Drug Administration • Box 43.4

techniques, including biofeedback, visual guided imagery, and structured counseling, have been shown to assist in the development of adequate coping skills.71 Participation in a day program for acute psychological intervention has been valuable for some of our patients, specifically those with significant psychiatric coillness. More detailed explanations of the various psychological interventions have been provided in a previous section.

 

CHAPTER 43

Management of Neuropathic Pain

1. Nonpharmacologic Treatment Hypnosis, biofeedback, visual guided imagery TENS, physical therapy, occupational therapy Individual and family therapy (day program if required) 2. Pharmacologic Therapy Acetaminophen, NSAIDs Tricyclic anti-depressants (e.g. amitriptyline, nortriptyline, doxepin); start at low doses, 0.1 mg/kg, and advance slowly Anti-convulsants (gabapentin, pregabalin, carbamazepine, phenytoin, and clonazepam), systemic local anesthetics (mexiletine, lidocaine) Serotonin and norepinephrine reuptake inhibitors Opioids (morphine, methadone administered orally, intravenously, or via a regional technique [epidural or intrathecal], especially in cancer patients) 3. Regional Blockades for Chronic Pain Epidural, subarachnoid and sympathetic plexus, peripheral catheter blockade Sympathetic blockade for CRPS 1 Continuous catheter techniques may be used for five to seven days Epidural and subarachnoid block for cancer patients: left in place for longer periods by subcutaneous tunneling Neurolytic blockade for cancer CRPS, Complex regional pain syndrome; NSAIDs, nonsteroidal anti-inflammatory drugs; TENS, transcutaneous electrical nerve stimulation.

626

PA RT 4 Clinical Conditions: Evaluation and Treatment

(FDA) has issued a warning for increased suicidiality81 with these medications, and families should be counseled prior to initiating therapy. Selective Serotonin Reuptake Inhibitors and SerotoninNorepinephrine Reuptake Inhibitors. Despite the lack of proven efficacy of the use of selective serotonin reuptake inhibitors in the management of pain in children and adolescents, they are occasionally used to treat psychological comorbidities, including depression associated with pain.82 More recently, serotonin-norepinephrine reuptake inhibitors have been successfully used to treat NP, especially in patients with psychological comorbidity.83 Systemic Vasodilators.  Several patients with RSD have benefited from the use of vasodilators such as prazosin, nifedipine, and phenoxybenzamine. However, the overwhelming adverse effects of orthostatic hypotension often offset the efficacy of this therapy. Regional Anesthesia and Sympathetic Blocks. A common treatment for these syndromes is to interrupt the apparent pathologic reflexes by performing sympathetic blocks (Box 43.5). Regional anesthesia, although used often in adults for the diagnosis and management of CRPS, is generally introduced in children after pharmacologic, physical therapy, and cognitive behavior management have been exhausted.5 Recently, Zerkinow et al. synthesized a review of invasive procedures for children between 8 and 15 years of age with complex regional pain syndromes. They found 36 studies with a total of 173 patients who underwent a procedure, and the procedures varied depending on the decade they were performed. Because of the poor quality of the studies and lack of control, the effectiveness of invasive therapies in pediatric CRPS remains uncertain, and further randomized controlled studies are required.84 In this section, we discuss the different regional techniques that can be useful in children for the management of CRPS. Central neuraxial blockade is used in children with severe pain to facilitate the introduction of physical therapy. An indwelling epidural catheter is placed in the lumbar or cervical area and infused with a low-concentration local anesthetic solution, which allows better cooperation from the patient and the parents to introduce a physical therapy regimen. In addition, intrathecal analgesia has been reported to be an effective method for treating refractory CRPS 1 in children.85,86 Bier block has been used for mild to moderate cases of CRPS 1 as a primary modality for providing analgesia and sympathetic blockade. Although a myriad of substances have been used to provide a Bier block, a local anesthetic in combination with either an α2-agonist or an NSAID appears to produce better results. In our case series of children who received intravenous regional anesthesia with lidocaine and ketorolac, we demonstrated a marked improvement in symptoms and the ability to perform physical therapy.70 • Box 43.5

Peripheral nerve blocks are used to facilitate physical therapy while providing a sympathectomy and have become more plausible, especially with the use of ultrasound guidance.87 Serial peripheral nerve blocks may be performed, which provides pain relief that may outlast the duration of conduction blockade. This may be because of reduced central sensitization, as well as interruption of the circuit established between the nociceptor, central nervous system, and motor unit.88 Continuous peripheral nerve blocks (CPNBs) have been reported to be effective in controlling pain and facilitating physical therapy in children with CRPS.89 Despite such reports, limited data exist regarding the feasibility, safety, and efficacy of CPNBs in children.90 After perineural catheter placement, a dilute solution of local anesthetic is infused with the view of providing analgesia while allowing physical activity. The catheter is left in place for four to five days; this can be done on an inpatient basis, or the patient may be sent home with a portable infusion device. We prefer sciatic nerve catheter placement for the lower extremities (see Fig. 43.1) and interscalene or infraclavicular brachial plexus catheters for the upper extremities. Concurrent physical therapy is indicated to improve the range of motion and function. We instituted physical therapy at the time of provision of a nerve block to enhance the patient’s experience with therapy. Sympathetic blockade was used in children after exhausting the aforementioned techniques. A stellate ganglion block may be performed under ultrasound guidance for upper extremity CRPS (see Fig. 43.2), and a lumbar sympathetic block is performed

Regional Anesthesia for Complex Regional Pain Syndrome Type 1

• Intravenous regional anesthesia-guanethidine, bretylium, lidocaineketorolac • Epidural analgesia (continuous) • Intrathecal analgesia • Sympathetic chain blocks • Stellate ganglion blocks • Lumbar sympathetic blocks • Brachial plexus catheters • Sciatic nerve catheters

• Figure 43.1  Sciatic nerve catheter for the management of complex regional pain syndrome type 1.

Th

IJ

CA Tr E LC

Tr = trachea Th = thyroid E = esophagus CA = carotid artery

IJ = internal jugular vein LC = longus coli muscle = stellate ganglion = needle

• Figure 43.2  Image of ultrasound guided stellate ganglion blockade. under fluoroscopic guidance for lower extremity CRPS.91 A crossover trial of fluoroscopically guided lumbar sympathetic blocks demonstrated a decrease in allodynia and pain intensity compared with intravenous injection of lidocaine in adolescents with CRPS.92 Neuromodulation via spinal cord stimulation, though commonly performed in adults for refractory cases of CRPS, is very rarely used in the pediatric setting.93 Spinal cord stimulation has been reported to achieve favorable outcomes in adolescents with therapy-resistant CRPS.94 The use of peripheral nerve stimulators is gaining ground in the pediatric setting and may benefit children with refractory CRPS with a nerve distribution.

Headaches Headaches are common in children and adolescents. Few physicians discussed headaches in children until 1873, when William Henry Day, a British pediatrician, devoted a chapter to the subject of headaches in his book Essays on Diseases in Children.95 Modern medical literature and the study of pediatric headaches have grown significantly. In 1962, Bille published a landmark study of 9000 children, showing reported migraine headaches in 3.9% of children younger than 12 years and a 6.8% incidence of nonmigrainous headaches daily.96 Since then, the reported incidence has grown. In a meta-analysis of 27,000 children between 1977 and 1991, it was reported that up to 51% of children experienced a significant headache by the age of 7 years, which gradually increased to nearly 82% by age 15 years.97 Most headaches in children are linked to either organic or nonorganic causes and may be deemed acute or chronic based on the duration of the headaches. Chronic daily headache is classified as a headache that occurs at least 15 times monthly for three months and can last for more than 4 hours daily.98

Evaluation of Headache A thorough history and physical examination helped determine the nature of the headache. Specific questions about neurologic symptoms, such as ataxia, lethargy, seizures, and visual impairment, should be asked. Other medical conditions, such as hypertension, sinusitis, and emotional disturbances, must be evaluated. Physical examination, including a thorough neurologic examination and blood pressure measurement, is mandatory for children with

 

CHAPTER 43

Pediatric Chronic Pain Management

627

headaches. Neuroimaging may be required, and lumbar puncture may be advised in some cases. Benign intracranial hypertension or idiopathic intracranial hypertension is a constellation of symptoms and signs, including headaches, diplopia, tinnitus, and eye pain. These conditions usually have normal imaging results.99 Although a diagnostic lumbar puncture may be needed in some settings, patients with chronic daily headaches may be prone to post-lumbar puncture headaches.99

Pathophysiology of Headache Headache is modulated by extracranial and intracranial structures (Box 43.6).

Classification of Headache Classification of headaches is based on the presumed location of the abnormality, its origin, its pathophysiology, or the symptom complex that the patient has (Box 43.7). • Box 43.6

Pathophysiology of Headache

1. Pain-Sensitive Headache • Extracranial • Skin • Subcutaneous tissue • Muscles • Mucous membranes • Teeth • Larger vessels • Intracranial • Vascular sinuses • Larger veins • Dura surrounding the veins • Dural arteries • Arteries at the base of the brain 2. Pain-Insensitive Headache • Brain • Cranium • Most of the dura • Ependyma • Choroid plexus

• Box 43.7

Classification of Headaches: Differential Diagnosis

Acute headache Systemic illness Subarachnoid hemorrhage Trauma Toxins such as lead or carbon monoxide Electrolyte imbalances Hypertension Acute recurrent headache Migraine Tension headache Chronic progressive headaches Organic brain disease Ventriculoperitoneal shunt malfunction Chronic nonprogressive headache Functional in quality Mixed headache

628

PA RT 4 Clinical Conditions: Evaluation and Treatment

Evaluation of Headache Comorbid symptoms are associated with headaches. Sleep deprivation is the most common comorbidity. Delayed sleep is a frequent disorder observed in children with headaches. Many also have symptoms of dizziness, which may be associated with postural hypotension and tachycardia (postural orthostatic tachycardia syndrome). Orthostatic hypotension should be treated by increasing fluid intake, and in some cases, a β-blocker may be needed. A history of a new-onset severe headache, pain that awakens a child from sleep, headaches associated with straining, changes in chronic headache patterns, or the presence of a headache accompanied by nausea or vomiting suggests a more pathologic origin of the headache and must be carefully evaluated (Box 43.8). It is imperative to evaluate any relevant neuroimaging studies before the patient’s appointment in the pain clinic. After establishing that the headaches are not secondary to any intracranial pathology, the following information is obtained: 1. Neurologic status, including a complete neurologic examination. 2. Physical/functional status of the patient. 3. Does the headache prevent the child from performing normal activities (e.g. interacting with others and participating in sports)? 4. Is there a history of school absenteeism? 5. What is the child’s interaction with the parents and siblings at home? 6. Are there any factors that relieve the headache? 7. Has the child been taking medications for pain? Has there been any improvement in the clinical characteristics of the pain? 8. Are postural changes associated with headaches? Is there a diurnal variation in headaches? 9. Family history is crucial in these children; a family history of migraine is suggestive of childhood migraine. After careful evaluation and classification of the type of headache, treatment is initiated in a stepwise fashion. An example of an algorithm for the management of headaches is presented in Fig. 43.3. Patients with migraine headaches are frequently managed by neurologists and are referred to the pain clinic only in refractory cases. We have intervened in providing peripheral nerve blocks for headaches. A trigeminal nerve block for frontal headaches and occipital nerve blocks for persistent occipital pain have been shown to be effective in children.100

• Box 43.8

Evaluation for Headache

1. General Physical Examination Blood pressure, postural hypotension Careful skin examination for café-au-lait spots, adenoma sebaceum, hypopigmented lesions, petechiae 2. Neurologic Examination Cranial circumference measurement Bruit on auscultation of the cranium Tenderness in the sinuses or presence of occult trauma indicating a battered child Funduscopic examination- optic atrophy, papilledema Cranial nerve examination for the presence of damage Mental status Alteration in language skills Alteration in gait Cranial nerve examination 3. Laboratory Tests Electroencephalography-very non-specific Computed tomography scan, especially with contrast enhancement, may be useful in determining vascular abnormalities. Magnetic resonance imaging- best for delineating abnormalities in the sella turcica, posterior fossa, and temporal lobes Lumbar puncture helpful in determining acute infectious causes Psychological tests to determine whether the headache has a psychological basis Tilt test- if postural hypotension is present (postural orthostatic tachycardia syndrome) Angiography (venous or arterial) if intracranial pathology is suspected.

A tension-type headache is perhaps the most common type of headache that we observed in our pain clinic. These patients frequently complain of debilitating frontotemporal or frontoparietal headaches. Headaches result from contraction of the temporalis muscle and tension on the scalp muscle.101 Management of tension-type headaches includes the use of relaxation techniques, as well as biofeedback. These patients frequently benefit from the routine use of nonsteroidal agents.102 Migraine headaches can be treated with abortive medications such as triptans or with common analgesics, including acetaminophen, aspirin, ibuprofen, naproxen, or opioids such as hydrocodone or tramadol. Medication overuse headache can occur with the

Headache

Organic cause

Non-organic cause

Neurosurgical consult Diagnostic imaging Surgical management

Diagnostic imaging Neurology evaluation

Pathology

Complementar y therapy Acupuncture Massage therapy

Cognitive-behavior therapy Biofeedback Guided imager y

No pathology

Pharmacotherapy Peripheral nerve blockade Frontal: Trigeminal blocks Occipital: Occipital nerve blocks

• Figure 43.3  Algorithm for the management of headaches. If the patient experiences nausea, vomiting, or other signs of increased intracranial pressure, neurosurgical consultation should be obtained.

 

CHAPTER 43

Pediatric Chronic Pain Management

629

frequent use of these medications and can occur if medication use is more than 10 days per month or more than 15 days per month for a period greater than three months.103 In these cases, preventative medications should be considered, such as propranolol, amitriptyline, topiramate, or similar medications. OnabotulinumtoxinA and erenumab-aooe are injectable medications that have been approved for the prevention of migraines. However, studies regarding its efficacy in pediatric patients are lacking.104 Children occasionally have persistent neuropathic headaches. This commonly occurs in patients who have undergone ventriculoperitoneal shunt revision or surgical decompression for Chiari malformation. After CBT, we attempted to use serial peripheral nerve blocks in these patients. This includes trigeminal nerve blocks for the frontal and occipital nerve blocks for occipital headaches. An ultrasound guided approach to the occipital nerve allows easy access to the C2 nerve root, thereby providing a more robust blockade than can be achieved with a peripheral subcutaneous injection.105 Local anesthetic is injected with or without a small dose of steroid to provide analgesia.

inhibitors and serotonin-norepinephrine reuptake inhibitors have also been tested in JPFS, given the high prevalence of comorbid depression and anxiety. However, the “black box warning” for suicidal ideation in adolescents with a history of major depressive disorder should be considered and monitored with close parental and psychiatric follow up.109 Opioid antagonists, such as low dose naltrexone, have been actively researched in recent years for the treatment of adult fibromyalgia syndrome. It is hypothesized that low doses of naltrexone, 1–5 mg daily, inhibit glial inflammatory response by Toll-like receptor 4 modulation and systemically upregulate endogenous opioid providing analgesia. In adults, it has been shown to decrease pain and anxiety and improve sleeping habits from baseline after a three month treatment period.110 Typical doses range from 1–5 mg daily. Despite a lack of studies on its use in pediatric patients, it has a relatively low side effect profile and relative tolerability by patients, making it an ideal adjunct in the treatment of JPFS. Other medications that have been trialed without variable support include gabapentinoids, muscle relaxers, and nonsteroidal anti-inflammatory drugs.

Juvenile Primary Fibromyalgia Syndrome

Abdominal Pain

Juvenile primary fibromyalgia syndrome (JPFS) is an idiopathic pain syndrome that affects up to 6% of children and adolescents.106,107 It is a condition characterized by chronic widespread musculoskeletal pain, sleep disturbance, fatigue, and multiple discrete tender points to palpation. Clinical diagnosis is based on history, physical examination, the absence of other pathologic conditions that would explain fatigue and pain, and normal laboratory workup. Other associated symptoms include chronic anxiety, chronic headaches, soft tissue swelling, and pain modulated by physical activity, weather, and emotional stress.108 There is significant morbidity associated with JPFS, including poor school attendance, difficult physical functioning, poor social acceptance, and comorbid mood disorders.107 Adolescent patients with JPFS have a high likelihood of continuing symptoms into adulthood.28 It most frequently affects adolescents between 10 and 15 years of age and has a propensity to affect females more than males.106

Diagnosis of Juvenile Primary Fibromyalgia Syndrome

Previously, the diagnosis of JPFS was made using the Yunus and Masi 1985 criteria, including three months of associated fatigue, sleepy difficulty, anxiety, and painful tender points on examination.107 However, it lacked validation and critical analysis. In 2010, Wolfe et al. proposed criteria for adult fibromyalgia that included the Widespread Pain Index (WPI) and Symptom Severity (SS) Scale for key symptoms of fibromyalgia Table 43.4. This has been found to be an effective screening and diagnostic tool in the adolescent female population with JPFS and is the diagnostic tool utilized in our clinic.

Treatment of Juvenile Primary Fibromyalgia Syndrome

A multi-disciplinary model is the most accepted treatment strategy for JPFS. This includes biobehavioral, pharmacologic, and exercisebased modalities. Psychological therapies, most prominently CBT, have significant evidence demonstrating efficacy in the treatment of JPFS. There is a paucity of data regarding the pharmacologic treatment of JPFS. Various medication classes have been trialed in treating JPFS. However, efficacy data remain limited.106 As such, pharmacologic treatment strategies are extrapolated from validated adult studies. Tricyclic anti-depressants (TCA), most notably amitriptyline, have been found to be effective in several parameters in adult fibromyalgia syndrome. Selective serotonin reuptake

Abdominal pain is a frequently encountered problem in infants, children, and adolescents. When evaluating abdominal pain, it is imperative that all organic causes are eliminated. Abdominal pain may be classified as visceral, parietal, or functional.111 Functional abdominal pain (FAP) is defined as pain unrelated to an identifiable organic gastrointestinal disorder.112 Once a diagnosis of FAP is established, CBT along with family centered therapy has proven effective.113 Several authors have described an affective component of FAP.114 Furthermore, Walker et al. suggested that children with FAP are at increased risk for the development of chronic pain in adulthood.115 This may be because of mechanisms linked to heightened central sensitization. Amitriptyline has been described as an effective treatment for FAP in children, although a randomized prospective trial demonstrated no significant difference between control and amitriptyline.116 Diagnosis of anterior cutaneous nerve entrapment syndrome (ACNES) is often missed because of the focus on the visceral system as well as misdiagnosis of FAP.111 However, Siawash et al. found that ACNES was present in 13% of pediatric patients with abdominal pain.117 Pain can often be superficially localized and described as a stabbing or burning sensation. Given that it is primarily a condition of the abdominal wall, the pain can be aggravated by daily activities such as running or cycling. Commonly, patients show a positive Carnett sign, which involves increased tenderness in painful locations with muscle tension.117 Serial nerve blocks in children with abdominal pain, particularly those in whom NP develops after abdominal surgery. The use of serially performed ultrasound guided rectus sheath blocks or transversus abdominis plane blocks has decreased abdominal pain in our cohort as well as in patients with ACNES.118 By blocking the thoracolumbar nerve roots, analgesia is provided to the anterior abdominal wall (see Fig. 43.4). Ilioinguinal neuralgia following hernia repair is an underreported cause of abdominal pain in older children and adolescents119 and is probably secondary to major dissection during surgery. TENS may be helpful, and peripheral nerve blocks can be used to manage pain. Serial ultrasound guided ilioinguinal nerve blocks have been demonstrated to be effective.120 A perineural catheter may be left in place in severe cases. Implantable peripheral nerve stimulation for inguinal post-surgical neuralgias

630

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 43.4

Widespread Pain Index (WPI) and Symptom Severity (SS) in the Diagnosis of Fibromyalgia

Widespread Pain Index A.  Have you had pain in the following location in the last week? Shoulder, right

Shoulder, left

Upper arm, right

Upper arm, left

Lower arm, right

Lower arm, left

Hip (buttock), right

Hip, left buttock

Upper leg, right

Upper, left

Lower leg, right

Lower leg, left

Jaw, right

Jaw, left

Chest

Abdomen

Upper back

Lower back

Neck

Symptom Severity (SS) B.  How much of a problem have the following been for you during the past week? No problem

Slight mild problem, generally mild or intermittent

Moderate, considerable problem, often present

Severe, pervasive, continuous, life disturbing problem

Fatigue

0

1

2

3

Waking still feeling tired

0

1

2

3

Concentration or memory problems

0

1

2

3

C.  Have you had problems with any of the following during the past three months? Muscle pain

Headache

Sun sensitivity

Chest Pain

Muscle weakness

Dizziness

Blurred vision

Hair loss

Numbness/tingling

Shortness of breath

Loss/changes in taste

Fever

Irritable bowl syndrome

Nervousness

Hearing difficulties

Thinking problems

Abdominal pain/cramps

Depression

Ringing in the ears

Dry mouth

Diarrhea

Fatigue/tiredness

Easy bruising

Dry eyes

Constipation

Insomnia

Frequent urination

Itching

Heartburn

Loss of appetite

Bladder spasms

Wheezing

Vomiting

Rash

Painful urination

Oral Ulcers

Nausea

Hives/welts

Seizures

Raynaud’s

Part C Score: O = No symptoms, 1 = Few symptoms, 2 = Moderate number of symptoms, 3 = Many symptoms WPI = A Score SS = B Score + C Score Fibromyalgia if WPI greater than or equal to 7 and SS greater than or equal to 5 or WPI 3–6 and SS greater than or equal to 9.

has promising results in the adult population. However, data are limited in pediatrics.121

Chest Pain Chest pain is a common symptom in older children and adolescents. A study conducted in Belgium reported a greater preponderance in men.122 Most children encountered in the emergency department complained of chest tightness with pain located lateral to the sternum.123 In a study of 96 patients with a mean age of 13 years, 37% had idiopathic chest pain. A major life event, such

as a family divorce or death of a relative, was a significant factor predisposing to chest pain in more than 30% of these children.124

Causes of Chest Pain The most common causes of chest pain include chest wall pain (64.5%), cardiac (5%), respiratory (13%), gastrointestinal (3%), psychological (9%), and traumatic causes (5%). After cardiac causes are ruled out with an electrocardiogram and a careful physical examination, other causes of chest pain should be considered.124 Each has similar initial symptoms, although the diagnostic workup may be different, depending on the physical findings (Table 43.5).

 

CHAPTER 43

Pediatric Chronic Pain Management

631

Pulmonary Causes

The most common respiratory emergencies manifesting as acute chest wall pain occur in children with acute asthma attacks, who may have primarily chest pain without concurrent respiratory symptomatology. Other common causes include bronchial pneumonia and respiratory illnesses, including severe lower respiratory tract illnesses. Management includes treating respiratory illness with antibiotics, anticholinergics, and inhaled bronchodilators.

EO

Cardiac Causes

Cardiac causes of chest pain are probably the most compelling reasons for a thorough diagnostic workup. The most common cardiac causes of chest pain include mitral valve prolapse and dysrhythmias. Workup may include echocardiography, electrocardiography, and, in some cases, Holter monitoring for diagnosis. It is important to address pain in an expeditious manner with a close evaluation.

IO

TA

Abdominal Causes

Gastroesophageal reflux is the most common abdominal cause of continued chest pain in children. In addition, the presence of eosinophilic esophagitis should be ruled out by upper endoscopy because it can usually be treated. • Figure 43.4  Sonographic

anatomy of the transversus abdominis (TA) plane. EO, External oblique muscle; IO, internal oblique muscle.

TABLE 43.5

Causes of Chest Pain

Cause

Manifestations

Chest wall pain

Musculoskeletal chest wall pain, costochondritis, Tietze’s syndrome

Respiratory disease

Pneumonia, pleuritis, asthma, upper respiratory infection

Psychogenic

Anxiety, depression, hyperventilation

Traumatic

Soft tissue injury, pneumothorax

Cardiac

Carditis, arrhythmia, mitral valve prolapse, ischemia

Digestive

Esophagitis, gastritis

Miscellaneous

Sickle cell disease, cystic fibrosis related

Chest Wall Pain

This is often seen in teenagers and manifests as acute pain along the costal margin. The most common chest wall pain is secondary to costochondritis.124 The diagnosis is made by eliciting pain along the costochondral margin with deep pressure. Other chest wall pain syndromes include Tietze’s syndrome and slipping rib cage syndrome,125 which usually consists of the use of NSAIDs. We have seen several patients with slipping rib cage syndrome who have not experienced relief despite surgical resection of the slipping rib. We used CBT as well as alternative therapies, including acupuncture and massage therapy, for these children. In addition, we successfully placed intercostal nerve blocks under ultrasound guidance and achieved good relief in children with severe recurring chest wall pain. Serial blocks are performed with adequate resources available for biofeedback and massage therapy to alleviate any pain associated anxiety.

Psychogenic Causes

Usually, there is a family history of intercurrent cardiac illness, including a recent myocardial infarction in an older family member or possibly the death of a family member from cardiac causes that can lead to chest wall pain. In most cases, adequate family therapy should be offered.126 With the increasing availability of diagnostic methodologies, the diagnosis is far more accurate in these children than it was several decades ago.

Back Pain Back pain is a common problem in adults and is now becoming a significant health issue in children.127,128 With high impact sports that involve a greater degree of stress on the back muscles, such as gymnastics, children seem to have a higher degree of back injury.129 Common back problems include spondylolysis,130 spondylolisthesis, disk degeneration, disk herniation,131,132 tumors of the spinal cord, and other diseases, including sickle cell disease. Given that up to 57% of back pain in children is because of a non-organic cause,133 management in children is usually conservative, with an emphasis on exercises for the back. A study of 177 pediatric patients in the emergency setting found that 77% of the visits were non-pathologic in nature. Imaging was performed in 38% of patients, and positive findings were only noted in 17% of radiographs.134 Advanced imaging, such as CT or MRI, is warranted in refractory back pain, nighttime pain, association with systemic symptoms, or if sensory or motor radicular symptoms exist. If conservative treatment fails, epidural steroid injections may be considered with appropriate imaging studies. Alternative medicine, including massage therapy and acupuncture, is used for the management of children and adolescents with back pain. These therapies may be especially effective when pain has a myofascial component.

Pelvic Pain Pelvic pain is often reported in female adolescents.135 A thorough history has to be obtained, including a history of sexual activity. Children with a history of sexual abuse have a greater

632

PA RT 4 Clinical Conditions: Evaluation and Treatment

preponderance of chronic pelvic pain.136 Although not common, a subpopulation of these adolescent girls has a history of endometriosis. This could lead to severe pelvic pain and may need to be treated more aggressively than occasional pelvic pain. Alteration of the ovulatory cycles with birth control pills, as well as the use of strong NSAIDs, should be implemented in these patients. We have had success with the use of active massage therapy and physical therapy as adjuncts for the management of these patients.

Cancer-Related Pain Cancer remains the second leading cause of death in children. Cancer is diagnosed in more than 12,000 children annually, and 2200 children die each year of this disease.137 Pain is a common symptom during different phases of cancer treatment. The incidence of cancer-related pain in children at the time of diagnosis is estimated to be 75%, with ongoing pain affecting 50%.138,139 However, the incidence of pain in the terminal phase of the disease is likely to be higher than 89%.139 Cancer pain in children is because of several reasons: (1) cancer-related pain (e.g. solid tumor or bony metastatic tumors), (2) pain caused by treatment (e.g. mucositis or surgical pain), and (3) NP secondary to tumor invasion or surgery. Pain caused by treatment and procedural pain are cited as the most frequent types of pain experienced by children with cancer.140 Management of pediatric cancer-related pain must be individualized, and caregivers must be empathetic to family needs and concerns. Although more than most pain complaints can be managed by the implementation of the World Health Organization cancer pain ladder paradigm, a significant number of children may require additional therapies or techniques for pain management because of escalating or intractable pain. Only allopathic techniques are discussed in this section. The pediatric doses for most medications are off-label recommendations, and dosing is based on the current pediatric clinical literature.

Oral Medications Most pain management is achieved with oral maintenance dosing. Around-the-clock scheduling is supplemented with the as-needed analgesic doses for breakthrough pain. Oral techniques include sublingual and transmucosal applications for breakthrough and procedural pain. Sublingual application of morphine is as effective as intravenous morphine for pediatric postoperative pain.141 Because sublingual administration avoids hepatic first-pass dosing, it is comparable to intravenous administration. Sublingual morphine may be a suitable alternative to intravenous morphine for pain control in children with cancer-related pain if enteral tolerance or intravenous access is limited. Sublingual buprenorphine, 5–7 µg/kg per dose, has demonstrated similar analgesic efficacy as intravenous morphine, 150 µg/kg.142 Oxycodone concentrate prepared at 20 mg/mL is appropriate for sublingual application, but small changes in volume can cause large changes in dose. When using this concentrated formulation, an increment of 0.1 mL (from 0.2–0.3 mL) constitutes a 50% increase in dose; an additional 0.1 mL increase (from 0.2–0.4 mL) represents a 100% increase or doubling of the dose administered. Thus prescribing dosing increments that are less than 5 mg may result in variations in the actual amount of oxycodone concentrate delivered. Oxycodone concentrate is not recommended for use in small children. Intravenous preparations administered via the transmucosal route have been attempted with some success. Oral administration

of the intravenous formulation of fentanyl can achieve a pharmacokinetic distribution similar to that of oral transmucosal fentanyl citrate (OTFC) lozenges, but there is much interpatient variability. OTFC lozenges have been used to treat breakthrough and procedural pain in children. Oral mucositis pain treated with 200 µg OTFC lozenges is tolerated but ineffective in adult cancer patients.143 The effective oral dosage range for postoperative pain management is 10–15 µg/kg for buccal application.144 Schechter et al.145 found 15–20 µg/kg of OTFC to be effective for pediatric procedural pain, but one-third of the children experienced vomiting. Transmucosal oxycodone (200 µg/kg) provides relief similar to 10 µg/kg of OTFC for procedure-related pain.143 Tablets designed for buccal delivery aim to enhance bioavailability and drug uptake and speed the onset of pain relief. Hepatic first-pass effects are avoided.146 Studies on fentanyl effervescent buccal tablets have revealed pain relief onset times of 10–15 minutes. The efficacy of the system is dependent on pH because higher plasma levels are achieved at a lower pH. Another benefit of the technique is its discrete nature since the tablets are held between the cheek and gum without telltale evidence of drug intake. The buccal tablet is designed for faster onset than with oral or transmucosal delivery, and thus it is particularly useful in the management of breakthrough pain and may be helpful in cases of anticipated incident pain or potentially noxious activity. This formulation may be an alternative route of administration for those with an inability to swallow medications because of dysphagia or a history of pill aversion.

Integumentary Applications Transdermal Delivery Systems

Transdermal delivery systems of analgesics and adjuvants can be effective for treating chronic pain. The ideal characteristics of a transdermal delivery system include low molecular weight, lipophilicity, high potency, and reliable patch adhesion.147 The solubility of the drug in the adhesive, its diffusion coefficient, and its permeability coefficient also play major roles in the time to steady-state release into the skin.148 The release rates of the agent are dependent on the drug concentration and type of matrix used. A steady-state skin flux is required to yield consistent rates of drug release with zero-order kinetics. Several transdermal systems are available for opioids, α2-agonists, and anesthetics. Fentanyl.  Transdermal fentanyl was approved for use in children in 2002.149 A prospective study has cited improvement in pain and quality of life in children 2–16 years of age who had established opioid requirements for cancer and chronic noncancer pain.150 In pediatric oncology studies, 75%–90% have reported that transdermal fentanyl therapy is “good” or “very good” for the relief of cancer-related pain. These findings suggest that transdermal fentanyl is effective and acceptable for children and their families.151 Buprenorphine. Transdermal buprenorphine has been used for the treatment of nociceptive pain and NP. Buprenorphine is a long-acting, partial µ-opioid agonist with antagonistic action at κ-opioid and δ-opioid receptors.152 Reversal of respiratory depression and sedation from this mixed agonist-antagonist is difficult to achieve with naloxone.153 Patients with previous opioid use have experienced up to a 30% dose reduction in analgesic requirements. Pediatric tolerance is associated with marked ventilatory reduction with buprenorphine in comparison to morphine and warrants close observation for the initial 24 hours of use.153 Clonidine.  The transdermal application of clonidine has been the most studied mode of delivery of α2-agonists. Transdermal

clonidine is well studied in adults, but it is difficult to use for the management of acute or chronic pain. Although neuraxial clonidine has a role in cancer and chronic pain management, it has limited evidence of analgesic efficacy or opioid sparing.154 However, transdermal application does appear to increase the release of enkephalin-like substances and may therefore be an agent enhancer in balanced analgesia techniques.155 Lidocaine Patch

The 5% lidocaine patch is a topical peripheral analgesic that has been approved by the United States FDA for the treatment of postherpetic neuralgia.156 It has been used for nociceptive pain and NP in non-cancer patients. This technique may be useful for treating malignancy-induced peripheral nerve diseases. Unlike other transdermal delivery systems, which work by systemic uptake, the lidocaine contained in the patch penetrates the skin to act locally on damaged or dysfunctional nerves and soft tissue under the skin. Each 10 × 14 cm 5% lidocaine patch contains 700 mg of lidocaine in an aqueous base. It should be applied to intact skin only because of the risk of systemic uptake. The patch is applied directly or beside the area of pain. Patches can be cut before the release liner is removed to fit the target area. The recommended use is a 12-hour-on, 12-hour-off dosing schedule. It should be used with caution in patients taking oral local anesthetic antiarrhythmic drugs, such as mexiletine, to prevent additive effects. Patients sensitive to amide local anesthetics, such as bupivacaine or ropivacaine, should not use the lidocaine patch. The 5% lidocaine patch has not been studied extensively in children. However, a recent study showed excellent tolerance in patients with vasoocclusive crisis.157

Topical Local Anesthetic

Eutectic Mixture of Local Anesthetics.  A four percent tetracaine gel and a eutectic mixture of local anesthetics (EMLA), lidocaine and prilocaine, as a cream or patch have proved effective in relieving pain in children undergoing cancer-related procedures.158 Studies in children 3–21 years of age have shown these commercial preparations to be beneficial in reducing the pain associated with lumbar puncture, venipuncture, and central port access. These preparations should not be used in premature infants because of the risk of local anesthetic toxicity. The plasma concentrations of lidocaine and prilocaine were well below the toxic level for each agent. Moderate plasma lidocaine levels (4.5–7.5 µg/mL) may cause restlessness, dizziness, blurred vision, or tremors. At high levels (>7.5 µg/mL), lidocaine can produce generalized tonicclonic seizures.159 Buccal application of EMLA has not led to local anesthetic toxicity. A study of 12 subjects showed peak concentrations at 40 minutes for lidocaine and prilocaine, and the maximum concentration measured in any subject was 418 ng/mL for lidocaine and 223 ng/mL for prilocaine, each below toxic plasma levels.160 Methemoglobinemia from prilocaine has been reported with the application of EMLA onto newly regenerated postburn or abraded skin.161 An occlusive dressing was also used in both cases. Methemoglobin levels below 3% are nontoxic, but skin cyanosis may occur. Levels above 3% can be associated with agitation, and levels higher than 50% result in coma, seizures, arrhythmias, and acidosis.162 Adverse effects of EMLA include transient skin blanching, erythema, urticaria, allergic contact dermatitis, irritant contact dermatitis, hyperpigmentation, and purpura. Liposome-Encapsulated Lidocaine.  Another option for topical pain control before venipuncture is 4% liposomal lidocaine (L-M-X4), an over-the-counter topical local anesthetic that poses

 

CHAPTER 43

Pediatric Chronic Pain Management

633

no risk for methemoglobinemia because it does not contain prilocaine. Both 4% tetracaine gel and 4% liposomal lidocaine are effective within 30 minutes of application. Compounding Topicals

Creams and gels applied topically to the skin target the primary site of pain and discomfort. Pluronic lecithin organogel is a poloxamer used for topical delivery with a bioavailability of 10%–60%.163 The advantage of using topical medications is that a high concentration of the drug is deposited exactly where it is needed, and purportedly little drug is taken up systemically. This would reduce or eliminate the usual side effects of these medications when administered orally. With a prescription, compounding pharmacies can locally prepare selected agents into topical preparations that are not currently available in the open market. However, variations in concentration, sterility, and lack of FDA regulatory control require caution when used with these agents. Commonly compounded agents for topical application include NSAIDs (e.g. aspirin and ketoprofen), membrane stabilizers (e.g. amitriptyline, clonidine, gabapentin, lidocaine), muscle relaxants (e.g. cyclobenzaprine, baclofen), and antibiotics (e.g. amoxicillin and clavulanate). The topical application of clonidine has been shown to be beneficial in children with cancer. The successful use of topical clonidine ointment in a child with herpetic neuralgia after bone marrow transplantation relieved the associated pain, pruritus, and insomnia.164

Parenteral Medications Subcutaneous Infusions

Subcutaneous infusions are considered equivalent to intravenous infusions once a steady plasma state is achieved. Up to 5 mL/h can be absorbed by subcutaneous infusion, thus making this route of delivery feasible for pediatric cancer pain management.165 This technique should be considered when oral management is not practical, but long-term opioid requirements have been substantiated. The success of this technique depends on patient selection, ongoing home health care support, and the choice of analgesic drug. Highly concentrated solutions were well tolerated and resulted in lower infusion rates. Opioid concentrations of up to 30 mg/mL have been used in adults and tolerated for up to seven days, with rotation of the site of delivery every 72 hours.166 Patient-controlled analgesia (PCA) can be delivered by subcutaneous infusion if intravenous access is not possible. Access via smallcaliber needles, such as a 27-gauge butterfly needle, or access with a 22-gauge tunneled intravenous catheter can be maintained in situ for infusion. Combined subcutaneous and intravenous infusion techniques may be indicated when venous access is limited, but titration of individual agents is needed. Intravenous Infusions

Outpatient use of intravenous opioids and adjuvants is indicated for gastroenteric intolerance, escalating pain inadequately controlled with adjusted oral medications or intolerable side effects from oral agents. Intravenous access via peripheral catheters or central ports and catheters is often used in situ for chemotherapy or nutrition. Because of limited access, the coadministration of analgesics with parenteral nutrition should be considered to limit the interruption of access and control the risk of infection. Trissel and coworkers167 studied the compatibility of parenteral nutrition solutions with selected drugs during simulated Y-site administration. They reported that parenteral nutrition solutions are compatible with many agents, including opioids, for 4 hours

634

PA RT 4 Clinical Conditions: Evaluation and Treatment

at 23°C, and morphine, fentanyl, hydromorphone, and oxymorphone are compatible via a filter with total parenteral nutrition. Despite visual compatibility testing, admixtures of analgesics in nutritive solutions are not advised. Delivery of the analgesic drug at the Y-site in the central catheter system was the best. Neuraxial Delivery System

Children with solid tumor disease compounded by extension of the neoplasm to peripheral nerves or nerve roots at the neuraxis are more likely to require larger opioid doses than children with nonsolid tumors (e.g. leukemia).168 It has been proposed that hyperalgesia and NP are associated with reduced opioid antinociception and contribute to the massive dose requirements. Systemic morphine doses as high as 518 mg/kg/h have been cited in the pediatric literature.169 The use of neuraxial (epidural and intrathecal) analgesia is indicated for the management of cancer pain when other routes are impractical or yield intolerable side effects. Retrospective reviews of adult and pediatric populations suggest that neuraxial (epidural or intrathecal) infections are rare. A review by Strafford et al.170 revealed no serious complications in 1620 general pediatric subjects who underwent short-term epidural catheterization. Bacterial colonization of caudal and lumbar epidural catheters in children has been studied prospectively. Kost-Byerly et al. associates171 found a 35% colonization rate of epidural catheters and an 11% occurrence of local inflammatory changes when catheters remained in situ for up to five days (mean duration, three days). Long-standing epidural analgesia is effective and safe for the spectrum of cancer-related pain, as well as for terminally ill patients, but proper management of infection risk and strict catheter care are imperative. Tunneling of epidural catheters is performed to decrease the likelihood of infection, improve catheter stability, and aid patient mobility during prolonged administration of neuraxial analgesia. A percutaneously inserted tunneled catheter connected to an externalized pump is a feasible technique for prolonged care (Figs 43.5 to 43.8). Use of a 0.2 µm filter, regular changing of the pump tubing, and weekly or biweekly dressing site care performed with sterile technique may decrease the risk of infection. In a retrospective pediatric study of 25 children, the externalized catheters remained in place for up to 240 days without the occurrence of an epidural abscess or meningitis.172 The duration of tunneled catheter use by region was 22 days for thoracic (three catheters), 240 days for lumbar (12 catheters), and 42 days for caudal (10 catheters). The risks and benefits of tunneled epidural analgesia in patients with cancer and coexisting NPs should be closely weighed. It is recommended that totally implanted systems be considered for patients with NP.173 The signs and symptoms of epidural infection include fever, escalating back pain, back or neck ache, MRI evidence of inflammation, elevated sedimentation rate, C-reactive protein level, and white blood cell count. Superficial infection may include local tenderness, erythema, subcutaneous phlegmon,

• Figure 43.5  Positioning for epidural placement in a child.

• Figure 43.6  Percutaneous placement of an epidural. and exudates at the exit site. The presence of an epidural abscess is confirmed by aspiration of exudates, an epidurogram with dye loculation at the catheter tip or retrograde flow, positive culture of the catheter tip, or positive culture of epidural lavage material. Removal of the epidural catheter is indicated in those with temperatures of 39°C or higher, and if any of the aforementioned signs and symptoms are present. Superficial infections are treated with a 7–14 day course of antibiotics. Epidural abscess management includes six weeks or more of intravenous antibiotics with or without neurosurgical drainage of the epidural abscess.174 Analgesia via the neuraxial route is associated with less sedation and fewer adverse effects because significantly smaller doses of opioids are used. Spinal opioids provide selective pain blockade without sympathetic nervous system blockade.175 The more hydrophilic or hydrophobic opioids have limited uptake in epidural fat and its vasculature and yield greater rostral spread in cerebrospinal fluid (CSF) than hydrophobic lipophilic opioids such as fentanyl. Intrathecal opioids bypass the bloodstream and have a direct CSF spread. The onset of action of intrathecal morphine is 15–45 minutes. Delayed respiratory depression is a concern for spinal opioids. Gregory and coworkers176 noted that peak morphine levels in the medulla coincided with peak ventilatory depression 6 hours after lumbar intrathecal injection. Nichols et al.177 injected 0.020 mg/ kg of morphine into the intrathecal space at the L4-5 interspace; this showed the greatest depressed ventilatory response to carbon dioxide at 6 hours that persisted for up to 18 hours, and infants 4–12 months of age responded in a similar fashion to children 2–15 years old. Other side effects do not appear to be dose dependent and include nausea, vomiting, pruritus, and urinary retention. However, side effects are worse with intrathecal administration than with epidural opioids. The most commonly used adjuvants to improve pain and decrease opioid requirements include local anesthetics and α2agonists. The literature has consistently documented appreciable pain control when clonidine is administered by the intravenous and neuraxial routes as an adjuvant to opioids or local anesthetics.178 The benefits of clonidine as an adjuvant include the following: (1) reduction in the amount of opioid required for analgesia and thus a probable decrease in side effects because of opioids; (2) titrated sedation and anxiolysis without additive respiratory depression when administered in combination with opioids; and (3) vasodilation and improved circulation of the cerebral, coronary, and visceral vascular beds.178

 

CHAPTER 43

Pediatric Chronic Pain Management

2

635

2

1

B

A 2

D

C

• Figure 43.7  A, The epidural catheter is threaded, and the second needle is tunneled to exit the initial

(first needle) entry site. This is performed before the removal of the first needle to avoid shearing of the catheter. B, The second needle acts as a trocar. This step can be repeated for a longer tunneled section that can be brought to the anterior. C, The first needle is removed, and the catheter is threaded in a retrograde fashion into the tip of the second needle and exits the hub. D, The second needle is then withdrawn.

Pain in Terminal Illness

• Figure 43.8  The externalized catheter can be connected to a balloontype pump or patient-controlled analgesia apparatus.

Continuous intravenous infusion of clonidine has been cited as a safe adjuvant for pain control in adult and pediatric populations, but the question of long-term impact on neurobehavioral function has been raised. The amount of opioid required by patients experiencing procedural pain was reduced by 30%. Hemodynamic stability was maintained within normal limits because patients experienced less than a 10% change in mean blood pressure. Clonidine has the further advantage of producing sedation associated with only small reductions in minute ventilation and has no effect on hypercapnic or hypoxic respiratory drive.179

There has recently been a surge in treatment modalities for pain, and treatment of children is now part of a cure-oriented and technologybased healthcare system. Recently, with the involvement of facilities such as hospices, the care of terminally ill children has been based on the same philosophy as that for adults.180 Pain can be a significant problem in children who require terminal care. When some children with a life-threatening illness have a significant setback, there may be no firm criteria to stop treatment and direct palliative care. Alternative novel methods for providing analgesia have been used by our pain service for children who do not have intravenous access. Nebulized opioids181 or transdermal delivery systems have been used to offset pain in children with intractable pain. Adverse effects associated with the long-term use of opioids include tolerance and withdrawal. Careful rotation of opioids, along with the judicious use of other adjuvants such as N-methyl-d-aspartate receptor antagonists, should be considered in the care of children and adolescents. Several approaches to pain management can be taken depending on the state of the patient, involvement of the disease process, and the general state of the caregivers. PCA has been widely used in our institution for homebound patients with terminal cancers. Smaller, more user-friendly pumps have been devised for easy programming

636

PA RT 4 Clinical Conditions: Evaluation and Treatment

and less frequent changes. In patients without venous access, we recommend the use of subcutaneous PCA. Other drugs are useful for terminally ill children. NSAIDs and steroids are particularly helpful in the management of bone pain because of metastasis. Carbamazepine, gabapentin, pregabalin, and TCAs are useful in the management of NP. Hypnosis, biofeedback, and distraction techniques can be used effectively in children who are not heavily sedated. A child’s view of death is very different from that of an adult. There is a consistent progression of the conceptual aspects of death as children grow older. Finally, a school-age child understands the permanence of death. Home care may be useful for families to cope with grief and sorrow. It also allows other siblings to spend some time with the loved one. A home care coordinator should be available to manage adverse conditions. Knowing the family helps the

coordinator understand the goals of the family. One basic tenet of hospice care is to enable the patient to lead a full life, of the best quality, for whatever time remains. Cooperation between the family and caregiver should allow the child to die with as much dignity as possible. It is the responsibility of the home coordinator to provide caregivers with sufficient information about the management of pain. Targeted and titrated delivery of antinociception is becoming a reality, as more receptor-specific agents have been devised. More pediatric studies are needed to substantiate the use of the agents and techniques discussed for the management of cancer-related pain in children and adolescents. Regardless of how creative advancements in pain management may become, patient safety must be put first. Novel applications of older agents have broadened the armamentarium of pediatric anesthesiologists and pain management specialists.

Conclusion Chronic pain in children is underrecognized. Early diagnosis and intervention help ensure adequate recovery. A dedicated CBT program is a helpful adjunct to medical management and physical therapy. Complementary therapy, including massage, acupuncture, and biofeedback, can be used to reduce pain and decrease the need for additional pain medication. Interventional techniques, including serial nerve blocks, can be helpful in refractory

cases. A dedicated pain treatment center facilitates adequate and early management of pain in children to ensure rapid recovery to normal function. Future research in the paradigms for managing chronic pain in children needs to be conducted to shape treatment strategies and develop novel approaches to care for this challenging group of patients.

Key Points • Assessment of pain in children involves a multi-disciplinary approach specifically tailored to the biomedical, psychological, and social elements of each patient and family. • Psychological interventions can treat pain effectively by modifying the child’s cognitive, affective, and sensory experiences of pain, behavior in response to pain, and environmental and interactional factors that influence the pain experience. • Pediatric CRPS management includes physical therapy, pharmacologic therapy, regional and sympathetic blockade, neuromodulation, and psychological interventions. • Headaches in children should be evaluated carefully to determine their cause before initiating treatment. • Headache management includes pharmacologic therapy, CBT, peripheral nerve blocks, and complementary therapy.

• FAP is best treated with CBT, anti-depressants, and serial rectus sheath or transversus abdominis plane blocks. • Noncardiac chest wall pain may be treated with nonsteroidal anti-inflammatory drugs, CBT, and complementary techniques, including acupuncture and massage therapy. Nerve blocks may be used in refractory cases. • Common causes of pediatric back pain include spondylolysis, spondylolisthesis, disk degeneration, disk herniation, tumors of the spinal cord, and other diseases, including sickle cell disease. • Management of pediatric cancer-related pain is individualized and based on family needs and concerns. • Pain can pose a significant problem in children who require terminal care. Approaches to pain management are based on the state of the patient, involvement of the disease process, and the general state of the caregivers.

Suggested Readings

parents were enrolled in an intensive interdisciplinary pediatric pain treatment program. Pain. 2012;153:1863–1870. Olsson GL, Meyerson BA, Linderoth B. Spinal cord stimulation in adolescents with complex regional pain syndrome type I (CRPS-I). Eur J Pain. 2008;12:53–59. Vetter TR. Clinical profile of a cohort of patients referred to an anesthesiology-based pediatric chronic pain medicine program. Anesth Analg. 2008;106:786–794, table of contents. Weiss JE, Stinson JN. Pediatric pain syndromes and non-inflammatory musculoskeletal pain. Pediatr Clin North Am. 2018;65:801–826. Weydert JA, Brown ML, McClafferty H. Integrative medicine in pediatrics. Adv Pediatr. 2018;65:19–39. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with cancer. N Engl J Med. 2000;342:326–333. Zernikow B, Wager J, Brehmer H, Hirschfeld G, Maier C. Invasive treatments for complex regional pain syndrome in children and adolescents: A scoping review. Anesthesiology. 2015;122:699–707.

Brett T, Rowland M, Drumm B. An approach to functional abdominal pain in children and adolescents. Br J Gen Pract. 2012;62:386– 387. Dubrovsky AS. Nerve blocks in pediatric and adolescent headache disorders. Curr Pain Headache Rep. 2017;21:50. Eccleston C, Palermo TM, Williams AC, et al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev. 2014;5:CD003968 Jacobson CJ, Farrell JE, Kashikar-Zuck S, Seid M, Verkamp E, Dewitt EM. Disclosure and self-report of emotional, social, and physical health in children and adolescents with chronic pain: A qualitative study of PROMIS pediatric measures. J Pediatr Psychol. 2013;38:82– 93. Lewis DW. Headaches in children and adolescents. Curr Probl Pediatr Adolesc Health Care. 2007;37:207–246. Logan DE, Conroy C, Sieberg CB, Simons LE. Changes in the willingness to self-manage pain among children and adolescents and their

The references for this chapter can be found at ExpertConsult.com.

References 1. Vetter TR. A clinical profile of a cohort of patients referred to an anesthesiology-based pediatric chronic pain medicine program. Anesth Analg. 2008;106(3):786–794, table of contents. doi:10.1213/ ane.0b013e3181609483. 2. van Dijk M, de Boer JB, Koot HM, Tibboel D, Passchier J, Duivenvoorden HJ. The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain. 2000;84(2-3):367–377. doi:10.1016/s0304-3959(99)00239-0. 3. de Blécourt AC, Schiphorst Preuper HR, Van Der Schans CP, Groothoff JW, Reneman MF. Preliminary evaluation of a multidisciplinary pain management program for children and adolescents with chronic musculoskeletal pain. Disabil Rehabil. 2008;30(1):13–20. doi:10.1080/09638280601178816. 4. Goddard JM. Chronic pain in children and young people. Curr Opin Support Palliat Care. 2011;5(2):158–163. doi:10.1097/ SPC.0b013e328345832d. 5. Kato J, Gokan D, Ueda K, Shimizu M, Suzuki T, Ogawa S. Successful pain management of primary and independent spread sites in a child with CRPS type I using regional nerve blocks. Pain Med. 2011;12(1):174. doi:10.1111/j.1526-4637.2010.01014.x. 6. Gatchel RJ, McGeary DD, McGeary CA, Lippe B. Interdisciplinary chronic pain management: Past, present, and future. Am Psychol. 2014;69(2):119–130. doi:10.1037/a0035514. 7. Varni JW, Rapoff MA, Waldron SA, Gragg RA, Bernstein BH, Lindsley CB. Chronic pain and emotional distress in children and adolescents. J Dev Behav Pediatr. 1996;17(3):154–161. 8. McGrath PJ, Beyer J, Cleeland C, Eland J, McGrath PA, Portenoy R. American Academy of Pediatrics report of the subcommittee on assessment and methodologic issues in the management of pain in childhood cancer. Pediatrics. 1990;86(5 Pt 2):814–817. 9. Jacobson CJ, Farrell JE, Kashikar-Zuck S, Seid M, Verkamp E, Dewitt EM. Disclosure and self-report of emotional, social, and physical health in children and adolescents with chronic pain- a qualitative study of PROMIS pediatric measures. J Pediatr Psychol. 2013;38(1):82–93. doi:10.1093/jpepsy/jss099. 10. Jaworski TM, Bradley LA, Heck LW, Roca A, Alarcón GS. Development of an observation method for assessing pain behaviors in children with juvenile rheumatoid arthritis. Arthritis Rheum. 1995;38(8):1142–1151. doi:10.1002/art.1780380818. 11. Palermo TM, Valenzuela D, Stork PP. A randomized trial of electronic versus paper pain diaries in children: Impact on compliance, accuracy, and acceptability. Pain. 2004;107(3):213–219. doi:10.1016/j.pain.2003.10.005. 12. Vaalamo I, Pulkkinen L, Kinnunen T, Kaprio J, Rose RJ. Interactive effects of internalizing and externalizing problem behaviors on recurrent pain in children. J Pediatr Psychol. 2002;27(3):245–257. doi:10.1093/jpepsy/27.3.245. 13. Dorn LD, Campo JC, Thato S, et al. Psychological comorbidity and stress reactivity in children and adolescents with recurrent abdominal pain and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003;42(1):66–75. doi:10.1097/00004583-200301000-00012. 14. Kovacs M. Rating scales to assess depression in school-aged children. Acta Paedopsychiatr. 1981;46(5-6):305–315. 15. Silverman WK, Goedhart AW, Barrett P, Turner C. The facets of anxiety sensitivity represented in the childhood anxiety sensitivity index: Confirmatory analyses of factor models from past studies. J Abnorm Psychol. 2003;112(3):364–374. doi:10.1037/0021-843x.112.3.364. 16. Martin AL, McGrath PA, Brown SC, Katz J. Anxiety sensitivity, fear of pain and pain-related disability in children and adolescents with chronic pain. Pain Res Manag. 2007;12(4):267–272. doi:10.1155/2007/897395. 17. Birmaher B, Brent DA, Chiappetta L, Bridge J, Monga S, Baugher M. Psychometric properties of the screen for child anxiety related emotional disorders (SCARED): A replication study. J Am Acad Child Adolesc Psychiatry. 1999;38(10):1230–1236. doi:10.1097/00004583-199910000-00011.

18. Spence SH. A measure of anxiety symptoms among children. Behav Res Ther. 1998;36(5):545–566. doi:10.1016/S0005-7967(98)00034-5. 19. March JS, Parker JD, Sullivan K, Stallings P, Conners CK. The multidimensional anxiety scale for children (MASC): Factor structure, reliability, and validity. J Am Acad Child Adolesc Psychiatry. 1997;36(4):554–565. doi:10.1097/00004583-199704000-00019. 20. Reynolds CR, Richmond BO. What I think and feel: A revised measure of children’s manifest anxiety. J Abnorm Child Psychol. 1978;6(2):271–280. doi:10.1007/BF00919131. 21. Walker LS, Garber J, Smith CA, Van Slyke DA, Claar RL. The relation of daily stressors to somatic and emotional symptoms in children with and without recurrent abdominal pain. J Consult Clin Psychol. 2001;69(1):85–91. 22. Walker LS, Smith CA, Garber J, Claar RL. Testing a model of pain appraisal and coping in children with chronic abdominal pain. Health Psychol. 2005;24(4):364–374. doi:10.1037/02786133.24.4.364. 23. Reid GJ, Gilbert CA, McGrath PJ. The pain coping questionnaire: Preliminary validation. Pain. 1998;76(1-2):83–96. doi:10.1016/ s0304-3959(98)00029-3. 24. Walker SM, Cousins MJ. Complex regional pain syndromes: Including “reflex sympathetic dystrophy” and “causalgia. Anaesth Intensive Care. 1997;25(2):113–125. doi:10.1177/0310057X9702500202. 25. Crombez G, Bijttebier P, Eccleston C, et al. The child version of the pain catastrophizing scale (PCS-C): A preliminary validation. Pain. 2003;104(3):639–646. doi:10.1016/S0304-3959(03)00121-0. 26. Hershey AD, Powers SW, Bentti AL, LeCates S, deGrauw TJ. Characterization of chronic daily headaches in children in a multidisciplinary headache center. Neurol. 2001;56(8):1032–1037. doi:10.1212/wnl.56.8.1032. 27. Palermo TM, Witherspoon D, Valenzuela D, Drotar DD. Development and validation of the child activity limitations interview: A measure of pain-related functional impairment in school-age children and adolescents. Pain. 2004;109(3):461–470. doi:10.1016/j. pain.2004.02.023. 28. Kashikar-Zuck S, Flowers SR, Claar RL, et al. Clinical utility and validity of the functional disability inventory among a multicenter sample of youth with chronic pain. Pain. 2011;152(7):1600–1607. doi:10.1016/j.pain.2011.02.050. 29. L.K. BBJMHZ. Pain-associated disability syndrome. In: M. SNLBCBY (ed). Pain in Infants, Children and Adolescents. 2nd ed. Lippincott Williams & Wilkins; 2002:841–848. 30. Varni JW, Seid M, Knight TS, Uzark K, Szer IS. The PedsQL 4.0 generic core scales: Sensitivity, responsiveness, and impact on clinical decision-making. J Behav Med. 2002;25(2):175–193. doi:10.1023/a:1014836921812. 31. Powers SW, Patton SR, Hommel KA, Hershey AD. Quality of life in childhood migraines: Clinical impact and comparison to other chronic illnesses. Pediatrics. 2003;112(1 Pt 1):e1–e5. doi:10.1542/ peds.112.1.e1. 32. Ljlalw JE. The child health questionnaire manual. In: Health Institute NEMCB. 33. Varni JW, Seid M, Rode CA. The PedsQL: Measurement model for the pediatric quality of life inventory. Med Care. 1999;37(2):126– 139. doi:10.1097/00005650-199902000-00003. 34. Walker LS, Garber J, Greene JW. Somatization symptoms in pediatric abdominal pain patients: Relation to chronicity of abdominal pain and parent somatization. J Abnorm Child Psychol. 1991;19(4):379–394. doi:10.1007/BF00919084. 35. Harter S. The perceived competence scale for children. Child Dev. 1982;53(1):87–97. 36. Walker LS, Claar RL, Garber J. Social consequences of children’s pain: When do they encourage symptom maintenance? J Pediatr Psychol. 2002;27(8):689–698. doi:10.1093/jpepsy/27.8.689. 37. Wicksell RK, Melin L, Olsson GL. Exposure and acceptance in the rehabilitation of adolescents with idiopathic chronic pain- a pilot study. Eur J Pain. 2007;11(3):267–274. doi:10.1016/j. ejpain.2006.02.012. 636.e1

636.e2

References

38. Eccleston C, Palermo TM, Williams ACdC, et  al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev. 2014;5:CD003968. doi:10.1002/14651858.CD003968.pub4. 39. Logan DE, Conroy C, Sieberg CB, Simons LE. Changes in willingness to self-manage pain among children and adolescents and their parents enrolled in an intensive interdisciplinary pediatric pain treatment program. Pain. 2012;153(9):1863–1870. doi:10.1016/j. pain.2012.05.027. 40. Eccleston C, Fisher E, Craig L, Duggan GB, Rosser BA, Keogh E. Psychological therapies (Internet-delivered) for the management of chronic pain in adults. Cochrane Database Syst Rev. 2014;2(2):CD010152. doi:10.1002/14651858.CD010152.pub2. 41. Chen E, Cole SW, Kato PM. A review of empirically supported psychosocial interventions for pain and adherence outcomes in sickle cell disease. J Pediatr Psychol. 2004;29(3):197–209. doi:10.1093/ jpepsy/jsh021. 42. Robins PM, Smith SM, Glutting JJ, Bishop CT. A randomized controlled trial of a cognitive-behavioral family intervention for pediatric recurrent abdominal pain. J Pediatr Psychol. 2005;30(5):397–408. doi:10.1093/jpepsy/jsi063. 43. Lee BH, Scharff L, Sethna NF, et  al. Physical therapy and cognitive-behavioral treatment for complex regional pain syndromes. J Pediatr. 2002;141(1):135–140. doi:10.1067/mpd.2002.124380. 44. Degotardi PJ, Klass ES, Rosenberg BS, Fox DG, Gallelli KA, Gottlieb BS. Development and evaluation of a cognitivebehavioral intervention for juvenile fibromyalgia. J Pediatr Psychol. 2006;31(7):714–723. doi:10.1093/jpepsy/jsj064. 45. Kashikar-Zuck S, Swain NF, Jones BA, Graham TB. Efficacy of cognitive-behavioral intervention for juvenile primary fibromyalgia syndrome. J Rheumatol. 2005;32(8):1594–1602. 46. Schanberg LE, Lefebvre JC, Keefe FJ, Kredich DW, Gil KM. Pain coping and the pain experience in children with juvenile chronic arthritis. Pain. 1997;73(2):181–189. doi:10.1016/S03043959(97)00110-3. 47. Zeltzer LK, Bush JP, Chen E, Riveral A. A psychobiologic approach to pediatric pain: Part II. Prevention and treatment. Curr Probl Pediatr. 1997;27(7):261–284. doi:10.1016/S0045-9380(97)80014-X. 48. Eccleston C, Malleson PN, Clinch J, Connell H, Sourbut C. Chronic pain in adolescents: Evaluation of a programme of interdisciplinary cognitive behaviour therapy. Arch Dis Child. 2003;88(10):881–885. doi:10.1136/adc.88.10.881. 49. Palermo TM, Chambers CT. Parent and family factors in pediatric chronic pain and disability: An integrative approach. Pain. 2005;119(1-3):1–4. doi:10.1016/j.pain.2005.10.027. 50. DE Logan, Scharff L. Relationships between family and parent characteristics and functional abilities in children with recurrent pain syndromes: An investigation of moderating effects on the pathway from pain to disability. J Pediatr Psychol. 2005;30(8):698– 707. doi:10.1093/jpepsy/jsj060. 51. Walker LS, Williams SE, Smith CA, Garber J, Van Slyke DA, Lipani TA. Parent attention versus distraction: Impact on symptom complaints by children with and without chronic functional abdominal pain. Pain. 2006;122(1-2):43–52. doi:10.1016/j.pain.2005.12.020. 52. McGrath PJ, Humphreys P, Keene D, et al. The efficacy and efficiency of a self-administered treatment for adolescent migraine. Pain. 1992;49(3):321–324. doi:10.1016/0304-3959(92)90238-7. 53. Larsson B, Carlsson J. A school-based, nurse-administered relaxation training for children with chronic tension-type headache. J Pediatr Psychol. 1996;21(5):603–614. doi:10.1093/jpepsy/21.5.603. 54. Hicks CL, von Baeyer CL, McGrath PJ. Online psychological treatment for pediatric recurrent pain: A randomized evaluation. J Pediatr Psychol. 2006;31(7):724–736. doi:10.1093/jpepsy/jsj065. 55. Palermo TM, de la Vega R, Dudeney J, Murray C, Law E. Mobile health intervention for self-management of adolescent chronic pain (WebMAP mobile): Protocol for a hybrid effectiveness-implementation cluster randomized controlled trial. Contemp Clin Trials. 2018;74:55–60. doi:10.1016/j.cct.2018.10.003.

56. Connelly M, Rapoff MA, Thompson N, Connelly W. Headstrong: A pilot study of a CD-ROM intervention for recurrent pediatric headache. J Pediatr Psychol. 2006;31(7):737–747. doi:10.1093/ jpepsy/jsj003. 57. Weydert JA, Brown ML, McClafferty H. Integrative medicine in pediatrics. Adv Pediatr. 2018;65(1):19–39. doi:10.1016/j.yapd. 2018.04.011. 58. Bodner K, D’Amico S, Luo M, et al. A cross-sectional review of the prevalence of integrative medicine in pediatric pain clinics across the United States. Complement Ther Med. 2018;38:79–84. doi:10.1016/j.ctim.2018.05.001. 59. Harris EJ, Schimka KE, Carlson RM. Complex regional pain syndrome of the pediatric lower extremity: A retrospective review. J Am Podiatr Med Assoc. 2012;102(2):99–104. doi:10.7547/1020099. 60. Low AK, Ward K, Wines AP. Pediatric complex regional pain syndrome. J Pediatr Orthop. 2007;27(5):567–572. doi:10.1097/ BPO.0b013e318070cc4d. 61. Güler-Uysal F, Başaran S, Geertzen JH, Göncü K. A 2 1/2-year-old girl with reflex sympathetic dystrophy syndrome (CRPS type I): Case report. Clin Rehabil. 2003;17(2):224–227. doi:10.1191/026 9215503cr589oa. 62. Wilder RT, Berde CB, Wolohan M, Vieyra MA, Masek BJ, Micheli LJ. Reflex sympathetic dystrophy in children. Clinical characteristics and follow-up of seventy patients. J Bone Joint Surg Am. 1992;74(6):910–919. 63. Konen A. Measurement of nerve dysfunction in neuropathic pain. Curr Rev Pain. 2000;4(5):388–394. doi:10.1007/s11916-0000023-5. 64. Richlin DM, Carron H, Rowlingson JC, Sussman MD, Baugher WH, Goldner RD. Reflex sympathetic dystrophy: Successful treatment by transcutaneous nerve stimulation. J Pediatr. 1978;93(1):84–86. doi:10.1016/s0022-3476(78)80610-6. 65. Kozin F, Haughton V, Ryan L. The reflex sympathetic dystrophy syndrome in a child. J Pediatr. 1977;90(3):417–419. doi:10.1016/ s0022-3476(77)80704-x. 66. Gierthmühlen J, Maier C, Baron R, et al. Sensory signs in complex regional pain syndrome and peripheral nerve injury. Pain. 2012;153(4):765–774. doi:10.1016/j.pain.2011.11.009. 67. Sethna NF, Meier PM, Zurakowski D, Berde CB. Cutaneous sensory abnormalities in children and adolescents with complex regional pain syndromes. Pain. 2007;131(1-2):153–161. doi:10.1016/j.pain.2006.12.028. 68. Sarikaya A, Sarikaya I, Pekindil G, Firat MF, Pekindil Y. Technetium-99m sestamibi limb scintigraphy in post-traumatic reflex sympathetic dystrophy: Preliminary results. Eur J Nucl Med. 2001;28(10):1517–1522. doi:10.1007/s002590100615. 69. Hsu ES. Practical management of complex regional pain syndrome. Am J Ther. 2009;16(2):147–154. doi:10.1097/MJT.0b013e31817 15671. 70. Suresh S, Wheeler M, Patel A. Case series: IV regional anesthesia with ketorolac and lidocaine: Is it effective for the management of complex regional pain syndrome 1 in children and adolescents? Case series. Anesth Analg. 2003;96(3):694–695, table of contents. doi:10.1213/01.ane.0000048034.99454.75. 71. Cho S, McCracken LM, Heiby EM, Moon DE, Lee JH. Pain acceptance-based coping in complex regional pain syndrome Type I: Daily relations with pain intensity, activity, and mood. J Behav Med. 2013;36(5):531–538. doi:10.1007/s10865-012-9448-7. 72. Kesler RW, Saulsbury FT, Miller LT, Rowlingson JC. Reflex sympathetic dystrophy in children: Treatment with transcutaneous electric nerve stimulation. Pediatrics. 1988;82(5):728–732. 73. Richeimer SH, Bajwa ZH, Kahraman SS, Ransil BJ, Warfield CA. Utilization patterns of tricyclic antidepressants in a multidisciplinary pain clinic: A survey. Clin J Pain. 1997;13(4):324–329. doi:10.1097/00002508-199712000-00010. 74. Bonilla S, Nurko S. Focus on the use of antidepressants to treat pediatric functional abdominal pain: current perspectives. Clin Exp Gastroenterol. 2018;11:365–372. doi:10.2147/CEG.S146646.

References 636.e3

75. Burgess CD, Montgomery S, Wadsworth J, Turner P. Cardiovascular effects of amitriptyline, mianserin, zimelidine and nomifensine in depressed patients. Postgrad Med J. 1979;55(648):704–708. doi:10.1136/pgmj.55.648.704. 76. Tong HC, Nelson VS. Recurrent and migratory reflex sympathetic dystrophy in children. Pediatr Rehabil. 2000;4(2):87–89. doi:10.1080/13638490110045447. 77. Ross EL. The evolving role of antiepileptic drugs in treating neuropathic pain. Neurol. 2000;55(Suppl 1):S41–S46 5discussion S54-58. 78. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005;115(3):254–263. doi:10.1016/j.pain.2005.02.032. 79. Rosner H, Rubin L, Kestenbaum A. Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain. 1996;12(1):56–58. doi:10.1097/00002508-199603000-00010. 80. Cooper TE, Wiffen PJ, Heathcote LC, et  al. Antiepileptic drugs for chronic non-cancer pain in children and adolescents. Cochrane Database Syst Rev. 2017;8:CD012536. doi:10.1002/14651858. CD012536.pub2. 81. Food and Drug Administration. Pregabalin FDA approved label. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/labe l/2018/021446s035,022488s013lbl.pdf. 82. Smith AJ. The analgesic effects of selective serotonin reuptake inhibitors. J Psychopharmacol. 1998;12(4):407–413. doi:10.1177/ 026988119801200413. 83. Meighen KG. Duloxetine treatment of pediatric chronic pain and co-morbid major depressive disorder. J Child Adolesc Psychopharmacol. 2007;17(1):121–127. doi:10.1089/cap.2006.0042. 84. Zernikow B, Wager J, Brehmer H, Hirschfeld G, Maier C. Invasive treatments for complex regional pain syndrome in children and adolescents: A scoping review. Anesthesiology. 2015;122(3):699– 707. doi:10.1097/ALN.0000000000000573. 85. Farid IS, Heiner EJ. Intrathecal local anesthetic infusion as a treatment for complex regional pain syndrome in a child. Anesth Analg. 2007;104(5):1078–1080, tables of contents doi:10.1213/01.ane.0 000260563.39299.9c. 86. Lundborg C, Dahm P, Nitescu P, Appelgren L, Curelaru I. Clinical experience using intrathecal (IT) bupivacaine infusion in three patients with complex regional pain syndrome type I (CRPS-I). Acta Anaesthesiol Scand. 1999;43(6):667–678. doi:10.1034/ j.1399-6576.1999.430613.x. 87. Vlassakov KV, Narang S, Kissin I. Local anesthetic blockade of peripheral nerves for treatment of neuralgias: Systematic analysis. Anesth Analg. 2011;112(6):1487–1493. doi:10.1213/ ANE.0b013e31820d9787. 88. Naja ZM, Al-Tannir MA, Zeidan A, El-Rajab M, Ziade F, Baraka A. Nerve stimulator-guided repetitive paravertebral block for thoracic myofascial pain syndrome. Pain Pract. 2007;7(4):348–351. doi:10.1111/j.1533-2500.2007.00149.x. 89. Dadure C, Motais F, Ricard C, Raux O, Troncin R, Capdevila X. Continuous peripheral nerve blocks at home for treatment of recurrent complex regional pain syndrome I in children. Anesthesiology. 2005;102(2):387–391. doi:10.1097/00000542-200502000-00022. 90. Ganesh A, Rose JB, Wells L, et  al. Continuous peripheral nerve blockade for inpatient and outpatient postoperative analgesia in children. Anesth Analg. 2007;105(5):1234–1242, table of contents. doi:10.1213/01.ane.0000284670.17412.b6. 91. Irazuzta JE, Berde CB, Sethna NF. Laser Doppler measurements of skin blood flow before, during, and after lumbar sympathetic blockade in children and young adults with reflex sympathetic dystrophy syndrome. J Clin Monit. 1992;8(1):16–19. doi:10.1007/BF01618082. 92. Meier PM, Zurakowski D, Berde CB, Sethna NF. Lumbar sympathetic blockade in children with complex regional pain syndromes: A double blind placebo-controlled crossover trial. Anesthesiology. 2009;111(2):372–380. doi:10.1097/ALN.0b013e3181aaea90. 93. Zernikow B, Dobe M, Hirschfeld G, Blankenburg M, Reuther M, Maier C. Please don’t hurt me!: A plea against invasive procedures

in children and adolescents with complex regional pain syndrome (CRPS). Bitte nicht noch mehr verletzen!: Pladoyer gegen eine invasive schmerztherapie bei kindern mit komplexem regionalem schmerzsyndrom (CRPS). Schmerz (Berl Germany). 2012;26(4):389–395. doi:10.1007/s00482-012-1164-2. 94. Olsson GL, Meyerson BA, Linderoth B. Spinal cord stimulation in adolescents with complex regional pain syndrome type I (CRPS-I). Eur J Pain. 2008;12(1):53–59. doi:10.1016/j.ejpain.2007.02.007. 95. Day WH. Essays on Diseases in Children. Churchill; 1873. 96. Bille BS. Migraine in school children. A study of the incidence and short-term prognosis, and a clinical, psychological and electroencephalographic comparison between children with migraine and matched controls. Acta Paediatr Suppl. 1962;136:1–151. 97. Winner P. Classification of pediatric headache. Curr Pain Headache Rep.2008;12(5):357-360. doi:10.1007/s11916-008-0060-z. 98. Mack KJ. An approach to children with chronic daily headache. Dev Med Child Neurol. 2006;48(12):997–1000. doi:10.1017/ S0012162206002192. 99. Lopez JI, Kabbouche M. Pediatric and adolescent migraine. Headache. 2012;52(9):1451–1453. doi:10.1111/j.1526-4610.2012.02253.x. 100. Dubrovsky AS. Nerve blocks in pediatric and adolescent headache disorders. Curr Pain Headache Rep. 2017;21(12):50. doi:10.1007/ s11916-017-0650-8. 101. Hershey A, Kabbouche M, Powers S. Tension-type headache in the young. Curr Pain Headache Rep. 2006;10(6):467–470. doi:10.1007/s11916-006-0080-5. 102. Lewis DW. Headaches in children and adolescents. Curr Probl Pediatr Adolesc Health Care. 2007;37(6):207–246. doi:10.1016/j. cppeds.2007.03.003. 103. Kelly M, Strelzik J, Langdon R, DiSabella M. Pediatric headache: Overview. Curr Opin Pediatr. 2018;30(6):748–754. doi:10.1097/ MOP.0000000000000688. 104. Oskoui M, Pringsheim T, Billinghurst L, et al. Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Headache Society. Headache. 2019;59(8):1144–1157. doi:10.1111/head.13625. 105. Greher M, Moriggl B, Curatolo M, Kirchmair L, Eichenberger U. Sonographic visualization and ultrasound-guided blockade of the greater occipital nerve: A comparison of two selective techniques confirmed by anatomical dissection. Br J Anaesth. 2010;104(5):637–642. doi:10.1093/bja/aeq052. 106. Weiss JE, Stinson JN. Pediatric pain syndromes and noninflammatory musculoskeletal pain. Pediatr Clin North Am. 2018;65(4):801– 826. doi:10.1016/j.pcl.2018.04.004. 107. Ting TV, Barnett K, Lynch-Jordan A, Whitacre C, Henrickson M, Kashikar-Zuck S. 2010 American College of Rheumatology adult fibromyalgia criteria for use in an adolescent female population with juvenile fibromyalgia. J Pediatr. 2016;169:181–187, e1 doi:10.1016/j.jpeds.2015.10.011. 108. Anthony KK, Schanberg LE. Juvenile primary fibromyalgia syndrome. Curr Rheumatol Rep. 2001;3(2):165–171. doi:10.1007/ s11926-001-0012-7. 109. Gmuca S, Sherry DD. Fibromyalgia: Treating pain in the juvenile patient. Paediatr Drugs. 2017;19(4):325–338. doi:10.1007/ s40272-017-0233-5. 110. Metyas S, Chen CL, Yeter K, Solyman J, Arkfeld DG. Low dose naltrexone in the treatment of fibromyalgia. Curr Rheumatol Rev. 2018;14(2):177–180. doi:10.2174/1573397113666170321120329. 111. Siawash M, Mol F, Tjon-A-Ten W, et al. Anterior rectus sheath blocks in children with abdominal wall pain due to anterior cutaneous nerve entrapment syndrome: A prospective case series of 85 children. Paediatr Anaesth. 2017;27(5):545–550. doi:10.1111/pan.13084. 112. Brett T, Rowland M, Drumm B. An approach to functional abdominal pain in children and adolescents. Br J Gen Pract. 2012;62(600):386–387. doi:10.3399/bjgp12X652562. 113. Saps M, Hudgens S, Mody R, Lasch K, Harikrishnan V, Baum C. Seasonal patterns of abdominal pain consultations among adults

636.e4

References

and children. J Pediatr Gastroenterol Nutr. 2013;56(3):290–296. doi:10.1097/MPG.0b013e3182769796. 114. Walker LS, Sherman AL, Bruehl S, Garber J, Smith CA. Functional abdominal pain patient subtypes in childhood predict functional gastrointestinal disorders with chronic pain and psychiatric comorbidities in adolescence and adulthood. Pain. 2012;153(9):1798– 1806. doi:10.1016/j.pain.2012.03.026. 115. Walker LS, Dengler-Crish CM, Rippel S, Bruehl S. Functional abdominal pain in childhood and adolescence increases risk for chronic pain in adulthood. Pain. 2010;150(3):568–572. doi:10.1016/j.pain.2010.06.018. 116. Saps M, Youssef N, Miranda A, et  al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology. 2009;137(4):1261– 1269. doi:10.1053/j.gastro.2009.06.060. 117. Siawash M, de Jager-Kievit JW, Ten WT, Roumen RM, Scheltinga MR. Prevalence of anterior cutaneous nerve entrapment syndrome in a pediatric population with chronic abdominal pain. J Pediatr Gastroenterol Nutr. 2016;62(3):399–402. doi:10.1097/ MPG.0000000000000966. 118. Pak T, Mickelson J, Yerkes E, Suresh S. Transverse abdominis plane block: A new approach to the management of secondary hyperalgesia following major abdominal surgery. Paediatr Anaesth. 2009;19(1):54–56. doi:10.1111/j.1460-9592.2008.02740.x. 119. Kehlet H. Chronic pain after groin hernia repair. Br J Surg. 2008;95(2):135–136. doi:10.1002/bjs.6111. 120. Suresh S, Patel A, Porfyris S, Ryee MY. Ultrasound-guided serial ilioinguinal nerve blocks for management of chronic groin pain secondary to ilioinguinal neuralgia in adolescents. Paediatr Anaesth. 2008;18(8):775–778. doi:10.1111/j.1460-9592.2008.02596.x. 121. Stinson Jr LW, Roderer GT, Cross NE, Davis BE. Peripheral subcutaneous electrostimulation for control of intractable post-operative inguinal pain: A case report series. Neuromodulation. 2001;4(3):99– 104. doi:10.1046/j.1525-1403.2001.00099.x. 122. Massin MM, Bourguignont A, Coremans C, Comté L, Lep age P, Gérard P. Chest pain in pediatric patients presenting to an emergency department or to a cardiac clinic. Clin Pediatr Phila. 2004;43(3):231–238. doi:10.1177/000992280404300304. 123. Thull-Freedman J. Evaluation of chest pain in the pediatric patient. Med Clin North Am. 2010;94(2):327–347. doi:10.1016/j. mcna.2010.01.004. 124. Son MB, Sundel RP. Musculoskeletal causes of pediatric chest pain. Pediatr Clin North Am. 2010;57(6):1385–1395. doi:10.1016/j. pcl.2010.09.011. 125. Saltzman DA, Schmitz ML, Smith SD, Wagner CW, Jackson RJ, Harp S. The slipping rib syndrome in children. Paediatr Anaesth. 2001;11(6):740–743. doi:10.1046/j.1460-9592.2001.00754.x. 126. Lipsitz JD, Gur M, Albano AM, Sherman B. A psychological intervention for pediatric chest pain: Development and open trial. J Dev Behav Pediatr. 2011;32(2):153–157. doi:10.1097/ DBP.0b013e318206d5aa. 127. Cardon GM, de Clercq DL, Geldhof EJ, Verstraete S, de Bourdeaudhuij IM. Back education in elementary schoolchildren: The effects of adding a physical activity promotion program to a back care program. Eur Spine J. 2007;16(1):125–133. doi:10.1007/ s00586-006-0095-y. 128. Reneman MF, Poels BJ, Geertzen JH, Dijkstra PU. Back pain and backpacks in children: Biomedical or biopsychosocial model? Disabil Rehabil. 2006;28(20):1293–1297. doi:10.1080/ 09638280600554785. 129. Young WK, d’Hemecourt PA. Back pain in adolescent athletes. Phys Sportsmed. 2011;39(4):80–89. doi:10.3810/psm.2011.11.1942. 130. McCleary MD, Congeni JA. Current concepts in the diagnosis and treatment of spondylolysis in young athletes. Curr Sports Med Rep. 2007;6(1):62–66. doi:10.1007/s11932-007-0014-y. 131. Korovessis P, Zacharatos S, Koureas G, Megas P. Comparative multifactorial analysis of the effects of idiopathic adolescent scoliosis and Scheuermann kyphosis on the self-perceived health status of

adolescents treated with brace. Eur Spine J. 2007;16(4):537–546. doi:10.1007/s00586-006-0214-9. 132. Sachs B, Bradford D, Winter R, Lonstein J, Moe J, Willson S. Scheuermann kyphosis. Follow-up of Milwaukee-brace treatment. J Bone Joint Surg Am. 1987;69(1):50–57. 133. Combs JA, Caskey PM. Back pain in children and adolescents: A retrospective review of 648 patients. South Med J. 1997;90(8):789– 792. doi:10.1097/00007611-199708000-00004. 134. Brooks TM, Friedman LM, Silvis RM, Lerer T, Milewski MD. Back pain in a pediatric emergency department: Etiology and evaluation. Pediatr Emerg Care. 2018;34(1):e1–e6. doi:10.1097/ PEC.0000000000000798. 135. Hicks CW, Rome ES. Chronic pelvic pain in the adolescent. Endocr Dev. 2012;22:230–250. doi:10.1159/000326696. 136. Champion JD, Piper JM, Holden AE, Shain RN, Perdue S, Korte JE. Relationship of abuse and pelvic inflammatory disease risk behavior in minority adolescents. J Am Acad Nurse Pract. 2005;17(6):234–241. doi:10.1111/j.1041-2972.2005.00038.x. 137. Houlahan KE, Branowicki PA, Mack JW, Dinning C, McCabe M. Can end of life care for the pediatric patient suffering with escalating and intractable symptoms be improved? J Pediatr Oncol Nurs. 2006;23(1):45–51. doi:10.1177/1043454205283588. 138. Miser AW, Dothage JA, Wesley RA, Miser JS. The prevalence of pain in a pediatric and young adult cancer population. Pain. 1987;29(1):73–83. doi:10.1016/0304-3959(87)90180-1. 139. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with cancer. N Engl J Med. 2000;342(5):326– 333. doi:10.1056/NEJM200002033420506. 140. Ljungman G, Kreuger A, Gordh T, Sörensen S. Pain in pediatric oncology: Do the experiences of children and parents differ from those of nurses and physicians? Ups J Med Sci. 2006;111(1):87–95. doi:10.3109/2000-1967-023. 141. Engelhardt T, Crawford M. Sublingual morphine may be a suitable alternative for pain control in children in the postoperative period. Paediatr Anaesth. 2001;11(1):81–83. doi:10.1046/j.1460-9592.2001.00598.x. 142. Maunuksela EL, Korpela R, Olkkola KT. Comparison of buprenorphine with morphine in the treatment of postoperative pain in children. Anesth Analg. 1988;67(3):233–239. 143. Binstock W, Rubin R, Bachman C, Kahana M, McDade W, Lynch JP. The effect of premedication with OTFC, with or without ondansetron, on postoperative agitation, and nausea and vomiting in pediatric ambulatory patients. Paediatr Anaesth. 2004;14(9):759– 767. doi:10.1111/j.1460-9592.2004.01296.x. 144. Sharar SR, Carrougher GJ, Selzer K, O’Donnell F, Vavilala MS, Lee LA. A comparison of oral transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care. J Burn Care Rehabil. 2002;23(1):27–31. doi:10.1097/00004630-200201000-00006. 145. Schechter NL, Weisman SJ, Rosenblum M, Bernstein B, Conard PL. The use of oral transmucosal fentanyl citrate for painful procedures in children. Pediatrics. 1995;95(3):335–339. 146. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 2006;22(9):805– 811. doi:10.1097/01.ajp.0000210932.27945.4a. 147. Roy SD, Gutierrez M, Flynn GL, Cleary GW. Controlled transdermal delivery of fentanyl: Characterizations of pressure-sensitive adhesives for matrix patch design. J Pharm Sci. 1996;85(5):491– 495. doi:10.1021/js950415w. 148. Kogan A, Garti N. Microemulsions as transdermal drug delivery vehicles. Adv Colloid Interface Sci. 2006:123–126:369–385. doi:10.1016/j.cis.2006.05.014. 149. Noyes M, Irving H. The use of transdermal fentanyl in pediatric oncology palliative care. Am J Hosp Palliat Care. 2001;18(6):411– 416. doi:10.1177/104990910101800612. 150. Finkel JC, Finley A, Greco C, Weisman SJ, Zeltzer L. Transdermal fentanyl in the management of children with chronic severe pain: Results from an international study. Cancer. 2005;104(12):2847– 2857. doi:10.1002/cncr.21497.

References 636.e5

151. Hunt A, Goldman A, Devine T, Phillips M, FEN-GBR-14 study group. Transdermal fentanyl for pain relief in a paediatric palliative care population. Palliat Med. 2001;15(5):405–412. doi:10.1191/026921601680419456. 152. Likar R, Kayser H, Sittl R. Long-term management of chronic pain with transdermal buprenorphine: A multicenter, open-label, follow-up study in patients from three short-term clinical trials. Clin Ther. 2006;28(6):943–952. doi:10.1016/j.clinthera.2006.06.012. 153. Olkkola KT, Leijala MA, Maunuksela EL. Paediatric ventilatory effects of morphine and buprenorphine revisited. Paediatr Anaesth. 1995;5(5):303–305. doi:10.1111/j.1460-9592.1995.tb00311.x. 154. Owen MD, Fibuch EE, McQuillan R, Millington WR. Postoperative analgesia using a low-dose, oral-transdermal clonidine combination: Lack of clinical efficacy. J Clin Anesth. 1997;9(1):8–14. doi:10.1016/S0952-8180(96)00218-8. 155. Nakamura M, Ferreira SH. Peripheral analgesic action of clonidine: Mediation by release of endogenous enkephalin-like substances. Eur J Pharmacol. 1988;146(2-3):223–228. doi:10.1016/00142999(88)90296-8. 156. Gammaitoni AR, Alvarez NA, Galer BS. Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: A review of the literature. J Clin Pharmacol. 2003;43(2):111–117. doi:10.1177/0091270002239817. 157. Rousseau V, Morelle M, Arriuberge C, et  al. Efficacy and tolerance of lidocaine 5% patches in neuropathic pain and pain related to vaso-occlusive sickle cell crises in children: A prospective multicenter clinical study. Pain Pract. 2018;18(6):788–797. doi:10.1111/papr.12674. 158. Holdsworth MT, Raisch DW, Winter SS, et al. Pain and distress from bone marrow aspirations and lumbar punctures. Ann Pharmacother. 2003;37(1):17–22. doi:10.1345/aph.1C088. 159. Naguib M, Magboul MM, Samarkandi AH, Attia M. Adverse effects and drug interactions associated with local and regional anaesthesia. Drug Saf. 1998;18(4):221–250. doi:10.2165/00002018199818040-00001. 160. Vickers ER, Marzbani N, Gerzina TM, McLean C, Punnia-Moorthy A, Mather L. Pharmacokinetics of EMLA cream 5% application to oral mucosa. Anesth Prog. 1997;44(1):32–37. 161. Kopecky EA, Jacobson S, et  al. Safety and pharmacokinet ics of EMLA in the treatment of postburn pruritus in pediatric patients: A pilot study. J Burn Care Rehabil. 2001;22(3):235–242. doi:10.1097/00004630-200105000-00010. 162. Brisman M, Ljung BM, Otterbom I, Larsson LE, Andréas son SE. Methaemoglobin formation after the use of EMLA cream in term neonates. Acta Paediatr. 1998;87(11):1191–1194. doi:10.1080/080352598750031202. 163. Perrin JH. Hazard of compounded anesthetic gel. Am J Health Syst Pharm. 2005;62(14):1445–1446. doi:10.2146/ajhp050087. 164. Hagihara R, Meno A, Arita H, Hanaoka K. A case of effective treatment with clonidine ointment for herpetic neuralgia after bone marrow transplantation in a child. Masui. 2002;51(7): 777–779. 165. Coyle N, Cherny NI, Portenoy RK. Subcutaneous opioid infusions at home. Oncol (Williston Park). 1994;8(4):21–27; discussion 31-2, 37.

166. Bruera E, MacEachern T, Macmillan K, Miller MJ, Hanson J. Local tolerance to subcutaneous infusions of high concentrations of hydromorphone: A prospective study. J Pain Symptom Manage. 1993;8(4):201–204. doi:10.1016/0885-3924(93)90128-i. 167. Trissel LA, Gilbert DL, Martinez JF, Baker MB, Walter WV, Mirtallo JM. Compatibility of parenteral nutrient solutions with selected drugs during simulated Y-site administration. Am J Health Syst Pharm. 1997;54(11):1295–1300. doi:10.1093/ajhp/54.11.1295. 168. Othman AH, Mohamad MF, Sayed HA. Transdermal fentanyl for cancer pain management in opioid-naive pediatric cancer patients. Pain Med. 2016;17(7):1329–1336. doi:10.1093/pm/pnw004. 169. Collins JJ. Intractable pain in children with terminal cancer. J Palliat Care. 1996;12(3):29–34. 170. Strafford MA, Wilder RT, Berde CB. The risk of infection from epidural analgesia in children: A review of 1620 cases. Anesth Analg. 1995;80(2):234–238. doi:10.1097/00000539-199502000-00006. 171. Kost-Byerly S, Tobin JR, Greenberg RS, Billett C, Zahurak M, Yaster M. Bacterial colonization and infection rate of continuous epidural catheters in children. Anesth Analg. 1998;86(4):712–716. doi:10.1097/00000539-199804000-00007. 172. Aram L, Krane EJ, Kozloski LJ, Yaster M. Tunneled epidural catheters for prolonged analgesia in pediatric patients. Anesth Analg. 2001;92(6):1432–1438. doi:10.1097/00000539-200106000-00016. 173. Hayek SM, Paige B, Girgis G, et  al. Tunneled epidural catheter infections in noncancer pain: Increased risk in patients with neuropathic pain/complex regional pain syndrome. Clin J Pain. 2006;22(1):82–89. doi:10.1097/01.ajp.0000151872.97148.f6. 174. Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O. Seven hundred forty-seven hepatectomies in the 1990s: An update to evaluate the actual risk of liver resection. J Am Coll Surg. 2000;191(1):38–46. 175. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology. 1984;61(3):276–310. 176. Gregory MA, Brock-Utne JG, Bux S, Downing JW. Morphine concentration in brain and spinal cord after subarachnoid morphine injection in baboons. Anesth Analg. 1985;64(9):929–932. 177. Nichols DG, Yaster M, Lynn AM, et  al. Disposition and respiratory effects of intrathecal morphine in children. Anesthesiology. 1993;79(4):733–738; discussion 25A. 178. Eisenach JC, De Kock M, Klimscha W. Alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology.1996;85(3):655–674.doi:10.1097/00000542-19960900000026. 179. Ambrose C, Sale S, Howells R, et al. Intravenous clonidine infusion in critically ill children: Dose-dependent sedative effects and cardiovascular stability. Br J Anaesth. 2000;84(6):794–796. doi:10.1093/ oxfordjournals.bja.a013594. 180. Feudtner C, Feinstein JA, Satchell M, Zhao H, Kang TI. Shifting place of death among children with complex chronic conditions in the United States, 1989-2003. JAMA. 2007;297(24):2725–2732. doi:10.1001/jama.297.24.2725. 181. Cohen SP, Dawson TC. Nebulized morphine as a treatment for dyspnea in a child with cystic fibrosis. Pediatrics. 2002;110(3):e38. doi:10.1542/peds.110.3.e38.

44

Geriatric Pain Management

KEELA A. HERR, STAJA Q. BOOKER, LYNN NAKAD, DAVID J. DERRICO

Introduction The global population is aging rapidly, with demographic shifts resulting in the proportion of adults ages over 65 years and above significantly increasing globally from 6.1% to 8.8%.1 The rising prevalence of chronic conditions, of which persistent pain is a common and distressing symptom,2 is strongly associated with advancing age. Multimorbidity, the presence of three or more interacting chronic conditions, is a major contributor to persistent pain.3 Persistent pain, which exists beyond the expected healing time, often has no identifiable physical cause, and bothersome pain afflicts 52.9% or 18.7 million older adults.4 In nursing home residents, Lapane and colleagues found that 27.9% reported mild pain, 46.6% moderate pain, and 25.6% reported severe pain.5 Besides increasing age, risk factors associated with the development of persistent pain include sex, as women are more likely to report greater persistent pain than men,6 low income,7 mental health conditions such as depression and anxiety, and obesity.8 Prevalent causes of persistent pain in older adults are osteoarthritis, cancer, injuries/falls, chronic low back pain, and diabetes (i.e. diabetic neuropathy).9 Conditions such as frailty10 and the residual effects of emerging health threats like that of communicable diseases such as Ebola and coronavirus-2 (SARS-CoV-2; known as COVID-19) may increase the risk and burden of chronic pain, especially in older adults who make up 80% to 95% of all COVID-19 fatalities in the United States and Europe, respectively.11 In fact, some speculate that COVID-19 will indeed increase chronic pain overall in the general population citing infections, inflammation, and psychological triggers as underlying drivers.12 This will likely result in new challenges in effectively managing multiple types of pain in older adults and perhaps necessitate multidisciplinary rehabilitation13 and implementation of COVID-19 pain guidelines.14 Unrelieved persistent pain in later life has many debilitating consequences, including psychological distress, social isolation, impaired sleep quality, physical disability, increased fall risk, and loss of independence.3,15 Optimizing pain management is important, but obstacles to the identification, assessment, and management of pain underscore the importance of providing close attention to older patients.16 Consideration of an older adult’s health, functional capacities, and cognition are essential in relation to the patient’s ability to reliably report pain, and when formulating a pain management plan where they can engage in their care. This chapter provides the reader with an overview of

the most current perspectives on the assessment and management of persistent pain in older adults and describes challenges healthcare providers may encounter when delivering pain care to older persons.

Barriers to Successful Pain Management in the Older Patient Physiologic and Sensory Impairments Anatomic and physiologic changes normally observed as part of the aging process are progressive, and concomitant injury or disease can rapidly worsen the health status of the older individual. Changes in pain transmission, tolerance, and threshold can decrease the speed of processing nociceptive stimuli and thus reduce older adults’ ability to sense and respond to early pain stimuli.17 Therefore older adults may have a greater susceptibility to burns and other injuries such as lacerations because they are not as likely to sense the initial pain and do not respond (e.g. removing hand) as quickly as younger adults. These alterations may reflect aging-associated reductions in peripheral intraepidermal nerve fiber density and small fiber neuropathy and contribute to sensory losses and pain. Additionally, sensory impairments are common among older adults and can negatively impact the management of pain.18 Visual impairments such as cataracts, macular degeneration, and diabetic retinopathy that can make it difficult to read prescription labels or participate in recommended exercise programs.18 Use of good lighting in patient exam rooms, asking older patients to wear eyeglasses, and providing reading materials in large font can help mitigate the negative impact of poor vision on pain care. Hearing impairments are also common.19 Handheld amplifiers, speaking slowly while facing the older patient directly to allow for lip reading, and providing written instructions can help to decrease the negative impact of hearing loss when managing pain among older adults with hearing deficits.

Cognitive Impairment Cognitive deficits are common in later life but remain under recognized and under treated.20 Although a recent study suggests pain treatment in those with moderate-severe dementia has improved, 45% of residents experienced moderate to severe pain21 and still less likely to receive pain treatment than cognitively intact

637

638

PA RT 4 Clinical Conditions: Evaluation and Treatment

residents.22–24 Numerous barriers exist to provide appropriate analgesia to this group, both at the patient and provider levels. Communication is a major challenge to both assessing and managing pain in this patient population, and cognitively impaired older patients tend to under report pain.25 Manifestation of pain in cognitively impaired older patients can also vary, from behavioral disturbances, such as lethargy and physical aggression, to more expected reactions such as groaning and grimacing.26 Cognitive impairment creates additional challenges to assessing pain in older adults. As the severity of cognitive impairment increases, a patient’s ability to self-report pain diminishes, particularly if experiencing multiple cognitive issues such as delirium, agitation, and dementia.23,27

Caregiving As the prevalence of pain increases among older adults, so does the demand for caregivers, especially informal caregivers. Informal caregivers and unpaid caregivers, such as family members, relatives, friends, and partners, who take care of loved ones are playing a greater role in their managing the older adult’s condition and symptoms.28 One of the most challenging tasks for caregivers is the management of pain, and caregivers encounter a variety of barriers related to the management of their loved one’s pain, including lack of education, ineffective communication with providers, and their own wellbeing. Attention to these needs is essential as the caregiver could be a great asset or adjunct to pain management across the life span.29 Adequate pain management skills training and education of caregivers can improve patient outcomes.30

Beliefs and Attitudes About Aging and Pain Certain beliefs that older adults and providers have about pain and pain treatments may negatively influence their expectations, behaviors, and decisions regarding treatment recommendations and engagement and/or adherence. As noted, many older individuals consider pain as a natural part of getting older, and rather than seek care,31 often consider it as something to bear.32 Beliefs such as these can lead to stoicism or acceptance of the status quo.32 Although relatively little research has examined whether these beliefs are associated with specific health behaviors, beliefs can negatively affect an older patient’s willingness to seek treatment or adhere with a recommended treatment plan.31 Prior research has also shown that some older adults endorse beliefs and fears (e.g. addiction and dependence) about pain medications that decrease their willingness to engage in or adhere with pharmacologic interventions.33–34 These concerns may also be voiced by older patients’ caregivers, often a spouse or an adult child. Thus some healthcare providers may be more reluctant to prescribe opioid medications for older patients with non-cancer pain because of a fear of causing patient harm.35 Older adults with pain who endorse this belief report minimizing medication use except when the pain is “very bad.”34 Others show that severe pain is associated with opioid and psychotropic medication use in older adults.36 Providers should be diligent in ascertaining these beliefs during regular clinical encounters and provide research-based education to counter ageist misconceptions. Within a pain management context, this would mean asking patients open questions about their views on the origins and cause of pain, the meaning and impact of pain, their views about treatment and treatment goals, and educational needs.

Cultural Differences Pain assessment and management must be individualized and consider an older person’s culture and language. Pain specialists may provide pain care to patients of different racial groups, cultures, religions, and recent migrants. Pain beliefs and behaviors are further influences by factors such as acculturation, time since migration, and sex. Understanding and appreciating cultural diversity in older patients’ pain beliefs and behaviors can help in the provision of appropriate and acceptable pain care.37 However, this can be challenging when little evidence is available to support bias-free best practices in diverse groups. Older adults who are members of minority groups (race, religion, gender) face particular barriers to adequate pain management. Some evidence suggests that older adults of some ethnic minority groups (1) are more reluctant to report pain, (2) have a higher prevalence of more severe, persistent pain, functional limitations, and health consequences, (3) may be less likely to seek help for their pain, and (4) are less likely to receive consistent and adequate medical treatment.38–39 Reasons for the established disparities in pain management are complex but include socioeconomic disadvantage, discriminatory healthcare systems, and healthcare policies, and misguided pain beliefs and behaviors. We acknowledge that “minority” is not synonymous with socioeconomic disadvantage but is an important consideration for many older adults. Socioeconomic disadvantage and broader discriminatory systems cannot easily be changed by providers but can be improved by providers taking the time to understand each patient’s circumstance and perspective. A simple cultural framework that applicable in clinical settings is the “ASKED MYSELF” mnemonic, which has been adapted for Black Americans with pain but can be easily used in multiple racial/ethnic groups.40 Each letter of the mnemonic guides providers through knowledge- and attitude-based questions about their ability to care for Black Americans with pain; for example, A = Awareness: Am I aware that Black Americans experience immense pain disparities related to diagnosis, treatment, and outcomes?(p. 66), K = Knowledge: Am I knowledgeable about pain-related beliefs, practices, and cultural values, such as the use of spirituality?(p. 67) Language barriers may require additional help in communicating or the services of interpreters (“translators”) within health care. This also includes having validated pain assessment scales translated into multiple languages. Recent and older migrants may find health care challenging if they are not fluent in the country’s dominant language and may rely on family or friends as means of accessing health care and communication with providers. An informal interpreter may influence a consultation, not only because of the accuracy of language translation but also because of cultural beliefs and social roles in the healthcare interaction, which may be influenced by age, sex, and social position.41 Not only must providers be aware of language barriers but also the different ways in which cultural groups verbally and non-verbally communicate pain and its impact.

Access to Healthcare Services and Technology The proportion of older adults in the population is increasing more rapidly in rural areas where access to health services is limited and expensive. This has motivated efforts to identify new and efficient healthcare delivery models, especially for chronic condition management, such as pain management.42 There is a potential for technology to overcome these barriers by decreasing or

eliminating the need for patients or providers to travel to deliver or attend to health services and pain management.43 In addition, technology can help facilitate and promote self-management of pain, which is routinely encouraged for chronic pain.43–44 Technology, such as digital devices (e.g. smartphones, tablets, computers, voice-assistants, or other internet-enabled devices) and software (e.g. email, video-chat applications, online healthcare portals, social networking/media) can be used to improve patient care through more effective monitoring of treatment outcomes, enhanced patient-provider communication, and by providing new ways to deliver treatment.9,43 These technologies are referred to as eHealth (electronic health) or mHealth (mobile health). eHealth is a broad concept that often encompasses telehealth and telecare technologies but can also include online education and patienthealth professional consultations. Telecare involves monitoring aspects of patient’s activity (e.g. fall alarms, motion sensors, wearable activity trackers), while telehealth technologies require active involvement from the patient to take readings (e.g. blood pressure and online pain diary) that are regularly submitted to providers for review.42 Other technologies, such as virtual reality, can supplement as adjuvant non-pharmacologic treatment options in older adults.45 Implementation of eHealth or other technologies to support pain management should be gradual and begin with supplementation of existing care and should be mindful of a patient’s circumstances, capability, current use of everyday technology, and TABLE 44.1

 

CHAPTER 44

Geriatric Pain Management

639

preferences. The acceptance of technology among older adults may relate to existing personal and social contact levels and may be greater where technologic help is not perceived as replacing in person care.44

Assessing Pain in the Older Adult Although accurate assessment of pain is the critical first step in the pain management process, this step can challenge even seasoned clinicians. Older adults typically present with multiple symptoms and medical conditions, leaving healthcare providers little time to address pain in the context of a busy office visit. We described the implications of these barriers in the prior sections of this chapter. Recognizing these challenges and taking steps to address them is an important first step in the assessment and management of pain in older adults. The key to developing an effective treatment plan is a comprehensive evaluation for the underlying cause of pain, pain characteristics, and impact on physical and psychosocial function and quality of life. Pain and common associated factors (e.g. anxiety, depression, beliefs, insomnia, biomechanical issues) can cause impairment or dysfunction, and each should be considered. Identifying underlying diseases known to be painful (Table 44.1) and current and prior prescription and over-the-counter analgesic history (regarding effectiveness and adverse effects) provides

Types of Pain and Management Approaches

Type of Pain & Description

Pain Characteristics & Related Presentation

Example Pain Conditions

Nociceptive - Responds best to non-opioid (e.g. acetaminophen, NSAIDs) and opioid medications along with non-pharmacologic therapies (e.g. heat, acupuncture, massage, exercise, aquatic therapy, TENS). Somatic: tissue injury of bones, soft tissue, joints, muscles

Well-localized, constant; aching, stabbing, gnawing, throbbing

Arthritis, low back pain, tendonitis, acute postoperative, fracture, bone metastases

Visceral: tissue injury of visceral organs including heart, lungs, testes, and biliary system

Diffuse, poorly localized, referred to other sites, intermittent, paroxysmal; dull, colicky, squeezing, deep, cramping; often accompanied by nausea, vomiting, diaphoresis

Renal colic, constipation, urinary tract infection

Neuropathic - Often treated with adjuvant medications, e.g. anti-convulsants, (tricyclic anti-depressants, selective serotonin, and norepinephrine reuptake inhibitors) and opioids if needed; non-pharmacologic therapy that act on nervous system mechanisms is important (e.g. neurostimulation, CBT). Peripheral nervous system: injury to the nervous system—nerves

Prolonged, usually constant, but can have paroxysms; sharp, burning, pricking, tingling, pins-and-needles, shooting electricshock-like; associated with other sensory disturbances, such as paresthesia and dysesthesias; allodynia, hyperalgesia, impaired motor function, atrophy, or abnormal deep tendon reflexes

Cervical or lumbar radiculopathy, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, phantom limb pain, herniated intervertebral disc, drug toxicities

Central nervous system: injury to the nervous system at the brain or spinal cord level

Same as above. Pain may be experienced above, below, or at the level of the spinal cord

Central post-stroke syndrome; spinal cord injury-related neuropathic pain; multiple sclerosis

Mixed or Nociplastic - Treatment may consist of non-pharmacologic therapy (e.g. exercise, CBT), non-opioids, opioids, and adjuvant medications to manage multiple characteristics of pain Central, undetermined, or mixed: pain from altered nociception despite no clear evidence of actual or threatened tissue damage; neurologic dysfunction and/or nociceptive issues and uncertain causes

No identifiable pathologic processes or symptoms out of proportion to identifiable organic pathology; widespread musculoskeletal pain, stiffness, and weakness; fatigue, sleep disturbance; taut bands of muscles and trigger points; sensitivity to sensory stimuli

Myofascial pain syndrome, somatoform pain disorders, fibromyalgia; post-stroke pain; temporomandibular joint dysfunction, tension headache

CBT, Cognitive behavior therapy; NSAIDs, nonsteroidal anti-inflammatory; TENS, transcutaneous electrical nerve stimulation. Adapted from Reuben et al. Geriatrics at Your Fingertips. 22nd edition. New York: American Geriatrics Society; 2020. Used with permission from the American Geriatrics Society.

640

PA RT 4 Clinical Conditions: Evaluation and Treatment

important information to guide treatment planning. Assessment of basic and instrumental activities of daily living helps determine the impact of the pain on function. A complete physical examination of the pain source and the musculoskeletal, peripheral vascular, and neurologic systems is important to identify treatment targets. The physical examination should also target potential pain contributors (e.g. leg length discrepancy, myofascial pain, sacroiliac joint syndrome) that can be addressed. Although laboratory and diagnostic tests can be used to establish an etiologic diagnosis, radiographic evidence of degenerative joint disease is often not associated with pain severity, and imaging studies may not be justified.46 This aligns with the International Association for the Study of Pain’s updated definition of pain, “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”47 Older patients should be asked routinely about pain (and because many older adults will not endorse experiencing “pain,” they should also be queried about the presence of ache, hurting, discomfort, or burning sensations) at each visit. Description of pain is essential to determine the type of pain for treatment planning. Gathering information on physical and psychosocial function is important to fully understand pain and its impact and guide treatment planning.15 Table 44.2 and the following section outline age-appropriate approaches and assessment tools for use with both cognitively intact and cognitively impaired older adults.

Assessment Tools A wide range of assessment tools is available for use with older adults, many of which are well validated. Unidimensional pain scales (e.g. those that assess pain intensity only) are feasible for use in the context of a busy clinical encounter. Examples include the verbal pain descriptor (none, mild, moderate, or severe) and numeric rating (0–5 or 0–10) scales, the Pain Thermometer, and Faces Pain Scale, all of which have been validated for use in older populations to include individuals with mild to moderate cognitive impairment.48 Using instruments that capture the multidimensional experience of pain to include its impact on function is strongly recommended.49 Brief measures that assess pain and its impact on function that can be readily incorporated into geriatric pain practice include the Brief Pain Inventory-Short Form (BPI-SF), the Pain, Enjoyment, and General Activity (PEG) Scale, or the Functional Pain Scale (FPS).50

Assessing Pain in Older Patients With Cognitive Impairment Cognitive impairment occurring in dementia can alter the pain experience and contribute to difficulty interpreting pain signals increasing vulnerability to pain.51 Pain assessment in older patients with cognitive impairment requires an adapted approach to recognize potential pain problems that include a search for diagnoses or conditions known to be painful, observe pain-related behaviors and changes in interactions, activity patterns or routines, or mental status, obtain proxy input from family or caregivers, and ultimately, if necessary, use an analgesic trial to validate pain presence.16,52 These steps are amplified in Table 44.2. Behaviors that suggest underlying pain include facial expressions (grimacing, frowning), vocalizations (noisy breathing), changes in activity patterns (eating, sleeping), changes in mental status (confusion, irritability), body movements (guarding,

bracing), and interpersonal interactions (aggressive, disruptive, social withdrawal).51 Numerous observational tools are available and can help providers assess pain among older patients who cannot communicate verbally. The most recent systematic review of behavioral pain scales identified the strongest supported tools as the Pain Assessment IN Advanced Dementia (PAINAD), Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC), and DOLOPLUS-2.51 Two new tools that attempt to delineate the behaviors that are best to identify pain in those with dementia may guide practice recommendations in the future.53–54 Observation of behaviors should occur during movement and not just at rest.16 The information collected using pain assessment or behavior scales will help in developing a comprehensive management plan.

Management of Pain in Older Adults Various biologic, social, and psychological factors contribute to pain, and whether acute or chronic, require a strategic multimodal pain management plan that integrates best evidence with patient preferences. Treatment should be viewed broadly, not focused only on reducing pain intensity but also in addressing contributing factors and preventing long-term effects of pain. Developing a pain management plan involves evaluation of the patient goals for outcomes and treatment options with risk/benefit analysis to ensure safety and quality. A multimodal management plan is a personalized approach that includes multiple non-pharmacological strategies, medications, techniques, and pain management devices to gain the best control of pain (Fig. 44.1). This treatment plan might always include analgesics but should start with nonpharmacologic interventions, as many are accessible, inexpensive, easy to use, and result in fewer side effects.55 Recent guidelines from the American College of Rheumatology recommend managing osteoarthritis pain using a comprehensive approach.56

Non-Pharmacologic Management and Self-Management With rising concerns of opioid misuse and the greater likelihood of older adults to experience adverse effects from polypharmacy and medication interactions, consider non-pharmacologic pain management as early options when managing pain in the older patient. A range of physical and psychological modalities are available for persistent pain and include physical techniques such as repositioning, use of heat and cold, massage, transcutaneous electrical stimulation and therapeutic touch, and psychological therapies, such as distraction, relaxation, and guided imagery.57–58 Research evaluating their use in the cognitively impaired population is limited; however, based on their efficacy in cognitively intact older adults, their general use can be inferred in this population. Individualize the appropriate complementary therapy as the level of cognitive impairment may limit the use of certain interventions, particularly behavioral modifications. Physical activity and exercise can help reduce pain-related disability and increase physical function and quality of life for older adults with persistent pain. With regular moderate exercise (at least 150 minutes per week for all United States adults), older adults can increase physical function, slow the progression of physical deterioration, and improve range of motion. However, fear of pain and pain itself is often cited as a barrier to initiating and maintaining physical activity and exercise, and this can result in

TABLE 44.2

 

CHAPTER 44

Geriatric Pain Management

641

Steps for Focused Pain Assessments in Older Adults

Cognitively Intact and/or Able to Self-Report

Cognitively Impaired and Unable to Self-Report

Step 0: Determine willingness, ability, and reliability to provide self-report pain by observing coherence of verbal communication, assessing conceptual understanding on how to use a pain scale by asking where mild pain and severe pain are represented on a zero to ten pain scale, and/or administering a cognitive screen, such as the Mini-COG or mini-mental status exam (MMSE). Older adults who score 18 or above on MMSE can usually reliably self-report pain.

Step 0: Determine willingness, ability, and reliability to provide selfreport pain, and also note if there is a diagnosis of cognitive impairment or dementia. Some older adults with mild-moderate dementia remain able to self-report; in these situations, refer to the left column. If unable to selfreport, continue with steps one to five in this column.

Step 1: Be attentive or identify potential sources and causes of pain by reviewing the health history, physical examination, diagnostic tests, laboratory values, and medication history. There may be multiple sources/ locations and types of pain resulting from multiple morbidities. See Table 44.2.

Step 1: Search for possible etiologies of pain such as a history of pain conditions, pathological (e.g., chronic diseases, infections), procedural (e.g., postoperative pain, blood pressure cuff pain, wound care), accidental (e.g., skin tears), trauma (e.g., falls, concussions, elder abuse), and emotional causes (e.g., depression, anxiety, PTSD).

Step 2: Determine presence/absence and intensity of pain by asking older adult if s/he is experiencing pain “right now” or “at this moment.” Alternative descriptors, such as ache, sore, hurt, and discomfort, should be used if “pain” is denied. Measure self-reported pain intensity using a valid, reliable, and preferred pain scale such as the Faces Pain Rating Scalerevised (FPS-r), Revised Iowa Pain Thermometer (IPT-R), Verbal Descriptor Scale, or Numeric Rating Scale.48,73 The verbal descriptor scale with or without a thermometer is preferred by most older adults, although best practice is to ask the older adult the tool they prefer to use. Also, ask about location and radiation, duration, frequency or pattern, and precipitating and ameliorating factors to help determine the cause.

Step 2: Attempt self-report to determine the presence and intensity of pain. A patient with limited verbal and cognitive skills may provide a simple yes/no, other vocalizations, or gestures to communicate pain. See adjacent text.

Step 3: Assess the impact of pain on function to determine pain tolerability and interference with life activities. Different patients will find different pain intensities more tolerable, and this information is essential to establish pain treatment goals. Use established measures such as the BPI-SF, the FPS, or the PEG.50

Step 3: Observe for potential pain behaviors using an appropriate pain behavior observation tool. Observation of facial expressions, verbalizations/vocalizations, body movements, changes in interpersonal interactions, changes in activity patterns or routines, and mental status changes may help confirm pain. When there is a change in older adults’ behavior, consider pain as an etiology. Select a recommended pain behavior observation tools, such as the Pain Assessment in Advanced Dementia Scale (PAINAD) or the Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC-II) to consistently evaluate pain-related behaviors;16 other pain behavior tools may be appropriate and clinically usable for different populations, settings of care, and languages.

Step 4: When appropriate, engage the patient care team and family or unpaid caregivers in the assessment. The patient care team can include the patient, selected family and significant others, caregivers, and healthcare providers who may be able to provide additional recognition of the presence of pain and its impact on function when the older adult is reluctant to report pain.

Step 4: Engage the patient care team and family to obtain proxy reporting (e.g., nurse, certified nursing assistant) about older adult’s usual behavior, communication style, functional patterns, and mood. Proxies need recent knowledge of pain problems, activity level, and normative behavior to recognize subtle changes that may otherwise go unnoticed.99

Step 5: Develop and implement a comprehensive plan for management guided by realistic goals for comfort, function, and mood. A comprehensive plan is driven by patients’ goals and preferences for care and integrates both pharmacological and non-pharmacological interventions. Continue to re-assess regularly based on pain severity and type using the same self-report pain intensity scale.

Step 5: Initiate analgesic trial if (a) pain is the suspected cause of behaviors as demonstrated by a pain behavior observation tool, (b) behaviors do not respond to non-drug interventions, or (c) etiology known to be painful and other causes ruled out. The type of pain suspected (e.g., nociceptive or neuropathic), comorbidities, and contraindications determine the stepped approach taken. The trial length can range from one to seven days. Improved behavior after administration of an analgesic is support for assuming pain is present; then develop a multimodal treatment plan guided by attainable goals for continued comfort, function, mood, and behavioral improvement. Continue to re-assess behaviors using the same pain behavior observation tool. If unresponsive to analgesic trial, explore other potential causes and/or consult a pain management specialist.

Used with permission Booker S, Herr KA. © 2020. The University of Iowa, College of Nursing.

642

PA RT 4 Clinical Conditions: Evaluation and Treatment

the avoidance of movement and consequentially reduced physical function and greater pain.59 Prescribed exercise should be individualized, supervised for those with either severe pain or significant physical disability, and include flexibility, strength, and endurance exercises.55 Alternative movement-based therapies, such as tai chi and yoga are safe and low impact strategies to engage older adults in physical activity.55 Poor coping skills and negative beliefs about pain and its management make managing persistent pain difficult regardless of patient age. Psychological therapies, such as cognitive behavior therapy (CBT), acceptance and commitment therapy, and mindfulness promote positive pain coping, beliefs, and behaviors. Consideration of the treatment goals of older patients is important for these therapies, such as increased social interaction and functional independence for activities of daily living. CBT aims to promote and reinforce self-management and positive health behaviors and pain beliefs.55 CBT is recommended for older adults with persistent pain disorders and can be provided as a structured, professional-led program, which can be delivered on an individual or group basis, in person or online.9 However, the limited number of providers skilled in delivering psychological therapies may restrict their availability.9 Self-management strategies, both physical and psychological, are important aspects of chronic pain management.9,55–56 Pain selfmanagement is a patient-centered process involving the acquisition, practice, and execution of skills needed to respond to and manage pain and its associated symptoms. Successful and optimized pain management requires that older patients be confident and manage the everyday symptoms and consequences of pain. Identifying older patients who are already effective self-managers and those who would benefit from additional support remains a difficult area. Factors such as pain beliefs, attitudes, and motivation, also influence self-management participation.31,60 For older patients who require additional support, various materials and interventions are available, including professional or lay-led group courses (delivered in person or online), educational resources (i.e. manuals, pamphlets, websites, videos), and self-help groups. Decisions about how best to support older patients’ self-management will largely be determined by what is available and accessible to the patient locally. However, to the extent possible, older patients should be encouraged to choose between available formats, selecting individual strategies that best meet their needs. Clinicians must discuss non-pharmacologic and self-management strategies with older patients. These strategies can improve quality of life and reduce pain and the associated impact of pain upon daily life by adopting positive pain behaviors and coping responses. Although many strategies can appear harmless, unknown risks may exist. For example, some dietary supplements or herbal remedies may pose a risk to the older patient when taken with particular pharmacologic agents.61 It is therefore imperative that clinicians ascertain the full extent of their older patients’ pain and pain management behaviors, and consider cultural, lifestyle, and socioeconomic factors that may influence these experiences.

Pharmacologic Management General principles for pharmacologic management of pain in older patients include a collaborative assessment of pain, administration of around-the-clock analgesics, frequent reassessment of the verbal, behavioral, and functional responses to treatment, and timely titration of analgesics.62 The United States Centers for Disease Control and Prevention opioid guidelines recommend

non-pharmacologic and non-opioid therapy first,63 but implementation challenges have been raised, and analgesic medications continue to constitute the primary treatment for older adults with persistent pain.64–65 Older persons with chronic non-cancer pain regard analgesics as an important method for managing pain, particularly when other interventions are difficult to access.64,66 In a study of older home care adults with chronic pain in Germany, 81.4% used pain medication regularly.67 Nonetheless, a multimodal pain management plan should be inclusive of pharmacologic medications and non-pharmacologic therapies. Determination of the best pharmacologic approach hinges on evaluating individual characteristics and risk/benefit analyses for the options available. Age-related changes in both pharmacokinetics (alteration of absorption, distribution, metabolism, and excretion of drugs) and pharmacodynamics (drug-related adverse side effects) necessitate a modified approach to pain management in the older patient.62,68 Renal impairment is quite common, leading to increased half-lives of medications that are excreted by the kidneys. In addition, hepatic function can decline, reducing arterial hepatic blood flow and increasing elimination time for hepatically metabolized drugs. Reductions in dose strength and frequency of analgesic dosing are necessary to decrease toxicity risk. Older age is also associated with a change in the volume of distribution. Total body fat increases while total body water decreases, translating into higher peak plasma concentrations for water-soluble drugs and prolonged half-lives for lipid soluble drugs. Lower albumin levels in frail older adults impact drugs that bind primarily to proteins. Pharmacologic management of persistent pain in older adults is often only partially effective and limited by side effects, including urinary retention, constipation, sedation, cognitive impairment, and increased risk of falls.69 Barriers to effective pharmacologic management of pain among older adults are diverse and include age-related physiologic changes that often dictate altering dose and frequency of analgesic administration. For many classes of painrelieving medications, older patients may demonstrate increased analgesic sensitivity.70 However, it is important to remember that older adults are a highly heterogeneous group, so dosing guidelines must carefully weigh a patient’s pain, its’ impact on their functional status, and the patient’s comorbidities and other factors (e.g. polypharmacy, sociodemographic, health literacy issues). Older adults with a persistent pain disorder frequently have multiple chronic conditions (MCCs) such as diabetes, hypertension, and osteoporosis, which must be considered when formulating a treatment plan. MCCs often result in many older adults experiencing polypharmacy (defined as the use of multiple medications with five or more being a typical threshold criterion) that frequently complicates the pharmacologic management of pain.3 Various patient sociodemographic factors can also operate as barriers. Although adequate social support enhances medication adherence,71 many older adults live alone with limited social support.7 In addition, many older adults cannot afford the costs of certain pain medications. Furthermore, some older adults may lack the necessary skills to read and process basic healthcare information, including understanding pill bottle instructions, information present in patient hand-outs, and clinicians’ instructions about medication side effects.72 Low health literacy can lead to problems with medication adherence, such as taking too much or too little pain medication. Among older adults with persistent pain, commonly prescribed analgesic agents include non-opioids, opioids, and adjuvant therapies (Fig. 44.1). Issues related to the safety and efficacy of these three analgesic classes are briefly summarized.

 

CHAPTER 44

Geriatric Pain Management

643

ASSESSMENT

Screening of Pain Presence and intensity of pain

Focused Assessment of Pain Underlying cause of pain, pain characteristics, and impact on physical and psychosocial function and quality of life.

Pain Monitoring Continued and repeated assessment of pain, especially post-treatment

TREATMENT

Mild Pain (Score of 1-3; limited functional impairment)

Moderate Pain (Score of 4-7 interference with active function)

Severe Pain (Score of 8-10; impact function and quality of life)

Non-Pharmacologic Education Self-management (i.e. CBT, ACT, coping and stress reduction strategies) Self-administered Treatment (i.e. heat, cold, distraction, relaxation, mindfulness meditation, music, TENS) Non-self-administered Treatment (i.e. massage, acupuncture) Exercise/Physical Therapy (i.e. walking, water therapy, yoga, tai chi, manual therapy)

Pharmacologic Step 1: Non-opioid (Acetaminophen, nonacetylated salicylates, counterirritants, topical analgesics, topical NSAIDs, NSAIDs/Cox-2 antiinflammatory drug)

Pharmacologic Pain not alleviated with nondrug interventions and medicine from Step 1 and/or if pain worsens Step 2: Short-acting opioids Adjuvants (i.e. antidepressants, anticonvulsants for neuropathic pain, mixed pain syndrome, or refractory persistent pain) Dronabinol, Nabilone, & Marijuana

Pharmacologic Pain not alleviated with nondrug interventions and medicine from Step 2 Step 3: Opioids (avoid if history of falls or concurrent use of benzodiazepine)

Minimally Invasive Implantable device Steroid injection

Invasive Surgery Ablative procedures

• Figure 44.1  Assessment and treatment approaches for pain management in older adults. (Copyright 2020 K. Herr. Used with permission K. Herr, University of Iowa, College of Nursing.)

Non-Opioids Guidelines recommend acetaminophen as the first line agent for mild to moderate chronic pain in older adults. It is the most commonly prescribed analgesic for the treatment of mild to moderate persistent pain because of its low cost, overall safety profile, and modest efficacy.73 Acetaminophen is an ingredient in more than 600 over-the-counter (OTC) and prescription drugs; therefore unintentional overdose can easily occur and lead to acute liver failure.74 Unintentional overdose remains the leading cause

of acetaminophen-induced hepatotoxicity as a result of treating pain.75 Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used for chronic pain in older adults when acetaminophen fails to control the pain effectively. NSAIDs are particularly helpful in treating an inflammatory type of pain where acetaminophen has limited efficacy.76 NSAIDs continue to be one of the most commonly prescribed and consumed analgesic agents, particularly as OTC products. Although oral NSAIDs are widely considered more effective pain relievers than acetaminophen, NSAID use has

644

PA RT 4 Clinical Conditions: Evaluation and Treatment

significant limitations in the form of renal, gastrointestinal, and cardiovascular toxicity, particularly among older patients. Compared with younger patients, older patients are at increased risk of experiencing gastrointestinal (GI) complications in the form of peptic ulcer disease and GI bleeding.77 Use of either cyclooxygenase-2 (COX-2) selective inhibitor NSAIDs (e.g. celecoxib) or non-selective NSAIDs is associated with increased risk for myocardial infarction, stroke, and mortality.78–79 Given the risks associated with oral NSAID use, increasing attention has focused on the development and testing of topical NSAIDs. Topical NSAIDs have been approved for use by the United States Food and Drug Administration, and numerous topical agents are available OTC as well.80 A systematic review and network meta-analysis examined the relative efficacy found that topical NSAIDs were effective and safe for osteoarthritis. Diclofenac patches were the most effective topical NSAID for pain relief, while no serious gastrointestinal or renal adverse events were observed. A retrospective cohort study of patients with rheumatoid arthritis who were newly starting therapy with non-selective topical NSAIDs or oral NSAIDs found the topical NSAID group had a 36% lower risk for cardiovascular events than the oral NSAID group (hazard ratio, 0.64; 95% confidence interval 0.43–0.95).79

Opioids Although well-accepted as a means of treating both acute and cancer pain, opioid analgesics remain controversial in the treatment of persistent non-cancer pain.73 Nonetheless, opioids are considered the most powerful pain-relieving drugs available for older adults with moderate to severe persistent pain.81 Use of opioids by older adults has increased, particularly in long term care settings where challenging pain problems exist; however, there remains limited evidence of long term effects of opioid use for chronic pain.82 Opioids for chronic pain management in older adults may be justifiable when less potent medications have failed or are contraindicated.83 Many older adults and healthcare providers are reluctant to use opioids because of fears of addiction and side effects, such as nausea, pruritus, constipation, drowsiness, cognitive effects, and respiratory depression.83 Clinical monitoring and supervision are needed to manage potential side effects associated with opioids, including dry mouth, constipation, sedation, nausea, delirium, urinary retention, respiratory depression, and cognitive impairment. Other less common side effects are hypogonadism, immunosuppression, and hyperalgesia.46 Despite these side effects, evidence from trials shows that opioid therapy for older adults can be safe and effective with appropriate cautions, including the lower starting doses, slower titration, longer dosing interval, and more frequent monitoring.84 Still, a risk/ benefit/cost analysis, along with adequate education, should be completed prior to initiating long-term opioid therapy. Benefits may occur when clear treatment goals for opioid use are established, and patients are educated about the risks and benefits of opioid drugs.85 According to the American Geriatrics Society’s Beers Criteria 2019 Update for Potentially Inappropriate Medication Use in Older Adults, opioids should be avoided except for pain management in the setting of severe acute pain (e.g. recent fractures or joint replacement) because they may cause ataxia, impaired psychomotor function, syncope, and falls.86 If opioids must be used, reduce simultaneous use of other central nervous system–active medications that increase risk of falls and fractures and implement strategies to reduce fall risk.86 Further, kidney function must be closely monitored, and persons with existing

kidney disease may have contraindications to morphine. Medications with codeine should be avoided. A recent systematic review demonstrated that both improvements and impairments to cognition occurred in studies with higher mean opioid doses.87 A brief screening tool to assess cognition changes might be useful. Opioid misuse. Opioid misuse refers to opioid use in any way not directed by a prescriber, including use without a prescription of one’s own or use in greater amounts than prescribed.88 The prevalence of opioid misuse is increasing among adults ≥65 years old, a population rapidly growing in number that requires special consideration, monitoring, and management when on opioid treatment.89 Results from multivariable analyses among older adults visiting emergency departments suggest that the odds of opioid misuse among adults aged 65–74 years old are 6.75 times (p < 0.001) larger than otherwise similar adults aged 85 years and older, and the odds of opioid misuse among adults aged 75–84 years old are 2.16 times (p < 0.001) larger than their otherwise similar adults aged 85 years and older.90 However, while the use of opioids under clinician supervision provides many older adults with necessary pain relief, some older adults may use opioids without a prescription, without pain, or without medical indication.88 Although clinicians should remain vigilant about the possibility of misuse/abuse of opioid agents among all patients irrespective of age, it is important to note that advancing age is associated with a significantly decreased risk of opioid misuse/abuse.91 Consequently, opioid misuse may go unrecognized in older adults because of provider perceptions about older adults’ behavior and the absence of efforts to screen for such misuse in this population. Older studies suggested that the underuse of opioids in older populations constitutes a bigger problem.92 However, recent trends reveal that emergency department visits by older adults with opioid use disorder rose by 220% from 2006–2014 in the United States.90 In Canada, the hospital admission rates from opioid overdose are higher for older adults (≥65) than younger adults.93 Given these increases, it is important that clinicians screen for potential risk for misuse/abuse and use a valid tool such as the Opioid Risk Tool.

Adjuvant Agents Adjuvant agents are medications administered in conjunction with analgesics to relieve pain, including anti-depressants and anti-convulsants, which are typically prescribed to treat neuropathic pain.94 However, two Cochrane reviews did not find sufficient evidence to support the use of tricyclic anti-depressants (TCAs), such as nortriptyline and desipramine, for the treatment of chronic neuropathic pain conditions.95,96 Although the use of low doses can mitigate side effect occurrence, many older adults experience treatment limiting anticholinergic side effects in the form of dry mouth, urinary retention, and constipation as well as an increased fall risk. Therefore the use of these medications must be considered in the context of what has been tried and the effect of pain on function; the small effects of TCAs may still be worthwhile for some older adults with severe pain. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that has been shown to be effective in lowering pain levels among patients.94 Patients co-prescribed an opioid were less likely to report a pain response to venlafaxine, suggesting that clinicians may wish to consider either non-opioid or alternative anti-depressant approaches to pain management in these complex patients.97 Nausea is a commonly reported side effect with both SNRIs.

Anti-convulsant drugs such as carbamazepine are considered front line therapy for neuralgia management.76 A particular area of concern in older adults is the risk of hyponatremia with carbamazepine because studies show that older patients with hyponatremia are more likely to have injuries from falls than those without hyponatremia. 98,99 Therefore routinely monitor sodium levels carefully with carbamazepine administration, initiated with low dosages, and slowly increased. Anti-convulsant drugs pregabalin and gabapentin have also been useful in treating neuropathic pain.94 Side effects such as sedation, confusion, and peripheral edema can limit the use of pregabalin. Gabapentin in older patients has been associated with increased rates of falls; consequently, it is important to screen all older patients for fall risk when prescribing anti-convulsants.98 The 2019 Beers Criteria indicates that anticonvulsants and anti-depressants, including SNRIs, may cause ataxia, impaired psychomotor function, syncope, and falls. Therefore the safety and need for these medications must be evaluated carefully and compared to their other medications to minimize increased central nervous system adverse effects.

Practice Recommendations Here, we provide recommendations for the assessment and management of pain in older adults.

 

CHAPTER 44

Geriatric Pain Management

645

• Ask about the presence of pain, then measure its intensity and impact on function and quality of life using valid and culturally appropriate pain and function scales. • For cognitively impaired individuals, determine ability to reliably self-report, and if impairments limit communication of pain, use a valid pain behavior tool to observe for changes as condition changes. • Assess pain at regular intervals to establish changes in pain character (frequency, duration, triggers, and intensity) and location.

Management • Incorporate non-pharmacologic agents to enhance relief and sense of pain control. Promote and support self-management. • Engage older adults and any caregivers in shared treatment decision making. • Assess and manage changing physical and cognitive abilities that can influence treatment trajectories. • Target analgesic selection based on pain etiology and mechanism after careful individual evaluation for risks and benefits. • If treatment goals are unmet and the patient is tolerating the therapy, consider advancing the dose before prescribing another therapy, in addition to introducing a new non-pharmacologic therapy.

Assessment • Identify pain-causing etiologies and perform a thorough physical exam, including any appropriate laboratory tests.

Conclusion Older adults deserve quality pain care derived from robust research, provider expertise, and patient values. Although numerous challenges and barriers exist that make assessment and treatment complex, online resources are available to guide providers,

patients, and caregivers (e.g. geriatricpain.org). The goals are to detect pain early and treat it safely and effectively so that older adults can thrive and survive.

Key Points • Evidence-based approaches to assessment and management can help older adults thrive and have a good quality of life. • A wide range of validated tools are available to assess pain in older adults, including individuals with cognitive impairment. • A multimodal, comprehensive approach to pain management is imperative. • Providers need to be aware of and work to address barriers that often occur in assessing and managing pain in this age group,

to physical and cognitive impairments as well as social and cultural issues. • The full range of available pharmacologic, non-pharmacologic pain management and coping approaches should be considered. • Providers are strongly encouraged to support older patients’ efforts to become active participants in their own care.

Suggested Readings

nomically disadvantaged area of Los Angeles: Social, behavioral, and health determinants. Int J Environ Res Public Health. 2019;16(20):3894. Guerriero F. Guidance on opioids prescribing for the management of persistent non-cancer pain in older adults. World J Clin Cases. 2017;5(3):73–81. Hadjistavropoulos T, Herr K, Prkachin KM, et al. Pain assessment in elderly adults with dementia. Lancet Neurol. 2014;13(12):1216– 1227. Herr K, Coyne PJ, Ely E, Gélinas C, Manworren RCB. Pain assessment in the patient unable to self-report: Clinical practice recommendations in support of the ASPMN 2019 position statement. Pain Manag Nurs. 2019;20(5):404–417. Miaskowski C, Blyth F, Nicosia F, et al. A biopsychosocial model of chronic pain for older adults. Pain Med. 2019;17.

Booker S, Herr K. Pain in older adults. In: Hogans B, Barreveld A, eds. Pain Care Essentials. New York: Oxford University Press; 2020:319–338. Booker S, Herr K, Tripp-Reimer T. Black American older adults’ motivation to engage in osteoarthritis treatment recommendations for pain selfmanagement: A mixed methods study. Int J Nurs Stud. 2019:103510. Clauw DJ, Häuser W, Cohen SP, Fitzcharles MA. Considering the potential for an increase in chronic pain after the COVID-19 pandemic. Pain. 2020;161(8):1694–1697. Dunham M, Schofield P, Knaggs R. Evidence-based clinical practice guidelines on the management of pain in older people–A summary report. Brit J Pain. 2020;1–8. Evans MC, Bazargan M, Cobb S, Assari S. Pain intensity among community-dwelling African American older adults in an eco-

646

PA RT 4 Clinical Conditions: Evaluation and Treatment

Nakad L, Booker S, Gilbertson-White S, Chi N-C, Shaw C, Herr K. Pain and multimorbidity in late life. Curr Epidemiol Rep. 2020;7:1–8. Patel KV, Guralnik JM, Phelan EA, et al. Symptom burden among community-dwelling older adults in the United States. J Am Geriatr Soc. 2019;67(2):223–231. Portenoy R. A practical approach to using adjuvant analgesics in older adults. J Am Geriatr Soc. 2020;68:691–698. Schofield P. The assessment of pain in older people: UK national guidelines. Age Ageing. 2018;47(1):i1–i22.

Shade MY, Herr K, Kupzyk K. Self-reported pain interference and analgesic characteristics in rural older adults. Pain Manag Nurs. 2019;20(3):232–238. Guerriero F, Reid MC. Linking persistent pain and frailty in older adults. Pain Med. 2020;21(1):61–66. The references for this chapter can be found at ExpertConsult.com.

References 1. Cheng X, Yang Y, Schwebel DC, et al. Population ageing and mortality during 1990–2017: A global decomposition analysis. PLoS Med. 2020;17(6):e1003138. 2. Patel KV, Guralnik JM, Phelan EA, et al. Symptom burden among community-dwelling older adults in the United States. J Am Geriatr Soc. 2019;67(2):223–231. 3. Nakad L, Booker S, Gilbertson-White S, Chi N-C, Shaw C, Herr K. Pain and multimorbidity in late life. Curr Epidemiol Rep. 2020;7:1–8. 4. Patel KV, Guralnik JM, Dansie EJ, Turk DC. Prevalence and impact of pain among older adults in the United States: Findings from the 2011 national health and aging trends study. Pain. 2013;154(12):2649–2657. 5. Lapane KL, Hume AL, Morrison RA, Jesdale BM. Prescription analgesia and adjuvant use by pain severity at admission among nursing home residents with non-malignant pain. Eur J Clin Pharmacol. 2020;76(7):1021–1028. 6. Timmermans EJ, de Koning EJ, van Schoor NM, et  al. Withinperson pain variability and physical activity in older adults with osteoarthritis from six European countries. BMC Musculoskelet Disord. 2019;20(1):12. 7. Evans MC, Bazargan M, Cobb S, Assari S. Pain intensity among community-dwelling African American older adults in an economically disadvantaged area of Los Angeles: Social, behavioral, and health determinants. Int J Environ Res Public Health. 2019;16(20):3894. 8. Brandauer A, Berger S, Freywald N, et al. Quality of life in nursing home residents with pain: Pain interference, depression and multiple pain-related diseases as important determinants. Qual Life Res. 2020;29(1):91–97. 9. Reid MC, Eccleston C, Pillemer K. Management of chronic pain in older adults. BMJ. 2015;350:h532. 10. Guerriero F, Reid MC. Linking persistent pain and frailty in older adults. Pain Med. 2020;21(1):61–66. 11. The United Nations. Policy Brief: The impact of COVID-19 on older persons. May 2020, pp. 1-16. Available at: https://unsdg. un.org/sites/default/files/2020-05/Policy-Brief-The-Impact-ofCOVID-19-on-Older-Persons.pdf. 12. Clauw DJ, Häuser W, Cohen SP, Fitzcharles MA. Considering the potential for an increase in chronic pain after the COVID-19 pandemic. Pain. 2020;161(8):1694–1697. 13. Kemp HI, Corner E, Colvin LA. Chronic pain after COVID-19: Implications for rehabilitation. Br J Anaesth. 2020. ePub. 14. Eccleston C, Blyth FM, Dear BF, et  al. Managing patients with chronic pain during the COVID-19 outbreak: Considerations for the rapid introduction of remotely supported (eHealth) pain management services. Pain. 2020;161(5):889–893. 15. Miaskowski C, Blyth F, Nicosia F, et al. A biopsychosocial model of chronic pain for older adults. Pain. Med. 2019;17. 16. Herr K, Coyne PJ, Ely E, Gélinas C, Manworren RCB. Pain assessment in the patient unable to self-report: Clinical practice recommendations in support of the ASPMN 2019 position statement. Pain Manag Nurs. 2019;20(5):404–417. 17. Walco GA, Krane EJ, Schmader KE, Weiner DK. Applying a lifespan developmental perspective to chronic pain: Pediatrics to geriatrics. J Pain. 2016;17(9):T108–T117. Suppl. 18. Correia C, Lopez KJ, Wroblewski KE, et  al. Global sensory impairment in older adults in the United States. J Am Geriatr Soc. 2016;64(2):306–313. 19. Goman AM, Lin FR. Prevalence of hearing loss by severity in the United States. Am J Public Health. 2016;106(10):1820–1822. 20. Husebo BS, Achterberg W, Flo E. Identifying and managing pain in people with Alzheimer’s disease and other types of dementia: A systematic review. CNS Drugs. 2016;30(6):481–497. 21. Ersek M, Nash P, Hilgeman M, et al. Pain patterns and treatment among nursing home residents with moderate-severe cognitive impairment. J Am Geriatr Soc. 2020;68(4):794–802.

22. Nakashima T, Young Y, Hsu W-H. Do nursing home residents with dementia receive pain interventions? Am J Alzheimer’s Dis Other Demen. 2019;34(3):193–198. 23. Pergolizzi J, Raffa R, Paladini AN, Varrasi G, LeQuang JA. Treating pain in patients with dementia and the possible concomitant relief of symptoms of agitation. Pain Manag. 2019;9(6):569–582. 24. Hunt LJ, Covinsky KE, Yaffe K, et al. Pain in community-dwelling older adults with dementia: Results from the national health and aging trends study. J Am. Geriatr Soc. 2015;63(8):1503–1511. 25. Corbett A, Husebo B, Malcangio M, et al. Assessment and treatment of pain in people with dementia. Nat Rev Neurol. 2012;8(5):264–274. 26. Gagliese L, Gauthier LR, Narain N, Freedman T. Pain, aging and dementia: Towards a biopsychosocial model. Prog Neuropsychopharmacol Biol Psychiatry. 2018;87(Pt B):207–215. 27. Ahn H, Horgas A. The relationship between pain and disruptive behaviors in nursing home residents with dementia. BMC Geriatr. 2013;13:14. 28. Glose S. Family caregiving during the hospitalization of an older relative. J Gerontol Nurs. 2020;46(3):45–52. 29. Yasmeen I, Krewulak KD, Zhang C, Stelfox HT, Fiest KM. The effect of caregiver-facilitated pain management interventions in hospitalized patients on patient, caregiver, provider, and health system outcomes: A systematic review. J Pain Symptom Manage. 2020. ePub. 30. Chi N-C, Barani E, Fu Y-K, Nakad L, et al. Interventions to support family caregivers in pain management: A systematic review. J Pain Symptom Manage. 2020. 31. Makris UE, Higashi RT, Marks EG, et al. Ageism, negative attitudes, and competing comorbidities- why older adults may not seek care for restricting back pain: A qualitative study. BMC Geriatr. 2015;15:39. 32. Booker SQ, Tripp-Reimer T, Herr KA. Bearing the pain”: The experience of aging African Americans with osteoarthritis pain. Glob Qual Nurs Res. 2020;7:2333393620925793. 33. Selten EMH, Geenen R, Schers HJ, et al. Treatment beliefs underlying intended treatment choices in knee and hip osteoarthritis. Int J Behav Med. 2018;25(2):198–206. 34. Booker S, Herr K, Tripp-Reimer T. Patterns and perceptions of self-management for osteoarthritis pain in African American older adults. Pain Med. 2019;20(8):1489–1499. 35. Spitz A, Moore AA, Papaleontiou M, Granieri E, Turner BJ, Reid MC. Primary care providers’ perspective on prescribing opioids to older adults with chronic non-cancer pain: A qualitative study. BMC Geriatrics. 2011;11:35. 36. Bazargan M, Cobb S, Wisseh C, Assari S. Psychotropic and opioidbased medication use among economically disadvantaged AfricanAmerican older adults. Pharmacy (Basel). 2020;8(2):74. 37. Robinson-Lane SG, Booker SQ. Culturally responsive pain management for black older adults. J Gerontol Nurs. 2017;43(8):33–41. 38. KO Anderson, Green CR, Payne R. Racial and ethnic disparities in pain: Causes and consequences of unequal care. J Pain. 2009;10(12):1187–1204. 39. Meints SM, Cortes A, Morais CA, Edwards RR. Racial and ethnic differences in the experience and treatment of non-cancer pain. Pain Manag. 2019;9(3):317–334. 40. Booker SQ. Are nurses prepared to care for black American patients in pain? Nurs. 2015;45(1):66–69. 41. White J, Plompen T, Osadnik C, Tao L, Micallef E, Haines T. The experience of interpreter access and language discordant clinical encounters in Australian health care: A mixed methods exploration. Int J Equity Health. 2018;17(1):151. 42. DeMonte CM, DeMonte WD, Thorn BE. Future implications of eHealth interventions for chronic pain management in underserved populations. Pain Manage. 2015;5(3):207–214. 43. Ware P, Bartlett SJ, Paré G, et al. Using eHealth technologies: Interests, preferences, and concerns of older adults. Interact J Med Res. 2017;6(1):e3. 44. Currie M, Philip LJ, Roberts A. Attitudes towards the use and acceptance of eHealth technologies: A case study of older adults living with chronic pain and implications for rural healthcare. BMC Health Serv Res. 2015;15(1):1–12. 646.e1

646.e2

References

45. Benham S, Kang M, Grampurohit N. Immersive virtual reality for the management of pain in community-dwelling older adults. OTJR. 2019;39(2):90–96. 46. Reuben DB, Herr KA, Pacala JT, Pollock BG, Potter JF, Semla TP. Geriatrics at Your Fingertips®. 22nd ed. New York: American Geriatrics Society; 2020. 47. Raja SN, Carr DB, Cohen M, et al. The revised international association for the study of pain definition of pain concepts, challenges, and compromises. Pain. 2020. ePub. 48. Ware LJ, Herr KA, Booker SS, et al. Psychometric evaluation of the revised Iowa pain thermometer (IPT-R) in a sample of diverse cognitively intact and impaired older adults: A pilot study. Pain Manag Nurs. 2015;16(4):475–482. 49. Schofield P. The assessment of pain in older people: UK national guidelines. Age Ageing. 2018;47(1):i1–i22. Suppl. 50. Booker SQ, Herr KA. Assessment and measurement of pain in adults in later life. Clin Geriatr Med. 2016;32(4):677–692. 51. Achterberg W, Lautenbacher S, Husebo B, Erdal A, Herr K. Pain in dementia. Pain Rep. 2019;5(1):e803. 52. Dyer S, Harrison S, Laver K, Whitehead C, Crotty M. An overview of systematic reviews of pharmacological and non-pharmacological interventions for the treatment of behavioral and psychological symptoms of dementia. Int Psychogeriatr. 2018;30(3):295–309. 53. Kunz M, de Waal MWM, Achterberg WP, et  al. The pain assessment in impaired cognition scale (PAIC15): A multidisciplinary and international approach to develop and test a meta-tool for pain assessment in impaired cognition, especially dementia. Eur J Pain. 2020;24(1):192–208. 54. Ersek M, Herr K, Hilgeman MM, et al. Developing a pain intensity measure for persons with dementia: Initial construction and testing. Pain Med. 2019;20(6):1078–1092. 55. Savvas SM, Gibson SJ. Overview of pain management in older adults. Clin Geriatr Med. 2016;32(4):635–650. 56. Kolasinksi SL, Neogi T, Hochberg MC, et  al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol. 2020;72(2):220–233. 57. Anderson AR, Deng J, Anthony RS, Atalla SA, Monroe TB. Using complementary and alternative medicine to treat pain and agitation in dementia. A review of randomized controlled trials from long-term care with potential use in critical care. Crit Care Crit Care Nurs Clin North Am. 2017;29(4):519–537. 58. Shropshire M, Stapleton SJ, Dyck MJ, Kim M, Mallory C. Nonpharmacological interventions for persistent, non-cancer pain in elders residing in long-term care facilities: An integrative review of the literature. Nurs Forum. 2018;53(4):538–548. 59. Booker SQ, Herr K, Fillingim RB. The Reciprocal relationship of pain and movement in African American older adults with multijoint osteoarthritis. Res Gerontol Nurs. 2019:1–11. 60. Booker S, Herr K, Tripp-Reimer T. Black American older adults’ motivation to engage in osteoarthritis treatment recommendations for pain self-management: A mixed methods study. Int J Nurs Stud. 2019:103510. 61. Shade MY, Witry M, Robinson K, Kupzyk K. Analysis of oral dietary supplement use in rural older adults. J Clin Nurs. 2019;28(9-10): 1600–1606. 62. Marcum ZA, Duncan NA, Makris UE. Pharmacotherapies in geriatric chronic pain management. Clin Geriatr Med. 2016;32:705–724. 63. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain- United States, 2016. MMWR Recommendations Rep. 2016;65(1):1–49. 64. Beissner K, Brooks G, Neville K, Trachtenberg M, Murtaugh CM, Reid MC. Pain-related drug use among older adults with activity limiting pain who received home care services. Home Healthc Now. 2020;38(3):147–153. 65. Kroenke K, Alford D, Argoff C, et al. Challenges with implementing the centers for disease control and prevention opioid guideline: A consensus panel report. Pain Med. 2019;29(4):724–735.

66. Kennedy MC, Cousins G, Henman MC. Analgesic use by ageing and elderly patients with chronic non-malignant pain: A qualitative study. Int J Clin Pharm. 2017;39(4):798–807. 67. Schneider J, Algharably E, Budnick A, Wenzel A, Dräger D, Kreutz R. Deficits in pain medication in older adults with chronic pain receiving home care: A cross-sectional study in Germany. PLoS One. 2020;15(2):e0229229. https://doi.org/10.1371/journal.pone. 022922. 68. Booker S, Herr K. Pain in older adults. In: Hogans B, Barreveld A (eds). Pain Care Essentials. New York: Oxford University Press; 2020:319–338. 69. Domenichiello AF, Ramsden CE. The silent epidemic of chronic pain in older adults. Prog Neuropsychopharmacol Biol Psychiatry. 2019;93:284–290. 70. Hall T. Management of persistent pain in older people. J Pharm Pract Res. 2016;46(1):60–67. 71. Lima L, Pinto C, Rui Sousa M, Cândida P, Bastos C, Martins MM, Santos CSV. Social support and medication adherence in older adults. August 2016; 30th Conference of European Society of Health Psychology. 72. Shade MY, Herr K, Kupzyk K. Self-reported pain interference and analgesic characteristics in rural older adults. Pain Manag Nurs. 2019;20(3):232–238. 73. Arnstein P, Herr KA, Butcher HK. Evidence-based practice guideline: Persistent pain management in older adults. J Gerontol Nurs. 2017;43:20–31. 74. Horgas AL. Pain management in older adults. Nurs Clin North Am. 2017;52(4):e1–e7. 75. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-induced hepatotoxicity: A comprehensive update. J Clin Transl Hepatol. 2016;4(2):131–142. 76. Ali A, Arif AW, Bhan C, et al. Managing chronic pain in the elderly: An overview of the recent therapeutic advancements. Cureus. 2018;10(9):e3293. 77. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57(8): 1331–1346. 78. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal antiinflammatory drugs: Network meta-analysis. BMJ. 2011;342:c7086. 79. Lin TC, Solomon DH, Tedeschi SK, Yoshida K, Yang Y-HK. Comparative risk of cardiovascular outcomes between topical and oral non-selective NSAIDs in Taiwanese patients with rheumatoid arthritis. J Am Heart Assoc. 2017;6(11):e006874. 80. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med. 2010;11(4):535–549. 81. Guerriero F. Guidance on opioids prescribing for the management of persistent non-cancer pain in older adults. World J Clin Cases. 2017;5(3):73–81. 82. Suriaga A, Tappen R. A systematic review of opioid use in LTC. Ann Longterm Care. 2020. ePub. 83. Gazelka H, Leal M, Lapid M, Rummans TA. Opioids in older adults: Indications, prescribing, complications, and alternative therapies for primary care. Mayo Clin Proc. 2020;95(4):793–800. 84. Dunham M, Schofield P, Knaggs R. Evidence-based clinical practice guidelines on the management of pain in older people–A summary report. Brit J Pain. 2020;1–8. 85. Guerriero F, Reid MC. New opioid prescribing guidelines released in the US: What impact will they have in the care of older patients with persistent pain? Curr Med Res Opin. 2017;33(2):275–278. 86. American Geriatrics Society 2019. Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674–694. 87. Pask S, Dell’Olio M, Murtagh FEM, Boland JW. The effects of opioids on cognition in older adults with cancer and chronic non-cancer pain: A systematic review. J Pain Symptom Manage. 2020;59(4):871–893 e1.2020.

References

88. Agency for Healthcare Research and Quality. Prevention, diagnosis, and management of opioids, opioid misuse and opioid use disorder in older adults. Available at: https://effectivehealthcare.ahrq. gov/products/opioids-older-adults/protocol#toc_js_6. 89. Han B, Compton W, Blanco C, Crane E, Lee J, Jones CM. Prescription opioid use, misuse, and use disorders in U.S. adults: 2015 National Survey on Drug Use and Health. Ann Intern Med. 2017;167(5):293–301. 90. Carter MW, Yang BK, Davenport M, Kabel A. Increasing rates of opioid misuse among older adults visiting emergency departments. Innov Aging. 2019;3(1):igz002. 91. Han B, Sherman S, Palamar J. Prescription opioid misuse among middle-aged and older adults in the US, 2015-2016. Prev Med. 2019;121:84–98. 92. Auret K, Schug SA. Underutilisation of opioids in elderly patients with chronic pain: Approaches to correcting the problem. Drugs Aging. 2005;22:641–654. 93. Rieb LM, Samaan Z, Furlan AD, et  al. Canadian guidelines on opioid use disorder among older adults. Can Geriatr J. 2020;23(1):123–134.

646.e3

94. Portenoy R. A practical approach to using adjuvant analgesics in older adults. J Am Geriatr Soc. 2020;68:691–698. 95. Hearn L, Moore RA, Derry S, Wiffen PJ, Philips T. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;2014(9):CD011003. 96. Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1(1):CD011209. 97. Stahl S, Jung C, Weiner D, Peciña M, Karp JF. Opioid exposure negatively affects antidepressant response to venlafaxine in older adults with chronic low back pain and depression. Pain Med. 2019. ePub. 98. Haslam C, Nurmikko T. Pharmacological treatment of neuropathic pain in older persons. Clin Interv Aging. 2008;3(1):111–120. 99. Kuo SCH, Kuo PJ, Rau CS, Wu SC, Hsu SY, Hsieh CH. Hyponatremia is associated with worse outcomes from fall injuries in the elderly. Int J Environ Res Public Health. 2017;14(5):460.

45

Managing Pain During Pregnancy and Lactation

GEETA NAGPAL, FEYCE M. PERALTA, JAMES P. RATHMELL

Use of Medications During Pregnancy Medical management of the pregnant patient should begin with attempts to minimize the use of all medications and use nonpharmacologic therapies whenever possible. When opting for drug therapy, the clinician must consider any potential for harm to the mother or the fetus and the course of the physiologic state of pregnancy itself. The degree of protein binding and lipid solubility of the medication, speed of maternal metabolism, and molecular weight all affect the placental transfer of medications from mother to fetus. Except for large polar molecules (such as heparin and insulin) and ionized molecules (glycopyrrolate), almost all medications will reach the fetus to some degree. Approximately 3% of newborns will have a significant congenital malformation.1 Only 25% of fetal malformations have a known genetic cause, and only 2%–3% have a clear environmental link, such as maternal medication exposure during organogenesis.2 One of the major limitations in evaluating any medication’s potential for causing harm to a developing human fetus is the degree of species specificity for congenital disabilities. A classic example of this specificity is the drug thalidomide; nonprimate studies have revealed no teratogenic effects, but severe limb deformities occurred in human offspring when thalidomide was prescribed during pregnancy.3 The most critical period for minimizing maternal drug exposure is during early development, from conception through the tenth menstrual week of pregnancy (the tenth week following the last menstrual cycle). Drug exposure prior to organogenesis (prior to the fourth menstrual week) usually causes an all-or-none effect; that is, the embryo either does not survive or develops without abnormalities.4 Drug effects later in pregnancy typically lead to single- or multiple-organ involvement, developmental syndromes, or intrauterine growth retardation.2 Certain medications may not influence fetal organ development directly but have the potential to influence the physiology of pregnancy adversely. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset of labor, decrease amniotic fluid volume, or place a newborn at risk for pulmonary hypertension or renal injury. The United States Food and Drug Administration (FDA) had developed a well known five-category labeling system for all approved drugs in the United States with pregnancy letter categories (A, B, C, D, and X). Based on available scientific and clinical evidence, this labeling system rated the potential risk for

teratogenic or embryotoxic effects. In 2014 this labeling system was removed as it was determined to be confusing and did not accurately or consistently communicate differences in degrees of fetal risk. Effective 2015, a gradual process was started to remove pregnancy letter categories by June 2020. Because the risk-benefit decisions regarding the use of a drug during pregnancy are more complex than the category designations suggest, reliance on these may result in inadequately informed clinical decision making. To replace the lettering system, narrative summaries of the risk of a drug during pregnancy and discussions of the data supporting those summaries are given to provide more meaningful information to healthcare providers. Because few medications have undergone large-scale testing during human pregnancy, most medications have summaries indicating incomplete knowledge and potential for benefit and harm with drug therapy. More specifically, our present knowledge about the adverse effects of uncontrolled pain and the risks of administering medications during pregnancy remain incomplete. The physician will be left to weigh the risks against the benefits of instituting pharmacologic therapy for each individual.

Use of Medications in the Breastfeeding Mother Many mothers are inappropriately advised to discontinue breastfeeding or avoid taking essential medications because of fears of adverse effects on their infants. This over cautious approach may be unnecessary in many cases as only a small proportion of medications are contraindicated in breastfeeding mothers or are associated with adverse effects in the infants. The same physicochemical properties that facilitate transplacental drug transfer affect drug accumulation in breast milk. High lipid solubility, low molecular weight, minimal protein binding, and the un-ionized state all facilitate the excretion of medications into breast milk. The neonatal dose of most medications obtained through breastfeeding is 1%–2% of the maternal dose.5 Even with minimal exposure via breast milk, neonatal drug allergy and slower infant drug metabolism must be considered.6 Only small amounts of colostrum are excreted during the first few postpartum days. Thus early breastfeeding poses little risk to the infant whose mother received medications during delivery.7 Most breast milk is synthesized and excreted during and immediately following breastfeeding. Taking medications after 647

648

PA RT 4 Clinical Conditions: Evaluation and Treatment

breastfeeding or when the infant has the longest interval between feedings and avoidance of long-acting medications will minimize drug transfer via breast milk.8 However, effective treatment of chronic pain often necessitates the use of long-acting medications, particularly long-acting opioids. To weigh the risks and benefits of breastfeeding, multiple factors should be considered: (1) the need for the drug by the mother, (2) the potential effect on milk production, (3) the amount of drug excreted in the milk, (4) the extent of absorption by the infant, (5) potential adverse effect on the infant, (6) the age of the breastfeeding child. As with the categorical ranking of medications for use during pregnancy, the American Academy of Pediatrics (AAP) retired their grading system for the use of a drug and compatibility with breastfeeding (categories one to three). Per the FDA changes in 2015, labels now must have three headings for breastfeeding risks: risk summary, clinical considerations, and data. In a clinical report published in 2013, the AAP provides guidance to physicians regarding drug exposure and reaffirms the recommendation that most medications are safe during lactation.9 It is difficult for any publication to keep up with the rapidly changing information from published studies and drug approvals. Providers prescribing to the lactating mother should be familiar with a current and comprehensive database called LactMed (Drugs and Lactation Database), which can be found through the National Institute of Health.

Medications Commonly Used in Pain Management Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Acetaminophen NSAIDs have both analgesic and anti-inflammatory properties and are commonly used for musculoskeletal pain.10 Although the exact mechanism of action is uncertain, NSAIDs decrease pain by acting as non-selective inhibitors of cyclooxygenase (COX) and then inhibiting prostaglandin synthesis.10 During pregnancy, prostaglandins modulate many key processes, including stimulation of uterine activity, maintaining patency of the fetal ductus arteriosus (essential for adequate in utero blood flow), and promoting fetal urine production (which contributes to the level of amniotic fluid in the second and third trimesters). As expected, alteration of prostaglandin metabolism then has varied effects on the pregnancy, depending on the timing and duration of use. For example, short-term use of indomethacin in the second trimester is effective for the treatment of pain caused by degenerating fibroids; use for long periods (more than 48 hours) in the third trimester has been associated with narrowing of the ductus arteriosus11,12 and oligohydramnios.13 To complicate this picture further, aspirin, the prototypical NSAID, is used in a therapeutic manner in low doses (80–160 mg/day) to decrease the incidence of pregnancy complications in certain high-risk groups but is associated with premature narrowing of the ductus arteriosus at higher doses.14 Therefore NSAID use in pregnancy must be carefully planned to achieve the proposed benefit and avoid fetal risk. In general, if NSAID use is indicated, the duration should be short (less than 48 hours) without monitoring fetal ductus flow and amniotic fluid volume. All NSAID use for pain should be discontinued by 34 weeks of gestation to prevent pulmonary hypertension in the newborn.15 NSAIDs are among the most commonly used drugs during the first trimester of pregnancy.16,17 Over the counter use of this

medication is very common in this population. With their use so common, many women may not realize that there is potential for deleterious effects on them or their developing fetuses. Furthermore, as the age of first-time mothers increases, more women are likely to take NSAIDs for conditions such as joint and musculoskeletal pain. The effects of NSAID exposure on the fetus in the third trimester are well documented, associated with premature narrowing of the ductus arteriosus leading to pulmonary hypertension in the newborn. However, there is controversy as to the risk associated with maternal exposure and other congenital anomalies.18 There is no role for routine use of NSAIDs for pain in pregnancy other than that related to rheumatologic disease or uterine fibroids. In the largest published series of NSAID use during pregnancy to date, Ostensen and Ostensen19 have detailed a series of 88 women with rheumatic disease, comparing the outcome in 45 who received NSAID therapy during pregnancy with 43 who were not treated during pregnancy. The most common agents used were naproxen (23/45) and ibuprofen (8/45). NSAIDs were most frequently used during the first and second trimesters because many patients stopped therapy once pregnancy was recognized. Many of the rheumatic conditions remitted later in pregnancy. They found no significant differences in pregnancy outcome (duration of pregnancy and labor, vaginal delivery rate, maternal bleeding requiring transfusion, or incidence of congenital anomalies) or the health status of offspring at long-term follow up (ranging from six months to 14 years). The authors concluded that NSAID therapy limited to periods of active rheumatic disease until weeks 34–36 did not adversely affect the neonate.19 However, it is noted that women with rheumatic disease have poor pregnancy outcomes in general; thus these outcome data should not be applied to the general obstetric population. More recently, Ofori and collegues18 published a case-control study regarding the risk of congenital anomalies in pregnant users of NSAIDs. Using a population-based pregnancy registry from 1997–2003 in Quebec, they identified 93 births with congenital anomalies in 1056 women (8.8%) who filled prescriptions for NSAIDs in the first trimester of pregnancy, compared to 2478 in 35,331 (7%) women who did not. They concluded that there might be a greater risk of having children with congenital anomalies, particularly those related to cardiac septal closure. Despite the physiologic effects of NSAIDs, the results of the Collaborative Perinatal Project have suggested that first trimester exposure to aspirin does not pose an appreciable teratogenic risk,20 nor does ibuprofen or naproxen, the most commonly used NSAIDs. Patients who conceive while taking NSAIDs can be reassured that this will not impair pregnancy outcomes. However, NSAIDs can interfere with implantation and placental circulation. In a population-based cohort study, the risk of miscarriage was 1.8 (95% confidence interval [CI] 1.0, 3.2) with any NSAID use and was increased to 8.1 (95% CI 2.8, 23.4) if used for more than one week around the time of conception.21 Aspirin has well known platelet-inhibiting properties and, theoretically, may increase the risk of peripartum hemorrhage. Neonatal platelet function is inhibited for up to five days after delivery in aspirin-treated mothers.22 Although low dose aspirin therapy (60–80 mg/day) has not been associated with maternal or neonatal complications, higher doses appear to increase the risk of intracranial hemorrhage in neonates born prior to 35 weeks of gestation.13 Low dose aspirin has been used to improve pregnancy outcomes for women with both preeclampsia and anti-phospholipid antibodies.23 However, as with other NSAIDs, aspirin crosses the

 

CHAPTER 45

placenta. Although it has not been implicated in causing congenital abnormalities, it has been associated with an increased risk of vascular disruptions, particularly gastroschisis.23,24 Data from two retrospective meta-analyses suggest that there may be a two- to three-fold increase risk of gastroschisis with aspirin exposure.24,25 However, there are reassuring data from over 30,000 women in randomized, control trials of low dose aspirin verses placebo that have not shown any significant risk of intraventricular hemorrhage, other neonatal bleeding, or poor pregnancy outcomes.23 Ketorolac is an NSAID available for oral and parenteral administration. According to the manufacturer’s prescribing information,26 ketorolac did not cause congenital disabilities in the offspring of pregnant rabbits. However, ketorolac administration during labor did lead to dystocia in rodents. Ketorolac shares the platelet-inhibiting properties of other NSAIDs.27 Although ketorolac has not undergone evaluation for its effects on the fetal ductus arteriosus or renal vasculature, it is likely to have effects similar to those of other NSAIDs. Until more information is available, it may be prudent to choose more extensively studied NSAIDs for use during pregnancy. Based on our clinical experience and a review of the available literature, we have formulated recommendations for the use of NSAIDs during pregnancy (Box 45.1). NSAIDs use in pregnancy must be carefully planned to achieve benefit and avoid fetal risk. In general, if NSAID use is indicated, the duration should be short (48 hours) in the absence of monitoring fetal ductus flow and amniotic fluid volume. Chronic use of NSAIDs should be avoided in pregnancy, especially in the third trimester. Before the 24th week of pregnancy, the use of NSAIDs should be used with caution. It is preferable to use both low dose and short half-life NSAIDs. Because of the anti-platelet properties of NSAIDs, many anesthesiologists are concerned about the risk of epidural hematoma formation as a result of epidural catheter placement. To date, there are no outcome studies on which to base practice recommendations. There is no evidence that low dose aspirin therapy or the use of other NSAIDs increases the risk of epidural hematoma formation following spinal or epidural placement.28 As part of our routine history and physical examination of the parturient, we screen for any evidence of bleeding diathesis or easy bruising and, in their absence, proceed with epidural placement without further laboratory testing. This practice is consistent with the practice guidelines published by the American Society of Regional Anesthesia.29 Salicylic acid is excreted into breast milk in breastfeeding women, with higher doses of aspirin resulting in disproportionately higher milk concentrations. If continuous, high dose therapy • Box 45.1

Recommendations for the Use of NSAIDs During Pregnancy

• Consider non-pharmacologic management or acetaminophen use first. • Consider the use of a mild opioid or opioid-acetaminophen combination analgesic. • Continue aspirin or other NSAID if the symptoms cannot be controlled non-pharmacologically or with acetaminophen alone. • Institute close fetal monitoring during the second trimester. If high doses of NSAIDs are required, periodic fetal ultrasound, including fetal echocardiography, should be used to monitor amniotic fluid volume and patency of the ductus arteriosus. • Discontinue NSAID use after weeks 34–36 to reduce the risks of peripartum bleeding, neonatal hemorrhage, and persistent fetal circulation. NSAID, Nonsteroidal anti-inflammatory drug.

Managing Pain During Pregnancy and Lactation

649

is considered, an alternate drug would be preferred. With the use of daily, low dose aspirin (75 to 325 mg), no aspirin is excreted into breastmilk, and salicylate levels are low. Caution should still be exercised if more than occasional or short term aspirin use is contemplated during lactation because neonates have very slow elimination of salicylates.30 High-dose aspirin can lead to rashes, platelet abnormalities, and bleeding in nursing infants. As for the use of NSAIDs for pain management in breastfeeding women, ibuprofen is the preferred agent because of its short half-life and safety profile for use in infants. The doses used for infants are much lower than what is excreted in breast milk. While naproxen is considered compatible with breastfeeding, other agents may be preferred because of the longer half-life. Diclofenac and indomethacin are also considered acceptable, but other agents may be preferred because of minimal data available.31 Little information is available on the safety of maternal ketorolac use during lactation. One study has found that ketorolac concentrations ranged from 1%–4% of maternal serum levels in breastmilk.32 The analysis of the breast milk in 10 women given ketorolac 10 mg PO Q6 hours for four days resulted in clinically insignificant levels that the nursing infant would be exposed to.32 Considering the bioavailability of ketorolac after oral administration, this would likely result in neonatal blood levels between 0.16% and 0.40% of the maternal dose. Ketorolac is commonly given after Cesarean section. However, the colostrum has very little excreted. The manufacturer indicates a contraindication with breastfeeding; therefore another agent should be considered 24–72 hours after birth when more breast milk is produced. Acetaminophen is a frequently used painkiller and antipyretic drug among pregnant women. It provides similar analgesia without the anti-inflammatory effects seen with NSAIDs. Acetaminophen has no known teratogenic properties, does not inhibit prostaglandin synthesis or platelet function, and is hepatotoxic only in extreme overdosage.13,33 As with most drugs, there are no controlled studies in pregnant women in the first trimester. In animal studies, acetaminophen has not demonstrated fetal risk. Data obtained from 88,142 patients in the Danish National Birth Cohort (1996–2003) who had information on acetaminophen use during the first trimester of pregnancy indicated that ingestion of acetaminophen during pregnancy is not related to an overall increased prevalence of congenital abnormality or an increased prevalence of the most frequent abnormalities.34 If persistent pain demands the use of a mild analgesic during pregnancy, acetaminophen appears to be a safe and effective first-choice agent. Acetaminophen does enter breast milk, although maximal neonatal ingestion would be less than 2% of a maternal dose.35 Acetaminophen is considered compatible with breastfeeding.9

Opioid Analgesics Many women of childbearing age are prescribed opioids for intermittent or continual pain management. Much of our present knowledge about the effects of chronic opioid exposure during pregnancy is derived from the study of opioid-abusing patients.36-38 Chronic opioid use in pregnancy is associated with low birth weight and decreased head circumference. However, the contribution of comorbidities, including polysubstance abuse and smoking, is not clear. Enrollment and compliance with methadone therapy for opioid dependence improves birth weight and prolongs gestation, supporting the role of therapy during gestation.38 Until recently, there was no evidence to suggest a relationship between exposure to any of the opioid agonists or

650

PA RT 4 Clinical Conditions: Evaluation and Treatment

agonist-antagonists during pregnancy and large categories of major or minor malformations. The Collaborative Perinatal Project monitored 50,282 mother-child pairs and included exposures to codeine, propoxyphene, hydrocodone, meperidine, methadone, morphine, or oxycodone.20 Only codeine was found to have an association with malformation (respiratory), but other studies have not confirmed this. No evidence was found for either agent to suggest a relationship to large categories of major or minor malformations. In the spring of 2011, a study by Broussard and colleagues used data gathered from the National Birth Defects Prevention Study (1997–2005), which consisted of an ongoing multi-site, population-based, case-control study of over 30 types of major structural congenital disabilities.39 They reported that opioid treatment between one month prior to pregnancy and through the first trimester was associated with a greater risk of conoventricular septal defects, atrioventricular septal defects, hypoplastic left heart syndrome, spina bifida, and gastroschisis. Codeine and hydrocodone represented 69% of all reported exposures. However, these results should be interpreted with caution, as some sample sizes were borderline, and further investigation is necessary. It is important to understand that the increased relative risk of a rare congenital disability with exposure to medications usually only translates into a modest absolute increase in risk above baseline. Healthcare providers must weigh the risks and benefits when prescribing to pregnant women or those of childbearing age. It is important to note that there is an increased risk warning for neonatal opioid dependence when mothers are treated with opioid medications for prolonged periods during pregnancy. Abrupt cessation of opioids in the opioid dependent patient late in pregnancy can precipitate fetal withdrawal in utero, characterized by fetal tachycardia and fetal death.40 Therefore pregnant women who are opioid dependent, regardless of whether the use is prescription or illicit, should not undergo acute withdrawal late in pregnancy without careful fetal monitoring. The general recommendation is to offer continuation of narcotic medication (for prescription use) or opioid substitution therapy such as methadone or buprenorphine for women using illicit drugs, with entry into treatment programs.41-43 Additional benefits of treatment programs include improved prenatal care, higher birth weight, and reduced infectious risk to the neonate. Neonates exposed to opioid medications in utero can develop dependence and manifest withdrawal symptoms in the first few days of life, known as neonatal abstinence syndrome (NAS). Characterized in mild cases by irritability and increased tone, severe neonatal withdrawal is associated with poor feeding and seizures.44 NAS occurs in 30%–90% of infants exposed to heroin, methadone, or buprenorphine in utero37,38,42,45 when mothers are treated for illicit opioid use. Patients requiring methadone to treat chronic pain tend to require lower doses of methadone, and their infants have a lower incidence of NAS, approximately 11%.46 Most infants who have narcotic withdrawal are symptomatic by 48 hours postpartum, but there are reports of withdrawal symptoms beginning 7–14 days postpartum.37 Neonates with prenatal exposure to opiates for long periods may require very slow weaning (as slow as a 10% reduction every third day) to prevent withdrawal symptoms.47 The AAP considers methadone to be compatible with breastfeeding.9 Recognition of infants at risk for NAS and institution of appropriate supportive and medical therapy typically results in little short-term consequence to the infant.48,49 The long-term effects of in utero opioid exposure are unknown. Chasnoff has considered environmental and socioeconomic factors that influence child

development and concluded that no definite data exist to demonstrate long-term developmental sequelae from in utero opioid exposure.50 Buprenorphine, a partial μ-opioid agonist and κ-opioid antagonist, is currently used for office-based treatment of opioid dependence but is increasing in use for the treatment of chronic pain.51,52 Obstetricians and anesthesiologists will encounter patients treated with buprenorphine with increasing frequency. This drug’s low intrinsic receptor efficacy results in a ceiling effect and a diminished risk of overdose compared with methadone.43 While methadone has been used for over 40 years in the treatment of opioid dependence, buprenorphine is now advocated as first line therapy.42 The literature that reports buprenorphine in pregnancy remains limited, but buprenorphine has been found to be superior to methadone in reducing signs of withdrawal in newborns, thus requiring less medication and hospitalization time for the babies. In a randomized, double-blind trial comparing 175 women and infants treated with methadone versus buprenorphine, infants who had prenatal exposure to buprenorphine required significantly less morphine for the treatment of NAS, a significantly shorter period of NAS treatment, and significantly shorter hospitalization than those with prenatal exposure to methadone. However, there was no difference in the number of neonates requiring NAS treatment, peak NAS score, head circumference, or any other neonatal or maternal outcome.43,53 However, in buprenorphine-maintained patients, acute pain can be challenging to treat because of the partial antagonist activity at the mu receptor. While treatment of opioid dependence requires only once-daily dosing, opioid dependent patients receiving buprenorphine with mild pain may receive analgesia simply by splitting the same daily dose into dosing intervals every 6 hours.54 According to the drug manufacturer insert, buprenorphine is not recommended during breastfeeding. However, it appears to be safe.42 Because of the low levels in breast milk and the poor oral bioavailability in the infant, the infant is exposed to about 1%–1.4% of the maternal weight-adjusted dose. The risk of breast milk induced addiction appears unlikely, and there is no reason to time breastfeeding to avoid peak levels of buprenorphine. The amount of buprenorphine in the milk may not be sufficient to prevent neonatal withdrawal, and treatment of the infant may be required.55 Fentanyl is one of the most common parenteral opioid analgesics administered during the perioperative period. As with all opioid analgesics, administration of fentanyl to the mother immediately prior to delivery may lead to respiratory depression in the newborn.56 Maternal administration of fentanyl or other opioids may also cause loss of the normal variability in fetal heart rate. Loss of fetal heart rate variability can signal fetal hypoxemia; thus the administration of opioids during labor may deprive obstetric caregivers of a useful tool for assessing fetal wellbeing.57 Meperidine undergoes extensive hepatic metabolism to normeperidine, which has a long elimination half-life (18 hours). Repeated dosing can lead to accumulation, especially in patients with renal insufficiency.58 Normeperidine causes excitation of the central nervous system that manifests as tremors, myoclonus, and generalized seizures.59 Significant accumulation of normeperidine is unlikely in the parturient who receives single or infrequent doses. However, meperidine offers no advantages over other parenteral opioids. Although mixed agonist-antagonist opioid analgesic agents are widely used to provide analgesia during labor, they do not appear to offer any advantage over pure opioid agonists. In a blinded randomized comparison of meperidine and nalbuphine during labor,

 

CHAPTER 45

the two agents appeared to provide comparable analgesic effects as well as similar neonatal Apgar and neurobehavioral scores.60 Use of nalbuphine61 or pentazocine62 during pregnancy can lead to NAS. Nalbuphine may also cause a sinusoidal fetal heart rate pattern after maternal administration, thereby complicating fetal assessment.63 Low-affinity opioid agonists, such as tramadol (Ultram), are being used with increasing frequency, in part because of a perceived lessening of the abuse and addiction potential. There is no evidence that acute use of tramadol for labor analgesia has any advantages over more traditional opioids. According to the manufacturer’s prescribing information, no drug related teratogenic effects were observed in the progeny of rats treated orally with combination tramadol and acetaminophen at 1.6 times the maximum human daily dose. However, at this dose, embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs.64 The intramuscular application of tramadol in mothers in labor reaches the neonate almost freely, confirming a high degree of placental permeability. The neonate already possesses the complete hepatic capacity for the metabolism of tramadol into its active metabolite.65 However, the renal elimination of the active tramadol metabolite M1 is delayed, in line with the slow maturation process of renal function in neonates. Neonates born to women who are chronically receiving tramadol during pregnancy carry a risk of withdrawal. There are no studies on the relative rates of NAS comparing tramadol with other opioid analgesics. Postoperative analgesia for most pregnant women undergoing non-obstetric surgery can be readily provided using narcotic analgesics (Tables 45.1 and 45.2). Fentanyl, morphine, and hydromorphone are all safe and effective alternatives when a potent opioid is needed for parenteral administration. There are a range of safe and effective oral analgesics. For mild pain, acetaminophen alone or in combination with hydrocodone is a good alternative. For moderate pain, oxycodone alone or in combination with acetaminophen is effective. More severe pain may require morphine or hydromorphone, both of which are available for oral administration. Narcotic analgesics can also be administered into the intrathecal or epidural compartments to provide postoperative analgesia. Such neuraxial administration of hydrophilic agents, e.g. morphine, greatly reduces total postoperative opioid requirements while providing excellent analgesia.66 Spinal or epidural delivery of opioids can be used to minimize maternal plasma concentrations, thereby reducing placental transfer to the fetus or exposure of the breastfeeding infant. Maternal use of opioids can result in infant drowsiness, central nervous depression, and even death. Opioids are excreted into breast milk. Pharmacokinetic analysis has demonstrated that breast milk concentrations of codeine and morphine are equal to or somewhat higher than maternal plasma concentrations.67 Meperidine use in breastfeeding mothers via patientcontrolled analgesia (PCA) has resulted in significantly greater neurobehavioral depression of the breastfeeding newborn than equianalgesic doses of morphine.68 After absorption from the infant’s gastrointestinal tract, opioids contained in ingested breast milk undergo significant first-pass hepatic metabolism. Morphine undergoes glucuronidation to inactive metabolites.67 Meperidine undergoes N-demethylation to the active metabolite normeperidine.69 Normeperidine’s half-life is markedly prolonged in the newborn,70 so that regular breastfeeding leads to accumulation and the resultant risks of neurobehavioral depression and seizures. The AAP considers the use of many opioid

Managing Pain During Pregnancy and Lactation

651

TABLE Oral Analgesics for Treating Pain During 45.1 Pregnancy*

Equianalgesic Oral Dose (Equianalgesic Oral Dose) (mg)

Drug

How Supplied

Acetaminophen

—

325, 500, 625 mg tabs; 500 mg/15 mL elixir

Codeine

60

15, 30, 60 mg tabs; 15 mg/5 mL elixir

Acetaminophen with codeine

—

300 • 15,300 • 30, 300 • 60 mg tabs; 120 • 12/5 mL elixir

Hydrocodone

60

—‡

Acetaminophen with hydrocodone

—

500 • 2.5, 500 • 5, 500 • 7.5, 660 • 10 mg  tabs; 500 • 7.5/15 mL elixir

Oxycodone

10

5 mg tabs; 5 mg/5 mL elixir

Acetaminophen with oxycodone

—

325 • 5, 500 • 5 mg tabs; 325 • 5/5 mL elixir

Morphine

20

15, 30 mg tabs; 10, 20 mg/5 mL elixir

Hydromorphone

2

2, 4, 8 mg tabs; 5 mg/5 mL elixir

*There is wide variability in the duration of analgesic action from patient to patient. All the oral agents listed are generally started with dosing every 4–6 hours. The dosing interval can then be adjusted as needed to maintain adequate analgesia. ‡

There is no oral formulation of hydrocodone alone available in the United States.

analgesics, including codeine, fentanyl, methadone, morphine, and propoxyphene, to be compatible with breastfeeding.9 There are insufficient data to determine the safety of buprenorphine with breastfeeding. However, the excretion of buprenorphine into breast milk is minimal.71 TABLE Analgesics for Moderate to Severe Pain During 45.2 Pregnancy*

Drug

Equianalgesic Parenteral Dose

Equianalgesic Oral Dose

Fentanyl

50 µg

—

Hydromorphone

1 mg

2–4 mg

Morphine

5 mg

30–60 mg

Meperidine

50 mg

150–300 mg

*There is wide variability in the duration of analgesic action from patient to patient. All the parenteral agents listed are generally started with parenteral dosing every 3–4 h and the oral agents every 4–6 h. The dosing interval can then be adjusted as needed to maintain adequate analgesia.

652

PA RT 4 Clinical Conditions: Evaluation and Treatment

Local Anesthetics Few studies have focused on the potential teratogenicity of local anesthetics. Lidocaine and bupivacaine do not appear to pose a significant developmental risk to the fetus. In the Collaborative Perinatal Project,20 only mepivacaine had any suggestion of teratogenicity. However, the number of patient exposures was inadequate to draw conclusions. Animal studies have found that continuous exposure to lidocaine throughout pregnancy does not cause congenital anomalies but may decrease neonatal birth weight.72 Continuous exposure to local anesthetics is unusual but might be seen with the frequent use of local anesthetic patches or creams, which are used for postherpetic neuralgia and other neuropathic pain states. Neither lidocaine nor bupivacaine appear in measurable quantities in breast milk after epidural local anesthetic administration during labor.7 Intravenous infusion of high doses (2–4 mg/min) of lidocaine to suppress cardiac arrhythmias has led to minimal levels in breast milk.73 Based on these observations, continuous epidural infusion of dilute local anesthetic solutions for postoperative analgesia should result in only small quantities of drug reaching the fetus. The AAP considers local anesthetics to be safe for use in the nursing mother.9 Mexiletine is an orally active antiarrhythmic agent with structural and pharmacologic properties similar to those of lidocaine. This agent has shown promise in the treatment of neuropathic pain. Mexiletine is lipid-soluble and freely crosses the placenta. There are no controlled studies in humans of mexiletine use during pregnancy. However, studies in rats, mice, and rabbits using doses up to four times the maximum daily dose in humans have demonstrated an increased risk of fetal resorption but not teratogenicity.74 Mexiletine appears to be concentrated in breast milk. However, based on expected breast milk concentrations and average daily intake of breast milk, the infant would receive only a small fraction of the usual pediatric maintenance dose of mexiletine.75 The AAP considers mexiletine use to be compatible with breastfeeding.9

Steroids Corticosteroids may be used commonly in pregnancy in patients with autoimmune disease and those with premature rupture of membranes. There is variability in placental metabolism and transplacental passage of steroids depending on the preparation.10 Most corticosteroids cross the placenta, although prednisone and prednisolone are inactivated by the placenta,2 while dexamethasone and betamethasone do not undergo significant metabolism.10 Fetal serum concentrations of prednisone are less than 10% of maternal levels. No increase in malformations was seen among 145 patients exposed to corticosteroids during their first trimester of pregnancy.20 The use of corticosteroids during a limited trial of epidural steroid therapy in the pregnant patient probably poses a minimal fetal risk (see further discussion later in this chapter). In breastfeeding mothers, less than 1% of a maternal prednisone dose appears in the nursing infant over the next three days.76 This amount of steroid exposure is unlikely to affect infant endogenous cortisol secretion.76

Benzodiazepines Benzodiazepines are among the most frequently prescribed drugs and are often used as anxiolytic agents to treat insomnia and as skeletal muscle relaxants in patients with chronic pain.77 First

trimester exposure to benzodiazepines may be associated with an increased risk of congenital malformations. Diazepam may be associated with cleft lip or cleft palate,78 and with congenital inguinal hernia.79 However, epidemiologic evidence has not confirmed the association of diazepam with cleft abnormalities. The incidence of cleft lip and palate remained stable after the introduction and widespread use of diazepam.80 Epidemiologic studies have confirmed the association of diazepam use during pregnancy with congenital inguinal hernia.80 Benzodiazepine use immediately before delivery also increases the risk of fetal hypothermia, hyperbilirubinemia, and respiratory depression.81 Two other benzodiazepines have been evaluated for teratogenicity. Chlordiazepoxide has been reported to produce a four-fold increase in congenital anomalies, including spastic diplegia, duodenal atresia, and congenital heart disease.82,83 However, a study of over 200,000 Michigan Medicaid recipients did not support these earlier findings.84 Instead, this study found a high co-prevalence of alcohol and illicit drug use in patients receiving benzodiazepines. Benzodiazepine use alone did not appear to be a risk factor for congenital anomalies. Oxazepam use during pregnancy has also been associated with congenital anomalies, including a syndrome of dysmorphic facial features and central nervous system defects.85 In addition to the risks of teratogenesis, neonates who are exposed to benzodiazepines in utero may experience withdrawal symptoms immediately after birth.86 Diazepam and its metabolite desmethyldiazepam in the breastfeeding mother can be detected in the infant’s serum for up to 10 days after a single maternal dose. This is caused by the slower metabolism in neonates than in adults.87 Clinically, infants who are nursing from mothers receiving diazepam may show sedation and poor feeding.87 It appears most prudent to avoid any use of benzodiazepines during organogenesis, near the time of delivery, and during lactation.

Anti-depressants Anti-depressants are often used in the management of migraine headaches, as well as for analgesic and anti-depressant purposes in chronic pain states. Selective serotonin reuptake inhibitors (SSRIs) have become the mainstay for the treatment of depression and are widely prescribed. As with most medications, increased use has been associated with increased reports of adverse effects in pregnancy and neonates. Although initially thought to be safe in early pregnancy, unpublished epidemiologic reports from GlaxoSmithKline have raised concern that paroxetine, one of the most widely prescribed anti-depressants, may be associated with an increase in malformations when used in the first trimester, particularly cardiovascular malformations.88 This recent retrospective epidemiologic study of 3581 pregnant women exposed to paroxetine or other anti-depressants during the first trimester has suggested an increased risk of overall major congenital malformations for paroxetine than other anti-depressants (odds ratio [OR], 2.20; 95% CI, 1.34–3.63). There was also an increased risk for cardiovascular malformations with the use of paroxetine than other antidepressants (OR, 2.08; 95% CI, 1.03–4.23); 10 out of 14 infants with cardiovascular malformations had ventricular septal defects. Use late in pregnancy has also recently become a concern, with reports of NAS, including jitteriness or seizures,89 and pulmonary hypertension in the newborn.90 While paroxetine is generally discouraged in pregnancy, citalopram, and sertraline are considered an option and have not been associated with congenital disabilities. It is important to note that although the relative risk of adverse outcomes has increased, the incidence of malformations (1%–3%)

 

CHAPTER 45

and pulmonary hypertension (0.5%–1%) remain low, whereas the presence of severe depression in pregnant women is high (15%). As with all medications, the risk of no medication must be carefully weighed against the risk of treatment. Many women will need to remain on anti-depressants throughout pregnancy, and the low incidence of adverse outcomes remains reassuring. Although tricyclic anti-depressants have had a more limited role in the treatment of depression, they can be of benefit in patients with chronic pain.91 Amitriptyline is teratogenic in hamsters (encephaloceles) and rats (skeletal defects).13 Imipramine has been associated with several congenital disabilities in rabbits but not in rats, mice, or monkeys.92 Although there have been case reports of human neonatal limb deformities after maternal amitriptyline and imipramine use, large human population studies have not revealed association with any congenital malformation, with the possible exception of cardiovascular defects after maternal imipramine use.13 There have been no reports linking maternal desipramine use with congenital disabilities. Withdrawal syndromes have been reported in neonates born to mothers using nortriptyline, imipramine, and desipramine, with symptoms including irritability, colic, tachypnea, and urinary retention.13 Amitriptyline, nortriptyline, and desipramine are all excreted into human milk. Pharmacokinetic modeling has suggested that infants are exposed to about 1% of the maternal dose.93 In a critical review of the literature regarding the use of anti-depressants during breastfeeding, Wisner and colleagues have concluded that amitriptyline, nortriptyline, desipramine, clomipramine, and sertraline are not found in quantifiable amounts in nurslings and reported no adverse effects. They recommended the use of these agents as the antidepressants of choice for breastfeeding women.93 Fluoxetine is also excreted into human milk and has a milk-to-plasma ratio of about 0.3. No controlled studies are available to guide fluoxetine therapy during lactation.13 However, colic and high infant serum levels have been reported.94 Maternal doxepin use has also been associated with elevated plasma levels of the metabolite N-desmethyldoxepin and respiratory depression in a nursing infant.95 The AAP considers all anti-depressants to have unknown risk during lactation.9 Duloxetine, a selective norepinephrine reuptake inhibitor (SNRI), is representative of a new class of drug that combines inhibition of serotonin and norepinephrine reuptake. Duloxetine is efficacious for depression and neuropathic pain and may have particular efficacy in diabetic neuropathy. Neonates born to mothers receiving SSRI or SNRI drugs may have a withdrawal reaction, as discussed earlier. Although the relative risks and benefits of breastfeeding when a woman is receiving duloxetine have not been fully evaluated, the manufacturer advises against its use during breastfeeding.

Anti-convulsants Several anti-convulsant medications are used in chronic pain management. However, most data regarding the fetal risk of major malformation in women taking anti-convulsants are derived from the treatment of epilepsy. Although epilepsy itself is not associated with an increased risk of congenital malformations, some theoretical risk may exist. Despite this, data from anti-convulsant use in epileptic women is used to assess the risk of the same medications when used for pain conditions. The American Academy of Neurology and American Epilepsy Society subcommittee recently undertook a systematic review of the evidence for teratogenic potential and perinatal outcomes among pregnant women on antiepileptic medication.96,97 The review found that valproic acid exposure, especially in the first trimester, contributes to neural

Managing Pain During Pregnancy and Lactation

653

tube defects, facial cleft, and possibly hypospadias. They also found that neonates of women taking anti-convulsants were also more likely to be small for gestational age and have lower Apgar scores. Treatment with valproic acid is more likely to be associated with major congenital malformation than treatment with carbamazepine or lamotrigine. There is a possible dose relationship for the development of congenital malformations for valproic acid during the first trimester. Though not consistent throughout all studies, a valproic acid dose of greater than 1000 mg daily may be associated with the greatest risk of malformations. In the same review, carbamazepine was associated with an increased risk of cleft palate, but this was not confirmed by another study focusing specifically on carbamazepine using the European Surveillance of Congenital Anomalies (EUROCAT) database. Though this study did not find an association between carbamazepine and clefts, it did find an association with spina bifida. Data suggests that topiramate (Topamax) and its generic version increase the risk of cleft lip and cleft palate in babies born to women who use the medication during pregnancy.98 Its use has also been linked to low birth weight.99 Gabapentin is an anti-convulsant that is being used for the treatment of neuropathic pain syndromes. Little information exists about the safety of gabapentin in pregnant women, and thus far, the Gabapentin Registry Study does not show an increased risk for adverse maternal and felt events.100 In their prescribing information, the manufacturer101 has reported a series of nine women who received gabapentin during their pregnancies. Four women elected pregnancy termination, four had normal outcomes, and one neonate had pyloric stenosis and an inguinal hernia. Insufficient data exist to counsel patients regarding the fetal risk of gabapentin use during pregnancy. A drug similar to gabapentin is pregabalin, which combines anti-convulsant activity and affinity to the g-aminobutyric acid receptor. The main applications of pregabalin are for the treatment of pain associated with diabetic neuropathy and postherpetic neuralgia. Patients contemplating childbearing who are receiving anticonvulsants should have their pharmacologic therapy critically evaluated. Those taking anti-convulsants for neuropathic pain should strongly consider discontinuation during pregnancy, particularly during the first trimester. Consultation with a perinatologist is recommended if continued use of anti-convulsants during pregnancy is being considered. Frequent monitoring of serum anti-convulsant levels and folate supplementation should be initiated, and maternal a-fetoprotein screening may be considered to detect fetal neural tube defects. The use of anti-convulsants during lactation does not seem to be harmful to infants. Phenytoin, carbamazepine, and valproic acid appear in small amounts in breast milk, but no adverse effects have been noted.13 There are limited data on both pregabalin and gabapentin.

Ergot Alkaloids Ergotamine can have significant therapeutic efficacy for the episodic treatment of migraine headaches. However, even low doses of ergotamine are associated with significant teratogenic risk, and higher doses have caused uterine contractions and spontaneous abortion.91 During lactation, ergot alkaloids are associated with neonatal convulsions and severe gastrointestinal disturbances.13 Occasionally, methyl-ergonovine is systemically administered to treat uterine atony and maternal hemorrhage immediately after delivery. This brief exposure does not contraindicate breastfeeding.102

654

PA RT 4 Clinical Conditions: Evaluation and Treatment

Caffeine

β-Blockers

Caffeine is a methylxanthine often used in combination with analgesics for the management of vascular headaches. It is readily absorbed from the gastrointestinal (GI) tract and crosses the placenta such that concentrations in the fetus are similar to maternal plasma levels.103 Early studies of caffeine ingestion during pregnancy suggested an increased risk of intrauterine growth retardation, fetal demise, and premature labor,104 while more recent studies do not.105 Although the data are not strongly compelling against caffeine use in pregnancy, most obstetricians recommend that pregnant women limit caffeine intake to less than 300 mg per day. To date, there is no evidence for congenital disabilities related to caffeine.106 Caffeine use is also associated with certain cardiovascular changes. Ingestion of modest doses of caffeine (100 mg/m2, a dose similar to that found in two cups of brewed coffee) in caffeine-naïve subjects produces modest cardiovascular changes in mother and fetus, including increased maternal heart rate and mean arterial pressure, increased peak aortic flow velocities, and decreased fetal heart rate.107 The modest decrease in fetal heart rate and increased frequency of fetal heart rate accelerations may confound the interpretation of fetal heart tracings. Caffeine ingestion is also associated with an increased incidence of tachyarrhythmia in the newborn, including supraventricular tachyarrhythmias, atrial flutter, and premature atrial contractions.108 Many over-the-counter analgesic formulations contain caffeine (typically in amounts from 30–65 mg/dose), and the use of these preparations must be considered when determining total caffeine exposure. Moderate ingestion of caffeine during lactation (up to two cups of coffee/day) does not appear to affect the infant. Breast milk usually contains less than 1% of the maternal dose of caffeine, with peak breast milk levels appearing 1 hour after maternal ingestion. Excessive caffeine use may cause increased wakefulness and irritability in the infant.

Propranolol and other b-blockers are used for chronic prophylaxis against migraine and non-migraine vascular headaches. Most of the studies on b-blocker use during pregnancy involve women being treated for hypertension instead of migraine prophylaxis, and hypertension itself may increase the risk for SGA.114 A 2009 Cochrane review looking at b-blocker use for mild to moderate hypertension during pregnancy found that the effect of b-blockers on the perinatal outcome is unclear.115 There is no evidence that propranolol is teratogenic. Fetal effects noted with maternal consumption of propranolol include decreased weight, potentially because of a modest decrease in maternal cardiac output, with consequent diminished placental perfusion.116 Patients should be aware that fetal toxicity can result in complications, including intrauterine growth retardation, hypoglycemia, bradycardia, and respiratory depression.116 Longer acting agents should lead to less fluctuation in maternal and fetal blood concentrations and perhaps less fluctuation in the drug effects on fetal heart rate. In the lactating mother, propranolol doses of up to 240 mg/day appear to have minimal neonatal effects, resulting in subtherapeutic exposure to the infant.

Sumatriptan Sumatriptan is a selective serotonin agonist that has achieved widespread use because of its efficacy in the treatment of migraine headaches. It has been associated with fetal malformations in rabbits but not in rats.109 Limited data in humans have not demonstrated any strong teratogenic effects.91,110 Sumatriptan is advantageous in the treatment of migraine headache in pregnancy because it does not share uterine contractile properties with ergotamine and would not likely have abortifacient effects.111 Beginning in January 1996, Glaxo Welcome established a registry to prospectively evaluate the risk of sumatriptan use during pregnancy.112 The accumulated evidence from sumatriptan’s pregnancy registry and other studies suggest that this drug is a safe therapeutic option for the treatment of migraine attacks in pregnant women. A minimal amount of sumatriptan is excreted into breast milk, and it is considered safe in breastfeeding. The use of sumatriptan during lactation has not been well studied. One study of a single 6 mg dose of subcutaneous sumatriptan given to lactating women found total breast milk sumatriptan to be only 0.24% of the maternal dose. Because sumatriptan is poorly absorbed from the infant GI tract, only 14% of the drug ingested by the fetus would be bioavailable. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 h after injection.113

Marijuana Marijuana is the most commonly used dependent substance in pregnancy.117 This is likely because of increased use in the generalized population for medical and recreational use and de-stigmatization of the substance. California first made marijuana legal in 1996, and its use in the United States has steadily increased since that time. At the time of writing this chapter, 33 states and the District of Columbia have medical cannabis programs, 11 states have legalized recreational use, and another 16 states have decriminalized. This increase in legalization has also increased the perception of safety, although the chemical concentration of tetrahydrocannabinol (THC) has increased dramatically. While the potency of THC was about 4% on average in marijuana in 1995, it has increased to about 12% now. Over a similar time frame, the number of women of reproductive age who believe there is no risk to regular marijuana use has increased from 4.6%–19%.118 The American College of Obstetricians and Gynecologists118 and the Centers for Disease Control117 currently recommend that all pregnant women are screened for the use of marijuana and encouraged to discontinue use during pregnancy. It is known that THC does cross the placenta and into breast milk, resulting in fetal and neonatal exposure. There is a limitation of evidence for outcomes with marijuana use during pregnancy and breastfeeding as most of the studies are retrospective and based on patient self-reporting, likely leading to underreporting. Additionally, many studies do not adjust for confounding factors such as tobacco use and socioeconomic status. However, there is enough human and animal data to suggest potential harm with the use of cannabis. Marijuana use may be associated with long-term adverse neurobehavioral outcomes, preterm birth, stillbirth, growth restriction, and neonatal intensive care admissions. Therefore women should be educated to refrain from marijuana use during pregnancy and lactation.118

Evaluation and Treatment of Pain During Pregnancy Pain medicine specialists may be asked to consult on patients with uncontrolled pain during the course of pregnancy. Often, severe pain can arise from an extreme form of one of the more common

 

CHAPTER 45

musculoskeletal pain syndromes of pregnancy, including abdominal wall and ligamentous pain, hip pain, and pelvic girdle pain. Thus working knowledge of the painful musculoskeletal conditions that occur during pregnancy is essential. Low back pain and migraine headaches are very common and will be discussed during pregnancy because these are among the most common problems encountered in practice. Finally, although sickle cell pain crisis is less common, it provides a good example of the approach to managing chronic recurrent pain during the course of pregnancy and will be discussed below

Managing Pain During Pregnancy and Lactation

Area of hematoma

Musculoskeletal Considerations in Pregnancy

Pain radiates

Abdominal Wall and Ligamentous Pain Abdominal wall pain during pregnancy typically results in prompt evaluation by an obstetrician. One of the most common causes of abdominal pain early in pregnancy is miscarriage, which presents with abdominal pain and vaginal bleeding. Unruptured ectopic pregnancy and ovarian torsion may present with vague hypogastric pain and suprapubic tenderness. Once these conditions requiring the immediate attention of an obstetrician have been ruled out, myofascial causes of abdominal pain should be considered. The round ligaments stretch as the uterus rises in the abdomen. If the pull is too rapid, small hematomas may develop in the ligaments (Fig. 45.1). This usually begins at 16–20 weeks of gestation, with pain and tenderness localized over the round ligament, which radiates to the pubic tubercle.119 Treatment is bed rest and local warmth, along with oral analgesics in more severe cases. Less common is abdominal pain arising from hematoma formation within the sheath of the rectus abdominis muscle (Fig. 45.2). As the uterus expands, the muscles of the abdominal wall become greatly overstretched. Rarely, the rectus muscle may dehisce, or the inferior epigastric veins rupture behind the muscle. Severe pain localized to a single segment of the muscle often follows a bout of sneezing. Diagnosis of rectus hematoma is made when localized pain is exacerbated by tightening the abdominal muscles (raising the head in the supine position). Ultrasonography can help confirm the diagnosis. Conservative management with bed rest, local heat, and mild analgesics are often all that is needed.

Round ligament

• Figure 45.1  Abdominal pain arising from stretch and hematoma forma-

tion in the round ligament usually presents between 16 and 20 weeks of gestation, with pain and tenderness over the round ligament, which radiates to the pubic symphysis. (Adapted with permission from Chamberlain G. ABC of antenatal care. Abdominal pain in pregnancy. Br Med J. 1991;302:1390–1394.)

Superior epigastric vessels

Rectus abdominis External oblique

Hip Pain Two relatively rare conditions, osteonecrosis and transient osteoporosis of the hip, occur with somewhat greater frequency during pregnancy.120 Although the exact cause is unknown, high levels of estrogen and progesterone in the maternal circulation and increased interosseous pressure may contribute to the development of osteonecrosis.121 Transient osteoporosis of the hip is a rare disorder characterized by pain and limitation of motion of the hip and osteopenia of the femoral head.122 Both conditions present with hip pain during the third trimester, which may be sudden or gradual in onset. Osteoporosis is easily identified, with plain radiography demonstrating osteopenia of the femoral head and preservation of the joint space. Osteonecrosis is best evaluated with magnetic resonance imaging (MRI), which will demonstrate changes before they appear on plain radiographs. Both conditions are managed symptomatically during pregnancy. Limited weight bearing is essential in transient osteoporosis of the hip to avoid fracture of the femoral neck.122

655

Area of hematoma Inferior epigastric vessels

• Figure 45.2  Stretch

of the abdominal wall in pregnancy can tear the rectus abdominis muscle or inferior epigastric veins and form a painful hematoma within the rectus sheath. Pain is well localized and can be severe, often starting after a bout of coughing or sneezing. (Adapted with permission from Chamberlain G. ABC of antenatal care. Abdominal pain in pregnancy. Br Med J. 1991;302:1390–1394.)

656

PA RT 4 Clinical Conditions: Evaluation and Treatment

• Box 45.2

Signs and Symptoms of the Syndrome of “Pelvic Girdle Pain”

• A history of time- and weight-bearing–related pain in the posterior pelvis, deep to the gluteal area • A positive “posterior pelvic provocation test” (Fig. 45.5) • A pain drawing with well defined markings of stabbing pain in the buttocks distal and lateral to the L5–S1 area, with or without radiation to the posterior thigh or knee, but not into the foot (Fig. 45.6) • Free movements in the hips and spine and no nerve root symptoms • Pain when turning in bed Adapted with permission from Ostgaard HC, Zetherström G, Roos-Hanson E, et al. Reduction of back and posterior pelvic pain in pregnancy. Spine.1994;19:894–900.

Pelvic Girdle Pain Causative Factors and Clinical Presentation Pelvic girdle pain (PGP) is a clinical syndrome with pain localized from the posterior iliac crest and gluteal fold over the anterior and posterior elements of the bony pelvis. Many other terms have described the syndrome, including symphysis pubis dysfunction, pelvic joint insufficiency, pelvic girdle relaxation, and posterior pelvic pain.123 This pain entity is distinct from pregnancy related low back pain (Box 45.2). Pain is often described as stabbing, sometimes burning in the region of the sacroiliac joints, and can extend anteriorly to the region of pubic symphysis. Radiation patterns can include the groin, perineum, and posterior thigh in a non-dermatomal pattern. The location of pain can change during the course of pregnancy. Onset can be from the first trimester to one month postpartum, though most regard the third trimester as the peak of symptoms. In most patients, symptoms subside by six months postpartum. The incidence is difficult to establish given various diagnostic criteria used. Some report the incidence to be between 16% and 25%.124,125 The cause of PGP remains unclear but is likely multifactorial with mechanical, hormonal, and genetic influences. Mechanical factors relate to the separation of the pubic symphysis during pregnancy. Hormonal changes include elevated levels of progesterone and relaxin. Genetic influence is based on epidemiologic findings of increased prevalence among first-degree relatives.

Back Pain Causative Factors and Clinical Presentation Pregnancy related low back pain (PLBP) is characterized as pain in the lumbar region. Fifty percent of women will experience low back pain during pregnancy, which is commonly looked upon as a normal part of pregnancy (Fig. 45.3).126 In one-third of pregnant women, back pain is a severe problem that compromises everyday activity.127 The pain resembles the low back pain of the nonpregnant state and is often described as dull and aching in nature. There can be a limitation to the range of motion of the lumbar spine, and the pain is exacerbated by both forward flexion and palpation of the erector spinae muscles.128 As with PGP, the cause of PLBP is likely multifactorial. To balance the anterior weight of the womb, the lumbar lordosis becomes markedly accentuated during pregnancy and may represent a mechanical cause for the pain.129 Endocrine changes during pregnancy may also play a role in the development of back pain.

Relaxin, a polypeptide secreted by the corpus luteum, softens the ligaments around the pelvic joints and cervix, accommodating the developing fetus and facilitating vaginal delivery. This laxity may cause pain by allowing an exaggerated range of motion.130 The onset of low back pain is usually around the 18th week of pregnancy, with the peak intensity between the 24th and 36th weeks.128 However, the pain can start as early as the first trimester or as late as three weeks postpartum. Sixteen percent of women with PLBP report persistent pain six years later, thus representing pregnancy as a risk factor for persistent low back pain.131 Although radicular symptoms often accompany low back pain during pregnancy, herniated nucleus pulposus (HNP) only has an incidence of 1:10,000.132 Pregnant women do not have an increased prevalence of lumbar disc abnormalities.133 Direct pressure of the fetus on the lumbosacral nerves or lumbar plexus has been postulated as the cause of radicular symptoms.

Evaluation of the Patient With Back and Pelvic Girdle Pain Evaluation of the pregnant patient with low back pain and PGP must begin with a thorough history and physical examination.134 The aim is to exclude other causes of pain as obstetric complications (preterm labor, abruption, degeneration of uterine fibroids, round ligament pain, and chorioamnionitis) may also present with low back pain.135,136 Urologic disorders, including hydronephrosis, pyelonephritis, and renal calculi, may also present with low back discomfort.137 Major morphologic changes occur in the collecting system of pregnant women, including dilation of the calices, renal pelvis, and ureters (Fig. 45.4).138 The physical examination should include complete back and neurologic evaluations. Particular attention should be directed toward the pelvis and sacroiliac joints during the examination. Posterior pelvic pain (sacroiliac dysfunction) can often be distinguished from other causes of low back pain based on physical examination (Figs. 45.5 and 45.6; Table 45.3; Box 45.2). During the physical examination, positive straight leg raise (typical low back pain with or without radiation to the ipsilateral lower extremity) is consistent with sacroiliac subluxation or HNP. Unilateral loss of knee or ankle reflex or the presence of a sensory or motor deficit is suggestive of lumbar nerve root compression. X-ray imaging techniques such as computed tomography are not ideal in pregnancy. However, pregnancy is not an absolute contraindication to radiographic evaluation. Radiation exposure during pregnancy leads to concerns about resultant congenital anomalies, mental retardation, and increased risk of subsequent cancers.139 No detectable growth or mental abnormalities have been associated with fetal exposure to less than 10 rad; the dose received during a typical three-view spinal series typically does not exceed 1.5 rad.140 Plain radiographs will contribute vital information primarily when fracture, dislocation, and destructive lesions of the bone are suspected. MRI has revolutionized diagnostic imaging during pregnancy, proving effective and reliable in the diagnosis of many structural abnormalities.141 Although MRI appears to be safe during pregnancy, there are no long-term studies examining the safety of fetal exposure to intense magnetic fields during gestation.142 Schwartz140 has presented a thorough and insightful review of neurodiagnostic imaging of the pregnant patient. Practical guidelines for the use of radiographic studies in the evaluation of pregnant patients are given in Box 45.3. Electromyography and nerve conduction studies (collectively referred to as EMG) serve as good screening tests in patients with new onset of low back pain accompanied by sensory or motor

 

CHAPTER 45

A

Managing Pain During Pregnancy and Lactation

B

657

C

• Figure 45.3  A

group of 855 women studied between 12 menstrual weeks of pregnancy and delivery reported three types of pain. Back pain was reported by 49% of the women at some point during pregnancy. A, High back pain (10%). B, Low back pain (40%). C, Sacroiliac pain (50%). (Adapted with permission from Ostgaard HC, Andersson GBJ, Karlsson K. Prevalence of back pain in pregnancy. Spine. 1991;16:549–552.)

symptoms. When the clinical presentation is confusing, EMG can aid in differentiating peripheral nerve lesions, polyneuropathies, and plexopathies from single radiculopathies. However, false-negative EMG results are common, especially in the case of a HNP causing compression of a single nerve root.143

aless backache than a control group who did not receive similar instruction.144 Aerobic exercise can be prescribed safely throughout pregnancy.144 However, maintenance of good physical conditioning may not alter the incidence of back pain during pregnancy.145 Nonetheless, the American College of Obstetricians

Prevention and Treatment of Back and Pelvic Girdle Pain Few of the commonly used strategies to prevent low back pain during pregnancy are universally effective. Patients who were instructed in basic lifting techniques experienced significantly

• Figure 45.4  Elevated

progesterone levels and pressure from the expanding uterus lead to dilation of the ureters in pregnancy. Stasis in the urinary tract can lead to pyelonephritis. (Adapted with permission from Chamberlain G. ABC of antenatal care. Abdominal pain in pregnancy. Br Med J. 1991;302:1390–1394.)

• Figure 45.5 

The posterior pelvic provocation test. (Adapted with permission from Ostgaard HC, Zetherstrom G, Roos-Hanson E, et al. Reduction of back and posterior pelvic pain in pregnancy. Spine. 1994;19:894–900.)

658

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE Sacroiliac Subluxation: Criteria for Diagnosis 45.3 and Common Confirmatory Signs

Criterion or Sign

Description

Diagnostic Criterion Sacral pain

The pain is usually unilateral and, in some cases, radiates to the buttock, lower abdomen, anterior medial thigh, groin, or posterior thigh.

Positive Piedallu’s sign

Forward flexion of the lower back results in asymmetric movement of the posterior superior iliac spines (PSISs), with one PSIS becoming higher than the other.

Positive pelvic compression

Pain in the sacral area is provoked by direct bilateral downward pressure on the anterior superior iliac spines (ASISs).

Asymmetry of the ASIS

The ASISs should be examined with the patient in the supine position to eliminate the effect of leg length discrepancy; in sacroiliac subluxation, one ASIS will be higher than the other.

• Figure 45.6 

Areas where pain is felt when the posterior provocation test is performed in women with posterior pelvic pain. (Adapted with permission from Ostgaard HC, Zetherström G, Roos-Hanson E, et al. Reduction of back and posterior pelvic pain in pregnancy. Spine. 1994;19:894–900.)

and Gynecologists recommends specific muscular conditioning exercises to promote good posture and prevent low back pain during pregnancy.146 Treatment of pregnancy related low back and PGP begins with the education of the common causes of pain during pregnancy. Back care classes are available that focus on anatomy, ergonomics, correct posture, and relaxation techniques. If the pain remains poorly controlled, referral to a physical therapist for instruction in body mechanics and low back exercises may be beneficial. In a recent Cochrane review of the treatment of low back pain, pregnant-specific exercise programs, physiotherapy, and acupuncture added to the usual prenatal care appeared to reduce back pain more than just usual prenatal care. Moreover, acupuncture may be more effective than physiotherapy. Participation in water gymnastics programs also reduced the number of back pain related work absences.147 Although the incidence of HNP during pregnancy is low, radicular symptoms are common and often accompany sacroiliac subluxation and myofascial pain syndromes. The use of epidural steroids outside of pregnancy remains controversial.148 The strongest evidence for the efficacy of epidural steroids appears to be in patients with symptoms attributable to acute disk pathology.149 Whereas the risk to the fetus following a single dose of an epidural corticosteroid appears to be low, it is our opinion that epidural steroids should be reserved for the parturient with the new onset of signs (e.g. unilateral loss of deep tendon reflex, sensorimotor change in a dermatomal distribution) and symptoms consistent with lumbar nerve root compression. We believe that it is reasonable to proceed with epidural steroid placement prior to obtaining

Confirmatory Sign Straight leg raise

Passive raising of the patient’s leg, with the knee extended and the patient in the supine position, causes pain, usually at the end range.

Flexion block

With the patient in the supine position, the knee is flexed at 90 degrees and then passively pressed toward the chest; flexion is blocked to half the expected range on the painful side.

Positive Patrick’s test

Placing one heel on the opposite knee, in the recumbent position, and simultaneously rotating the leg outward provokes pain.

Pain at Baer’s point

A point of acute tenderness is found just to the side and below the umbilicus on the painful side, which is about one-third of the way between the umbilicus and ASIS.

Adapted with permission from Daly JM, Frame PS, Rapoza PA. Sacroiliac subluxation: a common, treatable cause of low back pain in pregnancy. Fam Pract Res J. 1991;11:149–159.

imaging studies in such patients. Resolution of the radicular symptoms after epidural steroid treatment may well obviate the need for imaging studies. Guided local anesthetic injection into the sacroiliac joint or the pubic symphysis can have diagnostic and therapeutic value.

 

CHAPTER 45

• Box 45.3

Managing Pain During Pregnancy and Lactation

659

Recommendations for the Use of ­ eurodiagnostic Imaging in the N ­Pregnant Patient

• Determine the necessity of a radiologic examination and the risks involved. • If possible, perform the examination only during the first 10 postmenses days. If the patient is pregnant, delay the examination until the third trimester, or preferably postpartum. • Determine the most efficacious use of radiation for the problem. • Use magnetic resonance imaging (MRI) if possible. • Avoid direct exposure to the abdomen and pelvis. • Avoid contrast agents. • Do not avoid radiologic testing purely for the sake of pregnancy. Remember, you are responsible for providing the best possible care for the patient. The risk to the pregnant patient of not having an indicated radiologic examination is also an indirect risk to the fetus. • If significant exposure is incurred by a pregnant patient, have a radiation biologist (usually stationed in the radiology department) review the radiology examination history carefully so that an accurate dose estimate can be ascertained. • The decision to terminate pregnancy because of excessive radiation exposure is an extremely complex issue. Because any increased risk of malformations is considered negligible unless radiation doses exceed 0.1–0.15 Gy (10–15 rad). The amount of exposure that an embryo or fetus would likely receive from diagnostic procedures is well below the level for which a therapeutic abortion should be considered. • Consent forms are neither required nor recommended. The patient should be informed verbally that any radiologic examinations ordered during pregnancy are considered necessary for her medical care. She should also be informed that the risks to the fetus from computed tomography or plain film radiography are very low and that there are no known risks to humans of MRI. Having the patient sign a consent increases the perceived risks and adds needlessly to her concerns during and after the examination. Adapted with permission from Schwartz RB. Neurodiagnostic imaging of the pregnant patient. In: O Devinsky, E Feldmann, B Mainline (eds). Neurologic Complications of Pregnancy. New York, Raven Press; 1994: 243–248.

As mentioned previously, most clinicians wish to limit exposure to ionizing radiation during pregnancy. Surface ultrasound can be used to aid in entry into the sacroiliac joint. Relief after an intraarticular injection is indicative only of intra-articular pathology. Extra-articular pathologies contributing to PGP, such as strain of superficial long sacroiliac joint ligament, are unlikely to improve after intra-articular injection. Treatment options during pregnancy are limited by the presence of and potential hazard to the fetus. After delivery, the majority of women have improvement of their symptoms within a few months. Non-pharmacologic treatment modalities used during pregnancy include physical therapy with pelvic tilt exercises, use of support belts (Fig. 45.7), rotational manipulation of the sacroiliac joint, water gymnastics, transcutaneous electrical nerve stimulation (TENS), and acupuncture.147 With the use of the TENS unit during pregnancy, there is a theoretical concern about inadvertent induction of labor through the use of certain acupuncture points and fetal cardiac conduction disturbances with the passage of current through the fetal heart. Limited data suggest that TENS is safe during pregnancy. A recent Cochrane review on the use of TENS for the treatment of pain during labor found no deleterious effects on the mother or the fetus.150 Given the theoretical concerns, one recommendation for TENS use during pregnancy is to keep the current density low and avoid certain acupuncture points.151

• Figure 45.7  Proper placement of a trochanteric belt to stabilize painful pelvic joints and decrease back pain.

Migraine Headache During Pregnancy Causative Factors and Clinical Presentation The clinician is often confronted with the occurrence of headaches during pregnancy as recurring headaches happen most commonly during the childbearing years. Migraine can be a disabling disorder that is more prevalent among women than men, thought in part because of the influence of female sex hormones.152 Migraine headaches vary with female reproductive events, including menarche, menstruation, oral contraceptives, pregnancy, and menopause.153 Eighty percent of female migraineurs report the onset of migraine at 10–39 years, suggesting that sex hormones play a significant role in the pathogenesis.154 They typically improve in the first trimester of pregnancy when there is a sudden and sustained increase in estradiol levels.155 In fact, 50%–80% of patients who suffer from migraines experience a significant reduction in frequency or total cessation of migraine attacks during pregnancy. However, women with headaches persisting into the second trimester are less likely to improve after that. Migraine headaches rarely begin during pregnancy, but if they do, they typically occur during the first trimester. Many clinicians believe that the initial presentation of headaches during pregnancy should initiate a thorough search for potentially serious causes.91,156 One report of nine women presenting with migraine-like headaches during pregnancy found that four were severely thrombocytopenic, two met the criteria for preeclampsia,

660

PA RT 4 Clinical Conditions: Evaluation and Treatment

and one had a threatened abortion.156 The literature is replete with reports of intracranial pathology that mimicked migraines during pregnancy, including strokes, pseudotumor cerebri, tumors, aneurysms, arteriovenous malformations, and cerebral venous thrombosis.91 Metabolic causes of headache during pregnancy include illicit drug use (most notably, cocaine157), anti-phospholipid antibody syndrome, and choriocarcinoma.158

Evaluation Patients who present with their first severe headache during pregnancy should be aggressively evaluated. Only when secondary causes of headache in pregnancy, including head trauma, cerebral venous thrombosis, preeclampsia, ICH or subarachnoid hemorrhage, ischemic stroke, vasculitis, or dehydration, have been ruled out should pregnant women be diagnosed with a primary headache. The first step is a detailed history and neurologic examination. Focal neurologic abnormalities, papilledema, and seizures in the setting of headaches warrant further investigation. Suggested diagnostic tests for new onset headache during pregnancy include urinalysis, blood chemistries, hematologic studies, liver function tests, and coagulation studies.154 Brain imaging is also an important component of the workup. MRI without gadolinium is safe in all trimesters and should be the modality of choice during pregnancy.154 In the patient who presents with sudden onset of the “worst headache of my life,” a subarachnoid hemorrhage should be ruled out.91 If the brain computed tomography (CT) is negative for hemorrhage, a lumbar puncture should be performed, and the spinal fluid should be evaluated for subarachnoid blood. Progressively worsening headaches in the setting of sudden weight gain should suggest preeclampsia or pseudotumor cerebri. The triad of elevated blood pressure, proteinuria, and peripheral edema point toward preeclampsia. Furthermore, hyperreflexia and elevated serum uric acid are also found in patients with preeclampsia. Treatment and Prevention For pregnant women with a history of migraines prior to pregnancy and a normal neurologic examination, the therapeutic challenge is to achieve control of the headaches while minimizing the risk to the fetus. Non-pharmacologic techniques, including relaxation, biofeedback, and elimination of certain foods, often suffice for treatment. Marcus and colleagues159 have demonstrated a significant reduction in headache that continued throughout pregnancy and at the one-year follow up using a combination of relaxation training, thermal biofeedback, and physical therapy exercises. If pharmacologic therapy appears warranted, acetaminophen with or without caffeine is safe and effective.160 A drawback to acetaminophen is the potential for medication overuse and rebound headache, which could lead to the development of daily chronic headaches. Ibuprofen and naproxen are the most commonly used NSAIDs for abortive management of migraines. However, as discussed in the prior section, they can have significant effects on pregnancy. The short-term use of mild opioid analgesics such as hydrocodone, alone or in combination with acetaminophen, also appears to carry little risk (Table 45.1). When oral analgesics prove ineffective, hospital admission and administration of parenteral opioids may be required (Table 45.2). Until more information is available on the safety of sumatriptan during pregnancy, it should be used only after other strategies have failed. Triptans are the most used abortive agent in nonpregnant patients but are rarely used during pregnancy. There are pregnancy registries for both sumatriptan and naratriptan to

track pregnancy outcomes after exposure to these medications. At this time, there does not seem to be an increased incidence of teratogenicity or adverse pregnancy outcomes with use in the first trimester. Ergot preparations should be avoided during pregnancy and lactation. They are known to cause prolonged and marked uterine tone and impaired placental flow leading to fetal distress or spontaneous abortion. A history of three to four incapacitating headaches per month warrants consideration of prophylactic therapy.160 If the frequency of the headache is less than three to four per month, but they are severe and unmanageable with acute therapies, prophylactic therapy should be considered to prevent dehydration to the mother, which could cause fetal distress. Daily oral propranolol or atenolol are reasonable choices, although patients should understand that their use is associated with small for gestational age infants. Longer acting agents should lead to less fluctuation in maternal and fetal blood concentrations and perhaps less fluctuation in the drug effects on fetal heart rate. We prefer to use long-acting agents (e.g. atenolol or sustained-release propranolol) based on this theoretical advantage. Although anti-depressants are effective for prophylactic therapy in nonpregnant patients, the most commonly used medications of this class (imipramine, amitriptyline, and nortriptyline) are typically avoided because of insufficient information in the pregnant patient. The selective serotonin receptor inhibitors can be used with caution, especially if there is comorbid depression. Limited anecdotal experience with calcium channel blockers (verapamil, nifedipine, and diltiazem) and mini dose aspirin (81 mg/day) suggests that they may be effective prophylactic agents during pregnancy.91,160

Migraine and Lactation Postpartum headache is common and can occur in 30%–40% of all women.153 Most occur in the first week, and about 50% of those who experience relief of their migraine during pregnancy have recurrence a short time after delivery. This phenomenon may be secondary to the rapid ovarian withdrawal of progesterone and estradiol. Lactation can inhibit ovulatory cycles during the puerperium and is characterized by increased prolactin levels and low estradiol levels. In bottle-feeding women, the hormonal cycle is rapidly restored, which may contribute to it being the main risk factor for postnatal recurrence of migraine.162

Pain in the Pregnant Patient With Sickle Cell Disease Causative Factors and Clinical Presentation Sickle cell disease is an inherited multisystem disorder. The presence of abnormal hemoglobin in red blood cells leads to the cardinal features of the disease, chronic hemolytic anemia, and recurrent painful episodes. Vaso-occlusive crisis is the most common maternal complication noted in parturients with sickle cell hemoglobinopathies.161 Vaso-occlusive crises follow a characteristic pattern of sudden, recurrent pain attacks, usually involving the abdomen, chest, vertebrae, and extremities. One prospective study has demonstrated that the clinical course of women with sickle cell disease is not adversely affected by their pregnancy, as measured by the rate of painful episodes over 100 days.163 The rate was constant before, during, and after the first pregnancy and subsequent pregnancies. Painful episodes occurred at some time during the course of 50% of pregnancies.

 

CHAPTER 45

Most crises during pregnancy are vaso-occlusive and are often precipitated by urinary tract infection, preeclampsia or eclampsia, thrombophlebitis, or pneumonia. Clinically, the individual will describe pain in the bones or joints but may also perceive the soft tissues as being affected. Visceral pain is also common and may be related to events in the liver or spleen. Painful episodes can be variable in severity and duration, with most episodes lasting from three to five days.164

Evaluation Because laboratory evaluation is nonspecific, diagnosis of vasoocclusive crisis begins with excluding other causes for the painful episode, particularly occult infection.162 Complete assessment and the acute management of sickle cell crisis in pregnancy has been reviewed by Martin and coworkers.165

Treatment Management of vaso-occlusive crisis during pregnancy is primarily supportive and symptomatic. A 2009 Cochrane review of intervention for treating a sickle cell crisis during pregnancy attempted to assess the effectiveness and safety of commonly used treatment regimens including red cell transfusion, oxygen therapy, intravenous hydration, analgesic drugs, and steroids. There are no randomized clinical trials on this topic, in part because pregnant women tend to be excluded from clinical trials.166 Most clinicians begin management with aggressive hydration to increase intravascular volume and decrease blood viscosity.165 Supplemental oxygen is essential in those patients with hypoxemia. Partial exchange transfusions to reduce polymerized hemoglobin S remain an integral part of the management of sickle cell disease.167 Prophylactic transfusions may reduce the incidence of severe sickling complications during pregnancy.168 Education about how pregnancy interacts with sickle cell disease can help reduce depression or anxiety, often decreasing the pain that the patient is experiencing. Biofeedback has been shown to reduce the pain of sickle cell crises and the number of days that analgesics were taken.169 Physical therapy techniques (e.g. exercise, splinting, local application of heat) can also be helpful.170 TENS may be helpful when pain is isolated to a limited region.171 The severity of pain dictates the pharmacologic approach to managing sickle cell pain. Although non-opioid analgesics may suffice, oral or parenteral opioids are often required (Tables 45.1 and 45.2). Acetaminophen remains the non-opioid analgesic of choice during pregnancy. Although NSAIDs can be useful adjuncts, particularly for controlling bone pain, they should be used cautiously during pregnancy. Oral analgesic combinations containing acetaminophen and hydrocodone or another weak to moderate potency opioid can be added for more severe pain. For the hospitalized patient with severe sickle cell pain, potent opioid analgesics administered intravenously may be necessary to control pain adequately (Table 45.2). Morphine sulfate is well tolerated and effective for control of severe sickle cell pain.172 Fentanyl and hydromorphone provide reasonable alternatives for patients who cannot tolerate morphine. Administration of morphine via PCA device allows patients a sense of control over their illness. Weisman and Schecter173 have noted that significantly higher doses of opioids may be necessary for the control of vaso-occlusive crisis pain than postoperative pain. In our practice, we aggressively treat individuals with severe sickle cell pain with potent opioids administered via PCA (most often using morphine). As the pain of vaso-occlusive crisis begins to resolve, patients are transitioned to a long-acting oral opioid (such as sustained-release morphine).

Managing Pain During Pregnancy and Lactation

661

This approach allows earlier ambulation and hospital discharge. All opioids are then tapered over the following 7–10 days. The use of regional anesthesia has not been formally studied in sickle cell disease. There are case reports describing epidural analgesia to treat a sickle cell crisis during pregnancy in parturients with pain localized to the trunk or lower extremities.174,175 This technique offers the theoretical advantage of increased microvascular blood flow while providing pain relief without opioids.

Acute Pain in Opioid Dependent Patients Acute pain in the pregnant patient is most often encountered during labor and delivery. Both pain control and withdrawal symptoms are mediated through the m-opioid receptor. Therefore opioid pain medication requires the availability of the m-opioid receptor, which in opioid dependent patients is also occupied by opioid agonist therapy for dependence. No randomized or controlled studies are available to determine whether anesthetic needs differ in opioid dependent patients compared to control patients. One descriptive study has found that 24% of opioid dependent women had difficulty with labor analgesia, and 74% had difficulty with postCesarean analgesia.176 These statistics may overestimate the difficulty in pain control because it was not clear that treatment of opioid dependence was adequate prior to treatment for acute pain. When opioid dependence is untreated and combined with acute pain, opioid needs reflect the combined therapies rather than treatment for pain alone. Although no randomized clinical trials have been performed, we have found that epidural analgesia with a standard dose of local anesthetic and low dose opioid (e.g. 0.0625% bupivacaine with fentanyl, 2 mg/mL) provides adequate intrapartum analgesia. Intrathecal or epidural analgesia using only opioids may not be effective in reducing the need for systemic opioids. Sustained administration of m-opioid agonists by any route can induce both opioid tolerance and abnormal pain similar to neuropathic pain.177 Although previously attributed to pharmacologic tolerance, patients maintained on methadone may experience opioidinduced hyperalgesia, a paradoxical effect mediated in part by the neurotransmitter N-methyl-d-aspartate and possibly by the novel neuropeptide dynorphin.178 Interestingly, dynorphin may be an important mediator of chronic neuropathic pain, a common complaint among opioid dependent patients. There are no trials that investigate opioid use and pain control after vaginal or abdominal delivery in opioid-tolerant patients. Recently published guidelines for the treatment of acute pain in patients maintained on methadone or buprenorphine provide a reasonable approach until more data are available.54 Patients maintained on methadone for opioid dependence should have their methadone continued at the same dose in addition to standard dose opiates as needed for acute pain. The use of non-opioid analgesics should be included, but additional opioid medication should not be withheld. This additional short-acting opioid medication can be gradually discontinued as clinically indicated. If patients cannot tolerate oral medication, methadone can be administered intramuscularly or subcutaneously in two to four divided doses. Patients maintained on buprenorphine pose a more difficult dilemma in the postoperative period. As a combined opioid agonist-antagonist, continued administration of buprenorphine can block the m-mediated analgesic effect of additional short-acting opioids.179 It is of note that although nonpregnant patients receive a combination of buprenorphine and naloxone, monotherapy is prescribed during pregnancy with buprenorphine to avoid naloxone exposure by the neonate.180 Pain control options

662

PA RT 4 Clinical Conditions: Evaluation and Treatment

and non-opioid analgesics include the following54: adding shortacting opioids with the realization that larger doses may be needed or dividing the daily dose of buprenorphine into 6 hour intervals, which can take advantage of the short-term analgesic effect of buprenorphine. Suppose buprenorphine is going to be discontinued with the initiation of another opioid, such as methadone.

In that case, this approach is best attempted with the help of an addiction specialist because restarting the buprenorphine after the acute pain has been resolved can precipitate withdrawal if not carefully managed. In general, buprenorphine should be restarted only when patients have mild withdrawal symptoms (not before) to prevent antagonistic effects at the m-opioid receptor.

Conclusion Many physicians find themselves apprehensive about treating pain in pregnant patients. Evaluation and treatment are limited by the relative contraindication of radiography in the workup and the risks associated with pharmacologic therapy during pregnancy. Nonetheless, familiarity with common pain problems and the

maternal and fetal risks of pain medications can allow the pain physician to help women achieve a more comfortable pregnancy. A single healthcare provider should be designated to coordinate specialist evaluations and integrate their suggestions into a single integrated care plan.

Key Points • Medical management of the pregnant patient should begin with attempts to minimize the use of all medications and use non-pharmacologic therapies whenever possible. • The most critical period for minimizing maternal drug exposure is during early development, from conception through the tenth menstrual week of pregnancy. • Most breast milk is synthesized and excreted during and immediately following breastfeeding. Taking medications after breastfeeding or when the infant has the longest interval between feedings and avoidance of long-acting medications will minimize drug transfer via breast milk. • There is no role for routine use of NSAIDs for pain other than that related to rheumatologic disease or uterine fibroids. • All NSAID use for pain should be discontinued by 34 weeks gestation to prevent pulmonary hypertension in the newborn. • All opioid analgesics carry teratogenic risk but can be used to monitor acute and chronic pain. • For the opioid dependent parturient, buprenorphine has been found to be superior to methadone in reducing signs of withdrawal in newborns, thus requiring less medication and hospitalization time for the babies. • Benzodiazepines should be avoided during organogenesis, near the time of delivery, and during lactation.

• Fifty percent of women will experience low back pain during their pregnancy, and it is commonly looked upon as a normal part of pregnancy. • Although the incidence of HNP during pregnancy is low, radicular symptoms are common and often accompany sacroiliac subluxation and myofascial pain syndromes. • Migraine headaches rarely begin during pregnancy, but if they do, they typically occur during the first trimester. • Patients who present with their first severe headache during pregnancy should be aggressively evaluated, and only when secondary causes of headache in pregnancy have been ruled out should pregnant women be diagnosed with a primary headache. • Postpartum headache is common and can occur in 30%–40% of all women. Most occur in the first week, and about 50% of those who experience relief of their migraine during pregnancy have recurrence a short time after delivery. • Vaso-occlusive crisis is the most common maternal complication noted in the parturient with sickle cell hemoglobinopathies. • Evaluation and treatment of the parturient with pain are limited by the relative contraindication of radiography in the workup and the risks associated with pharmacologic therapy during pregnancy.

Suggested Readings

nested case-control study. Birth Defects Res B Dev Reprod Toxicol. 2006;77:268–279. Rebordosa C, Kogevinas M, Horváth-Puho E, et al. Acetaminophen use during pregnancy: effects on risk for congenital abnormalities. Am J Obstet Gynecol. 2008;198:178.e1–178.e7. Sachs HC, Committee On Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132:e796–e809. Stickrath E. Marijuana use in pregnancy: an updated look at marijuana use and its impact on pregnancy. Clin Obstet Gynecol. 2019;62:185–190.

Alto WA, O’Connor AB. Management of women treated with buprenorphine during pregnancy. Am J Obstet Gynecol. 2011;205:302–308. Kanakaris NK, Kanakaris NK, Roberts CS, Giannoudis PV. Pregnancyrelated pelvic girdle pain: an update. BMC Med. 2011;9:15. Menon R, Bushnell CD. Headache and pregnancy. Neurologist. 2008;14:108–119. Nappi RE, Albani F, Sances G, et al. Headaches during pregnancy. Curr Pain Headache Rep. 2011;15:289–294. Ofori B, Oraichi D, Blais L, et al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a

The references for this chapter can be found at ExpertConsult.com.

References 1. Klingberg MA, Weatherall JA. Epidemiologic Methods for Detection of Teratogens. New York: S Karger; 1990:203–211. 2. Niebyl JR. Nonanesthetic drugs during pregnancy and lactation. In: Chestnut DH (ed). Obstetric Anesthesia: Principles and Practice. St. Louis: Mosby; 1994:229–240. 3. Blake DA, Niebyl JR. Requirements and limitations in reproductive and teratogenic risk assessment. In: Niebyl JR (ed). Drug Use in Pregnancy. Philadelphia: Lea & Febiger; 1988:1–9. 4. Rice SA. Anaesthesia in pregnancy and the fetus: toxicology aspects. In: Reynolds F (ed). Effects on the Baby of Maternal Analgesia and Anaesthesia. London: WB Saunders; 1993:88–89. 5. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 1989;84:924–936. 6. Berlin CM. Pharmacologic considerations of drug use in the lactating mother. Obstet Gynecol. 1981;58(Suppl):17S–23S. 7. Dailland P. Analgesia and anaesthesia and breastfeeding. In: Reynolds F (ed). Effects on the Baby of Maternal Analgesia and Anaesthesia. London: WB Saunders; 1993:268–296. 8. Vorherr H. Drug excretion in breast milk. Postgrad Med. 1974;56: 97–104. 9. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2013;132:e796–e809. 10. Makol A, Wright K, Amin S. Rheumatoid arthritis and pregnancy: safety considerations in pharmacological management. Drugs. 2011;71:1973–1987. 11. Moise KJ, Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor. Effects on the fetal ductus arteriosus. N Engl J Med. 1988;319:327–331. 12. Leal SD, Cavallé-Garrido T, Ryan G, et  al. Isolated ductal closure in utero diagnosed by fetal echocardiography. Am J Perinatol. 1997;14:205–210. 13. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. Baltimore: Williams & Wilkins; 1990. 14. Coomarasamy A, Honest H, Papaioannou S, et al. Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol. 2003;101:1319–1332. 15. Alano MA, Ngougmna E, Ostrea EM Jr, et  al. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics. 2001;107:519–523. 16. Olesen C, Steffensen FH, Nielsen GL, et  al. Drug use in first pregnancy and lactation: a population-based survey among Danish women. The EUROMAP group. Eur J Clin Pharmacol. 1999;55:139–144. 17. Vroom F, van den Berg PB, et al. Prescribing of NSAIDs and ASA during pregnancy; do we need to be more careful? Br J Clin Pharmacol. 2008;65:275–276. 18. Ofori B, Oraichi D, Blais L, et  al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol. 2006;77:268–279. 19. Ostensen M, Ostensen H. Safety of nonsteroidal antiinflammatory drugs in pregnant patients with rheumatic disease. J Rheumatol. 1996;23:1045–1049. 20. Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S. Aspirin and congenital malformations. Lancet. 1976;1:1373– 1375. 21. Li DK, Liu L, Odouli R, et  al. Exposure to non-steroidal antiinflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ. 2003;16:368 327. 22. Stuart MJ, Gross SJ, Elrad H, et  al. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis. N Engl J Med. 1982;307:909–912.

23. James AH, Brancazio LR, Price T. Aspirin and reproductive outcomes. Obstet Gynecol Surv. 2008;63:49–57. 24. Werler MM, Sheehan JE, Mitchell AA. Maternal medication use and risks of gastroschisis and small intestinal atresia. Am J Epidemiol. 2002;155:26–31. 25. Kozer E, Nikfar S, Costei A, et al. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol. 2002;187:1623–1630. 26. Ketorolac prescribing information. Palo Alto, CA: Syntex Laboratories; 1997. 27. Dordoni PL, Della Ventura M, Stefanelli A, et al. Effect of ketorolac, ketoprofen and nefopam on platelet function. Anaesthesia. 1994;49:1046–1049. 28. Sage DJ. Epidurals, spinals and bleeding disorders in pregnancy: a review. Anaesth Intensive Care. 1990;18:319–326. 29. American Society of Regional Anesthesia. Practice guidelines, 2006. Available at: http://www.asra.com/ConsensusStatements. 30. Levy G, Garrettson LK. Kinetics of salicylate elimination by newborn infants of mothers who ingested aspirin before delivery. Pediatrics. 1974;53:201–210. 31. Skeith KJ, Wright M, Davis P. Differences in NSAID tolerability profiles. Fact or fiction? Drug Saf. 1994;10:183–195. 32. Wischnik A, Manth SM, Lloyd J, Bullingham R, Thompson JS. The excretion of ketorolac tromethamine into breast milk after multiple oral dosing. Eur J Clin Pharmacol. 1989;36:521–524. 33. Paracetamol. International Agency for Research on Cancer. Monogr Eval Carcinog Risks Hum. 1990;50:307–332. 34. Rebordosa C, Kogevinas M, Horváth-Puho E, et al. Acetaminophen use during pregnancy: effects on risk for congenital abnormalities. Am J Obstet Gynecol. 2008;198:178.e1–178.e7. 35. Notarianni LJ, Oldham HG, Bennett PN. Passage of paracetamol into breast milk and its subsequent metabolism by the neonate. Br J Clin Pharmacol. 1987;24:63–67. 36. MacGregor SN. Drug addiction and pregnancy. In: Dilts PV, Sciarra JJ (eds). Gynecology and Obstetrics. Philadelphia: JB Lippincott; 1976:1–18. 37. Zelson C, Lee SJ, Casalino M. Neonatal narcotic addiction. Comparative effects of maternal intake of heroin and methadone. N Engl J Med. 1973;289:1216–1220. 38. Strauss ME, Andresko M, Stryker JC, et al. Methadone maintenance during pregnancy: pregnancy, birth, and neonate characteristics. Am J Obstet Gynecol. 1974;120:895–900. 39. Broussard CS, Rasmussen SA, Reefhuis J, et  al. National birth defects prevention study: maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol. 2011;204:314. e1–314.e11. 40. Rementeriá JL, Nunag NN. Narcotic withdrawal in pregnancy: stillbirth incidence with a case report. Am J Obstet Gynecol. 1973;116:1152–1156. 41. Rayburn WF, Bogenschutz MP. Pharmacotherapy for pregnant women with addictions. Am J Obstet Gynecol. 2004;191:1885– 1897. 42. Alto WA, O’Connor AB. Management of women treated with buprenorphine during pregnancy. Am J Obstet Gynecol. 2011;205:302–308. 43. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363:2320–2331. 44. Osborn DA, Jeffery HE, Cole M. Opioid treatment for opi oid withdrawal in newborn infants. Cochrane Database Syst Rev. 2005;3:CD002059. 45. Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of neonatal narcotic withdrawal. J Pediatr. 1976;88:642–645. 46. Sharpe C, Kuschel C. Outcomes of infants born to mothers receiving methadone for pain management in pregnancy. Arch Dis Child Fetal Neonatal Ed. 2004;89:F33–F36.

662.e1

662.e2

References

47. Franck LS, Gregory GA. Clinical evaluation and treatment of infant pain in the neonatal intensive care unit. In: Schecter NL, Berde CB, Yaster M (eds). Pain in Infants, Children, and Adolescents. Baltimore: Williams & Wilkins; 1993:527–528. 48. Finnegan LP, Connaughton JF, Kron RE, et al. Neonatal abstinence syndrome: assessment and management. Addict Dis. 1975;2:141– 158. 49. Levy M, Spino M. Neonatal withdrawal syndrome: associated drugs and pharmacologic management. Pharmacotherapy. 1993;13:202– 211. 50. Chasnoff IJ. Effects of maternal narcotic versus nonnarcotic addiction on neonatal neurobehaviour and infant development. In: Pinkert TM (ed). Consequences of Maternal Drug Abuse. Washington DC: National Institute on Drug Abuse; 1985:84–85. 51. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2008;2:CD002207. 52. Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manage. 2005;29:297–326. 53. Jones HE, Johnson RE, Jasinski DR, et  al. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug Alcohol Depend. 2005;79:1–10. 54. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. 2006;144:127–134. 55. Jernite M, Diemunsch P, Kintz P, et al. Passage of buprenorphine into mother’s milk. Ann Fr Anesth Reanim. 1999;18(Suppl 1):109S. 56. Carrie LES, O’Sullivan GM, Seegobin R. Epidural fentanyl in labour. Anaesthesia. 1981;36:965–969. 57. Rayburn W, Rathke A, Leuschen MP, et al. Fentanyl citrate analgesia during labor. Am J Obstet Gynecol. 1989;161:202–206. 58. Hagmeyer KO, Mauro LS, Mauro VF. Meperidine-related seizures associated with patient-controlled analgesia pumps. Ann Pharmacother. 1993;27:29–32. 59. Tang R, Shimomura S, Rotblatt M. Meperidine-induced seizures in sickle-cell patients. Hosp Formul. 1980;76:764–772. 60. Frank M, McAteer EJ, Cattermole R, et al. Nalbuphine for obstetric analgesia. A comparison of nalbuphine with pethidine for pain relief in labour when administered by patient-controlled analgesia (PCA). Anaesthesia. 1987;42:697–703. 61. Sgro C, Escousse A, Tennenbaum D, et al. Perinatal adverse effects of nalbuphine given during labour. Lancet. 1990;336:1070. 62. Scanlon JW. Letter: pentazocine and neonatal withdrawal symptoms. J Pediatr. 1974;85:735–736. 63. Feinstein SJ, Lodeiro JG, Vintzileos AM, et al. Sinusoidal fetal heart rate pattern after administration of nalbuphine hydrochloride: a case report. Am J Obstet Gynecol. 1986;154:159–160. 64. Product information. Ultram. Raritan, NJ: McNeil Pharmaceuticals; 1997. 65. Claahsen-van der Grinten HL, Verbruggen I, van den Berg PP, et al. Different pharmacokinetics of tramadol in mothers treated for labour pain and in their neonates. Eur J Clin Pharmacol. 2005;61:523–529. 66. Eisenach JC, Grice SC, Dewan DM. Patient-controlled analgesia following cesarean section: a comparison with epidural and intramuscular narcotics. Anesthesiology. 1988;68:444–448. 67. Findlay JWA, DeAngelis RL, Kearney MF, et al. Analgesic drugs in breast milk and plasma. Clin Pharmacol Ther. 1981;29:625–633. 68. Wittels B, Scott DT, Sinatra RS. Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study. Anesthesiology. 1990;73:864–869. 69. O’Donoghue SEF. Distribution of pethidine and chlorproma zine in maternal, foetal and neonatal biological fluids. Nature. 1971;229:124–125. 70. Kuhnert BR, Kuhnert PM, Philipson EH, et  al. Disposition of meperidine and normeperidine following multiple doses during labor. II. Fetus and neonate. Am J Obstet Gynecol. 1985;151:410–415. 71. Marquet P, Chevrel J, Lavignasse P, et al. Buprenorphine withdrawal syndrome in a newborn. Clin Pharmacol Ther. 1997;62:569–571.

72. Fujinaga M, Mazze RI. Reproductive and teratogenic effects of lidocaine in Sprague-Dawley rats. Anesthesiology. 1986;65:626–632. 73. Zeisler JA, Gaarder TD, DeMesquita SA. Lidocaine excretion in breast milk. Drug Intell Clin Pharm. 1986;20:691–693. 74. United States Pharmacopeial Convention. Drug Information for the Health Care Professional. 12th ed. Rockville, MD: United States Pharmacopeia Dispensing Information; 1992. 75. Lewis AM, Johnston A, Patel L, Turner P. Mexilitene in human blood and breast milk. Postgrad Med J. 1981;57:546–547. 76. Katz FH, Duncan BR. Letter: entry of prednisone into human milk. N Engl J Med. 1975;293:1154. 77. Dellemijn PLI, Fields HL. Do benzodiazepines have a role in chronic pain management? Pain. 1994;57:137–152. 78. Safra MJ, Oakley GP Jr. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet. 1975;2:478–480. 79. Laegreid L, Olegård R, Wahlström J, et al. Abnormalities in children exposed to benzodiazepines in utero. Lancet. 1987;1:108–109. 80. Rosenberg L, Mitchell AA, Parsells JL, et  al. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med. 1983;309:1282–1285. 81. Scanlon JW. Letter: effect of benzodiazepines in neonates. N Engl J Med. 1975;292:649–650. 82. Milkovich L, Van den Berg BJ. Effects of prenatal meprobamate and chlordiazepoxide hydrochloride on human embryonic and fetal development. N Engl J Med. 1974;291:1268–1271. 83. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol. 1979;109:433–439. 84. Bergman U, Rosa FW, Baum C, Wiholm BE, Faich GA. Effects of exposure to benzodiazepine during fetal life. Lancet. 1992;340:694–696. 85. Laegreid L, Olegård R, Walström J, Conradi N. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr. 1989;114:126–131. 86. Athinarayanan P, Pierog SH, Nigam SK, et al. Chloriazepoxide withdrawal in the neonate. Am J Obstet Gynecol. 1976;124:212–213. 87. Erkkola R, Kanto J. Diazepam and breast-feeding. Lancet. 1972;1:1235–1236. 88. Williams M, Wooltorton E. Paroxetine (paxil) and congenital malformations. CMAJ. 2005;173:1320–1321. 89. Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005;293:2372–2383. 90. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et  al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354:579–587. 91. Hainline B. Headache. Neurol Clin. 1994;12:443–460. 92. Shepard TH. Catalog of Teratogenic Agents. Baltimore: Johns Hopkins University Press; 1989:345. 93. Wisner KL, Perel JM, Findling RL. Antidepressant treatment during breast-feeding. Am J Psychiatry. 1996;153:1132–1137. 94. Lester BM, Cucca J, Andreozzi L, et al. Possible association between fluoxetine hydrochloride and colic in an infant. J Am Acad Child Adolesc Psychiatry. 1993;32:1253–1255. 95. Matheson I, Pande H, Alertsen AR. Respiratory depression caused by N-desmethyldoxepin in breast milk. Lancet. 1985;2:1124. 96. Harden CL, Hopp J, Ting TY, et  al. Practice parameter update: management issues for women with epilepsy- focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73:126–132. 97. Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy–focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73:133–141.

References

98. Hunt S, Russell A, Smithson WH, et al. Topiramate in pregnancy: preliminary experience from the UK epilepsy and pregnancy register. Neurology. 2008;71:272–276. 99. Hernandez-Diaz S, Mittendorf R, Holmes LB. Comparative safety of topiramate during pregnancy. Birth Defects Res A. 2010;88:408. 100. Montouris G. Gabapentin exposure in human pregnancy: results from the gabapentin pregnancy registry. Epilepsy Behav. 2003;4:310–317. 101. Gabapentin prescribing information. New York: Pfizer; 1996. 102. Del Pozo E, Brun Del Re R, Hinselmann M. Lack of effect of methyl-ergonovine on postpartum lactation. Am J Obstet Gynecol. 1975;123:845–846. 103. Kuczkowski KM. Caffeine in pregnancy. Arch Gynecol Obstet. 2009;280:695–698. 104. Van Den Berg BJ. Epidemiologic observations of prematurity: effects of tobacco, coffee, and alcohol. In: Reed DM, Stanley FJ (eds). The Epidemiology of Prematurity. Baltimore: Urban and Schwarzenberg; 1977:157–176. 105. Brent RL, Christian MS, Diener RM. Evaluation of the reproductive and developmental risks of caffeine. Birth Defects Res B Dev Reprod Toxicol. 2011;92:152–187. 106. Browne ML, Hoyt A, Feldkamp M, et al. Maternal caffeine intake and risk of selected birth defects in the National birth defects prevention study. Birth Defects Res A Clin Mol Teratol. 2011;91:93–101. 107. Miller RC, Watson WJ, Hackney AC, Seeds JW. Acute maternal and fetal cardiovascular effects of caffeine ingestion. Am J Perinatol. 1994;11:132–136. 108. Hadeed A, Siegel S. Newborn cardiac arrhythmias associated with maternal caffeine use during pregnancy. Clin Pediatr. 1993;32:45–47. 109. Ezaki H, Utusumi M, Tokado H. Reproductive study on sumatriptan succinate in rats by oral route. Yakuri Chiryo. 1993;21:2071– 2091. 110. Humphrey PPA, Feniuk W, Marriott AS, Tanner RJ, Jackson MR, Tucker ML. Preclinical studies on the anti-migraine drug, sumatriptan. Eur Neurol. 1991;31:282–290. 111. Feniuk W, Humphrey PP, Perren MJ. GR43175 does not share the complex pharmacology of the ergots. Cephalgia. 1989;9:35–39. 112. Eldridge R. [Personal communication], Jun 1997. 113. Wojnar-Horton RE, Hackett LP, Yapp P, et  al. Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol. 1996;41:217–221. 114. Nakhai-Pour HR, Rey E, Bérard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Birth Defects Res B Dev Reprod Toxicol. 2010;89:147–154. 115. Magee LA. Oral beta-blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2009. 116. Pruyn SC, Phelan JP, Buchanan GC. Long-term propranolol therapy in pregnancy: maternal and fetal outcome. Am J Obstet Gynecol. 1979;135:485–489. 117. Thompson R, Dejong K, Lo J. Marijuana use in pregnancy: a review. Obstet Gynecol Surv. 2019;74(7):415–428. 118. Stickrath E. Marijuana use in pregnancy: an updated look at marijuana use and its impact on pregnancy. Clin Obstet Gynecol. 2019;62:185–190. 119. Chamberlain G. ABC of antenatal care. Abdominal pain in pregnancy. BMJ. 1991;302:1390–1394. 120. Heckma JD, Sassard R. Musculoskeletal considerations in pregnancy. J Bone Joint Surg. 1994;76a:1720–1730. 121. Hungerford DS, Lennox DW. The importance of increased intraosseous pressure in the development of osteonecrosis of the femoral head: implications for treatment. Orthop Clin North Am. 1985;16:635–654. 122. Bruinsma BJ, La Ban MM. The ghost joint: transient osteoporosis of the hip. Arch Phys Med Rehabil. 1990;71:295–298. 123. Ostgaard HC, Zetherström G, Roos-Hansson E, Svanberg B. Reduction of back and posterior pelvic pain in pregnancy. Spine. 1994;19:894–900.

662.e3

124. Kanakaris NK, Roberts C, Giannoudis P, et al. Pregnancy-related pelvic girdle pain: an update. BMC Med. 2011;9:15. 125. Albert HB, Godskesen M, Westergaard J, et  al. Incidence of four syndromes of pregnancy-related pelvic joint pain. Spine. 2002;27:2831–2834. 126. Ostgaard HC, Andersson GBJ, Karlsson K. Prevalence of back pain in pregnancy. Spine. 1991;16:549–552. 127. Mogren IM, Pohjanen AI. Low back pain and pelvic pain during pregnancy: prevalence and risk factors. Spine. 2005;30:983–991. 128. Vermani E, Mittal R, Weeks A. Pelvic girdle pain and low back pain in pregnancy: a review. Pain Pract. 2010;10:60–71. 129. MacEvilly M, Buggy D. Back pain and pregnancy: a review. Pain. 1996;64:405–414. 130. Daly JM, Frame PS, Rapoza PA. Sacroiliac subluxation: a common, treatable cause of low-back pain in pregnancy. Fam Pract Res J. 1991;11:149–159. 131. Gutke A, Ostgaard HC, Oberg B. Predicting persistent pregnancyrelated low back pain. Spine. 2008;33:E386–E393. 132. LaBan MM, Perrin JCS, Latimer FR. Pregnancy and the herniated lumbar disc. Arch Phys Med Rehabil. 1983;64:319–321. 133. Weinreb JC, Wolbarsht LB, Cohen JM, et al. Prevalence of lumbosacral intervertebral disk abnormalities on MR images in pregnant and asymptomatic nonpregnant women. Radiology. 1989;170:125–128. 134. Rungee JL. Low back pain during pregnancy. Orthopedics. 1993;16:1339–1344. 135. Iams JD, Stilson R, Johnson RF, Williams RA, Rice R. Symptoms that precede preterm labor and preterm premature rupture of the membranes. Am J Obstet Gynecol. 1990;162:486–490. 136. Katz M, Goodyear K, Creasy RK. Early signs and symptoms of preterm labor. Am J Obstet Gynecol. 1990;162:1150–1153. 137. Roy C, Saussine C, LeBras Y, et al. Assessment of painful ureterohydronephrosis during pregnancy by MR urography. Eur Radiol. 1996l6;6:334–338. 138. Waltzer WC. The urinary tract in pregnancy. J Urol. 1981;125:271– 276. 139. Little JB. Biologic effects of low-level radiation exposure. In: Taveras JM (ed). Radiology: Diagnosis, Imaging, Intervention. Philadelphia: JB Lippincott; 1994:3–6. 140. Schwartz RB. Neurodiagnostic imaging of the pregnant patient. In: Devinsky O, Feldmann E, Mainline B B (eds). Neurological CompliCations of Pregnancy. New York: Raven Press; 1994:243–248. 141. Mattison DR, Angtuaco T, Miller FC, Quirk JG. Magnetic resonance imaging in maternal and fetal medicine. J Perinatol. 1989;9:411–419. 142. Kanal E. Pregnancy and the safety of magnetic resonance imaging. Magn Reson Imaging Clin N Am. 1994;2:309–317. 143. Wilbourn AJ, Aminoff MJ. Electrodiagnosis. In: Rothman RH, Simeone FA (eds). The Spine. Philadelphia: WB Saunders; 1992:163–171. 144. Wolfe LA, Hall P, Webb KA, et al. Prescription of aerobic exercise during pregnancy. Sports Med. 1989;8:273–301. 145. Berg G, Hammar M, Möller-Nielsen J, et al. Low back pain during pregnancy. Obstet Gynecol. 1988;71:71–75. 146. American College of Obstetricians and Gynecologists. Planning for Pregnancy, Birth and Beyond. New York: Dutton; 1996:92–95. 147. Pennick VE, Young G. Interventions for preventing and treating pelvic and back pain in pregnancy. Cochrane Database Syst Rev. 2007;(2): Art No: CD001139. doi: 10.1002/14651858. CD001139.pub2. 148. Koes BW, Scholten RJPM, Mens JMA, Bouter LM. Efficacy of epidural steroid injections for low-back pain and sciatica: a systematic review of randomized clinical trials. Pain. 1995;63:279–288. 149. Benzon HT. Epidural steroid injections for low back pain and lumbosacral radiculopathy. Pain. 1986;24:277–295. 150. Dowswell T, Bedwell C, Lavender T, Neilson JP. Transcutaneous electrical nerve stimulation (TENS) for pain relief in labour. Cochrane Database Syst Rev. 2009;(2): Art No.: CD007214. doi: 10.1002/14651858.CD007214.pub2 .

662.e4

References

151. Coldron Y, Crothers E, Haslam J, et al. ACPWH guidance on the safe use of transcutaneous electrical nerve stimulation for musculoskeletal pain during pregnancy: Association of Chartered Physiotherapists in Women’s Health Website. Available at: http://www.oaa-anaes.ac.uk/ assets/_managed/editor/File/PDF/info_for_mothers/TENS%20 Statement%20JUNE%2007%20ACPWH%20Final.pdf. 152. Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of headache in a general population- a prevalence study. J Clin Epidemiol. 1991;44:1147–1157. 153. Kvisvik EV, Stovner LJ, Helde G, et  al. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain. 2011;12:443–451. 154. Menon R, Bushnell CD. Headache and pregnancy. Neurologist. 2008;14:108–119. 155. Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology. 1972;22:355–365. 156. Chancellor AM, Wroe SJ, Cull RE. Migraine occurring for the first time during pregnancy. Headache. 1990;30:224–227. 157. Levine SR, Brust JC, Futrell N, et al. Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med. 1990;323:699–704. 158. Donaldson JO. Thrombophilic coagulopathies and preg nancy-associated cerebrovascular disease. Curr Obstet Gynaecol. 1991;1:186–190. 159. Marcus DA, Scharff L, Turk DC. Nonpharmacological man agement of headaches during pregnancy. Psychosom Med. 1995;57:527–535. 160. Silberstein SD. Headaches and women: treatment of the pregnant and lactating migraineur. Headache. 1993;33:533–540. 161. Nappi RE, Albani F, Sances G, et al. Headaches during pregnancy. Curr Pain Headache Rep. 2011;15:289–294. 162. Powars DR, Sandhu M, Niland-Weiss J, et al. Pregnancy in sickle cell disease. Obstet Gynecol. 1986;67:217–228. 163. Smith JA, Espeland M, Bellevue R, et al. Pregnancy in sickle cell disease: experience of the cooperative study of sickle cell disease. Obstet Gynecol. 1996;87:199–204. 164. Shapiro BS. The management of pain in sickle cell disease. Pediatr Clin North Am. 1989;36:1029–1045. 165. Martin JN, Martin RW, Morrison JC. Acute management of sickle cell crisis in pregnancy. Clin Perinatol. 1986;13:853–868. 166. Martí-Carvajal AJ, Peña-Martí GE, Comunián-Carrasco G, MartíPeña AJ. Interventions for treating painful sickle cell crisis during pregnancy. Cochrane Database Syst Rev. 2009 Jan 21;1:CD006786.

167. Wayne AS, Kevy SV, Nathan DG. Transfusion management of sickle cell disease. Blood. 1993;81:1109–1123. 168. Howard RJ, Tuck SM, Pearson TC. Pregnancy in sickle cell disease in the UK: results of a multicentre survey of the effect of prophylactic blood transfusion on maternal and fetal outcome. Br J Obstet Gynaecol. 1995;102:947–951. 169. Cozzi L, Tryon WW, Sedlacek K. The effectiveness of biofeedbackassisted relaxation in modifying sickle cell crises. Biofeedback Self Regul. 1987;12:51–61. 170. Alcorn R, Bowser B, Henley EJ, et al. Fluidotherapy and exercise in the management of sickle cell anemia. A clinical report. Phys Ther. 1984;64:1520–1522. 171. Wang WC, George SL, Wilimas JA. Transcutaneous electrical nerve stimulation treatment of sickle cell pain crises. Acta Haematol. 1988;80:99–102. 172. Chamberlain G. ABC of antenatal care. Medical problems in pregnancy, II. BMJ. 1991;302:1327–1330. 173. Weisman SJ, Schechter NL, et  al. Sickle cell anemia: pain management. In: Sinatra RS, Hord AH, Ginsberg B, et al (eds). Acute Pain: Mechanisms and Management. St. Louis: Mosby Year Book. 1992:508–516. 174. Finer P, Blair J, Rowe P. Epidural analgesia in the management of labor pain and sickle cell crisis- a case report. Anesthesiology. 1988;68:799–800. 175. Winder AD, Johnson S, Murphy J, Ehsanipoor RM. Epidural analgesia for treatment of a sickle cell crisis during pregnancy. Obstet Gynecol. 2011;118:495–497. 176. Cassidy B, Cyna AM. Challenges that opioid-dependent women present to the obstetric anaesthetist. Anaesth Intensive Care. 2004;32:494–501. 177. Doverty M, White JM, Somogyi AA, et al. Hyperalgesic responses in methadone maintenance patients. Pain. 2001;90:91–96. 178. Vanderah TW, Gardell LR, Burgess SE, et al. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci. 2000;20:7074–7079. 179. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349:949–958. 180. United States Department of Health and Human Services. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction (Publ. No. 04-3939, treatment improvement [protocol:40]). Rockville, MD: United States Department of Health and Human Services; 2004:67–69.

46

Rheumatologic Conditions

DAVID ANDREW WALSH

Introduction Rheumatology is the study of rheumatism, arthritis, and other disorders of the joints, muscles, and ligaments.1,2 Rheumatologic conditions are highly prevalent. Nearly one-fifth of the United Kingdom population reports a chronic musculoskeletal system condition. Rheumatologic conditions commonly begin during working life, with the peak incidence of gout and rheumatoid arthritis in late working life, although many people are afflicted by inflammatory arthritis in early adulthood or even childhood. Rheumatologic conditions are complex and heterogeneous and require multi-disciplinary approaches to their management. Health systems across the world structure rheumatologic care in different ways, often involving physicians with rheumatologic and general medical expertise, orthopedic surgeons, experts in metabolic bone disease, nurses, physiotherapists, occupational therapists, orthotists, podiatrists, and others. The patient should always be at the center of the team. Pain is the main, although not the only, problem described by people with rheumatologic conditions. Rheumatologic pain management depends on principles and research from other disciplines, incorporating both pharmacologic and non-pharmacologic approaches. Specific aspects of the function of the musculoskeletal system and the nature of rheumatologic conditions may require disease-specific approaches to pain management. Pain and function are closely integrated, and physiotherapy and occupational therapy aim to address both concurrently. Common chronic conditions such as osteoarthritis, rheumatoid arthritis, and gout illustrate persistent chronic and episodic acute pain associated with musculoskeletal disease. Osteoarthritis is the most common form of arthritis, and its prevalence increases with age. Osteoarthritis subgroups may be defined based on the joint distribution (e.g. knees, hips, or small joints of the hands) or precipitating factors (e.g. primary, posttraumatic, or secondary to inflammatory arthritis). Osteoarthritis affecting major weight-bearing joints substantially impacts mobility and function, although small joint osteoarthritis in the hands or feet can also cause substantial distress and disability. Rheumatoid arthritis is the most common form of inflammatory arthritis, affecting approximately 1%-2% of the Western population. People with inflammatory arthritis report pain as their highest priority for improvement.3,4 Inflammatory arthritis is an autoimmune condition characterized by immune-mediated inflammation of the joint lining (synovitis) and, if inadequately controlled, consequent joint damage and secondary osteoarthritis. Seronegative inflammatory arthritis may be associated with

psoriasis, colitis, ankylosing spondylitis, or reactive arthritis that may follow infection, and each has its own specific genetic and immunologic characteristics. Rheumatoid arthritis has a predilection for small joints of the hands and feet and often affects the knees, shoulders, ankles, or wrists in a symmetrical polyarticular distribution. Seronegative spondyloarthropathies often affect small numbers of weight-bearing joints (oligoarthritis) and/or the axial skeleton, although polyarticular distributions are not uncommon. Seronegative spondyloarthropathies are characterized by enthesopathy (inflammation at ligament insertions) and tendon sheath inflammation. Therefore inflammatory pain might not always be associated with localized joint swelling, and “tender points” because of inflammation might overlap with those associated with fibromyalgia. Pain and stiffness in inflammatory arthritis vary during the day, with the most pronounced symptoms usually in the morning, explained in part by diurnal variation in endogenous glucocorticoids. Disease onset may be acute or insidious, and early disease may be difficult to diagnose. Classifying these conditions as “inflammatory” does not deny the important contributions of inflammation to joint pain in osteoarthritis and gout. Crystal diseases are characterized by acute, severe episodes of pain caused by the innate inflammatory responses triggered by crystal deposits. High circulating uric acid concentrations because of inadequate renal clearance or increased production (e.g. during chemotherapy) may favor urate crystal deposition and attacks of gout. In calcium pyrophosphate deposition (CPPD), crystals may trigger attacks that are indistinguishable from gout and are therefore called pseudogout. Calcium pyrophosphate deposition in articular cartilage may be detected radiologically as chondrocalcinosis, even in the absence of acute attacks. In CPPD, crystal formation may be associated with various metabolic disorders involving divalent cations (e.g. Wilson’s disease). Gout and pseudogout may be associated with OA. Attacks typically affect a single joint, such as the knee, or, particularly in gout, first metatarsophalangeal, or interphalangeal joint. However, any synovial joint may be affected, and oligoarthritis or even polyarticular acute presentations may occur. Non-inflammatory genetic connective tissue disorders associated with hypermobility are commonly associated with chronic musculoskeletal pain. Hypermobility syndromes include Marfan syndrome, Ehlers-Danlos syndrome, and Stickler syndrome, associated with genetic variation in fibrillin-1, collagen Col3/Col5, or Col2/9/11, respectively.5 However, most people with joint hypermobility (perhaps 10% of the population) have a medically benign condition on a polygenetic background.

663

664

PA RT 4 Clinical Conditions: Evaluation and Treatment

The Experience of Rheumatologic Pain Pain is rarely a single experience, and people with rheumatologic conditions may report multiple qualities of pain. Rheumatologic pain may be described using any of the terms embedded within the McGill pain questionnaire, both those commonly associated with nociceptive and those characteristic of neuropathic pain.6 The characteristics of osteoarthritis, inflammatory arthritis, and crystal disease often overlap, and these conditions may be comorbid. Evidence and experience from one rheumatologic condition may sometimes be generalizable to others, although caution should be exercised when such generalizations are not based on sound evidence. In osteoarthritis, pain may occur only on weight-bearing or during joint movement or may be persistent at rest. Intermittent pain may be short-lived but severe, interspersed with periods that are pain-free or with less intense but constant pain.7 Acute flares may be spontaneous and unexplained or may be attributed to unaccustomed activity. Periods of exacerbation might last weeks or months, and the unpredictability of intermittent pain can prevent forward planning. Pain may be progressive or may subside or resolve. In rheumatoid arthritis, pain is often associated with joint inflammation, as evidenced by soft tissue swelling, synovial effusion, increased local temperature, and tenderness. Each of these features typically varies over time, either spontaneously or with treatment. However, such variations in inflammation and pain are not always concurrent. An increase in pain may herald an imminent inflammatory flare, and reductions in acute phase reactants on blood tests may precede symptomatic improvement. Episodic and severe pain characterizes crystal arthropathies, such as gout or pseudogout. During an attack, the affected joint becomes red, hot, and swollen and is exquisitely tender to the extent that movement or weight-bearing might be impossible, and the weight of bed clothes can be intolerable. These signs resemble acute infection, which is an important differential diagnosis that must be excluded. However, between attacks, the joint is typically pain-free. Pain is not the only symptom of rheumatologic disease, and people differ in how they understand or separate their pain from comorbid symptoms. Pain exists alongside fatigue, stiffness, and disability. Sleep disturbance and depressive symptoms are more common in people with inflammatory arthritis than in the general population.8 Joint stiffness is particularly a feature of inflammatory joint diseases such as rheumatoid arthritis when it characteristically varies during the day and increases with increased inflammatory disease activity. Morning stiffness lasting more than an hour is not unusual during active synovitis, even though it may ease joint movement and activity. People with osteoarthritis also describe stiffness, which may reflect the inflammatory components of their disease. The reduced movement might also be because of structural changes, such as loss of articular cartilage, bony outgrowths at joint margins (osteophytes), or joint capsule fibrosis and tendon contracture. This type of stiffness, unlike stiffness associated with inflammation, displays slight diurnal variation. Stiffness is a symptom rather than a sign, and the feeling that a joint does not move freely results from multiple mechanisms in and around the joint and in the central nervous system. Central mechanisms contribute to stiffness. People with rheumatoid arthritis who have undergone limb amputation may describe phantom stiffness, which varies during the day, and with generalized inflammatory

flares of their arthritis.9 People often find it difficult to disentangle their experiences of pain and stiffness. Indeed “stiffness,” which is unpleasant and associated with tissue damage, would satisfy the International Association for the Study of Pain (IASP) definition of pain10 and might therefore be considered a component of the pain experience. Fatigue is a common accompaniment of rheumatologic pain and has been reported as the second most troublesome symptom in people with rheumatoid arthritis. People may attribute their fatigue to sleep disturbance, for example, being woken by joint pain when turning during the night. However, sleep disturbance, unpleasant in its own right, is not an inevitable cause of fatigue, and additional biopsychosocial factors are important. Sleep disturbance and fatigue may be associated with evidence of central sensitization in osteoarthritis or rheumatoid arthritis,11 as it is also associated with widespread chronic pain. Circulating cytokines may contribute to fatigue in people with systemic inflammation.12 Fatigue is associated with a low mood, even in the absence of chronic musculoskeletal pain. Regardless of its underlying mechanisms, fatigue is associated with chronic musculoskeletal pain, is an important symptom in its own right, and can be a barrier to effective pain management. Overwhelming fatigue challenges the individual’s ability to cope with their pain and limits their ability to exercise as a form of therapy. Difficulties with acceptance, psychological distress (anxiety and depression), catastrophizing, and cognitive impact are key components of rheumatologic pain, not less than in other chronic pain states. Patients may have difficulty accepting their rheumatologic condition, which in most cases will not be amenable to cure, but instead, require lifelong treatment with associated risks and inconvenience. When newly diagnosed, people often display psychological reactions comparable to grieving, reflecting their permanent loss of good health. Persistent pain may be interpreted (both by patient and clinician) to indicate persistent inflammation, treatment failure, and ongoing joint damage, even when inflammation has been completely suppressed. Fear that pain on activity inevitably indicates ongoing joint damage can be a barrier to rehabilitation and exacerbates declining function. In addition to constituting the key emotional components of pain, psychological distress may be associated with central sensitization,13 augmenting nociceptive signaling, and the sensory dimensions of pain. Pain’s ability to distract attention and impair cognitive processing can compromise both work and leisure. With modern immunosuppressive therapy, people now developing rheumatoid arthritis might expect to live normal lives, engage in work, sports, and other activities alongside those without disease. However, the unpredictability of flares can prevent the planning of valued activities, including work and vacations, and undermine an individual’s self-esteem. Self-efficacy and successful self-management require control over persistent and intermittent symptoms and suppression of the underlying pathology. Suppressing pain in people with rheumatologic conditions is urgently needed. Furthermore, delays in effective pain management can lead to disability and loss of gainful employment, which may be difficult to reverse. Inadequate pain management in people with rheumatologic conditions is a risk factor for future pain, psychological distress, lost work productivity, healthcare utilization, and poor response to later definitive interventions such as joint replacement surgery.6,14 Pain management aims to improve symptoms and modify a key risk for future adverse outcomes, both for the patient and society.

 

CHAPTER 46

Why Are Rheumatologic Conditions Painful? Mechanisms of rheumatologic pain include changes in the peripheral musculoskeletal system, sensitization of peripheral and central nociceptive pathways, changes in brain connectivity, experience, and interpretation within a psychosocial context. Each pain mechanism is modulated by constitutional risk factors and comorbidities. Mechanisms may be shared or may differ between diseases, between individuals, and across time within an individual. Different mechanisms underlie different aspects of the pain experience, including pain quality, periodicity, associated symptoms, impact, and response to treatment. The musculoskeletal system is designed for weight-bearing and movement, and biomechanical factors contribute significantly to rheumatologic pain. Pain on normal movement might indicate sensitization within either the peripheral or central nervous system. Sensitization might result from actions on peripheral nerves by chemical mediators, including growth factors or cytokines. Structural changes may redistribute forces within the joint. Thinned, irregular, or inelastic articular cartilage may be unable to adequately dissipate force, thereby activating nerves that are normally present in the subchondral bone. Hypermobility, for example, may be associated with patellar maltracking and consequent anterior knee pain. Nociceptive transduction may be increased by abnormal interactions between sensory nerve terminals and adjacent connective tissue molecules. Loss of osteochondral integrity can expose subchondral nerves to molecules generated by the synovium, which may further stimulate subchondral inflammation and neuronal sensitization. Normal forces may activate nerves that have grown into the articular cartilage or knee menisci during structural disease progression.15,16 These joint structures were not innervated in the normal joints. Peripheral sensitization is a key component of rheumatologic pain. Inflamed or damaged tissues generate cyclo-oxygenase products, bradykinin, and nerve growth factor (NGF). These may either activate or sensitize the peripheral terminals of the primary nociceptive afferents. Urate (gout) or calcium pyrophosphate dihydrate (pseudogout) crystals trigger leukocyte degranulation and an acute innate immune response. In chronic rheumatoid arthritis or osteoarthritis, NGF, cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)α, and chemokines may be upregulated in the synovium and subchondral bone.17 NGF has been identified as a key cause of peripheral sensitization in osteoarthritis18 and may also contribute to pain in rheumatoid arthritis.19 NGF induces phosphorylation of transient receptor potential cation channel subfamily V member 1 (TRPV1). It increases the expression of substance P, calcitonin gene-related peptide (CGRP), and brain-derived neurotrophic factor in the dorsal root ganglion and increases the levels of transmitters and modulators at the first synapse within the dorsal horn. Systemic factors, such as circulating autoantibodies or immune complexes, might also interact with primary afferent nociceptors to increase sensitization in rheumatologic conditions.20 Persistent nociceptive barrage, the release of growth factors, and glial cell activation within the central nervous system, and changes in descending nociceptive control, contribute to central sensitization in rheumatologic conditions. With persistent joint pathology and nociceptive drive, central pain mechanisms become increasingly important. Functional connectivity may be enhanced between brain areas involved in sensory and emotional experien­ ces, aggravating the emotional component of pain.21 Pain experience depends on psychosocial context. An increased understanding of the underlying mechanisms of rheumatologic

Rheumatologic Conditions

665

disease has led to major advances in immunologic treatments in recent decades. However, pain and inflammation can be discordant.22 A patient who is informed that their inflammatory disease is well controlled may feel that their pain experience is invalidated or not believed. Pain does not even need to be present in order to be a problem, for example, if a patient fears future severe or unpredictable flares. Different individuals experience pain differently, despite apparently similar rheumatologic pathologies. Such diversity depends, in part, on genetic heterogeneity. Genotyping studies in painful osteoarthritis have identified polymorphisms in genes that are anticipated to influence joint shape and structure, but also in genes that regulate neuronal function or analgesic responses. Sex differences in rheumatologic pain similarly reflect both the propensity for joint pathology and differences in nociceptive processing.23

Assessment of Painful Rheumatologic Conditions Pain is the dominant symptom in most rheumatologic conditions, and patient-centered assessment should include evaluation of the nature, severity, and consequences of pain. Assessment should also address pain mechanisms, such as using biomarkers linked to diagnosis or pathology, to demystify this most bothersome symptom and help select treatments most likely to be of benefit. Careful attention to multimorbidity can inform prognosis, maximize health benefits, and reduce risks from pain treatments. Understanding and informing patients’ expectations and preferences facilitates treatment convergence

Rheumatologic Pain Pain assessment aims to identify its nature, severity, and importance to the patient and is essential for evaluating treatment response. Where pain is the presenting problem, assessment is inevitably incomplete without a detailed pain assessment. Pain is a subjective experience, and only patients can provide the gold standard measurement. Tools for evaluating pain may be generic or disease-specific. Assessment tools used in clinical practice often differ from those used in research because of the different requirements of validity, feasibility, and sensitivity to change. In the clinic, we are interested in the individual’s pain, whereas research often seeks to understand the average effects across populations. Research might seek to explore mechanistic subgroups for whom there is currently no effective treatment, whereas clinical practice aims to identify problems for which interventions may be helpful. Pain is a subjective experience whose mechanisms are complex and are often unknown. Therefore assessment should embrace the patient’s subjectivity rather than seek objective indices that might bear little relevance to the patient’s problem. In general, patient-centered pain outcome measures focus on the impact of pain on function (physical, psychological, sleep). Putative mechanistic tools, such as measuring neuropathic-like qualities, may inadequately address the problems of people with rheumatologic conditions.24 Pain rarely occurs as a symptom in isolation, such that rheumatologic-specific outcome measures often include pain alongside other factors such as stiffness and fatigue.25,26 Pain outcome measures might be incorporated into the more generic quality of life tools such as the medical outcomes study short form 36 (SF36) and EuroQol questionnaires. These

666

PA RT 4 Clinical Conditions: Evaluation and Treatment

quality of life measures lack focus on individual joints but instead address the overall burden of commonly comorbid painful conditions. More specific outcome tools might be more able to detect responses to treatments that target a single joint or pain mechanism. Osteoarthritis pain may be measured using self-report tools such as the intermittent and constant osteoarthritis pain (ICOAP) questionnaire,7 pain subscales of the Western Ontario and McMaster Universities arthritis index (WOMAC),27 or knee injury, and osteoarthritis outcome score (KOOS).28 WOMAC contains five items related to weight-bearing or non-weight-bearing pain and has demonstrated a two factor structure through which weightbearing and non-weight-bearing OA pain may be associated with different pathologic mechanisms. For example, weight-bearing pain was specifically associated with bone marrow lesions in weight-bearing joint compartments on MRI.29 KOOS extends the WOMAC items to improve targeting for people with lower pain intensities or musculoskeletal injuries. The ICOAP was developed following qualitative assessment of pain in people with knee or hip OA and displayed a two factor structure corresponding to the intermittent or constant pain. People with early disease may experience predominantly intermittent pain, whereas those with advanced OA report intermittent on a background of constant pain, suggesting changes in pain mechanisms when the structural disease progresses. The management of rheumatoid arthritis has traditionally focused on suppressing joint inflammation. Pain is assessed as one of the cardinal features of inflammation. However, pain in rheumatoid arthritis may also involve non-inflammatory mechanisms. The 28 joint disease activity score (DAS28) is a frequently used outcome measure in clinical trials of immunomodulatory treatments and clinical practice.6 This composite tool incorporates tender joint counts (TJC) and swollen joint counts (SJC) based on a standardized set of 28 joints that are relatively frequent and specific for rheumatoid arthritis. TJC is classified by the application of standardized pressure (to blanch the assessor’s nail bed) over each joint line. SJC is determined by the soft tissue swelling observed by a clinician. TJC and SJC are combined with a 100 mm visual analog scale of general health over the past week (VAS-GH) and a laboratory measure of an acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]). VAS-GH is highly correlated with patient-reported pain. Therefore DAS28 comprises self-reported (VAS-GH and TJC) and observed (ESR/CRP and SJC) components. Synovitis may increase ratings for each component, whereas central sensitization may selectively increase VAS-GH and TJC. Therefore the difference between TJC and SJC has been proposed as an index of noninflammatory pain mechanisms in rheumatoid arthritis.30 High DAS28 is used in several countries as a criterion for commencing or continuing immunomodulatory treatments. The use of DAS28 in this way depends on a clear understanding of the contribution of pain to inflammatory disease assessment. Inappropriate escalation of immunomodulatory treatments in people whose pain is attributable to non-inflammatory mechanisms exposes them to risks with little likelihood of benefit.

Pain-Related Biomarkers Biomarkers can help direct the treatment of rheumatologic conditions by indicating diagnosis and identifying and measuring peripheral or central pain mechanisms. Biomarkers may predict the prognosis or treatment outcomes. In general, those who have suffered worse pain in the past may have a worse pain prognosis,

and those whose pain will persist or deteriorate stand to gain the most benefit from treatment. Treatments that target a particular mechanism might be expected to work best for those in whom this mechanism drives pain. Biomarker levels might change before patient-reported outcomes deteriorate or improve, opening opportunities for early intervention and accelerating the development of new treatments. Biomarkers may enable early discontinuation to minimize the risk of treatment in those destined to not respond and those who will suffer adverse events.

Diagnostic Biomarkers and Genetic Risk Despite the overlap in pain mechanisms across diseases, the nature and responses to treatment of rheumatologic pain may vary between diagnoses. Biomarkers may be used to aid diagnosis. Specific connective tissue genetic variants directly cause hypermobility syndromes, such as Ehrlers’ Danlos syndrome. Other genetic variants may predispose to rheumatologic conditions (for example, human leukocyte antigen B27 [HLA-B27] in spondyloarthropathies). Genetic variants encoding neuronal proteins, such as ion channels, may either predispose to or protect against rheumatologic pain. Other genetic variants, such as μ-opioid receptors, might influence the responsiveness to analgesic drugs. Circulating autoantibodies to citrullinated peptides or doublestranded DNA have moderate to high specificity for rheumatoid arthritis and systemic lupus erythematosus, respectively. Radiographic features contribute to diagnostic classification, such as osteophytes for osteoarthritis, bony erosions at joints affected by inflammatory arthritis, and spinal syndesmophytes or sacroiliac joint fusion in ankylosing spondylitis. Hyperuricemia is a risk factor for gout and radiographic chondrocalcinosis for pseudogout, although the definitive diagnosis of these conditions requires the identification of crystals in joint fluid aspirates. Diagnostic biomarkers might be particularly important in early disease when the link between diagnosis and pain mechanism may be the strongest. Comorbid osteoarthritis or fibromyalgia may reflect increasing mechanistic complexity of pain with increasing time from disease onset. Diagnostic classification may help predict pain prognosis and treatment response. Radiographic evidence of osteoarthritis predicts pain persistence and persistent pain severity in people with knee pain.31 Diagnosis may also predict the response to treatment. However, diagnostic uncertainty may prevail, particularly in cases of early disease. The earliest stages of osteoarthritis might not be reliably classified by plain radiographs, and early rheumatoid arthritis may be mimicked by self-limiting parvovirus infection. Diagnostic uncertainty should not prevent adequate pain management. Biomarkers of Peripheral Pain Mechanisms Biomarkers that may point to pain mechanisms within the joint and are amenable to intervention include indices of inflammation and joint structural pathology. Acute phase reactants such as ESR or CRP and ultrasound or MRI evidence of inflammation are useful indicators of peripheral drives to rheumatologic pain across multiple diagnoses, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Raised acute phase in rheumatoid arthritis predicts worse structural outcomes, but not pain outcomes,32 perhaps because modern treatments can effectively suppress the inflammatory components of the disease. Similarly, raised acute phase or MRI evidence of spinal inflammation in ankylosing spondylitis predicts better outcomes on biologic therapy.33 However, precise

 

CHAPTER 46

mechanisms of rheumatologic pain often remain ill-defined, and these “indices” should not be over-interpreted as direct causes of pain. For example, CRP production in the liver is dependent on IL-6, and IL-6 blocking antibodies reduce circulating CRP concentrations irrespective of their effect on pain. Shortly after the onset of polyarthritis, the high acute phase might paradoxically be associated with a good prognosis if, rather than rheumatoid arthritis, the patient has an acute synovitic response to viral infection. Greater joint space narrowing on weight-bearing knee radiographs is associated with greater pain severity in cross-sectional studies and predicts worse pain outcomes in longitudinal community studies of osteoarthritis but better outcomes from joint replacement surgery (Fig. 46.1). However, the association between radiographic changes and pain in osteoarthritis is weak. Radiographic erosive joint damage or comorbid hand osteoarthritis at presentation with rheumatoid arthritis may be only weakly associated with pain and does not predict chronic pain with long term treatment,34 consistent with a predominant drive to pain from non-structural mechanisms. MRI may provide more detailed biomarkers of the peripheral pain mechanisms. In osteoarthritis, subchondral bone marrow lesions and synovitis have consistently been associated with pain, both in cross-sectional and longitudinal studies.35 Other MRI features, including knee meniscal extrusion or cartilage defects, may also be associated with pain, and close associations between different aspects of osteoarthritis structural pathology raise uncertainty about which features directly cause pain.

Biomarkers of Central Pain Mechanisms Quantitative sensory testing (QST) evidence of sensitization is associated with higher concurrent pain severity in osteoarthritis,36 and rheumatoid arthritis.37 Mechanical stimulation modalities such as blunt or cuff-induced pressure or punctate stimulation of the skin may be more relevant to rheumatologic pain than thermal modalities, although it is uncertain whether sensitization mechanisms

Rheumatologic Conditions

667

are specific to particular nociceptor subtypes. Baseline QST evidence of sensitization predicts worse pain at follow up and worse pain progression.38 Much evidence has been derived from static mechanical QST modalities, such as pressure pain detection thresholds (PPT). PPT distal or remote from affected joints has been taken as an indication of central sensitization, whereas PPT at the joint may reflect a combination of peripheral and central sensitization.39 Dynamic QST modalities such as temporal summation (TS) and conditioned pain modulation (CPM) more directly reflect central sensitization. Greater TS may indicate sensitization at the spinal cord, whereas lower CPM may indicate supraspinal deficiencies in endogenous analgesic mechanisms. Dynamic QST modalities may better predict pain outcomes in rheumatologic diseases than does PPT.37,38 Evidence of central sensitization might predict worse pain outcomes in rheumatologic conditions by indicating resistance to treatments directed at the peripheral nociceptive drive. Several phenotypic characteristics have been associated with QST evidence of central sensitization, leading to the proposal that self-report questionnaires might be used to indicate central sensitization in people with rheumatologic conditions.13 In people with knee pain, psychological distress (depressive or anxiety symptoms), catastrophizing, sleep disturbance, fatigue, cognitive interference, neuropathic-like symptoms, and more widespread pain were each associated with lower PPT distal to the affected knee. These eight characteristics each contributed to a single factor, the central mechanisms trait, which was more strongly associated with PPT than was any one of the eight characteristics alone. Higher central mechanisms trait scores were associated with more severe pain and predicted worse pain outcomes in community dwellers with knee pain.40 Similar self-report characteristics predict poor pain outcomes in other rheumatologic and non-rheumatologic conditions,41 and contribute to the diagnostic classification of fibromyalgia.

• Figure 46.1  Radiographic change in osteoarthritis and rheumatoid arthritis. (A) Posteroanterior radiograph of the knee of a person with

structural changes of tibiofemoral osteoarthritis. The lateral joint compartment can be identified by the localization of the fibula. The medial tibiofemoral joint space is narrowed, with marginal osteophytes (green arrows) and subchondral sclerosis. (B and C) Plain radiographs of second metacarpophalangeal joints of two people with rheumatoid arthritis. B shows erosive damage (red arrows) at joint margins. C displays erosive change also, and more severe joint space narrowing plus marginal osteophytes. It is not possible from plain radiographs to determine whether the individuals concerned were experiencing pain, nor how severe any pain was. The osteoarthritic changes in C may represent comorbid osteoarthritis that preceded the onset of rheumatoid arthritis or may show secondary osteoarthritis following earlier erosive damage. Disease modifying treatments may reduce the progression of erosive damage in rheumatoid arthritis but do not always eliminate pain.

668

PA RT 4 Clinical Conditions: Evaluation and Treatment

Comorbidities and Multimorbidity Comorbid conditions may be associated with rheumatologic disease. Rheumatoid arthritis is associated with cardiovascular diseases, diabetes mellitus, and fibromyalgia. Rheumatologic conditions increase in prevalence with age. Therefore multimorbidity is common, with or without causal association between diseases. Multimorbidity is associated with increased pain severity and worse pain prognosis,6 and contributes to frailty and loss of resilience to future health challenges. Concurrent morbidities might augment pain from rheumatologic conditions. Therefore treatment of comorbidities might improve pain outcomes. Morbidities or risk factors for future development may influence the choice of pain management strategy. Some, but not all, immunosuppressive therapies help with both cutaneous psoriasis and psoriatic arthritis. Comorbidities might be risk factors for adverse events from treatment, such as gastrointestinal bleeding on nonsteroidal antiinflammatory drugs (NSAIDs) or analgesic medication abuse. Morbidities that pose an anesthetic or surgical risk, such as hypertension or obesity, should be addressed before elective surgical intervention should be considered. A holistic approach is required to avoid interruption of pain management by intervening in acute medical needs. Morbidities may be painful or non-painful. Rheumatologic conditions coexist with comorbidities, which further influence the pain experience. Fibromyalgia is a common accompaniment of both inflammatory and non-inflammatory rheumatologic conditions. The extent to which phenotypic similarities between rheumatologic conditions and fibromyalgia reflect shared mechanisms remains uncertain. Chronic widespread pain in people with hypermobility might be associated with comorbid fibromyalgia or central sensitization but might also be an indication of widespread abnormalities in peripheral nerve function. Fibromyalgia may be considered as a comorbid diagnosis, and also fibromyalgianess may be viewed as a continuous trait linked to pain mechanisms. Each may be classified or measured in people with rheumatologic conditions by questionnaires; the Symptom Severity Scale, which addresses fatigue, cognitive, and somatic symptoms, together with WideSpread Pain Index.42 Osteoarthritis is a common accompaniment of other rheumatologic conditions. Primary osteoarthritis (OA) is a prevalent condition. Similar to all non-fatal, incurable conditions, osteoarthritis increases in prevalence with age. Rheumatologic conditions may predispose patients to osteoarthritis. Hypermobility may be associated with joint trauma and inflammatory arthritis with erosive joint damage, each of which is a risk factor for secondary osteoarthritis. Obesity is associated with osteoarthritis and increased pain. The association of body weight with osteoarthritis is multifactorial, partly based on genetic and biomechanical factors. Adipokines may contribute to augmented pain processing.43 Reciprocally, where arthritis pain is a barrier to exercise, weight reduction may be difficult to achieve. Diabetes mellitus may be associated with obesity and is an autoimmune condition associated with inflammatory rheumatologic conditions. Diabetes mellitus is associated with increased pain, even in the absence of demonstrable neuropathy.44 A negative association between osteoarthritis pain and hypertension has been attributed to the use of β-blocking medications,45 although causality awaits demonstration by a randomized controlled trial. Rheumatoid arthritis and systemic lupus erythematosus are associated with an increased risk of cardiovascular disease, which might be attributed to the effects of systemic inflammation or the adverse effects of treatments such as glucocorticoids or NSAIDs.

Cardiovascular risk assessment tools incorporate rheumatoid conditions, including age, sex, smoking status, diabetes mellitus, hypertension, ischemic heart disease, and chronic kidney disease.46

Treatment History, Expectations, and Preferences Assessment should include detailed documentation of treatment expectations and preferences. Expectations influence concordance with treatment plans and may contribute to analgesic efficacy or adverse events. A high expectation of benefit might facilitate placebo analgesia, whereas anticipating adverse events might contribute to nocebo responses. Expectations may be driven by the patient’s understanding of the natural history and mechanisms of their disease and its treatment. The threat of pain is greater if pain is beyond an individual’s comprehension or control. It is important to link the current biomechanical, structural, inflammatory, and neuronal mechanistic understanding of pain to the patient’s experience. Explanations that clearly align treatments with the patient’s informed understanding of the underlying mechanisms can enhance the therapeutic context and improve patient satisfaction. A patient’s previous treatment experience of pain strongly will influence their expectations from future treatment. In this respect, the patient’s recollection may be the most important. Pain recollection might be unreliable beyond one week, whereas immunomodulatory drugs used for inflammatory arthritis often have a slow (several weeks) onset of specific analgesic benefits. Pain relief from high dose glucocorticoids may be rapid and easily appreciated by people with inflammatory arthritis. However, prospective pain documentation may be needed to understand the analgesic benefits of slower acting disease modifying anti-rheumatic drugs (DMARDs). Long term efficacy and side effect profiles might be preferable for DMARDs compared to glucocorticoids, even though the rapid analgesic benefit from glucocorticoids may be more easily appreciated. Previous treatment failure may create expectations of similar future treatment failure, and repeated treatment failure may lower expectations for all future treatments, not only those that have failed in the past. Treatments that are most likely to help and are least likely to cause adverse events should be selected for an individual. Patient expectations may differ from predictions from evidence-based prognostic tools, and this should be addressed to help patients choose optimal treatment. Different individuals place different emphasis on treatment characteristics when making choices. Someone whose husband has just died from myocardial infarction may be averse to commencing an NSAID irrespective of their own personal risk. People with moderate to severe knee osteoarthritis generally place more emphasis on the likely analgesic efficacy rather than known adverse events.47 Holistic assessment is needed to ensure that patients can make the best treatment decisions based not only on statistical models but also accounting for personal values and perspectives.

Pain Prognosis and Treatment Outcomes Those people at the highest risk of poor outcomes stand to gain most from changes to their treatment. Assessment of a patient with a rheumatologic condition should lead to an understanding of likely pain prognosis, the likely impact of treatment on future pain, and the risk of treatment-related adverse events. Pain risk assessment overlaps with but does not equate to the risks of other outcomes, such as the risk of joint structural damage.

 

CHAPTER 46

In populations undergoing usual care, worse knee pain at follow up may be predicted by a range of general and disease-specific risk factors. Across rheumatologic and non-rheumatologic conditions, being female, older age, higher body mass index (BMI), anxiety, depression, catastrophizing, and more widespread pain at baseline predicted worse pain outcomes, and indices of central sensitization, either using QST or questionnaires, also predict worse pain outcomes.38,40 The average outcomes in a population conceal diverse pain trajectories in individuals. In osteoarthritis, pain progression is not inevitable, with pain deteriorating over time in some individuals but improving in others.48 In people with early or established rheumatoid arthritis, subgroups have been identified whose pain may return to levels observed in non-diseased populations, whereas for others, pain may persist unchanged over several years.32 Factors that predict the pain trajectory that an individual will follow overlap with those that predict persistent pain at follow up. Specific interventions for rheumatologic conditions can change an individual’s pain trajectory and outcome. Predictors of treatment response may differ, therefore, from predictors of pain outcomes in untreated populations. The raised acute phase might predict poor outcome in the absence of treatment for rheumatoid arthritis but predicts a more favorable pain trajectory on immunomodulatory treatment.32 Joint space narrowing predicts worse outcomes in people with knee pain but predicts better outcomes in response to arthroplasty. Risk is therefore dependent on the treatment context, and we can anticipate that the adverse risk factors of today will become positive prognostic factors with treatments in the future. Joint inflammation indices predict the analgesic benefits of immunomodulatory therapies in rheumatoid arthritis. DAS28 scores have been recommended by some for the selection of people who may be offered biologic immunomodulatory therapy. DAS28 requires careful interpretation because of the influence of noninflammatory pain mechanisms. Randomized controlled trials in rheumatoid arthritis often require minimum thresholds of acute phase reactants and SJC to be met prior to treatment initiation. An individual’s risk factors and pain mechanisms may vary over time. This helps explain why a previously effective treatment might no longer be so, whereas another treatment that has previously failed might now help. For example, pain in early rheumatoid arthritis might respond well to immunomodulatory therapy, whereas in later disease, if central sensitization or joint damage becomes dominant, continuing to suppress inflammation might not relieve pain. A single risk factor might make only a small contribution to pain outcomes, even if it displays highly significant associations in large cohort studies. For example, a high BMI predicts worse outcomes from joint replacement surgery, but people with high BMI can still gain important clinical benefits and should not be denied surgery.49 Combinations of multiple risk factors may only explain a small proportion of treatment outcomes. For example, less than one-fifth of people destined to have poor outcomes from arthroplasty can be identified by a combination of currently known presurgical risk factors.50 Risk factors should be discussed with the patient to help them minimize their risks while selecting what is appropriate for their care. The analgesic response is not entirely attributable to specific effects and depends on contextual factors that might also be observed with placebo treatments. Only half of the total analgesic benefit experienced by the patient may be attributable to the specific effects of treatment.51 The predictors of placebo response may differ from those of specific pharmacologic effects. This

Rheumatologic Conditions

669

mixed mode of analgesic action challenges outcome prediction. For example, ultrasound evidence of synovitis may predict pain in people with knee pain,31 but has little ability to predict the response to intra-articular glucocorticoid injection. Improved biomarkers of pain mechanisms are required to determine the effective targeting of mechanism-specific treatments. Central mechanisms may predict worse pain outcomes in part by posing barriers to treatment response. A low mood might reduce treatment uptake or persistence, where the future seems hopeless. Anxiety and catastrophizing may reduce concordance with medical or physiotherapeutic interventions, where adverse events are feared, or where patients are concerned that by masking their pain, they will damage their joint. Sleep disturbance and chronic fatigue reduce motivation and the ability to engage in physical activity and therapies or to travel and attend to health care. Cognitive interference may impair the understanding or adherence to therapeutic plans. Multisite pain may compromise therapies targeting a particular joint, for example, by limiting mobility. Treating one joint may unmask the limitations of another. Identifying risk factors for poor outcomes as barriers to treatment benefit can reveal targets for interventions that might synergize with pain management. Pain in rheumatologic conditions may persist for years, and long term benefits from analgesic medications are often unproven. Continued use of medications in those gaining little benefit exposes them to unnecessary risk of adverse events. Response to treatment should be assessed after an adequate therapeutic trial and should be confirmed before considering its continuation. What constitutes an adequate trial may vary between interventions. Two weeks might be adequate to evaluate response to an NSAID, whereas treatment with biologic DMARDs might be continued for up to six months before the benefit can be excluded, particularly if there are concomitant changes to glucocorticoid doses. Where treatment aims to reduce the frequency of pain flares, the duration of an adequate trial of treatment will depend on baseline flare frequency. For acute gout attacks, treatment should be titrated to achieve serum urate levels in the lower half of the normal range, and equivalent biomarkers are needed to satisfactorily reduce the risk of pain flares in inflammatory arthritis or osteoarthritis. New treatments with different efficacy and risk profiles will increase the choices available to patients and their clinicians and increase the range of risk factors that need to be assessed. Pharmaceutical development of NGF inhibitors for osteoarthritis pain, for example, has identified risks from drug-induced rapidly progressive osteoarthritis, leading to the incorporation of risk screening tools such as large joint radiography into developmental treatment pathways.18

Management General Principles Box 46.1 summarizes the key management recommendations from recent guidelines for health professional contributions to rheumatologic pain management.52–54 Guidelines recommend holistic patient assessment and a stepped care approach, incorporating steps of increasing treatment intensity and cost from education and selfmanagement through specialist and multi-disciplinary care. A personalized approach depends on an individual’s risk factors, needs, and values. Not all treatments are necessary or appropriate for all patients. A personalized management plan guided by shared decisions can help in implementing this approach.

670

PA RT 4 Clinical Conditions: Evaluation and Treatment

• BOX 46.1

Health Professional Management of Pain in Rheumatologic Conditions

Education: • Educational materials, brochures/online resources encouraging to stay active, sleep hygiene guidelines • Psychoeducation by a health professional • Self-management interventions; online/face to face

Physical activity and exercise: • Advice to stay active • Physiotherapy; individually tailored graded physical exercise or strength training • Multi-disciplinary intervention; cognitive behavior therapy addressing fear of movement and catastrophizing

Occupational therapy, orthotist, orthopedic shoemaker: • • • •

Splints, braces, gloves, sleeves, insoles, and shoes Daily living aids: e.g. tin openers Assistive devices: e.g. cane, rollator Ergonomic adaptation at home/workplace

Psychological or social interventions: • Basic social and psychological management support • Referral to a psychologist, social worker, self-management support program, cognitive behavior therapy

Sleep interventions: • Basic education; sleep hygiene • Referral to sleep therapist/program or specialized sleep clinic

Weight management: • Dietitian, psychologist, community lifestyle services, or bariatric clinic/ surgery

Pharmacologic and joint-specific pain: • Advice on prescribed and over-the-counter pain relief • Refer for medical advice if concerns about safe/effective use or if additional pharmacologic treatment may be indicated

Multi-disciplinary treatment: • If more than one treatment option is indicated or if monotherapy failed Box 46.1 summarizes the key management recommendations from the EULAR guidelines for health professional contributions to rheumatologic pain management.52 Comparable guidelines have been issued by the American College of Rheumatology.53 The Osteoarthritis Research Society International (OARSI) has published guidelines using evidence for knee, hip, or generalized osteoarthritis, including benefits in outcomes additional to pain.54 All patients should be offered personalized advice and guidance, beyond which a stepped care approach provides treatment access to those who may most benefit. Individuals or professional groups may have particular skills in specific treatment areas, although treatment may be delivered by a range of professional and non-professional team members.

Optimal management requires consideration of the nature and impact of rheumatologic pain alongside other symptoms that the patient seeks to address and risk factors for future pain progression. Realistic expectations should be encouraged based on evidence-based information on likely outcomes for individuals with or without treatment. Decisions to initiate treatment depend on individual benefits balanced against adverse events and risks, focusing on the patient’s perspective. Response to any single treatment may vary between individuals, and treatment should

be continued where benefits outweigh the risk. Modifiable risk factors such as low mood, anxiety, or obesity might be indications for treatment in their own right and improve pain prognosis. The risk of gastrointestinal bleeding on NSAIDs can be reduced by co-prescription of proton pump inhibitors, and that of osteoporosis on glucocorticoids can be reduced by bisphosphonates in the context of adequate calcium and vitamin D intake. Different pain mechanisms and qualities in an individual may demand a combination treatment. Interventions might aim to suppress constant, ongoing pain or to prevent, suppress, or abort intermittent pain episodes. Oral NSAIDs can relieve rheumatologic pain, but their use may be limited by the patient’s baseline cardiovascular, gastrointestinal, or renal risks. Opiate analgesics may acutely relieve rheumatologic pain. However, despite the absence of evidence of sustained analgesic benefits from opioids in inflammatory arthritis, their use progressively increased from 2002 to 2015.55 Many patients choose to use analgesic medications on an “as required” basis, according to hour-to-hour variations in symptoms, pre-emptively to facilitate a specific activity or to help manage a pain flare. Such intermittent treatment might help optimize the balance between benefit and risk, and randomized controlled trials have not demonstrated clear superiority of regular over “as required” analgesic use. However, “as required” usage should be strongly discouraged for slow-acting treatments, such as DMARDs, urate-lowering therapies, or antineuropathic analgesics. Some treatments might effectively reduce pain across multiple diagnoses, whereas others have demonstrable efficacy only for a single disease. Intra-articular glucocorticoid injections may reduce pain in rheumatoid arthritis or osteoarthritis. Systemic glucocorticoids might reduce pain in rheumatoid arthritis,56 but are not recommended for osteoarthritis. TNFα blocking antibodies might reduce pain from rheumatoid arthritis or psoriatic arthritis, whereas IL-6 blockade might reduce pain only in RA, and IL-17 blockade only in psoriatic arthritis (Table 46.1).57 For some conditions, specific treatments are not available, and generic pain management approaches should be adopted. Hypermobility syndrome is determined by genetic variants that cannot be modified by specific treatments. Quadriceps strengthening may improve hypermobility-associated anterior knee pain, and strategies developed for people with fibromyalgia may be helpful, although exercises aimed at increasing mobility should be avoided by these people. Exercise therapies are commonly prescribed and may reduce rheumatologic pain, improve strength, balance, and endurance, reduce frailty and falls, and improve general health outcomes. Exercises may need to be individualized based on patient comorbidities. Formal knee exercises may need to be performed in the presence of significant hip disease. Aerobic exercise might be precluded in patients with unstable angina, although increasing aerobic fitness might ultimately reduce cardiovascular risk. Rheumatologic treatments are often complex and might be challenging for people with cognitive impairment or if motivation is compromised by a low mood. Attendance in group exercise may be precluded by agoraphobia or personality disorders.

Osteoarthritis Randomized controlled trials in osteoarthritis have focused predominantly on major weight-bearing joints such as the knee or hip. Evidence may be less robust for the management of hand OA pain, and although shared principles of analgesia and exercise might be valid, therapies may need adaptation to the particular

 

CHAPTER 46

TABLE 46.1

Rheumatologic Conditions

671

Targeted Immunologic Therapies for Inflammatory Arthritis Direct Actions on Peripheral Sensory Nerves

Molecular Target

Pharmaceutical Agent

Rheumatologic Condition

Tumor Necrosis Factor-α

infliximab, etanercept, adalimumab, certolizumab, golimumab

Rheumatoid arthritis, Psoriatic arthritis, Ankylosing spondylitis

Sensitizes voltage gated sodium channels70 Upregulates NaV1.7 currents71 Increases gene expression; CGRP, adrenomedullin, CCL2, MMP9,72 Nav1.6,73 Nav1.7,74 BDNF75 Increases neurite outgrowth76

Interleukin-1 β

anakinra

Rheumatoid arthritis

Increases CGRP expression77 Increases CGRP,77 and SP release78

Interleukin-6

tocilizumab, sarilumab

Rheumatoid arthritis

Increases TRPV1 and NK1 receptor expression79

Interleukin-17

secinumab, ixekizumab, brodalumab

Psoriatic arthritis, Ankylosing spondylitis

Increases axonal outgrowth and mitochondrial function80

Interleukin-12/23

ustekinumab, guselkumab

Psoriatic arthritis

Unknown

CD20 (B cell depletion)

rituximab

Rheumatoid arthritis, Systemic lupus erythematosus

Unknown

CD80/86 (T cell costimulator)

abatacept

Rheumatoid arthritis

Unknown

JAK kinase/STAT3

baricitinib, tofacitinib

Rheumatoid arthritis, Psoriatic arthritis

Mediates TNFα induced gene expression73

Direct effects on dorsal root ganglion neurons of molecular targets for biologic DMARDs (bDMARDs) and targeted immunomodulatory agents. The predominant analgesic action of bDMARDs is because of the suppression of peripheral inflammation and may be attributed to the suppression of the release of other sensitizing agents. However, molecular targets may themselves sensitize peripheral nociceptors, and direct effects on nerve function may precede the secondary effects of immune suppression. Biologic agents have very low penetration across the blood-brain barrier, such that their analgesic actions are likely to be peripherally mediated. Inhibitors of JAK kinase/STAT3 might have additional effects, for example, on glial cells within the central nervous system.

needs of different joint groups. International guidelines on the management of OA recommend core treatments for arthritis education and structured land-based exercise programs comprising strengthening, cardiovascular fitness, balance training, and neuromuscular control, or mind-body exercises such as tai chi or yoga.54 These core treatments aim to improve both pain and functional capacity. Meta-analysis of exercise trials suggests that mind-body exercise might be more effective than muscle strengthening exercises for improving knee pain.58 However, further research is required to determine whether different treatment approaches may be more acceptable or effective for different individuals. Core exercise therapies may be supplemented by aquatic exercise, gait aids, or self-management programs in people at high risk of poor outcomes. In addition, they might be offered analgesic medications such as topical NSAIDs or oral NSAIDs, if these are not contraindicated, together with proton pump inhibitors for gastroprotection. Topical capsaicin may also provide clinically important pain relief from knee or hand OA, with similar overall efficacy as topical NSAIDs, although different people might respond better to one or other of these medications.59 Current evidence does not allow accurate prediction of which analgesic medications will best help which patient, and if the first tried intervention is ineffective, a second treatment should be considered. Intra-articular corticosteroid injection may reduce OA pain, often for some weeks, but cannot be self-administered and

can rarely be associated with important adverse events, such as accelerated structural damage.60 Other analgesic medications have limited specific benefits for osteoarthritis pain. Randomized controlled trials have not unequivocally demonstrated the benefit of paracetamol in osteoarthritis, which is less effective for OA pain than are NSAIDs. Paracetamol has a narrow therapeutic window above which liver toxicity may be significant as well as other adverse events comparable to those observed with NSAIDs.61 Oral or transdermal opioids do not have evidence of sustained benefits for OA pain, and risks of nausea, constipation, cognitive impact, falls, and dependency may outweigh any benefit. There is an urgent need for more effective medical treatments for OA pain, several of which are in development.18 Where core and supplemental interventions do not adequately control osteoarthritis pain, intra-articular hyaluronic acid injections might be considered as also may combination of exercise with cognitive behavior therapy.54 However, failure of conservative pain management approaches may indicate a need for surgical intervention. Better pre- and perioperative pain control, lack of musculoskeletal comorbidities including fibromyalgia, low indices of central sensitization, low BMI, more joint space narrowing, good mental health, and low catastrophizing predicted better outcomes from large joint arthroplasty. However, these factors explain only a small proportion of the variation in outcome and should be viewed as targets to improve outcome rather than hurdles that must be overcome before surgery is offered. For appropriately selected

672

PA RT 4 Clinical Conditions: Evaluation and Treatment

patients, pain improvement following arthroplasty is usually pronounced, particularly with hip replacement surgery. However, up to 20% of people undergoing total knee arthroplasty continue to suffer from pain.62 Relieving pain alone might not be sufficient to enable people to return to their valued activities. Adjunctive therapies, addressing fear avoidance, low mood, and comorbidities, play important roles.

Inflammatory Arthritis Optimal management of pain in inflammatory arthritis can reduce the burden of symptoms and enable patients to better manage their inflammatory disease. People with inflammatory arthritis report major concerns with pain, fatigue, stiffness, and disability, whereas physicians often pay more attention to biomarkers of inflammation or joint damage. This discrepancy has been associated with worse outcomes after treatment.63 The aim of modern DMARDs is to induce and maintain inflammatory disease remission, but many patients continue to experience intermittent flares or persistent low-grade inflammation. Non-inflammatory pain mechanisms may persist despite resolution of inflammation, and improvements in pain on treatment, although clinically important, may not be complete, even when inflammation is completely suppressed.32

Rheumatoid Arthritis Suppressing inflammation can reduce pain in active rheumatoid arthritis,6 and reduce stiffness and joint swelling. Immunosuppressive therapies can slow or stop structural damage and are referred to as DMARDs. A wide variety of DMARDs are available, with high-quality randomized controlled trial evidence of clinically important benefits for pain. These include conventional synthetic DMARDs such as methotrexate and targeted biologic agents including TNF-α blockers, B cells (rituximab) or T cells (abatacept) directed therapies, IL-6 blocking antibodies (tocilizumab, sarilumab), and small molecule JAK/STAT kinase inhibitors (e.g. baricitinib, tofacitinib; Table 46.1).64 Each significantly increases the risk of infection, and several may have potential liver or hematologic toxicity. Regular blood monitoring during treatment may reduce risks by detecting adverse events before they become clinically apparent. The requirement for subcutaneous or intravenous delivery of biologic agents, need for monitoring, and cost may necessitate provision through secondary care services. Immunosuppressive therapies usually do not have immediate benefit, and depending on the chosen agent, treatment for up to six months may be required to definitively assess the benefit. Pain may be severe, and there is both a practical and ethical imperative to relieve pain before these slow-acting treatments can take effect. More rapid suppression of inflammation at disease onset or during flares might be achieved by glucocorticoids. These may be administered by local (e.g. intra-articular) injection or systemically by tablet, intramuscular injection, or intravenous infusion. Systemic glucocorticoids administered by any of several routes may provide effective analgesia for inflammatory pain in rheumatoid arthritis and reduce stiffness, joint swelling, and fatigue. Adverse events with short-duration treatment are usually not troublesome, although high doses of glucocorticoids can precipitate or destabilize diabetes mellitus or induce psychosis. Short courses of low dose systemic glucocorticoids, such as prednisolone (7.5 mg daily or less), may be less likely to cause problems but might be less effective at reducing pain. Long term glucocorticoid use is associated with reduced symptomatic benefit and increased risk of

adverse events, some of which can be mitigated by concomitant medication (e.g. bisphosphonates to reduce osteoporosis risk). Patients who experience a good symptomatic response to high dose glucocorticoids shortly after disease onset might be reluctant to engage with maintenance DMARD treatment in light of the latter’s slow onset of (and therefore less noticeable) symptomatic benefit and potential for adverse events. However, long term glucocorticoid use itself has high risk and low efficacy and does not retard structural damage in established inflammatory arthritis. DMARDs should be introduced to permit the eventual withdrawal of any initial glucocorticoid therapy. NSAIDs may also reduce inflammatory pain in rheumatoid arthritis and improve joint stiffness. They have the advantage of ready availability and may be used “as required.” Topical NSAIDs or topical capsaicin may be beneficial in rheumatoid arthritis, even in the absence of concurrent osteoarthritis, although evidence is less robust than in osteoarthritis. Glucocorticoids also inhibit cyclo-oxygenases, and concurrent use of NSAIDs with glucocorticoids substantially increases the risk of gastrointestinal bleeding. However, concurrent NSAIDs may provide analgesic benefits over and above the analgesia from low dose glucocorticoids below 7.5 mg prednisolone daily. The peak age of onset of rheumatoid arthritis is now >50 years, and comorbid cardiovascular or renal disease or anticoagulant treatment may limit the number of people who can benefit from oral NSAIDs.

Other Forms of Inflammatory Arthritis Pain in psoriatic, enteropathic (e.g. ulcerative colitis and Crohn’s disease), reactive arthritis, and ankylosing spondylitis displays similar characteristics, periodicity, and responds to many similar treatments as rheumatoid arthritis pain, although with some important differences (Table 46.1). The molecular pathways of inflammatory pain differ between diseases. For example, IL-17 blockade may effectively reduce pain in psoriatic arthritis but is not currently recommended for rheumatoid arthritis.64 Different forms of inflammatory arthritis may have different comorbidities, and treatments should be selected to reduce the symptoms and impact of comorbidities. For example, TNF-α inhibitors may improve spinal and peripheral joint pain and improve skin disease in psoriatic arthritis. Seronegative inflammatory arthritis may be associated with uveitis, sometimes sight threatening, and a diffi­ cult balance may be needed between symptomatic benefit from some biologic agents and their potential to precipitate or aggravate ocular disease. TNF-α inhibition has not been conclusively shown to slow the progression of bone structural changes in inflammatory spinal disease, but excellent symptomatic benefit alone justifies the associated risks of immunosuppressant therapies. Non-inflammatory Pain and Inflammation Nonselective Interventions in Inflammatory Arthritis Even when inflammatory disease is in remission, people with inflammatory arthritis may continue to experience unacceptable pain. An acutely painful joint in someone whose arthritis is otherwise well controlled should always raise the relatively rare possibilities of other diagnoses, such as infection or insufficiency fracture. Chronically persistent and disabling pain is reported by up to 30% of patients with rheumatoid arthritis,32 or psoriatic arthritis65 despite objective evidence of inflammatory disease remission. This disappointing average outcome conceals subgroups in which pain remits to levels reported by normal populations, but also other subgroups who appear to gain little analgesic benefit from the introduction of DMARD treatment.32 Persistent non-inflammatory

 

CHAPTER 46

pain is, therefore, a major problem for these patients. Furthermore, the assessment of inflammatory disease activity and clinical scores used to determine the response to immunomodulatory treatments are strongly influenced by pain.26,30 Pain improvement may be necessary to persuade patients and clinicians that inflammatory diseases are adequately controlled and avoid unnecessary escalation and risks from immunosuppression. Persistent “non-inflammatory” pain may be because of preexisting morbidities or be a consequence of earlier active inflammatory disease. Half of the patients presenting to secondary care with early rheumatoid arthritis already have radiographic osteoarthritis of the hands or feet.66 Up to a third of people with established rheumatoid arthritis, psoriatic arthritis, or spondylarthritis may satisfy the classification criteria for the diagnosis of fibromyalgia.67 Fibromyalgia diagnosis may be only the tip of the iceberg, and fibromyalgianess affects many people who do not meet the fibromyalgia classification criteria for a formal diagnosis. Treatments recommended for primary fibromyalgia or osteoarthritis should be offered to people with inflammatory arthritis when diagnosed with these comorbidities. Indeed, pain management strategies used in non-inflammatory pain conditions can be helpful for people with inflammatory arthritis, even in the absence of a comorbid diagnosis. Care from health professionals should use a patient-centered framework with a personalized management plan, pharmacologic and joint pain-specific treatments, and a multi-disciplinary approach.52,53 Strong research evidence supports the use of education, aerobic exercise, cognitive behavior therapy, and weight loss in obese individuals. In addition, there is some evidence for benefit from strength training, hypnotherapy, biofeedback, balneotherapy, yoga, tai chi, neuromodulation, acupuncture, chiropractic, manual, and massage therapy. Comorbid inflammatory arthritis raises additional concerns in people with fibromyalgia or osteoarthritis. Each of these conditions may be associated with “pain flares,” and patients and clinicians may struggle to understand whether any particular flare indicates a need to escalate anti-inflammatory treatment or to pursue more intensive pain management strategies. Misattribution of pain to non-inflammatory causes might prevent access to effective treatments, whereas repeated courses of high dose glucocorticoids are inappropriate for fibromyalgia or osteoarthritis pain flares. Engagement with chronic pain management interventions may be limited if patients believe that their pain will resolve once they are established on effective DMARD treatment. Graded physiotherapy may be helpful for osteoarthritis and fibromyalgia, but an increase in pain during an exercise program may indicate a need for further individual assessment of inflammatory disease activity. In summary, treatments for fibromyalgia and osteoarthritis are not contraindicated in patients with inflammatory arthritis, and many modalities have benefits for both inflammatory and non-inflammatory pain. Many patients require many months of DMARD treatment

Rheumatologic Conditions

673

adjustments before inflammatory disease enters remission. Early and effective management of non-inflammatory pain should aim to minimize suffering during this period, reduce the risk of chronic pain and equip the patient for effective self-management in the long term.

Gout and Pseudogout The key aims of gout management are to relieve acute pain during an attack and prevent future attacks by controlling serum urate levels.68 Prevention is not currently possible for pseudogout, for which management focuses on treating acute attacks.69 Gout is associated with significant renal, cardiovascular, and metabolic comorbidities that may complicate treatment and require management in their own right. Rapid pain reduction during acute attacks of gout or pseudogout may be achieved using colchicine, NSAIDs, and/or glucocorticosteroids. Colchicine inhibits microtubule function, thereby reducing leukocyte degranulation. Microtubules also regulate gastrointestinal epithelial and neuronal function, such that colchicine may also often cause diarrhea, with neuropathy, if use is prolonged. NSAIDs are similarly effective for treating acute crystal-induced pain. However, NSAIDs may be contraindicated for people whose gout is associated with significant renal disease, a cause of hyperuricemia, or metabolic syndrome and associated cardiovascular disease. By intraarticular injection or systemic administration, glucocorticoids may also rapidly reduce pain during an acute crystal attack. However, their use requires the prior exclusion of joint infections. Despite the severity of pain during crystal attacks, strong opioids are usually unnecessary because more effective analgesia can be achieved with specific therapies directed at inflammatory mechanisms. In addition, to acute gout attacks, management aims to reduce the risk of recurrence. Recognized precipitants of gout attacks may be avoided, such as alcohol intake or medication changes such as thiazide diuretics. However, long term urate-lowering treatments, such as allopurinol, should be considered for those at high risk of future attacks, such as those who have experienced more than a single attack or those with very high serum urate levels. With effective urate-lowering therapy, complete prevention of acute attacks is possible. Disappointingly, many patients continue to experience repeated attacks of gout over many years. The reasons for this are complex. A lack of understanding that treatment offers control rather than cure might lead people to discontinue once the patient feels well. Reduction in serum uric acid concentrations on medication may vary considerably between individuals, and dosage titration is required to achieve serum urate concentrations in the lower half of the normal range if acute attacks are to be prevented. Acute attacks may be triggered by either increasing or decreasing urate levels, and patients may not understand that an attack shortly after starting treatment, while serum urate levels are decreasing, does not predict long term treatment failure.

Conclusions Rheumatologic conditions are commonly associated with both acute and chronic pain. Many have clearly defined pathologic mecha­nisms, enabling specific treatments to offer rapid and effective pain relief. However, pain in rheumatologic conditions is multifactorial and complex, and suppression of underlying disease often does not eliminate pain. Advances in targeted immunosuppressive therapy have made inflammatory disease remission a realistic goal for most patients with rheumatoid arthritis. However, non-inflammatory pain mechanisms remain resistant to treatment, and new treatments are urgently needed. More could be gained

from existing therapies by careful and timely selection and targeted access for those most likely to benefit. The multitude of potentially useful pain management strategies offers hope to those seeking help, but some feel lost and unable to find the best way forward. This journey is shared by patients, family members, friends, and professionals. Rheumatologic pain management demands a personalized approach based on the individual’s values and aspirations and a clear explanation from healthcare professionals regarding their evidence-based understanding of pain mechanisms, treatment benefits, and risks.

674

PA RT 4 Clinical Conditions: Evaluation and Treatment

Key Points • People with rheumatologic conditions suffer from diverse pains, which may vary in severity, quality, and impact over time, and between individuals. • Multiple and changing mechanisms underlie rheumatologic pain, including peripheral nociception and nociplastic pain associated with mechanisms in the central nervous system. • Pain in rheumatologic conditions is often linked to comorbid symptoms of fatigue, stiffness, disability, low mood, and anxiety. Pain should be managed alongside these other symptoms to maximally improve the quality of life. • Pain mechanisms and, therefore, some treatment recommendations overlap between inflammatory and non-inflammatory rheumatologic conditions and with other non-rheumatologic chronic pain. • General principles of rheumatologic pain management reflect those in other chronic pain conditions, benefiting from a personalized, multi-disciplinary approach proportionate to the needs of the patient. • Treatments targeting molecular pathways of specific immunity can effectively reduce pain in inflammatory rheumatic conditions

Suggested Readings Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for nonsurgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr Cartil. 2019;27(11):1578–1589. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthr Rheumatol. 2020;72(6):879–895. Geenen R, Overman CL, Christensen R, et al. EULAR recommendations for health professional’s approach to pain management in inflammatory arthritis and osteoarthritis Ann Rheum Dis. 2018;77(6):797–807. Hassan H, Walsh DA. Central pain processing in osteoarthritis: implications for treatment. Pain Manage. 2014;4(1):45–56. Luchetti MM, Benfaremo D, Gabrielli A. Biologics in inflammatory and immunomediated arthritis. Curr Pharmaceut Biotechnol. 2017;18(12):989–1007. Macmullan P, McCarthy G. Treatment and management of pseudogout: insights for the clinician. Therapeut Adv Musculoskelet Dis. 2012;4(2):121–131. Neogi T. Structural correlates of pain in osteoarthritis. Clin Exp Rheumatol. 2017;35(5);(Suppl 107):75–78.

•

•

•

•

such as rheumatoid arthritis, but residual non-inflammatory pain remains a major treatment challenge. Intermittent pain, often severe and unpredictable, has a major impact on people with rheumatologic conditions. In gout, maintenance urate-lowering therapy can prevent flares if adequately implemented, but adequate flare prevention in other rheumatologic conditions requires further research. Painful and non-painful comorbidities are common in people with rheumatologic conditions and should inform treatment choices to maximize benefits for the person as a whole and to minimize the risks of adverse events. Individuals have diverse values and might place more or less emphasis on pain and its relief, other symptoms, cost and inconvenience of treatment, and other potential or experienced adverse events. Treatment should be tailored to the individual’s needs and values. Pain management is a moral and personal necessity that should not be delayed while establishing optimal disease modification, which may take several months.

Syx D, Tran PB, Miller RE, Malfait AM. Peripheral mechanisms contributing to osteoarthritis pain. Curr Rheumatol Rep. 2018;20(2):9. Syx D, De Wandele I, Rombaut L, Malfait F. Hypermobility, the Ehlers-Danlos syndromes, and chronic pain. Clin Exp Rheumatol. 2017;35(5);(Suppl 107):116–122. Walsh DA, McWilliams DF. Mechanisms, impact, and management of pain in rheumatoid arthritis. Natur Rev Rheumatol. 2014;10(10):581– 592. Walsh DA. Contextual aspects of pain: Why does the patient hurt? In: M Doherty (ed). Oxford Textbook of Osteoarthritis and Crystal Arthropathy. 3rd ed. Oxford: Oxford University Press; 2016. doi:10.1093/med/9780199668847.003.0014. The references for this chapter can be found at ExpertConsult.com.

Permissions and Courtesies No borrowed materials are included in this manuscript (whether text or illustrative).

References 1. Bijlsma J, Hachulla E (eds). EULAR Textbook on Rheumatic Diseases. 3rd ed. United Kingdom: British Medical Association; 2018. 2. Me D. Oxford Textbook of Osteoarthritis and Crystal Arthropathy. 3rd ed. Oxford: Oxford University Press; 2016. 3. Lee YC. Effect and treatment of chronic pain in inflammatory arthritis. Curr Rheumatol Rep. 2013;15(1):300. 4. Garrido-Cumbrera M, Poddubnyy D, Gossec L, et al. The European map of axial spondylarthritis: capturing the patient perspective-an analysis of 2846 patients across 13 countries. Curr Rheumatol Rep. 2019;21(5):19. 5. Syx D, De Wandele I, Rombaut L, Malfait F. Hypermobility, the Ehlers-Danlos syndromes and chronic pain. Clin Exp Rheumatol. 2017;35(5):116–122 Suppl 107. 6. Walsh DA, McWilliams DF. Mechanisms, impact and management of pain in rheumatoid arthritis. Natur Rev Rheumatol. 2014;10(10): 581–592. 7. Hawker GA, Davis AM, French MR, et al. Development and preliminary psychometric testing of a new OA pain measure - an OARSI/ OMERACT initiative. Osteoarthr Cartil. 2008;16(4):409–414. 8. Hegarty RS, Treharne GJ, Stebbings S, Conner TS. Fatigue and mood among people with arthritis: carry-over across the day. Health Psychol. 2016;35(5):492–499. 9. Haigh RC, McCabe CS, Halligan PW, Blake DR. Joint stiffness in a phantom limb: evidence of central nervous system involvement in rheumatoid arthritis. Rheumatol. 2003;42(7):888–892. 10. IASP. IASP terminology. Available at: https://www.iasp-pain.org/ Education/Content.aspx?ItemNumber=1698#Pain. 11. Lee YC, Lu B, Edwards RR, et al. The role of sleep problems in central pain processing in rheumatoid arthritis. Arthr Rheum. 2013;65(1):59–68. 12. Norheim KB, Jonsson G, Omdal R. Biological mechanisms of chronic fatigue. Rheumatol. 2011;50(6):1009–1018. 13. Akin-Akinyosoye K, Frowd N, Marshall L, et  al. Traits associated with central pain augmentation in the knee pain in the community (KPIC) cohort. Pain. 2018;159(6):1035–1044. 14. Lundblad H, Kreicbergs A, Jansson KA. Prediction of persistent pain after total knee replacement for osteoarthritis. J Bone Joint Surg Brit V. 2008;90(2):166–171. 15. Aso K, Shahtaheri SM, Hill R, et al. Contribution of nerves within osteochondral channels to osteoarthritis knee pain in humans and rats. Osteoarthr Cartil. 2020;28(9):1245–1254. 16. Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Natur Rev Rheumatol. 2012;8(7):390–398. 17. Syx D, Tran PB, Miller RE, Malfait AM. Peripheral mechanisms contributing to osteoarthritis pain. Curr Rheumatol Rep. 2018;20(2):9. 18. Schmelz M, Mantyh P, Malfait AM, et al. Nerve growth factor antibody for the treatment of osteoarthritis pain and chronic low-back pain: mechanism of action in the context of efficacy and safety. Pain. 2019;160(10):2210–2220. 19. Ashraf S, Bouhana KS, Pheneger J, Andrews SW, Walsh DA. Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis. Arthr Res Ther. 2016;18(1):97. 20. Bersellini Farinotti A, Wigerblad G, Nascimento D, et al. Cartilagebinding antibodies induce pain through immune complex-mediated activation of neurons. J Exp Med. 2019;216(8):1904–1924. 21. Kaplan CM, Schrepf A, Ichesco E, et al. Association of inflammation with pronociceptive brain connections in rheumatoid arthritis patients with concomitant fibromyalgia. Arthr Rheumatol. 2020;72(1):41–46. 22. McWilliams DF, Ferguson E, Young A, Kiely PD, Walsh DA. Discordant inflammation and pain in early and established rheumatoid arthritis: Latent Class Analysis of Early Rheumatoid Arthritis Network and British Society for Rheumatology Biologics register data. Arthr Res Ther. 2016;18(1):295. 23. Walsh DA. Contextual aspects of pain; why does the patient hurt? In: Doherty M (ed). Oxford Textbook of Osteoarthritis and Crystal Arthropathy. 3rd ed. Oxford: Oxford University Press; 2016.

24. Clarke SP, Moreton BJ, das Nair R, Walsh DA, Lincoln NB. Personal experience of osteoarthritis and pain questionnaires: mapping items to themes. Disabil Rehab. 2014;36(2):163–169. 25. Fransen J, Langenegger T, Michel BA, Stucki G. Feasibility and validity of the RADAI, a self-administered rheumatoid arthritis disease activity index. Rheumatol. 2000;39(3):321–327. 26. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath ankylosing spondylitis disease activity index. J Rheumatol. 1994;21(12):2286–2291. 27. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15(12):1833–1840. 28. Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee injury and osteoarthritis outcome score (KOOS) - development of a self-administered outcome measure. J Orthop Sport Phys Ther. 1998;28(2):88–96. 29. Aso K, Shahtaheri SM, McWilliams DF, Walsh DA. Association of subchondral bone marrow lesion localization with weight-bearing pain in people with knee osteoarthritis: data from the osteoarthritis initiative. Arthr Res Ther. 2021;23(1):35. 30. McWilliams DF, Kiely PDW, Young A, Joharatnam N, Wilson D, Walsh DA. Interpretation of DAS28 and its components in the assessment of inflammatory and non-inflammatory aspects of rheumatoid arthritis. BMC Rheumatol. 2018;2:8. 31. Sarmanova A, Hall M, Fernandes GS, et  al. Association between ultrasound-detected synovitis and knee pain: a population-based case-control study with both cross-sectional and follow-up data. Arthr Res Ther. 2017;19(1):281. 32. McWilliams DF, Dawson O, Young A, Kiely PDW, Ferguson E, Walsh DA. Discrete trajectories of resolving and persistent pain in people with rheumatoid arthritis despite undergoing treatment for inflammation: results from three UK cohorts. J Pain. 2019;20(6):716–727. 33. Baraliakos X, Szumski A, Koenig AS, Jones H. The role of C-reactive protein as a predictor of treatment response in patients with ankylosing spondylitis. Sem Arthr Rheum. 2019;48(6):997–1004. 34. McWilliams DF, Zhang W, Mansell JS, Kiely PD, Young A, Walsh DA. Predictors of change in bodily pain in early rheumatoid arthritis: an inception cohort study. Arthr Care Res. 2012;64(10):1505–1513. 35. Neogi T. Structural correlates of pain in osteoarthritis. Clin Exp Rheumatol. 2017;35(5):75–78 Suppl 107. 36. Hassan H, Walsh DA. Central pain processing in osteoarthritis: implications for treatment. Pain Manage. 2014;4(1):45–56. 37. Heisler AC, Song J, Muhammad LN, et  al. Association of dysregulated central pain processing and response to disease-modifying anti-rheumatic drug therapy in rheumatoid arthritis. Arthr Rheumatol. 2020;72(12):2017–2024. 38. Georgopoulos V, Akin-Akinyosoye K, Zhang W, McWilliams DF, Hendrick P, Walsh DA. Quantitative sensory testing and predicting outcomes for musculoskeletal pain, disability, and negative affect: a systematic review and meta-analysis. Pain. 2019;160(9):1920–1932. 39. Suokas AK, Walsh DA, McWilliams DF, et al. Quantitative sensory testing in painful osteoarthritis: a systematic review and meta-analysis. Osteoarthr Cartil. 2012;20(10):1075–1085. 40. Akin-Akinyosoye K, Sarmanova A, Fernandes GS, et  al. Baseline self-report ‘central mechanisms’ trait predicts persistent knee pain in the knee pain in the community (KPIC) cohort. Osteoarthr Cartil. 2020;28(2):173–181. 41. Neblett R, Cohen H, Choi Y, et al. The central sensitization inventory (CSI): establishing clinically significant values for identifying central sensitivity syndromes in an outpatient chronic pain sample. J Pain. 2013;14(5):438–445. 42. Wolfe F, Clauw DJ, Fitzcharles MA, et  al. 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Sem Arthr Rheum. 2016;46(3):319–329. 674.e1

674.e2

References

43. Perruccio AV, Mahomed NN, Chandran V, Gandhi R. Plasma adipokine levels and their association with overall burden of painful joints among individuals with hip and knee osteoarthritis. J Rheumatol. 2014;41(2):334–337. 44. Eitner A, Pester J, Vogel F, et al. Pain sensation in human osteoarthritic knee joints is strongly enhanced by diabetes mellitus. Pain. 2017;158(9):1743–1753. 45. Valdes AM, Abhishek A, Muir K, Zhang W, Maciewicz RA, Doherty M. Association of beta-blocker use with less prevalent joint pain and lower opioid requirement in people with osteoarthritis. Arthr Care Res. 2017;69(7):1076–1081. 46. Ozen G, Sunbul M, Atagunduz P, Direskeneli H, Tigen K, Inanc N. The 2013 ACC/AHA 10-year atherosclerotic cardiovascular disease risk index is better than SCORE and QRisk II in rheumatoid arthritis: is it enough? Rheumatol. 2016;55(3):513–522. 47. Turk D, Boeri M, Abraham L, et  al. Patient preferences for osteoarthritis pain and chronic low back pain treatments in the United States: a discrete-choice experiment. Osteoarthr Cartil. 2020;28(9):1202–1213. 48. Mills K, Eyles JP, Martin MA, Hancock MJ, Hunter DJ. Exploratory study of 6-month pain trajectories in individuals with predominant patellofemoral osteoarthritis: a cohort study. J Orthop Sport Phys Ther. 2019;49(1):5–16. 49. Judge A, Batra RN, Thomas GE, et  al. Body mass index is not a clinically meaningful predictor of patient reported outcomes of primary hip replacement surgery: prospective cohort study. Osteoarthr Cartil. 2014;22(3):431–439. 50. Valdes AM, Doherty SA, Zhang W, Muir KR, Maciewicz RA, Doherty M. Inverse relationship between preoperative radiographic severity and postoperative pain in patients with osteoarthritis who have undergone total joint arthroplasty. Sem Arthr Rheum. 2012;41(4):568–575. 51. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67(12):1716–1723. 52. Geenen R, Overman CL, Christensen R, et  al. EULAR recommendations for the health professional’s approach to pain management in inflammatory arthritis and osteoarthritis. Ann Rheum Dis. 2018;77(6):797–807. 53. American College of Rheumatology Pain Management Task Force. Report of the American College of Rheumatology pain management task force. Arthr Care Res. 2010;62(5):590–599. 54. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr Cartil. 2019;27(11):1578–1589. 55. Lee YC, Kremer J, Guan H, Greenberg J, Solomon DH. Chronic opioid use in rheumatoid arthritis: prevalence and predictors. Arthr Rheumatol. 2019;71(5):670–677. 56. Gøtzsche PC, Johansen HK. Short-term low-dose corticosteroids vs placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. Cochrane Database Syst Rev. 2002;2:CD000189. 57. Luchetti MM, Benfaremo D, Gabrielli A. Biologics in inflammatory and immunomediated arthritis. Curr Pharmaceut Biotech. 2017;18(12):989–1007. 58. Goh SL, Persson MSM, Stocks J, et al. Relative efficacy of different exercises for pain, function, performance and quality of life in knee and hip osteoarthritis: systematic review and network meta-analysis. Sport Med. 2019;49(5):743–761. 59. Persson MSM, Stocks J, Varadi G, et al. Predicting response to topical non-steroidal anti-inflammatory drugs in osteoarthritis: an individual patient data meta-analysis of randomized controlled trials. Rheumatol (Oxford). 2020;59(9):2207–2216. 60. Samuels J, Pillinger MH, Jevsevar D, Felson D, Simon LS. Critical appraisal of intra-articular glucocorticoid injections for symptomatic osteoarthritis of the knee. Osteoarthr Cartil. 2021;29(1):8–16. 61. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552–559.

62. Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open. 2012;2(1):e000435. 63. Sacristan JA, Dilla T, Diaz-Cerezo S, Gabas-Rivera C, Aceituno S, Lizan L. Patient-physician discrepancy in the perception of immune-mediated inflammatory diseases: rheumatoid arthritis, psoriatic arthritis and psoriasis. A qualitative systematic review of the literature. PLoS One. 2020;15(6):e0234705. 64. NICE. Arthritis; NICE interactive flowchart. Available at: https:// pathways.nice.org.uk/pathways/musculoskeletal-conditions/arthritis. 65. Kilic G, Kilic E, Nas K, Kamanlı A, Tekeoglu İ. Residual symptoms and disease burden among patients with psoriatic arthritis: is a new disease activity index required? Rheumatol Int. 2019;39(1):73–81. 66. McWilliams DF, Marshall M, Jayakumar K, et al. Erosive and osteoarthritic structural progression in early rheumatoid arthritis. Rheumatol (Oxford). 2016;55(8):1477–1488. 67. Zhao SS, Duffield SJ, Goodson NJ. The prevalence and impact of comorbid fibromyalgia in inflammatory arthritis. Best practice & research. Clin Rheumatol. 2019;33(3):101423. 68. FitzGerald JD, Dalbeth N, Mikuls T, et  al. 2020 American College of Rheumatology guideline for the management of gout. Arthr Rheumatol. 2020;72(6):879–895. 69. Macmullan P, McCarthy G. Treatment and management of pseudogout: insights for the clinician. Ther Adv Musculoskelet Dis. 2012; 4(2):121–131. 70. Leo M, Argalski S, Schäfers M, Hagenacker T. Modulation of voltage-gated sodium channels by activation of tumor necrosis factor receptor-1 and receptor-2 in small DRG neurons of rats. Mediators Inflamm. 2015;2015:124942. 71. de Macedo FHP, Aires RD, Fonseca EG, et al. TNF-alpha mediated upregulation of NaV1.7 currents in rat dorsal root ganglion neurons is independent of crmp2 sumoylation. Mol. 2019;12(1):117. 72. Chen Y, Zhang Y, Huo Y, Wang D, Hong Y. Adrenomedullin mediates tumor necrosis factor-alpha-induced responses in dorsal root ganglia in rats. Brain Res. 2016;1644:183–191. 73. Ding HH, Zhang SB, Lv YY, et  al. TNF-α/STAT3 pathway epigenetically upregulates NaV1.6 expression in DRG and contributes to neuropathic pain induced by L5-VRT. J Neuroinflamm. 2019;16(1):29. 74. Tamura R, Nemoto T, Maruta T, et  al. Up-regulation of NaV1.7 sodium channels expression by tumor necrosis factor-alpha in cultured bovine adrenal chromaffin cells and rat dorsal root ganglion neurons. Anesth Analg. 2014;118(2):318–324. 75. Bałkowiec-Iskra E, Vermehren-Schmaedick A, Balkowiec A. Tumor necrosis factor-alpha increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner. Neurosci. 2011;180:322–333. 76. Saleh A, Smith DR, Balakrishnan S, et  al. Tumor necrosis factoralpha elevates neurite outgrowth through an NF-κ B-dependent pathway in cultured adult sensory neurons: diminished expression in diabetes may contribute to sensory neuropathy. Brain Res. 2011;1423:87–95. 77. Hou L, Li W, Wang X. Mechanism of interleukin-1 beta-induced calcitonin gene-related peptide production from dorsal root ganglion neurons of neonatal rats. J Neurosci Res. 2003;73(2):188–197. 78. Morioka N, Takeda K, Kumagai K, et al. Interleukin-1beta-induced substance P release from rat cultured primary afferent neurons driven by two phospholipase A2 enzymes: secretory type IIA and cytosolic type IV. J Neurochem. 2002;80(6):989–997. 79. von Banchet GS, Kiehl M, Schaible HG. Acute and long-term effects of IL-6 on cultured dorsal root ganglion neurones from adult rat. J Neurochem. 2005;94(1):238–248. 80. Habash T, Saleh A, Roy Chowdhury SK, Smith DR, Fernyhough P. The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats. Exp Neurol. 2015;273:177–189.

47

Pain Management in Patients With Comorbidities

NATALIE H. STRAND, ANDREA L. CHADWICK

Introduction Pain is defined by the International Association of Pain (IASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with actual or potential tissue damage.”1 Given that pain is not only a symptom but also an independent disease, it is highly likely that patients with chronic pain may also have other medical comorbidities and disorders that will influence the scope of treatments that are recommended. In any patient with chronic pain, the severity, frequency, and tolerance to the condition are variable and are influenced by a variety of factors, including one’s cultural background, expectations, behaviors, and physical and emotional health. In patients with comorbid conditions such as renal and hepatic diseases, diabetes, and the elderly, an understanding of how these conditions may influence pain treatment is of utmost importance. The appropriate selection of non-pharmacologic, pharmacologic, and interventional treatments based on the underlying comorbid conditions has the potential to improve physical functioning, emotional wellbeing, and overall quality of life. The scope of this chapter is to understand how pain management strategies need to be understood and tailored to specific comorbid medical conditions, including renal disease, liver disease, diabetes, and the frail/elderly population.

Renal Disease Prevalence Chronic kidney disease (CKD) is a global public health problem that is increasing in incidence and prevalence and is associated with poor patient outcomes and high medical costs.2 CKD is defined as the progressive and gradual loss of the kidneys to concentrate urine, excrete wastes and metabolites, secrete hormones, and conserve electrolytes. There is a distinction between CKD and end stage renal disease (ESRD), which is the deterioration of kidney function to the point where renal dialysis or transplantation is required for survival. Patients with CKD and ESRD experience a high severity and prevalence of physical symptoms related to their diseases. The symptom burden in these populations is greater than that of the general population, and despite this well-described complication, many patients have underrecognized, underestimated, and undertreated symptoms related to their CKD and ESRD.3–5 Pain is one of the most common symptoms encountered in CKD and ESRD, with the reported prevalence of pain

ranging from 30 to over 58%.6–9 In patients with ESRD who are on hemodialysis (HD) or peritoneal dialysis (PD), the prevalence of acute and chronic pain has recently been shown to be up to 80%.10 Of these patients who report pain, it has been shown that over half report pain as moderate to severe in intensity.8,9,11,12

Etiologies Similar to the underlying disease processes present in CKD and ESRD, the pain experienced by patients with kidney disease is often multifactorial. Etiologies of pain can be either straightforward or complex and related to a multitude of issues (Table 47.1). Symptoms can be caused as a direct result of the primary underlying kidney disease process, such as pain related to autosomal dominant polycystic kidney disease, or they can be related to associated underlying systemic and comorbid diseases such as diabetes, peripheral vascular disease, and various musculoskeletal processes.7 Pain may also be experienced as a direct result of HD or PD procedure itself.10,12 It is also important to remember that additional pain related diagnoses such as anxiety, depression, and sleep problems may coexist with the chronic pain syndromes experienced by CKD/ESRD patients and that these conditions may feed into the challenges that coincide with treating chronic pain in these populations. As in any patient with acute or chronic pain, determining the type and severity of the pain can provide an excellent roadmap for outlining treatment plans. Listening to the patient about their symptoms and experiences surrounding their pain provides a great opportunity to provide them with compassion and validation of the significance of their problem and is an important piece of the therapeutic relationship. Acute and chronic pain can be classified as nociceptive, neuropathic, nociplastic, or mixed pain. By definition, nociceptive pain arises from actual or threatened damage to non-neural tissue and results from the activation of nociceptors, while neuropathic pain is a clinical description that requires a definite lesion or a specific disease process that affects the somatosensory nervous system. The persistence of nociceptive stimuli can lead to several functional and structural changes in the central nervous system, known as central sensitization.13 Many chronic pain conditions are characterized by central sensitization, widespread pain, and altered descending pain modulation.14 The IASP has recently introduced a new term, nociplastic pain, defined as conditions that arise from altered nociception, without clear evidence of actual or threatened 675

676

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 47.1

Pain Origins in Chronic Kidney Disease and End Stage Renal Disease

Pain Origin

Examples

Intrinsic Kidney Pathologies

Calciphylaxis Renal osteodystrophy (bone pain) Limb ischemia because of dialysis access steal syndrome Dialysis related amyloid arthropathy

Underlying or Comorbid Disease Processes

Autosomal dominant polycystic kidney disease Urinary tract infections Vascular peripheral neuropathy Diabetic peripheral neuropathy Amyloidosis Phantom limb pain Dermatologic conditions Malignancy Osteoporosis

Dialysis Related

AV fistula/graft surgical creation Needlestick cannulation of HD AV access Instillation of PD fluid PD associated peritonitis, low back pain Muscle cramping from dialysis ultrafiltration Pruritis Headache Chest pain associated with intradialytic hypotension Dyspnea Infected HD catheter

Pain Unrelated to Kidney Disease

Osteoarthritis Malignancy Degenerative disc disease Radiculopathies Migraines Gout Fibromyalgia Restless leg syndrome Entrapment neuropathies

Clinical Presentation and Assessment of Pain in CKD/ESRD.

tissue damage or lesions, or disease of the somatosensory nervous system. Patients with ESRD may suffer from nociceptive, neuropathic, nociplastic, or mixed pain states. Ascertaining the mechanism of chronic pain is essential in the choice of mechanism-based analgesic therapies.15,16 A thorough and complete pain assessment includes determining several attributes that contribute to acute and chronic pain, such as pain severity, pain quality (described in the previous paragraph), eliciting and attenuating factors, impact of pain on daily activities and physical functioning, pain interference with mood and sleep, and effects of pain on quality of life. No instruments have been specifically designed and validated for pain assessment in CKD/ESRD patients. However, several approaches can be used. One-dimensional scales are instruments used to identify pain severity, while multidimensional scales can be utilized to reflect the biopsychosocial model of pain that integrates social and psychological paradigms with the biologic mechanisms of pain. The most commonly used one-dimensional scale for pain assessment is the 11 point numeric rating scale (NRS), where zero

indicates no pain and ten is the worst imaginable pain, and the 10 cm (100 mm) continuous visual analog scale (VAS), which is anchored by the two verbal descriptors for each extreme (“no pain” and “pain as bad as it could be”). Many of the same assessment tools that exist for patients with non-kidney disease pain are valid and reliable in the CKD/ESRD population. The McGill pain questionnaire (MPQ) and the brief pain inventory (BPI) are the most common multidimensional scales used to assess pain. The MPQ has been in use since 1975 and is a widely used instrument to evaluate pain and helps determine both quantitative and qualitative aspects of pain, such as location, grade, temporal characteristics, and intensity.17 The BPI, initially developed for cancer patients but validated for use in chronic non-cancer pain, uses an 11 point NRS for pain intensity, requests the patient to draw the site(s) of pain on a body diagram, and uses an 11 point NRS to assess pain interference in seven domains, including general activity, mood, walking ability, work, relations with other people, sleep, and enjoyment of life.18 Assessment tools such as the modified Edmonton symptom assessment system (m-ESAS v. 2),19 and palliative care outcome scale-renal (POS-renal)20 are renal-specific screening tools that may be more appropriate for routine clinical screening for pain in renal patients. These assessments identify the presence of pain and provide opportunities for discussions about appropriate palliative and supportive care treatment options.

Barriers to Pain Management in Kidney Disease As mentioned previously, chronic pain is very common in patients with CKD and ESRD. However, it has historically been underrecognized and often poorly managed. It is well known that poorly controlled pain leads to decreased quality of life, poor physical functioning, reduced mobility, increased healthcare utilization, and longer hospital stays.16 Numerous reasons have been reported for insufficient pain management in CKD and ESRD, including inadequate pain assessment, concerns about analgesic-related adverse effects, and misconceptions.3,5,16 As described in the previous section, an adequate pain assessment requires an accurate medical history, thorough physical examination, and the application of validated tools for the identification of pain intensity and quality. The presence and severity of pain should be regularly assessed in patients with CKD and ESRD, and if applicable, during each HD session. Pain is generally undertreated in patients with CKD and ESRD because of the fear of the potential toxicity of analgesic drugs. Overtreatment, overdose, and inadequate analgesia can result from inappropriate dosing of non-opioid and opioid analgesics. Unfortunately, quality data or guidelines on the pharmacokinetics, clinical efficacy and safety of many common analgesics in this population are lacking. Indeed, the translation of pharmacologic pain management methods used in non-CKD/ESRD populations can be dangerous, as patients with CKD and ESRD have reduced renal function and altered pharmacokinetics.21 Alterations in metabolism and excretion may lead to significant adverse toxicities and side effects. Renal dose adjustments are required for most analgesics.

Setting Expectations At the initiation of any pain management treatment program, the provider must discuss with the patient the expectations of therapy. These expectations should include the identification of reasonable therapeutic goals, including the level of pain that is acceptable for

 

CHAPTER 47

a patient’s quality of life, the risks and benefits of the treatment(s), the potential duration of pharmacologic therapy, and if applicable, the components of a pain contract for continued care. The overall goal of both immediate and long term pain management should be to improve the functional status. Moreover, a discussion that the patient should not expect to be pain-free is of importance and that a reasonable expectation should be that pain may not be completely resolved or controlled and that a 30% reduction in pain symptomology is often identified as clinically meaningful.22

Pain Management Approach in Patients With CKD and ESRD With or Without Hemodialysis General Principles Pain treatment should be tailored to each individual according to the type and severity of pain. In general, non-pharmacologic options should be used first. Non-pharmacologic treatment options can be broadly categorized as psychosocial/behavioral interventions (e.g. cognitive behavior therapy (CBT), mindfulness) and physical interventions (e.g. exercise, physical therapy, yoga, acupuncture, electrical stimulation). Although most of these have not been specifically tested in CKD/ESRD, they have been proven to be effective in other chronic pain states and thus provide an encouraging approach for the treatment of pain in this population, either alone or as an adjunct to pharmacologic treatment. Pharmacologic analgesic therapy should be based on the type of pain, severity of pain, and when the benefits of medications are cautiously weighed against possible side effects, drug-drug interactions, and coexisting medical morbidities. It is recommended that patients initiate therapy on a minimal dose of an analgesic medication and up-titrated slowly based on response and tolerance with very close monitoring for side effects or adverse events. An opioid-sparing approach is recommended in most cases.

Non-pharmacologic Therapies The non-pharmacologic approach is the first step in pain management. In particular, in patients where drugs are not free of risks, non-pharmacologic techniques should be encouraged. Non-pharmacologic interventions include biofeedback, CBT, massage, and physical therapy/exercise programs. CBT has become a well-established and accepted treatment for chronic pain in the general population. Robust evidence from a meta-analysis of 35 trials (>4700 patients) supports its efficacy for improving chronic pain symptoms and pain related physical disability in the general population. However, the effect size may be small, and the long term effects are not durable.23 In the CKD/ ESRD population, CBT is effective in improving depression, but its effect on pain has not been tested.24 CBT has been shown to be effective in the general non-cancer chronic pain population and is based on concepts surrounding poor self-management skills, self-efficacy, and coping skills, which typically exist in this patient population. There is a strong premise that CBT may be a successful non-pharmacologic pain management strategy. The potential benefits of complementary and alternative medicine have not been adequately investigated in patients with CKD/ ESRD. These interventions include relaxation techniques, mindfulness, and acupuncture. A systematic review of randomized control trials investigating the effect of relaxation techniques in >400 patients with chronic pain in the general population found no significant benefit in reducing pain. However, the studies were of low quality, and thus the data are not conclusive at this time.25 In HD

Pain Management in Patients With Comorbidities

677

patients, two small studies have shown that relaxation techniques may improve pain intensity and health-related quality of life.26,27 Mindfulness-based techniques including meditation, which involves focusing the mind on experiences (e.g. sensations, emotions, thoughts) in the present moment, have shown some promise in improving pain in the non-ESRD population.28 Moreover, a recent pilot study demonstrated that a brief, individualized, chairside mindfulness meditation intervention was feasible and acceptable for HD patients.29 A recent Cochrane analysis evaluated 24 studies on various types of acupuncture in patients with CKD. There is a paucity of evidence on the efficacy of acupuncture for fatigue, depression, sleep disturbance, and uremic pruritus in HD patients. Moreover, data on possible acupuncture-related harm are lacking. Therefore no conclusions may be drawn on its safety.30 In the multimodal approach to chronic pain, invasive interventional pain techniques may potentially play a role in treating pain refractory to conventional pharmacologic treatment or to reduce the dose of analgesics in patients with CKD/ESRD. There is a paucity of literature on this topic. However, spinal cord stimulation (SCS) could be useful in HD patients suffering from peripheral vascular disease, stump pain after amputation, and painful diabetic neuropathy (PDN), but current guidelines only support a weak recommendation.31

Pharmacologic Therapies The World Health Organization ladder for analgesic pain control, originally created for cancer pain treatment, has been validated for use in the CKD/ESRD population.32 The modified ladder uses a three-step approach for pain management. Mild pain is generally treated in step 1 using non-opioid analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Step 2 treats moderate pain with the addition of mild or weak opioids such as tramadol, low dose oxycodone, and low dose hydromorphone. Step 3 initiates higher-dose opioids, such as higher doses of oxycodone/hydromorphone, fentanyl, methadone, and buprenorphine to treat severe pain. Adjunctive medications, such as gabapentin, pregabalin, tricyclic anti-depressants (TCAs), and serotonin norepinephrine reuptake inhibitors (SNRIs), can be added at any step of the ladder.33 When pharmacologic interventions for pain management in CKD/ESRD are being implemented, it is best to identify the level of current renal function. Moreover, special emphasis should be placed when choosing pharmacologic therapies to prevent further deterioration of renal function and protection of existing renal function in patients with moderate to severe impairment. Therefore, drug adjustments may be required for CKD/ESRD. Two methods of dosing regimen adjustment have been recommended: (1) extending the time between doses while maintaining the same dose size (reducing the number of daily doses) or (2) to reduce the size of the individual prescribed dose at the same dosing interval.16 Sometimes, a combination method can be needed when both these methods (interval extension and dose reduction) are used. The interval extension method is generally not indicated for drugs with a short half-life because of the risk of a prolonged period with a subtherapeutic drug concentration. However, it is recommended for drugs with a relatively long half-life.16

Non-opioid Medications Acetaminophen is the most commonly used non-opioid analgesic for ESRD.34 Notably, the National Kidney Foundation promotes acetaminophen as the non-narcotic analgesic of choice for mild

678

PA RT 4 Clinical Conditions: Evaluation and Treatment

to moderate pain in CKD/ESRD.8 The proposed adjustment in HD patients suggests dosing every 8 h.35 Clinical studies have shown the effective removal of acetaminophen and its metabolites by HD.36 NSAIDs are commonly prescribed for their inflammatory and analgesic properties. However, they are known to have gastrointestinal, cardiovascular, and renal toxicity. Clinical investigations on NSAIDs in patients with CKD/ESRD are typically singledose studies or trials conducted for short periods and were not designed to evaluate efficacy and safety.16 Limited information is currently available regarding the use of NSAIDs in patients undergoing HD. Considering the potential for nephrotoxicity, it is strongly recommended to avoid NSAIDs in patients with CKD/ESRD.16 Despite this, the literature suggests that they continue to be commonly prescribed in this population. In a cohort study of 972 subjects with CKD, 16.9% used NSAIDs every day or several times a week, which increased to 35% among those on HD.37 In 46.7% of these cases, the CKD/ESRD patients used NSAIDs without being advised to do so by a medical professional and were unaware of the potential side effects of the painkillers, and the remaining were prescribed by physicians or pharmacists. Over 40% of the exposed patients experienced renal function deterioration in this cohort, 37.6% experienced peptic ulcer disease, and 18.2% experienced altered blood pressure control.37 Thus if NSAID use is considered in patients with kidney disease, a full description of risks and benefits should be discussed with the patient, and ongoing monitoring of renal function throughout treatment should be performed. Topical NSAIDs, such as diclofenac gel, can be effectively used without significant systemic adverse effects.38 Anti-convulsants, particularly gabapentinoids, are strongly recommended as first line treatment for the management of neuropathic pain conditions, which are common in CKD/ESRD patients.39 Gabapentin and pregabalin have been specifically evaluated in patients with CKD/ESRD. Dose adjustment is required in terms of dose reduction and interval extension with these medications. Gabapentin has a favorable pharmacokinetic profile. It is excreted unchanged by the kidneys in urine, and plasma concentrations and toxicity correlate with impaired renal function. Its half-life, 6 to 8 h in healthy subjects, decreases to 4 h after HD and increases to 132 h without HD in ESRD patients.40 The low protein binding makes gabapentin easy to dialyze (approximately 35%). The recommended dose in HD patients is up to 300 mg daily, with a supplemental 200 to 300 mg dose after each HD session.41 Similarly, pregabalin is easily dialyzable because it has a low molecular weight, a low volume of distribution (0.5 L/kg), and is not bound to plasma protein.42 The maximum recommended dose of pregabalin in ESRD patients is reduced to 25 to 75 mg/day, with mental doses after HD. However, a recent prospective, openlabel, single-arm study on pregabalin for neuropathic pain in patients undergoing HD evaluated 45 patients carefully titrated to 150 mg during a 12 week study period.43 The authors reported a 22.2% withdrawal rate because of side effects (mainly drowsiness and dizziness) without serious drug-related adverse events. Pregabalin has been shown to be effective in reducing pain scores and improving QoL.43 These medications are associated with an increased risk of falls, cognitive impairment, and altered mental status in a dose-dependent fashion.44 These effects may be more pronounced in the elderly population. Alternative neuropathic analgesics such as SNRI and tricyclic anti-depressants (TCA) have been extensively studied and are

reported to be efficacious in non-CKD/ESRD populations and are recommended as first or second line treatment in many neuropathic chronic pain conditions. However, data supporting the safety and efficacy of these medications in CKD/ESRD are not available. These medications are not removed by HD, and the anticholinergic and serotonergic effects of these medications may be intensified in patients with ESRD. A recent systematic review concluded that most studies on anti-depressants for depression in ESRD patients involved a small number of subjects and were observational, leading to possible bias. Dose reduction is currently recommended for duloxetine, amitriptyline, venlafaxine, desvenlafaxine, and milnacipran.45 In general, anti-depressants should be started at lower doses and carefully titrated to the effective dose to reduce the risk of side effects.46

Opioid Medications Opioids are widely used in chronic pain management and historically have been the mainstay of pharmacologic treatment for severe and refractory chronic pain. However, there is no highquality clinical evidence for their long term use in chronic noncancer pain, and systematic reviews have only reported a moderate benefit.47 The Centers for Disease Control and Prevention (CDC) current guidelines recommend a cautious opioid prescription for chronic pain in which non-opioid therapy is indicated as the preferred treatment for chronic pain and opioid use is suggested only when the benefits for pain and function are expected to outweigh the risks.48 Compared with the general population, patients with CKD and ESRD are likely to be undertreated with opioids because of provider concerns about decreased metabolism and clearance and the increased risk of adverse events.49 Should opioid use be initiated in CKD/ESRD patients, it is recommended that they be started with the lowest possible dose and using immediate release formulations (instead of extended release).50 If the pain does not respond with an improvement in pain using a low dose, the pain may not be opioid-responsive. If the pain responds slightly, for either a lower degree or a shorter period than desired, it may be reasonable to increase the dose or frequency. Prescribers should be cautious with opioids at a morphine milligram equivalent daily dose (MME) above 50 mg. Concurrent benzodiazepines and other sedatives should be avoided in line with the current CDC guidelines. The therapeutic window for opioid medications is narrow, even in a generally healthy population. Individuals with CKD or ESRD have not been included in many trials of opioid use in chronic pain, so the specific analgesic impact of opioids is not known in this population. However, individuals with CKD and ESRD likely experience many known side effects of opioids, including sedation, confusion, and constipation. While the literature on these specific adverse effects is limited in populations with CKD/ ESRD, they are well documented in the elderly, which represents a high proportion of individuals with CKD/ESRD. Even low dose opioids are associated with increased morbidity and mortality in the context of ESRD.51,52 ESRD and HD lead to additional complications related to the metabolism and dialyzability of opioid medications. Most naturally occurring opioids have active metabolites, which may lead to increased toxicity in patients with CKD/ESRD. For example, morphine and codeine are metabolized in the liver to the active metabolites morphine-6-glucuronide (M6G) and morphine3-glucuronide (M3G), respectively.33,53 These metabolites are known to accumulate in patients with impaired kidney function,

 

CHAPTER 47

and their accumulation can lead to potential neurotoxicity and other adverse reactions, such as nausea, vomiting, and respiratory depression. The active metabolite of meperidine, normeperidine, is renally excreted and highly neurotoxic.33,53 When it accumulates in patients with CKD and ESRD, it places them at a high risk of seizures. Morphine, codeine, and meperidine are generally avoided in patients with decreased kidney function, similar to a few other opioids (Table 47.2). Semi-synthetic opioids such as hydromorphone, synthetic opioids (e.g. fentanyl and methadone), and the semi-synthetic opioid buprenorphine do not have active metabolites and are reported to have a higher safety profile in patients with CKD and ESRD.16,50 Although oxycodone is metabolized by the liver into active metabolites that may accumulate in CKD/ESRD, it may be used cautiously in these patients. However, sustainedrelease formulations should be avoided because of the risk of accumulation and toxicity.16,50 Buprenorphine has a lower risk profile and can be utilized with either split dosing or a continuous transdermal patch.54 Tramadol belongs to a class of medications with a dual mode of action, both as an agonist of the µ-opioid receptor and as an SNRI. Since its metabolism depends on an individual’s cytochrome P450 profile, its opioid metabolism and resultant potency are highly variable and unpredictable.55 It is generally considered safe in the general population and in CKD and ESRD in its immediate release formulation.8,56 However, given the variability in effect, it should be used cautiously, starting with the smallest dose in patients with ESRD. Limited data exist for the safety of extended release tramadol in CKD and ESRD, and as such, its use in this population is not recommended.8,56 As in any patient population, when prescribing opioids, providers should educate patients on the risks of opioid overdose and incorporate risk mitigation strategies into the treatment

TABLE 47.2

Pain Management in Patients With Comorbidities

679

plan. This includes considering a prescription for naloxone, an opioid antagonist, when risk factors for opioid overdose, such as a history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/d), or concurrent benzodiazepine use, are present.48

Liver Disease Prevalence Liver disease is a major public health problem, accounting for over 700,000 deaths annually.57 Pain is very common in patients with liver disease, and it is often difficult for practitioners to manage because of underlying medical comorbidities. Pain has been reported in up to 82% of patients with liver cirrhosis and is chronic in over half of the patients with liver it.58 Despite the high prevalence of pain in this population and its potential for adverse consequences, there is limited research, knowledge, and guidance on the management of pain in liver disease and cirrhosis, with most available literature focusing on pain assessment and treatment in cirrhotic disease.

Assessment of Pain in Liver Disease and Cirrhosis An evaluation of pain in patients with liver disease or cirrhosis can be accomplished via standard screening assessments, such as numeric or visual analog rating scales. As with the general population, as discussed in detail in the previous section on renal disease, once pain has been identified as being present, the next step is to determine the nature and likely mechanism of the pain, including location, quality, and duration, and perform a physical examination to assess underlying etiology.58

Opioid Medications to be Avoided in Chronic Kidney Disease/End Stage Renal Disease

Medication

Pharmacokinetics in CKD and ESRD

Known Observed Toxicities

Morphine

Active metabolite morphine-6-glucuronide (M6G) is renally cleared M6G accumulates in renal insufficiency M6G concentrations are 15 times higher in HD patients than those with normal renal function

Respiratory depression Central nervous system depression Seizures Myoclonus Lethal overdose

Codeine

Hepatic metabolism into active metabolites Reduced clearance of parent drug and metabolites in renal insufficiency Risk for drug accumulation in HD patients

Nausea and vomiting Hypotension Respiratory depression or arrest CNS depression

Hydrocodone

Limited data in renal disease and failure 85% of an oral dose is excreted as parent drug or metabolite in the urine within 24 h Risks of adverse effects are increased with renal insufficiency and drug accumulation

Tapentadol

Limited data on use in renal insufficiency and failure Undergoes first pass metabolism into inactive metabolites, 99% of which are excreted in the urine AUC of the metabolite is increased 5.5 times in severe renal insufficiency

Meperidine

Hepatic metabolism into active metabolite normeperidine, which is renally excreted Half-life of normeperidine is increased in renal insufficiency HD has been reported in case of overdose, suggesting the drug can be dialyzed

Mental status changes, seizures

Tramadol (especially Extended Release)

Limited data - Has not been studied in renal disease

Seizures Serotonin syndrome

680

PA RT 4 Clinical Conditions: Evaluation and Treatment

Special Considerations in Patients With Liver Disease and Cirrhosis Most patients with liver disease and cirrhosis reporting pain describe abdominal pain as their primary pain area. However, a large proportion of patients also report pain in the lower back, large joints, and diffusely.59 As non-alcoholic fatty liver disease increases in prevalence, it may overlap with other common nonhepatic painful conditions, such as osteoarthritis, which is a common etiologic factor of obesity. As with renal disease, specific considerations should be noted that are intrinsic and related to the disease process itself. The high prevalence of abdominal pain in patients with liver disease and cirrhosis is likely related to several factors, including liver capsular distension, ascites, peritonitis, and splenomegaly.58,59 Notably, cirrhosis is a pro-inflammatory state, and the same cytokines associated with cirrhosis are also associated with pain. Fibromyalgia-like syndrome has been found in both hepatitis C virus (HCV) and non-HCV-related liver disease, which may be related to this systemic inflammation.60

Pain Management Approach in Patients With Liver Disease General Principles The management of pain in patients with liver disease and cirrhosis is complex, and the risk of an adverse event related to pain treatment is high.61 Similar to the treatment of pain in any patient, the pain management plan for patients with liver disease or cirrhosis should focus on improving physical and other functional outcomes. The treatment plan should be individualized with consideration of physical, behavioral, pharmacologic, and procedural approaches and is best accomplished with a multi-disciplinary approach, including behavioral health, palliative care, or chronic pain specialists.61 Much of the apprehension and barriers to treatment of pain in liver disease and cirrhosis stems from the risk of encephalopathy, bleeding, hepatorenal syndrome, and the association of many analgesic agents, such as acetaminophen and NSAIDs, with additional drug-induced liver injury. Furthermore, there is also an increased risk of adverse drug reactions, including over-sedation or overdose, constipation, and altered drug metabolism and pharmacokinetics in patients with chronic liver disease. As such, to provide effective analgesia and reduce the risk of adverse events or side effects, it is important to consider how severe liver disease can alter the metabolism and action of analgesic agents. There is a considerable paucity of literature to guide physicians in this area, given the public health impact of liver disease.62,63 Drug Metabolism in Liver Disease and Cirrhosis The liver plays an important role in the distribution and elimination of most drugs, including analgesic therapies. Generally, drug metabolism in the liver occurs through 1) conjugation; 2) oxidation, reduction, or hydrolysis reactions via hepatic cytochrome P450 (CYP) enzymes; and 3) biliary excretion and elimination.57 The efficiency of removal of the analgesic drug relies on a variety of factors, including blood flow, plasma protein binding, and intrinsic activity of CYP enzymes. Liver disease and cirrhosis affect all these processes and can alter the metabolism and elimination of many drugs. Generally speaking, the more advanced the liver disease, the greater the impairment of these processes. Unlike renal disease, there is no accurate measure of liver disease severity that

can be used to guide dose adjustment. It is recommended that in patients with more advanced or decompensated liver disease, who are at greater risk of adverse drug reactions, close monitoring is employed, and gradual dose uptitration be utilized while balancing side effects such as sedation.61

Nonpharmacologic Pain Management in Patients With Liver Disease or Cirrhosis As described previously, in patients with renal disease, a biopsychosocial approach to pain includes nonpharmacologic options such as simple heat and cold therapy, weight loss, physical therapy, massage therapy, acupuncture/acupressure, CBT, and meditation. Unfortunately, there are no data regarding the efficacy or use of these modalities in patients with liver disease or cirrhosis. Pharmacologic Pain Management in Patients With Liver Disease or Cirrhosis As discussed previously, the pharmacologic approach to pain management is particularly challenging in patients with liver disease and cirrhosis because of altered and often unpredictable drug metabolism. Non-opioid Medications Although commonly used by the general public for analgesia, acetaminophen is often avoided in patients with liver disease because of its well-described and potentially fatal hepatotoxicity at higher doses. However, although limited data exist regarding the use of chronic daily acetaminophen in liver disease, it has been reported that a reduced dose of 2 g/day is generally considered safe in patients with cirrhosis.61–63 This was a double-blind study in which 20 patients with chronic liver disease (of undocumented severity) were treated with acetaminophen (4 g/day) or placebo for 13 days followed by crossover to the alternative treatment for 13 days with no resultant significant changes in liver function laboratory tests.64 As such, low dose acetaminophen (≤2 gm/day) has been recommended as a first line analgesic for patients with cirrhosis.58 Given concerns about hepatic damage with acetaminophen use, patients with liver disease and cirrhosis often take or are prescribed NSAIDs. NSAIDs are likely to be more dangerous in this population.58 NSAIDs are primarily metabolized by CYP enzymes and are heavily protein-bound. As such, patients with liver disease and cirrhosis are at a much higher risk of renal dysfunction and bleeding complications when using NSAIDs. One case-control study reported an association between NSAID use and an increase in variceal bleeding.65 Given these significant risks, NSAIDs have been reported as contraindicated in patients with cirrhosis and advanced liver disease.58 Non-opioid adjuvant analgesic agents are occasionally required for neuropathic pain from peripheral neuropathy secondary to comorbid diabetes, alcohol use, or HCV-associated cryoglobulinemia.66 As described previously, gabapentin and pregabalin play a prominent role in the treatment of neuropathic pain. Gabapentin and pregabalin undergo minimal hepatic metabolism with unchanged drug excretion from the kidney.67 Gabapentin has no significant effects on hepatotoxicity and has been recommended as a first line agent to treat neuropathic pain with a maximum dose of 3600 mg/day, assuming normal renal function. Pregabalin has rare reports of idiopathic liver injury and, although rare, should thus be considered and used as a second line agent to treat gabapentin.68 Gabapentin and pregabalin are both reasonable first line medications for the treatment of neuropathic pain. However, they can cause sedation and have the potential to lead to cognitive or

 

CHAPTER 47

mental status depression. As with many other analgesics, the doses should again be slowly initiated and carefully up-titrated with preferential dosing before bed. Anti-depressants have also been frequently used with moderate success in the treatment of chronic pain, especially neuropathic pain. Tricyclic anti-depressants (TCAs) are commonly used for the treatment of neuropathic pain, are metabolized by CYP enzymes, and rely on renal elimination. As a result, drug accumulation can be observed in progressive liver disease. However, its use in patients with liver disease and cirrhosis has been reported to be relatively safe at low doses and in the short term.69 Starting TCA therapy at the lowest dose with slow titration is suggested with co-administration of laxatives to prevent constipation-induced encephalopathy.61 SNRIs, including venlafaxine and duloxetine, have also been used in the treatment of neuropathic pain but have been reported to not be good options for patients with severe liver disease or cirrhosis. Duloxetine carries a manufacturer warning of hepatotoxicity, given its implication in numerous cases of drug-induced liver injury, and is not recommended in patients with chronic liver disease.70 Concerning venlafaxine, significant dose reduction is recommended, which relies heavily on hepatic CYP.71 Selective serotonin reuptake inhibitors (SSRIs) have generally not been shown to be recommended for the treatment of neuropathic pain in the general population as they have a lower efficacy than TCAs. However, given the risks outlined previously for TCAs and SNRIs, SSRIs could be considered, although more work is needed to determine the effectiveness of SSRIs for chronic pain in this population.

Opioid Medications Opioid pharmacotherapy needs to be approached with caution in patients with liver disease or cirrhosis, as they are known to cause sedation, constipation, and encephalopathy. Opioid medications are primarily metabolized via CYP450 (CYP2D6 and CYP3A4) and glucuronidation, and both are affected by liver disease.61,72 Liver disease and cirrhosis are risk factors for prescription opioid toxicity and/or overdose, and it has been reported that opioid use is associated with poor liver transplant outcomes.73,74 Furthermore, a history of substance abuse is common in patients with liver disease and cirrhosis. As such, prescription opioids can lead to dependence, addiction, and use disorder, particularly among those with a history of addiction; in general, opioids should not be administered as first line analgesic therapy to the extent possible in this population. The decision making process for the use of opioids for the treatment of chronic pain is difficult even in the general population and should only be employed when all non-pharmacologic and non-opioid treatment options have been exhausted. The potential gain in patient function and quality of life is felt to outweigh the significant risks of long term opioids. To date, no “safe” prescribing limits of opioid medications have been established in the context of liver disease and cirrhosis. However, they are likely much lower than those of the general population. Total daily doses of >50 MME per day have been shown to lead to an increased overdose risk in the general population.75 However, pre-liver transplant opioid doses as low as 10 MME per day were shown to be associated with significant increases in post-transplant mortality in one study.74 Extended or sustainedrelease opioids should be avoided because of the risk of a toxic drug or metabolite accumulation in liver disease or cirrhosis. The combination of opioid-acetaminophen pills should be avoided

Pain Management in Patients With Comorbidities

681

in patients with cirrhosis because of the potential for additional liver toxicity because of acetaminophen. The metabolism and data regarding the different opioid types are outlined in Table 47.3, based on recent systematic and narrative reviews on opioid use in liver disease.57,58,61,76 It is highly recommended to ensure that constipation is mitigated through the use of lactulose or other laxatives, as hepatic encephalopathy can occur.62

Diabetes Diabetes is a metabolic disorder that results in impaired glucose tolerance because of deficiency or absence of insulin. According to the American Diabetes Association, approximately 34 million Americans live with type 1 or type 2 diabetes, which accounts for more than 10% of the United States population. It is worth noting that in pain medicine, we will be treating many patients with diabetes for ailments related to and unrelated to diabetes. Chronic pain is the most common complication of diabetes.77 This pain syndrome is discussed in more detail in Chapter 34.

Diabetic Peripheral Neuropathy Diabetic peripheral neuropathy is the most common type of pain syndrome related to diabetes. Like other peripheral neuropathies, it presents as a length-dependent neuropathy in the typical stocking and glove distribution. As many as 26% of patients with diabetes develop diabetic peripheral neuropathy.78 Glycemic control is seen as an important preventative measure and may help slow the progression of neuropathy after it has been presented. Painful diabetic peripheral neuropathy can have severe effects on a patient’s wellbeing. Patients often experience mood disturbances, decreased quality of sleep, increased levels of pain, and reduced quality of life.79 Painful diabetic peripheral neuropathy (PDPN) is a difficult to treat condition, and many of the medications used to treat this condition are only mildly helpful, leaving the patient in continued distress despite treatment. First line therapies include medications such as tricyclic anti-depressants, serotonin-noradrenaline reuptake inhibitors, and anti-convulsants. Opioids are often reserved for second or third line therapies because of their limited effect on neuropathic pain and the risk of side effects.

Other Painful Conditions Related to Diabetes While diabetic peripheral neuropathy is the most common and well known painful condition related to diabetes, there are several other diagnoses that the pain medicine practitioner should be familiar with as approximately 50% of people with diabetes will experience a clinically significant neuropathy.80 Painful neuropathies include mononeuropathy, cranial neuropathy, and plexus neuropathy. Mononeuropathy: This is characterized by pain and motor dysfunction in the distribution of a single nerve. This can be because of ischemic damage and compressive lesions.81 The most common nerves affected are the oculomotor and median nerves. Cranial neuropathy: The most common cranial neuropathy in diabetic patients is oculomotor neuropathy and typically presents as a third nerve palsy with pupillary sparing.82 Radiculopathy: Patients with diabetes can have radiculopathy without degenerative spine changes or disc herniation.81 This is important to avoid unnecessary decompression surgery, as diabetes is a cause of non-compressive radiculopathy.

682

PA RT 4 Clinical Conditions: Evaluation and Treatment

TABLE 47.3

Opioids Medications in Liver Disease

Medication

Metabolism

Recommendation

Oxycodone

Metabolized into α and β oxycodone metabolites by CYP3A4 and CYP2D6 In advanced liver disease, plasma concentration is increased up to 40%, and the half-life of the IR formulation is increased from 6.4 to 24.6 h (average 14 h, normal half-life is 3.5 h) Bioavailability is dramatically increased

The initial dose should be reduced to 30%-50% of the usual starting dose The interval between doses should be lengthened

Codeine

Prodrug, which is converted to morphine by CYP2D6 Limited metabolism may lead to poor analgesic effects Morphinemia because of delayed clearance of metabolite may lead to significant respiratory depression and overdose

Not recommended for use in liver disease or cirrhosis

Meperidine

Converted to normeperidine through hydrolysis by CYP3A4 and CYP2B6 Clearance is reduced, and half-life prolonged Accumulation can lead to respiratory depression, seizures, CNS depression, and encephalopathy

Not recommended for use in liver disease or cirrhosis

Methadone

Metabolized by CYP3A4 and CYP12A Clearance is reduced in liver disease, and the compound has a long half-life Does not produce toxic metabolites High affinity for binding to proteins

In mild hepatic disease, may use with caution and start low/go slow as data has shown no change in dose is required with mild impairment In patients with moderate liver disease with or without hypoalbuminemia, caution is advised with dose reduction and less frequent dosing Contraindicated in severe liver disease

Tramadol

Metabolized by CYP3A4 and CYP2D6 Metabolism to active metabolites may be reduced, thus decreasing analgesic efficacy

More research needed, alternative therapies are recommended Caution advised if used in patients with a seizure disorder or concomitant SNRI, TCA, or SSRI use

Morphine

Undergoes significant first pass metabolism via glucuronidation Liver disease decreases glucuronidation and therefore leads to increased bioavailability, decreased clearance, and a prolonged half-life

Caution advised Decreased dosing with an increased time between dosing and slow titration

Hydromorphone

Does not require metabolism to an active metabolite Undergoes significant first pass metabolism via glucuronidation, which is decreased in liver disease Leads to higher bioavailability Metabolites not known to be neurotoxic

Decrease usual start dose by 50%-75%, titrate slowly

Fentanyl

Metabolized by CYP3A4 Clearance can be decreased in liver disease with decreased hepatic blood flow Heavily protein-bound Pharmacokinetics of single intravenous dose similar to healthy controls in well-compensated liver disease with preserved hepatic blood flow These findings cannot be extrapolated to transdermal fentanyl preparations

Transdermal preparation not adequately studied can assume decreased absorption, metabolism, and clearance. Should be avoided in patients with severe hepatic impairment

Hydrocodone

Pre-drug that is metabolized into hydromorphone and oxymorphone by CYP2D6 Half-life is increased in liver disease

Decrease initial dose by at least 50% and titrate slowly, with a possible increase in time between dosing

Mononeuritis multiplex affects multiple nerve trunks that cause dysesthesia and paresthesia, likely related to ischemia.83 Insulin neuritis/treatment-induced neuropathy. Secondary to aggressive control of glucose levels in a previously hyperglycemic patient, insulin neuritis presents as a symmetric distal neuropathy combined with autonomic dysfunction and acute pain after rapid glucose regulation, such as initiation of insulin therapy.84 The condition is often reversible, but the pain can be persistent and is often difficult to treat and refractory to typical neuropathic pain medication therapy.

Medication Management Tricyclic Anti-depressants

Originally designed for mood disorders, it is common to utilize this class of medications for neuropathic pain within the pain medicine community. Commonly used medications in this class include nortriptyline, amitriptyline, and desipramine. Dosing is initiated at a low nightly dose, such as 10 to 25 mg per night. The dose was then increased every five to seven days until a goal dose was attained, pain relief was achieved, or adverse effects were encountered. Compared to the SSRI and SNRI type of medications, pain

 

CHAPTER 47

relief with TCAs is similarly delayed in onset.85 Unfortunately, adverse effects are not uncommon and include somnolence, dizziness, urinary retention, and increased risk of falls.86 Extra caution should be exercised in patients with urinary retention, baseline increased fall risk, and underlying cardiac disease. Typically, the first medication trialed in this category is amitriptyline, with nortriptyline as a secondary alternative if amitriptyline is ineffective or poorly tolerated. Desipramine is often not utilized because of the increased risk of adverse effects compared to amitriptyline and nortriptyline. Serotonin-Norepinephrine Reuptake Inhibitors/Selective Serotonin Reuptake Inhibitors

Serotonin agonists are another category of medications that are frequently used for the treatment of PDPN. One of the most commonly used agent is duloxetine. This is initiated at 30 mg daily for two weeks and then increased to 60 mg daily for most patients. This medication can take up to 12 weeks to take full effect, and studies have shown that while the 60 mg and 120 mg daily doses are successful in treating PDN, the 20 mg daily dose is not.87 Patients must be counseled about this delayed onset to encourage compliance. Common adverse effects include nausea, dry mouth, sweating, and constipation. Many of these can be abated by starting the medication at a lower dose to develop tolerance to serotonin effects. SNRIs may help treat pain when there is also a mood disorder. Anti-convulsants

To date, the most common anti-convulsants utilized for neuropathic pain are gabapentin and pregabalin, and they have both been shown to be effective for PDPN.88,89 Gabapentinoids, which include both gabapentin and pregabalin, act by inhibiting calcium currents by binding with the alpha two δ subunit of voltage-gated calcium channels.90 The benefit of gabapentin is that it is inexpensive, typically well tolerated, and has proven efficacy. This medication was started at a low dose and titrated to effect as tolerated. Many times for neuropathic pain, patients will need to titrate up to 2700 mg/day or higher. While some patients will experience substantial pain relief with pregabalin, most will have moderate pain relief, and many will have no relief at all.91 Opioids

Opioids are not the first line therapeutic agents for PDPN. However, some are more successful in treating neuropathic pain than others. Medications that combine activity at the NMDA receptor and the opioid receptor may have a higher likelihood of treating neuropathic pain than pure mu agonists. Examples of these opioids include tramadol and methadone. Low dose naltrexone, a reversible competitive antagonist of μ-opioid and κ-opioid receptors, is also gaining popularity. When used at low doses of 1 to 5 mg daily, naltrexone acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation.92 Topical Agents

Often, topical agents are used for PDPN with mixed results. The efficacy of 0.075% capsaicin lotion was similar to that of placebo in one study, but it was well tolerated.93 In another study, a single 30 min application of the capsaicin 8% dermal patch provided 12 weeks of pain relief and improved quality of sleep.94 In this scenario, patients can undergo repeat treatment with the capsaicin 8% dermal patch as needed.

Pain Management in Patients With Comorbidities

683

In summary, many medications are options for the treatment of PDPN and other diabetes-related painful conditions. They must all be tailored to each patient’s specific needs and risk factors to create a personalized approach that maximizes the response and minimizes the side effect profile.95 In the United Kingdom, the National Institute for Health and Care Excellence (NICE) recommends amitriptyline, duloxetine, pregabalin, and gabapentin as the initial treatment for PDPN. If this is not effective, combination therapy will be the next step.96 If medication management is ineffective, other strategies for pain control should be considered. Botulinum Toxin

Botulinum toxin A has been shown to significantly improve PDPN.97 Botulinum toxin A has long been known to decrease neuropathic pain by preventing the fusion of synaptic vesicles with the cell membrane, thus halting the release of neurotransmitters.98 With peripheral neuropathy, BTa is injected in the area of pain, utilizing a grid-like pattern. Pain relief typically presents within one to two weeks of injection and can last for up to 12 weeks. Scrambler Therapy

When PDPN fails to respond to conventional first and second line treatments, scrambler therapy may be an option for otherwise intractable neuropathy.99 Scrambler therapy is similar to TENS in that the electrodes are placed on the skin. However, in scrambler therapy, electrodes are placed in the non-painful area. During treatment, the patient perceives non-painful sensations, such as itching or pressure, in the previously painful area. The proposed analgesic mechanism of scrambler therapy includes the electrodes sending non-painful impulses to the peripheral receptors, with the A δ and C fibers relaying the stimuli to the CNS. Scrambler therapy has been shown to be effective in some neuropathic pain syndromes.99 Integrative therapies, including mindfulness and progressive relaxation, have been shown to reduce chronic pain in women with diabetes.77 In addition, Rozworska et al. demonstrated that participation in mindfulness-based stress reduction leads to an improvement in pain related outcomes.100 Acupuncture has also been shown to improve symptoms of PDPN symptoms.101 Exercise has also been considered to reduce pain interference in this patient population without actually decreasing the pain score itself.102 Regenerative Medicine

Growing evidence suggests that increased inflammatory factors, combined with a deficiency of angiogenic factors, contribute to the underlying pathology of PDPN. Studies have shown that bone marrow-derived stem cells (BMCs) may be a promising strategy for tissue repair.103 Known to inhibit inflammation and promote angiogenesis, BMCs may be a novel therapeutic option for patients with PDPN. Spinal Cord Stimulation

SCS has been shown to reduce pain experienced by PDPN.104 As peripheral blood flow is a fundamental part of the pathophysiology of PDPN, peripheral vasodilation, and improved blood flow are potentially beneficial secondary effects of SCS is peripheral vasodilation and improved blood flow.105 Surgery

Surgery can be utilized for the treatment of superimposed peripheral nerve entrapment syndrome in patients with diabetic peripheral

684

PA RT 4 Clinical Conditions: Evaluation and Treatment

neuropathy, sometimes with pain relief and restored sensation. One study evaluated the effects of microsurgical decompression of multiple entrapped peripheral nerves in patients with refractory PDPN of the lower limbs. Bodily pain was significantly reduced two weeks after the procedure.106

Conclusion For pain medicine practitioners treating patients with diabetes, it is important to consider their overall health when initiating therapy for painful conditions. Opioid medications may lead to increased nausea in patients with diabetes-related gastroparesis. Steroid injections may also lead to hyperglycemia. The dosing of medications may need to be adjusted in the setting of renal failure or dialysis. With comprehensive analysis and attention to detail, we can treat these patients safely and offer them the full spectrum of multi-disciplinary pain management in hopes of restoring function and improving their quality of life.

Pain Management in Older Adults Background An estimated 51 million Americans are over the age of 65 years, which is about 16% of the American population (United States Census Bureau, population projections). Up to 65% of people over the age of 65 years experience pain, and up to 30% have chronic pain (painconsortium.nih.gov). Older adults are more likely to experience pain than younger individuals.107 Diagnosing and treating pain in older individuals can be difficult because of differences in patient reporting, communication barriers, and underlying comorbidities. The most common chronic pain conditions are arthritis, back or neck pain, and joint pain, which are present in 48%, 45%, and 41% of older Americans, respectively.108,109 Up to 50% of patients in nursing homes use analgesic therapy for the treatment of pain, and some sources report that up to 80% of nursing home patients suffer from pain.110 Hence, this is a significant problem in the aging population. Pain physicians need to have a thorough understanding of the mechanisms underlying pain in this population and the physiologic changes that affect the efficacy and side effect profile of our treatment options. For many reasons, both provider-related and patient-related pain is significantly under treatment in this patient population.111 The importance of pain management in this population cannot be overstated. Poor pain control can lead to a lack of socialization, poor sleep, depression, increased healthcare costs, and reduced quality of life.112,113

Evaluation: Assessment and Physical Examination

studies, can all help identify the source of pain. Prior to obtaining the patient’s history, the ability of the patient to report pain should be assessed. If the patient cannot provide history, the provider should supplement the history with other proxies for self-reporting. The history should detail the onset of pain, the location of the pain, the character of the pain, and any recent changes in the way the pain is present. Be mindful to use words other than pain, as patients in this cohort may identify with words like “ache” or “discomfort” more than pain. Methods to understand baseline pain and determine the response to paindirected treatments are similar to those of younger patients. However, self-reported pain relief may need to be supplemented by behavioral observation, data from caregivers and family members, and pain behavior tools. The lack of appropriate assessment tools can be a barrier to appropriate pain assessment.115 Our most common pain assessment tool, the VAS, does not work well for older patients with pain.116 A variety of other pain assessment tools are used to include the faces pain scale, NRS, verbal descriptor scale, pain thermometer, pictorial pain scales.112,116 In addition, cultural beliefs about the importance of stoicism in this age group may lead to underreporting by the patient.117 Therefore rewording questions are useful. A patient may report low levels of pain, but when questioned about discomfort or aches, significant findings will be reported. It is helpful to take note of nonverbal cues during history and physical examination to assess for pain that is underreported or not effectively communicated. The checklist of nonverbal pain indicators (CNPI) and the pain assessment in advanced dementia are two behavioral observation tools available.118 These tools are discussed in Chapters 43 (geriatric pain management), 79 (pain evaluation in patients with limited ability to communicate), and 84 (outcome domains in chronic and acute pain). In addition to pain severity, it is crucial to understand the level of interference pain that may affect individuals’ function and quality of life. The level of interference can be evaluated by asking about fatigue, disturbed sleep, activity level, mental health, and quality of life.119

Physical Examination Physical examination should be comprehensive, focusing mostly on the musculoskeletal and neurologic systems. When assessing neurologic function, it is important to evaluate the strength, response to light touch and pinprick, and sensation. When assessing musculoskeletal function, examining joint swelling, range of motion, tenderness to palpation, muscular pain, and straight leg raise are all useful.112 Deconditioning, reduced flexibility, and reduced muscle mass were observed. In addition, age-related loss of tendon reflexes is important to note, and attention should be paid to asymmetric changes instead of a global decrease in reflexes.120

##

Assessment Understand that the older patient population may not present in the same way as younger individuals, and failure to recognize pain leads to an inability to treat pain. Older adults often present with multiple painful conditions. Therefore there is a need for comprehensive evaluation.114 In addition, multiple comorbidities may make it difficult to determine the underlying cause of pain. A careful history, thorough physical examination, and ­diagnostic studies, including imaging and nerve conduction

Evaluation of Common Painful Syndromes Osteoarthritis Osteoarthritis (OA) is a very common condition in geriatric patients and can significantly affect the quality of life and ability to be active. Symptoms of OA include stiffness, pain, decreased range of motion, and disability. Age is an independent risk factor for OA, along with obesity, metabolic disease, gender, genetics, and ethnicity.121

 

CHAPTER 47

Neck Pain Neck pain is common in the geriatric population and is often multifactorial with pain generators, including osteoarthritis, disc degeneration, myofascial pain, cervical spondylosis, and trauma.122 Neck pain is the fourth leading cause of disability in adults.123 Available imaging includes plain film (X-ray), computed tomography (CT), magnetic resonance imaging (MRI), and CT myelography.124 The differential diagnosis and imaging workup of neck pain was determined based on relevant pieces of the patient’s history and physical examination. Common indications for cervical imaging include trauma, neurologic deficits, myelopathy or “red flag symptoms,” radiculopathy, and persistence of symptoms.125 Back Pain Chronic low back pain is exceedingly common in the elderly population, with up to 25% of those 65 years and older with chronic low back pain.126 Chronic low back pain is currently the most common cause of disability worldwide.127 Common causes of low back pain include osteoarthritis, facet joint arthropathy, myofascial pain, lumbar spondylosis, lumbar stenosis, and vertebral compression fractures. Less common causes include infection and tumors. Available imaging includes plain film (X-ray), CT, MRI, and CT myelography. The differential diagnosis and imaging workup of low back pain are determined based on relevant pieces of the patient’s history and physical examination. Common indications for lumbar imaging include trauma, neurologic deficits, myelopathy or “red flag symptoms,” radiculopathy, and persistence of symptoms.

Pain Management in Patients With Comorbidities

685

Medication Considerations for Use in Older Adults One of the most concerning aspects of pain management in older adults is concerns about the adverse effects of medication therapy. This is a valid concern and may also lead to the treatment of pain in this population. Rather than avoiding medication usage in elderly patients, the pain physician should focus on having a detailed understanding of the differences in dosing and adverse effects in this population to create a sense of security in treating pain and efficiency in recognizing potential adverse effects. Renal: Avoid medications that can affect renal function, as this is already reduced in elderly patients. In addition, underlying renal issues need to be considered when determining the appropriate dosage to avoid the buildup of toxic metabolites. While NSAIDs are effective agents for inflammatory processes, they are associated with renal toxicity, and severe side effects from NSAIDs are more common among elderly patients.128 Hepatic metabolism: Secondary to decreased liver mass and decreased liver perfusion, the first pass effect on medications that are highly cleared by the liver may have increased bioavailability.129 Dosing decreases should be considered for medications that undergo p450 dependent metabolism. Pharmacokinetic and pharmacodynamic changes: With advanced age, we know that a reduction in renal and hepatic clearance occurs. In addition, there is an increased volume of distribution of lipid-soluble drugs that can lead to a prolonged elimination half-life.130 Pharmacodynamic changes lead to increased sensitivity to several classes of medications.130

Conclusion In summary, the evaluation and management of elderly patients requires a thorough understanding of how to assess pain in this population, various pain scales to compensate for possible changes in cognition, the most common pain syndromes, and the management of medications in a population that may have pharmacodynamic and pharmacokinetic differences related to aging. Pain

should not be undertreated because of barriers in communication, difficulty in physical examination, or a bias that pain is just a part of getting older. With proper care, many elderly patients can have a higher quality of life with minimal interference from their daily activities because of chronic pain.

Summary and Conclusions When treating patients with chronic pain, it is important to consider their overall health and potential complications when initiating medications and considering interventions. Many of these patients with renal or liver disease, diabetes, and the elderly are often excellent candidates for multi-disciplinary pain management, including psychology/behavioral health services, functional restoration programs, physical therapy, occupational therapy, and advanced interventional procedures to include neuromodulation. Treatment requires a thorough understanding of the unique charac-

teristics of these patient populations, including altered pharmacokinetics, metabolism, and clearance. Understanding that history and physical evaluation may require different assessments than patients without these chronic conditions or non-elderly patients. Pain medicine providers should be familiar with the most common pain syndromes in these populations and how to treat them. In addition, it is of paramount importance to remember that pain is often undertreated in these patient populations and that with proper care, patients can have increased function and improved quality of life.

Key Points • Common medical comorbidities that can be encountered in chronic pain conditions are kidney disease, liver disease, diabetes, and the care of elderly patients. • Pain is one of the most common symptoms of CKD, ESRD, and liver disease. • The pain experienced by patients with kidney and liver disease is often multifactorial and can be because of the underlying organrelated disease process, hemodialysis, or comorbid diseases.

• Many non-pharmacologic and non-opioid pain management strategies have been shown to be helpful for pain in kidney and liver disease patients. However, further research is needed to establish the efficacy of many of the behavioral and complementary therapies specifically for these populations. • When pharmacologic interventions for pain management in kidney and liver disease patients are being implemented, it is best to identify the level of current kidney and liver function,

686

PA RT 4 Clinical Conditions: Evaluation and Treatment

and the focus should be on preventing further damage and adjusting the drug dosage as indicated. • While diabetic peripheral neuropathy is the most common and well known painful condition related to diabetes, there are several other diagnoses that pain medicine practitioners should be familiar with, as approximately 50% of people with diabetes will experience clinically significant neuropathy. • The most common anti-convulsants utilized for neuropathic pain are gabapentin and pregabalin, both of which have been shown to be effective for PDPN.

• Opioids are not first line therapeutic agents for PDPN. • Pain is often undertreated in elderly patients. • Pain should not be undertreated because of barriers in communication, difficulty in physical examination, or a bias that pain is just a part of getting older. • The older population may have pharmacodynamic and pharmacokinetic differences related to aging, which should be considered when managing medication therapy.

Suggested Readings

Khdour MR. Treatment of diabetic peripheral neuropathy: A review. J Pharm Pharmacol. 2020;72(7):863–872. Klinge M, Coppler T, Liebschutz JM, et al. Assessment and management of pain in cirrhosis. Curr Hepatol Rep. 2018;17(1):42–51. Kress HG, Ahlbeck K, Aldington D, et al. Managing chronic pain in elderly patients requires a CHANGE approach. Curr Med Res Opin. 2014;30(6):1153–1164. Robinson CL. Relieving pain in the elderly. Health Prog. 2007;88(1):48– 53, 70. Rogal SS, Bielefeldt K, Wasan AD, et al. Inflammation, psychiatric symptoms, and opioid use are associated with pain and disability in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015;13(5):1009–1016. Rogal SS, Bielefeldt K, Wasan AD, et al. Fibromyalgia symptoms and cirrhosis. Dig Dis Sci. 2015;60(5):1482–1489. Selvarajah D, Petrie J, White D, et al. Multicentre, double-blind, crossover trial to identify the optimal pathway for treating neuropathic pain in diabetes mellitus (OPTION-DM): Study protocol for a randomized controlled trial. Trials. 2018;19(1):578. Williams A, Manias E. A structured literature review of pain assessment and management of patients with chronic kidney disease. J Clin Nurs. 2008;17(1):69–81.

Arendt-Nielsen L, Morlion B, Perrot S, et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. 2018;22(2):216–241. Davies M, Brophy S, Williams R, et al. Prevalence, severity, and impact of painful peripheral neuropathy in patients with type 2 diabetes. Diabetes Care. 2006;29(7):1518–1522. Davison SN, Koncicki H, Brennan F. Pain in chronic kidney disease: A scoping review. Semin Dial. 2014;27(2):188–204. Davison SN. Clinical Pharmacology considerations in pain management in patients with advanced kidney failure. Clin J Am Soc Nephrol. 2019;14(6):917–931. Dwyer JP, Jayasekera C, Nicoll A. Analgesia for the cirrhotic patient: A literature review and recommendations. J Gastroenterol Hepatol. 2014;29(7):1356–1360. Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med. 2001;17(3):457–78, vi. Imani F, Motavaf M, Safari S, Alavian SM. Therapeutic use of analgesics in patients with liver cirrhosis: A literature review and evidence-based recommendations. Hepat Mon. 2014;14(10):e23539. Kaye AD, Baluch A, Scott JT. Pain management in the elderly population: A review. Ochsner J. 2010;10(3):179–187.

The references for this chapter can be found at ExpertConsult.com.

References 1. Raja SN, Carr DB, Cohen M, et al. The revised international association for the study of pain definition of pain: Concepts, challenges, and compromises. Pain. 2020;161(9):1976–1982. 2. Williams A, Manias E. A structured literature review of pain assessment and management of patients with chronic kidney disease. J Clin Nurs. 2008;17(1):69–81. 3. Claxton RN, Blackhall L, Weisbord SD, Holley JL. Undertreatment of symptoms in patients on maintenance hemodialysis. J Pain Symptom Manage. 2010;39(2):211–218. 4. Weisbord SD, Carmody SS, Bruns FJ, et al. Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients. Nephrol Dial Transplant. 2003;18(7):1345–1352. 5. Kliuk-Ben Bassat O, Brill S, Sharon H. Chronic pain is underestimated and undertreated in dialysis patients: A retrospective case study. Hemodial Int. 2019;23(4):E104–E105. 6. Davison SN. The prevalence and management of chronic pain in end-stage renal disease. J Palliat Med. 2007;10(6):1277–1287. 7. Davison SN, Koncicki H, Brennan F. Pain in chronic kidney disease: A scoping review. Semin Dial Mar. 2014;27(2):188–204. 8. Koncicki HM, Unruh M, Schell JO. Pain management in CKD: A guide for nephrology providers. Am J Kidney Dis. 2017;69(3):451–460. 9. Gamondi C, Galli N, Schönholzer C, et al. Frequency and severity of pain and symptom distress among patients with chronic kidney disease receiving dialysis. Swiss Med Wkly. 2013;143:w13750. 10. Brkovic T, Burilovic E, Puljak L. Prevalence and severity of pain in adult end-stage renal disease patients on chronic intermittent hemodialysis: A systematic review. Patient Prefer Adherence. 2016;10:1131–1150. 11. Davison SN. Chronic kidney disease: Psychosocial impact of chronic pain. Geriatrics. 2007;62(2):17–23. 12. Davison SN. Pain in hemodialysis patients: Prevalence, cause, severity, and management. Am J Kidney Dis. 2003;42(6):1239–1247. 13. Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain. 2011;152(3):S2–S15. 14. Arendt-Nielsen L, Morlion B, Perrot S, et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. 2018;22(2):216–241. 15. Kress HG, Ahlbeck K, Aldington D, et al. Managing chronic pain in elderly patients requires a CHANGE of approach. Curr Med Res Opin. 2014;30(6):1153–1164. 16. Coluzzi F. Assessing and treating chronic pain in patients with endstage renal disease. Drugs. 2018;78(14):1459–1479. 17. Melzack R. The McGill pain questionnaire: Major properties and scoring methods. Pain. 1975;1(3):277–299. 18. Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the brief pain inventory for chronic nonmalignant pain. J Pain. 2004;5(2): 133–137. 19. Davison SN, Jhangri GS, Johnson JA. Longitudinal valida tion of a modified Edmonton symptom assessment system (ESAS) in haemodialysis patients. Nephrol Dial Transplant. 2006;21(11):3189–3195. 20. Murphy EL, Murtagh FE, Carey I, Sheerin NS. Understanding symptoms in patients with advanced chronic kidney disease managed without dialysis: Use of a short patient-completed assessment tool. Nephron Clin Pract. 2009;111(1):c74–c80. 21. Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol. 2009;65(8):757–773. 22. Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet. 2011;377(9784):2226–2235. 23. Williams AC, Eccleston C, Morley S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev. 2012;11(11):CD007407.

24. Mehrotra R, Cukor D, Unruh M, et  al. Comparative efficacy of therapies for treatment of depression for patients undergoing maintenance hemodialysis: A randomized clinical trial. Ann Intern Med. 2019;170(6):369–379. 25. Carroll D, Seers K. Relaxation for the relief of chronic pain: A systematic review. J Adv Nurs. 1998;27(3):476–487. 26. Heidari Gorji MA, Davanloo AA, Heidarigorji AM. The efficacy of relaxation training on stress, anxiety, and pain perception in hemodialysis patients. Indian J Nephrol Nov. 2014;24(6):356–361. 27. Rambod M, Sharif F, Pourali-Mohammadi N, Pasyar N, Rafii F. Evaluation of the effect of Benson’s relaxation technique on pain and quality of life of haemodialysis patients: A randomized controlled trial. Int J Nurs Stud. 2014;51(7):964–973. 28. Nathan HJ, Poulin P, Wozny D, et al. Randomized trial of the effect of mindfulness-based stress reduction on pain-related disability, pain intensity, health-related quality of life, and A1C in patients with painful diabetic peripheral neuropathy. Clin Diabetes. 2017;35(5):294–304. 29. Thomas Z, Novak M, Platas SGT, et  al. Brief mindfulness meditation for depression and anxiety symptoms in patients undergoing hemodialysis: A pilot feasibility study. Clin J Am Soc Nephrol. 2017;12(12):2008–2015. 30. Kim KH, Lee MS, Kim TH, Kang JW, Choi TY, Lee JD. Acupuncture and related interventions for symptoms of chronic kidney disease. Cochrane Database Syst Rev. 2016;6(6):CD009440. 31. Cruccu G, Garcia-Larrea L, Hansson P, et  al. EAN guidelines on central neurostimulation therapy in chronic pain conditions. Eur J Neurol. 2016;23(10):1489–1499. 32. Han B, Compton WM. Prescription opioids for pain management in patients on dialysis. J Am Soc Nephrol. 2017;28(12):3432–3434. 33. Lowe KM, Robinson Jr DR. Pain management for patients with chronic kidney disease in the primary care setting. Nurse Pract. 2020;45(1):18–26. 34. Wu J, Ginsberg JS, Zhan M, et al. Chronic pain and analgesic use in CKD: Implications for patient safety. Clin J Am Soc Nephrol. 2015;10(3):435–442. 35. Martin U, Temple RM, Winney RJ, Prescott LF. The disposition of paracetamol and its conjugates during multiple dosing in patients with end-stage renal failure maintained on haemodialysis. Eur J Clin Pharmacol. 1993;45(2):141–145. 36. Lee HS, Ti TY, Lye WC, Khoo YM, Tan CC. Paracetamol and its metabolites in saliva and plasma in chronic dialysis patients. Br J Clin Pharmacol. 1996;41(1):41–47. 37. Heleniak Z, Cieplińska M, Szychliński T, et al. Nonsteroidal antiinflammatory drug use in patients with chronic kidney disease. J Nephrol. 2017;30(6):781–786. 38. Davison SN. Clinical Pharmacology considerations in pain management in patients with advanced kidney failure. Clin J Am Soc Nephrol. 2019;14(6):917–931. 39. Deng Y, Luo L, Hu Y, Fang K, Liu J. Clinical practice guidelines for the management of neuropathic pain: A systematic review. BMC Anesthesiol. 2016;16:12. 40. Wong MO, Eldon MA, Keane WF, et al. Disposition of gabapentin in anuric subjects on hemodialysis. J Clin Pharmacol. 1995;35(6): 622–626. 41. Zand L, McKian KP, Qian Q. Gabapentin toxicity in patients with chronic kidney disease: A preventable cause of morbidity. Am J Med. 2010;123(4):367–373. 42. Yoo L, Matalon D, Hoffman RS, Goldfarb DS. Treatment of pregabalin toxicity by hemodialysis in a patient with kidney failure. Am J Kidney Dis. 2009;54(6):1127–1130. 43. Otsuki T, Higuchi T, Yamazaki T, Okawa E, Okada K, Abe M. Efficacy and safety of pregabalin for the treatment of neuropathic pain in patients undergoing hemodialysis. Clin Drug Investig. 2017;37(1):95–102. 44. Ishida JH, McCulloch CE, Steinman MA, Grimes BA, Johansen KL. Gabapentin and pregabalin use and association with adverse outcomes among hemodialysis patients. J Am Soc Nephrol. 2018;29(7): 1970–1978. 686.e1

686.e2

References

45. Nagler EV, Webster AC, Vanholder R, Zoccali C. Antidepressants for depression in stage 3-5 chronic kidney disease: A systematic review of pharmacokinetics, efficacy and safety with recommendations by European renal best practice (ERBP). Nephrol Dial Transplant. 2012;27(10):3736–3745. 46. Eyler RF, Unruh ML, Quinn DK, Vilay AM. Psychotherapeutic agents in end-stage renal disease. Semin Dial. 2015;28(4):417–426. 47. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic non-cancer pain. Cochrane Database Syst Rev. 2010;1(1):CD006605. 48. Dowell D, Haegerich TM, Chou R. CDC guideline for pre scribing opioids for chronic pain – United States, 2016. JAMA. 2016;315(15):1624–1645. 49. Kurella M, Bennett WM, Chertow GM. Analgesia in patients with ESRD: A review of available evidence. Am J Kidney Dis. 2003;42(2):217–228. 50. Jhamb M, Tucker L, Liebschutz J. When ESKD complicates the management of pain. Semin Dial. 2020;33(3):286–296. 51. Kimmel PL, Fwu CW, Abbott KC, Eggers AW, Kline PP, Eggers PW. Opioid prescription, morbidity, and mortality in United States dialysis patients. J Am Soc Nephrol. 2017;28(12):3658–3670. 52. Ishida JH, McCulloch CE, Steinman MA, Grimes BA, Johansen KL. Opioid analgesics and adverse outcomes among hemodialysis patients. Clin J Am Soc Nephrol. 2018;13(5):746–753. 53. Tawfic QA, Bellingham G. Postoperative pain management in patients with chronic kidney disease. J Anaesthesiol Clin Pharmacol. 2015;31(1):6–13. 54. Khanna IK, Pillarisetti S. Buprenorphine - an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859–870. 55. Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R. Trends in tramadol: Pharmacology, metabolism, and misuse. Anesth Analg. 2017;124(1):44–51. 56. Koncicki HM, Brennan F, Vinen K, Davison SN. An approach to pain management in end stage renal disease: Considerations for general management and intradialytic symptoms. Semin Dial. 2015;28(4):384–391. 57. Imani F, Motavaf M, Safari S, Alavian SM. The therapeutic use of analgesics in patients with liver cirrhosis: A literature review and evidence-based recommendations. Hepat Mon. 2014;14(10):e23539. 58. Klinge M, Coppler T, Liebschutz JM, et  al. The assessment and management of pain in cirrhosis. Curr Hepatol Rep. 2018;17(1): 42–51. 59. Rogal SS, Bielefeldt K, Wasan AD, et  al. Inflammation, psychiatric symptoms, and opioid use are associated with pain and disability in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015;13(5):1009–1016. 60. Rogal SS, Bielefeldt K, Wasan AD, Szigethy E, Lotrich F, DiMartini AF. Fibromyalgia symptoms and cirrhosis. Dig Dis Sci. 2015;60(5):1482–1489. 61. Dwyer JP, Jayasekera C, Nicoll A. Analgesia for the cirrhotic patient: A literature review and recommendations. J Gastroenterol Hepatol. 2014;29(7):1356–1360. 62. Chandok N, Watt KD. Pain management in the cirrhotic patient: The clinical challenge. Mayo Clin Proc. 2010;85(5):451–458. 63. Bosilkovska M, Walder B, Besson M, Daali Y, Desmeules J. Analgesics in patients with hepatic impairment: Pharmacology and clinical implications. Drugs. 2012;72(12):1645–1669 20. 64. Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther. 1983;33(1):95–101. 65. De Lédinghen V, Heresbach D, Fourdan O, et  al. Anti-inflammatory drugs and variceal bleeding: A case-control study. Gut. 1999;44(2):270–273. 66. Monaco S, Ferrari S, Gajofatto A, Zanusso G, Mariotto S. HCV-related nervous system disorders. Clin Dev Immunol. 2012;2012:236148.

67. Vollmer KO, von Hodenberg A, Kölle EU. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneim Forsch. 1986;36(5):830–839. 68. Einarsdottir S, Björnsson E. Pregabalin as a probable cause of acute liver injury. Eur J Gastroenterol Hepatol. 2008;20(10):1049. 69. Morgan MH, Read AE. Antidepressants and liver disease. Gut. 1972;13(9):697–701. 70. Vuppalanchi R, Hayashi PH, Chalasani N, et al. Duloxetine hepatotoxicity: A case-series from the drug-induced liver injury network. Aliment Pharmacol Ther. 2010;32(9):1174–1183. 71. Holliday SM, Venlafaxine Benfield P. A review of its pharmacology and therapeutic potential in depression. Drugs. 1995;49(2):280–294. 72. Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology. 1991;13(4):786–795. 73. Zedler B, Xie L, Wang L, et al. Risk factors for serious prescription opioid-related toxicity or overdose among veterans health administration patients. Pain Med. 2014;15(11):1911–1929. 74. Randall HB, Alhamad T, Schnitzler MA, et al. Survival implications of opioid use before and after liver transplantation. Liver Transpl. 2017;23(3):305–314. 75. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315–1321. 76. Soleimanpour H, Safari S, Shahsavari Nia K, Sanaie S, Alavian SM. Opioid drugs in patients with liver disease: A systematic review. Hepat Mon. 2016;16(4):e32636. 77. Hussain N, Said ASA. Mindfulness-based meditation versus progressive relaxation meditation: Impact on chronic pain in older female patients with diabetic neuropathy. J Evid Based Integr Med. 2019. 78. Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29(7):1518–1522. 79. Baba M, Kuroha M, Ohwada S, Murayama E, Matsui N. Results of mirogabalin treatment for diabetic peripheral neuropathic pain in Asian subjects: A phase 2, double-blind, randomized, placebocontrolled study. Pain Ther. 2020;9(1):261–278. 80. Gibbons CH. Chap 6. Diabetes-related neuropathies. In: Hsieh ST, Anand P, Gibbons C, Sommer C (eds). Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration. Singapore; 2019:59–72. 81. Callaghan BC, Price RS, Chen KS, Feldman EL. The importance of rare subtypes in diagnosis and treatment of peripheral neuropathy: A review. JAMA Neurol. 2015;72(12):1510–1518. 82. Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J. 2006;82(964):95–100. 83. Chabla-Penafiel L, Wright TB. Mononeuropathy, mononeuropathy multiplex, and other neuropathies. In: Abd-Elsayed A (ed). Pain: Switzerland: Springer; 2019:919–923. 84. Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy: A reversible painful autonomic neuropathy. Ann Neurol. 2010;67(4):534–541. 85. Sharma U, Griesing T, Emir B, Young Jr JP. Time to onset of neuropathic pain reduction: A retrospective analysis of data from nine controlled trials of pregabalin for painful diabetic peripheral neuropathy and postherpetic neuralgia. Am J Ther. 2010;17(6):577–585. 86. Randolph AC, Lin YL, Volpi E, Kuo YF. Tricyclic Antidepressant and/or gamma-aminobutyric acid-analog use is associated with fall risk in diabetic peripheral neuropathy. J Am Geriatr Soc. 2019;67(6):1174–1181. 87. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev. 2009;4(4):CD007115. 88. Moon DE, Lee DI, Lee SC, et  al. Efficacy and tolerability of pregabalin using a flexible, optimized dose schedule in Korean patients with peripheral neuropathic pain: A 10-week, randomized, double-blind, placebo-controlled, multicenter study. Clin Ther. 2010;32(14):2370–2385.

References

89. Xochilcal-Morales M, Castro EM, Guajardo-Rosas J, et al. A prospective, open-label, multicentre study of pregabalin in the treatment of neuropathic pain in Latin America. Int J Clin Pract. 2010;64(9):1301–1309. 90. Kremer M, Yalcin I, Nexon L, et  al. The antiallodynic action of pregabalin in neuropathic pain is independent from the opioid system. Mol Pain. 2016;12:12. 91. Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 2019;1:CD007076. 92. Trofimovitch D, Baumrucker SJ. Pharmacology update: Lowdose naltrexone as a possible non-opioid modality for some chronic, nonmalignant pain syndromes. Am J Hosp Palliat Care. 2019;36(10):907–912. 93. Kulkantrakorn K, Chomjit A, Sithinamsuwan P, Tharavanij T, Suwankanoknark J. Napunnaphat P. 0.075% capsaicin lotion for the treatment of painful diabetic neuropathy: A randomized, double-blind, crossover, placebo-controlled trial. J Clin Neurosci. 2019;62:174–179. 94. Blair HA. Capsaicin 8% dermal patch: A review in peripheral neuropathic pain. Drugs. 2018;78(14):1489–1500. 95. Khdour MR. Treatment of diabetic peripheral neuropathy: A review. J Pharm Pharmacol. 2020;72(7):863–872. 96. Selvarajah D, Petrie J, White D, et al. Multicentre, double-blind, crossover trial to identify the optimal pathway for treating neuropathic pain in diabetes mellitus (OPTION-DM): Study protocol for a randomised controlled trial. Trials. 2018;19(1):578. 97. Çakici N, Fakkel TM, van Neck JW, Verhagen AP, Coert JH. Systematic review of treatments for diabetic peripheral neuropathy. Diabet Med. 2016;33(11):1466–1476. 98. Rojewska E, Piotrowska A, Popiolek-Barczyk K, Mika J. Botulinum toxin type A-A modulator of spinal neuron-glia interactions under neuropathic pain conditions. Toxins (Basel). 2018;10(4). 99. Lee YS, Park MK, Park HS, Kim WJ. Scrambler therapy for the treatment of diabetic peripheral neuropathy pain: A case report. Med (Baltim). 2019;98(20):e15695. 100. Rozworska KA, Poulin PA, Carson A, Tasca GA, Nathan HJ. Mediators and moderators of change in mindfulness-based stress reduction for painful diabetic peripheral neuropathy. J Behav Med. 2020;43(2):297–307. 101. Nash J, Armour M, Penkala S. Acupuncture for the treatment of lower limb diabetic peripheral neuropathy: A systematic review. Acupunct Med. 2019;37(1):3–15. 102. Yoo M, D’Silva LJ, Martin K, et  al. Pilot study of exercise therapy on painful diabetic peripheral neuropathy. Pain Med. 2015;16(8):1482–1489. 103. Liu W, Yu F, Zhou Z, Li YC, Fan D, Zhu K. Autologous bone marrow-derived stem cells for treating diabetic neuropathy in metabolic syndrome. BioMed Res Int. 2017;2017:8945310. 104. Duarte RV, Andronis L, Lenders MW, de Vos CC. Quality of life increases in patients with painful diabetic neuropathy following treatment with spinal cord stimulation. Qual Life Res. 2016;25(7):1771–1777. 105. van Beek M, van Kleef M, Linderoth B, van Kuijk SM, Honig WM, Joosten EA. Spinal cord stimulation in experimental chronic painful diabetic polyneuropathy: Delayed effect of high-frequency stimulation. Eur J Pain. 2017;21(5):795–803. 106. Yang W, Guo Z, Yu Y, Xu J, Zhang L. Pain relief and health-related quality-of-life improvement after microsurgical decompression of entrapped peripheral nerves in patients with painful diabetic peripheral neuropathy. J Foot Ankle Surg. 2016;55(6):1185–1189. 107. Davis GC. Chronic pain management of older adults in residential settings. J Gerontol Nurs. 1997;23(6):16–22.

686.e3

108. DiBonaventura MD, Sadosky A, Concialdi K, et al. The prevalence of probable neuropathic pain in the US: Results from a multimodal general-population health survey. J Pain Res. 2017;10:2525–2538. 109. Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for US adults: National health interview survey, 2012. Vital Health Stat. 2014;260(260):1–161. 110. Ferrell BA, Ferrell BR, Osterweil D. Pain in the nursing home. J Am Geriatr Soc. 1990;38(4):409–414. 111. Kaye AD, Baluch A, Scott JT. Pain management in the elderly population: A review. Ochsner J. 2010;10(3):179–187. 112. Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med. 2001;17(3):457–478. 113. Robinson CL. Relieving pain in the elderly. Health Prog. 2007; 88(1):48–53 70. 114. Herr K. Pain assessment strategies in older patients. J Pain. 2011;12(3):S3–S13. 115. McAuliffe L, Nay R, O’Donnell M, Fetherstonhaugh D. Pain assessment in older people with dementia: Literature review. J Adv Nurs. 2009;65(1):2–10. 116. Jones KR, Vojir CP, Hutt E, Fink R. Determining mild, moderate, and severe pain equivalency across pain-intensity tools in nursing home residents. J Rehabil Res Dev. 2007;44(2):305–314. 117. Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain. 2007;23(1):S1–43. 118. Ersek M, Herr K, Neradilek MB, Buck HG, Black B. Comparing the psychometric properties of the checklist of nonverbal pain behaviors (CNPI) and the pain assessment in advanced dementia (PAIN-AD) instruments. Pain Med. 2010;11(3):395–404. 119. Salaffi F, Ciapetti A, Carotti M. Pain assessment strategies in patients with musculoskeletal conditions. Reumatismo. 2012;64(4): 216–229. 120. Romanovsky D, Mrak RE, Dobretsov M. Age-dependent decline in density of human nerve and spinal ganglia neurons expressing the α 3 isoform of Na/K-ATPase. Neurosci. 2015;310:342–353. 121. Gersing AS, Link TM. Imaging of osteoarthritis in geriatric patients. Curr Radiol Rep. 2016;4(1). 122. Moskovich R. Neck pain in the elderly: Common causes and management. Geriatrics. 1988;43(4):65–70 77, 81, 77, 81-82. 123. Cohen SP. Epidemiology, diagnosis, and treatment of neck pain. Mayo Clin Proc. 2015;90(2):284–299. 124. Tong C, Barest G. Approach to imaging the patient with neck pain. J Neuroimaging. 2003;13(1):5–16. 125. Costello JE, Shah LM, Peckham ME, Hutchins TA, Anzai Y. Imaging appropriateness for neck pain. J Am Coll Radiol. 2020;17(5):584–589. 126. Cannata F, Vadalà G, Ambrosio L, et al. Intervertebral disc degeneration: A focus on obesity and type 2 diabetes. Diabetes Metab Res Rev. 2020;36(1):e3224. 127. Hartvigsen J, Hancock MJ, Kongsted A, et al. What low back pain is and why we need to pay attention. Lancet. 2018;391(10137): 2356–2367. 128. Al-Azayzih A, Al-Azzam SI, Alzoubi KH, et al. Nonsteroidal antiinflammatory drugs utilization patterns and risk of adverse events due to drug-drug interactions among elderly patients: A study from Jordan. Saudi Pharm J. 2020;28(4):504–508. 129. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41(2):67–76. 130. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: Basic principles and practical applications. Br J Clin Pharmacol. 2004;57(1):6–14.

48

Major Opioids and Chronic Opioid Therapy

DAVID COPENHAVER, REBECCA HOSS, MEGAN H. CORTAZZO, IRIS VUONG, SCOTT M. FISHMAN

General Considerations of Opioid Administration Derivatives from the opium plant have been described as analgesics and used for pain control since 3500 bc. It was not until 1806 that a pure opioid substance was isolated. This substance was called “morphine,” named after the Greek god Morpheus.1 Since then, the opium plant has yielded other byproducts, and synthetic analogs of morphine have been produced for medicinal use. The use of opioid medications in the United States has fluctuated because of various factors, including but not limited to production, availability, governmental regulation, and physician and societal attitudes. Fluctuations have also occurred because of guidelines that have shifted their positions. Over the last 20 years, the prescription pattern of opioids has escalated significantly for several reasons. The increasing trend in prescription writing has been accompanied by a concordant rise in the incidence of diversion and abuse, as well as an increase in the incidence of complications, including overdose and death. Over the past several decades, evidence for a sustained benefit of opioids in alleviating chronic pain has remained weak and inadequate, either with results that are not substantially positive or negative or have poor scientific quality. However, evidence of the risk associated with the use of opioid drugs has been increasingly elucidated in the literature and from public health agencies. This change in which evidence of the efficacy of opioids has not changed, whereas risk has increased, should significantly impact treatment decisions based on a critical analysis of risks and benefits. This chapter aims to review clinically relevant aspects of selected opioids, including side effects and pharmacology, and review the current consensus on rational opioid prescription.

Opioid Receptors Endogenous opioids, in addition to multiple other endogenous systems, are involved in the modulation of pain perception. Natural endogenous opioids include the endogenous peptides β-endorphins, enkephalins, and dynorphins. Since the discovery of opioid receptors in the central nervous system (CNS) in 1973, the body of literature describing their function and location has grown immensely.2,3 Opioid receptors play integral roles in the

endogenous antinociceptive system and, accordingly, are located throughout the central and peripheral nervous systems. The best-described opioid receptors are labeled µ, κ, and δ and are prominently located in the CNS, particularly in the dorsal horn of the spinal cord,4 as well as in the dorsal root ganglia and peripheral nerves.5,6 The three opioid receptors identified, µ, κ, and δ, belong to a superfamily of guanine (G) protein-coupled receptors located at pre-synaptic and post-synaptic sites in the CNS and peripheral tissues.7 The µ-opioid receptor modulates input from mechanical, chemical, and thermal stimuli at the supraspinal level. The κ receptor is similar to the µ receptor in that it influences thermal nociception. However, it also modulates chemical visceral pain. The δ receptor influences mechanical and inflammatory pain.8 An opioid agonist, such as morphine, binds primarily to the µ opioid receptor to produce analgesia, as well as undesired side effects, such as respiratory depression and constipation. In a study using knockout mice that lacked the µ receptor, it was found that they did not respond to morphine with respect to analgesia, respiratory depression, constipation, or physical dependence.9

Distribution, Metabolism, and Excretion The amount of opioids required to produce analgesia has significant interindividual variability. The factors responsible for this variability include opioid receptor individuality and variations in opioid absorption and clearance. Such individual variability requires careful titration of opioids to the desired response. The onset, duration, and intensity of analgesia depend on the delivery of the drug to the target and the length of time that the receptor is occupied. The number of receptors occupied and the length of time that the opioid activates its target receptor depends on the perfusion, plasma concentration, pH, and permeability coefficient of the drug.10 The metabolic pathway for each opioid is based on the molecular variables of a specific opioid. Opioids with hydroxyl groups, such as morphine and hydromorphone, undergo hepatic metabolism via uridine diphosphate glucuronosyltransferase (UGT) enzymes. UGT adds a glucuronic acid moiety to form glucuronide metabolites such as hydromorphone 3-glucuronide (H3G), morphine 6-glucuronide (M6G), and morphine 3-glucuronide (M3G)). These metabolites 689

690

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

are excreted through the kidneys. Patients with renal impairment are particularly prone to the deleterious effects of metabolite accumulation.11 The cytochrome P-450 (CYP) system contains two polymorphic isoforms that metabolize certain opioids. The first CYP isoform responsible for the biotransformation of codeine, oxycodone, and hydrocodone is 2D6. It is estimated that up to 10% of white individuals lack this enzyme, thus making them “poor metabolizers” of certain opioids and providing another cause for the high interindividual variability seen in patients treated with opioids.11 The 3A4 isoform of the CYP system is involved in the biotransformation of fentanyl and methadone to their inactive forms.12 Because other drugs also interact with 3A4 isoenzymes, the metabolism of methadone and fentanyl can be problematically decelerated or accelerated. For example, macrolide antibiotics inhibit the enzyme, which decreases the clearance of methadone and fentanyl, whereas anti-convulsants such as phenytoin induce the activation of this enzyme system and increase the clearance of methadone and fentanyl.13,14 The excretion of most opioid metabolites occurs via the kidneys, but some of the glucuronide conjugates are excreted in bile, and methadone is excreted primarily in feces.11 The study of pharmacogenomic polymorphisms is important in understanding the interindividual variability in analgesic effects [the reader is directed to Chapter 13 on pharmacogenetics]. Opioid related therapies have a multiplicity of genetic factors that influence the metabolism and clearance of specified opioids. In the future, the use of regulator-approved pharmacogenomic assays may be advantageous for identifying many of these variant alleles. Understanding pharmacogenomic polymorphisms will most likely play a role in everyday clinical decision making to manage acute and chronic pain. As for safety and patient care benefit from detailed knowledge of specified polymorphisms, this science will most likely be incorporated into the standard of care for physicians.15

Administration Multiple routes of administration are among the many clinically useful characteristics of opioids. Administration can range from intrathecal, intravenous, or oral to rectal, sublingual, buccal, intranasal, or transdermal. Depending on the clinical situation, one route may be more advantageous than the other. For example, a patient who requires continuous opioid delivery but is unable to take medications orally may benefit from a transdermal delivery system, such as is currently available in a transdermal patch containing fentanyl and, more recently, the Food and Drug Administration (FDA) approved transdermal patch containing buprenorphine, which, in appropriate settings, has potential safety advantages over fentanyl. Fentanyl is also available as a rapid onset transmucosal delivery product. Neuraxial routes of opioid delivery are widely used in perioperative and postoperative care, as well as in terminally ill patients. The pharmacologic goal of effective opioid therapy for chronic pain is to provide sustained analgesia over regular intervals.16 This requires consideration of several factors, including knowledge of equianalgesic dosages between opioids and the pharmacologic properties and side effects of specific opioid agents. Pain in opioid tolerant patients is particularly challenging because typical dosages for opioid-naïve patients do not apply, and exact opioid requirements may require careful titration.

Whether fixed dosing is better than as-needed (PRN) dosing is controversial, with each method having advantages in specific patient settings. With fixed dosing, there is consistent opioid delivery, which can theoretically reach steady state levels.17 Presumably, this avoids the peak-and-trough effect that can be associated with on-demand dosing and may prevent delays in delivery that can occur with on-demand schedules. One problem for opioid-naïve patients who receive fixed doses of opioids with longer half-lives is that they may experience excessive side effects or toxicity because of the difficulty in predicting the exact opioid requirement and potential accumulation. For example, morphine may take less than 24 h to reach steady state levels, whereas methadone can take up to one week. When there is a need to assess a patient’s analgesia threshold, PRN dosing of an opioid with a short half-life may be used, or conservative fixed dosing of opioids with a short half-life, supplemented by PRN “rescue” dosing, may be used. Analgesic therapy with long-acting opioids (LAOs) offers convenient dose intervals to attain safe, effective, and steady state levels. Several controlled-release opioids are available, including morphine (MS Contin, Oramorph SR, Kadian), hydrocodone (Hysingla), oxycodone (OxyContin, Xtampza), fentanyl (Duragesic patch), hydromorphone (Exalgo), tapentadol (Nucynta ER), and oxymorphone. Methadone may be used as a relatively LAO (longer effect than short-acting opioids [SAO] but shorter than most LAOs), but it poses specific issues and concerns for clinicians that are distinct from those of other opioids (see later discussion). Methadone has a faster onset and longer analgesic effect than many other SAOs and may be ideal in some situations. However, other properties and adverse effects may limit their use. Methadone is not specifically formulated for a sustained release like other LAOs, which essentially release an SAO throughout the drug’s passage through the gastrointestinal (GI) tract. Methadone has an intrinsically longer plasma half-life than other typical opioids, such as hydromorphone (Dilaudid) and morphine, and can therefore be advantageous in patients with GI motility issues such as short gut syndrome. Although sustained- and immediate-release opioid preparations have made the oral route a practical option, some patients cannot tolerate oral delivery.18 In such cases, transdermal, buccal, rectal, intravenous, or subcutaneous infusions are often a practical alternative option. With infusion, the first-pass effect is eliminated, potentially offering some advantages. There may be a faster onset of analgesia with less complicated access when compared with the oral route. Compared with the intramuscular route, the administration is often less painful and may be safer in patients with bleeding disorders or reduced muscle mass.

Adverse Effects The most commonly encountered side effects associated with opioids include constipation, nausea, vomiting, sedation, urinary retention, pruritus, and hypogonadism. Although respiratory depression may not be as common, its potentially devastating effects make it a heightened concern. Any of these side effects can significantly limit therapy, but the resolution of most adverse effects may occur shortly after the initiation of opioids. However, constipation is a major exception because it does not resolve with the prolonged use of opioids. Particular attention should be given to older adults and patients with hepatic or renal insufficiency. Tolerance (drug effect wears off

 

CHAPTER 48

over time or higher dosage is needed to achieve the same effect) and physical dependency (sudden discontinuation produces withdrawal effects) are also commonly associated with opioid therapy. These are pharmacologic properties related to opioids that are frequently misinterpreted as indicators of addiction. Addiction is also a potential risk associated with opioid use (see later discussion). Physicians should anticipate any or all of these adverse effects, remain vigilant throughout therapy, and monitor patients closely, particularly when initiating therapy and escalating opioid doses.

μ

Constipation The most common side effect of opioid administration is constipation; unfortunately, tolerance to it does not generally develop. Constipation can cause significant discomfort, nausea, and emesis. One of the underlying mechanisms of opioid-induced constipation is thought to be decreased gastric motility because of opioid binding to highly concentrated -opioid receptors located in the antrum of the stomach and the proximal part of the small bowel.19,20 There is limited evidence that certain opioids at equianalgesic doses produce more or less constipation than others. Because the transdermal route bypasses initial exposure to the GI tract, transdermal fentanyl has been postulated to produce less constipation than orally administered opioids.21–23 However, current data are not convincing and transdermal opioids are well-known to result in significant constipation, such as that associated with oral opioids, which may require aggressive management. When initiating any opioid, it is important to prescribe medications to maintain regular bowel motility concomitantly. Treatment of opioid-induced constipation should include an active laxative such as senna, lactulose, or bisacodyl or osmotic agents such as polyethylene glycol; passive agents such as stool softeners or fiber-based bulking agents may be ineffective because they rely on triggering gastric motility, which in the case of opioids may be inhibited. Alternatively, the use of an adjunctive agent with a side effect profile that includes diarrhea, such as misoprostol, can coexist well with constipation. However, misoprostol should be used with caution in women of childbearing age because it can initiate uterine contractions and miscarriage.24,25 Peripheral opioid receptor antagonists have also been shown to be effective in refractory cases of opioid-induced constipation. Methylnaltrexone, a quaternary derivative of naltrexone, contains a permanently charged tetravalent nitrogen atom and cannot cross the blood-brain barrier.26,27 Methylnaltrexone is an antagonist of the µ receptor. It blocks the peripheral actions of opioids while sparing their central analgesic effects and reverses the slowing of bowel motility, which often occurs with opioid related therapy. Methylnaltrexone was approved by the United States FDA in 2008 as an indication of opioid-induced constipation. Alvimopan, which was also approved in 2008 by the FDA, functions as a peripherally acting µ-opioid antagonist with limited ability to cross the blood-brain barrier. Alvimopan, naloxegol, and naldemedine are opioid receptor antagonists that can treat constipation without, in most cases, affecting analgesia or precipitating withdrawal. The primary indication for this medication is the avoidance of postoperative ileus following partial large or small bowel resection with primary anastomosis.26,27 In addition to the opioid receptor antagonists, lubiprostone is approved by the FDA for the treatment of opioid-induced constipation. However, these options are currently proprietary and costly and

Major Opioids and Chronic Opioid Therapy

691

are usually reserved specifically for refractory opioid-induced constipation.

Nausea and Emesis Nausea and vomiting are frequently seen in patients who are treated with opioids, but it is usually a transient side effect that often lasts only two to three days. The underlying mechanisms of nausea and vomiting appear to be related to several causative factors. One is the activation of receptors in the brainstem, which produces afferent input to the medullary chemoreceptor trigger zone, which is responsible for afferent input to the emetic center of the brain. These areas are dense in neurotransmitter receptors, which correspond to the antiemetic agents used clinically. A potential cause of nausea is the stimulation of receptors in the vestibular apparatus.28,29 Another underappreciated cause of opioid related nausea is constipation, which often responds to treatments that increase motility. In evaluating a patient who reports nausea and vomiting while taking opioids, one should determine important history-related factors involved in the genesis of nausea, such as the time of the last bowel movement, whether it worsens with movement, or whether there is a temporal relationship between opioid ingestion and the onset of nausea. The choice of antiemetic agent depends on the historical aspects of the reported side effects. Patients who experience nausea when they are more ambulatory may be more likely to experience vestibule-related nausea. In such cases, drugs such as meclizine, promethazine, or scopolamine may be useful in relieving this type of induced nausea. Droperidol, prochlorperazine, ondansetron, or hydroxyzine may have greater benefit for nausea that is not associated with movement, a type of nausea thought to be related to chemoreceptor trigger zone-associated activation.30,31 However, cardiac adverse effects may be reflected on the electrocardiogram in QTc elongation. One should also ensure that reversible metabolic causes, intracranial pathology, or other factors such as medications are not the origin of nausea or emesis before it is attributed solely to opioids. Several approaches can be used to treat opioid-induced nausea and vomiting. An antiemetic may be added, often choosing an agent that offers secondary benefits such as promotility, sedative, antipruritic, anxiolytic, or antipsychotic effects, depending on the needs of the individual patient. Another option to reduce the frequency and severity of side effects is to decrease the opioid dose to the minimum acceptable dose that will still achieve adequate analgesia. Based on the observation that tolerance to opioid-induced nausea accrues rapidly, the dose that had previously been reduced may be titrated upward slowly to increase analgesia without inducing nausea. If nausea is protracted, one may consider changing to a different opioid. The emetogenic response to opioids is idiosyncratic. Therefore a different opioid may not produce nausea.32 Pruritus Opioid-induced pruritus occurs more frequently with opioids delivered via the intravenous or neuraxial route than with oral administration. Tolerance to pruritus usually develops reasonably quickly, but in rare cases, it can be more persistent. The underlying mechanism of pruritus appears to be related to the release of histamine, which activates C-fiber itch receptors on C fibers that are distinct from pain-transmitting C fibers. Clinically, pruritus is often limited to the face and perineum but can become generalized and severe. Treatment includes antihistamines, but the therapeutic effect may be related more to sedation than a direct antihistaminergic effect.32 In patients receiving intrathecal or intravenous

692

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

morphine with significant pruritus that is unresponsive to antihistamines, low dosages of nalbuphine, a µ-receptor antagonist and κ-receptor agonist, may effectively reduce pruritus without reversing the analgesia.33,34

Sedation Opioid-naïve patients or those chronically taking opioids who are undergoing dose escalation often experience sedation and drowsiness. Sedation is usually temporary as patients accommodate a new medication or dose, and it has been demonstrated that patients maintained on a stable dose of opioids for seven days rarely have psychomotor impairment.35–37 The importance of this fact cannot be overemphasized because the opioid prescription for patients with cancer- and non-cancer-related pain remains substantial, if not decreasing, since the recognition of the opioid crisis. Patients and others may question whether it is safe to operate a motor vehicle while taking opioids. This is a controversial issue, and strong arguments can be made on both sides. Some physicians may recommend taking no precautions, whereas others may counsel their patients to never drive while taking opioids. Emerging evidence is not completely clear on this issue, but some studies have suggested that patients managed with long-term opioid therapy may be alert enough to drive safely.38,39 However, it seems prudent to restrict driving, at least for one week or longer at the onset or with dose escalation of an opioid regimen. Despite an adequate adjustment period to the opioid dose, sedation that persists can become as problematic as the pain itself. In such cases, lowering the dose of opioid to the minimally acceptable analgesic level, increasing (widening) the dosing interval, or changing to another opioid that may not be as sedating may be considered.32 If the sedation is thought to be secondary to accumulating levels of the drug or its metabolites, changing to a different agent that is not as dependent on renal clearance or does not have active metabolites, such as fentanyl, may reduce the sedation. In patients with continued unremitting sedation after limiting CNS depressants, attempting opioid dose reduction, and excluding all other underlying causes, psychostimulants may be useful (e.g. amphetamines, modafinil). Recent attention has raised the importance of considering sedation associated with other medication-related causes (e.g. benzodiazepines, antiemetics, tricyclics, and anti-convulsants such as gabapentin and pregabalin), renal or hepatic dysfunction leading to accumulation or progression of the patient’s primary disease state itself. Gabapentinoids are commonly prescribed for pain, and there are rising concerns that drugs such as gabapentin are abusable and, in conjunction with co-prescribed opioids, may increase the risk of respiratory depression. A 2017 study by Gomes et al. found that concomitant use of gabapentin and opioids was associated with a substantially increased risk of opioid related death.40 Perioperative use of gabapentinoids may increase the risk of opioid overdose and other opioid related adverse events. There are also increasing concerns that, although gabapentin does not appear to have great addiction potential, it is abused and has illicit use street value.41 An FDA advisory from 2019 [https:// www.fda.gov/news-events/fda-brief/fda-brief-fda-requires-newwarnings-gabapentinoids-about-risk-respiratory-depression] stated “Reports of gabapentinoid abuse alone, and with opioids, have emerged, and there are serious consequences of this co-use, including respiratory depression and increased risk of opioid overdose death.” In light of this, the FDA has required updated labeling for gabapentinoids to warn against potential respiratory depression. According to the federal government, some states have

scheduled gabapentin as a potential drug of abuse, and pregabalin is schedule 4.

Respiratory Depression Respiratory depression is one of the most serious concerns and feared complications of opioid prescription. The underlying mechanism of respiratory depression is µ-receptor induced depression of brainstem centers that subserve respiratory drive.42 It has long been recognized to occur more rapidly in patients who have received combined intrathecal-epidural and oral or intravenous opioids. Although there is minimal evidence to support this claim, recognizing that this is a possible risk often supports an acceptable risk management-oriented approach to opioid administration. In addition, combining opioids with other sedating drugs can hasten respiratory depression. This is particularly important because of the escalating rates of unintended overdose deaths associated with opioids, many involving multiple drugs that include additional respiratory depressants such as benzodiazepines. Clinically, the patient manifests sedation as the first sign of respiratory depression, which can pose a problem in detection during the evening hours when the patient is sleeping. Because respiratory depression can occur after the administration of epidural and intrathecal opioids and is often delayed and does not appear until approximately 12 h after injection, the signs of sedation may be lost during sleep. Therefore it is advisable to use alarmed pulse oximetry in patients in whom clinical suspicion is warranted.32 Pain is a powerful physiologic stimulant of the respiratory drive and opposes the respiratory depressant effects of opioids. In patients in whom pain relief is anticipated from a non-opioid analgesic treatment (e.g. neurolytic procedure, radiation therapy, adjuvant analgesics, surgery), a reduction in opioid dose may be required.42 If a patient cannot be aroused and opioid-induced respiratory depression is suspected, the specific opioid receptor antagonist naloxone should be administered. Care must be taken when administering naloxone to patients who have been taking opioids for longer than one week or older adult patients because severe withdrawal symptoms, seizures, and severe pain can be induced. The administration of naloxone has also led to congestive heart failure in susceptible patients. Naloxone is often packaged in an ampule containing 0.4 mg for intravenous administration, which can then be diluted in 10 mL of normal saline and administered as 0.5 mL boluses (0.02 mg/0.5 mL) every 2 min.42

Opioids and Immunologic Effects Opioids have been suggested to play a role in the incidence of infection in heroin users and contribute to the pathogenesis of human immunodeficiency virus.27 Of note, despite the suggestion that exogenous opioids may cause immunosuppression, endogenous opioids such as endorphins promote immunoactivation.27 Inhibitory effects on antibody and cellular immune responses, natural killer cell activity, cytokine expression, and phagocytic activity have all been implicated in acute and chronic opioid administration.27,41 Furthermore, it has been noted that peripheral immune cells express opioid receptors, which allows intricate communication between cells and cytokines.27,43 Opioid-induced alteration of immune function can be categorized into central and peripheral components. It has been postulated that central opioid receptors mediate peripheral immunosuppression via the hypothalamic-pituitary-adrenal axis and autonomic nervous system.27,41,44 Interestingly, severe chronic pain has been suggested to be associated with a reduction in immune function.27,41,43

 

CHAPTER 48

Major Opioids and Chronic Opioid Therapy

693

Substantial differences that distinguish tolerance, dependence, and addiction from each other. Unfortunately, these concepts are frequently misunderstood. In 2001, the American Pain Society, American Academy of Pain Medicine, and American Society of Addiction Medicine approved definitions of addiction, physical dependence, and tolerance in the hope of reducing misguided treatment of patients who require opioids for pain treatment. In patients who are chronically administered opioids, it should be anticipated that physical dependence and tolerance will develop, but clinicians should remain vigilant for maladaptive changes in behavior witnessed in patients with addiction (see later discussion) while recognizing that these changes only occur in a minority of cases.53

purposes, the FDA has defined a patient who is opioid tolerant as one who has received at least 60 mg oral morphine equivalents for at least seven days. The mechanisms responsible for this phenomenon are not entirely understood, but the N-methyl-d-aspartate (NMDA) receptor has been demonstrated to be involved.54,55 The clinical usefulness of NMDA receptor involvement has yet to be determined fully, but nonhuman studies have continued to promulgate the potential for using NMDA receptor antagonists in conjunction with opioids to attenuate tolerance and physical dependence.56,57 A subpopulation of dorsal horn neurons expressing NMDA receptors and treated with high-dose morphine have been shown to have enhanced NMDA receptor-mediated activity.56 Furthermore, µ-receptor antagonist and NMDA receptor antagonist treatment of this subpopulation have attenuated the increased activity.56 Another study has demonstrated that in “morphine-tolerant” rats treated with an NMDA receptor antagonist, the morphine-induced tolerance reversed.57 The relevance of these findings at the bedside have, to date, not been clear. Human studies on the effects of NMDA receptors on tolerance have been less promising. There has been great hope that NMDA receptor antagonists such as ketamine or dextromethorphan might potentiate the analgesic effect of opioids, but no convincing evidence has emerged from replicated trials.58,59 In a double-blind controlled clinical trial comparing morphine and a combination of morphine and dextromethorphan, statistical differences in analgesia or dose were not seen between groups.60 Nonetheless, basic concepts continue to support the understanding that the NMDA receptor is a key component in the development of opioid-induced tolerance. In particular, ketamine continues to be a drug of major interest because of its potential to improve opioid performance by preventing tolerance and enhancing opioid-induced analgesia.61–63 When a patient is suspected of having become tolerant to one medication, the cause may be that the pain is not sensitive to opioids, the patient has become opioid tolerant, or it may be related to increased pain, which requires adjustment in dosing. The need for dose escalation in patients treated with chronic opioids should constantly stimulate consideration of the progression of the underlying disease. Opioid rotation can be performed when opioid-induced tolerance is present. This is based on the clinical observation that patients often have intraindividual analgesic responses to different opioids and that improved analgesia with fewer side effects may occur when a different opioid is used.64 Although the full mechanism of this phenomenon is not completely understood, it is usually thought to occur because of incomplete tolerance, possibly related to differing µ-opioid and other opioid receptor affinities of one opioid versus another. When opioid rotation is performed in opioid tolerant patients as opposed to opioid-naïve patients, equal analgesic doses may not be necessary. The patient may respond with analgesia to half the equianalgesic dose, and if not, the dose may be titrated to an adequate analgesic effect that is less than would be expected by calculation of equianalgesic conversion from standard formulas. This is a potentially useful phenomenon whereby the overall opioid requirement of the patient may be reduced, thereby achieving an opioid-sparing effect.

Tolerance The term opioid tolerance is often used to describe the phenomenon that occurs when a fixed dose of an opioid results in decreasing analgesia, thus requiring higher doses of medication to achieve the same or less effect over time.32 Because some opioids are only appropriate for use in opioid tolerant patients, for practical

Physical Dependence and Withdrawal Physical dependence is a physiologic state that occurs when a medication is abruptly stopped and withdrawal syndrome results. This is not synonymous with addiction. This separation of physical dependence and addiction is supported by evidence of two distinct anatomic areas within the CNS that are involved in physical

Opioids and Hormonal Changes The oral, intravenous, and intrathecal routes of administration of chronic opioid therapy have been well-described to alter hormonal effects in both men and women.27 In illicit drug users, serum hormones that are altered by opioid administration subsequently return to normal following suspension of the drug.44 Hormones disrupted by opioids are not relegated to testosterone (both total and free) but also include estrogen (estradiol), luteinizing hormone, gonadotropin-releasing hormone, dehydroepiandrosterone, adrenocorticotropin, corticotropin-releasing hormone, and cortisol.27,45–49 Opioid related endocrinology research focuses on androgen hormones because of the well-described symptomatic side effects. Sexual dysfunction (erectile dysfunction, decreased libido), depression, and fatigue are some of the many side effects that men may experience when prescribed chronic opioid therapy.27,45,46 Many of the side effects mentioned above have been correlated with hypogonadism. Symptoms such as depression and sexual dysfunction are not relegated to men; women can experience such side effects as well.27,45,46 Women also experience dysmenorrhea and potentially reduce bone mineral density. Testosterone levels appear to be reduced in women and may be correlated with body mass index.27,47–48

Opioid-Induced Sleep Disturbances A considerable number of studies on the effects of chronic opioid therapy on sleep are still needed. Despite the paucity of data, some studies suggest that opioids increase the number of shifts in sleepwaking states and reduce total sleep time, sleep efficiency, δ sleep, and rapid eye movement (REM) sleep.27,50–52 In various studies, it is difficult to separate the effect of opioids on sleep from those of comorbid conditions (e.g. cancer, addiction or dependence, postoperative pain). Research suggests that γ-aminobutyric acid (GABAergic) signaling via inhibition of acetylcholine release in the medial pontine reticular formation is the primary focus for the disruption of sleep by opioids.27,50–52 Morphine has been demonstrated to reduce REM sleep. The resulting disruption in sleep architecture affects the state of arousal during wakefulness.27,50–52

Opioid Tolerance and Physical Dependence

694

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

dependence versus addiction. Noradrenergic neurons within the locus coeruleus are implicated in the maintenance of dependence and development of withdrawal, whereas the ventral tegmental dopaminergic area and orbitofrontal glutamatergic projections to the nucleus accumbens are thought to subserve addiction.61,65 It has been shown that drugs of abuse such as heroin, cocaine, nicotine, alcohol, phencyclidine, and cannabis initiate habit-forming actions by activating a common reward pathway in the brain.66 There is also well as the involvement of noradrenergic neurons in the development of withdrawal. Not only do norepinephrine levels change in the brain following opioid dependence, but the administration of an α2-agonist such as clonidine or a β-antagonist such as propranolol also attenuates many of the symptoms of opioid withdrawal but does not reverse addiction.67 The clinical manifestations of opioid withdrawal usually begin with irritability, anxiety, insomnia, diaphoresis, yawning, rhinorrhea, and lacrimation. If it progresses without intervention, a flulike condition develops, with chills, myalgia, fever, abdominal cramping, nausea, diarrhea, tachycardia, and other features of a heightened adrenergic state. Although uncomfortable for patients, it is self-limited and lasts approximately three to seven days. Opioid withdrawal may occur in patients who abruptly discontinue opioids or who have relative discontinuation because of taking SAOs after accommodating the longer plasma half-life of LAOs.32 It is usually possible to taper patients from opioids without inducing withdrawal symptoms. Although faster tapering can be accomplished without the advent of withdrawal symptoms, if time allows, few patients will be symptomatic if the dose is decreased by 10%–20% every 48–72 h over a prolonged period (usually two to three weeks, depending on the dose).68 If withdrawal symptoms develop during discontinuation or taper, clonidine, 0.2–0.4 mg/day, may be used to decrease discomfort.69 Clonidine is often maintained for four days during taper of an SAO and 14 days during taper of an LAO. Once opioids have been discontinued, clonidine can be tapered for approximately one week.32 Other medications are also used for managing withdrawal symptoms, often drugs with GABA B receptor antagonism (i.e. tizanidine) and/or α2A adrenergic receptor agonists (i.e. lofexidine or tizanidine).

Opioid Use Disorder Opioids are associated with substance abuse at a rate that is high enough to be a significant concern. However, the exact rate of opioid use disorder as a result of therapeutic opioid use is controversial. Opioid use disorder (OUD) is characterized by opioid use that results in physical, psychological, or social dysfunction (or a combination of these) and continued use of opioids despite the dysfunction. The DSM-5 defines OUD as a problematic pattern of opioid use leading to clinically significant impairment or distress, with at least a 12-month period of at least two of the 11 symptoms (Box 48.1). Neurobiologic evidence has suggested that OUD may be subserved by positive reinforcement and sensitization of the dopaminergic system in the brain, which may explain the continued seeking of a substance destructive to the patient’s life.70 Patients who are receiving an inadequate dose of opioid medication may engage in drug-seeking behavior to obtain more pain medication for the relief of pain, which can be mistaken for the drug-seeking behavior associated with OUD. Physicians are often challenged to distinguish true use disorder from undertreated pain because undertreated pain may appear similar to OUD because of features such as drug-seeking and self-escalation. However, unlike OUD,

• BOX 48.1

Eleven Symptoms in Opioid Use Disorder

Taking opioids in larger amounts or over longer periods than intended Having a persistent desire to control opioid use Sending excess time obtaining, using, or recovering from opioid use Having opioid cravings Inability to fulfill work, home, or school responsibilities from continued opioid use Continued opioid use despite persistent interpersonal problems Lack of involvement in social, occupational, or recreational activities Opioid use in physically hazardous situations Continued opioid use despite persistent physical or psychological problems Tolerance, including the need for increased amounts of opioids Opioid withdrawal syndrome The DSM-5 defines OUD as a problematic pattern of opioid use leading to clinically significant impairment or distress, with at least a 12-month period of at least two of the 11 symptoms.

undertreated patients experience pain relief and improved function with increased doses of opioids. OUD directly contrasts with what is seen in a patient with undertreated pain who goes through dose escalation. With OUD, aberrant behavior not only continues despite an increase in opioids but is also usually further stimulated and promoted by increased exposure to the addicting drug. The Committee on Pain of the American Society of Addiction Medicine has defined OUD in the context of pain treatment with opioids as a persistent pattern of dysfunctional opioid use based on a comprehensive clinical assessment that includes history, physical examination, validated clinical scales that measure withdrawal symptoms, and urine drug testing.71 Patient behavior may be used cumulatively to support the diagnosis of addiction, but absolute conclusions cannot always be made, particularly without longitudinal information over extended periods. Many types of behavior may indicate the possibility of addiction (Box 48.2). Nonadherence to opioid therapy may be related to many possibilities, including adverse effects, forgetfulness, incompatibility with lifestyle, and confusion about the drug regimen. It may rarely be related to aberrant behavior such as diversion or drug abuse, and an astute physician will maintain a position of vigilance without feeling compelled to reach immediate conclusions. If a physician chooses to pursue pain treatment with an abusable drug in a patient at risk for addiction, collaboration with an addiction specialist or addiction psychiatrist is advised to ensure that the necessary resources to support an appropriate risk management program are available. Such resources are usually far greater than those available to the average prescriber, and without the necessary resources to ensure safety, prescribing should not begin. High vigilance and tempered judgments are always required. The exact rates of opioid misuse and abuse in patients with chronic pain are not exactly known. However, estimates range from 1%–40%.72 Treating chronic pain in a person with a history of substance use disorder is challenging and highly risky, but it is not absolutely contraindicated. Nonetheless, responsible prescribers of opioids must ensure that the appropriate resources for safe use are in place before initiating treatment. If appropriate risk management is not available, treatment should not be initiated. Moreover, treatment should not be initiated unless it can be terminated when necessary. Although a low percentage of the population with chronic pain appears to experience addiction, the remainder of the population has been shown to be at risk for receiving suboptimal analgesia because of prescribers’ fears of patient abuse of the opioid.73 A

 

CHAPTER 48

• Box 48.2

Aberrant Behavior Indicative of Addiction

Behavior Less Indicative of Addiction Expresses anxiety or desperation over recurrent symptoms Hoards medications Takes someone else’s pain medications Aggressively complains to the physician for more drugs Requests a specific drug or medication Uses more opioids than recommended Drinks more alcohol when in pain Expresses worry over changing to a new drug, even if it offers potentially fewer side effects Takes (with permission) someone else’s prescription opioids Raises the dose of opioids on one’s own Expresses concern to the physician or family members that pain might lead to the use of street drugs Asks for a second opinion about pain medications Smokes cigarettes to relieve pain Has used opioids to treat other symptoms

Behavior More Indicative of Addiction Buys pain medications from a street dealer Steals money to obtain drugs Tries to get opioids from more than one source Performs sex for drugs Sees two physicians at once without them knowing Performs sex for money to buy drugs Steals drugs from others Prostitutes others for money to obtain drugs Prostitutes others for drugs Forges prescriptions Sells prescription drugs From Passik SD, Kirsh KL, Donaghy KB, et al. Pain and aberrant drug-related behaviors in medically ill patients with and without a history of substance abuse. Clin J Pain 2006;22:173–181.

growing debate has emerged that focuses on understanding how opioids should be used in the setting of substantial rates of chronic pain while balancing the imperative for vigilant use of opioids with sufficient risk management for acceptable safety. If the decision is made to prescribe opioids, it is imperative to prescribe an opioid antagonist, most commonly intranasal naloxone, as a potentially life-saving antidote for patients with OUD. The United States FDA recommends making naloxone available to all patients with opioids. However, it is especially important to prescribe naloxone for those at increased risk of opioid overdose (patients with a history of OUD, patients with concomitant use of other CNS depressants, and patients with a history of opioid overdose).

Selected Opioids Although therapeutic options to provide analgesia continue to emerge, opioids remain the “gold standard” of currently available analgesics. Despite the widespread use of opioids to treat acute and chronic pain, controversy exists regarding the use of opioids for the treatment of chronic nonmalignant pain. There are proponents on each side of the controversy, and part of the fear of prescribing opioids stems from an inaccurate understanding of appropriate outcomes for prescribing opioids and the risk of abuse or side effects. Although opioids can be a useful tool to provide adequate analgesia for patients, fear of the development of OUD, dependence, or untoward side effects often precludes

Major Opioids and Chronic Opioid Therapy

695

physicians from prescribing opioids.74 If it is decided to initiate opioid therapy in patients with chronic nonmalignant pain, the decision should be based on a well-thought-out rationale for treatment, with clear end points in mind. If the decision is made to initiate opioid therapy, SAOs are generally preferred for the initial phase of management of chronic and non-cancer acute pain. LAOs are typically reserved for patients on well-established dosing and amounts of opioids. SAOs should be titrated slowly to the lowest effective dose, in increments of 25%–50% of the total daily dose. Generally, in treating chronic pain, expert guidelines generally suggest avoiding dosages above 90 mg or morphine mg equivalents given the increased risk of overdose and other adverse effects with higher dosages and lack of evidence for increased analgesia with excessive dosages. Guidelines now suggest avoiding high doses or quantities of opioids given the increase in the prevalence of OUD among the general population. SAOs are often initially prescribed for patients with chronic pain syndromes because they have relatively brief peak serum blood levels of active analgesic metabolites. However, the use of SAOs to treat persistent baseline chronic pain may require frequent dosing. This roller coaster effect is thought to promote nonoptimal pain related behavior, which is why LAOs have been used once the total opioid dose requirement is well-established in such cases. Nonetheless, science has not clearly demonstrated this advantage. SAOs are often combined with other analgesics, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or aspirin, which may offer drug-sparing effects because less medication may be used. Although combination opioids may help reduce opioid related side effects and toxicity, there is a potential for harm to major organs from non-opioid components (e.g. acetaminophen, NSAIDs, aspirin). When using combination opioids, physicians must be aware of renal and liver function problems, as well as the potential harm that could occur in the GI system. Patients must be educated about the risks of taking other analgesics, such as acetaminophen, NSAIDs, and aspirin, in conjunction with the combination opioids. Moreover, physicians must also consider that non-opioid drugs are likely to have a ceiling effect beyond which they are no longer efficacious. Because opioids induce tolerance and have no ceiling effect, the pharmacologically appropriate need for increased opioids may inadvertently push the dose of a combination drug to appropriate levels of the opioid component but to toxic levels of the non-opioid agent. Although reviewing all available opioids is beyond the scope of this chapter, we will review some of the most commonly used opioids for pain management. Minor opioids, such as hydrocodone, are discussed in Chapter 49.

Codeine Codeine is an alkaloid found in very low concentrations in opium. It is now derived from morphine. Codeine is frequently administered in combination with acetaminophen, butalbital, and caffeine.69 It has been shown to be an effective analgesic for chronic nonmalignant pain but has limitations.75 It is a weak µ-opioid agonist and has a half-life of 2.5–3 h. The major metabolic pathway leads to glucuronidation of codeine to codeine 6-glucuronide, with a minor metabolic pathway catalyzed by the polymorphically expressed enzyme CYP2D6 through N-demethylation of codeine to norcodeine and O-demethylation of codeine to morphine.10 Evidence has suggested that the analgesic effects of codeine rely on its conversion to morphine, and patients with genetic variations in the enzymes needed to make this conversion may find codeine to be less effective.76 The genetic polymorphism of

696

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

CYP2D6 is responsible for the variable response to the medication. Patients with the genotype CYP2D6 PM (poor metabolizers) do not achieve adequate analgesia with codeine. In addition, certain medications that inhibit CYP2D6, such as quinidine, paroxetine, fluoxetine, and bupropion, can alter the phenotype of normal patients with normal genetics and thus decrease the therapeutic analgesic effect of codeine.77 Urinary excretory products of codeine include codeine (70%), norcodeine (10%), morphine (10%), normorphine (4%), and hydrocodone (1%).69 This may be important to remember when interpreting the urine toxicology screens of patients taking codeine.

function, such as those with cirrhosis.10 In addition, glucuronides have been shown to undergo deconjugation back to the parent compound by colonic flora and reabsorbed as morphine.10 Morphine metabolites are excreted by the kidneys, so caution should also be taken when prescribing morphine to patients with renal impairment because the accumulation of M6G and M3G can be toxic. Available forms of morphine include short- and long-acting preparations. Short-acting agents may be compounded for almost any route of administration, and long-acting preparations generally use specialized sustained release matrix technologies, such as those found in MS Contin, Kadian, Oramorph SR, and Avinza.

Morphine

Oxycodone

Morphine, a hydrophilic phenanthrene derivative, is a prototypical opioid against which all other opioids are compared for equianalgesic potency. Because of its hydrophilic nature, it exhibits delayed transport across the blood-brain barrier, thus delaying its onset of action. Conversely, it has a longer duration of action, 4–5 h, than its plasma half-life of 2–3 h.25 Metabolism of morphine to its two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), occurs mainly in the liver (see Table 48.1). Although the parent compound produces analgesia and side effects, M6G may also produce some analgesia along with some adverse effects. M6G accounts for 5%–15% of morphine metabolites and is a µ- and δ-agonist, which accounts for its analgesic effects. It has been demonstrated that M6G does not exert antinociceptive effects in knockout mice lacking the µ-receptor.78 M3G, which accounts for 50% of morphine metabolites, does not appear to possess opioid agonism but may produce effects that oppose morphine’s analgesic actions, such as allodynia, hyperalgesia, myoclonus, and seizures.10 Oral administration of morphine has been shown to result in higher levels of M3G and M6G than those achieved with the intravenous, intramuscular, or rectal routes, which bypass hepatic metabolism.79 Chronic administration of morphine ultimately results in higher circulating levels of M3G and M6G metabolites than the parent compound.80 It has been found that patients receiving chronically high morphine doses metabolize morphine to hydromorphone and test positive for hydromorphone on urine toxicology screens.81 This is of critical importance in patients using morphine for chronic pain who undergo urine drug screening. Although extrahepatic metabolism of morphine has been shown to occur in gastric and intestinal epithelia, morphine should be used with caution in patients with decreased hepatic

Oxycodone is a semisynthetic opioid that is closely related to morphine. It has been available for analgesia since 1917 when it was introduced into clinical practice in Germany.82 It is processed from thebaine, an organic compound found in opium. Similar to morphine, currently available forms of oxycodone include short- and long-acting preparations. Short-acting oxycodone may be used alone (e.g. Roxicodone) or may be compounded with acetaminophen (e.g. Percocet, Roxicet, Endocet) or aspirin (e.g. Percodan). Long-acting oxycodone preparations are designed for oral administration and involve the use of specialized sustained release technology (e.g. OxyContin, Xtampza, and similar generics). Oxycodone has a bioavailability of 60% compared with morphine, which has a bioavailability of 33%, thus making oxycodone almost twice as potent as morphine.70 Oxycodone is a prodrug that undergoes hepatic metabolism via the CYP2D6 isoenzyme, whereby it is converted into its active metabolite oxymorphone, a µ-opioid agonist, and its inactive metabolite noroxycodone. Oxymorphone is reportedly often undetectable and is 14 times more potent than the parent compound. Similar to codeine, there is genetic polymorphism in 10% of the population, which accounts for significant variation in the metabolism of oxycodone. This variation explains why some patients require higher than usual doses of oxycodone to achieve analgesia. Another factor to be considered when prescribing oxycodone is whether other potential competitors of the CYP2D6 isoenzyme are being prescribed. Such interacting medications include neuroleptics, tricyclic anti-depressants, and selective serotonin reuptake inhibitors (SSRIs). Cases of serotonin syndrome have been described in the literature when SSRIs and oxycodone were used concomitantly.83,84

TABLE 48.1

Selected Opioids: Oral Bioavailability, Half-lives, Duration of Action, and Metabolites

Opioid

Availability (%)

Half-life (h)

Duration of Action (h)

Metabolites

Morphine

10–45

2–3

4–5

M6G, M3G

Oxycodone (OxyContin)

60–80

4.5

12

Oxymorphone, noroxycodone

Methadone

60–95

8–80 (average, 27)

6–8

—

Hydromorphone

24

2.3

3–4

H3G

Oxymorphone (Opana ER)

10

9±3

12

O3G, 6-hydroxyoxymorphone

H3G, Hydromorphone 3-glucuronide; M3G, morphine 3-glucuronide; M6G, morphine 6-glucuronide; O3G, oxymorphone 3-glucuronide.

 

CHAPTER 48

Meperidine The use of meperidine for analgesia has been declining recently because of its potential neurotoxicity. It is a weaker µ-opioid agonist than morphine with 10% potency, more rapid onset, and a shorter duration of action,85 with a half-life of 3 h, and it is hepatically demethylated to its neurotoxic metabolite normeperidine, which has a half-life of 12–16 h. Normeperidine has been welldocumented to cause CNS hyperactivity and seizures.25 Its excretion occurs via the kidneys. Therefore caution should be taken when administering meperidine to patients with renal impairment or those prone to CNS hyperactivity. Initially, the toxic effects may be seen as subtle changes in mood that can progress to naloxone-irreversible tremors, myoclonus, and seizures. Chronic administration of meperidine to patients with normal renal function and administration of meperidine in conjunction with SSRIs, monoamine oxidase inhibitors, tramadol, and methadone can also result in neurotoxic side effects.

Hydromorphone Hydromorphone has a strong affinity for the µ receptor. It is a hydrogenated ketone analog of morphine and can be formed by N-demethylation of hydrocodone.85 Hydromorphone is similar to morphine in that it is hydrophilic and has a comparable duration of analgesia, but it differs regarding side effects and potency. Pruritus, sedation, nausea, and vomiting occur frequently. Hydromorphone is five times more potent than morphine when administered orally (see Table 48.2) and seven times more potent when administered parenterally. Though essentially hydrophilic, it is ten times more lipophilic than morphine. This lipophilicity may be advantageous when treating patients who cannot take oral medications and cannot maintain intravenous access, such as in hospice environments. It can be administered subcutaneously at a dose of 10–20 mg/mL; this route delivers approximately 80% of the dose absorbed through intravenous delivery.85 The onset of analgesia occurs within 30 min after oral administration and 5 min after intravenous administration, with peak analgesic effects occurring within 8–20 min.85

TABLE 48.2

Equianalgesic Doses of Opioids

Opioid

Oral Equianalgesic Dose (mg)

Buprenorphine

0.3

Oxymorphone

1.5

Butorphanol

2

Hydromorphone

2

Oxycodone

7

Hydrocodone

10

Morphine

10

Methadone

10–20

Tramadol

40

Codeine

80

Meperidine

100

Major Opioids and Chronic Opioid Therapy

697

Hydromorphone is metabolized in the liver to H3G, and like its parent compound, it is excreted renally. Like M3G, H3G lacks an analgesic effect but may be an active metabolite that potentiates neurotoxic effects such as allodynia, myoclonus, and seizures.10 The production of H3G is relatively low. Hence, the risk of neurotoxic side effects is relatively low, except in patients with renal insufficiency, in whom H3G may accumulate.81

Fentanyl Fentanyl is a highly lipophilic agent with a high affinity for the µ-opioid receptor. It is 75–125 times more potent than morphine and has a faster onset of action.80 Because of its higher potency, smaller quantities of the medication can be delivered to the patient relative to other opioids. Although fentanyl is considered a short-acting medication, its lipophilic nature allows long-acting transdermal and very rapid onset transmucosal administration to treat chronic and acute pain, respectively.86,87 Although there are other minor pathways, fentanyl undergoes hepatic biotransformation via CYP3A4 N-dealkylation to norfentanyl. Its half-life and onset of action vary greatly depending on the route of administration. (Transmucosal fentanyl undergoes first-pass metabolism and has an onset of action within 5–10 min.)88 A transdermal fentanyl patch is used in some patients with chronic pain or pain related to cancer. Transdermal fentanyl has been used for acute postoperative pain but may be associated with hypoventilation.87 Transdermal patches are typically placed on a hairless part of the body that is flat and free of any defects that could interfere with patch adherence. Patients should be advised to avoid submerging the patch in hot water or placing a heating pad over the area because this influences absorption. Patients report local skin erythema or irritation as the most common side effect.87 Transdermal fentanyl is an alternative choice for patients with significant GI issues, such as persistent emesis, chronic nausea, or “short gut” syndrome, or for those believed to be at risk of diverting oral medications. The use of the patch offers the opportunity to allow patients to return the old patches for inspection at the time of prescription refill. Theoretically, transdermal delivery may induce less constipation than oral opioids because it avoids direct exposure to the GI tract, but this is questionable in light of the common finding of significant constipation in almost all patients who use transdermal opioids. Unlike other LAOs, transdermal fentanyl may be challenging to titrate because of variations in individual patient characteristics, such as skin perspiration, skin temperature, fat stores, and muscle bulk.10 The rate of achieving therapeutic serum levels can vary (ranging from 1–30 h with a mean of 13 h). Because of the wide variation in reaching therapeutic levels, a short-acting oral analgesic or intravenous patient-controlled analgesia may be necessary to address breakthrough pain, while the transdermal opioid effect is ramping up or to prevent withdrawal symptoms if rotation from another opioid has occurred. Achieving steady state levels may require up to six days, and the amount of SAO needed after a steady state is attained will help determine whether the dose of fentanyl must be increased.10 However, if the patch is removed, it may take up to 16 h for serum fentanyl concentrations to drop by 50%. Oral transmucosal fentanyl has a more rapid onset of analgesia than other SAOs and offers some advantages. Because it is transmucosal, it avoids the GI tract and first-pass hepatic metabolism and has a rapid onset of action within 10–15 min. One study

698

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

compared intravenous morphine with transmucosal fentanyl in an acute postoperative setting and demonstrated a similar onset of analgesia.88 Transmucosal fentanyl can be beneficial for patients with acute breakthrough pain. To date, a major limitation in using this route is the cost.

Methadone Methadone may be an attractive choice for analgesia because of its unique properties, but it also has many features distinguishing it from other opioids that have raised its potential for adverse outcomes. Methadone has become the most common opioid found to be related to unintended overdose deaths in the United States. Thus caution should be exercised with this drug. On the positive side of the methadone risk-benefit profile, its attributes include no known neurotoxic or active metabolites, high absorption and bioavailability, and multiple receptor activities, including µ- and δ-opioid agonism, NMDA antagonism, and serotonin reuptake blockade. Methadone has been shown to have a bioavailability that is approximately threefold that of morphine.89,90 In patients who require high-dose LAOs, methadone appears to be a theoretical second-line choice despite the lack of accumulation of neurotoxic metabolites that induce myoclonus, hallucinations, seizures, sedation, and confusion. Unfortunately, the unique pharmacokinetics and pharmacodynamics of methadone render its effects somewhat unpredictable. Methadone is structurally unrelated to other opioid-derived alkaloids. It is a racemic mixture of two enantiomers, the d-isomer (S-methadone) and the l isomer (R-methadone). R-Methadone accounts for its opioid receptor affinity and thus its opioid effect. Animal studies have demonstrated that methadone has a lower affinity than morphine for the µ-receptor.91 This may explain why methadone may have fewer µ-opioid related side effects than morphine. However, methadone has a higher affinity for the δ receptor than morphine. Methadone has a slow but variable elimination half-life that averages approximately 27 h, which may be related to its lipophilicity and extensive tissue distribution.91 The delayed clearance of methadone is the basis for its use in maintenance therapy. Surprisingly, although methadone may be efficacious for the purpose of opioid maintenance therapy because it potentially prevents withdrawal symptoms for 24 h or longer, its analgesic half-life is shorter than 24 h, usually found to range from 6–8 h. This discrepancy is related to the biphasic elimination. The α elimination phase lasts 8–12 h and correlates with the period of analgesia, which lasts approximately 6–8 h. The β elimination phase ranges from 30–60 h and is responsible for preventing withdrawal symptoms; this property is exploited in maintenance therapy.91 Methadone has multiple drug interactions related to inducers or inhibitors of the CYP system, particularly the 2D6 and 3A4 subtypes.92 Because these interactions rarely are seen with other opioids, drug interactions with methadone may not be as readily anticipated or detected. Besides interacting with drugs, 3A4 is an auto-inducible enzyme, which accounts for the fact that methadone can bring about its own metabolism and increase its clearance with prolonged use.91,92 Other issues affecting methadone absorption and accumulation are gastric and urinary pH. Decreased gastric pH, such as in patients taking proton pump inhibitors, results in increased rates of methadone absorption. Renal failure and hemodialysis do not alter the excretion of methadone. However, as urinary pH increases, methadone clearance in urine decreases. Urine pH

higher than six can reduce methadone clearance from 30% to almost 0%, thereby resulting in increased circulating levels. Most methadone is eliminated in feces.10 Another source of methadone’s potential metabolic instability relates to its avid protein binding. Acute changes in protein binding may lead to sudden increases or decreases in circulating methadone levels. The difference between methadone and other LAOs is that the duration of the effect of methadone is intrinsically long-acting, whereas most other LAOs are sustained-released forms based on compounding technology. This is beneficial for patients with impaired GI absorption. In addition, methadone is available as a powder, allowing it to be formulated for almost any route of administration. Methadone pills can be broken and cut in half, and it is also available as a liquid elixir (1 or 10 mg/mL). This avoids the need to crush pills, which offers a potential advantage in patients with gastrostomy tubes. In addition, because methadone elixir has a low-concentration formulation, careful and precise titration of methadone can be performed to achieve adequate analgesia. One of the most disturbing aspects of methadone use in the United States has been the reported increase in methadonerelated deaths.93,94,95 Although the mechanism for these deaths is not exactly clear, many appear to be related to overdose and drug interactions. In some cases, an overdose may be related to misunderstanding the standard conversion rates of methadone from other opioids. Contrary to conventional wisdom, methadone appears to be more potent (milligram for milligram) in patients whose treatment is being switched to methadone from high doses of other opioids. Although standard conversion tables may suggest that the ratio of conversion from morphine to methadone may be from 1:1 to 1:3, these ratios were taken from studies on acute pain or normal controls. Many of these conversion tables were developed over 20 years ago, far before recent increases in methadone use as a chronic analgesic. If much higher pre-switch dosages are converted to methadone, the appropriate morphine to methadone ratio may range from 1:5 to 1:20 or higher. Such a counterintuitive dosing phenomenon leads to the potential for overdose. Another possible source of methadone-related mortality includes torsade’s de pointes arrhythmias, which have been reported in some patients.96 Although a prospective study has demonstrated QT prolongation on electrocardiogram in patients taking methadone, it was also concluded that the magnitude of the increase is less than that with other antiarrhythmic drugs and is not higher than the QT widening caused by other drugs, such as tricyclic anti-depressants.96 The use of methadone requires awareness of possible QT prolongation and the possible additive effect that other QT-prolonging agents may have when combined with methadone. Table 48.1 shows the oral bioavailability, half-life, duration of action, and metabolites of selected opioids. Table 48.2 shows the equianalgesic doses of the different opioids. Methadone must be used with significant knowledge of the special properties that predispose it to substantial risk. Slow-dosing titration and careful monitoring are essential for safe use. If this and all other elements of safe prescription of opioids are not possible, the drug should not be prescribed.

Buprenorphine Buprenorphine demonstrates a high binding affinity and mixed agonist-antagonist activity at opioid receptors. A derivative of the morphine alkaloid thebaine, a semisynthetic opioid, possesses unique pharmacologic characteristics compared to traditional opioids, making it an appealing first choice option for chronic pain.

 

CHAPTER 48

μ

699

antinociception, while others have observed similar analgesic values to full -opioid agonists, such as morphine and fentanyl. The variability of interindividual responses to different opioids remains reliable. The clinical decision to utilize one opioid over another should be made with patient-specific circumstances in mind. μ

μ

Buprenorphine is a -opioid receptor agonist, a κ-opioid receptor antagonist, and is thought to act as a mild antagonist of the δ-opioid receptor. Antagonistic activity at the κ-receptor is believed to explain buprenorphine-associated anti-hyperalgesia, lessened sedation, euphoria, cravings, and dysphoria compared with conventional opioids, and its potential to act as an antidepressant. Distinctively, buprenorphine has been shown to activate the opioid receptor-like (ORL-1) receptor, which may account for a reduction in the development of opioid tolerance. Acting as a “chaperone” ligand, buprenorphine demonstrates the ability to boost -opioid receptor expression on cell membranes. Buprenorphine is a Schedule III controlled substance available in multiple dosage forms, including injection (IV, depo-SC, subdermal implant), transdermal, buccal, and sublingual routes. Buprenorphine is available independently or combined with naloxone in a 4:1 ratio. The addition of naloxone (an opioid receptor antagonist) to sublingual routes is intended to deter misuse and blunt opioid agonist effects if injected. The oral bioavailability of buprenorphine is poor (10%) because of high first-pass hepatic clearance. Buprenorphine is metabolized in the liver through cytochrome CYP3A4 to norbuprenorphine and is excreted primarily through feces. For patients with renal failure, buprenorphine is a preferred opioid analgesic; drug clearance is unchanged with renal impairment and is not removed by dialysis. Compared to traditional opioids, buprenorphine has an advantageous safety profile. Most notably, when used alone, buprenorphine exhibited a ceiling effect related to respiratory depression. It is essential to understand that when combined with respiratory depressants such as alcohol or benzodiazepines, this protective effect is diminished. Adverse effects such as constipation, sedation, hypogonadism, and tolerance are also seen to be less of a degree with buprenorphine than with other opioids. Similar to methadone, buprenorphine is an effective treatment for OUDs and opioid dependence. Buprenorphine exhibits slow dissipation from opioid receptors, and sublingual formulations have a prolonged plasma half-life (24–72 h). Delayed drug clearance and high lipophilicity make buprenorphine an ideal agent to prevent withdrawal symptoms, often for a period of up to three days. Interestingly, similar to methadone, buprenorphine displays a shorter analgesic half-life (6–8 h) and is often dosed two to four times daily for pain. It should be clarified that a Data-2000 waiver (additional prescriber training for addiction medicine) is needed to prescribe buprenorphine for OUD but is not required to prescribe buprenorphine for pain. As attractive as buprenorphine may be for chronic pain as a first choice opioid, compared with a full agonist opioid, logistical limitations exist around prescribing the drug itself. Challenges include a lack of coverage and reimbursement by third-party payers and hospital formularies, as well as a lack of education on the proper usage of buprenorphine. Clinical experience is recommended when transitioning a patient from a full-opioid agonist to buprenorphine. Careful timing of the window of clearance of the initial full-opioid agonist is necessary to prevent abrupt displacement by buprenorphine. The absence of this consideration may lead to severe precipitated withdrawal. Additionally, the equianalgesic data for buprenorphine are conflicting and incomplete. Conflict exists in the literature on whether to maintain the classification of buprenorphine as a “partial agonist” opioid. Buprenorphine displays low intrinsic activity in vitro, leading to a ceiling effect on analgesia in animal models and a ceiling effect on respiratory depression in humans. The question remains as to how this translates clinically. Some studies have shown bell-curve

Major Opioids and Chronic Opioid Therapy

Rational Opioid Prescribing Opioids work for some pain but not all. They may be problematic for many and even life-threatening for some but knowing who is susceptible is not always clear. Treatment of substantial pain may necessitate the use of opioid related medications. Opioids are not the first choice, nor should they necessarily be the last choice in the pain management armamentarium. A detailed diagnosis with a thorough history and physical examination and an essential focus on risks and benefits will drive the selection of specified analgesic treatments. Non-opioid treatments will often be the initial choice. The decision to use opioid therapy has undergone intense scrutiny as the public health epidemic of prescription drug abuse has been elevated to a national discussion. The importance of risk management with focal attention to the risk-benefit ratio for safe use of opioids underscores the serious potential for opioid abuse and overdose death that has been well documented through approximately 15 years of retrospective data. A history of psychiatric comorbidity and a history of substance abuse are known variables suggestive of increased risk for abuse and unintentional overdose death. A full discussion of the safe prescribing of opioids is beyond the scope of this chapter but can be found in other resources, such as from the Department of Health and Human Services [https://www.hhs. gov/opioids/prevention/safe-opioid-prescribing/index.html], from the CDC Guideline for Prescribing Opioids for Chronic Pain [https://www.cdc.gov/drugoverdose/prescribing/guideline. html], and from the FDA [https://www.fda.gov/consumers/ consumer-updates/guide-safe-use-pain-medicine]. Before initiating opioid therapy, a detailed evaluation is necessary. This evaluation must include risk stratification, assessment of functional activity, a thorough review of the patient’s medical history with special attention paid to previous experience with opioid analgesics, and a review of other related comorbid factors, including previous substance abuse, mental illness, hepatic, renal, or pulmonary dysfunction, or sleep apnea. Informed consent is a critical element of opioid treatment that requires patient education regarding the benefits and risks associated with treatment. The expectations and responsibilities of patients must be clarified early. Monitoring and management of opioid-induced side effects are imperative. The use of opioid agreements, urine drug screens, and well-defined boundaries of care must be considered before initiating treatment, as well as an exit strategy if treatment fails to be successful for a variety of reasons. If the patient is opioid-naïve and the benefits outweigh the risks, low-dose SAOs such as hydrocodone or oxycodone may be initiated and carefully titrated to establish an opioid requirement. Because of the rapid clearance and brief half-life of SAOs, toxic accumulation of the medications is less likely than with LAOs. The severity and duration of the patient’s pain should help guide whether PRN or fixed dosing is required. In patients with acute pain secondary to an injury or surgery for which rapid healing is expected, PRN dosing is reasonable. However, in patients with the expectation of prolonged recovery or with chronic pain and significant baseline or persistent pain, opioids may be administered in fixed dosing intervals and PRN intervals for breakthrough pain.

700

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

Scheduled dosing decreases clock-watching anxiety and reinforcement of pain behavior. However, it may cause drug accumulation. If a patient can tolerate an SAO and its side effects, consolidation of the daily opioid requirement into an equianalgesic LAO regimen may be an appropriate step. Although opioids may be excellent analgesics, they are often used as a second-line treatment for chronic pain, mainly because chronic pain may respond to non-opioid treatments that might carry fewer risks. When other pharmacologic, rehabilitative, or interventional procedures are not appropriate or are unsuccessful, chronic opioid therapy should be considered. It is not uncommon to combine opioid treatment with other modalities, including psychological and physical rehabilitation. Simultaneously, interventional pain procedures and adjunctive analgesics may be useful. The effectiveness of opioid therapy for certain types of chronic pain, such as neuropathic pain, remains controversial. Because anti-depressants and anti-convulsants have been shown to provide less than 50% pain relief on average, opioids have been used to treat chronic neuropathic pain despite their narrow therapeutic window.97 When treating neuropathic pain, it has been shown that opioid potency may be relatively lower than that for other conditions. This seems to be secondary to the changes that occur in the endogenous opioid system after nerve injury. It appears that endogenous peptide levels and opioid receptor density decrease in nociceptive pathways.97 It also appears that GABAergic tone decreases after nerve injury and that the inhibitory effect of morphine on dorsal horn neuron projections after nerve injury is reduced compared to its effect on non-injured nerves.98 Despite these findings, there is evidence in the literature that opioids are efficacious for neuropathic pain; a trial demonstrated that combining gabapentin and morphine for the treatment of neuropathic pain was superior to either alone.99. Nonetheless, gabapentinoids may also pose a risk for respiratory depression, drug abuse, and other adverse effects, particularly well established for gabapentin in the postoperative setting.100,101 In the form of chronic pain unrelated to nerve injury that does not respond well to other treatments, opioid therapy has been shown to be more effective than placebo or anti-inflammatory medications alone in reducing pain. However, studies have struggled to show substantial improvements in overall functioning with opioid therapy. Although opioids may be effective if used as the sole agent for changing all the primary and secondary effects of chronic pain, they may not be effective enough. The importance of a multi-disciplinary approach to the treatment of chronic pain syndromes cannot be overstated. The use of opioids requires a comprehensive risk-to-benefitbased strategy, including the consideration of other potentially effective therapies that have less risk. Rational prescription also requires consideration of all potential risks associated with the treatment and should include a plan to avoid or deal with these risks.

Considerations for Opioid Prescribers In response to a surging public health crisis regarding the misuse of prescription drugs, the Obama Administration in 2011 developed a prescription drug abuse prevention plan through the Office of National Drug Control Policy (ONDCP). The ONDCP plan entails specialized efforts concerning monitoring, proper medication disposal, enforcement, and education. Education of patients, parents, and youth is a key element of focus

for the White House-implemented drug misuse prevention plan. Equally important is the education of prescribing physicians and care providers. In 2014, the Federation of State Medical Boards (FSMB) of the United States revised and expanded the book Responsible Opioid Prescribing: A Clinician’s Guide.102 The revised guide reviews the new data on opioid risk and toxicity, including high rates of unintended overdose deaths, which were not available when the first edition was written in 2006. It offers clinicians examples of current federal guidelines and strategies to reduce the risk of addiction, abuse, and diversion of opioids. Moreover, the revised edition includes, but is not limited to, defined strategies for patient evaluation that include risk assessment, treatment plans that incorporate functional goals, periodic review and monitoring of patients, documentation, informed consent, and termination strategies for chronic opioid therapy. It also emphasizes the special care that is needed when using methadone and treating children and adolescents, as well as prescriber responsibilities for consumer education on the safe use of opioids. The use of defined risk stratification methods by prescribers of chronic opioid therapy has become paramount. In 2016, the CDC released its Guideline for Prescribing Opioids for Chronic Pain, and in 2017, the FSMB published its Guidelines for the Chronic Use of Opioid Analgesics. These guidelines offered granular details on the expectations of opioid prescriptions that have been well-received. However, overreactions to the intent of the CDC guidelines resulted in some clinicians leading to rapid and involuntary discontinuation of long-standing opioid prescription, which resulted in increased risks for some patients, including increased illicit drug use and suicide. As a result, the CDC reframed its recommendations in 2019 (see the suggested readings and Chapter 50). However, the risks of chronic opioid therapy, including toxicity, overdose, and OUD, are wellsupported by data. However, the benefits of chronic opioid therapy for chronic nonmalignant pain remain weak and inadequate. Therefore the analysis of risks and benefits must shift accordingly and is a critical basis for deciding whether opioids should be initiated. Gourlay and colleagues endorsed a universal precautions approach and suggested that addiction can only be elucidated on a behavioral prospective basis.103

Treatment End Points Pain is a subjective experience, using “pain relief ” as a treatment endpoint is a subjective and untestable marker of therapeutic success or failure. One of the most feared consequences of chronic opioid therapy is OUD, which, as discussed earlier, involves compulsive use of an opioid that causes dysfunction and continued use of the opioid despite the dysfunction (i.e. negative impact on or harm to the patient’s life). Because effective analgesia should improve function and because of the risk of the side effect of OUD, which hinges on dysfunction, a major focus of chronic opioid therapy should be on functional improvement as an objective endpoint. It is expected that patients who are treated carefully and judiciously with opioids and achieve analgesia should have functional gains. This contrasts with those struggling with an OUD who becomes impaired by substance misuse as manifested by dysfunction. The challenge for physicians treating chronic pain with opioids is to devise a system of objective markers that distinguish function from dysfunction and emphasize a wide spectrum of therapeutic goals. Several markers of functional improvement can be used in patients chronically treated with opioids. Several standardized

 

CHAPTER 48

functional measurements (e.g. the 36-item short-form health survey [SF-36] and Oswestry disability index [ODI]) can be used to subjectively measure the reduction in pain with supportive and objective evidence of improvement in functional status and effect on the quality of life. However, psychological and social factors, as well as the status of coexistent disease, may influence the perception of pain, suffering, and entitlement and can alter the overall assessment. Unfortunately, not all of these parameters will improve concomitantly or proportionately following the initiation of opioid therapy. If factors related to psychological and physical reconditioning have not been addressed, pain perception and reduction of pain after a trial of an opioid may be less than optimal. Determining effective treatment end points during an opioid trial may require flexibility in considering the many possible variations in efficacy and functional gain. A central question that may be useful at the beginning of an opioid trial is, “What do you need to do with this treatment that you cannot do now?” What follows should be the creation of a list of reasonably attainable functional goals that cover multiple domains of the patient’s life. Equally important in documenting this list is the process by which the goals will be attained and how the patient plans to document progress toward each functional goal for the clinician on every subsequent follow-up visit, which may include but are not limited to the use of non-opioid pain medicine, physical therapy, acupuncture, injections, and surgery. Each goal was monitored regularly and adjusted based on progress. Expectations may need to be reduced if goals are not met or may be advanced as the patient improves. One part of determining whether a patient is benefiting from opioid therapy is to gather collateral information from others involved in the patient’s care and life. Input from physical and occupational therapists, psychologists, family members, and caregivers may prove invaluable. Evidence of improved function may include gains in employment, increased activities of daily living, and socializing with family and friends. On the contrary, if a patient becomes dysfunctional in employment or social or private life, concerns about possible medication-related deterioration, including addiction, should be raised. However, a decreased function is not pathognomonic of OUD. This may be related to factors other than patient control, such as sedation, cognitive impairment, or other external causes. Suppose these or other external problems are not the cause of a patient’s deteriorating mental or physical health. In that case, it may help to consider seeking additional support in the form of a multi-disciplinary program or referral to other specialty providers, such as psychologists, social workers, psychiatrists, or addiction specialists.

Major Opioids and Chronic Opioid Therapy

701

It remains controversial whether subjective relief without objective evidence of the improved quality of life is sufficient to justify the chronic use of opioids. Pain reduction is a subjective variable. Its use as an assessment tool for therapeutic success represents only a single aspect of adequate chronic opioid therapy. For example, consider a patient with significant disability related to pain rated six on a pain severity scale of one to ten. Although opioid therapy may not significantly reduce subjective pain scores, this does not signify treatment failure. In fact, despite no reported reduction in pain scores, objective signs of a return to work and increased physical activity clearly demonstrate that treatment has improved the patient’s quality of life. Conversely, suppose an opioid trial is characterized by subjective reports of marked pain relief. In that case, there are no observable functional gains and possibly even signs of persistent sedation with decreased physical activity, voluntary unemployment, dysfunctional interpersonal relationships, or diminished physical activity; the physician must consider why the patient would regard this as a positive outcome and attempt to resolve any underlying conditions or misunderstandings. As noted by the FSMB, a critical aspect of safe opioid management is documentation of a patient’s care, including current functional status on initial evaluation and throughout follow up.104 Documentation not only requires clarity of events but should also offer transparency about the physician’s decision process, particularly concerning risk-benefit considerations, choices, and plans for risk management. Vigilance in detecting decreased function is important; this may help reveal problems such as OUD, progressive disease, or pain unresponsive to opioids. Another critical issue to consider before and during the course of treatment is the discontinuation of opioid therapy if the treatment is deemed ineffective. Many factors must be considered before treatment is considered to be a failure, including inadequate dosing, inappropriate dosing schedule, improper drug delivery route, opioid-insensitive pain, side effects limiting dose escalation, and social and psychological issues. The appropriate duration of effective opioid therapy remains controversial. Currently, there are no clear guidelines or consensus regarding this issue. The efficacy of treatment, adverse effects of opioid therapy, and progression of the underlying disease must be considered thoroughly when formulating decisions regarding the length of treatment, and these factors must be reconsidered regularly. Once opioid therapy has been initiated, it may be challenging to determine whether pain would be present without opioid therapy unless opioids are tapered.

Key Points • Opioid drugs have been used to control pain for thousands of years as reliable and potent analgesics, but they do not work for all pain, for everyone, or every condition and may pose serious risks. • Opioid therapy has undergone intense scrutiny as the opioid crisis, and public health epidemic of excessive prescription drug abuse has been elevated to a national discussion. • The evidence for sustained benefits of opioids in relieving chronic pain is weak and inadequate, whereas evidence of risk associated with the use of these drugs is clear and substantial. • Focal attention on the risk-benefit ratio for safe use of opioids underscores the serious potential for opioid abuse and overdose

• • • •

death, which has been well documented through approximately 15 years of retrospective data. There is increasing concern about opioid and gabapentinoid related respiratory depression. The exact rate of addiction because of prescription opioid use is relatively low but a significant concern. Sudden or involuntary discontinuation of opioids may be associated with adverse effects and morbidity. Methadone has many features that distinguish it from other opioids, including heightened risk and significant life-threatening adverse outcomes.

702

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

• A detailed diagnostic assessment with a thorough history and physical examination, as well as an essential focus on risks and benefits, will drive the selection of specific analgesic treatments. • The increased risk for abuse and unintentional overdose death requires increased risk management, including risk assessment, treatment plans that incorporate functional goals, periodic review and monitoring of patients, documentation,

informed consent, and termination strategies for chronic opioid therapy. • A thorough history of comorbid psychiatric conditions and a history of substance abuse are important elements of safe prescription. • Once opioid therapy has been initiated, it may be challenging to determine whether pain would be present without opioid therapy unless opioids are tapered.

Suggested Readings

Fishman MA, Kim PS. Buprenorphine for chronic pain: a systematic review. Curr Pain Headache Rep. 2018;22(12):83. Fishman SM. Responsible opioid prescription: a clinician guide, second edition. Expanded. Washington DC: Waterford Life Sciences, 2014. Jannetto PJ, Bratanow NC. Pharmacogenomic considerations in the opioid management of pain: review. Genome Med. 2010;2(9):66. Pergolizzi JV Jr, Raffa RB. Safety and efficacy of the unique opioid buprenorphine for the treatment of chronic pain. J Pain Res. 2019;12: 3299–3317. Rudolf GD. Buprenorphine in the treatment of chronic pain. Phys Med Rehabil Clin N Am. 2020;31(2):195–204. Soin A, Cheng J, Brown L, et al. Functional outcomes in patients with chronic nonmalignant pain on long-term opioid therapy. Pain Pract. 2008;8(5):379–384.

Centers for Disease Control and Prevention. CDC advises against misapplication of the guideline for prescribing opioids for chronic pain: Available at: https://www.cdc.gov/media/releases/2019/s0424-advisesmisapplication-guideline-prescribing-opioids.html. Davis MP. There are 12 reasons for considering buprenorphine as a frontline analgesic in the management of pain. J Support Oncol. 2012;10(6):209–219. Dowell D, Haegerich TM, Chou R. CDC Guideline for prescribing opioids for chronic pain- United States, 2016. JAMA. 2016;315(15):1624–1645. Dowell D, Haegerich TM, Chou R. No shortcuts to safer opioid prescribing. N Engl J Med. 2019;380(24):2285–2287. Federation of State Medical Boards. 2017 Guidelines for the chronic use of opioid analgesics. Available at: https://www.fsmb.org/siteassets/advocacy/policies/opioid_guidelines_as_adopted_april-2017_final.pdf.

The references for this chapter can be found at ExpertConsult.com.

References 1. Maher TJ. Opioids PC (bench). In: Smith HS (ed). Drugs for Pain. ­Philadelphia, PA: Hanley & Belfus; 2002:83–96. 2. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Sci. 1973;179(4077):1011–1014. doi:10.1126/science.179. 4077.1011. 3. Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic [3H]-etorphine to rat-brain homogenate. Proc Natl Acad Sci U S A. 1973;70(7):1947–1949. doi:10.1073/ pnas.70.7.1947. 4. Besse D, Lombard MC, Zajac JM, et al. Pre- and postsynaptic distribution of mu, delta and kappa opioid receptors in the superficial layers of the cervical dorsal horn of the rat spinal cord. Brain Res. 1990;521(1-2):15–22. doi:10.1016/0006-8993(90)91519-m. 5. Hassan AH, Ableitner A, Stein C, Herz A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neurosci. 1993;55(1):185–195. doi:10.1016/0306-4522(93)90465-r. 6. Stein C, Pflüger M, Yassouridis A, et  al. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest. 1996;98(3):793–799. doi:10.1172/ JCI118852. 7. Stoelting RK, Hillier S. Opioid agonists and antagonists. In: Stoelting RK, Hillier SC (eds). Handbook of Pharmacology and ­Physiology in Anesthetic Practice. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:78–117. 8. Martin M, Matifas A, Maldonado R, Kieffer BL. Acute antinociceptive responses in single and combinatorial opioid receptor knockout mice: distinct mu, delta and kappa tones. Eur J Neurosci. 2003;17(4):701–708. doi:10.1046/j.1460-9568.2003.02482.x. 9. Kieffer BL. Opioids: first lessons from knockout mice. Trends Pharmacol Sci. 1999;20(1):19–26. doi:10.1016/s0165-6147(98)01279-6. 10. Janicki PK, Parris WC. Clinical pharmacology of opioids. In: Smith HS (ed). Drugs for Pain. Philadelphia, PA: Hanley & Belfus; 2002:97–118. 11. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28(5):497–504. doi:10.1016/j.jpainsymman.2004.02.021. 12. Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos. 1997;25(9):1072–1080. 13. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer. 2001;9(2):73–83. doi:10.1007/s005200000180. 14. Tempelhoff R, Modica PA, Spitznagel Jr EL. Anticonvulsant therapy increases fentanyl requirements during anaesthesia for craniotomy. Can J Anaesth. 1990;37(3):327–332. doi:10.1007/ BF03005584. 15. Jannetto PJ, Bratanow NC. Pharmacogenomic considerations in the opioid management of pain. Genome Med. 2010;2(9):66. doi:10.1186/gm187. 16. Portenoy RK. Current pharmacotherapy of chronic pain. J Pain Symptom Manage. 2000;19(1):S16–S20. doi:10.1016/s08853924(99)00124-4 Suppl. 17. Reder RF. Opioid formulations: tailoring to the needs in chronic pain. Eur J Pain. 2001;5(Suppl A):109–111. doi:10.1053/eujp. 2001.0291. 18. Mercadante S, Fulfaro F. Alternatives to oral opioids for cancer pain. Oncol (Williston Park). 1999;13(2):215–220 225. discussion 226-229. 19. Polak JM, Bloom SR. Neuropeptides of the gut: a newly discovered major control system. World J Surg. 1979;3(4):393–405. 20. De Luca A, Coupar IM. Insights into opioid action in the intestinal tract. Pharmacol Ther. 1996;69(2):103–115. doi:10.1016/01637258(95)02053-5.

21. Choi YS, Billings JA. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage. 2002;24(1):71–90. doi:10.1016/s08853924(02)00424-4. 22. Radbruch L, Sabatowski R, Loick G, et  al. Constipation and the use of laxatives: a comparison between transdermal fentanyl and oral morphine. Palliat Med. 2000;14(2):111–119. doi:10.1191/026921600671594561. 23. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-fentanyl comparative trial group. J Pain Symptom Manage. 1997;13(5):254–261. doi:10.1016/s0885-3924(97)00082-1. 24. Agra Y, Sacristán A, González M, et al. Efficacy of senna versus lactulose in terminal cancer patients treated with opioids. J Pain Symptom Manage. 1998;15(1):1–7. doi:10.1016/S0885-3924(97)00276-5. 25. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;18(4):S3–13. doi:10.1097/00002508-200207001-00002 Suppl. 26. Becker G, Galandi D, Blum HE. Peripherally acting opioid antagonists in the treatment of opiate-related constipation: a systematic review. J Pain Symptom Manage. 2007;34(5):547–565. doi:10.1016/j.jpainsymman.2006.12.018. 27. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Phys. 2008;11(2 Suppl):S105–S120. 28. Simoneau II, Hamza MS, Mata HP, et al. The cannabinoid agonist WIN55,212-2 suppresses opioid-induced emesis in ferrets. Anesthesiol. 2001;94(5):882–887. doi:10.1097/00000542-20010500000029. 29. Foss JF, Bass AS, Goldberg LI. Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs. J Clin Pharmacol. 1993;33(8):747–751. doi:10.1002/j.1552-4604.1993. tb05618.x. 30. Frederich ME. Nonpain symptom management. Prim Care. 2001; 28(2):299–316. doi:10.1016/s0095-4543(05)70023-3. 31. Cherny NI, Portenoy RK. The management of cancer pain. CA Cancer J Clin. 1994;44(5):263–303. doi:10.3322/canjclin.44.5.263. 32. Ballantyne JC. Opioid therapy in chronic pain. Phys Med Rehabil Clin N Am. 2015;26(2):201–218. doi:10.1016/j.pmr.2014.12.001. 33. Charuluxananan S, Kyokong O, Somboonviboon W, et al. Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg. 2001;93(1):162–165. doi:10.1097/00000539-200107000-00032. 34. Charuluxananan S, Kyokong O, Somboonviboon W, et al. Nalbuphine versus ondansetron for prevention of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg. 2003;96(6):1789– 1793. doi:10.1213/01.ane.0000066015.21364.7d table of contents. 35. Zacny JP. Should people taking opioids for medical reasons be allowed to work and drive? Addiction. 1996;91(11):1581–1584. 36. Kurita GP, de Mattos Pimenta CA, Braga PE, et al. Cognitive function in patients with chronic pain treated with opioids: characteristics and associated factors. Acta Anaesthesiol Scand. 2012;56(10):1257– 1266. doi:10.1111/j.1399-6576.2012.02760.x. 37. Bruera E, Macmillan K, Hanson J, MacDonald NR. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain. 1989;39(1):13–16. doi:10.1016/03043959(89)90169-3. 38. Sabatowski R, Schwalen S, Rettig K, Herberg KW, Kasper SM, Radbruch L. Driving ability under long-term treatment with transdermal fentanyl. J Pain Symptom Manage. 2003;25(1):38–47. doi:10.1016/s0885-3924(02)00539-0. 39. Pergolizzi Jr JV, Taylor Jr R, LeQuang JA, et al. Driving under the influence of opioids: what prescribers should know. J Opioid Manag. 2018;14(6):415–427. doi:10.5055/jom.2018.0474. 40. Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Pater son JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case-control study. PLOS Med. 2017;14(10):e1002396. doi:10.1371/journal. pmed.1002396.

702.e1

702.e2

References

41. McAnally H, Bonnet U, Kaye AD. Gabapentinoid benefit and risk stratification: mechanisms over myth. Pain Ther. 2020;9(2):441–452. doi:10.1007/s40122-020-00189-x. 42. Algera MH, Kamp J, van der Schrier R, et  al. Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal. Br J Anaesth. 2019;122(6):e168–e179. doi:10.1016/j.bja.2018.12.023. 43. Peterson PK, Molitor TW, Chao CC. The opioid-cytokine connection. J Neuroimmunol. 1998;83(1-2):63–69. doi:10.1016/s01655728(97)00222-1. 44. Bawor M, Bami H, Dennis BB, et al. Testosterone suppression in opioid users: a systematic review and meta-analysis. Drug Alcohol Depend. 2015;149:1–9. doi:10.1016/j.drugalcdep.2015.01.038. 45. Antony T, Alzaharani SY, El-Ghaiesh SH. Opioid-induced hypogonadism: pathophysiology, clinical and therapeutics review. Clin Exp Pharmacol Physiol. 2020;47(5):741–750. doi:10.1111/14401681.13246. 46. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008;9(1):28–36. doi:10.1016/j.jpain.2007.08.005. 47. Daniell HW. DHEAS deficiency during consumption of sustainedaction prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production. J Pain. 2006;7(12):901–907. doi:10.1016/j.jpain.2006.04.011. 48. Oltmanns KM, Fehm HL, Peters A. Chronic fentanyl application induces adrenocortical insufficiency. J Intern Med. 2005;257(5):478– 480. doi:10.1111/j.1365-2796.2005.01483.x. 49. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of longterm intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85(6):2215–2222. doi:10.1210/jcem.85.6.6615. 50. Pickworth WB, Neidert GL, Kay DC. Morphinelike arousal by methadone during sleep. Clin Pharmacol Ther. 1981;30(6):796–804. doi:10.1038/clpt.1981.240. 51. Cao M, Javaheri S. Effects of chronic opioid use on sleep and wake. Sleep Med Clin. 2018;13(2):271–281. doi:10.1016/j. jsmc.2018.02.002. 52. Dimsdale JE, Norman D, DeJardin D, Wallace MS. The effect of opioids on sleep architecture. J Clin Sleep Med. 2007;3(1):33–36. 53. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/ or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9(4):444–459. doi:10.1111/j.1526-4637. 2007.00370.x. 54. Price DD, Mayer DJ, Mao J, Caruso FS. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage. 2000;19(1):S7–11. doi:10.1016/ s0885-3924(99)00121-9 Suppl. 55. Kreutzwiser D, Tawfic QA. Expanding role of NMDA recep tor antagonists in the management of pain. CNS Drugs. 2019;33(4):347–374. doi:10.1007/s40263-019-00618-2. 56. Zhao M, Joo DT. Subpopulation of dorsal horn neurons dis plays enhanced N-methyl-D-aspartate receptor function after chronic morphine exposure. Anesthesiol. 2006;104(4):815–825. doi:10.1097/00000542-200604000-00028. 57. Adam F, Bonnet F, Le Bars D. Tolerance to morphine analgesia: evidence for stimulus intensity as a key factor and complete reversal by a glycine site-specific NMDA antagonist. Neuropharmacol. 2006;51(2):191–202. doi:10.1016/j.neuropharm.2006.03.018. 58. Tucker AP, Kim YI, Nadeson R, Goodchild CS. Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain. BMC Anesthesiol. 2005;5(1):2. doi:10.1186/1471-2253-5-2. 59. Park PJ, Makhni MC, Cerpa M, Lehman RA, Lenke LG. The role of perioperative ketamine in postoperative pain control following spinal surgery. J Spine Surg. 2020;6(3):591–597. doi:10.21037/jss-19-306.

60. Galer BS, Lee D, Ma T, Nagle B, Schlagheck TG. MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, doubleblind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain. 2005;115(3):284–295. doi:10.1016/j.pain.2005.03.004. 61. Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162(8):1403–1413. doi:10.1176/appi.ajp.162.8.1403. 62. Lossignol DA, Obiols-Portis M, Body JJ. Successful use of ketamine for intractable cancer pain. Support Care Cancer. 2005;13(3):188–193. doi:10.1007/s00520-004-0684-4. 63. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004;99(2):482–495. doi:10.1213/01. ANE.0000118109.12855.07 table of contents. 64. Treillet E, Laurent S, Hadjiat Y. Practical management of opioid rotation and equianalgesia. J Pain Res. 2018;11:2587–2601. doi:10.2147/JPR.S170269. 65. Bozarth MA, Wise RA. Neural substrates of opiate reinforcement. Prog Neuropsychopharmacol Biol Psychiatry. 1983;7(4-6):569–575. doi:10.1016/0278-5846(83)90027-1. 66. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–773. doi:10.1016/ S2215-0366(16)00104-8. 67. Maldonado R. Participation of noradrenergic pathways in the expression of opiate withdrawal: biochemical and pharmacological evidence. Neurosci Biobehav Rev. 1997;21(1):91–104. doi:10.1016/0149-7634(95)00061-5. 68. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2015;90(6):828–842. doi:10.1016/j.mayocp.2015.04.003. 69. Wilsey BL, Fishman SM. Minor and short-acting opioids. In: Benzon HT, Raja SN, Molloy RE (eds). Essentials of Pain and Regional Anesthesia. Philadelphia, PA: Elsevier/Churchill Livingstone; 1999:107–112. 70. Kosten TR, Baxter LE. Review article: effective management of opioid withdrawal symptoms: a gateway to opioid dependence treatment. Am J Addict. 2019;28(2):55–62. doi:10.1111/ajad.12862. 71. American Society of Addiction Medicine. Public policy statement on definitions related to the use of opioids in pain treatment. American Society of Addiction Medicine. J Addict Dis. 1998;17(2):129–133. 72. Cheatle MD. Prescription opioid misuse, abuse, morbidity, and mortality: balancing effective pain management and safety. Pain Med. 2015;16(Suppl 1):S3–S8. doi:10.1111/pme.12904. 73. Covington EC, Argoff CE, Ballantyne JC, et  al. Ensuring patient protections when tapering opioids: consensus panel recommendations. Mayo Clin Proc. 2020;95(10):2155–2171. doi:10.1016/j. mayocp.2020.04.025. 74. Arkinstall W, Sandler A, Goughnour B, Babul N, Harsanyi Z, Darke AC. Efficacy of controlled-release codeine in chronic nonmalignant pain: a randomized, placebo-controlled clinical trial. Pain. 1995;62(2):169–178. doi:10.1016/0304-3959(94)00262-D. 75. Potter M, Schafer S, Gonzalez-Mendez E, et al. Opioids for chronic nonmalignant pain. Attitudes and practices of primary care physicians in the UCSF/Stanford collaborative research network. University of California, San Francisco. J Fam Pract. 2001;50(2):145–151. 76. Eckhardt K, Li S, Ammon S, Schänzle G, Mikus G, Eichelbaum M. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain. 1998;76(1-2):27–33. doi:10.1016/ s0304-3959(98)00021-9. 77. Susce MT, Murray-Carmichael E, de Leon J. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(7):1356–1358. doi:10.1016/j.pnpbp.2006.03.018.

References 702.e3

78. Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN. Mu Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res. 1998;54(2):321–326. doi:10.1016/s0169-328x(97)00353-7. 79. Peterson GM, Randall CT, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol. 1990;38(2):121–124. doi:10.1007/BF00265969. 80. Mahajan G, Fishman SM, et  al. Major opioids in pain management. In: Benzon HT, Raja SN, Molloy RE, et al (eds). Essentials of Pain and Regional Anesthesia. Philadelphia, PA: Elsevier/Churchill Livingstone; 2011:94–105. 81. Cone EJ, Heit HA, Caplan YH, Gourlay D. Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine. J Anal Toxicol. 2006;30(1):1–5. doi:10.1093/ jat/30.1.1. 82. Kalso E. Oxycodone. J Pain Symptom Manage. 2005;29(5 Suppl): S47–S56. doi:10.1016/j.jpainsymman.2005.01.010. 83. Karunatilake H, Buckley NA. Serotonin syndrome induced by fluvoxamine and oxycodone. Ann Pharmacother. 2006;40(1):155– 157. doi:10.1345/aph.1E671. 84. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer. 2001;9(2):84–96. doi:10.1007/s005200000183. 85. Coda B, Tanaka A, Jacobson RC, Donaldson G, Chapman CR. Hydromorphone analgesia after intravenous bolus administration. Pain. 1997;71(1):41–48. doi:10.1016/s0304-3959(97)03336-8. 86. Sandler A. Transdermal fentanyl: acute analgesic clinical studies. J Pain Symptom Manage. 1992;7(3 Suppl):S27–S35. doi:10.1016/0885-3924(92)90050-r. 87. Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncol. 2001;2(3):165–172. doi:10.1016/S1470-2045(00)002588. 88. Lichtor JL, Sevarino FB, Joshi GP, Busch MA, Nordbrock E, Ginsberg B. The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain. Anesth Analg. 1999;89(3):732– 738. doi:10.1097/00000539-199909000-00038. 89. Kristensen K, Blemmer T, Angelo HR, et al. Stereoselective pharmacokinetics of methadone in chronic pain patients. Ther Drug Monit. 1996;18(3):221–227. doi:10.1097/00007691-19960600000001. 90. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother. 2005;19(4):13–24. 91. Fishman SM, Wilsey B, Mahajan G, Molina P. Methadone reincarnated: novel clinical applications with related concerns. Pain Med. 2002;3(4):339–348. doi:10.1046/j.1526-4637.2002.02047.x. 92. Ahmad T, Valentovic MA, Rankin GO. Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics. Biochem Pharmacol. 2018;153:196–204. doi:10.1016/j.bcp.2018.02.020.

93. Lev R, Petro S, Lee A, et al. Methadone related deaths compared to all prescription related deaths. Forensic Sci Int. 2015;257:347–352. doi:10.1016/j.forsciint.2015.09.021. 94. Walker PW, Klein D, Kasza L. High dose methadone and ventricular arrhythmias: a report of three cases. Pain. 2003;103(3):321– 324. doi:10.1016/S0304-3959(02)00461-X. 95. Behzadi M, Joukar S, Beik A. Opioids and cardiac arrhythmia: a literature review. Med Princ Pract. 2018;27(5):401–414. doi:10.1159/000492616. 96. Gil M, Sala M, Anguera I, et al. QT prolongation and torsades de pointes in patients infected with human immunodeficiency virus and treated with methadone. Am J Cardiol. 2003;92(8):995–997. doi:10.1016/s0002-9149(03)00906-8. 97. Noori SA, Aiyer R, Yu J, White RS, Mehta N, Gulati A. Nonopioid versus opioid agents for chronic neuropathic pain, rheumatoid arthritis pain, cancer pain and low back pain. Pain Manag. 2019;9(2):205–216. doi:10.2217/pmt-2018-0052. 98. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and metaanalysis. Lancet Neurol. 2015;14(2):162–173. doi:10.1016/S14744422(14)70251-0. 99. Chen YP, Chen SR, Pan HL. Effect of morphine on deep dorsal horn projection neurons depends on spinal GABAergic and glycinergic tone: implications for reduced opioid effect in neuropathic pain. J Pharmacol Exp Ther. 2005;315(2):696–703. doi:10.1124/ jpet.105.091314. 100. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352(13):1324–1334. doi:10.1056/NEJMoa042580. 101. Bykov K, Bateman BT, Franklin JM, Vine SM, Patorno E. Association of gabapentinoids with the risk of opioid-related adverse events in surgical patients in the United States. JAMA Netw Open. 2020;3(12):e2031647. doi:10.1001/jamanetworkopen. 2020.31647. 102. Fishman SM. Responsible Opioid Prescribing: A Clinician’s Guide. 2nd ed. Washington DC: Waterford Life Sciences; 2014. 103. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med. 2005;6(2):107–112. doi:10.1111/j.15264637.2005.05031.x. 104. Federation of State Medical Boards of The United States. 2017 guidelines for the chronic use of opioid analgesics. Available at: http://www.fsmb.org/siteassets/advocacy/policies/opioid_guidelines_as_adopted_april-2017_final.pdf.

49

Minor Analgesics: Non-Opioid and Opioid Formulations

STEVEN P. STANOS, MARK D. TYBURSKI, SAGAR S. PARIKH

The use of naturally occurring plant material for the relief of pain dates back to early times. Advances in antipyretic and analgesic medications began in the late 1800s with the development of salicylic acid, antipyrine, phenacetin, and acetaminophen (APAP).1 These basic medications are still used today to various degrees in both over-the-counter (OTC) and prescription preparations—the minor analgesics salicylic acid and APAP are widely marketed and heavily consumed. Minor analgesics for acute and chronic pain include several prescription and OTC agents, which may be useful in isolation or as adjuvants in a more comprehensive multimodal pharmacologic approach. Many including minor analgesics, OTC medicines include a growing market area for managing acute and chronic pain conditions. Research has demonstrated that at least 80% of adults use OTC medicines as a first response to minor ailments, with great availability of OTCs in the approximately 54,000 pharmacies in the United States and more than 750,000 retail stores that carry these products.2 A population survey has reported that the use of OTC medications, many of which include minor analgesics, account for the most common method of relieving pain (53%). This is closely followed by physical exercise (52%) and prescription medications (35%).3 The minor analgesics reviewed in this chapter include oral APAP, opioid combination preparations (i.e. codeine, propoxyphene, hydrocodone, oxycodone, and tramadol), tapentadol, and buprenorphine products for chronic pain (buccal films and transdermal patch systems), steroids, and caffeine, as well as topical compounds and delivery systems. See the chapters in this text that discuss opioids, anti-convulsants, anti-depressants, and nonsteroidal anti-inflammatory drugs (NSAIDs) for complete information on these topics (Chapters 48, 53, 54, 55, 56, and 57). Additional combination OTC formulations with minor analgesics include convenience combinations—those that contain aspirin, APAP, or ibuprofen plus other remedies such as nasal decongestants, antihistamines, cough suppressants, or antacids. These medications help treat the sequelae of a primary illness (e.g. cold and flu symptoms, insomnia, cough) and any pain symptoms that may coexist.4 Prescribing habits regarding the use of analgesics for the treatment of various musculoskeletal conditions continue to evolve. Caudill-Slosberg and colleagues5 compared prescribing habits between 1980 and 1981 with those between 1999 and 2000 and demonstrated a significant increase in patients receiving prescriptions for acute and chronic musculoskeletal pain. Increases were seen in the use of NSAIDs and cyclooxygenase-2 (COX-2) agents, as well as more potent opioids, including combination opioid preparations containing APAP and NSAIDs.

Minor analgesics are used widely, with reported prevalence rates of twice-weekly use of approximately 8.7% for prescription drugs and 8.8% for OTC analgesics. Analgesics are usually the largest selling group of OTC medications in several population studies. Daily use was more common for prescribed analgesics, whereas OTC analgesics were used a few times per week.6,7 Among prescription and OTC medications, APAP, ibuprofen, and aspirin were the most commonly used (17%–23% of the population).8 Use of analgesics, many of which include minor agents, accounts for a significant amount of healthcare dollars. In a population study, analgesic cost ranked second behind diagnostic imaging in expenditures for the treatment of acute low back pain.7 Chronic use of prescription and OTC analgesics (i.e. aspirin, non-aspirincontaining NSAIDs, and APAP) may continue for longer than one year. In the same survey, approximately 2.3 million adults reported using non-aspirin-containing NSAIDs, and 2.6 million used APAP on a frequent basis for longer than five years.9 This widespread use occurs despite general knowledge of the increased risk for gastrointestinal (GI), renal, and cardiac toxicity with short-term and chronic use. Unfortunately, the perception remains that as a class of medications, OTC and prescription NSAIDs are relatively safe. This misbelief leads to frequent inappropriate use and the potential for serious adverse events.10 The increased availability and marketing of OTC agents have probably contributed to patient misuse, with consumers still being unaware of the potentially catastrophic risks associated with their use: 60% of people cannot identify the active ingredient in their analgesics, and 40% of Americans believe that OTC drugs are too weak to cause significant harm.11 The use of OTC and prescription analgesics is not only confined to the outpatient setting. Significant use of these agents in nursing home facilities was reported in a group of Medicare beneficiaries during 2001. Patients averaged 8.8 unique medications per month, including 2.9 OTC medications. Of these subjects, 70% used nonopioid OTC analgesics and 19.0% used non-opioid prescription analgesics.12

Specific Drugs Minor Opioids Minor opioids are defined as analgesic combination products with codeine, propoxyphene, hydrocodone, or oxycodone, and dual-mechanism opioid products, including tramadol and tapentadol. Additionally, the chapter will also review buprenorphine 703

Step 3

Opioid for moderate to severe pain Plus non-opioid with/without adjuvant analgesic

Step 2

Opioid for mild to moderate pain Plus non-opioid with/without adjuvant analgesic

Step 1

Non-opioid with/without adjuvant analgesic

Moderate to severe pain

Mild to moderate pain

Mild pain

Signs of toxicity or severe side effects, reduce dose or move down one step

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

Pain persisting, move up one step

704

• Figure 49.1  World Health Organization analgesic ladder. (Adapted from World Health Organization. Cancer Pain Relief. Geneva: World Health Organization; 1990.) formulations for the management of chronic pain, including buccal and transdermal systems or patches. These products continue to account for a large percentage of prescriptions written for chronic and persistent pain conditions. Combination opioid analgesics—compounds containing APAP or anti-inflammatory TABLE 49.1

medications—make up a significant number of opioids prescribed by primary care physicians and pain specialists. Combination analgesics are advocated in several treatment guidelines, including the three-step analgesic ladder of the World Health Organization (WHO) (step 2; Fig. 49.1).13,14 Opioid therapy increased dramatically between 1999 and 2010 with a decrease in prescribing in 2013, preceding the Centers for Disease Control and Prevention (CDC) Guideline on prescribing opioids for acute and chronic pain. Within that period, a substitution of opioids for non-opioid analgesics between 2003 and 2006 may have emerged in response to the emerging evidence of cardiovascular risks associated with non-opioid analgesics, primarily NSAIDs.15 Since the 1990s, the use of minor analgesic combinations containing oxycodone and hydrocodone continued to increase, whereas the use of those containing codeine declined. Clinic type (e.g. primary care, spine center, pain center), geographic, and socioeconomic variables may also affect prescribing practices.16 Opioid analgesics as a class can be categorized into three chemical groups: (1) synthetic phenylpiperidines (e.g. meperidine, fentanyl), (2) synthetic pseudopiperidines (e.g. methadone, propoxyphene), and (3) naturally occurring alkaloids derived directly from the poppy seed (e.g. morphine, codeine, thebaine) and their semisynthetic derivatives (e.g. hydromorphone, oxycodone, oxymorphone).17 This chapter reviews codeine, oxycodone, hydrocodone, and tramadol combination products, as well as formulations of tapentadol and buprenorphine products indicated for the treatment of chronic pain (Tables 49.1 and 49.2).

Minor and Short-Acting Opioids

Class

Name

Adult Dose

Natural opium alkaloids

Codeine with acetaminophen (APAP) or acetylsalicylic acid (ASA) (Tylenol No. 2, No. 3, No. 4; Empirin No. 3, No. 4; Capital with Codeine; Aceta with Codeine; Fioricet with Codeine; Fiorinal with Codeine)

PO: 15–60 mg q4h (max daily APAP-ASA dose, 4 g)

Phenanthrene derivatives

Hydrocodone plus ASA or APAP (Lortab, Lortab ASA, Vicodin, Norco, Vicoprofen, ZTuss, P-V-Tussin, Tussafed HC)

Diphenylheptane derivative

Half-Life (Onset)

Mechanism of Action

Other

2.5–3.5 h (30–60 min)

Opioid agonist activity at multiple receptors—µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects)

Compared with morphine—decreased analgesia, constipation, respiratory distress, sedation, emesis, and physical dependence; increased antitussive effects

PO: 5–10 mg q4–6h (max dose, 4 g)

3.8 h (10–30 min)

Opioid agonist activity at multiple receptors—µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects)

Compared with morphine equivalent analgesia—respiratory depression and physical dependency; equivalent antitussive effects

Oxycodone (with or without APAP or ASA) (OxyIR, Roxicodone); Oxycodone plus ASA (Percodan, Endodan, Roxiprin); Oxycodone plus APAP (Percocet, Endocet, Tylox, Roxicet, Roxilox)

PO: 5–30 mg q4–6h (4 g max dose of ASA/ APAP); sustainedrelease: 10/10–160 mg q12h

2–5 h (10-15 min)

Opioid agonist activity at multiple receptors: µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects)

Compared with morphine— more potent analgesia, constipation, antitussive effects, respiratory depression, sedation, emesis, and physical dependence

Propoxyphene, with or without APAP (Darvon, Darvon-N); Propoxyphene plus APAP (Darvocet A500, Propacet 100)

PO: 65 mg q4h (max, 390 mg/day); napsylate, 100 mg q4h (max, 600 mg/day)

6–12 h (15–60 min)

Opioid agonist activity at multiple receptors: µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects)

Compared with morphine — less analgesia, sedation, emesis, respiratory depression, and physical dependence

Vicodin, Lorcet-HD, Lortab, Norco, Maxidone, Anexsia Percocet, Endocet, Tylox, Roxicet, Roxilox

Aspirin/codeine phosphate

Hydrocodone bitartrate/ acetaminophen

Oxycodone/ acetaminophen

Acetylsalicylic acid/natural opium alkaloids

Paraaminophenol derivatives/ phenanthrene derivatives

Darvocet-N 50, Darvocet-N 100, Darvocet A500, Propacet 100

Propoxyphene napsylate/ acetaminophen

One to two tablets q4–6h

One to two tablets q4–6h

One tablet q4–6h

One to two tablets q4–6h

One tablet q4–6h

One tablet q4–6h

One to two tablets q4–6h

One to two tablets q4–6h

One to two tablets q4h

Comments

Structurally related to methadone; propoxyphene napsylate, max, 600 mg daily

Structurally related to methadone; propoxyphene HC1, max, 390 mg daily

Structurally related to methadone; propoxyphene HC1, max, 390 mg daily

Max dosage of ibuprofen, 2400–3200 mg daily

Marketed for short-term management of acute pain; NSAIDs may increase the risk for serious cardiovascular thrombotic events, myocardial infarction, stroke

Aspirin, max, 4000 mg daily

Acetaminophen, max, 4000 mg daily

Dosage typically limited by acetaminophen, max, 4000 mg daily

Codeine phosphate, max, 360 mg daily

Codeine phosphate, max, 360 mg daily; acetaminophen, max, 4000 mg daily

Codeine phosphate, max, 360 mg daily; acetaminophen, max, 4000 mg daily

Propoxyphene, 6–12 h; norpropoxyphene, 30–36 h; acetaminophen, 1–4 h

Propoxyphene, 6–12 h; norpropoxyphene, 30–36 h; aspirin, 2.5–3.5 h; caffeine, 3–6 h

Propoxyphene, 6–12 h; norpropoxyphene, 30–36 h; acetaminophen, 1–4 h

Oxycodone, 3.1–3.7 h; ibuprofen, 1.8–2.6 h

Hydrocodone, 3.5–4.1 h; ibuprofen, 4–6 h

Aspirin, 2.5–3.5 h; oxycodone, 3.1–3.7 h

Acetaminophen, 1–4 h; oxycodone, 3.1–3.7 h

Hydrocodone, 3.5–4.1 h

Aspirin, 2.5–3.5 h; codeine, 2.5–3 h

Acetaminophen, 1–4 h; codeine, 2.5–3 h

Acetaminophen, 1–4 h; codeine, 2.5–3 h

Half-Life

 

Minor Analgesics: Non-Opioid and Opioid Formulations

NSAIDs, Nonsteroidal anti-inflammatory drugs.

65/389/32.4 mg (tablet)

Darvon Compound 65

Propoxyphene HC1/aspirin/ caffeine

50/325 mg (N 50), 100/650 mg (N 100), 100/500 mg (A500) (tablets)

65/650 mg (tablet)

5/400 mg (tablet)

7.5/200 mg (tablet)

4.8/325 mg (tablet)

5/325 mg, 7.5/325 mg, 5/500 mg (Tylox), 7.5/500 mg, 10/325 mg, 10/650 mg (tablets); 5/500 mg (caplets; Roxicet); 5/325 mg/5 mL (solution) (Roxicet)

2.5/500 mg, 5/500 mg, 7.5/325 mg, 7.5/500 mg, 7.5/650 mg, 7.5/750 mg, 10/325 mg, 10/500 mg, 10/650 mg, 10/660 mg, 10/750 mg (tablets)

325/30 mg, 325/60 mg (tablets)

30–60 mg codeine q4–6h

650/30 mg (tablets)

Typical Dose Elixir—children 3.5

18–36

Prednisolone

5

4

0.6

2.1–3.5

18–36

Prednisone

5

4

0.6

3.4–3.8

18–36

Triamcinolone

4

5

0

2–5

18–36

Dexamethasone

0.75

20–30

0

3–4.5

36–54

Betamethasone

0.6

20–30

0

3–5

36–54

∗

Clinically—sodium and water retention, potassium depletion.

Adapted from Jacobs JWD, Bijlsma JWJ. Glucocorticoid therapy. In: W Kelly, E Harris, S Ruddy, et al. (eds). Kelly’s Textbook of Rheumatology. 7th ed. Philadelphia: Saunders; 2005: Table 57-1.)

 

CHAPTER 49

TABLE 49.11

Commonly Prescribed Oral Glucocorticoids Available Dose Form

Agent

Trade Name

Methylprednisolone

Medrol

2, 4, 8, 16, 24, 32 mg tablets

Prednisone

Deltasone, Sterapred

2.5, 5, 10, 20, 50 mg tablets

Prednisone Intensol (oral concentrate)

5 mg/mL

Decadron

0.25, 0.5, 0.75, 1.5, 4, 8 mg tablets

Decadron elixir (oral concentrate)

0.5 mg/5 mL

Dexamethasone

• Box 49.4   Common Glucocorticoid Dosing Schedules • Prednisone taper—prednisone, 10 mg tablets • Three tablets PO bid × four days, two tablets PO bid × three days, one tablet PO bid × three days • Medrol Dosepak—methylprednisolone, 4 mg tablets • Day one: two tablets before breakfast, one tablet after lunch and dinner, and two tablets at bedtime (total = six tablets). If given later in the day, may take all six tablets at once or in divided doses • Day two: one tablet before breakfast, one tablet after lunch and dinner, and two tablets at bedtime • Day three: same as day two, except one tablet at bedtime • Day four: one tablet before breakfast, after lunch, and at bedtime • Day five: one tablet after breakfast and at bedtime • Day six: one tablet after breakfast • Dexamethasone taper—dexamethasone, 8 mg tablets • Tapering schedule over seven days: 64, 32, 24, 16, 8, 8, 8 mg

Prednisone use during pregnancy is schedule D during the first trimester and schedule C in the second and third trimesters. First trimester exposure to systemic corticosteroids (category C) has been associated with intrauterine growth retardation and an increased incidence of cleft lip, with or without cleft palate. If necessary, the maternal benefits of short courses of oral corticosteroids may outweigh the fetal risks when given beyond the first trimester.165

Clinical Use Oral corticosteroids have a limited role in the treatment of painful conditions. They may be useful in the treatment of acute painful inflammatory conditions, including CRPS, carpal tunnel syndrome, rotator cuff arthropathy-adhesive capsulitis, and painful cervical or lumbar radiculopathy. Steroids have been and continue to be administered by multiple routes for the treatment of CRPS. An animal study of the effects of chronic methylprednisolone treatment on the rat CRPS type 1 model (tibia fracture) has revealed that glucocorticoids reverse hind paw edema and warmth after fracture, with persistent effects occurring after discontinuation of treatment. However, glucocorticoid treatment does not affect the allodynia, hind paw unweighting, or periarticular bone loss observed after tibia fracture.166 Early reports reported success with systemic steroids.167 Christensen and coworkers160 studied 23 patients and reported that 30 mg/day of oral prednisone is

Minor Analgesics: Non-Opioid and Opioid Formulations

717

significantly better than placebo based on their stated clinical outcome measures. Braus and colleagues167 studied the effects of methylprednisolone, 32 mg/day for two weeks, followed by a taper over two weeks, for the treatment of CRPS in post-stroke patients. This randomized study showed a significant clinical improvement in the steroid-treated patients at four weeks. More recent studies showed the efficacy of oral steroids in CRPS. Jamroz et al. treated CRPS patients with a typical prednisone regimen (60 mg followed by a taper of 5 mg per day until 20 mg, 40 mg before the taper was used in elderly, adolescent, and diabetic patients).168 Of the 39 patients, 19 (49%) reported complete pain relief, and 17 patients reported functional recovery. They noted that earlier treatment resulted in better outcomes, confirming an earlier study that showed limited efficacy of steroids in treating CRPS of more than three months.169 It appears that a low dose oral steroid regimen (200 mg total dose: 30 mg for three days, 20 mg over three days, 10 mg for three days, 5 mg from day ten to day 14, then discontinued) is comparable to that of a high-dose regimen (450 mg total dose) in alleviating symptoms in patients with CRPS I.170 The use of minor analgesics in the cancer pain population is common. The most commonly used opioid co-analgesics are NSAIDs and APAP, but up to 39% of cancer patients take various types of corticosteroids, with dexamethasone being the most common formulation. Conditions being treated include breast, lung, and colorectal cancer. Studies have documented the usefulness of corticosteroids for the rational polypharmacy of cancer pain management.161,171,172 Efficacy has been demonstrated for neuropathic pain caused by tumor compression (malignant compression of the spinal cord or brachial or lumbosacral plexus), tumor-induced bone pain, and hepatic capsule distention secondary to liver metastases.156,173 In addition to NSAIDs and disease-modifying antirheumatic drugs, low dose oral corticosteroids may also help manage joint symptoms caused by chemotherapy-induced arthropathy.174 Recruitment of cancer pain patients can be difficult.175 Despite the lack of controlled clinical trials, corticosteroids are frequently prescribed in an adjunctive role for palliation and control of the side effects of chemotherapy. Therefore these agents may play a dual role in selected patients. Many believe that corticosteroids may help in preventing chemotherapy-induced nausea and emesis and hypersensitivity reactions. In addition, they may also help ameliorate asthenic symptoms and fatigue, as well as stimulate appetite.158,176 Any effect of oral steroids on cancer-related dyspnea is limited by the low quality of published studies.177 The use of oral glucocorticoids in the form of methylprednisolone or prednisone burst or taper is common practice in the acute treatment of disk herniation with radicular pain complaints. Despite a significant increase in studies evaluating the efficacy of fluoroscopically guided epidural steroid injections (see Chapter 65), there is a paucity of reports on the usefulness of oral or systemic corticosteroids in this pain population. In a prospective, double-blind, randomized controlled trial evaluating the use of oral corticosteroids for the treatment of radicular pain, a tapering dose of dexamethasone over seven days was not superior to a placebo for early or long-term relief of lumbosacral radicular pain.178 However, dexamethasone was superior to placebo in reducing stretch-invoked pain during the straight-leg raise test. This study did allow the concurrent use of meperidine, oxycodone, and APAP for analgesia.178 Systemic dexamethasone taper via the intramuscular route has been studied to a limited degree, with conflicting results.179,180 The rationale for the use of oral corticosteroids is based on the observance that pro-inflammatory

718

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

mediators and neurosensitizing chemicals are released from the damaged intervertebral disk.181,182 There is a close relationship between injury and pain with most musculoskeletal injuries. Therefore individual treatments in a comprehensive management program may serve dual purposes— reducing inflammation to control local damage and concurrently reducing pain. Although few trials have evaluated the efficacy of oral corticosteroids for musculoskeletal injuries, clinical practice reveals that their use is widespread. A questionnaire-based study at a national sports medicine conference found that 59% of the physicians prescribe oral corticosteroids for musculoskeletal injuries, with prednisone being the most commonly used.183 The study did not differentiate whether the medication was prescribed specifically for pain or its anti-inflammatory properties, but prescriptions were written equally for acute and chronic conditions. Although the mainstays of treatment of carpal tunnel syndrome include neutral wrist splints, ergonomic evaluation and modification of biomechanics, oral NSAIDs, steroid injections, and surgical release of the transverse carpal ligament, there is evidence to suggest that oral corticosteroids may play a role in the shortterm management of patients with mild to moderate symptoms and in those not interested in or awaiting surgical release of the transverse carpal ligament. Studies have examined varied dosing and duration-of-treatment regimens with prednisolone (ten days to three weeks, doses of up to 25 mg daily). The results suggest that regardless of dosing, the global symptom score is improved in patients treated with oral corticosteroid versus placebo.157 Short-term dosing of oral prednisolone at variable doses has been studied for adhesive capsulitis. Binder and associates184 used 10 mg daily for four weeks, followed by 5 mg daily for two weeks. Night pain was significantly lower in the treatment group at eight weeks. However, by five months, this difference had resolved. Over the total eight-month period, no difference was found in pain at rest or with movement, range of motion, or the cumulative recovery curve between the oral steroid group and the control group, which received no specific therapy. Other studies have evaluated a three-week course of 30 mg prednisolone daily and reported a significant reduction in pain and disability, improved active range of motion, and better participant-rated improvement at three weeks. The improvements were still evident by six weeks, but none of the values were statistically significant. At 12 weeks, the placebo group was favored.158 A review of the treatments for adhesive capsulitis showed steroids as a component of the multimodal management that includes intraarticular steroid injection, physical therapy, manipulation under anesthesia, and arthroscopic capsular release.185 The use of oral corticosteroids for the treatment of rheumatoid arthritis has been studied since 1949 when Hench and coworkers186 showed the efficacy of the treatment in an uncontrolled trial. Although oral corticosteroids may show beneficial effects concerning the radiologic progress of the disease,187 they are more commonly used during episodes of symptomatic flares to control pain or as bridge therapy with slower-acting agents.188,189 A metaanalysis evaluating the effectiveness of low dose prednisolone versus placebo and NSAIDs found that low dose prednisolone (drugs-safety-and availability. 41. Butola S, Rajagopal MR. Ban on dextropropoxyphene is unjustifiable. J Palliat Care. 2015;21:3–7. 42. Benzon HT, Kendall MC, Katz JA, et  al. Prescription patterns of pain medicine physicians. Pain Pract. 2013;13:440–450. 43. Kalso E, Vainio A, Mattila MJ, et  al. Morphine and oxyco done in the management of cancer pain: plasma levels determined by chemical  and radioreceptor assays. Pharmacol Toxicol. 1990;67:322–328. 44. Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther. 1998;64:603–611. 45. Nozaki C, Saitoh A, Kamei J. Characterization of the antino ciceptive effects of oxycodone in diabetic mice. Eur J Pharmacol. 2006;535:145–151. 46. Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain. 1997;73:151–157.

719.e1

719.e2

References

47. Riley J, Ross JR, Rutter D, et  al. No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients. Support Care Cancer. 2006;14:56–64. 48. Lalovic B, Kharasch E, Hoffer C, et al. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther. 2006;79:461–479. 49. Holtman JR, Wala EP. Characterization of the antinociceptive effect of oxycodone in male and female rats. Pharmacol Biochem Behav. 2006;83:100–108. 50. Beaver WT. Analgesic Efficacy of Hydrocodone and its Combinations: A Review. Spring House, PA: Smith Simon; 1988. 51. Hardy JR.Opioids in cancer pain. In: M Davis, P Glare, J Hardy (eds). Hydrocodone. Oxford: Oxford University Press 2009:59–67. 52. Wideman GL, Keffer M, Morris E, et al. Analgesic efficacy of a combination of hydrocodone with ibuprofen in postoperative pain. Clin Pharmacol Ther. 1999;65:66–76. 53. Palangio M, Morris E, Doyle RT, et al. Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of moderate or severe acute low back pain. Clin Ther. 2002;24:87–99. 54. Palangio M, Wideman GL, Keffer M, et al. Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of postoperative obstetric or gynecologic pain. Clin Ther. 2000;22:600–612. 55. Palangio M, Damask MJ, Morris E, et al. Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain. Clin Ther. 2000;22:879–892. 56. Traynor K. FDA advisers support rescheduling of hydrocodone products. Am J Health Syst Pharm. 2013;70:383–384. 57. Bernhardt MB, Taylor RS, Hagan JL, et  al. Evaluation of opioid prescribing after rescheduling of hydrocodone-containing products. Am J Health Syst Pharm. 2017;74:2046–2053. 58. Fleming ML, Driver L, Sansgiry SS, et al. Drug enforcement administration rescheduling of hydrocodone combination products is associated with changes in physician pain management prescribing preferences. J Pain Palliat Care Pharmacother. 2019;33:22–31. 59. Singh DR, Nag K, Shetti AN, Krishnaveni N. Tapentadol hydrochloride: a novel analgesic. Saudi J Anaesth. 2013;7:322–326. 60. Fidman B, Nogid A. Role of tapentadol immediate release (nucynta) in the management of moderate-to-severe pain. Pharm Ther. 2010;35:330–357. 61. Raffa RB, Elling C, Tzschentke TM. Does “strong analgesic” equal “strong opioid?” Tapentadol and the concept of “µ-load. Adv Ther. 2018;35:1471–1484. 62. Lutfy K, Eitan S, Bryant CD, et al. Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci. 2003;23:10331–10337. 63. Pergolizzi J, Böger RH, Budd K, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an international expert panel with focus on the six clinically most often used world health organization step III opioid (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract. 2008;8:287–313. 64. Welsh C, Valadez-Meltzer A. Buprenorphine: a (relatively) new treatment for opioid dependence. Psychiatry. 2005;2:29–39. 65. Khanna IK, Pillarisetti S. Buprenorphine- an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859–870. 66. Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. Pain Ther. 2020;9:41–54. 67. Rauck RL, Potts J, Xiang Q, et al. Efficacy and tolerability of buccal buprenorphine in opioid-naïve patients with moderate to severe chronic low back pain. Postgrad Med. 2016;128:1–11. 68. Conaghan PG, O’Brien CM, Wilson M, et  al. Transdermal buprenorphine plus oral paracetamol vs an oral codeine-paracetamol

combination for osteoarthritis of hip and/or knee: a randomised trial. Osteoarthr Cartil. 2011;19:930–938. 69. Gordon A, Rashiq S, Moulin DE, et al. Buprenorphine transdermal system for opioid therapy in patients with chronic low back pain. Pain Res Manag. 2010;15:169–178. 70. American College of Rheumatology Subcommittee on Osteoarthritis. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology subcommittee on osteoarthritis guidelines. Arthritis Rheum. 2000;43:1905-1915. 71. Pendleton A, Arden N, Dougados M, et  al. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT). Ann Rheum Dis. 2000;59:936–944. 72. Prescott LF. Paracetamol (Acetaminophen): A Critical Bibliographic Review. 2nd ed. Florence, Ky: Routledge 2001. 73. Lucas R, Warner TD, Vojnovic I, et  al. Cellular mechanisms of acetaminophen:  role of cyclo-oxygenase. FASEB J. 2005;19:635– 637. 74. Shen H, Sprott H, Aeschlimann A, et al. Analgesic action of acetaminophen in symptomatic osteoarthritis of the knee. Rheumatology. 2006;45:765–770. 75. Heading RC, Nimmo J, Prescott LF, et  al. The dependence of paracetamol absorption on the rate of gastric emptying. Br J Pharmacol. 1973;47:415–421. 76. Toes MJ, Jones AL, Prescott L. Drug interactions with paracetamol. Am J Ther. 2005;12:56–66. 77. Lauterburg BH. Analgesics and glutathione. Am J Ther. 2002;9:225– 233. 78. Gebauer MG, Nyfort-Hansen K, Henschke PJ, et al. Warfarin and acetaminophen interaction. Pharmacotherapy. 2003;23:109–112. 79. Gadisseur AP, Van Der Meer FJ, Rosendaal FR. Sustained intake of paracetamol (acetaminophen) during oral anticoagulant therapy with coumarins does not cause clinically important INR changes: a randomized double-blind clinical trial. J Thromb Haemost. 2003;1:714–717. 80. Hylek EM, Heiman H, Skates SJ, et  al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998;279:657–662. 81. Kurtovic J, Riordan SM. Paracetamol-induced hepatotoxicity at recommended dosage. J Intern Med. 2003;253:240–243. 82. Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006;43:618–631. 83. Shayiq RM, Roberts DW, Rothstein K, et  al. Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury. Hepatology. 1999;29:451–463. 84. Rumack BH. Acetaminophen misconceptions. Hepatol. 2004;40: 10–15. 85. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272:1845–1850. 86. Smilkstein MJ, Rumack BH. Chronic ethanol use and acute acetaminophen overdose toxicity [abstract]. Clin Toxicol. 1998;36: 476. 87. Thummel KE, Slattery JT, Ro H, et al. Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults. Clin Pharmacol Ther. 2000;67:591–599. 88. Hansten PD, Horn JR.Cytochrome P450 enzymes and drug interactions. In: H Top (ed). Wash 100 Drug Interactions—A Guide to Patient Management. Edmonds: H Publications 2004:157–170. 89. Fored CM, Ejerblad E, Lindblad P, et al. Acetaminophen, aspirin, and chronic renal failure. N Engl J Med. 2001;345:1801–1808. 90. Asero R. Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin disorders. Ann Allergy Asthma Immunol. 1999;82:554–558.

References

91. Curhan GC, Willett WC, Rosner B, et al. Frequency of analgesic use and risk of hypertension in younger women. Arch Intern Med. 2002;162:2204–2208. 92. Dedier J, Stampfer MJ, Hankinson SE, et al. Nonnarcotic analgesic use and the risk of hypertension in US women. Hypertension. 2002;40:604–608 discussion 601. 93. Kurth T, Hennekens CH, Stürmer T, et al. Analgesic use and risk of subsequent hypertension in apparently healthy men. Arch Intern Med. 2005;165:1903–1909. 94. Seppälä E, Laitinen O, Vapaatalo H. Comparative study on the effects of acetylsalicylic acid, indomethacin and paracetamol on metabolites of arachidonic acid in plasma, serum and urine in man. Int J Clin Pharmacol Res. 1983;3:265–269. 95. Bradley JD, Brandt KD, Katz BP, et al. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325:87–91. 96. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2020;72:149–162. 97. Da Costa BR, Reichenbach S, Keller N, et  al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2017;390:e21–e33. 98. Case JP, Baliunas AJ, Block JA. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, doubleblind, placebo-controlled comparison trial with diclofenac sodium. Arch Intern Med. 2003;163:169–178. 99. Pincus T, Koch G, Lei H, et al. Patient preference for placebo, acetaminophen (paracetamol) or celecoxib efficacy studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis. Ann Rheum Dis. 2004;63:931–939. 100. Towheed TE, Judd MJ, Hochberg MC, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2003;2:CD004257. 101. Brandt KD, Mazzuca SA, Buckwalter KA. Acetaminophen, like conventional NSAIDs, may reduce synovitis in osteoarthritic knees. Rheumatology. 2006;45:1389–1394. 102. Ennis ZN, Dideriksen D, Vaegter HB, Handberg G, Pottegård A. Acetaminophen for chronic pain: a systematic review on efficacy. Basic Clin Pharmacol Toxicol. 2016;118:184–189. doi:10.1111/ bcpt.12527. 103. Roth SH. Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis. J Rheumatol. 1998;25:1358–1363. 104. Hennies HH, Friderichs E, Schneider J. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung. 1988;38:877–880. 105. Bianchi M, Rossoni G, Sacerdote P, et al. Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol. 1999;13:220–225. 106. Bianchi M, Broggini M, Balzarini P, et al. Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol. Int Immunopharmacol. 2003;3:1901–1908. 107. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43:879–923. 108. Gillen C, Haurand M, Kobelt DJ, et al. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol. 2000;362:116–121. 109. Valle M, Garrido MJ, Pavón JM, et al. Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, in rats. J Pharmacol Exp Ther. 2000;293:646–653. 110. Raffa RB, Nayak RK, Liao S, et al. The mechanism of action and pharmacokinetics of tramadol hydrochloride. Rev Cont Pharmacol. 1995;6:485–498.

719.e3

1 11. Tramadol—Biovail corporation. Drugs R D 2004;5:182-183. 112. Yanagita T. Drug dependence potential of 1-(m-methoxyphenyl)2-dimethylaminomethyl)-cyclohexan-1-ol hydrochloride (tramadol) tested in monkeys. Arzneimittelforschung. 1978;28:158–163. 113. Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend. 1991;27:7–17. 114. Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend. 1999;57:7–22. 115. Adams EH, Breiner S, Cicero TJ, et al. A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. J Pain Symptom Manage. 2006;31:465–476. 116. Ultram prescribing information. Raritan, NJ: Ortho-McNeil 2008. 117. Babul N, Noveck R, Chipman H, et  al. Efficacy and safety of extended-release, once-daily tramadol in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee. J Pain Symptom Manage. 2004;28:59–71. 118. Liao S, Hill JF. Nayak RK Pharmacokinetics of tramadol following single and multiple oral doses in man [abstract]. Pharm Res. 1992;9(Suppl):308. 119. Lintz W, Barth H, Osterloh G, et al. Bioavailability of enteral tramadol formulations. 1st communication: capsules. Arzneimittelforschung. 1986;36:1278–1283. 120. Lee CR, McTavish D, Tramadol Sorkin EM. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs. 1993;46:313–340. 121. Wu WN, McKown LA, Liao S. Metabolism of the analgesic drug ultram (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites. Xenobiotica. API: Miss and Miss. 2002;32:411–425. 122. Stamer UM, Lehnen K, Höthker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain. 2003;105:231–238. 123. Mattia C, Coluzzi F. Tramadol. Focus on musculoskeletal and neuropathic pain. Minerva Anestesiol. 2005;71:565–584. 124. Desmeules JA. The tramadol option. Eur J Pain. 2000;4(Suppl A): 15–21. 125. Nossol S, Schwarzbold M, Stadler T. Treatment of pain with sustained-release tramadol 100, 150, 200 mg: results of a post-marketing surveillance study. Int J Clin Pract. 1998;52:115–121. 126. Hallberg P, Brenning G. Angioedema induced by tramadol— a potentially life-threatening condition. Eur J Clin Pharmacol. 2005;60:901–903. 127. Hedenmalm K, Lindh JD, Säwe J, et  al. Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P450 2D6 gene. Eur J Clin Pharmacol. 2004;60:369–372. 128. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148:705–713. 129. Radomski JW, Dursun SM, Reveley MA, et  al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses. 2000;55:218–224. 130. Gillman PK, Whyte IM. Serotonin syndrome. In: P Haddad, S Dursun, B Deakin (eds). Adverse Syndromes and Psychiatric Drugs. Oxford: Oxford University Press: Oxford 2004:37–49. 131. Rastogi R, Swarm RA, Patel TA. Case scenario: opioid association with serotonin syndrome: implications to the practitioners. Anesthesiology. 2011;115:1291–1298. 132. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J M. 2003;96:635–642. 133. Dawson AH. Cyclic antidepressant drugs. In: RC Dart (ed). Medical Toxicology. 3rd ed. Vol 1. Baltimore: Lippincott Williams & Wilkins 2004:834-843.

719.e4

References

134. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Q J M. 2003;96:369–374. 135. Bamigbade TA, Davidson C, Langford RM, et al. Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth. 1997;79:352–356. 136. Gillman PK. A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry. 2006;59:1046–1051. 137. Sunshine A. New clinical experience with tramadol. Drugs. 1994;47(Suppl 1):8–18. 138. Stubhaug A, Grimstad J, Breivik H. Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison. Pain. 1995;62:111–118. 139. Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998;32:139–143. 140. Wilder-Smith CH, Hill LT, Laurent S. Postamputation pain and sensory changes in treatment-naïve patients: characteristics and responses to treatment with tramadol, amitriptyline, and placebo. Anesthesiology. 2005;103:619–628. 141. Akinci SB, Saricaoğlu F, Atay OA, et al. Analgesic effect of intraarticular tramadol compared with morphine after arthroscopic knee surgery. Arthroscopy. 2005;21:1060–1065. 142. Leppert W, Łuczak J. The role of tramadol in cancer pain treatment—a review. Support Care Cancer. 2005;13:5–17. 143. Simon L, Lipman AG, Jacox A, et al. Guidelines for the management of osteoarthritis, rheumatoid arthritis and juvenile chronic arthritis pain. Glenview, IL: American Pain Society 2002. 144. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50:1842–1846. 145. Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain. 1999;83:85–90. 146. Göbel H, Stadler TH. Treatment of pain due to postherpetic neuralgia with tramadol: results of an open, parallel pilot study vs clomipramine with or without levomepromazine. Clin Drug Investig. 1995;10:208–214. 147. Leppert W. Analgesic efficacy and side effects of oral tramadol and morphine administered orally in the treatment of cancer pain. Nowotwory. 2001;51:257–266. 148. Tallarida RJ, Raffa RB. Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram. Life Sci. 1996;58:PL23–PL28. 149. Medve RA, Wang J, Karim R. Tramadol and acetaminophen tablets for dental pain. Anesth Prog. 2001;48:79–81. 150. Schug SA. Combination analgesia in 2005- a rational approach: focus on paracetamol-tramadol. Clin Rheumatol. 2006;25Suppl (1):S16–S21. 151. Cicero TJ, Inciardi JA, Adams EH, et  al. Rates of abuse of tramadol remain unchanged with the introduction of new branded and generic products: results of an abuse monitoring system, 19942004. Pharmacoepidemiol Drug Saf. 2005;14:851–859. 152. Emkey R, Rosenthal N, Wu SC, et  al. CAPSS-114 study group. Efficacy and safety of tramadol/acetaminophen tablets (ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. J Rheumatol. 2004;31:5–7. 153. Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral ­tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage. 2002;23:121–130. 154. Glyn J. The discovery and early use of cortisone. J R Soc Med. 1998;91:513–517.

155. Hopkins RL, Leinung MC. Exogenous Cushing’s syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin North Am. 2005;34:371–384 ix. 156. Rousseau P. The palliative use of high-dose corticosteroids in three terminally ill patients with pain. Am J Hosp Palliat Care. 2001;18:343–346. 157. Chang MH, Ger LP, Hsieh PF, et al. A randomised clinical trial of oral steroids in the treatment of carpal tunnel syndrome: a long term follow up. J Neurol Neurosurg Psychiatry. 2002;73:710–714. 158. Buchbinder R, Hoving JL, Green S, et al. Short course prednisolone for adhesive capsulitis (frozen shoulder or stiff painful shoulder): a randomised, double blind, placebo controlled trial. Ann Rheum Dis. 2004;63:1460–1469. 159. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand. 1982;148:653–655. 160. Deltasone prescribing information. Kalamazoo, Mich: Pharmacia and Upjohn 2006. 161. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain management. Oncologist. 2004;9:571–591. 162. Amigo P, Mazuryk ME, Watanabe S, et al. Recent onset of abdominal pain in a patient with advanced breast cancer. J Pain Symptom Manage. 2000;20:77–80. 163. Curtis JR, Westfall AO, Allison J, et  al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 2006;55:420–426. 164. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet. 1999;86:242– 244. 165. Guo TZ, Wei T, Kingery WS. Glucocorticoid inhibition of vascular abnormalities in a tibia fracture rat model of complex regional pain syndrome type I. Pain. 2006;121:158–167. 166. Kozin F, McCarty DJ, Sims J, et  al. The reflex sympathetic dystrophy syndrome. I. Clinical and histologic studies: evidence for bilaterality, response to corticosteroids and articular involvement. Am J Med. 1976;60:321–331. 167. Braus DF, Krauss JK, Strobel J. The shoulder-hand syn drome after stroke: a prospective clinical trial. Ann Neurol. 1994;36:728–733. 168. Jamroz A, Berger M, Winston P. Prednisone for acute complex regional pain syndrome: a retrospective cohort study. Pain Res Manag. 2020:8182569. 169. Barbalinardo S, Loer SA, Goebel A, Perez RSGM. The treatment of long standing complex regional pain syndrome with oral steroids. Pain Med. 2016;17:337–343. 170. Park S, Kim HJ, Kim DK, Kim TH. Use of oral prednisone and a 3-phase bone scintigraphy in patients with complex regional pain syndrome type I. Healthcare (Basel). 2020;8:16. 171. Greenberg HS, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: results with a new treatment protocol. Ann Neurol. 1980;8:361–366. 172. Watanabe S, Bruera E. Corticosteroids as adjuvant analgesics. J Pain Symptom Manage. 1994;9:442–445. 173. Weissman DE. Glucocorticoid treatment for brain metastases and epidural spinal cord compression: a review. J Clin Oncol. 1988;6:543–551. 174. Kim MJ, Ye YM, Park HS, et al. Chemotherapy-related arthropathy. J Rheumatol. 2006;33:1364–1368. 175. Eastman P, Currow DC, Fazekas B, Brown L, Le B. Oral dexamethasone in the management of cancer-related pain: a feasibility study. Palliat Med. 2019;33:477–478. 176. Wooldridge JE, Anderson CM, Perry MC. Corticosteroids in advanced cancer. Oncology (Williston Park). 2001;15:225–234 discussion 234. 177. Haywood A, Duc J, Good P, et al. Systemic corticosteroids for the management of cancer-related breathlessness (dyspnoea) in adults. Cochrane Database Syst Rev. 2019;2:CD012704.

References

178. Haimovic IC, Beresford HR. Dexamethasone is not superior to placebo for treating lumbosacral radicular pain. Neurology. 1986;36:1593–1594. 179. Green LN. Dexamethasone in the management of symptoms due to herniated lumbar disc. J Neurol Neurosurg Psychiatry. 1975;38:1211– 1217. 180. Hedeboe J, Buhl M, Ramsing P. Effects of using dexamethasone and placebo in the treatment of prolapsed lumbar disc. Acta Neurol Scand. 1982;65:6–10. 181. McLain RF, Kapural L, Mekhail NA. Epidural steroid therapy for back and leg pain: mechanisms of action and efficacy. Spine J. 2005;5:191–201. 182. Ohtori S, Suzuki M, Koshi T, et al. Proinflammatory cytokines in the cerebrospinal fluid of patients with lumbar radiculopathy. Eur Spine J. 2011;20:942–946. 183. Harmon KG, Hawley C. Physician prescribing patterns of oral corticosteroids for musculoskeletal injuries. J Am Board Fam Pract. 2003;16:209–212. 184. Binder A, Hazleman BL, Parr G, et al. A controlled study of oral prednisolone in frozen shoulder. Br J Rheumatol. 1986;25:288–292. 185. Uppal HS, Evans JP, Smith C. Frozen shoulder: a systematic review of therapeutic options. World J Orthop. 2015;6:263–268. 186. Hench PS, Kendall EC, Slocumb CH, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24:181–197. 187. Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The arthritis and rheumatism council lowdose glucocorticoid study group. N Engl J Med. 1995;333:142–146. 188. Harris ED, Emkey RD, Nichols JE, et  al. Low dose prednisone therapy in rheumatoid arthritis: a double blind study. J Rheumatol. 1983;10:713–721. 189. Gøtzsche PC, Johansen HK. Meta-analysis of short-term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. BMJ. 1998;316:811–818. 190. Holroyd CR, Seth R, Bukhari M, et  al. The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis. Rheumatology. 2019;58:372. 191. Sawynok J, Yaksh TL. Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. Pharmacol Rev. 1993;45:43–85.

719.e5

192. Migliardi JR, Armellino JJ, Friedman M, et  al. Caffeine as an analgesic adjuvant in tension headache. Clin Pharmacol Ther. 1994;56:576–586. 193. Kuntz D, Brossel R. Analgesic effect and clinical tolerability of the combination of paracetamol 500 mg and caffeine 50 mg versus paracetamol 400 mg and dextropropoxyphene 30 mg in back pain. Presse Med. 1996;25:1171–1174. 194. Laska EM, Sunshine A, Zighelboim I, et al. Effect of caffeine on acetaminophen analgesia. Clin Pharmacol Ther. 1983;33:498–509. 195. Laska EM, Sunshine A, Mueller F, et al. Caffeine as an analgesic adjuvant. JAMA. 1984;251:1711–1718. 196. Godfrey L, Yan L, Clarke GD, et al. Modulation of paracetamol antinociception by caffeine and by selective adenosine A2 receptor antagonists in mice. Eur J Pharmacol. 2006;531:80–86. 197. Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A, Filipek B, Zimmer A, Müller CE. Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther. 2004;308:358–366. 198. Sawynok J, Yaksh TL. Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. Pharmacol Rev. 1993;45:43–85. 199. Fiebich BL, Candelario-Jalil E, Mantovani M, et  al. Modula tion of catecholamine release from rat striatal slices by the fixed combination of aspirin, paracetamol and caffeine. Pharmacol Res. 2006;53:391–396. 200. Currie SR, Wilson KG, Gauthier ST. Caffeine and chronic low back pain. Clin J Pain. 1995;11:214–219. 201. McPartland JM, Mitchell JA. Caffeine and chronic back pain. Arch Phys Med Rehabil. 1997;78:61–63. 202. Voicu VA, Mircioiu C, Plesa C, et al. Effect of a new synergistic combination of low doses of acetylsalicylic acid, caffeine, acetaminophen, and chlorpheniramine in acute low back pain. Front Pharmacol. 2019;10:607. 203. Lipton RB, Diener HC, Robbins MS, Garas SY, Patel K. Caffeine in the management of patients with headache. J Headache Pain. 2017;18:107. 204. Patel R, Urits I, Orhurhu V, et al. A comprehensive update on the treatment and management of postdural puncture headache. Curr Pain Headache Rep. 2020;24:24.

10 50

The U.S. Opioid and the Legal Chapter Title to Crisis Go Here and Legislative Implications CHAPTER AUTHOR

JORDAN STARR, MOHAMMED A. ISSA, AJAY WASAN

Introduction The opioid crisis has had a dramatic impact on medical care in the United States, affecting all medical providers, especially pain physicians and their patients. From 1999 to 2011, oxycodone use increased by 500%, with the quadrupling of opioid-related overdose deaths during the same period.1,2 Despite formal recognition of the opioid crisis in 2011 and subsequently reduced opioid prescriptions, 10.3 million Americans still misused opioids in 2018, 9.9 million of which inappropriately used prescription pain medications.3 This was associated with over 48,000 opioidrelated overdose deaths that year alone.4 Clearly, despite the efforts of numerous stakeholders in the United States government and medicine, combating the opioid epidemic is still necessary. As one of these stakeholder groups, pain physicians must not only understand ongoing efforts to contend with the opioid epidemic but also their specific roles in these efforts. Additionally, pain physicians have unique concerns about the initiation or limitation of prescription opioids, as well as public perception and backlash. In this context, this chapter reviews the history of the opioid crisis, current efforts, and the legal background that underlies these interventions.

Historical Perspective Opium use has been recorded since at least 3400 B.C. by the Sumerians in lower Mesopotamia, and its addictive properties were likely appreciated soon after.5 While opium use spread throughout Asia and Europe during the following millennia, the first recorded “opium epidemic” occurred in China from the end of the 18th century to the beginning of the 20th century.6 This was sparked by the introduction of smoking opium, rather than ingestion and dramatic increases in production and trade by the British.6 By 1906, it is estimated that 13.4% of the Chinese population was addicted to opium.6 The United States dealt with its own opioid epidemic in the late 19th and early 20th centuries.7 Morphine dependence increased after battlefield exposures during the civil war.7 This was exacerbated by the release of heroin in 1898, which was purported to carry no “danger of acquiring the habit.”8 Increasing opioid use in the United States and other Western countries, along with the unprecedented crisis in China, ultimately led to the formation of an international drug control system and widespread reforms, including the criminalization of non-clinical opioid use in the United States in 1915.6,7,9 720

The next wave of United States opioid use began in the 1960s– 70s, as approximately 20% of service members returned from the Vietnam War addicted to heroin.10,11 This was followed by a period of “opiophobia,” during which both patients and doctors limited prescription opioid use due to fears of iatrogenic opioid addiction.11,12

Recent History The modern opioid crisis can be traced back to the publication of two now infamous scientific articles in the 1980s. The first was a letter to the editor published in the New England Journal of Medicine in 1980 by Porter and Jick, which stated the following: Recently, we examined our current files to determine the incidence of narcotic addiction in 39,946 hospitalized medical patients who were monitored consecutively. Although there were 11,882 patients who received at least one narcotic preparation, there were only four cases of reasonably well-documented addiction in patients who had no history of addiction. Addiction was considered to be major in only one instance. The drugs implicated were meperidine in two patients, percodan in one, and hydromorphone in one. We conclude that despite the widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.13 The second was a retrospective review published in the International Association for the Study of Pain journal Pain in 1986 by Portenoy and Foley, which included 38 chronic pain patients managed with chronic opioid therapy. It concluded, “that opioid maintenance therapy can be a safe, salutary, and more humane alternative to the options of surgery or no treatment in patients with intractable non-malignant pain and no history of drug abuse.”14 These articles were widely presented and cited to support claims about the safety of chronic opioid therapy by physicians and the pharmaceutical industry.15,16 As “opiophobia” was being assuaged by the medical literature, the pharmaceutical industry was concurrently innovating to create theoretically less addictive opioids, leading to the introduction of OxyContin, an extended-release formulation of oxycodone, in 1995 by Purdue Pharma. This medication, an extensive advertising campaign, and sponsorship of more than 20,000 medical educational programs were associated with an acceleration in opioid prescribing beginning in 1996.17,18 Purdue Pharma also provided financial support to multiple professional societies that

 

CHAPTER 50

The U.S. Opioid Crisis and the Legal and Legislative Implications

subsequently advocated for increased attention to the treatment of pain and opioid use for chronic non-cancer pain.1,19,20 For example, the American Pain Society introduced the “pain is the Fifth Vital Sign” campaign in 1995.21 Beyond providing education, this campaign impacted policy among the major hospital accrediting bodies: the Department of Veterans’ Affairs in 1999 and the Joint Commission in 2001.22,23 These efforts were associated with a dramatic acceleration in opioid prescribing in the inpatient and outpatient setting in the following years (Fig. 50.1).24 Well-meaning physicians, pharmacists, and patients who previously minimized opioids due to fears of dependence and addiction were now utilizing opioids more liberally to avoid undertreatment of pain and be concordant with contemporary guidelines. Not all parties were found to be well-meaning. However, exacerbating the growth in opioid prescriptions during this period without resulting in patient benefit. For example, Purdue Pharma paid an $8.3 billion settlement in 2020 as part of a plea deal on three felony counts of criminal wrongdoing.25 They are not the only pharmaceutical companies to face penalties, as settlements have been reached involving Johnson & Johnson, Mallinckrodt, and Teva Pharmaceuticals.26 Physicians, pharmacists, physician assistants, nurses, organized crime, and street-level drug dealers have also been implicated in the spread of prescription opioids during this time.27 For example, one “pill mill” scheme in Arkansas involved recruiters who found patients to be inappropriately prescribed large amounts of opioids by a clinic. These patients would fill these prescriptions at the pharmacy involved in the scheme. The patients would then deliver the pills to drug dealers, and all parties involved received portions of the profits.27 Irregular, high-volume controlled substance prescription fills could theoretically be detected and reported by drug distribution companies, but this mechanism proved to be inadequate, leading to legal settlements involving the three largest drug distribution companies: AmerisourceBergen Corp., Cardinal Health Inc., and McKesson Corp.26 The influx of prescription opioids in the market led to a large increase in opioid exposure in the United States. Between 1988 and 1994, the prescription opioid use rate in the past 30 days among medical and non-medical users aged 20 and over was

3.4%.28 Between 1999 and 2002, this number grew to 5.0%, and from 2003 to 2006, this rate peaked at 6.9% and persisted until at least 2012,29 with increased opioid usage increased opioid overdose deaths among medical and non-medical users during the first wave of the opioid crisis from 1999 to 2010 (Fig. 50.2).30 The second wave of the opioid crisis began in 2010, with a dramatic inflection in opioid overdose deaths involving heroin.30 The rise in heroin use and deaths has been attributed to several factors: increased availability of high-purity heroin, prescription drug abusers turning to heroin, and heroin use beginning at a younger age.31 As a measure of availability, heroin seizures at the Southwest border increased 352% from 2008 to 2015, according to the United States Drug Enforcement Agency.31 Additionally, as law enforcement focused on limiting the distribution of illicit prescription opioids, an unintended consequence was opioid users being shunted to cheaper and readily available heroin. Prescription pain pill abusers were 19 times more likely to start using heroin than the general public.32 Furthermore, the average age of heroin users dropped to as low as 21.4 years old, which was associated with higher rates of polysubstance abuse and alcohol binge drinking.32 In 2011, the Obama administration formally addressed the prescription opioid epidemic and revealed a plan to combat the crisis.33 This plan detailed broad reforms involving many governmental agencies. Most notably, it initiated diverse education efforts, invested in prescription drug monitoring programs (PDMPs), encouraged appropriate drug disposal, and removed law enforcement barriers.33 Around this time, prescribed opioid overdose deaths stabilized, and morphine equivalents dispensed began to decline.24,30 However, heroin use continued to grow. In the setting of stable prescription opioid overdose deaths but increasing heroin associated deaths, the third wave of the opioid crisis began in 2013 with a rise in the use of fentanyl and other synthetic opioids.30 Increased law enforcement efforts made the production and shipment of heroin more difficult, which may have shifted drug production toward fentanyl. Fentanyl does not require harvesting poppies, and small shipments are profitable. Furthermore, fentanyl is found to be mixed with non-opioids such as cocaine and methamphetamine, suggesting that dealers

250

200 MMEs Dispensed Bn

721

150

100

50

19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 20 18

0

Source: IQVIA National Prescription Audit, Dec 2017; IQVIA Xponent, Feb 2019

• Figure 50.1  Narcotic Analgesic Dispensed Volumes in Morphine Milligram Equivalents (MME) billions.

The analysis is based on opioid medicines for pain management and excludes those medicines used for medication-assisted opioid use dependency treatment or overdose recovery.

722

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

• Figure 50.2  Opioid overdose death rates by year stratified by opioid type. (From the Centers for Disease Control and Prevention.)

may add fentanyl to non-opioids attempting to leverage its addictiveness.34,35 As the opioid crisis persisted, several professional organizations, states, and federal agencies began releasing opioid prescribing guidelines, but these guidelines varied in their use of evidence, methods of addressing conflicts of interest, and ultimately their specific recommendations.36 This motivated the creation of the Centers for Disease Control and Prevention (CDC) Guidelines for Prescribing Opioids for Chronic Pain released in 2016, which intended to advise primary care clinicians on how to avoid problematic prescribing habits for adults with chronic, non-cancer pain.36 Although all pain medicine clinicians should be familiar with the full text of the CDC guidelines, the 12 primary recommendations are listed in Box 50.1.36 This guideline with explicit morphine milligram equivalent thresholds has had a dramatic impact on opioid prescriptions.37 High-dose opioid prescriptions, concurrent opioid, and benzodiazepine prescriptions, and overall opioid prescription rates all declined more rapidly after the publication of the guideline.37 Before the end of his second term, President Obama signed two additional pieces of legislation into law to further combat the opioid crisis, the Comprehensive Addiction and Recovery Act (CARA) of 2016, followed by the 21st Century Cures Act.38,39 CARA dedicated new funding toward the opioid epidemic and focused on prevention, overdose reversal, treatment, recovery, law enforcement, and criminal justice reform.39 The 21st Century Cures Act supplemented this work with grant funding for substance abuse and mental health treatment.38

Current State In January 2017, Donald Trump was inaugurated as president of the United States. By October 2017, President Trump declared the opioid crisis a public health emergency, which remained designated as an emergency until October 2018.40 The emergency status led to reduced paperwork and wait times for several governmental efforts to address the crisis. However, the overall impact of this emergency declaration is a matter of debate.41 In November 2017, the President’s Commission on Combating Drug Addiction and the Opioid Crisis released its final report with 56 recommendations.42 This was followed in March 2018 by the release of President Donald J. Trump’s initiative to stop opioid abuse and reduce drug supply and demand.43 These two reports outline a variety of priorities and continue to impact actions by the administration. For example, they advocate increased funding of opioid-related government activities, a mass media prevention campaign, increasing access to treatment for substance use disorder, drug court rather than prison, legislation to assist former felons in finding work, and expanding law enforcement resources.42,43 A progress update published in May 2019 by the Trump administration touted examples of its progress toward the goals of these reports: $6 billion in funding over two years to fight the opioid crisis, a large ad campaign, a reduction in opioids dispensed, increased arrests and seizures by law enforcement, increased use of medication-assisted treatment (MAT), increased naloxone prescription, and several other reported measures of success.44

 

CHAPTER 50

• BOX 50.1

The U.S. Opioid Crisis and the Legal and Legislative Implications

723

Recommendations From the Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain - United States, 2016

1. Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. 2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how opioid therapy will be discontinued if the benefits do not outweigh the risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. 3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. 4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids. 5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day. 6. Long term opioid use often begins with the treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed. 7. Clinicians should evaluate benefits and harms with patients within one to four weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate the benefits and harms of continued therapy with patients every three months or more frequently. If benefits do not outweigh the harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or taper and discontinue opioids. 8. Before starting and periodically during the continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase the risk for opioid overdose, such as a history of overdose, history of a substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present. 9. Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every three months. 10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications and other controlled prescription drugs and illicit drugs. 11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible. 12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone combined with behavioral therapies) for patients with opioid use disorder.

Another effort by the Trump administration to combat the opioid crisis, the Prescription Interdiction and Litigation Task Force, was announced in February 2018. This task force aims to support local jurisdictions with the filing of lawsuits against prescription drug producers and distributors.45 For example, the task force filed a statement of interest in a federal court case that combined over 600 lawsuits lodged by disparate government entities against opioid manufacturers.46 In addition to efforts to reduce opioid use, another development in the opioid crisis is a “swing of the opioid pendulum” back toward rational but slightly more liberal opioid prescribing.47–49 Though the CDC guideline was in many respects a success, it also led to the creation of some inflexible policies and practices that were inconsistent with the original guidelines.47–49 For example, misapplication of the guidelines affected the care of patients with cancer, sickle cell crises, and opioid use disorders.47,50 The guidelines were also used to justify rapid tapers or complete discontinuation of opioids in some patients.47,49 Such practices are not only difficult for patients but can also be associated with an increased risk of overdose death in high risk populations.51 These concerns prompted several of the authors of the CDC guideline to provide further guidance regarding the proper application of the guidelines in April 2019.47,48 Individualized approaches were emphasized, and hard limits, abrupt tapering, and sudden discontinuation of opioids were discouraged.47,48 At the time of writing, there is room for optimism in the current state of the opioid crisis. Prescription opioid dispensing has

been declining every year since its peak in 2011, and it declined by 17% in 2018 alone.24 Deaths from opioid-related overdoses may have also plateaued since the peak of 48,580 deaths in November 2017, although deaths from synthetic opioids continue to rise.52 Overall life expectancy rose in 2018 for the first time since 2014. The CDC attributed this partially to decreased unintentional injuries, which includes opioid-related overdose deaths.53 Part of the decline in opioid-related overdose deaths may be due to increased use of MAT for opioid use disorder. From 2014 to 2018, MAT prescriptions increased 47%, from 11 to 16.2 million.24 Opioid misuse among youth in the United States is also trending down. For example, 2.7% of 12th-graders reported illicit prescription opioid use, the lowest percentage ever recorded since surveying began in 1991.54 Despite these encouraging trends, the opioid crisis remains a significant problem. More people die from opioid-related overdoses than car accidents in the United States, and the number of opioid-related overdose deaths has remained essentially unchanged from November 2017 to August 2019.52,55

Legal Landscape All past and present efforts to combat the opioid crisis are founded on a host of international treaties, federal and state laws, and legal precedent set by case law. While a full account of these influences is beyond the scope of this chapter, some of the most impactful are described in the following sections to provide context and a working understanding for the practicing pain clinician.

724

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

International The most important international treaty affecting prescription opioid distribution is the Single Convention on Narcotic Drugs of 1961, which was signed by 186 countries.56–58 The Single Convention encourages a balance between the dual obligations of minimizing opioid abuse and ensuring opioids are available for legitimate medical and scientific purposes.57,58 These requirements stipulate the authorization and licensing of all parties involved in the medical distribution of opioids, a valid prescription for patients to receive opioids, and barriers to abuse that are not so high as to limit reasonable use.57,58 Interestingly, much of the global work of the International Narcotics Control Board, the United Nations agency responsible for monitoring compliance with the Single Convention, has been focused on increasing access to opioids for appropriate medical needs.59 While the United States battles the opioid crisis, approximately 75% of the world population is without adequate access to medications containing opioids.59

Federal Until the early 20th century, opioid use was effectively unregulated in the United States.60 Opium, morphine, or heroin could be widely obtained.60 This changed with the passage of the Harrison Narcotics Tax Act of 1914.9,60 Initially intended as a law to regulate the opioid market, it became interpreted by law enforcement as a prohibition of all opioid use except for the medical treatment of pain.60 Non-prescription opioid use was outlawed within weeks, and MAT of opioid addiction was discontinued by 1924 due to interpretation of the Harrison Act.60 The next major piece of legislation to impact prescription opioid use in the United States was the Federal Food, Drug, and Cosmetic Act of 1962, which provided new authorities and teeth to the Food and Drug Administration (FDA).61 Prior to this, the FDA had no authority to enforce proper manufacturing processes or regulate all marketing, for example.62 This was eventually followed by the Food and Drug Administration Amendments Act of 2007, which was particularly relevant to opioid prescribing.63 It gave the FDA the authority to determine if drug manufacturers must submit risk evaluation and mitigation strategies (REMS) for medications with anticipated harms.63 Since then REMS programs have been established for a variety of opioid formulations, including transmucosal immediate-release fentanyl (TIRF) products and long-acting (LA) and extended-release (ER) products.64,65 REMS programs involve educating patients and providers, and they may increase knowledge and reduce harm.66 However, they also create a barrier to prescribing for some clinicians, thus limiting access for some patients.67 Between 1914 and 1970, 55 federal laws were passed to strengthen the Harrison Narcotics Tax Act.60 In the context of the Single Convention, modernization of the FDA, the rise of methadone maintenance in the mid-to-late 1960s under legal ambiguity, increasing recreational drug use in the late 1960s, and the subsequent “War on Drugs,” preexisting federal laws were consolidated into the Comprehensive Drug Abuse Prevention and Control Act of 1970, which included the Controlled Substances Act (CSA).60,68–70 The CSA is now the primary law dictating prescription opioid distribution in the United States, and it is primarily enforced by the Drug Enforcement Administration (DEA).68,71 Importantly, while trying to prevent the illicit distribution of opioids and other controlled substances, the CSA aims to conform to the Single Convention and ensure the availability of opioids for legitimate medical purposes.68,72 Furthermore, while controlling

the distribution of prescription opioids, the CSA does not define or give the DEA the authority to define appropriate medical practices. This responsibility is left to the state.68,71 The CSA is responsible for establishing the one through five scheduling classification schema of controlled substances.68 Controlled substances are placed into one of the schedules based on medical usefulness and abuse potential (Box 50.2).68 Briefly, Schedule I drugs are those with no accepted medical use and a high abuse potential.68 However, there is debate about which substances should belong in this class.73 For example, it includes “marijuana,” which has established medical value for a variety of conditions.68,73 Schedule II drugs are those with medical use and high abuse potential, which includes most opioids.68 Notably, Schedule II drugs can only be prescribed for up to 30 days and cannot be refilled, though they can be prescribed sequentially for up to 90 days.68,74 Schedule III medications have less abuse potential and include codeine combination products as well as buprenorphine.71 Schedule IV medications have even lower abuse potential and include tramadol.71 Both Schedule III and IV prescriptions can be refilled up to five times.68 Lastly, Schedule V includes the least abusable substances, like compounds with very low doses of opioids used for cough suppression or as antidiarrheals.71 Another significant component of the CSA was the explicit legalization of opioid prescription for addiction treatment, not just for pain.68 Opioid maintenance for addiction was distinguished from prescribing for pain. However, all sites must register as opioid treatment programs to be allowed to prescribe opioid detoxification or maintenance.68

State The power to regulate medical practice lies with states and their medical licensing boards, either through legislation or regulations. These regulatory powers must comply with federal law and the Single Convention.71 Though each states’ laws differ, nearly every state has adopted some form of the Federation of State Medical Boards’ 2017 Guidelines for the Chronic Use of Opioid Analgesics.71,76 These guidelines are intended as a resource for state medical boards in assessing physician use of opioids in a “medically appropriate manner.”76 Every clinician who manages pain should be aware of the laws and regulations specific to his or her state. Nevertheless, a variety of legal issues apply to all states.77 Maintaining a balance between the availability and regulation of opioids remains important, especially in the age of the opioid epidemic.77 For example, primary care providers in Washington must consult a pain physician for patients who receive a morphine equivalent dose (MED) greater than 120 mg.78 However, if pain physician consultations are not accessible due to distance or insurance coverage, this requirement could create an imbalance. Imbalance can also be created by overly restrictive prescription limitations in terms of quantities or days.77 Another issue is state classifications of addiction.77 Defining addiction by physiologic dependence or tolerance, without the necessary behavioral components, can falsely label patients on chronic opioid therapy as “addicts.”77,79 Beyond being incorrect, this can have other legal ramifications depending on opioid prescribing laws targeted toward those with true substance abuse disorders.71,77 Furthermore, for those with substance abuse disorders, laws should aim to limit abuse, but they should not prevent patients with substance abuse disorders from receiving adequate treatment for pain.71,77 Of equal importance to how laws and regulations are written is how they are interpreted. Regardless of what is intended,

 

CHAPTER 50

• BOX 50.2

The U.S. Opioid Crisis and the Legal and Legislative Implications

725

The United States Drug Enforcement Administration Drug Scheduling75

Schedule I Schedule I drugs, substances, or chemicals are defined as drugs with no currently accepted medical use and a high potential for abuse. Examples of Schedule I drugs are as follows: Heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote.

Schedule II Schedule II drugs, substances, or chemicals are defined as drugs with a high potential for abuse, potentially leading to severe psychological or physical dependence. These drugs are considered dangerous. Some examples of Schedule II drugs are as follows: Combination products with less than 15 mg of hydrocodone per dosage unit (Vicodin), cocaine, methamphetamine, methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, and Ritalin.

Schedule III Schedule III drugs, substances, or chemicals are defined as drugs with moderate to low potential for physical and psychological dependence. Schedule III drug abuse potential is less than that of Schedule I and Schedule II drugs but more than Schedule IV. Some examples of Schedule III drugs are as follows: Products containing less than 90 mg of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, testosterone.

Schedule IV Schedule IV drugs, substances, or chemicals are defined as drugs with a low potential for abuse and a low risk of dependence. Some examples of Schedule IV drugs are as follows: Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien, Tramadol.

Schedule V Schedule V drugs, substances, or chemicals are defined as drugs with a lower potential for abuse than Schedule IV and consist of preparations containing limited quantities of certain narcotics. Schedule V drugs are generally used for antidiarrheal, antitussive, and analgesic purposes. Some examples of Schedule V drugs are as follows: Cough preparations with less than 200 mg of codeine or per 100 mL (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin.

practitioner misperceptions of policy can lead to reluctance to prescribe opioids, potentially limiting access.71 In this sense, legal ambiguity itself is an issue within state control. Beyond laws and regulations, states also play a critical role in maintaining PDMPs. Forty-nine states, the District of Columbia, and Guam have operational PDMPs.80 The lone missing state is Missouri, though it has several city-level and countylevel PDMPs.81 Ideally, all PDMPs would provide near-real-time information, be readily accessible by clinicians at the time of prescription writing, and extract information from neighboring jurisdictions, if not all jurisdictions.76

Legal Decisions In addition to adopted legislation, there is a host of litigation that has set precedents relevant to opioid prescriptions. While many could be discussed, three illustrative cases are presented. The binding nature of case law depends on the jurisdiction of pending litigation, but these cases demonstrate the range of perspectives adopted by the courts. The first is the Estate of Henry James v. Hillhaven Corporation, which was decided in North Carolina in 1991. In this case, a patient with metastatic cancer achieved pain control in the hospital with opioid therapy. However, when he was admitted to a skilled nursing facility, a nurse determined that he was addicted to morphine and completely replaced his opioid with a sedative. After his stay, his estate sued the facility, arguing that a standard of

care existed, was not met, and led to suffering. His estate won this case at $15 million. This case suggests that patients have the right to effective pain relief.82 United States v. Rosen is a case decided by the United States Court of Appeal for the Fifth Circuit in 1978 on the opposite end of the prescribing spectrum. Dr. Rosen heavily prescribed medications as part of a weight loss practice, and he was charged with 25 counts of distribution of controlled substances, leading to a fiveyear prison sentence.83 To be convicted of these charges, the prosecution had to prove that he prescribed these medications without a legitimate medical purpose. By showing that his behavior was far outside standard medical practice, he was not treated as just a negligent physician who would be liable to malpractice or revocation of his license. Instead, he was prosecuted as a drug dealer and subject to criminal penalties. This case suggests that prescribing physicians can be treated as criminals if their behavior is far from the standard of care.71 An additional notable case was the DEA administrative decision to grant a DEA certificate of registration to Dr. David Gillis in 1993. The DEA initially attempted to deny Dr. Gillis the opportunity to register for a DEA license because they claimed he was prescribing opioids to known drug abusers. However, because it was shown that the physician was prescribing to treat pain, the physician’s actions were deemed legitimate by an administrative decision.84 This clarified the ability to prescribe to treat pain regardless of addiction. Ultimately, the purpose of prescribing is most relevant, not the patient himself/herself.71

Conclusions Opioids play a complex role in human history. They are undoubtedly essential tools in a physician’s toolbox, especially when treating acute pain. However, their addictive nature and lethality have plagued humanity. To remedy the current opioid crisis, a broad

swath of stakeholders is actively working under an evolving legal and regulatory landscape. As clinicians, we must understand and assist these efforts for the betterment of our patients, as well as the community at large.

726

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

Key Points • Opioids are an essential tool in a physician’s toolbox, but their addictive nature and lethality have also plagued humanity throughout history. • The development of OxyContin in 1996, combined with an advertising campaign and sponsorship of more than 20,000 educational programs, led to an acceleration in opioid prescription. • The first wave of the opioid epidemic began in 1999, with a large increase in prescription opioid overdose deaths. The second wave of the opioid epidemic began in 2010, as former prescription opioid users transitioned to heroin. The third wave of the opioid epidemic started in 2013, as fentanyl became more abundant in the illicit opioid supply. • The CDC guidelines for opioid prescription were released in 2016 and led to a decline in opioid use. However, clarification was released in 2019, emphasizing individualized approaches

Suggested Readings Gilson A. Laws and policies affecting pain management. In: Ballantyne J, Fishman S, and Rathmell J (eds). Bonica’s Management of Pain. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2018:166–183. Booth M. Opium: A History. New York: St. Martin’s Press; 1986. Centers for Disease Control and Prevention. The CDC advises against the misapplication of the guideline for prescribing opioids for chronic pain. Available at: https://www.cdc.gov/media/releases/2019/ s0424-advises-misapplication-guideline-prescribingopioids.html. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain- United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49.

•

• •

•

and the avoidance of hard limits, abrupt tapering, and sudden discontinuation of opioids. 10.3 million Americans misused opioids in 2018, 9.9 million of which misused prescription pain medications. This was associated with over 48,000 opioid-related overdose deaths that year alone. Ultimately, pharmaceutical companies, drug distributors, pharmacies, physicians, nurses, and pharmacists share some responsibility for the opioid epidemic. Current and future efforts to combat the opioid crisis are necessary, but all efforts must maintain a balance between preventing the abuse of opioids and making them available for legitimate medical purposes. Pain physicians must understand the ongoing efforts to contend with the opioid epidemic and their roles in these efforts.

James JR, Scott JM, Klein JW, et al. Mortality after discontinuation of primary care-based chronic opioid therapy for pain: A retrospective cohort study. J Gen Intern Med. 2019;34(12):2749–2755. Portenoy RK, Foley KM. Chronic use of opioid analgesics in nonmalignant pain: A report of 38 cases. Pain. 1986;25(2):171–186. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302(2):123. Quinones S. Dreamland. The True Tale of America’s Opiate Epidemic. New York: Bloomsbury Publishing; 2015. The references for this chapter can be found at ExpertConsult.com.

References 1. Kolodny A, Courtwright DT, Hwang CS, et  al. The prescription opioid and heroin crisis: A public health approach to an epidemic of addiction. Annu Rev Public Health. 2015;36:559–574. 2. Chen LH, Hedegaard H, Warner M. Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011. NCHS Data Brief. 2014;166(166):1–8. 3. Substance Abuse and Mental Health Services Administration. 2018 Nsduh Annual National Report. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2019. 4. Ahmad FB, Rossen LM, Sutton P. Overdose death rates. National Institute on Drug Abuse. https://www.drugabuse.gov/drug-topics/trendsstatistics/overdose-death-rates. Updated 2021. Accessed Aug 1, 2021. 5. Booth M. Opium: A History. New York: St. Martin’s Press; 1986. 6. United Nations Office on Drugs and Crime. World drug report 2008. Vienna, Austria: United Nations Office on Drugs and Crime, pp. 173–177. 7. Courtwright D. Dark Paradise: A History of Opiate Addiction In America. Cambridge, MA: Harvard University Press; 2001. 8. Daly JRL. A clinical study of heroin. Boston Med Surg J. 1900; 142(8):190–192. 9. Harrison Narcotics Tax Act of 1914, 38 U.S.C. Stat. 785. (1914). 10. Robins LN, Helzer JE, Hesselbrock M, Wish E. Vietnam veterans three years after Vietnam: How our study changed our view of heroin. Am J Addict. 2010;19(3):203–211. 11. Bushak L. How did opioid drugs get to be so deadly? A brief history of its transition from trusted painkiller to epidemic. Medical Daily website. Available at: https://www.medicaldaily.com/ opioid-drugs-heroin-epidemic-prescription-painkillers-abusehistory-392747?rel=most_shared5. 12. Bennett DS, Carr DB. Opiophobia as a barrier to the treatment of pain. J Pain Palliat Care Pharmacother. 2002;16(1):105–109. 13. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302(2):123. 14. Portenoy RK, Foley KM. Chronic use of opioid analgesics in nonmalignant pain: Report of 38 cases. Pain. 1986;25(2):171–186. 15. Meldrum ML. The ongoing opioid prescription epidemic: Historical context. Am J Public Health. 2016;106(8):1365–1366. 16. Leung PTM, Macdonald EM, Stanbrook MB, Dhalla IA, Juurlink DN. A 1980 letter on the risk of opioid addiction. N Engl J Med. 2017;376(22):2194–2195. 17. United States General Accounting Office. OxyContin abuse and diversion and efforts to address the problem. Washington, DC: United States General Accounting Office; 2003. 18. International Narcotic Control Board. The report of the international narcotics control board for 2007. Vienna, Austria: International Narcotic Control Board; 2007. 19. Gourd E. American Pain Society forced to close due to opioid scandal. Lancet Oncol. 2019;20(7):e350–8:e350. 20. American Academy of Pain Medicine and the American Pain Society. The use of opioids for the treatment of chronic pain. A consensus statement from the American Academy of Pain Medicine and the American Pain Society. Clin J Pain. 1997;13(1):6–8. 21. Campbell JN. APS 1995 presidential address. Pain Forum. 1996; 5(1):85–88. 22. Baker DW. History of the joint commission’s pain standards: Lessons for today’s prescription opioid epidemic. JAMA. 2017; 317(11):1117–1118. 23. Stephenson J. AIDS vaccine trial. JAMA. 1999;281(11):978. 24. IQVIA Institute for Human Data Science. Medicine use and spending in the U.S. A review of 2018 and outlook to 2023. Parsippany, NJ: IQVIA Institute for Human Data Science; 2019. 25. Mann B. Federal judge approves landmark $8.3 billion Purdue Pharma opioid settlement. Available at: https://www.npr. org/2020/11/17/936022386/federal-judge-approves-landmark8-3-billion-purdue-pharma-opioid-settlement#:∼:text=A%20

federal%20bankruptcy%20judge%20approved,other%20 highly%20addictive%20opioid%20medications. 26. CNN editorial research. Opioid crisis fast facts. Available at: https:// www.cnn.com/2017/09/18/health/opioid-crisis-fast-facts/index.html. 27. United States Attorney’s Office Eastern District of Arkansas. 140 charged in Arkansas as part of national prescription drug initiative. Available at: https://www.justice.gov/usao-edar/pr/140-chargedarkansas-part-national-prescription-drug-initiative. 28. Paulose-Ram R, Hirsch R, Dillon C, Losonczy K, Cooper M, Ostchega Y. Prescription and non-prescription analgesic use among the US adult population: Results from the third national health and nutrition examination survey (NHANES III). Pharmacoepidemiol Drug Saf. 2003;12(4):315–326. 29. Frenk SM, Porter KS, Paulozzi LJ. Prescription opioid analgesic use among adults: United States, 1999-2012. NCHS Data Brief. 2015;189(189):1–8. 30. Centers for Disease Control and Prevention. Understanding the epidemic. Available at: https://www.cdc.gov/drugoverdose/epidemic/ index.html. 31. United States Drug Enforcement Administration. 2016 National Drug Threat Assessment. United States: United States Drug Enforcement Administration; 2016. 32. United States: Substance Abuse and Mental Health Services Administration. Results from the 2015 National Survey on Drug Use and Health: Detailed Tables. United States: United States Substance Abuse and Mental Health Services Administration; 2016. 33. Executive Office of the President of The United States. Epidemic: Responding to America’s Prescription Drug Abuse Crisis. United States: Executive Office of the President of The United States; 2011. 34. Bebinger M. Fentanyl-linked deaths: The U.S. opioid epidemic’s third wave. Kaiser Health News. Available at: https://khn.org/news/ fentanyl-linked-deaths-the-u-s-opioid-epidemics-third-wave/. 35. National Institute on Drug Abuse, National Institutes of Health. Drug Facts: Fentanyl. National Institute on Drug Abuse, National Institutes of Health; 2019. 36. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain- United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49. 37. Bohnert ASB, Guy Jr GP, Losby JL. Opioid prescribing in the United States before and after the Centers for Disease Control and Prevention’s 2016 opioid guideline. Ann Intern Med. 2018;169(6):367–375. 38. H.R. 34 - 114th Congress: 21st Century Cures Act, Pub.L. 114255. (2016). 39. Comprehensive Addiction and Recovery Act of 2016, 42 USC 201. (2016). 40. Centers for Medicare and Medicaid Services. (2020, January 23). Ongoing emergencies. CMS. https://www.cms.gov/About-CMS/ Agency-Information/Emergency/EPRO/Current-Emergencies/ Ongoing-emergencies. 41. United States Government Accountability Office. Opioid Crisis: Status of Public Health Emergency Authorities. United States: United States Government Accountability Office; 2018. 42. Christie C, Baker C, Cooper R, Kennedy PJ, Madras B, Bondi P. The president’s commission on combating drug addiction and the opioid crisis. United States: Executive Office of the President of The United States; 2017. 43. Executive Office of the President of The United States. President Donald J. Trump’s Initiative to Stop Opioid Abuse and Reduce Drug Supply and Demand. United States: Executive Office of the President of The United States; 2018. 44. Executive Office of the President of The United States. An Update on the President’s Commission on Combating Drug and Addiction and the Opioid Crisis: One Year Later. United States: Executive Office of the President of The United States; 2019. 45. United States Department of Justice. Attorney general sessions announces new prescription interdiction & litigation task force. Available at: https://www.justice.gov/opa/pr/attorney-general-sessions-announces-new-prescription-interdiction-litigation-task-force. 726.e1

726.e2

References

46. Working Partners. Over lawsuits against opioid companies become one federal court case. Available at: https://www.workingpartners. com/over-600-lawsuits-against-opioid-companies-become-onefederal-court-case/. 47. Dowell D, Haegerich T, Chou R. No shortcuts to safer opioid prescribing. N Engl J Med. 2019;380(24):2285–2287. 48. Centers for Disease Control and Prevention. CDC advises against misapplication of the guideline for prescribing opioids for chronic pain. Available at: https://www.cdc.gov/media/releases/2019/ s0424-advises-misapplication-guideline-prescribing-opioids.html. 49. Comerci Jr G, Katzman J, Duhigg D. Controlling the swing of the opioid pendulum. N Engl J Med. 2018;378(8):691–693. 50. Kroenke K, Alford DP, Argoff C, et al. Challenges with implementing the Centers for Disease Control and Prevention opioid guideline: A consensus panel report. Pain Med. 2019;20(4):724–735. 51. James JR, Scott JM, Klein JW, et al. Mortality after discontinuation of primary care-based chronic opioid therapy for pain: A retrospective cohort study. J Gen Intern Med. 2019;34(12):2749–2755. 52. Ahmad FB, Rossen LM, Sutton P. Provisional drug overdose death counts. Hyattsville, MD: National Center for Health Statistics; 2020. 53. Kochanek KD, Anderson RN, Arias E. Changes in life expectancy at birth, 2010–2018. Hyattsville, MD: National Center for Health Statistics; 2020. 54. National Institute on Drug Abuse, National Institutes of Health. Monitoring the Future Survey: High School and Youth Trends. Washington, DC: National Institute on Drug Abuse, National Institutes of Health; 2019. 55. National Safety Council Injury. Odds of dying. Available at: https:// injuryfacts.nsc.org/all-injuries/preventable-death-overview/odds-ofdying/data-details/. 56. United Nations. Single convention on narcotic drugs. 1961, as amended by the protocol amending the single convention on narcotic drugs. Available at: https://treaties.un.org/Pages/ViewDetails. aspx?src=TREATY&mtdsg_no=VI-18&chapter=6&clang=_en#1. 57. United Nations. 1972 protocol amending the single convention on narcotic drugs, 1961. New York, NY: United Nations; 1972. 58. United Nations. Single Convention on Narcotic Drugs, 1961. United Nations; 1961. 59. International Narcotics Control Board. Availability of Internationally Controlled Drugs: Ensuring Adequate Access for Medical and Scientific Purposes: Indispensable, Adequately Available and Not Unduly Restricted. United Nations; 2016. 60. Brecher EM. Editors of consumer reports magazine. The consumers union report on licit and illicit drugs, 1972. 61. Federal Food, Drug, and Cosmetic Act, Title 21 USC 355. (1962). 62. Kefauver-harris amendments revolutionized drug development. US Food and Drug Administration. https://www.fda.gov/consumers/ consumer-updates/kefauver-harris-amendments-revolutionizeddrug-development. Updated 2012. Accessed Mar 16, 2020. 63. Food and Drug Administration. Amendments Act of 2007. United States: Food and Drug Administration; 2007. 64. United States Food and Drug Administration. Opioid analgesic REMS. Available at: https://www.accessdata.fda.gov/scripts/cder/ rems/index.cfm?event=RemsDetails.page&REMS=17.

65. United States Food and Drug Administration. Transmucosal immediate-release fentanyl (TIRF) products. Available at: https://www. accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails. page&REMS=60. 66. Cepeda MS, Coplan PM, Kopper NW, Maziere JY, Wedin GP, Wallace LE. ER/LA opioid analgesics REMS: Overview of ongoing assessments of its progress and its impact on health outcomes. Pain Med. 2017;18(1):78–85. 67. Slevin KA, Ashburn MA. Primary care physician opinion survey on FDA opioid risk evaluation and mitigation strategies. J Opioid Manag. 2011;7(2):109–115. 68. Controlled Substances Act, Pub L No. 91-513, 84. (1970). 69. Controlled Substances Act, Pub L No. 91-513, 84. (1970). 70. Institute of Medicine. United States committee on federal regulation of methadone treatment. In: Rettig RA, Yarmolinsky A (eds). Federal Regulation of Methadone Treatment. Washington DC: National Academies Press; 1995, pp. 5. 71. Ballantyne JC, Fishman SM, Rathmell JP. Bonica’s management of pain. 5th ed. Lippincott Williams & Wilkins; 2018:172–192. 72. Proceedings and debates of the 91st congress second session. Washington, DC: United States of America Congressional Record. 73. Andreae MH, Rhodes E, Bourgeoise T, et  al. An ethical exploration of barriers to research on controlled drugs. Am J Bioeth. 2016;16(4):36–47. 74. Drug Enforcement Administration. Issuance of multiple prescriptions for schedule Ii. Control Subst 2007: Docket no:DEA287f. 75. Drug Enforcement Administration. Drug scheduling. Available at: https://www.dea.gov/drug-scheduling. 76. Federation of State Medical Boards of The United States. Guidelines For the Chronic Use of Opioid Analgesics. United States: Federation of State Medical Boards of The United States; 2017. 77. Pain, Policy Studies Group. Achieving Balance in State Pain Policy: A Progress Report Card. University of Wisconsin Carbone Cancer Center: (CY2015), 2016. 78. Washington Medical Commission. Opioid Prescribing in Washington: What You Need to Know. United States: Washington Medical Commission; 2018. 79. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Dsm-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013. 80. Federation of State Medical Boards. Prescription drug monitoring programs state-by-state overview. Available at: http://www.fsmb. org/siteassets/advocacy/key-issues/prescription-drug-monitoringprograms-by-state.pdf. 81. Jackson County Missouri. Prescription Drug Monitoring Program. Available at: https://www.jacksongov.org/859/Prescription-DrugMonitoring-Program. 82. Shapiro RS. Liability issues in the management of pain. J Pain Symptom Manage. 1994;9(3):146–152. 83. United States v. Rosen. 1978. 84. David H. Gillis, M.D.; Granting of Registration. Springfield, VA: Drug Enforcement Administration. 58 FR 37507-01, 1993.

51

Evaluation for Opioid Management: Opioid Misuse Assessment Tools and Drug Testing in Pain Management

ROBERT N. JAMISON, SAMANTHA CURRAN

Background and Overview of Pain Issues Chronic pain, defined typically as pain lasting longer than three months,1 is a global problem that can negatively impact every facet of daily living.2,3 It is estimated that in the United States, there are between 50 and 100 million adults with chronic pain, affecting more individuals than heart disease, diabetes, and cancer combined.4 Chronic pain contributes to psychological distress, social isolation, sleep disturbances, and job loss and is the major reason people visit their primary care physicians.5 Chronic pain is known to interfere with routine daily activities and negatively affect appetite, mood, energy level, and sexual activity. Persons with chronic pain often have recurrent worried thoughts about finances, family interactions, and future disability.6 It is estimated that chronic pain costs up to $635 billion annually in healthcare expenses and lost productivity in the United States alone-more than any other chronic disease.4 Treatment for chronic pain is three times more expensive than treatment for similar conditions without chronic pain.7 The burden caused by chronic pain is escalating because of the increasing average age and associated medical comorbidities that come with living longer.5 Chronic pain represents a significant public health challenge because of the lack of adequate assessment and treatment and noted disparities in the experience of pain among population subgroups.4 Opioids are known to be useful in the treatment of acute and cancer-related pain.8 It is estimated that between 5 and 8 million Americans use opioids for the management of chronic non-cancer pain.9 More recently, providers have become reluctant to prescribe opioids for the treatment of chronic non-cancer pain because of concerns regarding tolerance, dependence, and addiction, as well as uncertainty about their long term benefit in this setting.10 There has been a dramatic increase in opioid-related deaths,11 and significant media attention to concerns of addiction predominately from prescription opioid use,12 resulting in what has been known as the “opioid crisis.”13,14 This crisis was attributed, in part, to the steady increase in the use of prescription opioids in the United States,15,16 that was seen as the main contributing factor to the increased incidence of prescription opioid abuse,17 and opioidrelated overdoses and hospitalizations.11,18 In the United States,

prescription opioids are responsible for more deaths than cocaine and heroin combined and are known as the most abused drug class.19,20 Although this percentage has been gradually decreasing, for a time the United States consumed an estimated 80% of all prescription opioids worldwide.21 Persons who abused prescription opioids in the past believed that they were safer and more accessible than street drugs, often available as left-over medication from family and friends, and perceived to be pure because of increased regulations on the manufacturing of prescription drugs. Many providers who manage patients with chronic pain have limited training in the assessment and treatment of pain. They are unaware of risk assessment strategies and methods for close monitoring of persons receiving prescription opioids. Studies have shown that those at risk of misusing opioids tend to be the ones most likely to be prescribed opioids for pain.22 In this chapter, we present definitions of terms related to opioid misuse and abuse and share information on the prevalence of prescription opioid misuse. We will give an overview of risk factors and risk assessment strategies designed to improve opioid compliance. Last, we will briefly discuss behavioral interventions designed to improve and maximize compliance and explore future considerations for improving patient engagement.

Terminology It is important to have a clear understanding of the terms used to describe the problem of prescription opioid abuse. Often abuse is used to describe non-medical use, misuse, and/or addiction. Therefore it is important to first define the terms used to describe this multidimensional problem. The definitions used in this chapter are presented in Table 51.1. For the purpose of this chapter, we define abuse as any repeated use of an illegal drug or the intentional self-administration of a medication for the express purpose of altering one’s state of consciousness and achieving euphoria (such as getting high).23,24 In contrast, misuse is the use of any drug in a manner other than indicated or prescribed, but not necessarily with unlawful intent. For example, a patient may split a pill to reduce the dose or double-up on the dose for added pain relief. In contrast, addiction is a primary,

727

728

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

TABLE 51.1

Definitions of Terms

Term

Definition

Aberrant drug-related behavior

Any behaviors that suggest the potential presence of substance abuse or addiction.

Abuse

Use of an illegal drug or the intentional self-administration of a medication for a non-medical purpose such as altering one’s state of consciousness, e.g. getting high.

Addiction

A primary, chronic, neurobiologic syndrome characterized by behaviors that include one or more of the following: (1) impaired control over drug use, (2) compulsive use (that may interfere with function and performance of regular duties), (3) continued use despite harm, and (4) craving (e.g. preoccupation and obsession).

Diversion

The transfer of a controlled substance from a lawful to an unlawful channel of distribution or use.

Misuse

Use of any drug in a manner other than indicated or prescribed, but not necessarily with unlawful intent.

Physical dependence

A state of adaptation manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of drug, and/or administration of an antagonist.

Pseudoaddiction

The presence of aberrant behaviors suggestive of abuse (e.g. “doctor shopping”) that in reality signifies undertreated pain.

Tolerance

The need for increasing doses to obtain the same effect.

chronic, neurobiologic syndrome characterized by behaviors that include impaired control over drug use, compulsive use (that may interfere with function and performance of regular duties), craving, and continued use despite harm. Addiction refers to a behavioral pattern of substance abuse characterized by overwhelming involvement with the use of a drug. The compulsive use of the drug results in physical, psychological, and social harm to the user, and use continues despite this harm. Iatrogenic addiction is an addiction that results from exposure to opioids for acute pain. Aberrant drug-related behaviors are any behaviors that suggest the potential presence of substance abuse or addiction (e.g. “doctor shopping”).10,25–27 Pseudoaddiction has been a term used to describe behavior that was thought to reflect addiction but which disappeared after suitable amounts of medication was given for the treatment of pain.28 For example, it was thought that any patient with undertreated pain, due perhaps to the provider’s fear of addiction or abuse, who sought care from another physician for the purpose of adequately relieving pain might have had signs of pseudoaddiction. It is uncertain whether this condition exists and was used in the past to support the increased use of opioids. However, this term has recently gone out of fashion. Physical dependence is a condition of physiologic withdrawal after the dose of many medications, including an opioid, is rapidly reduced. Withdrawal symptoms are generally specific for the class of substance involved, e.g. opioids, and benzodiazepines. This is noted to occur among all mammals who have been administered opioids over time. After a rapid dose reduction, including decreased blood levels of an opioid and/or administration of an antagonist, signs of withdrawal may include diarrhea, rhinorrhea, piloerection, insomnia, irritability, and psychomotor agitation.29,30 The effects of opioid withdrawal can be reduced by gradually tapering the dose downward over an extended period. Physical dependence is a common condition of anyone actively using opioid therapy on a chronic basis and is not considered an addiction. Tolerance is another phenomenon associated with the long term use of opioids, where there is a need for increasing doses to obtain the same effect.23,24,31 Diversion has been defined by the Drug Enforcement Administration as a redirection of a controlled substance for use in an

unlawful manner.32 Drugs can be diverted by being stolen or being sold on the street. Additionally, it includes obtaining the medication from a legitimate source for legitimate means but used for an illegal purpose such as selling the drug to get high. Among adults 50 years and older, the main source of receiving opioids is through a physician’s prescription, with this age group making up 25% of the individuals who self-reported opioid misuse. For individuals under 50 years old, it is more commonly reported that opioids were obtained from an illegal source.33

Prevalence of Prescription Opioid Misuse and Addiction Addiction is generally understood to be a chronic condition from which recovery is possible. However, the underlying neurobiologic dysfunction, once manifested, is believed to persist.12,34 Therefore the prescription of opioid analgesics to a patient with a predisposition for or history of addiction could initiate an addictive disorder or relapse. Some of the disparity between the results of studies reporting an extremely low risk of addiction for hospitalized patients and the high proportion of substance abuse in the general population can be explained by the unreliable methodology of existing surveys of iatrogenic addiction (e.g. addiction as a result of exposure to opioids for acute pain) in hospitalized patients. Although there has been a lack of high-quality evidence or consistent findings on the prevalence of substance abuse among persons with chronic pain, there is a trend to suggest that escalating doses of opioids among those with chronic non-cancer pain is associated with increased risks of substance use disorder and opioid-related adverse outcomes.19 Rates of opioid misuse and addiction among persons with chronic pain have been varied and were thought to be much higher than initially published in the 1980s.15,21,35 One reason given for the variable rates of addiction was because they were not obtained from representative chronic pain patients,30 and vague definitions of addiction were used.36 The studies in question examined the retrospective prevalence of cases rather than the incidence and onset of new cases of addiction.37,38 Additionally, those

 

CHAPTER 51

Evaluation for Opioid Management: Opioid Misuse Assessment Tools and Drug Testing in Pain Management

perceived to have mental health issues or substance abuse problems were often excluded. Patients with chronic pain often present with a mood disorder and a comorbid psychiatric condition, and they are likely to be prescribed opioids. Thus it has been assumed that early rates of prescription opioid abuse were low. Unfortunately, there are limited large-scale studies designed to determine reliable rates of addiction among individuals treated for chronic pain. A systematic review and meta-analysis of the incidence of iatrogenic opioid dependence and abuse revealed a pooled incidence of 4.7%.36 The authors found that when diagnostic and statistical manual of mental disorders (DSM) criteria were used, the rates of addiction were higher (11.3%) than when using ICD-9 criteria (1.3%). Vowles et al.39 found wide variability in prescription opioid addiction rates across studies (i.e. range: 8%–34.1%). The differences observed in opioid addiction rates are assumed to be due, in part, to differences in study populations, study designs, and settings in which opioids were prescribed. Unfortunately, when addiction is based on DSM-V criteria (opioid use disorder), the reported addiction rates tend to be much higher.

Prescription Opioid Misuse Risk Factors Guidelines from the Centers for Disease Control (CDC) recommend that healthcare providers make every effort to identify abuse and possible diversion of prescription opioids.18,32 The guidelines suggest that particular problematic behavior, such as seeking prescriptions from multiple providers, using illicit drugs, selling or diverting medications, snorting or injecting medications, and using drugs in a manner other than the way they were intended, should be carefully monitored. Despite the need to identify misuse of opioids and limit inappropriate prescribing, healthcare professionals need to provide appropriate pain relief for individuals who have evidence of genuine pain problems.29 Additional problems associated with chronic use of opioids include psychological dependence,40,41 impaired cognition, problems with psychomotor function,42 and possible development of opioid-induced hyperalgesia (OIH).43,44 High-dose opioids, which some define as greater than 180 mg morphine equivalent a day, have been known to lead to sleep apnea, respiratory depression, and disordered breathing. Of most concern is the risk that greater dependence on opioids can lead to addiction.12,21 This strongly supports the need for risk assessment at the point of opioid initiation and for continued careful monitoring,15,45,46 maintaining lower doses of opioids when indicated,18,20,47 tracking compliance,10,24,48 and offering an interdisciplinary approach to pain management.49,50 There are identifiable characteristics of those individuals who are at lower risk of misusing opioids. In particular, those who are older, who present with stable mood, have a record of being reliable in keeping appointments and in following medical recommendations, who have no history of overusing medications, who have no cognitive deficits, and who are generally pleasant are at lower risk of opioid misuse.20,50 Equally, there are characteristics of those who are at higher risk of medication misuse. These include those who are younger and have a history of risk-taking behavior, who have a history of legal problems, who are in frequent contact with others who misuse substances, who have a mood disorder, and who have a personal or family history of substance abuse.50 Additional factors include previous drug or alcohol rehabilitation, history of early childhood abuse and trauma, multiple stressors, smoking cigarettes, or regularly using other substances that lead to dependence (Table 51.2).51–53

TABLE 51.2 • • • • • • • • • • • •

729

Risk Factors for Opioid Misuse

Family history of substance abuse Personal history of substance abuse Young age Mood disorder such as extreme anxiety, depression, and/or irritability History of criminal activity and/or legal problems, including driving under the influence History of childhood abuse and/or trauma Regular contact with others who misuse substances Problems with past employers, family members, and friends (personality disorder) Risk-taking or thrill-seeking behavior Heavy tobacco use or use of substances that lead to dependence Psychosocial stressors Prior drug and/or alcohol rehabilitation

An important reminder to anyone prescribed opioids for chronic pain is that they ultimately are the ones who must manage the opioids in a responsible manner, and they need to be vigilant about factors that may contribute to opioid abuse. It is important to remind anyone using prescription opioids for pain of factors that may increase their susceptibility of encountering problems. These factors may include impulsivity,54,55 predispositions to selfmedicate symptoms of anxiety or depression,56,57 and experiencing drug liking or craving of the medications.58,59

Negative Affect and Opioid Misuse We know that there is an overlap between chronic pain and mood disorders, including depression, anxiety, and irritability perceived by some to be a normal response to prolonged pain.60,61 Psychiatric comorbidity is common among chronic pain patients.62 It is estimated that 30% to 40% of pain patients in primary care centers have a significant psychiatric comorbidity and show signs of negative affect.63,64 These percentages increase between 50% and 75% among patients treated at specialty pain centers.65 Additionally, there is a high incidence of self-reported physical or sexual abuse and early childhood trauma among persons with chronic pain,66 making psychiatric problems the most prevalent comorbidity in these patients.67,68 There is a well-established relationship between increased self-reported emotional distress and increased pain sensitivity and pain-related disability.68,69 An analysis of large insurance claims data performed by PharmMetrics of 36 million patients from 61 health plans comparing patients with anxiety and depression with matched controls found that those who had evidence of negative affect (high anxiety and depression) had more somatic complaints, more pain, and had greater utilization of medical services.70

Opioid Therapy and Mood Disorder In an earlier survey study conducted by Arkinstall and colleagues, patients prescribed opioids were found to have a 50% prevalence of a mood disorder.71 Grattan and others reported that it was more likely that patients would be prescribed opioids for their mood disorder and affective distress than their reported pain severity or physical pathology.65 Several studies have demonstrated that persons with chronic pain with significant psychopathology tend to demonstrate poorer outcomes than those with minimal psychopathology. These individuals

730

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

report greater pain intensity and more pain-related disability.72,73 Elevated anxiety and depression are common among chronic pain patients, and having a mood disorder is correlated with poor rates of return-to-work.74 In a blinded controlled trial examining the benefits of IV morphine compared with saline among chronic pain patients, those individuals who demonstrated higher levels of psychopathology reported the least reduction of pain when administered IV morphine.72 Thus there is consistent evidence that individuals with chronic pain and significant negative affect benefit less from opioids and many other treatments designed to control their pain.50,67 Studies have found that individuals with chronic pain and high rates of emotional distress and negative affect are much more likely to misuse opioid medications.65,75,76 There is some indication that certain patients use prescription opioids to help reduce their anxiety and depression.74 Although many patients with emotional distress and a mood disorder also have a substance use disorder, a study among chronic pain patients without a history of substance abuse showed that having increased anxiety and depression increased the incidence of opioid misuse.59,77 Taken together, there is evidence that attempts at reducing affective distress can cause reduced risk of substance abuse.58

in predicting opioid misuse among chronic pain patients.101 A systematic review by Lawrence and colleagues (2017) found the SOAPP-R, COMM, and PMQ to be most valid to assess the risk of problematic analgesic use among patients with chronic pain.102 The ORT has been popular because of its brevity (five items), and a revised ORT that omitted the question about prior childhood sexual abuse now finds comparable opioid risk between men and women.103 A brief checklist designed to reflect the content of a standard opioid agreement (opioid compliance checklist, OCC) has also been validated and used clinically.10,25 Although there are weaknesses with using any self-report measure of opioid risk, and it is always possible to under report problems, these validated self-report screening tools are one of several ways to gain some understanding of the chronic pain patient and help identify those with a predisposition for opioid misuse. It is important to state that while higher scores on these measures may not eliminate the option of prescribing opioids, they may draw attention to the need for more careful tracking and monitoring of certain individuals.102 Brief descriptions of these assessments and other tools are provided in Table 51.3.

Risk Assessment Tools

Practice Guidelines

With recent attention to the “opioid crisis,” healthcare providers have been challenged with the need to provide appropriate relief from pain while avoiding risks associated with the use of opioids. This has contributed to a greater need to employ risk assessment measures to identify those who are more predisposed to misuse of prescription opioids.40,41 Guidelines from healthcare organizations and regulatory institutions have strongly encouraged the use of risk assessment screening tools.78,79 Stressed within these guidelines is the importance of thoroughly evaluating all potential users of prescription opioids by conducting a complete social and medical history, with a medical examination and a review of medical records. There are several validated and reliable self-report screenings that can help to assess the risk of opioid misuse. Unfortunately, many of the recommended ways to assess substance use disorders and alcohol dependence, particularly through the criteria outlined in the DSM, fifth edition (DSM-V), have not been validated with chronic pain patients.80 These measures tend to use signs of opioid dependence and tolerance as indicators of abuse and addiction when no abuse exists. Over the years, several screening measures have been developed that have been shown to be particularly useful in assessing the risk of prescription opioid abuse among persons with chronic pain. These include the Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R),81–83 that is a trait measure of abuse risk. Shorter versions of this measure84–86 and a Spanish translation exist.87 A sister questionnaire that assesses states of abuse risk (e.g. can change over time) is the Current Opioid Misuse Measure (COMM).88,89 Both the SOAPP-R and COMM have been crossvalidated and used extensively in clinics and research protocols.90,91 A shortened version of the COMM also exists.92 Other self-report questionnaires include the Opioid Risk Tool (ORT),93,94 the Diagnosis, Intractability, Risk, and Efficacy (DIRE) scale,95 the Drug Use Disorders Identification Test (DUDIT),96 the Drug Abuse Screening Test (DAST),97,98 the Screening Instrument for Substance Abuse Potential (SISAP),99 the Pain Medication Questionnaire (PMQ),100 and a single item of catastrophizing that is useful

Treatment approaches are needed that balance the proper treatment of chronic pain while minimizing the risks associated with opioid use. There has been a dramatic increase in the use of opioids for non-cancer pain over the past few decades, and guidelines from the CDC and elsewhere have been published about the steps needed to reduce abuse, diversion, and addiction as a result of prescription opioids.104,105 These guidelines strongly recommend using validated screening instruments designed to identify individuals at higher risk of opioid misuse in clinical practice. The goal of these screening instruments is to reduce the risk of iatrogenic addiction. Risk assessment should be combined with a review of past medical records and a thorough history and physical examination—since each assessment process alone may not be accurate in identifying those individuals who are not suitable candidates for opioids or who might need very careful monitoring. Initial screening should also include the history of and current comorbidity of substance abuse. Urine toxicology screening is recommended, and the monitoring of prescribed opioids through a prescription drug monitoring program (PDMP). In addition, opioid therapy agreements and the practice of universal precautions are highly recommended.106,107 Together, these combined strategies help to reliably stratify risk levels and help tailor treatments to match this risk. There has been a recent trend to prescribe lower daily doses of opioids over a shorter period,108 although a recent systematic review suggests that prescribing higher doses of stronger opioids does not always predict increased incidence of opioid dependence and abuse.36

Strategies for Managing High Risk Patients

Urine Toxicology Screening The use of urine toxicology screens to establish prescription opioid compliance is well documented.109 Most hospital-based toxicology screens use immunoassay to determine the presence or absence of a class of drug in the urine sample. The use of gas chromatology/ mass spectrometry (GCMS) allows the determination of the quantity of each drug present. GCMS offers a test of creatinine levels to determine possible tapering and establishing the absence

TABLE 51.3

 

CHAPTER 51

Evaluation for Opioid Management: Opioid Misuse Assessment Tools and Drug Testing in Pain Management

731

Opioid and Medication Abuse Screening Assessments

Name of Questionnaire

References

Purpose of Questionnaire

Current Opioid Misuse Measure (COMM)

Butler et al. 2007; 2010; McCaffrey, 201988,89,92

Seventeen item self-report assessment developed for identifying chronic pain patients who are currently misusing prescription opioids. The opioid risk cutoff score is nine. The reliability and predictive validity of the COMM were found to be highly significant. A shorter version has been developed and validated.

Diagnosis, Intractability, Risk, and Efficacy (DIRE)

Belgrade et al. 200695

Predicts the feasibility of long term opioid treatment for non-cancer pain. Also used to pinpoint beneficial factors, if any, of an individual’s opioid use. The opioid risk cutoff score is 14.

Drug Abuse Screening Test (DAST-2)

Tiet, 2017; Giguere, 201797,98

Two item version of the longer DAST to assess evidence of substance use disorders. This test has not been validated for chronic pain patients.

Drug Use Disorders Identification Test (DUDIT)

Hildebrand, 201596

Eleven item drug use disorders assessment tool that was developed for those exposed to opioid analgesic therapy. This was not initially developed for persons with chronic pain.

Opioid Compliance Checklist (OCC)

Jamison et al. 2014; 201610,25

Twelve item questionnaire developed to assess compliance for chronic pain patients on long term prescription opioids. Five items were found to best predict subsequent aberrant behaviors based on multivariate logistic regression analyses.

Opioid Risk Tool (ORT)

Webster and Webster, 2005; Webster and Dove, 2007; Cheatle et al. 201993,94,103

Five item checklist that allows the physician to determine if a patient will display aberrant drugrelated behaviors. The opioid risk cutoff score is eight. An updated version without a history of childhood sexual abuse has been validated.

Pain Assessment and Documentation Tool (PADT)

Passik et al. 2004137

Forty-one item questionnaire that provides extensive documentation of the patient’s progress and objectively monitors a patient’s care. There is no numeric scoring method for this assessment.

Pain Catastrophizing Item

Lutz, 2017101

One item from the coping strategies questionnaire assessing catastrophizing that is shown to predict the risk of opioid misuse. It is highly correlated with the SOAPP-R.

Prescription Medication Questionnaire (PMQ)

Holmes, 2006100

A self-report questionnaire designed to assess risk for opioid medication misuse among chronic pain patients.

Prescription Drug Use Questionnaire (PDUQ)

Compton et al. 2008116

Forty-two item questionnaire used to identify subjects who are likely to be nonaddicted, substance abusing, or substance-dependent.

11. Screening Assessment for Substance Abuse Potential (SISAP)

Coambs et al. 199699

Five item self-report screening questionnaire for substance abuse potential catered mostly toward alcohol abuse.

12. Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

Butler et al. 2004; Butler et al. 2008; Butler et al. 2009; Butler et al. 2013; Finkelman et al. 2015, 2017; Black et al. 201881–87

Twenty-four item self-administered screening tool designed to predict aberrant medication-related behaviors for chronic pain patients being considered for long term opioid therapy. The opioid risk cutoff score is 18. The reliability and predictive validity of the SOAPP-R were found to be highly significant. Shorter versions have been developed and validated.

of prescribed opioids or the presence of nonprescribed or illicit substances.110 Providers rely on regular urine toxicology screenings as an objective way to assess compliance. Over time, despite their limitations, these tests have become more accurate with fewer false positives.109,111 For those prescribed opioids for pain who are perceived to be at lower risk of opioid misuse, a toxicology screening at least once a year is recommended. More frequent screens are recommended for those who are identified as at higher risk of opioid misuse.112 In a study of 226 patients with chronic pain, 46.5% of these patients prescribed opioids for pain showed evidence of an abnormal urine toxicology screen, which underscores the importance of urine screens.113 Many clinics use immunoassay urine screens as the first line of analysis, followed by the completion of GCMS

testing when it is important to detect the specific level of drug metabolite in the urine. Because random urine toxicology screening has revealed a high incidence of abnormality, the use of self-report measures of risk alone may not be optimal, and a combination of urine toxicology screens, opioid checklists, and tracking the PDMP would be optimal.

Prescription Drug Monitoring Program There has been an increased focus on government and regulatory action to help reduce opioid abuse and diversion. One instituted state-wide initiative has been PDMPs. This effort was designed to analyze and monitor electronic prescription data primarily from pharmacies. There has been a gradual increase in the use of PDMP

732

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

data among states.3 The goal is to obtain reliable data collection of opioid use to help identify the use of prescription opioids.

Opioid Therapy Agreements Specialty pain clinics have used opioid therapy agreements for many years to inform patients who are prescribed opioids for pain about the expectations and the proper use of opioids. These agreements are designed to inform the patients of potential risks with opioid use and to improve patient compliance with opioid medication.106,114 These agreements serve to educate the patients in their need to be responsible with their use of prescription opioids and to document the risks associated with misuse. By agreeing to the expectations of use, the providers and patients can acknowledge in writing what would be expected of all the parties for adherence to opioid use. Although the evidence is weak that opioid therapy agreements improve adherence, they are universally recommended. In most opioid therapy agreements, there are conditions required of the patient to remain on opioid therapy. Although not a legal document, the patients are made aware of potential risks and adverse effects associated with opioid use.10,25 Typically, patients are informed that they should use the medication only as prescribed, that they should receive opioid medication only from one provider and one pharmacy, that they will not be given extra medication if they run out early over the designated time of the prescription, and additional medication will not be substituted if lost or stolen. They also agree to periodic urine toxicology screens and to be responsible for keeping their clinic appointments. If, as perceived by the prescribing physician, it is determined that the risk of opioid therapy outweigh the benefits, then a gradual tapering of the opioids would take place.3,53 It is important to review each component of the agreement with the patient and to have a signed copy saved in the electronic medical record. Clarification of all components of the agreement is important so that all parties are aware of what is expected. Signing the agreement and distributing copies to all involved helps to acknowledge the conditions and responsibilities set by the clinic. It is recommended that this agreement be read and signed each year that opioids are being prescribed for pain. This will serve to remind the persons with pain of their responsibilities for using prescription opioids and the need to be very careful with these substances. Additionally, patients should be reminded periodically that violation of the agreement could result in a gradual discontinuation of the opioids. The opioid compliance checklist is an eight item checklist that is administered monthly to those prescribed opioids for pain and was created based on a typical opioid agreement.10,25 It serves to document adherence of the opioid users. The responsibility of maintaining compliance with opioids is up to the patients receiving this medication, but physicians should remain vigilant in tracking compliance and verifying adherence.3 Unfortunately, the evidence in support of the effectiveness of opioid therapy agreements in reducing opioid misuse and abuse has been weak, but their use is very much encouraged in opioid therapy guidelines.115

Behavioral Strategies to Improve Opioid Treatment Adherence Providers are often conflicted about ways to best manage chronic pain patients who have clear pathology to account for their pain but who also are at high risk for opioid misuse. Many choose

to avoid the use of prescription opioids altogether. If the need arises to consider opioid therapy for individuals who have predisposing factors for opioid misuse (e.g. postoperative pain; see Table 51.2), certain strategies may be needed to help increase opioid compliance and avoid opioid abuse. In a randomized trial, high risk patients with primary lower back pain either received interventions to assist with improving opioid compliance or were assigned to a treatment as the usual control condition. A low risk patient group was also recruited. All subjects were followed for six months. Those in the high risk experimental group were asked to give a urine toxicology screen at each monthly appointment, complete an opioid compliance checklist, attend individual cognitive behavior motivational counseling, and participate in monthly group sessions designed to address ways to avoid opioid misuse.53 Subjects who admitted to opioid misuse on the prescription drug use questionnaire (PDUQ),116 who had abnormal urine, or who showed a positive score on the physician-rated addiction behavior checklist (ABC)117 were classified as positive on the opioid misuse index (OMI). Results showed that those high risk subjects who were carefully monitored and who received motivational counseling showed significantly lower opioid misuse indexes than the high risk controls and, in fact, had as low an indication of opioid abuse as those designated as low risk subjects. These findings suggest that risk assessment and careful monitoring with cognitive behavior support can significantly improve opioid compliance and adherence. It has now been recommended that anyone prescribed opioids for pain should be administered a comprehensive assessment. This would include a self-report questionnaire and a detailed history and physical. All patients should read and sign an opioid agreement and be monitored based on their level of risk. However, for those at greatest risk for opioid misuse, a lower dose of prescription opioids, regular urine screens, completion of an opioid compliance checklist, and motivational counseling would be recommended. Some providers encourage the use of pill counts.3 The ultimate result is that with careful monitoring and risk assessment, the opportunities for opioid misuse will be mitigated.46

Future Considerations Newer opioid analgesics have been recently developed with the goal of deterring abuse. These so-called abuse-deterrent opioids intend to prevent abusers from injecting, crushing, snorting, and otherwise altering long-active opioid formulas.118,119 The goal is to create safe opioids to be used by patients while making them unattractive to those who want to use the opioids for purposes leading to euphoria. Different formulations have been developed that combine the opioid with an antagonist that is released when the drug is compromised.120,121 There is evidence that abuse-deterrent opioids have decreased the incidence of prescription opioid abuse in long-acting opioids.122,123 Innovative technology has been used to track opioid compliance and to educate pharmacists and physicians, which will continue to be developed. Containers and patient-specific serialized blister-packaging of opioids can be electronically monitored along with the date and time a medication is taken. There has been a rapid growth of mobile phone applications (apps) in pain assessment and management.124–126 The advent of mHealth (mobile health) technology using short messaging service and activity monitors has promoted ways for patients to communicate with healthcare providers and track activity between clinic visits.124,127 Not only is this technology useful in collecting information in

 

CHAPTER 51

Evaluation for Opioid Management: Opioid Misuse Assessment Tools and Drug Testing in Pain Management

clinical trials, but clinics can use this information to help document outcome and compliance. Currently, 95% of the world population has access to the internet, and remote tracking and monitoring are much more accessible to patients worldwide. There is a broadening of access to information and personal health data, which can improve coping and potentially reduce healthcare utilization. There is a call for better pain education among providers,47 increased use of social media, incorporation of online peer education, and daily support to chronic pain patients on opioid therapy.128–130 The future will likely include the use of artificial intelligence to identify those individual characteristics to help predict the optimal outcome from opioid therapy.130,131 Future identification of markers for opioid benefit and abuse within endogenous chemical reactive systems will shed light on our understanding of tolerance, OIH, craving, and potential opioid misuse.132 Longitudinal studies investigating demographic

733

variables or gender, ethnic origin, and personality characteristics will help in creating empirically based practice guidelines. Nanotechnology is used to deliver treatment to a specific targeted area, and the development of other delivery strategies like topical preparations will add to the treatment armamentarium. Increased understanding of how acute pain develops into a chronic pain condition will aid in identifying those at risk for developing chronic pain. Increasing the use of genome research and genetics testing to help identify markers for potential opioid abuse will make a positive impact on opioid risk assessment.133,134 There has been a recent emphasis on the use of behavioral interventions such as mindfulness to reduce craving and improve coping.135,136 The overall reduction of suffering related to chronic pain would be the long-range goal, and increased understanding of the mechanisms contributing to pain would be what is most hoped for in the future.

Summary and Conclusions Chronic pain is a global health problem that exacts enormous costs both in terms of money spent treating pain and lost productivity because of pain. Chronic pain inflicts an enormous human toll of suffering and disability and is often associated with psychiatric comorbidities such as emotional distress, negative affect, depression, and anxiety. There is a corresponding relationship between mood disorder and opioid misuse, abuse, and/or diversion. There has been an opioid epidemic because of lax opioid prescribing practices in the past. The future of opioid prescribing calls for careful monitoring

and risk assessment, opioid therapy agreements, urine toxicology screens, the use of PDMPs, and behavioral interventions designed to improve opioid compliance. There is a role for innovative technology to help healthcare providers manage chronic pain patients who are prescribed opioids for pain. Support is critically needed for future controlled trials to help in our understanding of the best ways to offer and manage chronic opioid therapy. Continued sponsorship of research to advance our empirical understanding of the use of opioids for pain is critically needed.

Key Points • Chronic pain inflicts an enormous human toll of suffering and disability and is often associated with psychiatric comorbidities such as emotional distress, negative affect, depression, and anxiety. • There is a corresponding relationship between mood disorder and opioid misuse, abuse, and/or diversion. • Because of suboptimal opioid prescribing practices in the past, there has been an opioid epidemic, and the future of opioid prescribing calls for careful monitoring and risk assessment.

• There are several validated and reliable self-report screenings that can help to assess the risk of opioid misuse. • Opioid therapy agreements, urine toxicology screens, the use of PDMPs, and behavioral interventions are designed to improve opioid compliance.

Suggested Readings

Kaye AD, Jones MR, Kaye AM, et al. Prescription opioid abuse in chronic pain: An updated review of opioid abuse predictors and strategies to curb opioid abuse: Part 1. Pain Physician. 2017;20:S93–S109. Lawrence R, Mogford D, Colvin L. Systematic review to determine which validated measurement tools can be used to assess risk of problematic analgesic use in patients with chronic pain. Br J Anaesth. 2017;119:1092–1109. McAuliffe Staehler TM, Palombi LC. Beneficial opioid management strategies: A review of the evidence for the use of opioid treatment agreements. Subst Abus. 2020;41:208–215. Pergolizzi JV Jr, Taylor R Jr, LeQuang JA, et al. Managing severe pain and abuse potential: The potential impact of a new abuse-deterrent formulation oxycodone/naltrexone extended-release product. J Pain Res. 2018;11:301–311. Reed B, Kreek MJ. Genetic vulnerability to opioid addiction. Cold Spring Harb Perspect Med. 2020;a039735. Voon P, Karamouzian M, Kerr T. Chronic pain and opioid misuse: A review of reviews. Subst Abuse Treat Prev Policy. 2017;12:36. Wolff C, Dowd WN, Ali MM, et al. The impact of the abuse-deterrent reformulation of extended-release OxyCon26tin on prescription pain reliever misuse and heroin initiation. Addict Behav. 2020;105:1068.

Ballantyne JC, Sullivan MD, Koob GF. Refractory dependence on opioid analgesics. Pain. 2019;160:2655–2660. Garland EL, Hanley AW, Kline A, Cooperman NA. Mindfulness-oriented recovery enhancement reduces opioid craving among individuals with opioid use disorder and chronic pain in medication assisted treatment: Ecological momentary assessments from a stage 1 randomized controlled trial. Drug Alcohol Depend. 2019;203:61–65. Hayes CJ, Krebs EE, Hudson T, et al. Impact of opioid dose escalation on the development of substance use disorders, accidents, self-inflicted injuries, opioid overdoses and alcohol and non-opioid drug-related overdoses: A retrospective cohort study. Addiction. 2020;115:1098–1112. Higgins C, Smith BH, Matthews K. Incidence of iatrogenic opioid dependence or abuse in patients with pain who were exposed to opioid analgesic therapy: A systematic review and meta-analysis. Br J Anesthesia. 2018;120:1335–1344. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011. Jamison RN, Edwards RR. Risk factor assessment for problematic use of opioids for chronic pain. Clin Neuropsychol. 2013;27:60–80. Jamison RN, Ross EL, Michna E, et al. Substance misuse treatment for high-risk chronic pain patients on opioid therapy: A randomized trial. Pain. 2010;150:390–400.

The references for this chapter can be found at ExpertConsult.com.

References 1. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: The IASP classification of chronic pain for the international classification of diseases (ICD-11). J Pain. 2019;160:19–27. 2. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011;11:770. 3. Jamison RN, Edwards RR. Risk factor assessment for problematic use of opioids for chronic pain. Clin Neuropsychol. 2013;27:60–80. 4. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011. 5. Mills S, Nicolson K, Smith B. Chronic pain: A review of its epidemiology and associated factors in population-based studies. Br J Anesth. 2019;123:e273–e283. 6. Katz J, Rosenbloom BN, Fashler S. Chronic pain, psychopathology, and DSM-5 somatic symptom disorder. Can J Psychiatry. 2015;60:160–167. 7. Gaskin DJ, Richards P. The economic costs of pain in the United States. J Pain. 2012;13:715–724. 8. Grewal N, Huecker MR. Opioids. In: StatPearls. Treasure Island, FL: StatPearls Publishing LLC; 2019. 9. National Institutes of Health. The Role of Opioids in the Treatment of Chronic Pain: Final Report. National Institutes of Health; U.S. Department of Health and Human Services, Washington DC, USA 2014. 10. Jamison RN, Martel MO, Edwards RR, et al. Validation of a brief Opioid compliance checklist for patients with chronic pain. J Pain. 2014;15:1092–1101. 11. Centers for Disease Control and Prevention. Prescription Pain Killer Overdoses. Centers for Disease Control and Prevention; 2012. 12. Everitt BJ, Robbins TW. Drug addiction: Updating actions to habits to compulsions ten years on. Annu Rev Psychol. 2016;67:23–50. 13. Rummans TA, Burton MC, Dawson NL. How good intentions contributed to bad outcomes: The opioid crisis. Mayo Clin Proc. 2018;93:344–350. 14. Häuser W, Schug S, Furlan AD. The opioid epidemic and national guidelines for opioid therapy for chronic non-cancer pain: A perspective from different continents. Pain Rep. 2017;2:e599. 15. Han B, Compton WM, Blanco C, Crane E, Lee J, Jones CM. Prescription opioid use, misuse, and use disorders in U.S. adults: 2015 national survey on drug use and health. Ann Intern Med. 2017;167:293–301. 16. Kiang MV, Humphreys K, Cullen MR, Basu S. Opioid prescribing patterns among medical providers in the United States, 2003-17: Retrospective, observational study. BMJ. 2020;368:el6968. 17. Lovrecic B, Lovrecic M, Gabrovec B, et  al. Non-medical use of novel synthetic opioids: A new challenge to public health. Int J Environ Res Public Health. 2019:16. 18. Dowell D, Haegerich T, Chou R. CDC guideline for prescribing opioids for chronic pain-United States, 2016. JAMA. 2016;315:1624–1645. 19. Voon P, Karamouzian M, Kerr T. Chronic pain and opioid misuse: A review of reviews. Subst Abuse Treat Prev Policy. 2017;12:36. 20. Hayes CJ, Krebs EE, Hudson T, et al. Impact of opioid dose escalation on the development of substance use disorders, accidents, self-inflicted injuries, opioid overdoses and alcohol and non-opioid drug-related overdoses: A retrospective cohort study. Addiction. 2020;115:1098–1112. 21. Mital S, Windle M, Cooper HLF, Crawford ND. Trends in nonmedical prescription opioids and heroin co-use among adults, 2003-2014. Addict Behav. 2018;86:17–23. 22. Jamison RN, Sheehan KA, Scanlan E, et al. Beliefs and attitudes about opioid prescribing and chronic pain management: Survey of primary care providers. J Opioid Manage. 2014;10:375–382. 23. American Society of Addiction Med, Definition of addiction, 2011. https://www.asam.org. Accessed September 2, 2021. 24. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. Washington, DC: American Psychiatric Association; 2013.

25. Jamison RN, Martel MO, Huang CC, et al. Efficacy of the opioid compliance checklist to monitor chronic pain patients receiving opioid therapy in primary care. J Pain. 2016;17:414–423. 26. Gilson AM, Kreis PG. The burden of the non-medical use of prescription opioid analgesics. Pain Med. 2009;10:S89–100. 27. McDonough M, Johnson JL, White JM, et  al. Measuring opioid dependence in chronic pain patients: A comparison between addiction clinic and pain clinic patient populations. J Opioid Manag. 2019;15:285–293. 28. Wikipedia. Pseudoaddiction: https://en.wiktionary.org>wiki> pseudoaddiction. Accessed September 1, 2021 29. Ballantyne JC, LaForge SK. Opioid dependence and addiction during opioid treatment of chronic pain. Pain. 2007;129:235–255. 30. Ballantyne JC, Sullivan MD, Koob GF. Refractory dependence on opioid analgesics. Pain. 2019;160:2655–2660. 31. American Academy of Pain Medicine. Use of opioids for the treatment of chronic pain. American Academy of Pain Medicine. Orlando, Florida. 2013 https://www.ashp.org/-/media/D943737A 8911463F81A8682D62AF4EF6.ashx. 32. Eiden C, Ginies P, Nogue E. High prevalence of misuse of prescribed opioid analgesics in patients with chronic non-cancer pain. J Psychoactive Drugs. 2019;51:371–376. 33. Schuler MS, Dick AW, Stein BD. Heterogeneity in prescription opioid pain reliever misuse across age groups: 2015-2017 national survey on drug use and health. J Gen Intern Medi. 2020;35:792–799. 34. Fluyau D, Charlton TE. Addiction. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2019. 35. Dydyk AM, Jain NK, Gupta M. Opioid Use Disorder. Treasure Island, FL: StatPearls Publishing; 2020. 36. Higgins C, Smith BH, Matthews K. Incidence of iatrogenic opioid dependence or abuse in patients with pain who were exposed to opioid analgesic therapy: A systematic review and meta-analysis. Br J Anesthesia. 2018;120:1335–1344. 37. Shei A, Rice JB, Kirson NY, et  al. Sources of prescription opioids among diagnosed opioid abusers. Curr Med Res Opin. 2015;31:779–784. 38. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/ or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9:444–459. 39. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: A systematic review and data synthesis. Pain. 2015;156:569–576. 40. Darnall BD, Stacey BR, Chou R. Medical and psychological risks and consequences of long-term opioid therapy in women: Risks and consequences of long-term opioid use in women. Pain Med. 2012;13:1181–1211. 41. Kahan M, Wilson L, Mailis-Gagnon A, Srivastava A. National opioid use guideline G. Canadian guideline for safe and effective use of opioids for chronic non-cancer pain: Clinical summary for family physicians. Part 2: Special populations. Can Fam Phys. 2011;57:1269–1276. 42. Mailis-Gagnon A, Lakha SF, Louffat A, et al. Chronic non-cancer pain: Characteristics of patients prescribed opioids by community physicians and referred to a tertiary pain clinic. Can Fam Phys Méd De Famille Canadien. 2011;57:97–105. 43. Hooten WM, Mantilla CB, Sandroni P, CO Townsend. Associations between heat pain perception and opioid dose among patients with chronic pain undergoing opioid tapering. Pain Med. 2010;11:1587–1598. 44. Kum E, Buckley N, de Leon-Casasola O, et al. Attitudes towards and management of opioid-induced hyperalgesia: A survey of chronic pain practitioners. Clin J Pain. 2020;36:359–364. 45. Brunes M, Häbel H, Altman D, et  al. Risk-factors for continuous long-term use of prescription opioid drugs three years after hysterectomy; a nationwide cohort study. Acta Obstet Gynecol Scand. 2020;99:1057–1063. 733.e1

733.e2

References

46. Jamison RN, Serraillier J, Michna E. Screening before embarking: How to screen for addiction risk in Opioid prescribing. In: Ballantyne JC, Tauben DJ (eds). Expert Decision Making on Opioid Treatment. New York: Oxford University Press; 2013:27–41. 47. Deyo RA, Hallvik SE, Hildebran C, et  al. Association between initial opioid prescribing patterns and subsequent long-term use among opioid-naïve patients: A statewide retrospective cohort study. J Gen Intern Med. 2017;32:21–27. 48. Ljungvall H, Rhodin A, Wagner S, Zetterberg H, Åsenlöf P. “My life is under control with these medications”: An interpretative phenomenological analysis of managing chronic pain with opioids. BMC Musculoskelet Disord. 2020;21:61. 49. Webster F, et  al. From opiophobia to overprescribing: A critical scoping review of medical education training for chronic pain. Pain Med. 2017;18:1467–1475. 50. Jamison RN, Edwards RR, Liu X, et al. Effect of negative affect on outcome of an opioid therapy trial among low back pain patients. Pain Pract. 2013;13:173–181. 51. Orhurhu V, Olusunmade M, Urits I, et  al. Trends of opioid use disorder among hospitalized patients with chronic pain. Pain Pract. 2019;19:656–663. 52. Jamison RN, Link CL, Marceau LD. Do pain patients at high risk for substance misuse experience more pain? A longitudinal outcomes study. Pain Med. 2009;10:1084–1094. 53. Jamison RN, Ross EL, Michna E, et al. Substance misuse treatment for high-risk chronic pain patients on opioid therapy: A randomized trial. Pain. 2010;150:390–400. 54. Reynolds CJ, Vest N, Tragesser SL. Borderline personality disorder features and risk for prescription opioid misuse in a chronic pain sample: Roles for identity disturbances and impulsivity. J Pers Disord. 2019;14:1–18. 55. Groenewald CB, Patel KV, Rabbitts JA, Palermo TM. Correlates and motivations of prescription opioid use among adolescents 12 to 17 years of age in the United States. Pain. 2020;161:742–748. 56. van Amsterdam J, van den Brink W. The misuse of prescription opioids: A threat for Europe? Curr Drug Abuse Rev. 2015;8:3–14. 57. Passik SD, Lowery A. Psychological variables potentially implicated in opioid-related mortality as observed in clinical practice. Pain Med. 2011;12(Suppl 2):S36–S42. 58. Martel MO, Dolman AJ, Edwards RR, et  al. The association between negative affect and prescription opioid misuse in patients with chronic pain: The mediating role of opioid craving. J Pain. 2014;15:90–100. 59. Wasan AD, Ross EL, Michna E, et al. Craving of prescription opioids in patients with chronic pain: A longitudinal outcomes trial. J Pain. 2012;13:146–154. 60. Mittinty MM, Kindt S, Mittinty MN, et al. A dyadic perspective on coping and its effects on relationship quality and psychological distress in couples living with chronic pain: A longitudinal study. Pain Med. 2020;21:e102–e113. 61. Baldacci F, Lucchesi C, Cafalli M, et  al. Migraine features in migraineurs with and without anxiety-depression symptoms: A hospital-based study. Clin Neurol Neurosurg. 2015;132:74–78. 62. Doan L, Manders T, Wang J. Neuroplasticity underlying the comorbidity of pain and depression. Neural Plast. 2015:504691. 63. Ligthart L, Gerrits MM, Boomsma DI, Pennix BW. Anxiety and depression are associated with migraine and pain in general: An investigation of the interrelationships. J Pain. 2013;14:363–370. 64. Hawker GA, Gignac MAM, Badley E, et al. A longitudinal study to explain the pain-depression link in older adults with osteoarthritis. Arthritis Care Res. 2011;63:1382–1390. 65. Grattan A, Sullivan M, Saunders KW, et al. Depression and prescription opioid misuse among chronic opioid therapy recipients with no history of substance abuse. Ann Fam Med. 2012;10:304–311. 66. Jamison RN, Craig KD. Psychological assessment of persons with chronic pain. In: Lynch ME, Craig KD, Peng PWH (eds). Clinical Pain Management: A Practice Guide. Oxford: Wiley-Blackwell Publishing; 2011:81–91.

67. Celestin J, Edwards RR, Jamison RN. Pretreatment psychosocial variables as predictors of outcomes following lumbar surgery and spinal cord stimulation: A systematic review and literature synthesis. Pain Med. 2009;10:639–653. 68. Golob AL, Wipf JE. Low back pain. Med Clin North Am. 2014; 98:405–428. 69. Edwards RR, Wasan A, Michna E, Greenbaum S, Ross E, Jamison RN. Elevated pain sensitivity in chronic pain patients at risk for opioid misuse. J Pain. 2011;9:953–963. 70. Mclaughlin TP, Khandker RK, Kruzikas DT, Tummala R. Overlap of anxiety and depression in a managed care population: Prevalence and association with resource utilization. J Clin Psychiatry. 2006;67:1187–1193. 71. Arkinstall W, Sandler A, Goughnour B, et al. Efficacy of controlledrelease codeine in chronic non-malignant pain: A randomized, placebo-controlled clinical trial. Pain. 1995;62:169–178. 72. Wasan AD, Kaptchuk TJ, Davar G, Jamison RN. The association between psychopathology and placebo analgesia in patients with discogenic low back pain. Pain Med. 2006;7:217–228. 73. Carpenter RW, Lane SP, Bruehl S, et  al. Concurrent and lagged associations of prescription opioid use with pain and negative affect in the daily lives of chronic pain patients. J Consult Clin Psychol. 2019;87:872–886. 74. Zubatsky M, Witthaus M, Scherrer JF, et  al. The association between depression and type of treatments received for chronic low back pain. Fam Pract. 2019;PII:cmz062. 75. McHugh RK, Weiss R, Cornelius M, Martel M, Jamison RN, Edwards RR. Distress intolerance and prescription opioid misuse among patients with chronic pain. J Pain. 2016;17:806–814. 76. Tolliver Bryan K, Anton Raymond F. Assessment and treatment of mood disorders in the context of substance abuse. Dialogues Clin Neurosci. 2015;17:181–190. 77. McKernan LC, Nash MR, Gottdiener WH, et al. Further evidence of self-medication: Personality factors influencing drug choice in substance use disorders. Psychodyn Psychiatry. 2015;43:243–275. 78. Chou R, Fanciullo GJ, Fine P, et al. Clinical guidelines for the use of chronic opioid therapy in non-cancer pain. J Pain. 2009;10:113–130. 79. Furlan AD, Reardon R, Weppler C. Opioids for chronic non-cancer pain: A new Canadian practice guideline. CMAJ. 2010;182:923–930. 80. First M, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV® Axis I Disorders (SCID-I), Clinician Version, Administration Booklet. American Psychiatric Pub; New York; 2012. 81. Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain. 2004;112:65–75. 82. Butler SF, Fernandez K, Benoit C, et al. Validation of the revised screener and opioid assessment for patients with pain (SOAPP-R). J Pain. 2008;9:360–372. 83. Butler SF, Budman SH, Fernandez KC, et al. Cross-validation of a screener to predict opioid misuse in chronic pain patients. J Addict Med. 2009;3:66–73. 84. Black RA, McCaffrey SM, Villapiano A, Jamison RN, Butler SF. Development and validation of an eight-item brief form of the SOAPP-R (SOAPP-8). Pain Med. 2018;19:1982–1987. 85. Finkelman MD, Kulich RJ, Zacharoff KL. Shortening the screener and opioid assessment for patients with pain-revised (SOAPP-R): A proof-of-principle study for customized computer-based testing. Pain Med. 2015;16:2344–2356. 86. Finkelman MD, Jamison RN, Kulich RJ. Cross-validation of short forms of the screener and opioid assessment for patients with painrevised (SOAPP-R). Drug Alcohol Depend. 2017;178:94–100. 87. Butler SF, Zacharoff KL, Budman SH, et  al. Spanish translation and linguistic validation of the screener and opioid assessment for patients with pain revised (SOAPP-R). Pain Med. 2013;14: 1032–1038. 88. Butler SF, Budman SH, Fernandez KC, et  al. Development and validation of the current opioid misuse measure. Pain. 2007;130: 144–156.

References

89. Butler SF, Budman SH, Fanciullo GJ, Jamison R. Cross-validation of the current opioid misuse measure (COMM) to monitor chronic pain patients on opioid therapy. Clin J Pain. 2010;26: 770–776. 90. Weiner SG, Horton LC, Green TC, et al. A comparison of an opioid abuse screening tool and prescription drug monitoring data in the emergency department. Drug Alcohol Depend. 2016;159:152–157. 91. Varney SM, Perez CA, Araña AA, et al. Detecting aberrant opioid behavior in the emergency department: A prospective study using the screener and opioid assessment for patients with pain-revised (SOAPP®-R), current opioid misuse measure (COMM)™, and provider gestalt. Intern Emerg Med. 2018;13:1239–1247. 92. McCaffrey SA, Black RA, Villapiano AJ, et al. Development of a brief version of the current opioid misuse measure (COMM): The COMM-9. Pain Med. 2019;20:113–118. 93. Webster LR, Webster RM. Predicting aberrant behaviors in opioidtreated patients: Preliminary validation of the opioid risk tool. Pain Med. 2005;6:432–442. 94. Webster LR, Dove B. Avoiding opioid abuse while managing pain: A guide for practitioners. North Branch, MN: Sunrise River Press; 2007:92. 95. Belgrade MJ, Schamber CD, Lindgren BR. The DIRE score: Predicting outcomes of opioid prescribing for chronic pain. J Pain. 2006;7:671–681. 96. Hildebrand M. The psychometric properties of the drug use disorders identification test (DUDIT): A review of recent research. J Subst Abuse Treat. 2015;53:52–59. 97. Tiet QQ, Leyva YE, Moos RH, et  al. Diagnostic accuracy of a two-item drug abuse screening test (DAST-2). Addict Behav. 2017;74:112–117. 98. Giguère CÉ, Potvin S. The drug abuse screening test preserves its excellent psychometric properties in psychiatric patients evaluated in an emergency setting. Addict Behav. 2017;64:165–170. 99. Coambs RB, Jarry JL, Santhiapillai AS, et al. The SISAP: A new screening instrument for identifying potential opioid abusers in the management of chronic malignant pain within general medical practice. Pain Res Manage. 1996;1:155–162. 100. Holmes CP, Gatchel RJ, Adams LL, et  al. An opioid screening instrument: Long-term evaluation of the utility of the pain medication questionnaire. Pain Pract. 2006;6:77–88. 101. Lutz J, Gross R, Long D, et al. Predicting risk for opioid misuse in chronic pain with a single-item measure of catastrophic thinking. J Am Board Fam Med. 2017;30:828–831. 102. Lawrence R, Mogford D, Colvin L. Systematic review to determine which validated measurement tools can be used to assess risk of problematic analgesic use in patients with chronic pain. Br J Anaesth. 2017;119:1092–1109. 103. Cheatle MD, Compton PA, Dhingra L, et al. Development of the revised opioid risk tool to predict opioid use disorder in patients with chronic nonmalignant pain. J Pain. 2019;20:842–851. 104. Kaye AD, Jones MR, Kaye AM, et al. Prescription opioid abuse in chronic pain: An updated review of opioid abuse predictors and strategies to curb opioid abuse: Part 1. Pain Physician. 2017;20:S93–S109. 105. Manchikanti L, Kaye AM, Knezevic NN, et al. Responsible, safe, and effective prescription of opioids for chronic non-cancer pain: American Society of Interventional Pain Physicians (ASIPP) guidelines. Pain Physician. 2017;20:S3–S92. 106. Ghodke A, Ives TJ, Austin AE, et al. Pain agreements and time-toevent analysis of substance misuse in a primary care chronic pain program. Pain Med. 2020;PII:pnaa033. 107. Gourlay D, Heit H, Almahrezi A. Universal precautions in pain medicine: A rational approach to the treatment of chronic pain. Pain Med. 2005;6:107–112. 108. Wen X, Kogut S, Aroke H, et al. Chronic opioid use in women following hysterectomy: Patterns and Predictors. Pharmacoepidemiol Drug Saf. 2020;29:493–503. 109. Mahajan G. Role of urine drug testing in the current opioid epidemic. Anesth Analg. 2017;125:2094–2104.

733.e3

110. Argoff CE, Alford DP, Fudin J, et al. Rational urine drug monitoring in patients receiving opioids for chronic pain: Consensus recommendations. Pain Med. 2018;19:97–117. 111. Leece P, Shantheran Y, Hassan S, et  al. Improving opioid guideline adherence: Evaluation of a multifaceted, theory-informed pilot intervention for family physicians. BMJ Open. 2020;10:e032167. 112. Reisfield GM, Salazar E, Bertholf RL. Rational use and interpretation of urine drug testing in chronic opioid therapy. Ann Clin Lab Sci. 2007;37:301–314. 113. Michna E, Jamison RN, Pham LD, et al. Urine toxicology screening among chronic pain patients on opioid therapy: Frequency and predictability of abnormal findings. Clin J Pain. 2007;23:173–179. 114. Sidorkiewicz S, Tran VT, Cousyn C, et  al. Discordance between drug adherence as reported by patients and drug importance as assessed by physicians. Ann Fam Med. 2016;14:415–421. 115. McAuliffe Staehler TM, Palombi LC. Beneficial opioid management strategies: A review of the evidence for the use of opioid treatment agreements. Subst Abus. 2020;41:208–215. 116. Compton PA, Wu SM, Schieffer B, et al. Introduction of a selfreport version of the prescription drug use questionnaire and relationship to medication agreement noncompliance. J Pain Symptom Manage. 2008;36:383–395. 117. Wu SM, Compton P, Bolus R, et al. The addiction behaviors checklist: Validation of a new clinician-based measure of inappropriate opioid use in chronic pain. J Pain Symptom Manage. 2006;32: 342–352. 118. Wolff C, Dowd WN, Ali MM, et  al. The impact of the abusedeterrent reformulation of extended-release OxyContin on prescription pain reliever misuse and heroin initiation. Addict Behav. 2020;105:106268. 119. Pergolizzi Jr JV, Taylor Jr R, LeQuang JA, et al. Managing severe pain and abuse potential: The potential impact of a new abusedeterrent formulation oxycodone/naltrexone extended-release product. J Pain Res. 2018;11:301–311. 120. Butler SF, Cassidy TA, Chilcoat H, et al. Abuse rates and routes of administration of reformulated extended-release oxycodone: Initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment. J Pain. 2013;14:351–358. 121. Lourenço LM, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant opioids: How valuable are novel formulations in thwarting non-medical use? Expert Opin Drug Delivery. 2013;10:229–240. 122. Petrilla A, Marrett E, Shen X, et al. Association between formulary coverage and use of abuse-deterrent prescription opioids, risk for abuse or overdose, and associated healthcare resource utilization. Am Health Drug Benefits. 2020;13:21–31. 123. Rossiter LF, Kwong WJ, Marrett E. Healthcare resource use and cost: The impact of adopting an abuse-deterrent formulation of extended release morphine. Clinicoecon Outcomes Res. 2020;12: 35–44. 124. Ross EL, Jamison RN, Nicholls L, Perry BM, Nolen KD. Clinical integration of a smartphone pain app for patients with chronic pain: Retrospective analysis of predictors of benefits and patient engagement between clinic visits. J Med Internet Res. 2020;22:e16939. 125. Jamison RN, Jurcik D, Edwards RR, Chuan-Chin H, EL Ross. A pilot comparison of a smartphone app with or without 2-way messaging among chronic pain patients: Who benefits from a pain app? Clin J Pain. 2017;33:676–686. 126. Ventura J, Chung J. The lighten your life program: An educational support group intervention that used A mobile app for managing depressive symptoms and chronic pain. J Psychosoc Nurs Ment Health Serv. 2019;57:39–47. 127. Ledel Solem IK, Varsi C, Eide H, et al. Patients’ needs and requirements for eHealth pain management interventions: Qualitative study. J Med Internet Res. 2019;21:e13205. 128. Young SD, Heinzerling K. The harnessing online peer education (HOPE) intervention for reducing prescription drug abuse: A qualitative study. J Subst Use. 2017;22:592–596.

733.e4

References

129. Young SD, Koussa M, Lee SJ, et al. Feasibility of a social media/ online community support group intervention among chronic pain patients on opioid therapy. J Addict Dis. 2018;37:96–101. 130. Young SD, Lee SJ, Perez H, et  al. Social media as an emerging tool for reducing prescription opioid misuse risk factors. Heliyon. 2020;6:e03471. 131. Jamison RN, Xu X, Wan L, Edwards RR, Ross EL. Determining pain catastrophizing from daily pain app assessment data: Role of computer-based classification. J Pain. 2019;20:278–287. 132. Enkema MC, Hallgren KA, Neilson EC, et al. Disrupting the path to craving: Acting without awareness mediates the link between negative affect and craving. Psychol Addict Behav. 2020;34:620–627. 133. Polimanti R, Walters RK, Johnson EC, et al. Leveraging genomewide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the psychiatric genomics consortium. Mol Psychiatry. 2020;25:1673–1687.

134. Reed B, Kreek MJ. Genetic vulnerability to opioid addiction. Cold Spring Harb Perspect Med. 2021 Jun 1;11:a039735. 135. Garland EL, Bryan CJ, et  al. Pain, hedonic regulation, and opioid misuse: Modulation of momentary experience by mindfulness-oriented recovery enhancement in opioid-treated chronic pain patients. Drug Alcohol Depend. 2017;173(Suppl 1): S65–S72. 136. Garland EL, Hanley AW, Kline A, Cooperman NA. Mindfulnessoriented recovery enhancement reduces opioid craving among individuals with opioid use disorder and chronic pain in medication assisted treatment: Ecological momentary assessments from a stage 1 randomized controlled trial. Drug Alcohol Depend. 2019;203: 61–65. 137. Passik SD, Kirsch KL, Whitcomb RK, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther. 2004;26:552–561.

10 52

Pain andTitle Addictive Challenge Chapter to Go Disorders: Here and Opportunity CHAPTER AUTHOR

SHANNON NUGENT, MARK BEITEL, GRETCHEN HERMES, MARINA GAETA GAZZOLA, DECLAN BARRY

Introduction The treatment of pain in patients with comorbid addiction or substance use disorders (SUDs) is complex.1 Traditionally, chronic pain and SUDs have been treated by separate providers in different clinical settings. Until recently, pain researchers routinely excluded individuals with SUDs from clinical trials of treatments for chronic pain. Since chronic pain and SUDs frequently cooccur, pain management specialists must be able to recognize these interrelated chronic relapsing medical conditions in the patients they are evaluating and incorporate appropriate treatment strategies for these patients. This chapter aims to provide pain providers with an up-to-date overview of research related to pain management in patients with SUDs. We focus most on opioid use disorder (OUD) because this is the most commonly examined SUD in pain management literature. After reviewing the nomenclature, the SUD diagnostic criteria, and the neurobiology of addiction, we discuss the prevalence and causes of comorbid pain and SUDs and the challenges of treating pain in this population, including patient clinical complexity and changing perspectives on the role of prescription opioid analgesics and non-opioid treatments. We review the screening, monitoring, and management of SUDs in patients with chronic pain and approaches to treat chronic and acute pain in patients with SUD, with a particular focus on cannabis use disorder and OUD. Throughout, we discuss the importance of collaboration between pain specialists and addiction clinicians and the essential role that pain providers play in treating patients with SUDs.

Nomenclature To promote a common taxonomy, the Board of Directors of the American Society of Addiction Medicine (ASAM) in December 2019, adopted the following definition: “Addiction is a treatable, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual’s life experiences. People with addiction use substances or engage in behaviors that become compulsive and often continue despite harmful consequences.”1 We draw the reader’s attention to three 1

The terms substance use disorders and addiction are used interchangeably in this chapter.

734

often overlooked implications of this definition: (1) addiction is a chronic relapsing medical condition or disease similar to diabetes or hypertension2; consequently, providers should expect patients with addiction to be symptomatic periodically, and providers should not automatically discharge patients from treatment for being symptomatic, (2) addictions are treatable; effective treatments for SUDs (i.e. those which attenuate substance use and reduce risk of overdose, infectious disease, and all-cause mortality) vary by the nature of the substance used; in the cases of addiction to alcohol, nicotine, or opioids, effective treatment often consists of a combination of Food and Drug Administration (FDA)-approved medications and counseling to facilitate lifestyle changes,3–6 and (3) the rates of success of addiction treatment are comparable to those for other chronic medical conditions.2 For example, the median 12 month medication adherence in a meta-analysis of patients receiving medication for OUD was 57% globally.7 In comparison, the mean medication adherence was 59% across studies in a meta-analysis of medication adherence in patients receiving antihypertensives, lipid-lowering agents, and oral anti-diabetics.8 The ASAM definition stands in stark contrast to common societal misconceptions that addiction is an acute condition because of a “moral defect” or character flaw.9–11 Since providers and patients may be influenced by such inaccuracies, clinicians need to be aware of their own assumptions (and possible biases) concerning SUDs and the people who have them.12 Language is one way that biases are manifested. Certain words or terms used by providers (and researchers) may promote stigma among patients. Consequently, in recent years, increased attention in addiction medicine scholarship and clinical practice has focused on using neutral and person-first terminology to avoid stigmatizing individuals (e.g. “person with a SUD” rather than “addict”) and to reinforce that SUDs are medical conditions.13–15 A recent paper suggests that medical students are still being exposed to pejorative terminology about SUDs in their materials when studying for the United States medical licensing examination.16 It is notable that government agencies and the legal system have historically used derogative language when describing addictions or the people who have them. For example, the Controlled Substances Act defines an “addict” as a person who “habitually uses any narcotic drug to endanger the public morals, health, safety, or who is so far addicted to the use of narcotic drugs as to have lost the power of self-control regarding his addiction.”17

 

CHAPTER 52

Provider language may be particularly important because patients with chronic pain and/or SUDs experience stigma and discrimination within the healthcare system, which in turn reduces treatment-seeking and the likelihood of disclosing substance use.12,18 Multiple studies have demonstrated that physicians underestimate pain among Black and Hispanic patients and that such patients are less likely than White patients to receive analgesia in acute pain settings.19 Providers may screen Black pain patients for drug use more than White patients and are more likely to discontinue treatment for Black patients if their drug screens are positive.20 However, Black patients are less likely than White patients to be referred for specialty pain management.21 Research also shows that social determinants of health, including education and wealth, might play a role in pain prevalence and severity, with patients with less wealth and lower education experiencing more and higher severity pain.22 Consequently, it is important for providers to solicit their patients’ experiences of pain and SUDs and engage in patient-centered shared decision making regarding treatment plans. We recommend that providers standardize screening and monitoring practices for patients, regardless of patient demographics (see the section on screening instruments).20,21 While SUDs are associated with brain and other biologic changes (see the section on neurobiology), diagnoses are based on behavioral patterns and patient reports. In the United States, providers use the Diagnostic and Statistical Manual, fifth edition (DSM-5) to diagnose SUDs.23 The DSM-5 criteria for “substance use disorder” require a maladaptive pattern of substance use leading to significant impairment or distress, as manifested by at least two of the following, occurring within a 12 month period (criteria have been abbreviated)23: 1. The substance is often taken in larger amounts or over a longer period than intended 2. There is a persistent desire or unsuccessful effort to cut down or control substance use 3. A great deal of time is spent on the activities necessary to obtain or use the substance or recover from its effects 4. Craving or a strong desire or urge to use the substance 5. Recurrent use of the substance results in failure to fulfill major role obligations 6. Use of the substance is continued despite causing or exacerbating persistent or recurrent social or interpersonal problems 7. Important social, occupational, or recreational activities are reduced because of substance use 8. Substance use occurs in situations in which it is physically hazardous 9. Continued substance use despite the knowledge that it has caused or exacerbated ongoing or recurrent physical or psychological problems 10. Tolerance2 11. Withdrawal2 The DSM-5 also includes one “non-substance-related disorder” under its classification of “addictive disorders”: gambling disorder.23 Anecdotally, we have heard that patients describe gambling or gaming as an activity that takes their focus off of pain, and the co-occurrence of gambling disorder and chronic pain is understudied.24–25 2 As outlined in the next section, which includes a description of tolerance and withdrawal, neither of these criteria are considered to have been met for individuals taking opioids solely under appropriate medical supervision.

Pain and Addictive Disorders: Challenge and Opportunity

735

Terms Related to the Treatment of Opioid Use Disorder The FDA has approved three medications for the treatment of OUD: methadone (full agonist), buprenorphine (partial agonist), and naltrexone (antagonist). Collectively, they were referred to as “medication-assisted treatment.” The preferred nomenclature is currently “medications for OUD,” in part to emphasize the central (and not secondary) role of the medications.26 See the section titled “Medications for Opioid Use Disorder” for more information. Opioid agonist treatment refers to the treatment of OUD involving either methadone or buprenorphine.

Neurobiology of Addiction Over the past several decades, basic and clinical research has uncovered neuroscientific explanations of SUDs. These explanations challenge stereotypes that invoke moral weakness as a reason for drug addiction and instead provide scientific reasons for addiction, offering guideposts to treatment-seeking patients and their doctors. Addictive substances, including opioids, cocaine, amphetamine, ketamine, nicotine, and marijuana, exert powerful effects on dopaminergic neurons, which produce euphoric states exceeding what is typically produced by endogenous levels of dopamine. These sharp increases in feelings of reward can be associated with the environmental stimuli that surround drug use. With chronic drug exposure, wear and tear on dopaminergic neurons begin to suppress the experience of reward itself, which in turn drives craving, anticipation, and the need for more drugs to satisfy drug urges.11,27 Notably, individuals with addiction are frequently confused by their ongoing use of drugs that no longer provide pleasure. Addiction can then be understood as a motivational push to avoid the discomfort associated with dysregulated reward circuity and the distress caused by feelings of being without sufficiently numbing, activating, or altering drugs.11,27 In the last decade, a useful heuristic has been developed that delineates the neuroanatomy, circuits, and signaling molecules involved in the cycle of addiction from stages of binge/intoxication to withdrawal/negative affect to preoccupation/anticipation. The delineation of these separable, tractable circuits and the signaling molecules involved establishes a framework for researchers to identify therapeutic targets, potential medications, validated animal models, and clinical trials to test new pharmacologic interventions based on rational therapeutic targets.11,27 This heuristic has had critical epistemologic value for the field researchers, clinicians, and patients—and is worth reviewing here. In the binge/intoxication phase of addiction, drug use is motivated primarily by positive, rewarding experiences subserved by the ventral and dorsal striatum, globus pallidus, and thalamus. Illicit drugs powerfully activate neurons in these brain regions with no connection to purposeful behavior. This overstimulation leads to progressive and insidious dysregulation of the brain’s natural reward mechanisms. Over time, there is a downregulation of positive reward pathways, and increasing drug levels are needed to trigger the brain reward system. Animal and human studies have shown that long term exposure to drugs of abuse impairs dopamine neurons and dopamine signaling in the nucleus accumbens. This effect appears to be mediated by the actual physical shrinkage of dopamine neurons in response to chronic drug administration.28 This underlying neuroanatomic change reduces the capacity for reward and leaves the addict “unrewarded,” amotivational, and often depressed in the absence of a drug. Research has shown that

736

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

drugs of abuse decrease the size of dopamine neurons in the ventral tegmentum and nucleus accumbens by depriving the neurons of the crucial nerve growth factor, brain-derived neurotrophic factor.28 What started off as euphoria in response to unanticipated reward turns over time into overwhelming behavior-modifying drug craving. During the withdrawal-negative-affect stage, the dopamine systems are compromised, contributing to dysphoric mood states while simultaneously assigning greater salience to drugs and drug related stimuli in the context of these aversive states, and healthy rewards lose motivational power as they fail to satisfy. Drug consumption triggers much smaller increases in dopamine levels in the presence of addiction (in both animals and humans). Over time, the attenuated release of dopamine renders the brain’s reward system much less sensitive to stimulation by both drug related and non drug related rewards. Individuals with addictions often seek a more potent release of dopamine in more explicitly risky settings. The human costs to relationships, community, and vocation increase as the drug produces less euphoria. Adaptations in the circuitry of the extended amygdala in the basal forebrain lead to the emergence of negative emotions. During the preoccupation-anticipation stage, those with addiction desire and pursue drug use. This stage of the addiction cycle is characterized by chronic relapse frequently triggered by the long term effects of drugs of abuse on the basolateral amygdala, hippocampus, and prefrontal cortex.11,27 Notably, the hippocampus is a target of opioid receptor agonists, such as morphine, methadone, heroin, and various short-acting opiates.29 The opioid system within the hippocampus underlies context-associative learning, which is essential for linking drugs with a particular place and set of events.30 In addition, chronic drug use impairs the prefrontal cortex and the capacity for self-regulation, decision making, and flexibility.11 Together, these combined effects in the amygdala, hippocampus, and prefrontal cortex explain how earnest plans to cease substance use are upended by desire, environmental context, and impulsivity. Finally, in addition to direct brain effects of drugs of abuse, considerable evidence from population-based studies supports a positive association between psychosocial adversity, chronic distress, and addiction.31 The contribution of stressors to substance use appeared to occur in a dose-dependent manner. Repeated or chronic prolonged stress can induce lasting changes in stress responsivity and the magnitude and duration of stress hormone response to a stressor, which in turn increases the risk of stressrelated disorders and addiction.31 Similar to drugs of abuse, stress exposure increases dopamine release in the nucleus accumbens. Given that both drugs of abuse and stress activate mesolimbic pathways, each results in synaptic adaptations in the ventral tegmental area dopamine neurons and the prefrontal cortex. While persistent and poorly controlled responses to environmental challenges contribute to the persistence of and relapse to self-administration of drugs of abuse and addiction, it is clear that vulnerability to drug use and relapse may exist prior to the use of addictive drugs on a genetic or acquired basis-histories of childhood neglect and abuse, for example, may lead to the acquisition of addiction because of underlying baseline differences in stress responsivity.29,31,32

Misconceptions About Physical Dependence and Addiction Many persons with SUDs report that compared with their first use, they increased the amount of the substance over time to obtain the same effect, or that the amount of the substance used to produce the

effect no longer does (i.e. tolerance). They also may report that upon abrupt cessation of substance use, their bodies exhibit a characteristic pattern of symptoms (i.e. withdrawal). Withdrawal symptoms vary according to the category of substances involved (e.g. alcohol and opioids). According to the DSM-5, an individual who takes the substance (or a similar substance) to relieve or avoid withdrawal symptoms is also considered to have met the criterion for withdrawal. Depending on the severity of the addiction and the type of substance, withdrawal symptoms can range from relatively mild (e.g. headache because of caffeine withdrawal) to life-threatening (e.g. seizures because of alcohol withdrawal). However, the presence of tolerance or withdrawal, which are hallmarks of physical dependence, is not associated with the presence of a SUD. Tolerance and withdrawal are related to pharmacologic properties. Both tolerance and withdrawal can occur when patients take prescription medications as prescribed (e.g. anti-depressants and anxiolytics). Consequently, the DSM-5 specifies that for those prescribed opioid analgesics and who take them as prescribed (in the absence of other illicit opioid use), tolerance and withdrawal should not be counted toward the number of criteria needed to meet the diagnostic threshold for OUD.

Prevalence of Substance Use and SUDs Among Those With Chronic Pain The estimated prevalence of SUDs among those with chronic pain ranges from 1%–40%. Reasons for this variability in estimates include study differences in time frames (e.g. current vs. lifetime), assessment methods (e.g. screening versus diagnostic assessment), and populations (e.g. in treatment vs. not in treatment).33 Nevertheless, it is clear that a sizable proportion of patients with chronic pain, including those receiving long term opioid therapy (LTOT), have comorbid SUDs.34 In 2019, an estimated 5.3% of the United States population aged 12 years or older had an alcohol use disorder, while an estimated 3.0% had an illicit SUD.35

Opioids A systematic review estimated that 8%–12% of those on LTOT met the criteria for OUD and 21%–29% met criteria for “opioid misuse.”36 Conversely, the rate of chronic pain among patients with OUD entering opioid agonist treatment is high, with estimates varying between 37% and 61% who report chronic pain.37–43 Tobacco Tobacco use is common among those with chronic pain, with prevalence estimates as high as 50% (twice that of the general population).44–46 Relatedly, nearly 60% of individuals with tobacco use disorder also experience chronic pain. In a nationally representative sample of 9,282 United States adults, respondents with lifetime chronic neck or back pain were 1.3 times more likely to smoke cigarettes than the general population, 1.8 times more likely to be diagnosed with a lifetime nicotine use disorder, and 2.4 times more likely to meet the criteria for past year nicotine use disorder.46 Previous research supports the theory that pain may contribute to the development of tobacco use problems,44 and that tobacco use, in turn, may contribute to the development of painful conditions such as back pain47 or rheumatoid arthritis.48 Cannabis Approximately 36% of those on LTOT report cannabis use,49 while as many as 15% of primary care patients report past 30 day cannabis use.33 Because of the rapidly expanding legalization and availability

 

CHAPTER 52

of cannabis, cannabis use disorder (CUD) is increasingly common in the general population,50 although the prevalence of CUD among those with chronic non-cancer pain has been understudied. One study identified that the rate of CUD in patients hospitalized for chronic pain increased from 1.9% in 2011 to 3.0% in 2015.51

Alcohol and Sedatives An estimated 25% of patients seeking treatment for pain report moderate to heavy alcohol use.52 In the general population, those with chronic neck or back pain compared to those without are nearly twice as likely to meet the criteria for alcohol use disorder.53 Alcohol has been linked to worse pain outcomes, such as increased pain disability and intensity. An estimated 9%–11% of those with chronic pain who are treated in a primary care setting meet the criteria for a sedative use disorder.54,55

Stimulants Chronic pain may be associated with an increased risk of stimulant use. Among a national sample of adults, stimulant use was almost twice as prevalent among those with versus those without chronic low back pain (cocaine: 22% vs. 14%; methamphetamine: 9% vs. 5%).56 A prior study of attendees at an outpatient pain management clinic estimated that the rates of cocaine and methamphetamine use were 5% and 2.5%.57 Importantly, stimulants and opioids influence dopaminergic receptors in the central nervous system either by activating the dopamine receptors directly or by way of the opioid receptors.58 For this reason, there is an enhanced risk of addiction and adverse events among those who concurrently use stimulants and opioids. Chronic Pain Among Patients With SUDs A recent study of participants in a large academic healthcare system found that most of those with SUD had chronic pain (opioid, 75%; cannabis, 64%; alcohol, 59%; tobacco, 60%).59 Other studies have found that patients receiving opioid agonist treatment with co-occurring chronic pain frequently report using tobacco and alcohol as well as non-medical use of cannabis, opioids, and benzodiazepines to manage pain.37,38 Given the extent of the coprevalence of chronic pain and addiction, it behooves pain providers and addiction providers to be knowledgeable about both chronic medical conditions.

Complexity and Confounds The presence of either chronic pain or SUD can obscure the diagnosis and treatment of the other.60 In SUD treatment settings, chronic pain is not routinely assessed or addressed, while the reverse holds for pain management settings. For some individuals with chronic pain and SUDs, chronic pain precedes the onset of SUD. For others, SUD precedes or occurs at approximately the same time as the onset of chronic pain.61,62 The order of onset may have implications for how patients self-identify (e.g. a woman whose pain occurred first and who reported developing an addiction to opioids that were prescribed for pain relief may view herself as a “pain patient” and downplay the presence of SUD). Although this field of research is nascent, one study found that among 170 patients seeking treatment for co-occurring chronic pain and OUD, those whose chronic pain preceded OUD were less likely to meet the criteria for a current non-opioid SUD compared to those whose OUD occurred first.63 Individuals with SUDs have high rates of medical problems, including trauma related to physical and sexual assault,64 and painful

Pain and Addictive Disorders: Challenge and Opportunity

737

illnesses such as cirrhosis, hepatitis C, and HIV.65–67 Accidents (e.g. motor vehicles) are among the most frequently reported causes of chronic pain among patients receiving opioid agonist treatment.68 Conversely, having pain increases the likelihood of exposure to controlled substances.60 High rates of psychiatric disorders, including anxiety, mood, and personality disorders, are accompanied by chronic pain, especially among those with OUD.69–71 We note that among patients on LTOT, psychiatric disorders are associated with higher opioid doses and a higher risk of accidental overdose.72 Given the reliance on self-report in the assessment of pain, patients with SUDs seeking opioids for the management of chronic pain may be unintentionally motivated to de-emphasize the effects nonopioid therapies may have on their pain.60 Conversely, increased focus in recent years on opioid-related harms may have dissuaded some patients on opioid agonist treatment to seek or take opioid analgesics in cases where it might be appropriate (e.g. prescribed by an emergency department provider to manage pain following a serious motor vehicle accident). Comorbid addiction complicates the treatment of pain in numerous ways. Patients may rely on the use of substances for analgesic and mood-enhancing properties and are more susceptible to worse pain outcomes.73 Those with comorbid addiction and pain are also at higher risk of adverse outcomes to opioid medications, including overdose and death.72 Consequently, pain clinicians should screen for addiction risk before and during treatments, especially for treatments involving controlled substances, and they should be prepared to either provide treatment for SUDs or offer treatment referrals.

Universal Precautions Screening tools for SUDs can be viewed as part of universal precautions in the treatment of pain, irrespective of the proposed pain intervention. Providers can check their state’s electronic prescription drug monitoring program; these data can be compared to the information provided by the patient. Patients’ relatives or significant others can also be important sources of collateral information. Gourlay and Heit developed guidelines for universal precaution guidelines for pain management comparable to those used for infection control.74 We suggest a modified version of these guidelines that concurs with the 2016 Centers for Disease Control and Prevention (CDC) guideline for prescribing opioids to patients with chronic non-cancer pain (Box 52.1).75 The original Gourlay and Heit step six, which assumed that opioids were appropriate as a first line pain management intervention for many patients with non-cancer chronic pain, has been revised in our modified version: “Initiate pain management intervention.” According to the CDC guidelines, for the modified step six, clinicians should consider non-opioid pharmacotherapies and evidence-based non-pharmacologic pain management interventions as first line treatment (see Chapters 34, 37 for treatment of neuropathic and chronic widespread pain; Chapters 53, 54, and 55 for non-opioid medications; and Chapters 58–61 for non-pharmacologic interventions) (Box 52.1).

Substance Use Disorder Screeners Since the rates of SUDs are high in persons with chronic pain, pain management providers should consider assessing for SUDs, regardless of the provision of opioid analgesics. We review below some common SUD screeners. If patients screen positive, they should be further assessed for DSM-5 SUDs.23

738

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

• BOX 52.1

The Modified Ten Steps of Universal Precautions in Pain Medicine

1. Diagnosis with appropriate differential 2. Psychological assessment, including the risk of substance use disorders (SUDs) 3. Informed consent 4. Treatment agreement 5. Pre/post intervention assessment of pain level and function 6. Initiate pain management intervention 7. Reassessment of pain score and level of function 8. Regularly assess the “four a’s” of pain medicine: analgesia, activity, adverse reactions, and aberrant behavior 9. Periodic review of diagnosis and comorbid conditions, including SUDs 10. Documentation Note: Step 6 of the original guideline was updated in line with the most recent CDC guidelines.

Screening for Risk of Mon-medical Opioid Use or Opioid Use Disorder While the 2016 CDC guideline for prescribing opioids for chronic non-cancer chronic pain does not recommend initiation of LTOT, some people with chronic pain will likely be prescribed LTOT. Additionally, a large number of patients are currently receiving LTOT or are being actively tapered off LTOT. Thus screening for non-medical opioid use and OUD is important.76

Opioid Specific Screeners The Screener and Opioid Assessment Tool for Patients with Pain, Revised (SOAPP-R),77 Opioid Risk Tool (ORT),78 Current Opioid Misuse Measure (COMM),79 and Pain Medication Questionnaire (PMQ)80 screen for non-medical opioid use behaviors. The DIRE (Diagnosis, Intractability, Risk, Efficacy) assesses the risks and benefits of continued LTOT.81 A comparison of these screens suggests that all have some value and are most useful when supplemented by a clinical interview.82

Non-opioid Screeners Common screening instruments for non-opioid substances include the alcohol use disorder identification test (AUDIT),83 and Cannabis Use Disorder Identification Test-Revised (CUDITR),84 the Drug Abuse Screening Test (DAST-10),85,86 and the World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST).87 Finally, the simple fouritem CAGE (Cut down, Annoyed, Guilty, Eye-opener) inventory was modified to screen for SUDs88 (Box 52.2).

The Opioid Crisis and Evolving Guidelines for the Use of Opioid Medications to Manage Pain As prescriptions for opioid medication for non-cancer chronic pain escalated in the 1990s, there were substantial increases in the rates of OUD, admissions to addiction treatment facilities, and overdose deaths.89 According to data from the Centers for Disease Control and Prevention (CDC), fatal poisonings involving opioids quadrupled between 2000 and 2014 from 1.5–5.9 deaths per 100,000.90 Because of the opioid crisis, a major focus of opioid-related research in the last decade has centered on the prevention and treatment of non-medical opioid use and OUD. Non-medical opioid use includes behaviors such as taking a higher dose of an opioid medi-

• BOX 52.2 1. 2. 3. 4.

CAGE* Questions Adapted to Include Drugs (CAGE-AID)

Have you felt you ought to cut down on your drinking or drug use? Have people annoyed you by criticizing your drinking or drug use? Have you felt bad or guilty about your drinking or drug use? Have you ever had a drink or used drugs first thing in the morning to steady your nerves or to get rid of a hangover (eye opener)?

*C, Cut down; A, annoyed; G, guilty; E, eye opener.

cation than prescribed, using prescription opioid medications to manage symptoms other than pain, including depressed mood and using non-prescribed substances in addition to opioid analgesics (e.g. alcohol or cannabis). While patients with non-medical opioid use do not automatically meet the diagnostic criteria for OUD, repeated exposure to opioids places those on LTOT with non-medical opioid use at a higher risk of adverse events, including addiction and overdose. As noted previously, a systematic review estimated that among individuals with chronic pain who are prescribed opioids, rates of non-medical opioid use were estimated to be between 21% and 29%, and rates of OUD were between 8% and 12%.36 Among those hospitalized for chronic pain between 2011 and 2015, the prevalence of OUD was approximately 7%, with an upward trend between 2011 and 2015.91 In 1990, OUD was the 11th leading cause of disability-adjusted life years; by 2016, it became the seventh.92 It is also important to note that the prevalence of non-medical opioid use is also relatively common among the general United States population. For example, in 2019, an estimated 10 million people aged 12 years and older had misused prescription opioids at least once in the past year.35 In response to the opioid crisis, in March 2016, the Centers for Disease Control and Prevention (CDC) released the guideline for prescribing opioids for chronic pain.75 Although the CDC guidelines were met with some controversy,93,94 subsequent studies continue to call into question the long term efficacy of LTOT and have found support for the risks associated with LTOT over time, especially at higher doses.95–98 However, it is important to emphasize that for patients receiving LTOT for whom benefits outweigh harm, a continuation of LTOT along with close monitoring is reasonable. It is not evidence-based or concordant with CDC guidelines to taper involuntarily patients who are not experiencing harm from LTOT, and this practice may pose additional risks.99 Bohnert et al. used a national data set of opioid prescriptions dispensed between 2012 and 2017 and identified decreases in rates of high dose and overall opioid prescribing following implementation of the CDC guidelines. In January 2012, the rate of high dose opioids (≥90 daily milligram morphine equivalents [MME]) was 683 per 100,000 persons, which decreased to 356 by December 2017. The overall opioid prescribing rate (per 100,000) decreased from 6577 opioid prescriptions dispenses (per 100,000 persons) in January 2012–4240 in December 2017.98

Medication for Opioid Use Disorder Medication for opioid use disorder (MOUD), in combination with behavioral counseling, is the standard of care treatment for OUD.3 MOUD reduces OUD related harm, including mortality and infectious disease transmission (e.g. HIV, hepatitis C, endocarditis).4,100–102 MOUD consists of opioid agonist treatment

 

CHAPTER 52

involving the long-acting full agonist methadone, partial agonist buprenorphine (most commonly prescribed in combination with the antagonist naloxone), or opioid antagonist naltrexone. Methadone is available from tightly regulated opioid treatment programs, which require six visits per week for supervised consumption for at least the first three months of treatment.103,104 Buprenorphine may be prescribed by physicians and other practitioners depending on state regulations (e.g. advanced practice nurses and physicians associates) who have sought additional training (8 h for physicians, 24 h for advanced practice nurses and physicians associates) to obtain a waiver from the Drug Enforcement Administration (DEA) to treat OUD.103 The government places patient limits on waivered providers: a 30 patient cap is in place the first year of waivered practice for most providers, with expansion to 100 patients in subsequent years. Providers with board certification in addiction medicine or psychiatry or who practice in certain settings can qualify for a 100 patient cap their first year, which expands to 275 the following year.105 There are no specialty limits on who can seek additional training and a DEA (Drug Enforcement Administration) waiver. Thus obtaining a waiver might be useful for pain physicians interested in treating OUD in their own clinics.105 Both methadone and buprenorphine are initiated at low, often sub-therapeutic doses, which are tapered over several weeks to find an individualized dose that reduces OUD symptoms without causing adverse effects (e.g. sedation).103

Iatrogenic Opioid Use Disorder The indicators of iatrogenic OUD (i.e. OUD that occurs in the course of medically supervised opioid analgesic therapy) can be more subtle than those displayed for OUD related to recreational opioid use.60 Loss of behavioral control, a key sign of addiction, may involve taking more opioids than prescribed, followed by visits to the emergency department or soliciting multiple prescribers for opioids; consequently, prescribers should check online state prescription drug monitoring programs to ascertain patients’ use of controlled medications. Family members may also be useful in ascertaining possible indicators of iatrogenic OUD (e.g. patients lose the thread of conversation or fall asleep at inappropriate times).60 Guidelines to date do not identify specific prescriber steps to take when concerns arise about medication-taking behaviors. However, a Delphi study of clinical experts suggests a patient-centered discussion of patients’ behaviors, a recapitulation of the opioid treatment agreement, and providing a clear rationale for any decision to discontinue or taper opioid therapy.106 However, it is important to note that some clinicians may encounter institutional or state policy pressure to discontinue opioids quickly.106,107

What to Do With Patients on Long-term Opioid Therapy With Suspected Opioid Use Disorder? The development of OUD among patients prescribed opioids is a leading concern for both pain providers and patients.108–110 Patient-centered tapering from LTOT may be appropriate in patients who feel their current opioid medication regimen is not effective or for whom risks outweigh the benefits.111 For many patients who have been prescribed LTOT, switching to nonopioid therapy may not be feasible or in their best interest. One promising strategy in this scenario is to transition from LTOT to buprenorphine, which has a lower risk of adverse events, particularly for patients who have been on high opioid doses

Pain and Addictive Disorders: Challenge and Opportunity

739

(>50 mg MME).112–114 Although buprenorphine is classified as a partial mu agonist, it was initially developed to treat pain, and research has demonstrated that its risk profile may be safer than other opioids, and it may be effective for a wide range of pain types.113–115 Additionally, there are options for patients who display signs or symptoms of OUD that still involve treating their pain. The standard of care treatment for OUD with MOUD is effective in reducing morbidity, mortality, and craving because of OUD.4,102 For patients who are not currently enrolled in treatment for OUD, the following steps may help determine whether to continue LTOT or alter the treatment regimen112: Step 1: Does the patient meet the criteria (see “Nomenclature”) for a DSM-5 OUD? If so, go to Step 2. If not, go to step three. Step 2: For patients meeting the criteria for OUD, urgent treatment using the standard of care, MOUD with methadone, buprenorphine, or naltrexone (see section “Medication for Opioid Use Disorder”). Opioid agonist therapy (methadone or buprenorphine) may be the preferred option among patients currently receiving LTOT because of the requirement of a seven to ten day washout period to prevent precipitated withdrawal with naltrexone.103 Referral to an addiction specialist or opioid treatment program in this instance is warranted unless the pain management clinic has practitioners who have completed the DEA waiver process to prescribe buprenorphine. Step 3: For patients not meeting the criteria for OUD, conduct a risk-benefit analysis for the continuation of LTOT. Factors that increase the risk of overdose or the development of OUD (i.e. medication interactions, age >65 years, reduced renal or hepatic function, and risk of respiratory depression).116 The 2016 CDC guidelines consider improved pain and functioning as benefits that might lead to the continuation of LTOT.75 For patients receiving doses below 50 mg MME of opioids and for whom the benefits of LTOT outweigh the harm, monitoring with routine reassessment may be appropriate. Switching to buprenorphine or approaching the topic of a patient-centered opioid taper is recommended for patients on daily doses greater than 50 mg MME or for those below 50 mg MME for whom benefits do not outweigh risks.117

Non-opioid Pharmacotherapy for Comorbid Pain and Substance Use Disorders There is increasing evidence that the potential for harms of LTOT outweigh the benefit,97,118 and non-opioid treatments are now the recommended first line treatment for anyone with chronic noncancer pain.75

Non-opioid Pharmacotherapy Depending on the type of pain being treated, medications to consider might include nonsteroidal anti-inflammatory drugs, anticonvulsant medications, and serotonin-norepinephrine reuptake inhibitors (SNRIs).75 However, we note that newer data indicate that the anti-convulsant medications gabapentin and pregabalin have misuse potential, and they may increase the risk of respiratory depression and overdose among those currently using opioid medications.119,120 Notably, some medications and non-pharmacologic therapies that treat pain have applications in the treatment of SUDs and vice versa.112 Pain providers are sometimes surprised to learn that medications prescribed to treat chronic pain may also be indicated in the treatment of SUDs.112 In the section below, we briefly describe pain and SUD use for common medications. We encourage pain clinicians to consult with their patients’ addiction

740

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

providers to discuss dosing and applications of such medications, as the effective dose for SUD treatment might differ from the typical pain regimen. For patients with OUD, it is also worthwhile to consider altering a patient’s pain regimen to incorporate medication that might treat their symptoms of both chronic pain and OUD, in collaboration with their addiction medicine provider. Notably, the use of adjunct medications that may cause sedation or increase the risk of respiratory depression (i.e. muscle relaxants, antiepileptics, benzodiazepines, and amitriptyline) is generally not recommended in patients currently receiving prescription opioids.113

Anti-convulsants Pain physicians are likely to be familiar with the application of anti-convulsants, including gabapentin, pregabalin, and oxcarbazepine for neuropathic pain and fibromyalgia,121,122 and topiramate for preventive migraine therapy. Topiramate has been investigated for neuropathic pain and fibromyalgia and found to have no benefit.123,124 Research suggests that gabapentin may offer clinical benefits to patients with alcohol use disorders. Multiple studies have demonstrated reductions in cravings and alcohol use behavior among patients with AUD (alcohol use disorder) taking gabapentin compared to placebo, with some reporting improvements in mood and insomnia.125–127 In December 2019, the FDA released a drug safety communication about the risk of respiratory depression with gabapentinoids combined with other central nervous system (CNS) depressants, particularly opioids, and how this impacts the future use of gabapentinoids in pain management is an evolving issue.128 Topiramate has also shown clinical benefit in AUD, and some initial studies suggest that it could be applied in cocaine use disorder and tobacco use disorder, although much more research is needed.129,130 Muscle Relaxants Baclofen has been used to treat spasticity and hypertonicity, particularly in conditions such as multiple sclerosis. Systematic reviews evaluating research into baclofen’s utility in treating alcohol use disorder have not demonstrated a clear benefit, but this is an area of active investigation,131,132 particularly among patients who are currently abstinent from alcohol.133 Please see Chapter 55 for a more detailed description of the role of muscle relaxants in treating pain. Benzodiazepines Although the combination of benzodiazepines and opioids increases the risk of overdose, sedation, and OUD development, estimates for co-prescription are as high as 40% in outpatient settings.134,135 Benzodiazepines are an important treatment for alcohol withdrawal syndrome that prevents seizures. However, outside of this indication, caution should be exercised when prescribing benzodiazepines in patients taking opioids. α-2 Agonists α-2 adrenergic receptor agonist drugs are commonly used for anesthesia.136 For example, clonidine can provide prophylactic cardiovascular protection during intubation, while tizanidine can assist in the management of spasticity related to cerebral palsy. Although the α-2 agonist lofexidine is FDA-approved to manage symptoms during opioid withdrawal, clonidine is commonly used off-label for a similar indication. Studies have demonstrated the clear efficacy of these agents. However, they may have more side effects not seen with other agents such as methadone and buprenorphine and

may not completely eliminate withdrawal syndrome-associated discomfort.137

Importance of Non-pharmacologic Pain Management Interventions A recent systematic review focused on non-invasive nonpharmacologic treatment for chronic pain (without SUD) concluded that exercise, multi-disciplinary rehabilitation, acupuncture, cognitive behavior therapy (CBT), mindfulness practices, and mind-body practices most consistently exhibit modest improvements in pain intensity and function for specific pain conditions compared to usual care, sham treatments, or attention controls.138 A narrative review that included 56 studies on psychosocial interventions for those with chronic pain and OUD underscored the promise that a similar group of psychosocial interventions including CBT, acceptance and commitment therapy, mindfulness-based cognitive therapy, mindfulness-based stress reduction, relapse prevention, and motivational enhancement therapy (MET).139 Recognizing triggers (for pain and substance use), awareness of negative emotions, enhancing positive coping strategies, and pleasurable activity planning from both pain and SUD approaches are important elements of a hybrid psychosocial intervention that addresses both pain and SUDs.140 A recent literature review focused specifically on treating those with pain and OUD described some evidence for stepped care approaches in primary care and emphasized the need for more integrated and multi-disciplinary services.141

Non-pharmacologic Interventions for Patients with Comorbid Pain and SUDs A growing body of literature has examined the efficacy and effectiveness of behavioral interventions among patients with concomitant SUD and chronic pain. Some trials included those with a heterogeneous group of SUDs, while others focused on specific SUDs. Among those with more heterogeneous SUDs, the eight week improving pain during addiction treatment behavioral pain management intervention, which focused on relapse prevention and pain management skills, was associated with higher pain tolerance in men and lower pain intensity in women compared to those randomized to a supportive psychoeducational control. However, there were no differences in substance-related outcomes.142 Other trials included those with specific SUDs. One recent study examined a mindfulness-oriented recovery enhancement intervention in patients with OUD and chronic pain and found that the eight week intervention improved opioid craving, pain unpleasantness, and increased positive affect compared to treatment as usual.143 Pilot studies have demonstrated the feasibility and efficacy of CBT combined with MOUD for patients with comorbid pain and OUD with both methadone144 and buprenorphine.145 In a 12 week pilot study among 40 patients with OUD and low back pain receiving MMT (methadone maintenance treatment), patients reported higher satisfaction with CBT compared to methadone drug counseling as usual, and the CBT group contained a higher proportion of patients with negative urine drug screens for illicit opioids, with similar results for pain interference in both groups.144 Another study demonstrated repeat attendance and high satisfaction in patients receiving MMT who attended CBT-informed counseling groups for pain.146 Finally, a study of a brief smoking cessation intervention among those with chronic pain found that those randomized to the intervention had increased willingness to consider cessation.145

 

CHAPTER 52

Pain and Addictive Disorders: Challenge and Opportunity

741

Managing Acute Pain in Patients With Chronic Pain and Opioid Use Disorder

Cannabis Use for Pain and Cannabis Use Disorder

Management of acute pain in patients receiving opioids, such as LTOT or MOUD, or with SUD histories, can be challenging. Patients who receive opioids may require increased doses of opioids to achieve pain relief because of increased tolerance to opioids and opioid-induced hyperalgesia.147,150 Physicians may be wary of prescribing opioids to patients with a history of SUD, depriving these patients of pain relief following trauma, surgery, or other procedures resulting in acute pain. Patients with SUDs may also be hesitant to receive opioids out of fear they might relapse or develop OUD. Concern about inappropriate opioid prescribing and how to manage the large population of patients hospitalized for acute or chronic pain has led professional societies to develop guidelines for post-procedure analgesia in all patients. While these guidelines are not targeted specifically for populations with SUDs or chronic pain, they are useful for clinical practice or when helping a patient prepare for a procedure or intervention.151–153 Strategies such as comprehensive pain plans for both individuals and institutions that include explicit guidance for emergency and hospital providers on how to manage an individual patient’s acute pain flares may also be helpful for certain conditions. For example, the implementation of individualized protocols for acute pain in sickle cell disease has been shown to reduce admissions and readmissions, improve patients’ pain, and provide patient satisfaction,154 and is recommended by expert guidelines.155 More research is needed on the optimal management of acute pain in patients receiving MOUD, but there is evidence that continuing MOUD during surgery or treatment for acute pain is important.149,156 The ASAM guidelines released in 2020 suggest that it may be appropriate to temporarily increase daily doses of opioid agonists or split doses to optimize pain management in patients receiving MMT and buprenorphine during acute pain episodes.149 Guidelines from ASAM and the Pain and Addiction Interdisciplinary Network support the use of high dose opioid agonists for refractory pain in patients receiving buprenorphine for OUD,157 and ASAM recommends this for patients receiving MMT as well. For patients receiving naltrexone, options during acute pain include local pain management (i.e. nerve blocks), use of sedatives including ketamine and benzodiazepines, non-opioid pharmacology, or overcoming the blockade of mu receptors with high potency opioids. In preparation for surgery, patients can discontinue naltrexone at a minimum of 72 h prior and require three to seven days without opioids before resuming naltrexone to avoid precipitated withdrawal.149 For patients who make the decision with their care team to stop methadone or buprenorphine before surgery, ASAM now recommends discontinuation only the day prior to or day of surgery and that prescribers should determine how to resume.149

The availability and use of cannabis for chronic pain is increasing despite mixed evidence for its effectiveness and potential for harm,158 including addiction (see also Chapter 56). Among regular users, cannabis use can lead to physiologic dependence with a withdrawal syndrome that may include dysphoric mood, disturbed sleep, gastrointestinal symptoms, and decreased appetite. Among adults, the overall prevalence of CUD is 2.5% over 12 months and 6.3% over a lifetime.50,23 Furthermore, among those reporting past year cannabis use, 36% met the criteria for CUD over the previous year.159 While CUD is more prevalent and of greater severity than many recognize, only 5% of those with CUD have sought treatment from a healthcare provider.50 Standard treatment of CUD includes psychotherapy, such as CBT, MET, or contingency management (CM).160 However, these treatments may be inaccessible as well as time-and resourceintensive. Currently, no FDA-approved pharmacotherapies are available for CUD, although a number (e.g. cannabinoids, antidepressants, anxiolytics, and glutamatergic modulators) have been proposed for off-label use.161 A recent systematic review on the treatment of CUD concluded that there is a dearth of evidence examining pharmacologic interventions for CUD, although there is evidence that several drug classes, including cannabinoids and selective SNRIs, are ineffective.162 Clinical considerations for those treating chronic pain among individuals with cannabis use include awareness of state, federal, and institutional policies regarding cannabis, the establishment of goals regarding cannabis use, screening for non-medical use and addiction, counseling patients on harms and risks, offering medical advice on routes of administration, continual monitoring of functional status, symptom severity, and use of other medications and substances; use of urine drug tests; monitoring for harms associated with cannabis (falls, cognitive issues, motor vehicle accidents), and providing advice on discontinuation or referral to SUD treatment.49

Importance of Coordinated Care Many providers who treat chronic pain may be wary of the clinical complexity of accepting a new patient who is currently receiving treatment for OUD. We encourage pain providers to connect with the patient’s MOUD program and prescriber. While research shows that providers treating chronic pain feel like they are less experienced in treating SUDs, addiction treatment providers reveal similar concerns about their experience and training surrounding pain treatment.163,164 Pain providers have a lot to offer their colleagues in addiction medicine in terms of knowledge and experience of managing pain. Coordination between the two specialties can result in a better experience for the patient and the providers.

Conclusion Chronic pain and SUDs are prevalent chronic medical conditions that often co-occur. Patients with both conditions are clinically complex and may have other comorbid psychiatric and medical conditions. While many patients have received long term opioid therapy for chronic pain over the last three decades, expert guidelines now recommend against LTOT for most patients, given the risk of opioid-related harm. There are high rates of chronic pain in patients with SUDs. Likewise, many patients with chronic pain have SUDs and may use substances to manage their pain. The clinical needs of patients can go untreated because of fragmented care for pain and SUDs. While there are effective treatments for

SUDs, particularly MOUD for those with OUD, many patients with SUDs do not receive evidence-based treatment. There are also promising non-opioid interventions for chronic pain and SUDs, including non-opioid pharmacotherapy and non-­pharmacologic pain management interventions. Pain treatment providers should screen for SUDs. If they are unwilling or unable to provide both SUD and pain management, they should consider coordinating care with addiction medicine providers. In the case of OUD, buprenorphine prescribing by licensed office-based clinicians provides an increased opportunity for pain providers to be part of the treatment for co-occurring chronic pain and OUD.

742

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

Key Points • Addiction is a chronic relapsing medical condition or disease with effective treatments, similar to diabetes or hypertension. • There are high rates of SUDs among patients with chronic pain and high rates of chronic pain among patients with SUDs.

• Pain clinicians should screen for addiction risk before and during treatments, especially for treatments involving controlled substances, and be prepared to either provide treatment for SUDs or offer treatment referrals.

Suggested Readings

Chronic Pain. Rockville, MD: Agency for Healthcare Research and Quality; 2020. Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harm: a systematic review. Ann Intern Med. 2017;167(5):319–331. SAMHSA. Become a buprenorphine waivered practitioner. Substance abuse and mental health administration. Available at: https://www. samhsa.gov/medication-assisted-treatment/become-buprenorphinewaivered-practitioner. Skelly AC, Chou R, Dettori JR, et al. AHRQ comparative effectiveness review In: Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review Update. Rockville, MD: United States Agency for Healthcare Research and Quality; 2020. Volkow ND, Koob GF, McLellan AT. Neurobiological advances from the brain disease model of addiction. N Engl J Med. 2016;374(4): 363–371. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156(4): 569–576.

Barry DT, Beitel M, Garnet B, et al. Relationship between psychopathology, substance use, and physical pain experiences in methadonetreated patients. J Clin Psychiatry. 2009;70(9):1213–1218. Chou R, Dana T, Blazina I, Grusing S, Fu R, Bougatsos C. U.S. preventive services task force evidence syntheses, formerly systematic evidence reviews. In: Interventions for Unhealthy Drug Use- Supplemental Report: A Systematic Review for The U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2020. Crotty K, Freedman KI, Kampman KM. Executive summary of the focused update of the ASAM national practice guideline for the treatment of opioid use disorder. J Addict Med. 2020;14(2):99–112. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain-United States, 2016. JAMA. 2016;315(15): 624–1645. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med. 2005;6(2):107–112. McDonagh MS, Selph SS, Buckley DI, et al. AHRQ comparative effectiveness review. In: Nonopioid Pharmacological Treatments for

The references for this chapter can be found at ExpertConsult.com.

References 1. American Society of Addiction Medicine. Definition of addiction. Rockville, MD: American Society of Addiction Medicine; 2019. 2. McLellan AT, Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284(13):1689–1695. 3. Chou R, Dana T, Blazina I, Grusing S, Fu R, Bougatsos C. U.S. Preventive Services Task Force Evidence Syntheses, Formerly Systematic Evidence Reviews. Interventions for Unhealthy Drug Use-Supplemental Report: A Systematic Review for The U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2020. 4. National Academies of Sciences, Engineering, and Medicine. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press; 2019. 5. Reus VI, Fochtmann LJ, Bukstein O, et  al. The American Psychiatric Association practice guideline for the pharmacological treatment of patients with alcohol use disorder. Am J Psychiatry. 2018;175(1):86–90. 6. Clinical Practice Guideline Treating Tobacco Use and Dependence 2008 Update Panel. A clinical practice guideline for treating tobacco use and dependence: 2008 update: a U.S. public health service report. Am J Prevent Med. 2008;35(2):158–176. 7. O’Connor AM, Cousins G, Durand L, Barry J, Boland F. Retention of patients in opioid substitution treatment: a systematic review. PLoS One. 2020;15(5):e0232086. 8. Cramer JA, Benedict A, Muszbek N, Keskinaslan A, Khan ZM. The significance of compliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: a review. Int J Clin Pract. 2008;62(1):76–87. 9. National Academies of Sciences, Engineering, and Medicine. Ending Discrimination Against People With Mental and Substance Use Disorders: The Evidence for Stigma Change. Washington, DC: National Academies Press (US); 2016. 10. Witte TH, Wright A, Stinson EA. Factors influencing stigma toward individuals who have substance use disorders. Subst Use Misuse. 2019;54(7):1115–1124. 11. Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. N Engl J Med. 2016;374(4):363–371. 12. van Boekel LC, Brouwers EPM, van Weeghel J, Garretsen HFL. Stigma among health professionals towards patients with substance use disorders and its consequences for healthcare delivery: systematic review. Drug Alcohol Depend. 2013;131(1-2):23–35. 13. Broyles LM, Binswanger IA, Jenkins JA, et  al. Confronting inadvertent stigma and pejorative language in addiction scholarship: a recognition and response. Subst Abus. 2014;35(3):217–221. 14. Kelly JF, Wakeman SE, Saitz R. Stop talking “dirty”: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128(1):8–9. 15. Zgierska AE, Miller MM, Rabago DP, et  al. Language matters: it is time we change how we talk about addiction and its treatment. J Addict Med. 2021;15(1):10–12. 16. Adams ZM, Fitzsousa E, Gaeta M. “Abusers” and “addicts”: towards abolishing language of criminality in US medical licensing exam step 1 preparation materials. J Gen Intern Med. 2021; 36(6):1759–1760. 17. Code Service United States §802 (1996)(1970). Controlled Substances Act, stat. Title 1242;21, Chapter 13. 18. Tsai AC, Kiang MV, Barnett ML, et  al. Stigma as a fundamental hindrance to the United States opioid overdose crisis response. PLoS Med. 2019;16(11):e1002969. 19. Mossey JM. Defining racial and ethnic disparities in pain management. Clin Orthop Relat Res. 2011;469(7):1859–1870. 20. Gaither JR, Gordon K, Crystal S, et al. Racial disparities in discontinuation of long-term opioid therapy following illicit drug use among black and white patients. Drug Alcohol Depend. 2018;192:371–376. 21. Hausmann LRM, Gao S, Lee ES, Kwoh KC. Racial disparities in the monitoring of patients on chronic opioid therapy. Pain. 2013;154(1):46–52.

22. Grol-Prokopczyk H. Sociodemographic disparities in chronic pain, based on 12-year longitudinal data. Pain. 2017;158(2):313–322. 23. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 24. Ronzitti S, Kraus SW, Decker SE, Ashrafioun L. Clinical characteristics of veterans with gambling disorders seeking pain treatment. Addict Behav. 2019;95:160–165. 25. Barry DT, Pilver CE, Hoff RA, Potenza MN. Pain interference, gambling problem severity, and psychiatric disorders among a nationally representative sample of adults. J Behav Addict. 2013;2(3):138–144. 26. National Academies of Sciences Engineering and Medicine. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press; 2019. 27. Koob GF, Buck CL, Cohen A, et  al. Addiction as a stress surfeit disorder. Neuropharmacol. 2014;76(B):370–382 Pt B. 28. Mazei-Robison MS, Koo JW, Friedman AK, et al. Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron. 2011;72(6): 977–990. 29. Kreek MJ, Nielsen DA, LaForge KS. Genes associated with addiction: alcoholism, opiate, and cocaine addiction. NeuroMolecular Med. 2004;5(1):85–108. 30. Randesi M, Zhou Y, Mazid S, et  al. Sex differences after chronic stress in the expression of opioid-, stress- and neuroplasticity-related genes in the rat hippocampus. Neurobiol Stress. 2018;8:33–41. 31. Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci. 2008;1141:105–130. 32. Koob GF, Schulkin J. Addiction and stress: an allostatic view. Neurosci Biobehav Rev. 2019;106:245–262. 33. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8(7):573–582. 34. Morasco BJ, Gritzner S, Lewis L, Oldham R, Turk DC, Dobscha SK. Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder. Pain. 2011;152(3):488–497. 35. SAMHSA. Key Substance Use and Mental Health Indicators In The United States: Results From The 2019 National Survey On Drug Use and Health (HHS Publication No. PEP20-07-01-001, NSDUH Series H-55). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration; 2020. 36. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156(4):569–576. 37. Barry DT, Beitel M, Joshi D, Schottenfeld RS. Pain and substancerelated pain-reduction behaviors among opioid dependent individuals seeking methadone maintenance treatment. Am J Addict. 2009;18(2):117–121. 38. Barry DT, Savant JD, Beitel M, et al. Pain and associated substance use among opioid dependent individuals seeking office-based treatment with buprenorphine-naloxone: a needs assessment study. Am J Addict. 2013;22(3):212–217. 39. Dhingra L, Masson C, Perlman DC, et  al. Epidemiology of pain among outpatients in methadone maintenance treatment programs. Drug Alcohol Depend. 2013;128(1-2):161–165. 40. Dunn KE, Finan PH, Tompkins DA, Fingerhood M, Strain EC. Characterizing pain and associated coping strategies in methadone and buprenorphine-maintained patients. Drug Alcohol Depend. 2015;157:143–149. 41. Jamison RN, Kauffman J, Katz NP. Characteristics of methadone maintenance patients with chronic pain. J Pain Symptom Manage. 2000;19(1):53–62. 42. Mertens JR, Lu YW, Parthasarathy S, Moore C, Weisner CM. Medical and psychiatric conditions of alcohol and drug treatment patients in an HMO: comparison with matched controls. Arch Intern Med. 2003;163(20):2511–2517. 742.e1

742.e2

References

43. Rosenblum A, Joseph H, Fong C, Kipnis S, Cleland C, Portenoy RK. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA. 2003;289(18):2370–2378. 44. Ditre JW, Brandon TH, Zale EL, Meagher MM. Pain, nicotine, and smoking: research findings and mechanistic considerations. Psychol Bull. 2011;137(6):1065–1093. 45. Hooten MW, Shi Y, Gazelka HM, Warner DO. The effects of depression and smoking on pain severity and opioid use in patients with chronic pain. Pain. 2011;152(1):223–229. 46. Zvolensky MJ, McMillan K, Gonzalez A, Asmundson GJ. Chronic pain and cigarette smoking and nicotine dependence among a representative sample of adults. Nicotine Tob Res. 2009;11(12): 1407–1414. 47. Shiri R, Karppinen J, Leino-Arjas P, Solovieva S, Viikari-Juntura E. The association between smoking and low back pain: a metaanalysis. Am J Med. 2010;123(1):87 e7-87.35. 48. Sugiyama D, Nishimura K, Tamaki K, et al. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010;69(1):70–81. 49. Savage SR, Romero-Sandoval A, Schatman M, et  al. Cannabis in pain treatment: clinical and research considerations. J Pain. 2016;17(6):654–668. 50. Hasin DS, Kerridge BT, Saha TD, et al. Prevalence and correlates of DSM-5 cannabis use disorder, 2012-2013: findings from the national epidemiologic survey on alcohol and related conditions-III. Am J Psychiatry. 2016;173(6):588–599. 51. Orhurhu V, Urits I, Olusunmade M, et al. Cannabis use in hospitalized patients with chronic pain. Adv Ther. 2020;37(8):3571–3583. 52. Kim CH, Vincent A, Clauw DJ, et al. Association between alcohol consumption and symptom severity and quality of life in patients with fibromyalgia. Arthritis Res Ther. 2013;15(2):R42. 53. Von Korff M, Crane P, Lane M, et  al. Chronic spinal pain and physical-mental comorbidity in the United States: results from the national comorbidity survey replication. Pain. 2005;113(3): 331–339. 54. Liebschutz JM, Saitz R, Weiss RD, et al. Clinical factors associated with prescription drug use disorder in urban primary care patients with chronic pain. J Pain. 2010;11(11):1047–1055. 55. Nielsen S, Lintzeris N, Bruno R, et al. Benzodiazepine use among chronic pain patients prescribed opioids: associations with pain, physical and mental health, and health service utilization. Pain Med. 2015;16(2):356–366. 56. Shmagel A, Krebs E, Ensrud K, Foley R. Illicit substance use in US adults with chronic low back pain. Spine (Phila Pa 1976). 2016;41(17):1372–1377. 57. Manchikanti L, Cash KA, Damron KS, Manchukonda R, Pampati V, McManus CD. Controlled substance abuse and illicit drug use in chronic pain patients: an evaluation of multiple variables. Pain Phys. 2006;9(3):215–225. 58. Trujillo KA, Smith ML, Guaderrama MM. Powerful behavioral interactions between methamphetamine and morphine. Pharmacol Biochem Behav. 2011;99(3):451–458. 59. John WS, Wu LT. Chronic non-cancer pain among adults with substance use disorders: prevalence, characteristics, and association with opioid overdose and healthcare utilization. Drug Alcohol Depend. 2020;209:107902. 60. Becker WC, Barry DT. Comorbid pain and addiction. In: Miller SC, Fiellin DA, Rosenthal RN, Saitz R, eds. The ASAM Principles of Addiction Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer; 2019. 61. Ilgen MA, Perron B, Czyz EK, McCammon RJ, Trafton J. The timing of onset of pain and substance use disorders. Am J Addict. 2010;19(5):409–415. 62. Hser YI, Mooney LJ, Saxon AJ, Miotto K, Bell DS, Huang D. Chronic pain among patients with opioid use disorder: results from electronic health records data. J Subst Abuse Treat. 2017;77:26–30.

63. Barry DT, Beitel M, Cutter CJ, et  al. Psychiatric comorbidity and order of condition onset among patients seeking treatment for chronic pain and opioid use disorder. Drug Alcohol Depend. 2021;221:108608. doi:10.1016/j.drugalcdep.2021.108608. 64. Khoury L, Tang YL, Bradley B, Cubells JF, Ressler KJ. Substance use, childhood traumatic experience, and posttraumatic stress disorder in an urban civilian population. Depress Anxiety. 2010;27(12): 1077–1086. 65. Degenhardt L, Peacock A, Colledge S, et al. Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review. Lancet Glob Health. 2017;5(12):e1192–e1207. 66. Wejnert C, Hess KL, Hall HI, et  al. Vital signs: trends in HIV diagnoses, risk behaviors, and prevention among persons who inject drugs- United States. MMWR Morb Mortal Wkly Rep. 2016;65(47):1336–1342. 67. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection related to injection drug use among persons aged ≤30 years Kentucky, Tennessee, Virginia, and West Virginia, 2006-2012. MMWR Morb Mortal Wkly Rep. 2015;64(17):453–458. 68. Barry DT, Beitel M, Garnet B, Joshi D, Rosenblum A, Schottenfeld RS. Relations among psychopathology, substance use, and physical pain experiences in methadone-maintained patients. J Clin Psychiatry. 2009;70(9):1213–1218. 69. Barry DT, Cutter CJ, Beitel M, Kerns RD, Liong C, Schottenfeld RS. Psychiatric disorders among patients seeking treatment for cooccurring chronic pain and opioid use disorder. J Clin Psychiatry. 2016;77(10):1413–1419. 70. Haller DL, Acosta MC. Characteristics of pain patients with opioiduse disorder. Psychosom. 2010;51(3):257–266. 71. Higgins C, Smith BH, Matthews K. Comparison of psychiatric comorbidity in treatment-seeking, opioid-dependent patients with versus without chronic pain. Addiction. 2020;115(2):249–258. 72. Bohnert AS, Ilgen MA, Ignacio RV, McCarthy JF, Valenstein M, Blow FC. Risk of death from accidental overdose associated with psychiatric and substance use disorders. Am J Psychiatry. 2012;169(1):64–70. 73. Martel MO, Shir Y, Ware MA. Substance-related disorders: a review of prevalence and correlates among patients with chronic pain. Prog Neuropsychopharmacol Biol Psychiatry. 2018;87(B):245–254. 74. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med. 2005;6(2):107–112. 75. Dowell D, Haegerich TM, Chou R. CDC guideline for pre scribing opioids for chronic pain- United States, 2016. JAMA. 2016;315(15):1624–1645. 76. Manhapra A, Arias AJ, Ballantyne JC. The conundrum of opioid tapering in long-term opioid therapy for chronic pain: a commentary. Subst Abus. 2018;39(2):152–161. 77. Butler SF, Budman SH, Fernandez KC, Fanciullo GJ, Jamison RN. Cross-validation of a screener to predict opioid misuse in chronic pain patients (SOAPP-R). J Addict Med. 2009;3(2):66–73. 78. Webster LR, Webster RM. Predicting aberrant behaviors in opioidtreated patients: preliminary validation of the opioid risk tool. Pain Med. 2005;6(6):432–442. 79. Butler SF, Budman SH, Fernandez KC, et  al. Development and validation of the current opioid misuse measure. Pain. 2007;130(12):144–156. 80. Adams LL, Gatchel RJ, Robinson RC, et al. Development of a selfreport screening instrument for assessing potential opioid medication misuse in chronic pain patients. J Pain Symptom Manage. 2004;27(5):440–459. 81. Belgrade MJ, Schamber CD, Lindgren BR. The DIRE score: predicting outcomes of opioid prescribing for chronic pain. J Pain. 2006;7(9):671–681. 82. Moore TM, Jones T, Browder JH, Daffron S, Passik SD. A comparison of common screening methods for predicting aberrant

References

drug-related behavior among patients receiving opioids for chronic pain management. Pain Med. 2009;10(8):1426–1433. 83. Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption–II. Addiction. 1993;88(6): 791–804. 84. Adamson SJ, Kay-Lambkin FJ, Baker AL, et al. An improved brief measure of cannabis misuse: the cannabis use disorders identification testrevised (CUDIT-R). Drug Alcohol Depend. 2010;110(1-2):137–143. 85. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7(4):363–371. 86. Yudko E, Lozhkina O, Fouts A. A comprehensive review of the psychometric properties of the drug abuse screening test. J Subst Abuse Treat. 2007;32(2):189–198. 87. WHO ASSIST Working Group. The alcohol, smoking and substance involvement screening test (ASSIST): development, reliability and feasibility. Addiction. 2002;97(9):1183–1194. 88. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94(3):135–140. 89. SAMHSA. Treatment Episode Data Set, 2002-2012: National Admissions to Substance Abuse Treatment Services. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014. 90. Centers for Disease Control and Prevention. Wide-ranging online data for epidemiologic research (WONDER) multiple-cause-ofdeath file 2000-2014. Available at: http://www.cdc.gov/nchs/data/ health_policy/AADR_drug_poisoning_involving_OA_Heroin_ US_2000-2014.pdf. 91. Orhurhu V, Olusunmade M, Urits I, et  al. Trends of opioid use disorder among hospitalized patients with chronic pain. Pain Pract. 2019;19(6):656–663. 92. United States Burden of Disease Collaborators, Mokdad AH, Ballestros K, et  al. The state of US health, 1990-2016: burden of diseases, injuries, and risk factors among US states. JAMA. 2018;319(14):1444–1472. 93. Dowell D, Haegerich T, Chou R. No shortcuts to safer opioid prescribing. N Engl J Med. 2019;380(24):2285–2287. 94. Kroenke K, Alford DP, Argoff C, et al. Challenges with implementing the centers for disease control and prevention opioid guideline: a consensus panel report. Pain Med. 2019;20(4):724–735. 95. Barry DT, Marshall BDL, Becker WC, et al. Duration of opioid prescriptions predicts incident nonmedical use of prescription opioids among US veterans receiving medical care. Drug Alcohol Depend. 2018;191:348–354. 96. Volkow ND, Jones EB, Einstein EB, Wargo EM. Prevention and treatment of opioid misuse and addiction: a review. JAMA Psychiatry. 2019;76(2):208–216. 97. Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA. 2018;319(9):872–882. 98. Bohnert ASB, Guy Jr GP, Losby JL. Opioid prescribing in the United States before and after the Centers for Disease Control and Prevention’s 2016 opioid guideline. Ann Intern Med. 2018;169(6):367–375. 99. Kertesz SG. Turning the tide or riptide? The changing opioid epidemic. Subst Abus. 2017;38(1):3–8. 100. Tsui JI, Evans JL, Lum PJ, Hahn JA, Page K. Association of opioid agonist therapy with lower incidence of hepatitis C virus infection in young adult injection drug users. JAMA Intern Med. 2014;174(12):1974–1981. 101. Johnson WD, Rivadeneira N, Adegbite AH, et al. Human immunodeficiency virus prevention for people who use drugs: overview of reviews and the ICOS of PICOS. J Infect Dis. 2020;222(Suppl 5):S278–S300. 102. Sordo L, Barrio G, Bravo MJ, et al. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ. 2017;357:j1550.

742.e3

103. SAMHSA. Medications for Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2020. 104. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015;9(5):358–367. 105. SAMHSA. Become a buprenorphine waivered practitioner. Available at: https://www.samhsa.gov/medication-assisted-treatment/ become-buprenorphine-waivered-practitioner. 106. Merlin JS, Young SR, Starrels JL, et al. Managing concerning behaviors in patients prescribed opioids for chronic pain: a Delphi study. J Gen Intern Med. 2018;33(2):166–176. 107. Merlin JS, Young SR, Azari S, et  al. Management of problematic behaviours among individuals on long-term opioid therapy: protocol for a Delphi study. BMJ Open. 2016;6(5):e011619. doi:10.1136/ bmjopen-2016-011619. 108. Conrardy M, Lank P, Cameron KA, et al. Emergency department patient perspectives on the risk of addiction to prescription opioids. Pain Med. 2016;17(1):114–121. 109. Jamison RN, Scanlan E, Matthews ML, Jurcik DC, Ross EL. Attitudes of primary care practitioners in managing chronic pain patients prescribed opioids for pain: a prospective longitudinal controlled trial. Pain Med. 2016;17(1):99–113. 110. Ebbert JO, Philpot LM, Clements CM, et  al. Attitudes, beliefs, practices, and concerns among clinicians prescribing opioids in a large academic institution. Pain Med. 2018;19(9):1790–1798. 111. Covington EC, Argoff CE, Ballantyne JC, et  al. Ensuring patient protections when tapering opioids: consensus panel recommendations. Mayo Clin Proc. 2020;95(10):2155–2171. 112. Edens E, Abelleira A, Barry DT, Becker, WC. You say pain, I say addiction. Let’s call the whole thing off. Psychiatric Times. 2020; 37:47–51. 113. Pergolizzi J, Böger RH, Budd K, et  al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract. 2008;8(4):287–313. 114. Davis MP, Pasternak G, Behm B. Treating chronic pain: an overview of clinical studies centered on the buprenorphine option. Drugs. 2018;78(12):1211–1228. 115. Webster L, Gudin J, Raffa RB, et al. Understanding buprenorphine for use in chronic pain: expert opinion. Pain Med. 2020;21(4): 714–723. 116. Volkow ND, McLellan AT. Opioid abuse in chronic pain- misconceptions and mitigation strategies. N Engl J Med. 2016;374(13): 1253–1263. 117. Chou R, Ballantyne J, Lembke A. Rethinking opioid dose tapering, prescription opioid dependence, and indications for buprenorphine. Ann Intern Med. 2019;171(6):427–429. 118. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a national institutes of health pathways to prevention workshop. Ann Intern Med. 2015;162(4):276–286. 119. Peckham AM, Fairman KA, Sclar DA. Prevalence of gabapentin abuse: comparison with agents with known abuse potential in a commercially insured US population. Clin Drug Investig. 2017;37(8):763–773. 120. Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioidrelated death: a population-based nested case-control study. PLoS Med. 2017;14(10):e1002396. 121. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938. 122. McDonagh MS, Selph SS, Buckley DI, et  al. AHRQ Comparative Effectiveness Reviews. Nonopioid Pharmacological Treatments for Chronic Pain. Rockville, MD: Agency for Healthcare Research and Quality; 2020.

742.e4

References

123. Wiffen PJ, Derry S, Lunn MPT, Moore RA. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2013;8(8):CD008314. 124. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards subcommittee of the American Academy of Neurology and the American Headache Society. Neurol. 2012;78(17):1337–1345. 125. Mason BJ, Quello S, Shadan F. Gabapentin for the treatment of alcohol use disorder. Expert Opin Investig Drugs. 2018;27(1): 113–124. 126. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014;174(1):70–77. 127. Brower KJ, Myra Kim H, Strobbe S, Karam-Hage MA, Consens F, Zucker RA. A randomized double-blind pilot trial of gabapentin versus placebo to treat alcohol dependence and comorbid insomnia. Alcohol Clin Exp Res. 2008;32(8):1429–1438. 128. Food and Drug Administration. FDA Warns About Serious Breathing Problems With Seizure and Nerve Pain Medicines Gabapentin (Neurontin, Gralise, Horizant) And Pregabalin (Lyrica, Lyrica CR) When Used With CNS Depressants or In Patients With Lung Problems. Rockville, MD: United States Food and Drug Administration; 2019. 129. Manhapra A, Chakraborty A, Arias AJ. Topiramate pharmacotherapy for alcohol use disorder and other addictions: a narrative review. J Addict Med. 2019;13(1):7–22. 130. Singh M, Keer D, Klimas J, Wood E, Werb D. Topiramate for cocaine dependence: a systematic review and meta-analysis of randomized controlled trials. Addiction. 2016;111(8):1337–1346. 131. Bschor T, Henssler J, Müller M, Baethge C. Baclofen for alcohol use disorder- a systematic meta-analysis. Acta Psychiatr Scand. 2018;138(3):232–242. 132. Minozzi S, Saulle R, Rösner S. Baclofen for alcohol use disorder. Cochrane Database Syst Rev. 2018;11(11):CD012557. 133. Agabio R, Sinclair JM, Addolorato G, et al. Baclofen for the treatment of alcohol use disorder: the Cagliari Statement. Lancet Psychiatry. 2018;5(12):957–960. 134. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ. 2017;356:j760. 135. Hirschtritt ME, Delucchi KL, Olfson M. Outpatient, combined use of opioid and benzodiazepine medications in the United States, 1993-2014. Prev Med Rep. 2018;9:49–54. 136. Giovannitti Jr JA, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31–39. 137. Srivastava AB, Mariani JJ, Levin FR. New directions in the treatment of opioid withdrawal. Lancet. 2020;395(10241):1938– 1948. 138. Skelly AC, Chou R, Dettori JR, et  al. AHRQ Comparative Effectiveness Reviews. Noninvasive Nonpharmacological Treatment for Chronic Pain: a Systematic Review Update. Rockville, MD: Agency for Healthcare Research and Quality; 2020. 139. Hruschak V., Cochran G., Wasan AD. Psychosocial interventions for chronic pain and comorbid prescription opioid use disorders: a narrative review of the literature. J Opioid Manag. 2018;14(5):345–358. https://doi.org/10.5055/jom.2018.0467 140. Morasco BJ, Greaves DW, Lovejoy TI, Turk DC, Dobscha SK, Hauser P. Development and preliminary evaluation of an integrated cognitive-behavior treatment for chronic pain and substance use disorder in patients with the hepatitis C virus. Pain Med. 2016;17(12):2280–2290. 141. Speed TJ, Parekh V, Coe W, Antoine D. Comorbid chronic pain and opioid use disorder: literature review and potential treatment innovations. Int Rev Psychiatry. 2018;30(5):136–146. 142. Ilgen MA, Coughlin LN, Bohnert ASB, et al. Efficacy of a psychosocial pain management intervention for men and women with

substance use disorders and chronic pain: a randomized clinical trial. JAMA Psychiatry. 2020;77(12):1225–1234. doi:10.1001/jamapsychiatry.2020.2369. 143. Garland EL, Hanley AW, Riquino MR, et al. Mindfulness-oriented recovery enhancement reduces opioid misuse risk via analgesic and positive psychological mechanisms: a randomized controlled trial. J Consult Clin Psychol. 2019;87(10):927–940. 144. Barry DT, Beitel M, Cutter CJ, et al. An evaluation of the feasibility, acceptability, and preliminary efficacy of cognitive-behavioral therapy for opioid use disorder and chronic pain. Drug Alcohol Depend. 2019;194:460–467. 145. Barry D, Schottenfeld RS. Cognitive-behavioral therapy with buprenorphine/naloxone: for chronic pain and opioid use disorder: a randomized controlled trial. 2020; Manuscript in Preparation. 146. Barry DT, Savant JD, Beitel M, et  al. The feasibility and acceptability of groups for pain management in methadone maintenance treatment. J Addict Med. 2014;8(5):338–344. 147. ASAM. The ASAM national practice guideline for the treatment of opioid use disorder: 2020 focused update. J Addict Med. 2020;14 (2S Suppl 1):1–91. 148. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. 2006;144(2):127–134. 149. Overton HN, Hanna MN, Bruhn WE, et  al. Opioid-prescribing guidelines for common surgical procedures: an expert panel consensus. J Am Coll Surg. 2018;227(4):411–418. 150. Farooqi OA, Bruhn WE, Lecholop MK, et  al. Opioid guidelines for common dental surgical procedures: a multidisciplinary panel consensus. Int J Oral Maxillofac Surg. 2020;49(3):397–402. 151. McLawhorn JM, Stephany MP, Bruhn WE, et al. An expert panel consensus on opioid-prescribing guidelines for dermatologic procedures. J Am Acad Dermatol. 2020;82(3):700–708. 152. Krishnamurti L, Smith-Packard B, Gupta A, Campbell M, Gunawardena S, Saladino R. Impact of individualized pain plan on the emergency management of children with sickle cell disease. Pediatr Blood Cancer. 2014;61(10):1747–1753. 153. NHLBI. Evidence-Based Management of Sickle Cell Disease, Expert Panel Report 2014. Rockville, MD: United States Department of Health and Human Services; 2014. 154. Veazie S, Mackey K, Peterson K, Bourne D. Managing acute pain in patients taking medication for opioid use disorder: a rapid review. J Gen Intern Med. 2020;35(Suppl 3):945–953. 155. Goel A, Azargive S, Weissman JS, et  al. Perioperative pain and addiction interdisciplinary network. Perioperative pain and addiction interdisciplinary network (PAIN) clinical practice advisory for perioperative management of buprenorphine: results of a modified Delphi process. Br J Anaesth. 2019;123(2):e333–e342. 156. Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review. Ann Intern Med. 2017;167(5):319–331. 157. Blanco C, Hasin DS, Wall MM, et  al. Cannabis use and risk of psychiatric disorders: prospective evidence from a US national longitudinal study. JAMA Psychiatry. 2016;73(4):388–395. 158. Sherman BJ, McRae-Clark AL. Treatment of cannabis use disorder: current science and future outlook. Pharmacother. 2016;36(5): 511–535. 159. Nielsen S, Gowing L, Sabioni P, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database Syst Rev. 2019;1:CD008940. 160. Kondo KK, Morasco BJ, Nugent SM, et al. Pharmacotherapy for the treatment of cannabis use disorder: a systematic review. Ann Intern Med. 2020;172(6):398–412. 161. Barry DT, Irwin KS, Jones ES, et  al. Opioids, chronic pain, and addiction in primary care. J Pain. 2010;11(12):1442–1450. 162. Beitel M, Oberleitner L, Kahn M, et al. Drug counselor responses to patients’ pain reports: a qualitative investigation of barriers and facilitators to treating patients with chronic pain in methadone maintenance treatment. Pain Med. 2017;18(11):2152–2161.

53

Anti-depressants

ANTHONY H. DICKENSON, RYAN PATEL, CHARLES E. ARGOFF

Introduction The second half of the 20th century saw the introduction of a range of therapeutic agents known to have an anti-depressant effect. These are currently classified partly based on their chemical structure and partly according to their primary in vivo effects (Box 53.1). Even before their introduction into clinical practice, the concept of an association between depression and pain was clear, and the possibility that this link was causal encouraged the use of anti-depressants for patients who exhibited features of both pain and depression. It is now recognized that the pain relief apparent with the use of anti-depressants can be independent of any alteration in mood caused by the drug,1 and the analgesic effects can occur more rapidly,2,3 at lower doses/serum levels than those required for anti-depressive effects.4,5 Our current understanding is that the primary mechanism of action of anti-depressant drugs in neuropathic pain is through blocking monoamine reuptake in descending modulatory pathways. In a normal state, activity within bulbospinal circuits are finely balanced to set the sensory gain at the spinal level, and these can rapidly adapt to amplify or suppress pain according to context. For example, neural circuits have been described that underly acute stress-induced analgesia and chronic stress-induced hyperalgesia,6 and placebo responses are also in part because of recruitment of descending opioidergic inhibitions.7 Serotonin (5-HT) originating from the dorsal raphe nuclei exerts bi-directional control of sensory neuronal activity at the spinal level dependent on the particular receptor subtype targeted. At the cellular level, 5-HT receptors can be excitatory (subtypes 2, 3, 4, 6, and 7) or inhibitory (subtypes 1, 5). However, the complexity of their ability to amplify or suppress sensory transmission is determined by their expression patterns on excitatory and inhibitory interneurons.8 The 5-HT2A and 5-HT3 receptors are the predominant faciliatory receptors in the dorsal horn, and their excitatory effects on pre-synaptic primary afferent terminals outweigh their actions on inhibitory interneurons.9,10 The 5-HT7 receptor conversely has a greater expression on inhibitory interneurons, and agonists suppress sensory transmission.11 Running parallel to these serotonergic projections to the dorsal horn are pontine derived noradrenergic pathways, particularly from the A5 and A6 (locus coeruleus) groups; these terminate upon spinal α1 and α2 adrenoceptors. Activation of the α2 adrenoceptor inhibits neuronal excitability, and these are largely expressed pre-synaptically on primary afferent terminals (α2A) and excitatory interneurons (α2C). Conversely, α1

adrenoceptors are excitatory and are expressed by both inhibitory and excitatory interneurons. However, their net effect on sensory transmission is considered to be faciliatory.8 There is compelling evidence that links a loss of noradrenergic inhibitory tone and enhanced serotonergic facilitation in the development and maintenance of chronic pain states.12–15 Consequently, this imbalance in descending monoaminergic control in neuropathic rats can also present as a loss of diffuse noxious inhibitory controls (DNIC).16 DNIC are a partly opioidergic and noradrenergic endogenous pain modulatory mechanism.16,17 In the absence of nerve injury, DNIC are activated when two distant noxious stimuli are applied, recruiting a bulbospinal inhibitory pathway that overlaps with the canonical descending pain modulatory network.18 The human counterpart measure to DNIC is referred to as conditioned pain modulation (CPM; see Chapter 21). Typically, CPM is performed by determining pain scores (on a visual analog scale) or a pain threshold to a noxious test stimulus, followed by a repeat of the test in the presence of a distant heterotopically applied noxious conditioning stimulus, e.g. cold pressor. Functional CPM is then quantified as the decrease in pain scores or increase in pain threshold to the test stimulus. The use of CPM as a sensory testing tool has gained much traction in recent years to study the role of descending modulation in the cause of pain. Low CPM is associated with numerous chronic pain states of neuropathic and non-neuropathic origin,19–23 and a higher risk of postoperative pain.24,25 As an illustration of how patients can be separated according to putative pathophysiologic mechanisms, a large scale study attempting to stratify chronic pain patients according to mechanisms of spinal gain (enhanced temporal summation) or loss of descending control (low CPM) reported 37% of patients with low CPM and 21% with both low CPM and enhanced temporal summation.26 Stratification will be key to future clinical trial design and treatment selection, given that nerve injury can induce numerous transcriptional changes and neuroplasticity throughout the sensory neuraxis. Any given drug with a defined mechanism of action would have to target the predominant pathophysiologic mechanism in a patient to provide relief. In this respect, it is perhaps unsurprising that many patients fail to achieve adequate pain relief. The focus of this chapter is on the potential pain-reducing capability of drugs otherwise associated with the treatment of depression. In most cases, the clinical studies cited within are based on non-stratified patient cohorts and commonly use patient reported ongoing pain scores as primary endpoints of efficacy. However,

743

744

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

• BOX 53.1

Classification of Anti-depressants

Tricyclic Anti-depressants Amitriptyline Clomipramine Desipramine Dothiepin Doxepin Imipramine Iprindole Lofepramine Nortriptyline Opipramol Protriptyline Trimipramine

Serotonin-Noradrenaline Reuptake Inhibitors Duloxetine Milnacipran Nefazodone Venlafaxine

Selective Serotonin Reuptake Inhibitors Alaproclate Citalopram Escitalopram Etoperidone Fluoxetine Fluvoxamine Paroxetine Sertraline Zimeldine

Dopamine Reuptake Inhibitors Amineptine Bupropion

Noradrenaline Reuptake Inhibitor Reboxetine

Monoamine Oxidase Inhibitors Harmaline Iproclozide Iproniazid Isocarboxazid Moclobemide Nialamide Selegiline

more recently, trans-etiological sensory phenotypes have been described, and each may have specific drug sensitivities determined by common underlying mechanisms (see Chapter 21).27 The prospects for mechanism-led treatment selection regarding anti-depressants will also be addressed.

Tricyclic Anti-depressants Mechanism of Action (Animal Models) In addition to increasing synaptic monoamine concentrations, tricyclic anti-depressants (TCAs; Fig. 53.1) exert many pharmacologic actions. Table 53.1 compares the receptor affinity profiles for various TCAs. All TCAs have a low affinity for dopamine transporters but different binding profiles for serotonin and noradrenaline transporters. Amitriptyline has a comparable affinity for both transporters, whereas desipramine has higher selectivity for noradrenaline transporters (approximately 40-fold) and clomipramine has higher selectivity for serotonin transporters (approximately 230-fold). Despite having a low affinity for dopamine reuptake transporters, systemic amitriptyline promotes dopamine release at the spinal level in neuropathic rats, and antinociception is partially blocked by a D2 receptor antagonist.28 A possible explanation is an interaction between monoamine systems at the spinal level. Plasticity in the expression of serotonergic or noradrenergic receptors on dopaminergic terminals could promote the release of dopamine. Alternatively, this interaction may occur in higher centers leading to a top-down increase in descending dopaminergic drive. A potential confound is the role of dopamine in motor function and motivation that could alter behavioral responses to painful stimuli. Dual blockers of serotonin and noradrenaline reuptake, such as most TCAs and serotonin-noradrenaline reuptake inhibitors (SNRIs), are known to be more effective for pain relief than the transporter selective drugs. As there is a considerable anatomic and functional interaction between the signaling systems, drug actions on one system will inevitably impact the other, which likely produces synergistic drug effects.29 Modulation of coerulospinal activity is central to the anti-nociceptive effects mediated by

Toloxatone Tranylcypromine

Selective Serotonin Reuptake Enhancer Tianeptine

Tetracyclic Anti-depressants Amoxapine Maprotiline Mianserin Mirtazapine

TCAs and SNRIs. At the spinal level, amitriptyline increases spinal noradrenaline concentrations in neuropathic rats, coinciding with a reversal of evoked hypersensitivity and restoration of DNIC.30 Increased release of noradrenaline within the locus coeruleus can exert excitatory or inhibitory effects on neuronal activity via α1 and α2 adrenoceptors, respectively. However, long-term desipramine and duloxetine dosing leads to the desensitization of α2 autoreceptors and may restore descending inhibition.31 Plasticity in channel function within the dorsal horn, such as increased receptor density and enhanced coupling to G-proteins, could also increase the magnitude of drug effects in pathophysiologic states.32,33 TCAs may mediate part of their analgesic effects via activation of opioidergic signaling.34–36 The anti-nociceptive effects of chronic nortriptyline dosing were reversed by naloxone and selective antagonists of δ- and κ-Opioid receptors,34 but not μ-Opioid receptors.35 TCAs tend to have a low affinity for opioid receptors. Therefore these effects are considered secondary to other mechanisms such as changes in monoamines. Concerning other central targets, TCAs might also act to reverse central sensitization by targeting NMDA receptors, either directly37 or through downregulation of NR2B subunits.38 More recent investigations have revealed novel insight into potential peripheral mechanisms of analgesia. TCAs have been proposed indirectly to modulate neuroimmune responses such as downregulation of tumor necrosis factor (TNF) α and the nuclear factor κB (NFκB) signaling pathway, which reduces inflammatory sensitization of peripheral sensory neurons.39–41 In vitro studies have shown that various TCAs are activation state- and use-dependent blockers of Nav1.3, Nav1.7, and Nav1.8 with IC50s in the range of therapeutic plasma concentrations for the treatment of depression and neuropathic pain.42,43 The latter channels Nav1.7 and Nav1.8 are almost exclusively expressed in nociceptors,44,45 whereas Nav1.3 is not normally expressed in adult neurons but is upregulated after nerve injury and promotes hyperexcitability.46 There are some suggestions that amitriptyline can also reduce peripheral neuronal hyperexcitability by inhibiting adenosine reuptake.47,48 However, there is no evidence that adenosine receptor agonists are effective against pain in clinical trials.49 In all of these cases, it is impossible to ascertain that the non-monoamine actions contribute to pain control at clinical doses.

 

CHAPTER 53

Anti-depressants

745

O

CH3

N

N

CH3 Amitriptyline

Doxepin

N

N

Cl

N

N

Clomipramine

Imipramine

N

H

H

N

N

Nortriptyline

Desipramine

• Figure 53.1  Tricyclic anti-depressants.

Clinical Management of Pain Drug efficacy is often evaluated in terms of the number needed to treat (NNT). In terms of analgesics, this represents the number of patients who need to take the treatment to obtain a 50% or greater reduction in their pain. A meta-analysis of double-blind placebo-controlled trials of TCAs in neuropathic pain calculates the NNT at 3.6 (Fig. 53.2),50 a higher efficacy than most other treatments. TCAs appear effective in peripheral and central origin neuropathies, including diabetic neuropathy,1,51–53 postherpetic neuralgia,54–56 peripheral nerve injury,57 spinal cord injury,58 central post-stroke pain,59 and multiple sclerosis.60 Limited effectiveness was observed in a trial involving HIV neuropathy patients,61 and radiculopathy.62 Amitriptyline is the most widely studied,1,53,56–61 but the NNT for desipramine,51,54,55 nortriptyline,55 and imipramine52 appear comparable albeit based on a smaller dataset. As TCAs can block serotonin and noradrenaline reuptake, it seems likely that inefficient CPM could predict analgesic efficacy as has

been demonstrated for duloxetine.23 Local or topical delivery of drugs has been explored as a method to reduce central side effects of analgesics, and the TCAs were considered a potential candidate because of numerous off-target effects at various ion channels known to be expressed in primary afferents. However, no randomized, double-blinded, placebo-controlled trials support the efficacy of topical amitriptyline.63 In patients unresponsive to oral TCAs, a small decrease in ongoing pain scores was observed with topical doxepin, but paresthesia, allodynia, and shooting pains were unaffected.64 Fibromyalgia is not classified as a neuropathic condition but shares features of neuropathic pain, such as central sensitization and altered central modulation. Dysregulation of descending modulation is apparent in some patients with fibromyalgia,65 and pain facilitation as well as a loss of pain inhibition during CPM has been reported.66 A meta-analysis of TCA trials in fibromyalgia indicates an overall small to moderate improvement of pain, sleep

746

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

TABLE 53.1

Affinity Profiles of TCAs for Various Transporters and Receptors SERT

NET

DAT

5-HT1A

5-HT2A

α1

α2

D1

D2

H1

H2

mACh

Amitriptyline

40

68

4000

450

21

15

581

89

885

1

66

16

Clomipramine

0.2

46

2600

>10,000

35

20

1862

219

143

22

209

37

Desipramine

112

2.9

>3000

>6400

350

49

2750

5462

2530

87

1549

205

Dothiepin

8.6

46

5310

ND

ND

ND

ND

ND

ND

ND

ND

64

Doxepin

68

30

>10,000

276

27

24

1185

ND

1380

0.27

ND

72

Imipramine

8.3

83

>8500

>5800

150

51

3150

>10,000

1115

9.3

550

62

Lofepramine

70

5.4

>10,000

4600

200

100

2700

ND

2000

245

4266

265

Nortriptyline

18

4

1130

294

ND

55

2000

ND

2570

3

645

37

Protriptyline

19.6

1.4

2100

ND

ND

130

6600

ND

2300

16.1

398

25

Trimipramine

149

2450

3780

ND

ND

24

680

ND

180

1

41

58

Values are Ki (nM) for human proteins, the smaller the Ki, the greater the binding affinity. TCAs are inhibitors of transporters and antagonists/inverse agonists of receptors. Data from the Psychoactive Drug Screening Program Ki database, Roth and Driscol, University of North Carolina. (SERT - serotonin reuptake transporter, NET - noradrenaline reuptake transporter, DAT - dopamine reuptake transporter, ND - not determined).

NNT (95% CI) CPSP, amitriptyline 75 mg, Leijon and Boivie (1989)

1.7 (1.2 to 3.0)

SCI, amitriptyline 150 mg, Rintala et al. (2007)

4.4 (2.0 to –17.4)

PPN, amitriptyline 150 mg, Max et al. (1987)

1.6 (1.2 to 2.3)

PPN, desipramine 25 mg, Max et al. (1991)

2.2 (1.4 to 5.1)

PPN, amitriptyline 75 mg, Vrethem et al. (1997)

3.0 (2.0 to 6.3)

PPN, maprotiline 75 mg, Vrethem et al. (1997)

11.0 (4.6 to –28.7)

PPN, amitriptyline 100 mg, Kieburtz et al. (1998)

50.0 (4.5 to –5.6)

PPN, imipramine 150 mg, Sindrup et al. (2003)

2.4 (1.6 to 4.8)

PHN, amitriptyline 73 mg, Watson et al. (1982)

1.6 (1.2 to 2.4) 1.9 (1.3 to 3.7)

PHN, desipramine 250 mg, Kishore-Kumar et al. (1990)

4.0 (2.6 to 8.9)

PHN, nortriptyline/desipramine 160 mg, Raja et al. (2002)

2.5 (1.4 to 10.6)

PNI, amitriptyline 100 mg, Kalso et al. (2006)

18.6 (3.5 to –5.5)

RADIC, nortriptyline 100 mg, Khoromi et al. (2007) MS, amitriptyline 75 mg, Österberg and Boivie (2005)

3.4 (1.7 to –63.0)

PPN, amitriptyline 75 mg, PhRMA and FDA 1008-040 (2007)

6.1 (3.3 to 52.5)

Combined (fixed effects)

3.6 (3.0 to 4.4) –2.5

–5

∞

5

NNT (harm)

2.5

1.67

1.25

1 NNT (benefit)

• Figure 53.2  NNT values (with 95% confidence intervals) are shown for each trial and for the overall es-

timate (fixed effects, Mantel-Haenszel) for tricyclic anti-depressants (15 studies, 948 participants). The size of the square represents the Mantel-Haenszel weight that the study exerts in the meta-analysis. CPSP, Central post-stroke pain; FDA, United States Food and Drug Administration; MS, multiple sclerosis; NNT, number needed to treat; PHN, postherpetic neuralgia; PhRMA, Pharmaceutical Research and Manufacturers of America; PNI, peripheral nerve injury; PPN, painful polyneuropathy; RADIC, painful radiculopathy; SCI, spinal cord injury pain. Data from Finnerup et al., Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–73.50

disturbances, and fatigue.67 A small number of patients benefited greatly from treatment with anti-depressants. However, a large number are also known to drop out of trials because of intolerable adverse effects. It was suggested that TCAs appear more effective for patients with comorbid insomnia, whereas SNRIs may be preferable for patients with comorbid depression. Based on a lower meaningful effect size (reduction of pain by 30%), the NNT for TCAs in fibromyalgia is 4.9.

SNRIs Mechanism of Action (Animal Models) SNRIs (Fig. 53.3) selectively block the reuptake of serotonin and noradrenaline. Milnacipran has an equal affinity for serotonin and noradrenaline transporters, whereas duloxetine and venlafaxine have 10-fold and 30-fold selectivity for serotonin transporters,

 

CHAPTER 53

Anti-depressants

747

O O

N

N

N

N

N H S O

N

Cl Duloxetine

Nefazodone

N

H

N

OH

N

O Desipramine

Venlafaxine

• Figure 53.3  Serotonin-noradrenaline reuptake inhibitors.

respectively. A single systemic dose of duloxetine and milnacipran increases spinal concentrations of serotonin and noradrenaline though interestingly, the temporal kinetics of transmitter accumulation differ. Milnacipran increases both transmitter levels gradually with time. In contrast, duloxetine rapidly increases serotonin concentrations that decline with time, whereas noradrenaline concentrations increase progressively.68 As discussed above, augmentation of noradrenergic signaling in the coerulo-spinal pathway is critical to the analgesic effects mediated by SNRIs. In neuropathic rats, duloxetine increases spinal noradrenaline content, and the anti-nociceptive effects are reversed by an intrathecal α2 adrenoceptor antagonist.69 In line with clinical observations,23 DNIC are absent after nerve injury and are also restored by duloxetine.69 There are conflicting data regarding the involvement of opioid signaling systems in the anti-nociceptive effects of SNRIs, and these effects differ according to the injury model and dosing protocols.36,40,70,71 As this is a feature shared with TCAs, it seems likely that activation of endogenous opioid signaling occurs secondary to blocking the reuptake of noradrenaline and serotonin,

which in turn could activate their respective receptors on inhibitory opioidergic interneurons in the dorsal horn. Peripheral actions of chronic duloxetine dosing have also been described, which rely on noradrenaline release from peripheral sympathetic terminals. This subsequently downregulates TNFα and NFκB pathways mediated via β2 adrenoceptors on non-neuronal satellite cells in the dorsal root ganglia of neuropathic mice.39,40

Clinical Management of Pain At present, duloxetine is the only licensed anti-depressant (in the United States) for the treatment of diabetic neuropathy, and approvals for fibromyalgia and chronic musculoskeletal pain have now been granted. A meta-analysis of double-blind placebocontrolled trials of SNRIs in neuropathic pain calculates the NNT at 6.4 (Fig. 53.4).50 Against the primary endpoint of average pain scores, most trials in diabetic neuropathy patients reported decreased pain with duloxetine treatment (60-120 mg) compared to a placebo,2,72–75 whereas one reported transient effects.76

748

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

NNT (95% CI)

PPN, venlafaxine 225 mg, Sindrup et al. (2003)

5.1 (2.6 to 68.8)

PPN, venlafaxine 150 mg, 225 mg, Rowbotham et al. (2004)

4.5 (2.7 to 13.5)

PPN, duloxetine 60 mg, 120 mg, Goldstein et al. (2005)

4.2 (2.9 to 7.2)

PPN, duloxetine 60 mg, 120 mg, Raskin et al. (2005)

7.0 (4.0 to 27.0)

PPN, duloxetine 60 mg, 120 mg, Wernicke et al. (2006)

4.8 (3.2 to 9.7)

PPN, duloxetine 120 mg, Gao et al. (2010)

30.2 (6.0 to –10.0)

PPN, duloxetine 40 mg, 60 mg, Y asuda et al. (2011)

5.2 (3.5 to 10.1)

PPN, duloxetine 60 mg, Rowbotham et al. (2012)

6.1 (2.9 to –48.5)

MS, duloxetine 60 mg NCT00755807, Vollmer et al. (2013)

15.1 (6.0 to –29.0)

PPN, desvenlafaxine 50–400 mg, NCT00283842

10.4 (5.0 to –109) 6.4 (5.2 to 8.4)

Combined (fixed effects) –5

–10

∞

10

NNT (harm)

5

3.3

2.5

2

NNT (benefit)

• Figure 53.4 

NNT values (with 95% confidence intervals) are shown for each trial and for the overall estimate (fixed effects, Mantel-Haenszel) for serotonin-noradrenaline reuptake inhibitors (10 studies, 2541 participants). The size of the square represents the Mantel-Haenszel weight that the study exerts in the meta-analysis. CI, Confidence interval; MS, multiple sclerosis; NNT, number needed to treat; PPN, painful polyneuropathy. Data from Finnerup et al., Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–73.

In addition, duloxetine improved several secondary quality of life endpoints across these studies, including sleep,72,75 mood,2,72 and mobility.72,75,76 In a study involving multiple sclerosis patients, duloxetine was more effective than placebo treatment, but notably, the NNT appears considerably higher than for diabetic neuropathy.77 The NNT for venlafaxine, and its active metabolite desvenlafaxine, is comparable to duloxetine.52,78,79 However, the dosage might require consideration as venlafaxine is proposed to act primarily as a selective serotonin reuptake inhibitors (SSRI) at a dose of 75 mg and as an SNRI at doses above 150 mg.80 Quantitative sensory tests indicate that venlafaxine inhibits evoked pains, including brush allodynia, pinprick hyperalgesia, and temporal summation in addition to ongoing pain.81 The high NNT values associated with anti-depressants, and other analgesics, have refocused trial design toward personalized approaches and predictive medicine. At present, there are no established sensory testing-led treatment algorithms, but in recent years there have been a few notable advances. Patients stratified according to hyperexcitable peripheral nociceptor function were more likely to benefit from the sodium channel blocker oxcarbazepine than those with a sensory loss phenotype.82 Post hoc analysis of an overall negative pregabalin trial in HIV neuropathy revealed pain relief in patients with severe pinprick hyperalgesia.83 Several have examined, with varying degrees of success, whether sensory phenotypes act as predictors of SNRI response.84–86 One of the more elegant examples to date demonstrated that CPM efficiency in diabetic neuropathy patients correlated with analgesic outcomes.23 The authors hypothesized that drugs should be prescribed according to the patient’s pattern of pain modulation, and drugs that augment descending inhibition would benefit those that exhibited low endogenous pain modulation. Duloxetine (30-60 mg) efficacy was greater in patients with less efficient pretreatment CPM levels, whereas those with efficient CPM achieved little relief.23 Similar outcomes have been observed with tapentadol (a dual μ-Opioid agonist/ noradrenaline reuptake inhibitor [NRI]),21 the common denominator with duloxetine being the NRI component. A caveat to interpreting CPM is that efficient CPM is considered the net inhibitory function extracted from the gross descending output. Hence an absence of CPM could result from enhanced facilitation, a loss of

inhibition, or a combination of both. In a back-translational rodent study descending inhibition after nerve injury was vastly diminished and reversed by blocking spinal noradrenaline reuptake, but enhanced spinal 5-HT3 mediated facilitations can mask residual inhibitory function, and DNIC was restored by a 5-HT3 antagonist alone.16 Thus an absence of effective CPM/DNIC could predict analgesia by agents capable of enhancing inhibitory signaling and/or reducing facilitatory activity.

SSRI Mechanism of Action (Animal Models) It was hoped that with the advent of anti-depressants with more specific modes of action, analgesia would still be associated with their use, and the potential to produce side effects would be reduced. However, studies in rodent models of neuropathy have produced mixed data on the efficacy of SSRIs (Fig. 53.5). Citalopram and fluoxetine do not appear to affect mechanical hypersensitivity after nerve injury.34,87,88 However, citalopram partially reverses heat hypersensitivity.87 At an effective dose, the SSRI fluoxetine attenuates nocifensive behaviors in short-term models of central sensitization, an effect that is diminished by depletion of endogenous serotonin.89 However, at higher doses of SSRIs, analgesic effects could be attributed to non-selective actions at the noradrenaline transporter as paroxetine can increase spinal noradrenaline release.90 In contrast, only spinal delivery of citalopram and fluoxetine restored deficient DNIC in neuropathic rats, whereas systemic doses were without effect suggestive of concomitant inhibitory/faciliatory actions at multiple sites. The effects of spinally delivered SSRIs were mediated via 5-HT7 receptors allowing DNIC to be restored via α2 adrenoceptors.91 Acute and chronic mechanisms of drug action in supraspinal structures can have complex actions on neuronal activity. Noradrenergic neurons in the locus coeruleus receive dense serotonergic projections, which exert tonic inhibitory influences on neuronal activity,92 and this is augmented by SSRIs.93 It is possible in a neuropathic state that the inhibitory spinal actions of SSRIs are countered

 

CHAPTER 53

Anti-depressants

749

Me HN N H

F

O N

O

Cl CF3

Cl Sertraline

NC

Fluoxetine

Escitalopram

H N

F

N

O

N

N

O

O O NC F Citalopram

Paroxetine

Br Zimeldine

• Figure 53.5  Selective serotonin reuptake inhibitors. by further top-down suppression of descending noradrenergic inhibition. Within the dorsal raphe, spontaneous activity of putative serotonergic neurons is inhibited by SSRIs in a 5-HT1A receptor dependent manner, but chronic dosing results in desensitization of 5-HT1A auto-receptors leading to a recovery of activity.94 In addition, cortico-limbic circuits are critical in assigning an emotional valence to sensory inputs, and these pathways are also subjected to serotonergic modulation. In a model of arthritis, inhibiting 5-HT2C receptors within the basolateral amygdala potentiated the analgesic effect of fluvoxamine on supraspinal-organized behaviors (vocalizations and anxiety-like behaviors) but not spinal reflexes to painful stimuli.95 The majority of rodent studies examine the acute effects of drugs. However, transcriptional changes can occur with chronic dosing, including altered expression of 5-HT2C receptors at spinal and supraspinal sites,96 and HDAC2 and mGlu2 receptors in the dorsal root ganglia, and dorsal horn, respectively.97

Clinical Management of Pain Data from clinical trials provide weak evidence for the efficacy of SSRIs in the treatment of neuropathic pain. The lack of suitable comparable studies means that a reliable NNT has been difficult to calculate,50 but is thought to be at least 6.7 for SSRIs, which is likely to be underestimated.98 Three crossover studies in diabetic neuropathy patients compared the effects of citalopram, fluoxetine, and paroxetine (all 40 mg doses) to a placebo. Fluoxetine was found

to be no better than placebo treatment,4 whereas citalopram produced marginal improvement of pain.99 Paroxetine reduced ongoing pain scores and paresthesia but provided no improvement in sleep disturbances and was considered less effective than imipramine.100 Results from studies in fibromyalgia mirror the studies in neuropathic pain and are mixed at best. After a course of treatment with citalopram (20–40 mg), no improvements in pain scores, tender points, or depression scores were found,101 and a separate study broadly reported similar findings with weak beneficial effects.102 Trials of fluoxetine have reported similar outcomes with limited to no improvement of pain scores and tender points and inconsistent improvements in secondary measures such as sleep disturbances, wellbeing scores, and depression scores.103–105

Noradrenaline Reuptake Inhibitors Mechanism of Action (Animal Models) Reboxetine is a selective NRI with little or no affinity for serotonin and dopamine reuptake transporters. In a rodent nerve injury model, intrathecal reboxetine reverses the functional deficit in descending noradrenergic control by inhibiting evoked hypersensitivity and ongoing pain (conditioned place preference paradigm).106 Similar actions are observed on evoked neuronal activity within the spinothalamic pathway in a pathophysiologic state dependent manner.107 Furthermore, functional DNIC are blocked by an intrathecal α2 adrenoceptor

750

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

antagonist, and intrathecal reboxetine restores absent DNIC in neuropathic rats.16 This underlying noradrenergic mechanism explains the relationship between low CPM and the use of tapentadol (dual μ-Opioid agonist/NRI) and duloxetine (SNRI) for treating neuropathic pain.21,23 Pontine derived noradrenaline projects throughout the neuraxis and has roles in regulating arousal, mood, learning, and memory. This functional dichotomy between the ascending and descending noradrenergic components may underly the negative side effects of systemic targeting of the noradrenergic system.108

Clinical Management of Pain No comprehensive data has indicated that NRIs are suitable for treating neuropathic pain. Two Pfizer-led trials for postherpetic neuralgia and diabetic neuropathy were terminated because of a lack of efficacy (NCT00348894, NCT00354094). However, in fibromyalgia, Pfizer reported a small but sustained improvement in overall pain scores (primary outcome) and fatigue (secondary outcome) compared to a placebo.109

Dopamine Reuptake Inhibitors Though classified as a dopamine reuptake inhibitor, bupropion also blocks noradrenaline reuptake transporters. Intrathecal dosing in neuropathic rats increases spinal concentrations of dopamine and noradrenaline, which produces anti-nociception in an α2 adrenoceptor and D2 receptor dependent manner.110 Evidence for efficacy in patients is limited, although a single study reported that 73% of subjects with neuropathic pain studied in their placebo-controlled trial obtained some pain relief with bupropion treatment.111 Tetracyclic Anti-depressants Limited evidence for an analgesic effect of tetracyclic antidepressants exists. Like the TCAs, the pharmacology of tetracyclics is diverse, but in general, these drugs block noradrenaline reup• BOX 53.2

take and have little affinity for serotonin and dopamine reuptake transporters. In a crossover study in patients with postherpetic neuralgia, amitriptyline was deemed to be more effective than maprotiline.112 A few rodent studies have demonstrated that maprotiline,113 mianserin,114 and mirtazapine,115 reverse evoked hypersensitivity in neuropathic models.

Monoamine Oxidase Inhibitors Renowned for their multiple side effects, drug interactions, and the necessity for a tyramine-free diet when used, monoamine oxidase inhibitors have no place in pain management. Little evidence exists for any analgesic effect.116 Safety and Side Effects The safety of anti-depressants can be considered both from the perspective of normal use (Box 53.2) and in overdose. An analysis of United Kingdom prescriptions provided an interesting insight into the potential dangers of anti-depressants when taken in overdose calculated as the number of deaths per million prescriptions (Table 53.2). It is unclear why the fatality rate for desipramine is higher than other TCAs but suggests that overdose risks should be judged on the data for individual drugs rather than the therapeutic class.117 In TABLE 53.2

TCAs

Anti-depressants: Safety and Side Effects

Weight - Weight gain is common with anti-depressants. When they are used for the treatment of depression, mood alteration may have an effect on appetite and wellbeing. TCAs are more likely than SSRIs to cause weight gain.122 Cholinergic-type side effects - including dry mouth, sedation, and urinary retention, may also complicate TCA use. Risk for falls - A study of United States veterans showed that of 2212 patients with hip fractures, 70% had taken medication before the fracture, which may have contributed to their fall. Patients were twice as likely to have taken a TCA or SSRI as a matched control.123 Use in pregnancy - anti-depressant usage has been associated with increased risk of cardiac malformations, preterm births and neonatal respiratory distress.124 Automobile Driving - After acute dosing of sedating anti-depressants (e.g. amitriptyline, imipramine, doxepin, mianserin), a measure of driving ability gave results comparable to those of individuals whose blood alcohol concentration was 0.8 mg/mL.125 It was also noted that concomitant use of a benzodiazepine with an anti-depressant makes driving impairment significant. When SSRIs are considered, no impairment in driving ability has been noted.126 Consequently, when a TCA is given, the patient should be warned to avoid driving until stabilization with a fixed dose of the TCA has occurred. SSRIs and NSAIDs - A study of 15,445 new users of anti-depressants with or without the use of nonsteroidal anti-inflammatory drugs (NSAIDs) reported that in the 691 individuals given TCAs who were not taking NSAIDs, the incidence of peptic ulcer drug request was 0.051%. In the SSRI-only group (1181 subjects), the incidence was 1.2%. When an SSRI was taken with an NSAID (86 subjects), the incidence of peptic ulcer drug request was 12.4% instead of 2.5% in the TCA-NSAID cohort. This would suggest that some caution needs to be taken when SSRIs are given to patients taking NSAIDs.127

SNRIs

SSRIs

NRIs

Numbers of Deaths per Million Prescriptions of Anti-depressants (in the United Kingdom)

Drug

Deaths per million prescriptions (95% confidence interval)

Desipramine

200.9 (92.0–381.6)

Dothiepin

53.3 (50.5–56.1)

Amitriptyline

38.0 (35.5–40.5)

Imipramine

32.8 (27.0–39.5)

Doxepin

25.2 (18.0–34.3)

Trimipramine

16.5 (11.7–22.5)

Clomipramine

12.5 (9.4–16.3)

Nortriptyline

5.5 (2.2–11.4)

Lofepramine

1.3 (0.6–2.4)

Butriptyline

0 (0–3372)

Iprindole

0 (0–1218)

Protriptyline

0 (0–39.2)

Venlafaxine

13.2 (9.2–18.5)

Nefazodone

0 (0–6.4)

Fluvoxamine

3.0 (0.3–10.9)

Citalopram

1.9 (0.6–4.5)

Sertraline

1.2 (0.5–2.4)

Fluoxetine

0.9 (0.5–1.4)

Paroxetine

0.7 (0.4–1.3)

Reboxetine

0 (0–21.1)

NRIs, Noradrenaline reuptake inhibitor; SNRIs, serotonin-noradrenaline reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic anti-depressants. Data from Buckley and McManus. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ. 2002;325(7376):1332–3.117

terms of overall comparative tolerability, it would be expected that the newer anti-depressants would be tolerated better than the TCAs. In a meta-analysis reviewing the tolerability of TCAs and SSRIs (when used for the treatment of depression), the number needed to harm (NNH)—in this case, the number of subjects receiving the treatment—for one subject to need to drop out because of side effects was calculated to be 4-30 for TCAs and 20-90 for SSRIs.118

 

CHAPTER 53

Anti-depressants

751

Similarly, in neuropathic pain, the NNH for TCAs was 13.4, and for SNRIs the NNH was 11.8.50 For SNRIs, in trials for neuropathic pain, the dropout rates for milnacipran (28%) appear to be higher than for duloxetine (4%-19%) and venlafaxine (9%).119 The most common adverse effects associated with duloxetine were nausea, dizziness, somnolence, and constipation, which were present in up to 30% of patients.

Conclusion There is extensive evidence that anti-depressant drugs that block both reuptake of serotonin and noradrenaline can be highly effective for a subset of patients with neuropathic pain. An inherent drawback of the older trials is that drug effects on different types of pain were not evaluated but only showed whether patients with different types of pain achieved pain relief in general. The NNT values of the more recent duloxetine trials tend to be higher than the older TCA trials and reflect an increase in the placebo response over time.120 Patients with neuropathic pain have been stratified according to their quantitative sensory testing profiles and broadly fall into three categories referred to as the mechanical phenotype, thermal phenotype, and sensory loss group.27 These sub-groups have been hypothesized to represent surrogate sensory biomarkers

of underlying pathophysiologic mechanisms. Concerning sensory profiles, post hoc analysis of clinical trials revealed that patients with sensory gain were more likely to benefit from imipramine treatment than those with sensory loss.85 Other mechanism-based approaches to stratifying patients include exacerbated temporal summation (spinal amplification) or loss of CPM (diminished descending pain control).121 Impaired CPM appears to be a much more reliable predictor of analgesic response to duloxetine,23 and this approach could be applied to other anti-depressants with similar mechanisms of action. Although this chapter has focused primarily on neuropathic pain, similar sensory phenotypes have been described in osteoarthritis and fibromyalgia, and the same principles would apply.

Key Points • Anti-depressants can be effective for treating neuropathic pain independently of their actions on comorbid depression. • The analgesic effects tend to occur more rapidly and at lower doses than those used for treating depression. • The primary mechanism of action is through a block of monoamine reuptake in descending modulatory pathways. However, many TCAs have an additional affinity for monoaminergic receptors, which can contribute to their analgesic effects. Side effects can also be attributed to a block of histaminergic and cholinergic receptors.

• Duloxetine and amitriptyline are considered first line therapies for neuropathic pain (NeuPSIG recommendation50), though duloxetine is often preferred because of a better side effect profile. • Low CPM represents a surrogate measure of dysregulated descending modulation in neuropathic pain. CPM could be valuable for mechanism-led treatment selection as low CPM values correlate with the analgesic effects of duloxetine. • There is little compelling evidence supporting the use of SSRI, noradrenaline reuptake inhibitors, dopamine reuptake inhibitors, tetracyclics, and monoamine oxidase inhibitors for the treatment of neuropathic pain.

Suggested Readings

Holbech JV, Bach FW, Finnerup NB, Jensen TS, Sindrup SH. Pain phenotype as a predictor for drug response in painful polyneuropathya retrospective analysis of data from controlled clinical trials. Pain. 2016;157(6):1305–13. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;4:CD005454. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012;153(6):1193–8.

Bannister K, Dickenson AH. The plasticity of descending controls in pain: Translational probing. J Physiol. 2017;595(13):4159–66. Bravo L, Llorca-Torralba M, Berrocoso E, Micó JA. Monoamines as drug targets in chronic pain: Focusing on neuropathic pain. Front Neurosci. 2019;13:1268. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–73. Häuser W, Wolfe F, Tölle T, Uçeyler N, Sommer C. The role of antidepressants in the management of fibromyalgia syndrome: A systematic review and meta-analysis. CNS Drugs. 2012;26(4):297–307.

The references for this chapter can be found at ExpertConsult.com.

References 1. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurol. 1987;37(4):589–596. 2. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116(1-2):109–118. 3. Hirschfeld RM, Mallinckrodt C, Lee TC, Detke MJ. Time course of depression-symptom improvement during treatment with duloxetine. Depress Anxiety. 2005;21(4):170–177. 4. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250–1256. 5. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: A meta-analysis of 39 placebocontrolled studies. Pain. 1992;49(2):205–219. 6. Francois A, Low SA, Sypek EI, et  al. A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by GABA and enkephalins. Neuron. 2017;93(4):822–839 e6. 7. Eippert F, Bingel U, Schoell ED, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63(4):533–543. 8. Millan MJ. Descending control of pain. Prog Neurobiol. 2002; 66(6):355–474. 9. Patel R, Dickenson AH. Modality selective roles of pro-nociceptive spinal 5-HT2A and 5-HT3 receptors in normal and neuropathic states. Neuropharmacol. 2018;143:29–37. 10. Suzuki R, Rahman W, Hunt SP, Dickenson AH. Descending facilitatory control of mechanically evoked responses is enhanced in deep dorsal horn neurons following peripheral nerve injury. Brain Res. 2004;1019(1-2):68–76. 11. Brenchat A, Nadal X, Romero L, et al. Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity. Pain. 2010;149(3):483–494. 12. Burgess SE, Gardell LR, Ossipov MH, et  al. Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J Neurosci. 2002;22(12):5129–5136. 13. De Felice M, Sanoja R, Wang R, et al. Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain. 2011;152(12):2701–2709. 14. Hughes SW, Hickey L, Hulse RP, Lumb BM, Pickering AE. Endogenous analgesic action of the pontospinal noradrenergic system spatially restricts and temporally delays the progression of neuropathic pain following tibial nerve injury. Pain. 2013;154(9):1680–1690. 15. Wei F, Dubner R, Zou S, et al. Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci. 2010;30(25):8624–8636. 16. Bannister K, Patel R, Goncalves L, Townson L, Dickenson AH. Diffuse noxious inhibitory controls and nerve injury: Restoring an imbalance between descending monoamine inhibitions and facilitations. Pain. 2015;156(9):1803–1811. 17. Le Bars D, Chitour D, Kraus E, Dickenson AH, Besson JM. Effect of naloxone upon diffuse noxious inhibitory controls (DNIC) in the rat. Brain Res. 1981;204(2):387–402. 18. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurons in the rat. Pain. 1979;6(3):283–304. 19. Albusoda A, Ruffle JK, Friis KA, et al. Systematic review with metaanalysis: Conditioned pain modulation in patients with the irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48(8):797–806. 20. Kosek E, Hansson P. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain. 1997;70(1):41–51. 21. Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A. Tapentadol potentiates descending pain inhibition in chronic

pain patients with diabetic polyneuropathy. Br J Anaesth. 2014;113(1):148–156. 22. Perrotta A, Serrao M, Ambrosini A, et al. Facilitated temporal processing of pain and defective supraspinal control of pain in cluster headache. Pain. 2013;154(8):1325–1332. 23. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012;153(6):1193–1198. 24. Wilder-Smith OH, Schreyer T, Scheffer GJ. Arendt-Nielsen L. Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: A pilot study. J Pain Palliat Care Pharmacother. 2010;24(2):119–128. 25. Yarnitsky D, Crispel Y, Eisenberg E, et  al. Prediction of chronic postoperative pain: Pre-operative DNIC testing identifies patients at risk. Pain. 2008;138(1):22–28. 26. Vaegter HB, Graven-Nielsen T. Pain modulatory phenotypes differentiate subgroups with different clinical and experimental pain sensitivity. Pain. 2016;157(7):1480–1488. 27. Baron R, Maier C, Attal N, et al. Peripheral neuropathic pain: A mechanism-related organizing principle based on sensory profiles. Pain. 2017;158(2):261–272. 28. Chen M, Hoshino H, Saito S, Yang Y, Obata H. Spinal dopaminergic involvement in the antihyperalgesic effect of antidepressants in a rat model of neuropathic pain. Neurosc Lett. 2017;649:116– 123. 29. Leventhal L, Smith V, Hornby G, Andree TH, Brandt MR, Rogers KE. Differential and synergistic effects of selective norepinephrine and serotonin reuptake inhibitors in rodent models of pain. J Pharmacol Exp Ther. 2007;320(3):1178–1185. 30. Matsuoka H, Suto T, Saito S, Obata H. Amitriptyline, but not pregabalin, reverses the attenuation of noxious stimulus-induced analgesia after nerve injury in rats. Anesth Analg. 2016;123(2):504–510. 31. Alba-Delgado C, Mico JA, Sánchez-Blázquez P, Berrocoso E. Analgesic antidepressants promote the responsiveness of locus coeruleus neurons to noxious stimulation: Implications for neuropathic pain. Pain. 2012;153(7):1438–1449. 32. Bantel C, Eisenach JC, Duflo F, Tobin JR, Childers SR. Spinal nerve ligation increases alpha2-adrenergic receptor G-protein coupling in the spinal cord. Brain Res. 2005;1038(1):76–82. 33. Birder LA, Perl ER. Expression of alpha2-adrenergic receptors in rat primary afferent neurons after peripheral nerve injury or inflammation. J Physiol. 1999;515(Pt 2):533–542. 34. Benbouzid M, Choucair-Jaafar N, Yalcin I, et  al. Chronic, but not acute, tricyclic antidepressant treatment alleviates neuropathic allodynia after sciatic nerve cuffing in mice. Eur J Pain. 2008;12(8):1008–1017. 35. Bohren Y, Karavelic D, Tessier L-H, et al. Mu-opioid receptors are not necessary for nortriptyline treatment of neuropathic allodynia. Eur J Pain. 2010;14(7):700–704. 36. Wattiez A-S, Libert F, Privat A-M, et al. Evidence for a differential opioidergic involvement in the analgesic effect of antidepressants: Prediction for efficacy in animal models of neuropathic pain? Br J Pharmacol. 2011;163(4):792–803. 37. Eisenach J, Gebhart G. Intrathecal amitriptyline acts as an N-MethylD-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats. Anesthesiol. 1995;83(5):1046–1054. 38. Sada H, Egashira N, Ushio S, Kawashiri T, Shirahama M, Oishi R. Repeated administration of amitriptyline reduces oxaliplatininduced mechanical allodynia in rats. J Pharmacol Sci. 2012; 118(4):547–551. 39. Bohren Y, Tessier L-H, Megat S, et  al. Antidepressants suppress neuropathic pain by a peripheral β2-adrenoceptor mediated antiTNFα mechanism. Neurobiol Dis. 2013;60:39–50. 40. Kremer M, Yalcin I, Goumon Y, et al. A dual noradrenergic mechanism for the relief of neuropathic allodynia by the antidepressant drugs duloxetine and amitriptyline. J Neurosci. 2018;38(46): 9934–9954. 751.e1

751.e2

References

41. Sud R, Spengler RN, Nader ND, Ignatowski TA. Anti-nociception occurs with a reversal in α2-adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro- to antiinflammatory. Eur J Pharmacol. 2008;588(2):217–231. 42. Dick IE, Brochu RM, Purohit Y, Kaczorowski GJ, Martin WJ, Priest BT. Sodium channel blockade may contribute to the analgesic efficacy of antidepressants. J Pain. 2007;8(4):315–324. 43. Horishita T, Yanagihara N, Ueno S, et al. Antidepressants inhibit Na(v)1.3, Na(v)1.7, and Na(v)1.8 neuronal voltage-gated sodium channels more potently than Na(v)1.2 and Na(v)1.6 channels expressed in Xenopus oocytes. Naunyn Schmiedebergs Arch Pharmacol. 2017;390(12):1255–1270. 44. Akopian AN, Souslova V, England S, et  al. The tetrodotoxinresistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci. 1999;2(6):541–548. 45. Djouhri L, Fang X, Okuse K, Wood JN, Berry CM, Lawson SN. The TTX-resistant sodium channel Nav1.8 (SNS/PN3): Expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J Physiol. 2003;550(Pt 3):739–752. 46. Black JA, Cummins TR, Plumpton C, et  al. Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J Neurophysiol. 1999;82(5):2776–2785. 47. Esser MJ, Chase T, Allen GV, Sawynok J. Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: Multiple interactions. Eur J Pharmacol. 2001;430(2-3):211–218. 48. Sawynok J, Reid AR, Esser MJ. Peripheral anti-nociceptive action of amitriptyline in the rat formalin test: Involvement of adenosine. Pain. 1999;80(1-2):45–55. 49. Zylka MJ. Pain-relieving prospects for adenosine receptors and ectonucleotidases. Trends Mol Med. 2011;17(4):188–196. 50. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173. 51. Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: A placebo-controlled trial. Pain. 1991;45(1):1–2 3-9. 52. Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS. Venlafaxine versus imipramine in painful polyneuropathy: A randomized, controlled trial. Neurol. 2003;60(8):1284–1289. 53. Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindström T, Thorell LH. A comparison of amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain. 1997;13(4):313–323. 54. Kishore-Kumar R, Max MB, Schafer SC, et  al. Desipramine relieves post-herpetic neuralgia. Clin Pharmacol Ther. 1990;47(3): 305–312. 55. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in post-herpetic neuralgia: A randomized, placebocontrolled trial. Neurol. 2002;59(7):1015–1021. 56. Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in post-herpetic neuralgia. Neurol. 1982;32(6):671–673. 57. Kalso E, Tasmuth T, Neuvonen PJ. Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. Pain. 1996;64(2):293–302. 58. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil. 2007;88(12):1547–1560. 59. Leijon G, Boivie J. Central post-stroke pain–a controlled trial of amitriptyline and carbamazepine. Pain. 1989;36(1):27–36. 60. Österberg A, Boivie J. Central pain in multiple sclerosis: A doubleblind placebo-controlled trial of amitriptyline and carbamazepine. Linköpings Universitet;. 2005;thesis. 61. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS clinical trial group 242 protocol team. Neurol. 1998;51(6):1682–1688.

62. Khoromi S, Cui L, Nackers L, Max MB. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain. 2007;130(1-2):66–75. 63. Thompson DF, Brooks KG. Systematic review of topical amitriptyline for the treatment of neuropathic pain. J Clin Pharm Ther. 2015;40(5):496–503. 64. McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: A randomized, double-blind, placebocontrolled study. Br J Clin Pharmacol. 2000;49(6):574–579. 65. O’Brien AT, Deitos A, Triñanes Pego Y, Fregni F, Carrillo-de-laPeña MT. Defective endogenous pain modulation in fibromyalgia: A meta-analysis of temporal summation and conditioned pain modulation paradigms. J Pain. 2018;19(8):819–836. 66. Potvin S, Marchand S. Pain facilitation and pain inhibition during conditioned pain modulation in fibromyalgia and in healthy controls. Pain. 2016;157(8):1704–1710. 67. Häuser W, Wolfe F, Tölle T, Uçeyler N, Sommer C. The role of antidepressants in the management of fibromyalgia syndrome: A systematic review and meta-analysis. CNS Drugs. 2012;26(4):297–307. 68. Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017;18(11):2483. 69. Ito S, Suto T, Saito S, Obata H. Repeated administration of duloxetine suppresses neuropathic pain by accumulating effects of noradrenaline in the spinal cord. Anesth Analg. 2018;126(1):298–307. 70. Marchand F, Alloui A, Chapuy E, et al. Evidence for a monoamine mediated, opioid-independent, antihyperalgesic effect of venlafaxine, a non-tricyclic antidepressant, in a neurogenic pain model in rats. Pain. 2003;103(3):229–235. 71. Schreiber S, Backer MM, Pick CG. The anti-nociceptive effect of venlafaxine in mice is mediated through opioid and adrenergic mechanisms. Neurosci Lett. 1999;273(2):85–88. 72. Raskin J, Pritchett YL, Wang F, et  al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6(5):346–356. 73. Rowbotham MC, Arslanian A, Nothaft W, et  al. Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT894 in patients with diabetic peripheral neuropathic pain. Pain. 2012;153(4):862–868. 74. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurol. 2006;67(8):1411–1420. 75. Yasuda H, Hotta N, Nakao K, Kasuga M, Kashiwagi A, Kawamori R. Superiority of duloxetine to placebo in improving diabetic neuropathic pain: Results of a randomized controlled trial in Japan. J Diabetes Investig. 2011;2(2):132–139. 76. Gao Y, Ning G, Jia WP, et  al. Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China. Chin Med J (Engl). 2010;123(22):3184–3192. 77. Vollmer TL, Robinson MJ, Risser RC, Malcolm SK. A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis. Pain Pract. 2014;14(8):732–744. 78. Allen R, Sharma U, Barlas S. Clinical experience with desvenlafaxine in treatment of pain associated with diabetic peripheral neuropathy. J Pain Res. 2014;7:339–351. 79. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: A doubleblind, placebo-controlled study. Pain. 2004;110(3):697–706. 80. Debonnel G, Saint-André E, Hébert C, de Montigny C, Lavoie N, Blier P. Differential physiological effects of a low dose and high doses of venlafaxine in major depression. Int J Neuropsychopharmacol. 2007;10(1):51–61. 81. Yucel A, Ozyalcin S, Talu GK, et al. The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: A double blind, placebo controlled study. Eur J Pain. 2005;9(4):407.

References

82. Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study. Pain. 2014;155(11):2263–2273. 83. Simpson DM, Schifitto G, Clifford DB, et al. Pregabalin for painful HIV neuropathy: A randomized, double-blind, placebo-controlled trial. Neurol. 2010;74(5):413–420. 84. Bouhassira D, Wilhelm S, Schacht A, et al. Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the randomized, double-blind, COMBODN study. Pain. 2014;155(10):2171–2179. 85. Holbech JV, Bach FW, Finnerup NB, Jensen TS, Sindrup SH. Pain phenotype as a predictor for drug response in painful polyneuropathy-a retrospective analysis of data from controlled clinical trials. Pain. 2016;157(6):1305–1313. 86. Matsuoka H, Iwase S, Miyaji T, et  al. Predictors of duloxetine response in patients with neuropathic cancer pain: A secondary analysis of a randomized controlled trial-JORTC-PAL08 (DIRECT) study. Support Care Cancer. 2020;28(6):2931–2939. 87. Bomholt SF, Mikkelsen JD, Blackburn-Munro G. Anti-nociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain. Neuropharmacol. 2005;48(2):252–263. 88. Jett M-F, McGuirk J, Waligora D, Hunter JC. The effects of mexiletine, desipramine and fluoxetine in rat models involving central sensitization. Pain. 1997;69(1):161–169. 89. Zhao ZQ, Chiechio S, Sun YG, et al. Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs. J Neurosci. 2007;27(22):6045–6053. 90. Nakajima K, Obata H, Iriuchijima N, Saito S. An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat. Pain. 2012;153(5):990–997. 91. Bannister K, Lockwood S, Goncalves L, Patel R, Dickenson AH. An investigation into the inhibitory function of serotonin in diffuse noxious inhibitory controls in the neuropathic rat. Eur J Pain. 2017;21(4):750–760. 92. Haddjeri N, de Montigny C, Blier P. Modulation of the firing activity of noradrenergic neurons in the rat locus coeruleus by the 5-hydroxytryptamine system. Br J Pharmacol. 1997;120(5): 865–875. 93. Szabo ST, de Montigny C, Blier P. Modulation of noradrenergic neuronal firing by selective serotonin reuptake blockers. Br J Pharmacol. 1999;126(3):568–571. 94. El Mansari M, Sánchez C, Chouvet G, Renaud B, Haddjeri N. Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: An in vivo electrophysiological study in rat brain. Neuropsychopharmacol. 2005;30(7):1269–1277. 95. Grégoire S, Neugebauer V. 5-HT2CR blockade in the amygdala conveys analgesic efficacy to SSRIs in a rat model of arthritis pain. Mol Pain. 2013;9:41. 96. Zammataro M, Merlo S, Barresi M, et al. Chronic treatment with fluoxetine induces sex-dependent analgesic effects and modulates HDAC2 and mGlu2 expression in female mice. Front Pharmacol. 2017;8:743. 97. Baptista-de-Souza D, Di Cesare Mannelli L, Zanardelli M, et al. Serotonergic modulation in neuropathy induced by oxaliplatin: Effect on the 5HT2C receptor. Eur J Pharmacol. 2014;735: 141–149. 98. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: An update and effect related to mechanism of drug action. Pain. 1999;83(3):389–400. 99. Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992;52(5):547–552.

751.e3

100. Sindrup SH, Gram LF, Brøsen K, Eshøj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42(2):135–144. 101. Nørregaard J, Volkmann H, Danneskiold-Samsøe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain. 1995;61(3):445–449. 102. Anderberg UM, Marteinsdottir I, von Knorring L. Citalopram in patients with fibromyalgia–a randomized, double-blind, placebocontrolled study. Eur J Pain. 2000;4(1):27–35. 103. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck Jr PE. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112(3):191–197. 104. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39(11):1852–1859. 105. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23(5):255–259. 106. Hughes S, Hickey L, Donaldson LF, Lumb BM, Pickering AE. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone. Pain. 2015;156(2):328–334. 107. Patel R, Qu C, Xie JY, Porreca F, Dickenson AH. Selective deficiencies in descending inhibitory modulation in neuropathic rats: Implications for enhancing noradrenergic tone. Pain. 2018;159(9):1887–1899. 108. Hirschberg S, Li Y, Randall A, Kremer EJ, Pickering AE. Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats. eLife. 2017;6. 109. Arnold LM, Hirsch I, Sanders P, Ellis A, Hughes B. Safety and efficacy of esreboxetine in patients with fibromyalgia: A fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2012;64(7):2387–2397. 110. Hoshino H, Obata H, Nakajima K, Mieda R, Saito S. The antihyperalgesic effects of intrathecal bupropion, a dopamine and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg. 2015;120(2):460–466. 111. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurol. 2001;57(9):1583–1588. 112. Watson CP, Chipman M, Reed K, Evans RJ, Birkett N. Amitriptyline versus maprotiline in post-herpetic neuralgia: A randomized, double-blind, crossover trial. Pain. 1992;48(1):29–36. 113. Banafshe HR, Hajhashemi V, Minaiyan M, Mesdaghinia A, Abed A. Anti-nociceptive effects of maprotiline in a rat model of peripheral neuropathic pain: Possible involvement of opioid system. Iran J Basic Med Sci. 2015;18(8):752–757. 114. Üçel Uİ, Can ÖD, Demir Özkay Ü, Öztürk Y. Antihyperalgesic and antiallodynic effects of mianserin on diabetic neuropathic pain: A study on mechanism of action. Eur J Pharmacol. 2015;756:92–106. 115. Zhu J, Wei X, Feng X, Song J, Hu Y, Xu J. Repeated administration of mirtazapine inhibits development of hyperalgesia/allodynia and activation of NF-κB in a rat model of neuropathic pain. Neurosci Lett. 2008;433(1):33–37. 116. Menkes DB, Fawcett JP, Busch AF, Jones D. Moclobemide in chronic neuropathic pain: Preliminary case reports. Clin J Pain. 1995;11(2):134–138. 117. Buckley NA, McManus PR. Fatal toxicity of serotoninergic and other antidepressant drugs: Analysis of United Kingdom mortality data. BMJ. 2002;325(7376):1332–1333. 118. Arroll B, Elley CR, Fishman T, et al. Antidepressants versus placebo for depression in primary care. The Cochrane Database Syst Rev. 2009(3):Cd007954. 119. Selvy M, Cuménal M, Kerckhove N, Courteix C, Busserolles J, Balayssac D. The safety of medications used to treat peripheral

751.e4

References

neuropathic pain, part 1 (antidepressants and antiepileptics): Review of double-blind, placebo-controlled, randomized clinical trials. Expert Opin Drug Saf. 2020:1–27. 120. Finnerup NB, Haroutounian S, Baron R, et al. Neuropathic pain clinical trials: Factors associated with decreases in estimated drug efficacy. Pain. 2018;159(11):2339–2346. 121. Yarnitsky D, Granot M, Granovsky Y. Pain modulation pro file and pain therapy: Between pro- and anti-nociception. Pain. 2014;155(4):663–665. 122. Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000;61(Suppl 11):37–41. 123. French DD, Campbell R, Spehar A, Cunningham F, Foulis P. Outpatient medications and hip fractures in the US: A national veterans study. Drugs Aging. 2005;22(10):877–885.

124. Bandoli G, Chambers CD, Wells A, Palmsten K. Prenatal antidepressant use and risk of adverse neonatal outcomes. Pediatrics. 2020;146(1):e2019–2493. 125. Ramaekers JG. Antidepressants and driver impairment: Empirical evidence from a standard on-the-road test. J Clin Psychiatry. 2003;64(1):20–29. 126. Ridout F, Meadows R, Johnsen S, Hindmarch I. A placebo controlled investigation into the effects of paroxetine and mirtazapine on measures related to car driving performance. Hum Psychopharmacol. 2003;18(4):261–269. 127. de Jong JC, van den Berg PB, Tobi H, de Jong-van den Berg LT. Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. Br J Clin Pharmacol. 2003;55(6): 591–595.

10 54

Adjunct Title Medications for Pain Chapter to Go Here Management CHAPTER AUTHOR

DANIEL B. LARACH, ANDREA L. CHADWICK, CHARLES E. ARGOFF, ROBERT W. HURLEY . Treatment of chronic pain involves understanding the delicate interplay of nociceptive, neuropathic, and nociplastic mechanisms involved in any given pain syndrome’s pathophysiology. Research into the underlying pathways for chronic pain has provided the mechanistic basis to utilize numerous non-opioid medications to treat chronic pain disorders. Non-opioid medications, often referred to as adjuvant medications, can take the form of amine reuptake inhibitors, such as the serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic anti-depressants (TCAs); neuronal membrane stabilizers, such as the sodium and calcium channel–blocking anti-convulsants; nonsteroidal antiinflammatory drugs (NSAIDs); topical analgesics; muscle relaxants; transient receptor potential vanilloid 1 (TRPV1) receptor agonists; N-methyl-d-aspartic acid (NMDA) receptor antagonists; opioid receptor antagonists; and botulinum toxin. The use of NSAIDs, topical analgesics, SNRIs, TCAs, and muscle relaxants in chronic pain disorders are described in other chapters in this text. For this chapter, we will discuss the use of neuronal membrane stabilizers, TRPV1 agonists (capsaicin), NMDA antagonists (ketamine), opioid receptor antagonists (low dose naltrexone), and botulinum toxin, along with data associated with their use for chronic pain management.

Membrane Stabilizers Alterations in the functioning of sodium and calcium channels have been well-described in the literature regarding the pathophysiology of many chronic pain syndromes.1,2 Clinically available agents that act on these ion channels include the membrane stabilizing agents typically used to treat epilepsy. Many of these agents have been tried with varying success in patients with pain. Multiple classes of medications that fall under the membrane stabilizer classification are beneficial in treating pain (Table 54.1). These agents include antiepileptic/anti-convulsants, local anesthetics, TCAs, and antiarrhythmic medications. As a group, they inhibit the development and propagation of ectopic neuronal discharges. The primary agents from this adjuvant drug class used to treat chronic pain include antiepileptic/anti-convulsants, local anesthetics, and the TCAs. TCAs are discussed in a separate chapter and not covered here. Gabapentin and pregabalin, also anti-convulsants, are discussed separately under calcium channel modulators because their mechanism of action differs from that of the other membrane stabilizing agents. 752

Calcium Channel Modulators Calcium channel modulators are widely used non-opioid medications for chronic pain and are first line treatment agents for many neuropathic and nociplastic chronic pain conditions.3 The intracellular free calcium ion concentration is only 1 in 10,000 that of the extracellular environment, and influx of calcium through calcium channels has important depolarizing effects on neurons. Voltage-gated calcium channels can be divided into high-voltage-activated (HVA) and low-voltage-activated (LVA) channels. Electrophysiologic characteristics allow division into HVA and LVA channels, depending on the threshold of activation. The HVA group is further divided into types L, P/Q, N, and R.4 These groups require large membrane depolarization and are mainly responsible for the entry of calcium and release of neurotransmitters from presynaptic nerve terminals. Low-voltage channels, such as the T-type, regulate firing by participating in bursting and intrinsic oscillations. The spike and wave discharges from the thalamus with absence seizures are dependent on T-type calcium channels; these discharges are inhibited by valproic acid or ethosuximide. The N-type HVA calcium channels are thought to be primarily responsible for the release of neurotransmitters at synaptic junctions and become inactivated rather quickly. The P/Q-type calcium channel is so named because it was first described in the Purkinje cells of the cerebellum. The T-type channel, named after the transient current elicited, starts to open with weak depolarization, near resting potential. L-type channels are found in high concentration in skeletal muscle and in many other tissues, such as neuronal and smooth muscle, where it has been most studied. The voltagegated calcium channel is composed of five polypeptide subunits and is the target of many drugs. Calcium channels consist of an α protein, along with several auxiliary subunits; the α protein forms the channel pore. The calcium channel modulators that are used to treat chronic pain, such as gabapentin and pregabalin, bind to the α2δ subunit of L-type voltage-gated calcium channels, and such binding results in decreased release of glutamate, norepinephrine, and substance P.5 Though structurally derived from the inhibitory neurotransmitter γ-aminobutyric acid (GABA), neither gabapentin nor pregabalin bind to or have activity at the GABA receptor. They also do not affect the uptake or metabolism of GABA.

 

CHAPTER 54

Adjunct Medications for Pain Management

753

TABLE Membrane Stabilizers for Pain 54.1

Membrane Stabilizer

Mechanism

Side Effects

Carbamazepine

Na channel blockade

Sedation, dizziness, gait abnormalities, hematologic changes

Oxcarbazepine

Na channel blockade

Hyponatremia, somnolence, dizziness

Lamotrigine

Stabilizes slow Na channel; suppress the release of glutamate from presynaptic neurons

Rash, dizziness, somnolence

Gabapentin/pregabalin

Binds to α2δ subunit of voltage-gated Ca channel

Dizziness, sedation

Valproic acid

Na channel blockade; increases GABA

Somnolence, dizziness, gastrointestinal upset

Topiramate

Na channel blockade; potentiates GABA inhibition

Sedation, kidney stones, glaucoma

Mexiletine

Na channel blockade

Nausea, blurred vision

Lacosamide

Na channel blockade

Dizziness, nausea, double vision, headache

GABA, γ-aminobutyric acid.

Gabapentin (Neurontin, Gralise, Horizant) Gabapentin is a non-opioid medication that has been ubiquitously used for chronic pain management. The standard initial dose of gabapentin is dependent on the particular gabapentin formulation used. For the first available preparation of gabapentin (Neurontin), it is 100 to 300 mg daily. Although the United States Food and Drug Administration (FDA)-approved therapeutic dose of this preparation for the treatment of postherpetic neuralgia (PHN) (the only chronic pain condition for which this preparation is FDA-indicated) is 1800 mg, many clinicians will start with a lower dose with a gradual increase to a maximum of 3600 mg/ day administered in three divided doses as tolerated (Table 54.2). To minimize the consequence of certain adverse effects such as sedation and dizziness, the initial dose is often given at bedtime. After two to five days, the dose is increased to 300 mg twice daily and, after another two to five days, to 300 mg three times daily after that. Then the dose can be increased by 300 to 600 mg every few days as tolerated until an effective dosage is obtained, the maximum daily dose is reached, or side effects appear. A gastric-retentive formulation of gabapentin (Gralise) has also been approved by the FDA for PHN. It is intended to provide a simpler dosing paradigm than needed with the traditional generic gabapentin through the use of a polymer-based technology that allows gastric retention of the pill for extended delivery of the active medication. Another formulation of gabapentin, gabapentin enacarbil (Horizant), was developed and initially approved to treat restless legs syndrome. It is an actively transported prodrug form of gabapentin that allows twice-a-day dosing because of increased stability in bioavailability compared to the standard formulation of gabapentin. In a randomized controlled trial (RCT), this prodrug formulation was also found to be effective in the treatment of PHN when given twice per day.6 This drug is approved by the FDA to treat PHN and restless leg syndrome. The primary dose-limiting side effects of gabapentin are fatigue, somnolence, and dizziness, which are often attenuated by gradual dose titration. Although gabapentin has few drug interactions, a reduced dosage is necessary for patients with renal insufficiency. However, starting dosages of gabapentin often do not provide immediate pain relief, and the slow titration requirements may

result in adequate pain relief taking up to two months to achieve when given as immediate-release gabapentin. When given as the extended-release formulation, therapeutic doses can be reached in approximately two weeks. Gabapentin has uses in multiple chronic pain conditions. Studies have been performed on patients being treated for PHN, complex regional pain syndrome (CRPS), painful diabetic neuropathy (PDN), and other forms of neuropathic pain (NP) and pain of controversial etiology, including fibromyalgia and opioid-induced hyperalgesia.7–9 A meta-analysis of 5914 participants in 37 studies found substantial benefits (at least 50% pain relief or “very much improved” on the patient global impression of change [PGIC] scale) for patients with PHN and PDN. Common side effects across the entire meta-analyzed population included dizziness (19%), gait disturbance (14%), somnolence (14%), and peripheral edema (7%). Among 2260 patients with PHN from eight studies, 32% of subjects had a substantial response to gabapentin ≥1200 mg daily compared with 17% of subjects receiving placebo (RR 1.8 [95% confidence interval [CI] 1.5 to 2.1]; number needed to treat (NNT) 6.7 [5.4 to 8.7]). When “moderate benefit” (at least 30% pain relief or PGIC of “much improved” or “very much improved”) was examined, 46% of PHN participants met these criteria compared with 25% of those taking placebo (RR 1.8 [95% CI 1.6 to 2.0]; NNT 4.8 [4.1 to 6.0]). Evidence for both of these outcomes was graded as moderate quality. The same meta-analysis found that among 1277 PDN patients across six studies, 38% receiving gabapentin ≥1200 mg/day derived substantial benefit compared with 21% of subjects receiving placebo (RR 1.9 [95% CI 1.5 to 2.3]; NNT 5.9 [4.6 to 8.3]). Similarly, 52% of subjects receiving gabapentin had moderate benefit, while 37% of those receiving placebo did (1439 total participants across seven studies; RR 1.4 [95% CI 1.3 to 1.6]; NNT 6.6 [4.9 to 9.9]). Evidence was again graded as moderate quality. Of note, very limited data are available for gabapentin use in other neuropathic pain conditions such as nerve injury, spinal cord injury, and radicular leg pain despite this medication being commonly used for these indications.10 Other meta-analyses have looked at gabapentin use in phantom limb pain, showing a mean Numerical Rating Scale (NRS) difference of –1.16 (95% CI –1.94 to –0.38) for gabapentin compared with placebo in a small total sample of 43 subjects,11 and in chronic low back

754

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

TABLE Dosing Recommendations for Neuropathic Pain 54.2

Membrane Stabilizer

Initial Dosage

Titration

Max Therapeutic Dosage

Carbamazepine

100–200 mg BID

Increase by 200 mg increments gradually

1200 mg QD

Oxcarbazepine

600 mg daily BID

Increase by 300 mg

1200–1800 mg TID

Lamotrigine

25–50 mg QHS

Increase by 50 mg every one to two weeks

300–500 mg QD

Gabapentin*

100–300 mg QHS

Increase by 100–300 mg or 100–300 mg TID every one to seven days as tolerated

3600 mg (1200 TID)

Gabapentin GR

300 mg QHS

Day one, 300 mg; day two, 600; days three to six, 900; days seven to ten, 1200; days 11–14, 1500, then 1800

1800 mg QHS

Pregabalin*

50 mg TID or 75 mg BID

Increase to 300 mg daily after three to seven days, then by 150 mg/day every three to seven days as tolerated

600 mg QD (200 mg TID or 300 mg BID)

Valproic acid

250 mg BID

Increase by 250 mg weekly

500 mg BID

Topiramate

50 mg QHS

Start at 50 mg BID after one week, then increase 100 mg BID after seven days

100 mg BID

Mexiletine

150 mg QD

Increase to 300 mg in three days and then 600 mg

Maximum: 10 mg/kg daily

*Reduce if impaired renal function. BID, twice daily; QHS, at bedtime; QD, daily; TID, three times daily.

pain (cLBP), unsurprisingly showing no significant improvement in pain compared with placebo in 185 subjects (mean NRS difference –0.22 [95% CI –0.5 to 0.07]), with low quality evidence.12 Overall, most guidelines for the treatment of NP include gabapentin as a first line agent.13 Recent attention has focused on the potential for misuse and use disorder related to gabapentin, as well as the risk of morbidity and mortality when this medication is co-prescribed with opioids. A systematic review of 59 studies examining gabapentinoid misuse and abuse found a 1.6% prevalence of abuse among the general population but prevalence ranging from 3%-68% among opioid abusers; overall risk factors for abuse included a history of substance misuse, particularly opioids, and psychiatric comorbidities. Prescribers should exercise caution with gabapentin in these populations.14 A population-based nested case-control study of 1256 opioid users who died of opioid-related causes and 4619 opioid users found that opioid and gabapentin coadministration significantly increased the odds of opioid-related death compared with opioid use without gabapentin (adjusted odds ratio 1.49, 95% CI 1.18 to 1.88).15 The FDA recently added a black box warning to gabapentin (as well as pregabalin, discussed below), cautioning that respiratory depression and sedation may occur in elderly patients or those with respiratory conditions receiving gabapentinoids concurrently with central nervous system (CNS) depressants such as opioids and benzodiazepines.16 Few studies have looked at the use of gabapentin on cLBP. One study by Atkinson et al. investigated gabapentin versus inert placebo for cLBP and found that within each treatment arm, there was statistically significant reductions in pain. However, when comparing gabapentin to placebo, there was no statistically significant difference in pain relief between the two groups.17 Gabapentin has been reported as useful in the treatment of fibromyalgia. However, only one rigorous RCT has been published investigating gabapentin versus placebo for this condition.

In this study by Arnold et al. 150 patients were randomized to either placebo or gabapentin (titrated to doses of 1200–2400 mg/day) for 12 weeks.18 Results showed that gabapentin-treated patients had significantly greater improvement in average pain scores of a modest effect.

Pregabalin (Lyrica) Like gabapentin, pregabalin is used to treat chronic pain and acts by binding to the α2δ subunit of L-type voltage-gated calcium channels, which results in decreased neuronal excitation. Pregabalin is approved by the FDA for the treatment of PHN, PDN, fibromyalgia, and spinal cord injury-associated pain. Initial pregabalin dosing is 150 mg/day given in two or three divided doses or 25 to 50 mg given at bedtime in elderly patients. Upward dose titration can be completed after three to seven days to 300 mg/day and subsequently increased to a maximum dose of 600 mg/day within two weeks of initiation. Similar to gabapentin, dosing of pregabalin must be decreased in patients with reduced kidney function. Advantages of pregabalin over gabapentin include a more rapid onset of pain relief, linear pharmacokinetics with low inter-subject variability,19 fewer dose-related side effects, thereby allowing faster upward dosage titrations, and twice daily versus three times a day dosing. Additionally, a maximum benefit often occurs after two weeks of treatment at target doses of 300 to 600 mg/day versus up to two months in gabapentin-treated patients. The advantage of pregabalin is its early response and favorable side effect profile.20 The most common adverse effects include somnolence and dizziness, and they occur more frequently with higher doses. When discontinuing pregabalin, it should be tapered down gradually over at least one week to minimize symptoms, including insomnia, nausea, headache, and diarrhea. As with gabapentin, pregabalin’s efficacy has been established in patients with PHN and PDN. One meta-analysis included

 

CHAPTER 54

11,906 patients from 45 studies.21 Among subjects with PHN, subjects taking pregabalin 300 mg daily were more likely to experience ≥50% pain relief (32% vs. 13%; RR 2.5 [95% CI 1.9 to 3.4]; NNT 5.3 [3.9 to 8.1] among 713 subjects across four studies) and ≥30% pain relief (50% vs. 25%; RR 2.1 [95% CI 1.6 to 2.6]; NNT 3.9 [3.0 to 5.6] among 589 subjects across three studies) compared with those taking placebo. A dose-response relationship was observed among this population: Subjects administered pregabalin 600 mg daily compared with those given placebo were more likely to attain ≥50% pain relief (41% vs. 15%; RR 2.7 [95% CI 2.0 to 3.5]; NNT 3.9 [3.1 to 5.5] among four studies with 732 participants) and ≥30% pain relief (62% vs. 24%; RR 2.5 [95% CI 2.0 to 3.2]; NNT 2.7 [2.2 to 3.7]) in three studies with 537 participants. Evidence for all PHN analyses was graded as moderate quality. For PDN, subjects administered pregabalin 300 mg daily compared with placebo were more slightly more likely to obtain ≥50% pain reduction (31% vs. 24%; RR 1.3 [95% CI 1.2 to 1.5]; NNT 22 [12 to 200] among 2931 participants in 11 studies) and ≥30% pain reduction (47% vs. 42%; RR 1.1 [95% CI 1.01 to 1.2]; NNTB 22 [12 to 200] among eight studies with 2320 participants), and substantially more likely to report “much” or “very much” improved PGIC (51% vs. 30%; RR 1.8 [95% CI 1.5 to 2.0]; NNT 4.9 [3.8 to 6.9] in five studies with 1050 participants). As with PHN, more improvement was observed with the 600 mg daily dose than with 300 mg, with ≥50% pain reduction noted in 41% of those taking this dose compared with 28% of patients taking placebo (RR 1.4 [95% CI 1.2 to 1.7]; NNT 7.8 [5.4 to 14] in five studies with 1015 participants) and ≥30% pain reduction seen in 63% versus 52% on placebo (RR 1.2 [95% CI 1.04 to 1.4]; NNT 9.6 [5.5 to 41]; 611 participants from two studies). In the PDN studies, evidence for the 300 mg daily dose was graded as moderate quality, while evidence for the 600 mg dose was graded as low quality. Benefit was also seen for pregabalin 600 mg daily dose in mixed or unclassified posttraumatic neuropathic pain: Metaanalysis of 1367 subjects from four studies showed ≥50% pain reduction in 34% of patients taking pregabalin compared with 20% of those taking placebo (RR 1.5 [1.2 to 1.9]; NNT 7.2 [5.4 to 11]; moderate quality evidence) and ≥30% pain reduction in 48% vs. 36% (RR 1.2 [1.1 to 1.4]; NNT 8.2 [5.7 to 15]; low quality evidence).21 Pregabalin was also more likely to be efficacious than placebo in central neuropathic pain. Among 562 participants in three studies, 26% (vs. 15%) obtained ≥50% pain relief (RR 1.7 [1.2 to 2.3]; NNT 9.8 [6.0 to 28]; low quality evidence) and 44% (vs. 28%) obtained ≥30% pain reduction (RR 1.6 [1.3 to 2.0]; NNT 5.9 [4.1 to 11]; also, low quality evidence). There was no evidence of benefit in HIV neuropathy when 674 subjects in two studies were meta-analyzed (moderate quality evidence) and limited data for other NP conditions, including cancer pain, polyneuropathy, back pain, and sciatica. Except for PHN, a daily pregabalin dose of 150 mg daily was found to be ineffective; clinicians should consider higher doses should therapy at lower doses prove unhelpful. Clinicians should also be cognizant of the potential for misuse, abuse, and respiratory depression with gabapentinoids, as discussed previously in this chapter. Two studies have investigated pregabalin compared to active control groups, and pregabalin was not found to be superior to opioids22 or celecoxib23 for treatment of cLBP. However, celecoxib plus pregabalin was superior to monotherapy in the study by Romano et al.23

Adjunct Medications for Pain Management

755

Many studies have been performed investigating the use of pregabalin for the treatment of fibromyalgia syndrome. Seven RCTs have investigated pregabalin monotherapy at varying doses ranging from 150 to 600 mg/day and were found to have superior pain relief compared to placebo. Arnold et al.24 and Mease et al.25 both found that daily total doses of 300/450/600 mg were all superior in pain efficacy to placebo. Crofford et al. found that only 450 mg/day dosing was superior to placebo for pain efficacy (not 150 or 300 mg/day).26 At doses of 300 or 450 mg/day, Ohta et al. reported superior efficacy of pregabalin over placebo.27 Arnold et al.28 and Clair29 et al. also reported superior efficacy of pregabalin in pooled groups of pregabalin doses (300-450 mg/day) over placebo. Pauer et al. published that only a modest statistically significant effect over placebo was noted at 450 mg/day (not at 300 or 600 mg/day).30 In a study by Gilron et al. combination therapy of pregabalin plus duloxetine versus placebo or monotherapy was investigated, and the authors reported that combination therapy is superior to placebo and pregabalin monotherapy.31

Zonisamide (Zonegran) Zonisamide is indicated as adjunctive therapy for partial seizures in adults and became available in the United States in 2000. It acts by blocking T-type calcium channels and sodium channels; its action also increases the release of GABA. The initial dose is 100 mg/day for two weeks with increases of 200 mg/week to a target of 600 mg/ day. There have been case reports on its usefulness for post-stroke pain and headache. A randomized, double-blind, placebo-controlled pilot study of the efficacy of zonisamide for the treatment of PDN revealed that pain scores on the visual analog scale (VAS) and Likert (psychometric response) scales decreased more in the zonisamide group than in the placebo group. However, these differences did not reach statistical significance.32 Side effects included ataxia, decreased appetite, rash, and renal calculi (resulting from the carbonic anhydrase inhibitor effect). Zonisamide is contraindicated in those with sulfonamide allergy because it is a sulfonamide derivative, and the drug is approximately 40% bound to plasma proteins. Children have an increased risk for oligohidrosis and susceptibility to hyperthermia. Convincing data for zonisamide’s efficacy in other chronic pain syndromes has yet to appear.33

Ziconotide (Prialt) Ziconotide is a ω-conopeptide (previously known as SNX-111) that is administered intrathecally because of its peptidic structure. It is derived from the venom of a marine snail (genus Conus). Ziconotide blocks calcium influx into N-type calcium channels in the dorsal horn laminae of the spinal cord, thus preventing afferent conduction of nerve signals. The administration is via an intrathecal infusion pump, and dosing should be started low, at a recommended dose of 2.4 µg/day (0.1 µg/h). Because of a lag time, it should be titrated up slowly at intervals of no more than two to three times per week to a recommended maximum of 19.2 µg/day.34 Ziconotide does not cause tolerance, dependence, or respiratory depression, and adverse effects primarily involve the CNS and range from dizziness, ataxia, confusion, and headache to frank psychosis and suicidal ideation. Ziconotide monotherapy’s effect on chronic NP has been meta-analyzed from three RCTs with a total of 586 subjects. The pooled OR of ≥30% pain reduction with ziconotide vs. placebo was 2.77 (95% CI 1.37 to 5.59).35 Serious adverse events were common in the included studies, but evidence shows that these

756

PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues

may be decreased by slow titration.36 A prospective multicenter observational registry of ziconotide use (either as monotherapy or with other intrathecal medications) observed ≥30% pain reduction in 17.4% of patients at 12 weeks and 38.5% of patients at 18 months. Nearly all patients included in the registry experienced side effects, including 22.6% with confusion.37 The role of ziconotide in the management of chronic pain has yet to be fully elucidated. Currently, ziconotide is approved for the management of severe chronic pain in patients in whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatments, including intrathecal opioids, local anesthetics, and α-adrenergic agonists. However, this medication should be used cautiously because of its poor side effect profile. Particular attention should be paid to patients with preexisting psychiatric disease.

Sodium Channel Blockers Sodium channel blockers are used as primary therapy or adjunctive treatment of neuropathic pain syndromes such as trigeminal neuralgia (TN), CRPS, PDN, radicular extremity pain, chemotherapy-induced peripheral neuropathy, and PHN. When using these agents, as with all membrane stabilizers, it is crucial to be knowledgeable of the proper dosages, toxicities, and their effects when coadministered with other drugs. As a general rule, the dose should be titrated to patient comfort within safety standards. When neurons are depolarized and approaching an action potential, the voltage-gated sodium channels quickly change conformation in response and permit the flow of sodium ions. Activation of sodium channels (and other voltage-gated ion channels) derives from the outward movement of charged residues because of an altered electrical field across the membrane. Sodium channels play an essential role in the action potentials of neurons and other electrically excitable cells. The flow of sodium ions is terminated by the inactivation of the channel in a few milliseconds (fast inactivation). Sodium channels can cycle open and close rapidly, which may result in seizures, neuropathic pain, or paresthesia. The structure of the channel is essentially a rectangular tube, with its four walls formed from four subunits, the four domains of a single polypeptide. A region near the N-terminus protrudes into the cytosol and forms an inactivating particle. It has been demonstrated that a short loop of amino acid residues, acting as a flap or hinge, blocks the inner mouth of the sodium channel and results in fast inactivation.38 The highly conserved intracellular loop is the inactivating gate that binds to the intracellular pore and inactivates it within milliseconds. Site-directed antibody studies against this intracellular loop have prevented this fast inactivation. The voltage-gated sodium channel can be divided into an α subunit and one or more auxiliary β subunits. At least nine α subunits have been functionally characterized—Nav1.1 through Nav1.9.39 The sodium channels 1.2, 1.8, and 1.9 are preferentially expressed on peripheral sensory neurons, where they are important in nociception and may be a future target for channel-specific analgesics.40 Seven of the nine sodium channel subtypes have been identified in sensory ganglia, such as the dorsal root ganglia and trigeminal ganglia. Nav1.7 is also present in large amounts in the peripheral nervous system. Nav1.2 is expressed in unmyelinated neurons, and Nav1.4 and Nav1.5 are muscle sodium channels. Sodium channel mutations that result in well-recognized syndromes have been described. A mutation in the gene encoding Nav1.4 is responsible for hyperkalemic periodic paralysis, and an inherited long QT syndrome can be caused by a mutation in the gene encoding Nav1.5. Mutations in SCN9A, which encodes

Na 1.7, have been associated with several pain disorders: Primary erythromelalgia and paroxysmal extreme pain disorder are caused by gain-of-function variants. In contrast, congenital insensitivity to pain is caused by a loss-of-function variant. Increased expression of sodium channels has been demonstrated in peripheral and central sensory neurons in patients with chronic pain; it is one mechanism for the observed hyperexcitability of pain pathways.41 Anti-convulsants that modulate the gating of sodium channels include phenytoin, lamotrigine, carbamazepine, oxcarbazepine, and zonisamide, with some evidence for topiramate and valproic acid. It is important to note that at clinical concentrations, the sodium channel is only weakly blocked when hyperpolarized. When the neuronal membrane is depolarized, there is a much greater inhibition of the channel. The binding of the channel by anti-convulsants is slow in comparison to local anesthetics. The slow binding of anti-convulsants ensures that the kinetic properties of normal action potentials are not altered. Generally, anticonvulsants have no role in the treatment of acute pain, although they have demonstrated efficacy in chronic pain conditions. Interestingly, local application of phenytoin and carbamazepine has an antinociceptive effect that is more potent than lidocaine.42 It has been demonstrated that phenytoin, carbamazepine, and lamotrigine bind to a common recognition site on sodium channels, probably as a result of their two phenol groups, which act as binding elements.43 At normal resting potentials, these medications have little effect on action potentials. Besides the fast current of the open channel, there is also a persistent sodium current. This current, carried by persistent openings, is a small fraction of the fast current but may have an important role in regulating excitability. There is evidence that several anti-convulsants, such as phenytoin, valproate, and topiramate, also act by blocking the persistent sodium current.

Phenytoin (Dilantin) Besides the widespread use of phenytoin for seizures, it was the first anti-convulsant to be used for NP, with a 1940s report on its use for TN. Phenytoin is known for its nonlinear metabolism, which is manifested as marked increases in plasma level with small increases in dose after saturation of metabolism. Around 95% of a phenytoin dose is excreted as metabolites from the cytochrome P-450 system. The initial dosage of phenytoin is 100 mg two to three times daily. It has primarily been used for the treatment of diabetic neuropathy. However, because of the mixed results of its efficacy and high side effects and medication interaction profile, it has fallen into disuse. Phenytoin provides pain relief by blocking sodium channels, thereby preventing the release of excitatory glutamate and inhibiting ectopic discharges. Intravenous phenytoin has been studied in the chronic pain setting, but data are limited. A systematic review and meta-analysis did not identify any studies warranting inclusion.44 Side effects of phenytoin include slowing of mentation and somnolence, with nystagmus and ataxia occurring in some patients. Among the epileptic drugs, phenytoin is unique in the development of facial alterations, including gum hyperplasia and coarsening of facial features. Fosphenytoin, an intravenously administered prodrug that converts to phenytoin, is used by some to avoid long dosing intervals or initial burning at the injection site. Phenytoin activates the cytochrome P-450 enzyme system in the liver, and hence careful assessment of co-therapy is warranted. For example, phenytoin decreases the efficacy of methadone, fentanyl, tramadol, mexiletine, lamotrigine, and carbamazepine.

 

CHAPTER 54

As a result, dosages of these medications should be adjusted accordingly. Coadministration with anti-depressants and valproic acid could lead to an increased blood concentration of phenytoin, thereby lowering the subsequent doses required for effect in patients. Most would not use phenytoin for the treatment of NP except perhaps in refractory situations.

Carbamazepine (Tegretol) Carbamazepine has been used in the United States since the 1980s to treat partial and generalized tonic-clonic seizures. Interestingly, it was first approved by the FDA for the treatment of TN, not for epilepsy. Besides its anti-convulsant and TN indications, it is used frequently for bipolar disorder. It was one of the first anti-convulsants studied for the relief of NP. The analgesic properties of carbamazepine were first reported in 1962.45 It is chemically related to the TCAs; reports have included studies of its use for PHN, PDN, post-stroke pain, and pain in Guillain-Barré syndrome. The initial dosage of carbamazepine is 100 to 200 mg twice daily, titrated to effect, with typical dose ranges of 300 to 1200 mg/day administered in two divided doses. Common maintenance doses are 600 to 800 mg. Common side effects include drowsiness, dizziness, nausea, and vomiting, which can often be limited by slow titration. Carbamazepine is associated with very deleterious side effects, including pancytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Carbamazepine is considered the pharmacologic treatment of choice for TN. Although the pathology of this severe neuropathic facial pain in one of the distributions of the trigeminal nerve has not been fully determined, the majority of cases are thought to be caused by compression of the trigeminal nerve at the pontine origin of the nerve by an aberrant loop of an artery or vein. Despite (and likely because of ) its longstanding history of use for this condition, high quality evidence for the efficacy of carbamazepine in TN was found lacking in a recent metaanalysis. Only two small placebo-controlled studies of short duration from the 1960s were included, with an overall RR of 6.02 (95% CI 2.82 to 12.85).46 However, societal guidelines emphasize the excellent treatment response seen in four such small studies, with 58% to 100% of patients obtaining meaningful pain relief compared with 0% to 40% in placebo groups and an NNT