Pain: The person, the science, the clinical interface 9780987290564

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IP Communications, Pty. Ltd., PO Box 1001 Research, Victoria, 3095 Australia. Phone: +61 0423 269 353 E-mail: [email protected] www.ipcommunications.com.au © Patricia Armati with Roberta Chow Authors retain copyright for their contributions to this volume First published 2015 This book is copyright. Subject to statutory exemption and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of IP Communications, P/L. ISBN: 978-0-9872905-6-4 National Library of Australia Cataloguing-in-publication data Title: Pain: the person, the science, the clinical interface/Patricia Armati, Roberta Chow, editors ISBN: 9780987290564 (paperback) Notes: Includes bibliographical references and index. Subjects: Pain—Diagnosis. Pain—measurement. Pain—Treatment. Pain—Social aspects. Pain—Psychological aspects. Other Creators/Contributors: A  rmati, Patricia J., editor. Chow, Roberta T., editor. Dewey Number: 616.0472 Edited by Gillespie & Cochrane, Pty. Ltd., Melbourne Text design by Club Tractor Production Services, Melbourne Typeset by Desktop Concepts Pty. Ltd., Melbourne Cover design by Anne-Marie Reeves, Melbourne, based on an illustration by Ben Roediger, Sydney Indexed by Mary Russell, Melbourne Printed by BPA Print Group, Pty. Ltd., Melbourne

Contents Guide to colour plates

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Preface ix Acknowledgements xi Foreword xiii About the editors

xv

About the authors

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Section 1 The person

1

Chapter 1

3

Pain and the front line – a general practitioner’s perspective

Roberta T Chow Chapter 2

Understanding the pathophysiology of pain

16

Philip J Siddall Chapter 3

Myofascial pain

33

Peter T Dorsher Chapter 4

The management of acute pain

45

Ian Mowat, Elystan Hughes, and Stephan A Schug Chapter 5

Postoperative pain

66

David A Scott and Pamela E Macintyre Chapter 6

Transition from acute to chronic neuropathic pain: potential new players on the horizon 90

Joshua E Adler, Amy Hinkle, and Anne M Skoff Chapter 7

fMRI and pain

99

Mark C Bicket and Paul J Christo Chapter 8

Migraine and other primary headache disorders

Peter J Goadsby

v

107

vi CONTENTS

Chapter 9

Neuropathic pain

129

Philip J Siddall Chapter 10 Pain management in cancer patients

145

Muhammad Salman Siddiqi and Paul Glare Chapter 11

Pain in children and adolescents

176

Matthew Crawford, Tamara Lang, Hsuan-Chih Lao, and David Champion

Section 2 The science Chapter 12

Opioids and their signalling mechanisms at opioid receptors

203 205

Macdonald J Christie Chapter 13

Gates and other theories of pain

221

Lucy A Bee and Anthony H Dickenson Chapter 14

Neuroinflammation, TNF, and pain

231

Kinshi Kato, Veronica I Shubayev, and Robert R Myers Chapter 15

Skin, neurons, neuroglia, and pain

239

Patricia J Armati

Section 3 The clinical interface

255

Chapter 16

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The biopsychosocial model of chronic pain

Tony Merritt, Louise Sharpe, and Jade Hucker Chapter 17

Psychological approaches to chronic pain

263

Tony Merritt, Louise Sharpe, and Jade Hucker Chapter 18

Integration of primary care into the management of chronic pain

278

Geoffrey Mitchell References 290 Index 375

Guide to colour plates The process of inflammation and peripheral sensitisation indicating the chemicals involved in the ‘sensitising soup’ released following trauma. Plate 2 Expression of sodium and calcium channels following nerve injury. Plate 3 Development of ectopic activity in primary afferents following nerve injury. Plate 4 Cellular processes involved in central sensitisation within dorsal horn neurons. Plate 5 Structures and chemicals involved in pain modulatory pathways. Plate 6 Brain processes involved in the perception of and response to pain. Plate 7 Biological processes involved in the experience of pain. Plate 8 Example of a myofascial trigger point and its referred pain pattern. Plate 9 Pathophysiology of migraine Plate 10 Activations identified on PET in migraine. Plate 11 Activations on PET in the region of the posterior hypothalamic grey matter in patients with acute cluster headache (A) and paroxysmal hemicrania (B). Plate 12 A. Morphine, a seemingly high intrinsic efficacy agonist, produces perhaps 50% of the µ receptor stimulus (G protein activation) compared with the highest intrinsic efficacy agonists known. B. Low intrinsic efficacy opioids such as buprenorphine have a much lower µ receptor stimulus than morphine, but produce good analgesia in opioid-naive individuals. Plate 13 A. Diagram of human skin showing organisation of the strata which are selectively innervated by C fibre subsets B. Immunostained human skin biopsy showing C fibre endings in the epidermis. Plate 14 Nodal area of rat nerve fibres immunostained with antibody to axonal neurofascin. Plate 15 Diagram of nervous system response to nociceptive pain. Plate 1



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Preface The person with pain is the centrepiece of this book. At some time, every person experiences pain; pain is part of the human experience and as old as humanity. It is a signal that demands attention. Pain cannot be seen, cannot be heard, and cannot be touched or measured. This means that assessing, diagnosing, and treating each person’s pain is a very personal and individual experience. A person’s pain can lead to a tsunami of events at the personal and professional level, while a single painful event rarely affects only the person. To emphasise the personal and individual nature of pain and its flow-on dilemma at all levels – the person, their families, friends, communities, villages, and the health budget of all countries – this book is organised so that the person with pain remains the focus and the recurrent theme. The possibility of personalised pain treatment should hold great hope in the not-too-distant future. Personalised pain regimes will be able to assess underlying pathophysiology, genetics, phenotypic variation, and probably factors as yet undefined. Ultimately, pain involves the nervous system and interpretation of the phenomenon of pain at the cortical level. As the functional complexity of the human nervous system is revealed, and in concert with the BRAIN initiative of US President Obama , the person in pain of the future may look forward to improved treatment. The chapter on fMRI provides a basis for this optimism. We are delighted to have assembled an international team of experts in their fields and we thank all the many authors who spent so many hours of their valuable time to contribute their chapters. To all of you – thank you. To the many experts and colleagues who read and commented on the chapters, we are very grateful, and each is acknowledged below. The hope is that this book will provide a different and useful focus from most pain books, and that the information is relevant and of use for pain teams, medical specialists, psychologists, nurses, physiotherapists, and other health professionals. The book is organised in three sections – The Person; The Science; and The Clinical Interface. Chapters have been edited to present information in an international context. The theme of the National Pain Strategy document for Australia 2010 has provided a roadmap. Chapters may be read individually or the book may be read cover-to-cover. Between each of the three sections is a short linking statement to ensure the focus is on the person in pain. Some

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x Preface

This diagram represents the complex and dynamic interactions between the person in pain, their relationships with family/carer, the community, and with medical professionals at all levels.Illustration: Ben Roediger

chapters have a ‘Recommended Reading’ list. The websites and recommended reading will be updated from time to time on the Brain and Mind Research Institute, Nerve Research Foundation, University of Sydney website: www.usyd.edu.au/nrf. Patricia Armati, Editor, with Roberta Chow January, 2015

Acknowledgements The editors would like to thank the following people for their advice and, in many cases, for reviewing chapters: Professor John Pollard MBBS BSc(Hons) FRACP FRCP (Lond), AO, Professor Michael Boyer MBBS, AM Dr Stanley Jacobson MBBCh Dr Emily Mathey BSc(Hons) PhD Dr Andrew Pembroke MBBS FANZCA We also thank Jill Henry, the Commissioning Editor, who was always available to answer our questions, endlessly encouraging, unfailingly helpful and always calm, and Elizabeth Pigott and Jeremy Cullis, Medical Science Faculty Liaison Librarians, University of Sydney. And finally, everyone needs a secret weapon – ours was Christine Box, who remained unfazed by anything.



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Foreword Professor Michael J Cousins AO MB BS MD DSc(Syd Uni) DSc(Hon McMaster Univ) FANZCA FRCA FFPMANZCA FAChPM(RACP) FFPMCAI(Hon) FAICD Professor and Head of Pain Management Research Institute Kolling Institute, University of Sydney at Royal North Shore Hospital Board Member, Painaustralia

As far as I know, this book represents the first collaboration between a professor of neuroscience (Patricia Armati) and a general practitioner/researcher (Roberta Chow). Thus, it comes as no surprise that the very first chapter describes general medical practice as ‘the frontline of pain management’. Few would argue with this proposition. Indeed, at the National Pain Summit of Australia (2010), a National Pain Strategy, supported by 150 healthcare and consumer organisations, placed the primary care level as key to advancing pain management. Subsequently, National Pain Strategies developed in Canada, the United Kingdom, the United States, and Europe have given similar emphasis to primary care. In Australia, a key step in implementing the National Pain Strategy has been formation of the advocacy body, Painaustralia, with a Board consisting of consumers and health professionals. Initiatives by state and Federal governments have been fostered by Painaustralia. All of these have emphasised the urgent need for education at all levels: community, undergraduate health professional curricula, specialist curricula, and primary, secondary, and tertiary levels of health care. Compared with the size of the healthcare problem posed by under-treatment of pain, the educational content devoted to pain in all settings is woefully inadequate; however, encouraging steps are now being taken. This enormous unmet need for education programs has been communicated to Painaustralia. One response has been a web-based Pain Education Program developed by a collaboration between the Royal Australian College of General Practitioners and the Faculty of Pain Medicine of the Australian & New Zealand College of Anaesthetists (ANZCA). This textbook is also an important primary care–oriented pain education initiative.



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Chronic pain is an extraordinarily complex field, with exciting advances in scientific knowledge, which extend down to the cellular, subcellular, and genetic levels, and up to clinical, epidemiological/population health levels, as well as to translational research/development. Thus, this text presents a sample of some of the ‘science’ (see chapters 2, 12–15) that currently seems to have the most application for clinical care, particularly at the primary care level. It is very important that the science of pain advances rapidly, since the clinician is currently hampered by significant gaps in understanding of pain mechanisms, and has too few really effective ‘tools’ to treat pain. In particular, powerful pharmacological and non-pharmacological options are needed to prevent transition from acute to chronic pain (see chapters 4–6) after injury, surgery, or other ‘medical conditions’ such as acute radicular pain. Herein lies a very large opportunity for preventive medicine. When one takes into account the current under-treatment worldwide of acute, chronic, and cancer pain, and associated costs to individuals, families, and the community, it is clear that pain is now the third most costly healthcare problem. It is costly because of the suffering of people in pain and because of the huge financial costs (over $34 billion per year in Australia, with a population of just over 20 million). Indeed, pain now should justifiably be a National Health Care Priority. In this context, an up-to-date text is a valuable education tool focusing on the key primary care level. Education is crucial to improved pain management. However, a major stimulus is needed to open the eyes of the community, governments, and health professionals to the plight of those millions of people worldwide who often suffer in silence. The International Pain Summit and its key outcome, The Declaration of Montreal, has provided at least part of such a stimulus. The Declaration says in part: ‘Access to Pain Management is a fundamental human right’ (Cousins and Lynch 2011). Subsequently, the World Medical Association has strongly supported the message of the Declaration, as has the International Federation of Health and Human Rights Organisations (IFHHRO). Such unprecedented events place even more emphasis on the need for a major new focus on education for all health professionals providing care for people in pain.

References Cousins MJ, Lynch ME (2011) Declaration of Montreal: access to pain management is a fundamental human right. Pain 152, 2673–2674. Cousins MJ (2013) Unrelieved pain: a major health care priority. Med J Aust 196, 372–373. National Pain Summit of Australia (2010) National Pain Strategy – Australia. www.painaustralia.org.au.

About the editors Patricia J Armati (BSc MSc PhD) is Honorary Professor in Neuroscience in the Central Clinical School, University of Sydney, and Mind and Brain Institute of the University of Sydney, with a long-standing interest in the relationship between neurons and neuroglia. She has published over 100 scientific papers and book chapters and is editor of The Biology of the Schwann Cell (Cambridge University Press, 2007), The Biology of Oligodendrocytes (Cambridge University Press, 2010), and Marsupials (Cambridge University Press, 2006), the first textbook on marsupials. She has been a board member of the International Peripheral Nerve Society and an editorial board member of the Journal of the Peripheral Nervous System. Currently, she is an editor of the Journal of Neurolipids. Roberta T Chow (MBBS (Hons) FRACGP PhD) is a general practitioner in private practice in Sydney, Australia, specialising in pain medicine at a primary-care level. During the course of her general practice, she has developed a special interest in pain medicine, with a diploma from the Pain Management and Research Centre, Royal North Shore Hospital, Sydney, and a PhD from the Faculty of Medicine, University of Sydney, that focused on a clinical trial of neck pain. She is an Honorary Research Associate at the Brain and Mind Institute at the University of Sydney, President of the Australian Medical Laser Society, and has been a member of the Steering Committee for development of the Australian National Pain Strategy, a guide to integrated and innovative planning for pain management across Australia. Dr Chow uses both orthodox and complementary therapies, particularly low-level laser therapy and acupuncture, for pain management.



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About the authors Joshua E Adler (MD PhD) received his postgraduate training in Neurology at New York Hospital-Cornell University Medical Center. Following residency, he served a post-doctoral fellowship under Dr Ira Black and then joined the faculty at Cornell. His research focused on novel neurotrophic factors and pain-related peptides such as substance P and somatostatin. He is Associate Professor, Neurology, Wayne State University, based at the Detroit Veterans Administration Medical Center in Detroit, providing clinical service and research. He is also Section Chief of Pain Management. He is currently working on an in vivo model of neuropathic pain that is considering both pathophysiologic mechanisms and potential novel modes of therapy. Lucy A Bee (BSc PhD) was an Associate Faculty Member of the Department of Neuroscience, Physiology and Pharmacology, University College, London. Dr Bee was concerned with investigating the sensory role of the brainstem rostral ventromedial medulla zone in normal and pathophysiological states, and in particular the part played by facilitatory neurons. This is achieved by pharmacologically manipulating neurons in the rostral ventromedial medulla and looking at the evoked responses of dorsal horn neurons in the spinal cord to a range of stimuli after nerve injury. More recently, she investigated the roles of ion channels in different pain states. She is currently a medical writer in health care. Mark C Bicket (MD) is currently Chief Resident in the Department of Anesthesiology and Critical Care Medicine at the Johns Hopkins University School of Medicine, Baltimore. He has worked with the American Society of Anesthesiologists, American Society of Regional Anaesthesia and Pain Medicine, and Health Volunteers Overseas. David Champion (MB BS MD FRACP FFMANZCA) is Honorary Research Associate, Department of Anaesthesia and Pain Medicine, Sydney Children’s Hospital, Randwick, New South Wales, and Associate Professor, School of Women’s and Children’s Health, University of New South Wales, Kensington. After a career in adult and paediatric rheumatology and pain medicine, he is now focused primarily on paediatric pain research. His publications in this field range widely from measurement and assessment, including the internationally applied Faces Pain Scale, through somatosensory testing, painrelated psychology, acute and chronic pain, to therapeutics. Currently, his xvi



About the authors

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major project is a twin family case-control study on the heritability and associations, including potentially causal influences, of the common pain disorders without disease. Macdonald J Christie (BSc (Hons) PhD) is Professor of Pharmacology and Associate Dean, Research, in the Sydney Medical School, University of Sydney, Australia. He was awarded his PhD in 1983 and then worked as a Fogarty International Fellow at MIT and the Vollum Institute in Oregon before being appointed as a continuing academic at the University of Sydney in 1990. He has been a Senior Principal Research Fellow of the National Health and Medical Research Council (NHMRC) since 2003. Prior to this he was a Medical Foundation Senior Principal Research Fellow from 1998 to 2002. He has served on numerous editorial boards, NHMRC grant committees, and NHMRC Academy since the mid-1990s. He has published over 200 peer reviewed research papers that have received more than 11 000 citations. His interests span cellular, molecular, and behavioural neuropharmacology, the biological basis of adaptations producing chronic pain and drug dependence, and preclinical development of novel pain therapeutics. Paul J Christo (MD MBA) is a board certified, Harvard-trained anaesthesiologist and Johns Hopkins-trained pain medicine specialist. He directed the Multidisciplinary Pain Fellowship Program at the Johns Hopkins Hospital, and directed the Blaustein Pain Treatment Center at Hopkins. Dr Christo is an invited lecturer both nationally and internationally, serves on two journal editorial boards, has published more than 60 articles and book chapters, coedited three textbooks on pain, and teaches medical students, residents, and pain fellows. He has been a course director or coordinator for many continuing medical education programs that focus on educating specialists and generalists on important aspects of pain diagnosis and treatment. Matthew Crawford (MB BS FANZCA FFPMANZCA FCICM) is Director of Pain and Palliative Care at the Sydney Children’s Hospital, Randwick, New South Wales, and is Senior Staff Specialist in Anaesthesia and Intensive Care, and Clinical Director of the Surgery and Anaesthesia Programs at Sydney Children’s Hospital. He has a particular interest in post-operative and chronic pain management in children. He has provided paediatric anaesthetic and intensive care services in a voluntary capacity for many South Pacific islands, Myanmar, and Rwanda. He has a research interest in physiology, anaesthesia, and intensive care procedures, and has published in international journals. Anthony H Dickenson (BSc PhD FMedSci FBPharm) is Professor of Neuropharmacology in the Department of Neuroscience, Physiology and Pharmacology at University College, London, with a PhD at the National Institute for Medical Research, London. He has held posts in Paris, California, and Sweden. His research interests are pharmacology of the brain, including the mechanisms of pain and how pain can be controlled in both normal and

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pathophysiological conditions, and how to translate basic science to the patient. He is an Honorary Member of the British Pain Society, a Fellow of the British Pharmacological Society, and a founding and continuing member of the London Pain Consortium. With his research team he has authored more than 290 refereed publications, and he has made many media appearances. Peter T Dorsher (MS MD) is Chair, Physical Medicine and Rehabilitation, Mayo Clinic, Florida, and was Assistant Professor, Physical Medicine and Rehabilitation Residency, Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, from 1985 to 1989. He attended medical school at Rush Medical College, Chicago, and obtained his Masters of Science, Biomedical Engineering, from Northwestern University, Evanston, Illinois, and Bachelors of Science, Biomedical Engineering, at Case Institute of Technology, Cleveland, Ohio. He has made numerous regional, national, and international presentations on myofascial pain, chronic pain, acupuncture, and their relationships. He has published over 30 journal articles, six book chapters, one book, and 20 miscellaneous publications on neurologic disorders, fibromyalgia, chronic pain, and Eastern medicine. He is currently working on development of the Mayo Spine Center for care of spine disorders. Paul Glare (MBBS MA MMed) is Chief of the Palliative Medicine Service and Attending Physician in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSKCC), New York. He is also Professor of Medicine at the Weill Cornell Medical College. He has published more than 70 peerreviewed articles on pain and palliative care, and more than 20 book chapters. He is the editor of textbooks on opioid pharmacology and on prognostication, both published by Oxford University Press. He is also an Associate Editor of the textbook Palliative Medicine, published by Elsevier in 2008. Peter J Goadsby (MD, PhD UCSF) obtained his basic medical degree and training at the University of New South Wales, Australia. His neurology training was done with Professor James W Lance in Sydney. After post-doctoral work in New York with Don Reis at Cornell, with Jacques Seylaz at Université VII, Paris, and postgraduate neurology training at Queen Square, London, with Professors C David Marsden, Andrew Lees, Anita Harding, and W Ian McDonald, he returned to the University of New South Wales and the Prince of Wales Hospital, Sydney, as a consultant neurologist and Associate Professor of Neurology. He was appointed a Wellcome Senior Research Fellow at the Institute of Neurology, University College, London in 1995. He was Professor of Clinical Neurology and Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square, London, until 2007. At the time of writing he was Professor of Neurology and Director of the Headache Center, Department of Neurology, University of California, San Francisco, but is currentlyProfessor of Neurology, King’s College, London, and Director, NIHR-Wellcome Trust Clinical Research Facility,



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King’s College Hospital, London. He is an Honorary Consultant Neurologist at the Hospital for Sick Children, Great Ormond St, London, and in the Department of Neurology, University of California, San Francisco, and Chair of the British Association for the Study of Headache. Amy Hinkle (MSc) holds a Master of Science from Wayne State University School of Medicine, United States, with a focus in neuroscience. She has ten years of research experience in industry and academia. Her early start working in a biochemistry lab at Oakland University at the age of 15 propelled her to a career as a Research & Development scientist at Oxford Biomedical Research. After completing undergraduate degrees in Biochemistry and Applied Mathematics at Oakland University, she moved on to complete her graduate program at a young age. Her primary interests in genetics and neuroscience stem from a family history of migraines and Complex Regional Pain Syndrome. Jade Hucker (BSc(Hons) MPsychol (Clin) (Hons)) is a clinical psychologist dedicated to work in the field of chronic conditions including chronic pain. She currently works at the Royal Prince Alfred Hospital Pain Management Centre, Camperdown, New South Wales, where she is responsible for clinical psychology services. She has extensive experience delivering individual and group-based programs for people with chronic pain, and provides education to other health professionals on managing chronic pain. Jade is also a Clinical Associate of the University of New South Wales, and a supervisor of Intern Clinical Psychologists. Elystan Hughes Elystan Hughes (BSc(Hons) MB BCh FRCA) is a Senior Registrar based at Queen Elizabeth Hospital, Birmingham, United Kingdom. Originally from West Wales, he studied Biochemistry at Imperial College, London, and Medicine at Cardiff University. Specialising in anaesthesia, his interests include acute pain management, trauma, and regional anaesthesia. He has undertaken Research and Regional Anaesthesia fellowships in Australia. Currently based in the United Kingdom, Dr Hughes works internationally and contributes to advancement of high quality pain management strategies. Kinshi Kato (MD PhD) is a spine surgeon and Assistant Professor in the Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan. He received his medical education and surgical training from Fukushima Medical University, and additional post-graduate education in molecular biology at the Peripheral Nerve Research Group in the Department of Anesthesiology, University of California, San Diego, United States. He now specialises in spine surgery and sports medicine, with a special interest in lumbar disorders, and received the Best Paper Award at the annual meeting of the International Society for the Study of the Lumbar

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About the authors

Spine (ISSLS). His clinical and research interests include neuropathic pain, cytokines in neuroinflammation, psychosocial factors in chronic low back pain, primary care for low back pain in athletes, and minimum invasive lumbar surgery for athletes. Tamara Lang (BPsychol (Hons) MPsychol (Clin) (Hons) DPhil) is a clinical psychologist specialising in children and adolescents. She has a Masters of Clinical Psychology from the University of New South Wales, and gained a Doctor of Philosophy at the University of Oxford, United Kingdom. Tamara works with children, adolescents, and their families requiring psychological assessment and treatment for a broad range of issues, such as chronic pain, depression, anxiety, stress, challenging behaviours, grief, loss, and social problems. She is currently working in the pain and palliative care team at Sydney Children’s Hospital, and is a Conjoint Lecturer in the Faculty of Medicine, University of New South Wales. Hsuan-Chih Lao (MD MSc) has been a senior supervising doctor in the Anaesthesia and Pain Department in Mackay Memorial Hospital, Taipei, Taiwan. She specialises in obstetric and paediatric cardiovascular anaesthesia and interventional pain management. Previous research has been related to labour analgesia and heart rate variability. She is a research fellow in the Pain and Palliative Care Department, Sydney Children’s Hospital, Australia, having completed the fellowship training program for adult pain management. She is also a lecturer in the Medical School of National Yang-Ming University, Taiwan, and Director of resident training programs in the department. Her current interest is pain management for children with autoimmune disease. Pamela E Macintyre (BMedSci MBBS MHA FANZCA FFPMANZCA) is an Associate Professor and Director of the Acute Pain Service at Royal Adelaide Hospital, South Australia, since it was established in 1989, the first such service in Australasia and one of the first in the world. She is a Foundation Fellow of the Faculty of Pain Medicine, Australian and New Zealand College of Anaesthetists, and an examiner for the Faculty. Her key areas of interest have been management of acute pain in more complex patients, safety of and education about acute pain management, and improving acute pain management practices in hospitals and after discharge. She has co-authored one and co-edited another book on acute pain management, co-authored a number of chapters and papers, and was senior editor for the second (2005) and third (2010) editions of Acute Pain Management: Scientific Evidence, published by ANZCA and the FPM. Tony Merritt (BA(Hons) MPsychol (Clin) (Hons) MAPS) is a clinical psychologist working in private practice in Sydney, Australia, and runs Sydney Clinical Psychology. He is an Associate Lecturer in the Masters of Clinical Psychology program at the University of New South Wales, and a clinical supervisor and clinical associate at the University of New South Wales, Mac-



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quarie University, and University of Sydney. He supervises many intern and qualified clinical psychologists. Tony has worked across various public and private services, including Royal Prince Alfred Hospital Pain Management Centre, St Vincent’s Hospital Gambling Treatment Service, and Prince of Wales Private Hospital. At the Black Dog Institute, Australia, Tony runs workshops on workplace mental health, professional development training for general practitioners, professional development training for mental health professionals on medications, and Bipolar Disorder. Geoffrey Mitchell (MBBS, PhD FRACGP FAChPM) is Professor of General Practice and Palliative Care at the University of Queensland, and Head of the MBBS program at Ipswich. His main research interest is the role of general practitioners in palliative care, cancer in general, and complex conditions. Current research includes interventions to improve outcomes for caregivers for people with advanced cancer, health services research in palliative care and primary care, and single patient trials. He has published over 150 peerreviewed publications. He has been a chief investigator on over $16 million of National Health & Medical Research Council, Australia, funding. He maintains a clinical general practice in Ipswich, Queensland, Australia. Ian Mowat (MA, MBBS, FRCA, EDRA) is an Anaesthetic Specialty Registrar with interests in regional anaesthesia, pre-operative assessment, peri-operative management, and acute pain. Educated at Cambridge University and Guy’s, King’s and St Thomas’ School of Medicine, Dr Mowat is currently a trainee in the St George’s School of Anaesthesia, London. His chapter was written during placement as an Anaesthetic Research Fellow at Royal Perth Hospital, Western Australia. Robert R Myers (PhD) is Professor Emeritus in the Departments of Anesthesiology and Pathology at the University of California, San Diego. His academic training is in bioengineering and neurosciences, and his principal interests are in the pathogenesis of neuropathic pain, particularly the role of cytokine mechanisms of nerve injury and pain. Other interests include the neurotoxicity of local anaesthetics, the neurophysiology of microcirculation, and the integrative pathophysiology mechanisms in nerve and spine injury that cause pain. He has led the Peripheral Nerve Research Group at University of California, San Diego, for many years, has been Editor-in-Chief of the Journal of the Peripheral Nervous System, and has trained international scholars in neurobiology, orthopaedics, and neurology. Stephan A Schug (MD FANZCA FFPMANZCA) is currently Professor and Chair of Anaesthesiology in the Pharmacology and Anaesthesiology Unit of the University of Western Australia, and Director of Pain Medicine at Royal Perth Hospital, Australia. Professor Schug is a German-trained specialist anaesthetist with an MD in pharmacology. He has previously worked at the

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University of Cologne, Germany, and then was Chair of Anaesthesiology at the University of Auckland in New Zealand. His main research interests are in the pharmacology of analgesics and local anaesthetics, the management of acute, chronic, and cancer pain, regional anaesthesia and analgesia, organisational structures for pain management, and reduction of adverse events in hospitals. Professor Schug has over 350 publications, including peer-reviewed journal articles, books, and book chapters, mainly in the areas of regional anaesthesia and acute and chronic pain management. Professor Schug is often invited to present at national and international conferences. David A Scott (MB BS PhD FANZCA FFPMANZCA) is Associate Professor and Director of Anaesthesia at St Vincent’s Hospital in Melbourne, Australia. He was Director of the Acute Pain Service at St Vincent’s from its inception in 1990 until 2010. He has clinical and research interests in a wide range of areas, including regional anaesthesia and acute pain management, and has researched and published extensively in these areas, including a number of book chapters. His other interests include the long-term cognitive impacts of anaesthesia. He completed a PhD on neuropathic pain in 2004. He is especially interested in the safety and outcomes related to acute pain management. Louise Sharpe (BA(Hons) MPsych PhD) is a Professor of Clinical Psychology in the School of Psychology, University of Sydney, Australia, and is a Senior National Health and Medical Research Council (NHMRC) Research Fellow. She completed her undergraduate and clinical training at the University of Sydney, and has a PhD from the University of London. She is an expert in health psychology and the development and evaluation of novel interventions for patients with a range of health problems, and has particular expertise in the management of chronic pain. She has been the recipient of over $3.5 million in competitive grant funding, with current funding from the Australian Research Council and NHMRC, and has published more than 120 peer-reviewed journal articles, including the results of nine randomised controlled trials of psychosocial interventions. Veronica I Shubayev (MD) is Associate Professor of Anesthesiology at the University of California, San Diego, United States, and Research Physiologist at the Veterans Affairs San Diego Healthcare System. She studies the role of immune responses associated with peripheral nerve injury in axonal regeneration, phenotypic changes and survival of Schwann cells and their remodelling, including the compact myelin lamellae, and functional recovery of peripheral nerve following damage or disease. Among her significant scientific contributions is the discovery of axonal transport of inflammatory cytokines, providing a mechanism of central neuroinflammation and neuropathic pain after peripheral lesions, and the work implicating matrix metalloproteinases (MMPs) and myelin basic protein as novel classes of pain mediators.



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Philip J Siddall (MBBS MM (Pain Mgt) PhD FFPMANZCA) is Director of the Pain Management Service at Greenwich Hospital in Sydney and Conjoint Professor in Pain Medicine at the University of Sydney, Australia. He spent three years in China studying acupuncture, after which he completed a PhD in pain physiology at the University of Sydney. He currently combines clinical pain medicine with research into the mechanisms and management of pain. His research interests are in the area of neuropathic pain, particularly following spinal cord injury, as well as the role of modulatory pathways and spiritual and existential issues in pain. Muhammad Salman Siddiqi (MD) was born and raised in Pakistan. He managed to secure merit scholarships in different examinations in his childhood, and graduated in medicine from the Rawalpindi Medical College, Pakistan. After completing his internship and residency training in Pakistan, he worked in hospitals, including Shifa International Hospital, one of the most prestigious American hospitals in Pakistan. He moved to the United States in 1998 and worked as a clinical research associate on Alzheimer’s Disease and Zellweger Syndrome at Johns Hopkins Bayview Medical Center, Baltimore. For several years he was the appointed Senior Vice President in a healthcare management company in Rockville, Maryland, for all medical, regulatory affairs, and clinical development programs. He completed his residency in Neurology from the University of Toledo Medical Center in Ohio in 2012 and passed his Neurology Board from American Board of Psychiatry and Neurology. He joined Memorial Sloan–Kettering Cancer Center, New York, and completed fellowship training in Hospice and Palliative Care in 2013. He is currently a neurologist with a special interest in hospice and palliative care at Tallahassee Memorial Healthcare Hospital, Tallahassee, affiliated with Florida State University. Anne M Skoff (BA MA PhD) received her Bachelors and Masters degrees in Biology from Boston University. She then received a doctorate in Molecular Immunology from Wayne State University, during which time she received several honours. Following her graduate studies, she worked in the laboratories of Drs Robert Lisak and Joyce Benjamins, studying the immunobiology of Schwann cells and their susceptibility to various cytokines. She joined Dr Adler’s laboratory in 1998 as Research Associate and has been responsible for many of the resulting behavioural and biochemical studies. Dr Skoff has been key in demonstrating the role of cytokines in secretion of nociceptive peptides.

Section 1

The person The person in pain is the starting point for this first section of the book. It begins with a general practioner’s view of the complexity of pain presentation at the front line, where the doctor manages a spectrum of pain conditions. While this is generally accepted as primary care in developed countries, the World Health Organization (WHO) defines primary care more broadly in emerging and developing countries where pain is managed in very different sets of circumstances (www. who.int/topics/primary_health_care/en). The following chapters address the current understanding of the pathophysiology and treatment regimens of both acute and persistent pain.

Chapter 1

Pain and the front line – a general practitioner’s perspective Roberta T Chow

Introduction General practice is, in the main, the front line of pain management. It is at the clinical interface of general practice that a person in pain most commonly seeks treatment, where most people first enter the healthcare system, and where they return for ongoing management after acute hospital care (Review of Chronic Pain Management Advisory Group 2008; Starfield et al. 2005). General practice is where the science of pain medicine and the art of clinical practice intersect in a way that is different from that of a person in pain presenting to hospital or to specialists. This chapter discusses the problems and the complexity of pain medicine from the perspective of a GP at the front line. One of the unique qualities and challenges of general practice is management of the diagnostic uncertainty of undifferentiated and evolving illnesses that have pain as the primary symptom. In this scenario, the person in pain comes to a general practitioner (GP) with a reasonable expectation of a diagnosis, appropriate investigation and treatment, including adequate pain relief. Such consultations with GPs occur by the millions worldwide, with predominantly positive outcomes. Nevertheless, behind this apparently simple scenario are layers of complexity that influence the person and the GP and can result in less than satisfactory long-term outcomes for many people in pain. Inability to address and manage these complexities, not only in general practice but also in the health system as a whole, underpins an epidemic of chronic pain, with costs of pain management measured in billions of dollars in industrialised countries (Access Economics 2007; Ekman et al. 2005; Lambeek et al. 2011; Wieser et al. 2011). Reasons for such

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an epidemic are complex and attributable to multiple factors. Howarth and colleagues consider it to be due to a failure in understanding the person in pain (Howarth et al. 2013), while Delpero suggests that it is the inadequacy of pain management guidelines (Delpero 2008). Turk and colleagues consider it to be a limitation in the translation of pain pathophysiology to effective treatments (Turk et al. 2011). Among the many problems are delays of months to years for referrals to tertiary level pain clinics (Lynch et al. 2007; Lynch et al. 2008) and an epidemic of iatrogenic opioid addiction (Garland et al. 2013; Ling et al. 2011; Manchikanti et al. 2012). These mounting problems have resulted in many people with pain seeking complementary and alternative therapies, which now play a large role at a primary care level (Rosenberg et al. 2008). Given the challenges of optimal pain management, the longitudinal nature of ongoing care unique to general practice (Green and Holden 2003) can mitigate the sense of loss of control experienced by people in pain and reduce their powerlessness by reducing fragmentation in care (Andre et al. 2012). Keeping the focus on the person as an active participant and at the centre of care, rather than a passive receiver of care, is a marker of quality care (Lapsley 2012), and is at the heart of general practice as well as the focus of this book.

What painful conditions do GPs treat? The first step in evaluating pain in general practice is to understand the nature and prevalence of pain in this clinical setting. The Better Evaluation and Care of Health (BEACH) and Supplementary Analysis of Nominated Data (SAND) studies, which evaluated 1.4 million GP consultations in Australian general practice, were among some of the earliest international studies to investigate this (Britt et al. 2008; Britt et al. 2010). These studies are particularly important, as general practice is identified as a critical intervention point for health care: about 83% of people visit a GP at least once a year. The data from these studies provide a basis for monitoring many aspects of public and individual health, including prevalence of diseases, assessing efficacy of treatment, and identifying potential strategies to improve outcomes. Britt and colleagues (2010) found a prevalence of 19.2% (95% CI = 17.4–21) for painful conditions, the third most common reason for people to visit a GP. Their pain was predominantly musculoskeletal, with 48% diagnosed as osteoarthritis, 29.2% as ‘back problems’, and 7.1% other forms of arthritis. Nearly one-third of people nominated ‘other condition’ as the cause of their chronic pain, of which 65.1% were musculoskeletal and 14.7% neurological. People with cancer-related pain constituted 2.4% of chronic pain consultations. These data are consistent with those of national (Blyth et al. 2003) and international population studies (Fitch and McComas 1985; Hoy et al. 2012), especially those related to low back pain. Such painful conditions are among the most



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common reasons for general practice consultations in many industrialised and non-industrialised countries (Murray et al. 2012).

The consultation Although epidemiological studies give a broad view of prevalence of pain nationally and internationally, in the face-to-face consultation with the GP a person in pain wants to know what is wrong with them, whether the condition is serious, and how the GP can most effectively treat the pain (Von Korff 1999). A person in severe pain is rarely interested in the science or the evidence, yet the treatment regime and even the language used by the GP at this early stage can have long-term consequences, both positive and negative. For example, early identification and management of risk factors for a person with back pain, such as catastrophising, can reduce progression of acute back pain to chronic (McGreevy et al. 2011, Weiner and Nordin 2010). Within that first consultation, therefore, the most important tool for the GP is effective communication (Elwyn et al. 2004), to establish a working diagnosis, but also to understand the person’s expectations, needs, and fears. Even the language used in the consultation can have a profound effect on the long-term outcome of the person’s pain (Darlow et al. 2013). Understanding the psychosocial elements of their pain will have the most important influence on therapeutic decisions and leads to improved outcomes (Huas et al. 2006; Müller-Schwefe et al. 2011). Pain is a highly individual experience. How the person perceives the meaning of pain in the context of her or his past experience and within their family will modulate the intensity of pain. Coexisting anxiety or depression are also well known comorbidities with pain, and form part of the complex milieu of the psychosocial aspects of pain management (Gambassi 2009, Holmes 2012, Worz 2003). Furthermore, cultural and ethnic differences in the perception of the meaning of pain can add to the complexity of a person’s pain experience, and there is a need for nuanced management (Green et al. 2003a; Rahim-Williams et al. 2012). The biopsychosocial aspects of a person’s pain that encompass all these elements are already present at the first GP encounter (Engel 1997; Lumley et al. 2011). The importance of the relationship between the GP and the person in pain in managing all these elements cannot be over-emphasised. It is the GP who has the advantage of understanding the context of the whole person and their personal situation and can therefore provide individualised care. Importantly, it is at this point in primary care that the first of the barriers that limit a person’s optimal pain management have been identified in the National Pain Strategy (NPS) of Australia (National Pain Summit of Australia 2010). (See also Chapter 17.) The NPS, an international first, brought together 150 representatives of professional organisations and patient advocates to

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systematically evaluate and find ways to overcome these and other barriers to better pain management. Canada followed with its first pain summit in 2012 (Canadian Pain Summit 2012), and other countries, such as the United States, are aware of the need for a national approach (Roehr 2011).

Pain To address one of the first barriers to effective pain management, there is a need to improve understanding of the nature of pain. Pain is a complex clinical phenomenon that is still poorly understood across many domains of medicine. Over the last two decades, an exponential increase in pain medicine research has led to better understanding of the physiological and pathophysiological interaction between both peripheral nervous system (PNS) and central nervous system (CNS), the immune system, and the emotion milieu of the person which results in chronic pain. (See also chapters 7, 15, 16, 17.) Until relatively recently, pain has been regarded as a secondary phenomenon caused by a primary pathology, and as something to be managed as a by-product of a disease. The Cartesian model proposes that if you treat the disease or the cause the pain will subside (Goldberg 2008). It is, however, now recognised that complex neurophysiological changes occur as a result of pain, whether it is caused by disease, injury, or surgery. Such change in thinking has led to the important concept of pain as a disease in its own right (Siddall and Cousins 2004). This then leads to a different management approach, directing the person in pain away from seeking a cure and towards optimising quality of life, even if pain persists. Strategies such as these are used in other chronic diseases, such as diabetes or asthma, and are applicable to chronic pain. Applications of new technology for examining systemic changes in the nervous system of a patient with pain, such as functional fMRI and near infrared spectroscopy (NIRS), provide a basis for the ‘pain as a disease’ model. These imaging techniques now demonstrate structural, though reversible, pain-induced changes in a number of brain areas, referred to as the ‘pain matrix’ (Iannetti and Mouraux 2010), rather than a single region of the brain. (See also chapters 7 and 11). Other studies relating to the pain matrix describe central sensitisation and wind up, which includes neural plasticity where the cells of both PNS and CNS, their neuroglia, the microglia of the brain and spinal cord, and the molecules that respond to and are modulated by nociceptive afferent stimulation (Apkarian et al. 2011, Coderre et al. 1993, Woolf and Salter 2000). (See also chapters 3 and 15.) The concept of pain as a disease is not universally accepted, however (Cohen et al. 2013). Cohen and colleagues (2013) suggest that it is a misinterpretation of current knowledge of pain pathophysiology and has the potential to obstruct more effective pain research. Cohen and colleagues do, however, acknowledge the critical



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importance of neuroplasticity and contextual aspects of a person’s pain. This clash of concepts has clinical implications for people in pain and GPs alike, when there is a need to reduce an unnecessary and potentially unhelpful search for a cure without ignoring new symptoms or trivialising the person’s ongoing pain. However it is conceptualised, pain is an important health challenge at both individual and public health levels (Goldberg and McGee 2011).

‘Diagnosing’ pain Pain presentations in general practice are characterised by their undifferentiated nature. By definition, this means they are ‘ambiguous, uncertain, unexplained and undiagnosed’, and the causes may only become clear as a disease evolves (Royal Australian College of General Practitioners 2011). Painful conditions presenting to a GP can range from benign but annoying problems to life-threatening illnesses: a headache may be symptomatic of a benign tension headache or an early sign of a brain tumour; neck pain can be mechanical in origin or the first sign of polymyalgia rheumatica with the potential of blindness from temporal arteritis. Even acute back pain can be an early symptom of a leaking aortic aneurysm. GPs are faced with such diagnostic challenges on a daily basis – acute pain in children, sports and motor vehicle trauma, postoperative pain following discharge from hospital (see Chapter 5), complex work-related injuries, and persistent pain in non-malignant conditions in older people. This unique quality imposes a focus for GPs that is different from that of specialists such as pain physicians, neurologists, rheumatologists, and others, who often first see people in pain weeks, months, or even years after the initial presentation. For GPs, a pain management plan must often be formulated without a precise diagnosis, and, as conditions are often evolving, textbook descriptions and classifications often do not apply. For example, a specific diagnosis of low back pain is not required to start a regime of effective pain management once serious disease or ‘red flags’ – that is, symptoms of serious illness – are excluded (McLain 2010; Sizer et al. 2007). Diagnosis must, however, always be kept under review (Savigny et al. 2009). A condition in the elderly such as spinal canal stenosis will potentially have multicomponent pathology, such as facet joint hypertrophy and disc prolapse as well as nerve impingement, all potentially causing concurrent painful symptoms (Yasar et al. 2009). Here a GP must simply manage the person’s pain; it is very difficult to treat each component individually. GPs also deal with people who, for treatment of their pain, have first gone to hospital emergency departments, where doctors make a diagnosis, initiate treatment, and refer the person back to their GP for further management. Similarly, people discharged from hospital after surgery or other procedures are often managed in general practice, with varying levels of information

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from the hospital. There is often little expectation that the person or the GP will have any further contact or practical support from those who provided care in the hospital setting.

Persistent pain Pain that persists for more than three months is defined as persistent pain. Persistent pain is pain that occurs after tissue healing should have been completed, and it reflects alteration in PNS and CNS processing without nociceptive input to maintain the pain. (See Chapter 13.) Examples of such clinical scenarios are failed back surgery syndrome (Chan and Peng 2011), and painful conditions with no clearly defined pathology, such as fibromyalgia (Mease 2005). In these and similar clinical scenarios, pain can occur in the absence of pathology on standard diagnostic imaging (DI) or show findings that may be coincidental rather than causal. ‘Failed back surgery syndrome’ is where surgery for back pain does not lead to pain relief, and the pain persists even though the mechanical ‘cause’ identified on DI has been corrected (Ash et al. 2008; Graves et al. 2012; Hussain and Erdek 2014; Kornelsen et al. 2013; Webster and Cifuentes 2010). In a study by Bentsen and colleagues (2007), only 16% of people reported no pain after surgery, while 38% continued to experience severe pain following spinal fusion. Moreover, a substantial percentage of people without a history of low back pain or sciatica can show abnormalities on X-ray or MRI (Jensen et al. 1994). Treatment of such DI findings for low back pain does not improve clinical outcomes once symptoms that indicate serious disease are eliminated (Carey 2009; Chou et al. 2009). People living with these and other conditions associated with persistent pain are a subgroup regarded as the most difficult to manage in general practice (Kenny 2004). Many have seen other clinicians, such as pain specialists, psychologists, and physiotherapists, often for only a short time. Their pain symptoms are often worsened by delays of months to years before they attend tertiary level pain clinics following referrals from GPs (Lynch et al. 2007; Lynch et al. 2008). Of those who do attend pain clinic programs, about half will return to general practice without having completed the program or obtained clinically relevant pain relief (Heiskanen et al. 2012). A proportion of these people will have opioid addiction complicating their pain management. This requires specific strategies and specialised support, which the GP has to manage (Holliday et al. 2013c). In this context, iatrogenic opioid addiction has emerged not only as problem for the GP but as a parallel public health problem. For example, deaths from opioids in the United States increased from 4030 in 1999 to 16 651 in 2010 (Centers for Disease Control and Prevention 2012; Manchikanti et al. 2012; Rosenblatt and Catlin 2012). (See also Chapter 12.) The challenge for the GP is to balance risks and benefits, especially as



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long-term effects are less well known (Holliday et al. 2013a; Holliday et al. 2013b). The problem of opioid medication is exacerbated for the GP and for people in pain because many doctors fear causing addiction. This can lead to a cycle of undertreatment of pain, where inadequate doses of medication are followed by requests by the person in pain for increased doses; this, in turn, can be interpreted as drug-seeking behaviour, leading to stigmatisation of the patient and poor pain relief (Breivik 2012; Lewis et al. 2010; Lewis and Trafton 2011).

Evaluating pain People in pain describe their experience in many different ways. Finding ways to measure pain intensity objectively in day-to-day practice presents another challenge. The lack of objective measurement tools is at least in part responsible for a worldwide under-recognition of pain, with consequent under-treatment across all branches of medicine (Müller-Schwefe et al. 2011; Tai-Seale et al. 2011). Evaluation of pain rests on indirect assessment tools, such as the Visual Analogue Scale (VAS) (Huas et al. 2006), or functional assessments, such as the Brief Pain Inventory (BPI) (Tan et al. 2004), or the Short-Form 36 (SF-36), which evaluates quality of life. These tools are only used in a limited way in general practice. For example, only 13% of French GPs used VAS (Huas et al. 2006). Pain-related questionnaires such as the BPI and SF-36 can be used but are time consuming, which limits their application in general practice. Evaluation of a patient’s pain is also influenced by a range of factors beyond assessment tools. A US study of videoconferencing of GP consultations with people in pain showed that white, older women were asked more about their pain intensity by male doctors than were younger males (Tai-Seale et al. 2011). This and other studies also illustrates that gender, age, and ethnicity, including racial differences between the doctor and the person, influences how pain is assessed and treated (Green et al. 2003b). Even when pain intensity was formally documented, levels of pain were underestimated compared with what a person later described (Müller-Schwefe et al. 2011; Tait and Chibnall 1997). Time limitations are a major barrier to a GP’s effective evaluation of a person’s pain. This applies not only to the time required to complete painrelated questionnaires. In a US study, the time spent in consultations addressing pain was a median of 2.3 minutes. This study identified the negative impact of limited time on assessment of a person’s pain and treatment (Tai-Seale et al. 2011). Financial constraints of medical practice contributed to time constraints, as GP income in countries without socialised medicine depends on the number of people a GP can see in a given time. There is, therefore, a disincentive to spend time on those with complex pain problems and an incentive to undertake more financially rewarding ser-

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vices which occupy less time and are less complex. Similarly, the paperwork demanded by insurance companies for people injured at work acts as a disincentive for GPs to manage them (Schatman 2011). In a workers’ compensation scenario, management of people in pain has to fit criteria designated by third parties who may include case managers with little medical training, rehabilitation providers who get bonuses when people return to full employment, and independent medical examiners with no training in pain medicine. Legal intervention, insurance company policies, and adverse psychosocial factors in the workplace – so-called ‘yellow flags’ – (Kendall et al. 1997; Schatman 2011) further complicate matters and influence outcomes of treatment. Persistent pain in this context often runs a chronic and unremitting course that leads to psychological dysfunction and physical disability (Bevan et al. 2009). (See also Chapter 16.)

Training of GPs in pain medicine Lack of training in pain medicine at undergraduate and postgraduate levels of medical education is a serious barrier to better pain management. A recent report by the Pain Education Special Interest Group of the British Pain Society described the pain education of healthcare undergraduates in the United Kingdom as woefully inadequate: the median time spent on pain management by a medical student was 13 hours, with some spending only 6 hours (Müller-Schwefe et al. 2011). Furthermore, the subject was not taught as a discrete module. Confirmation of a lack of basic pain medicine knowledge was apparent from a study showing that most doctors had limited awareness of the physiological differences between nociceptive and neuropathic pain (Müller-Schwefe et al. 2011). (See also Chapter 2.) Specific teaching in musculoskeletal medicine is also lacking in many medical schools worldwide (Chehade and Bachorski 2008). Chelade and Bachorski propose that, as the predominant pain presentations in general practice are musculoskeletal, a national multidisciplinary approach unifying the key musculoskeletal clinical and basic science disciplines should be integrated into undergraduate medical curricula. Currently, however, in Australia and the United Kingdom the most easily accessible and cost-free pain management education for GPs is often provided by pharmaceutical companies, and this can influence prescribing and pain management patterns (Prosser et al. 2003). Though strategies have been introduced at national levels to provide evidence-based prescribing education, such as those by Quality Use of Medicines in Australia and the National Institute for Health and Care Excellence (NICE) in the United Kingdom, obtaining education in pain medicine for GPs remains another barrier to optimal pain management for people in pain (Rosenblatt and Catlin 2012; Von Korff 2012).



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What about guidelines? General practice abounds with guidelines to assist GPs with best practice of evidence-based medicine for managing many conditions, including acute back pain (van Tulder et al. 2006), chronic back pain (Pillastrini et al. 2012), knee osteoarthritis (Royal Australian College of General Practitioners Osteoarthritis Working Group 2009), neuropathic pain (National Institute for Health and Care Excellence 2013), and for opioid prescribing (McCracken et al. 2012), but the evidence relating to their implementation and benefit is conflicting. French and US studies found that adherence to guidelines by primary care clinicians did not improve clinical outcomes for people with chronic musculoskeletal pain (Corson et al. 2011; Huas et al. 2006). A study of primary care physicians showed that, while they recognised the benefit of treatment algorithms, many expressed reluctance to follow the plan when treating people with chronic pain, mainly because of time constraints (Jamison et al. 2002). In the United Kingdom, a study using guidelines to stratify people with back pain into low, medium, and high risk groups showed better clinical and economic outcomes for these people than it did for those in nonstratified conventional care (Hill et al. 2011; Koes 2011). From a different perspective, it has been proposed that implementation of guidelines could reduce skills in the art of medicine by reducing medical decision-making to algorithm-driven care, with no focus on an individual’s needs (Battista et al. 1995; Delpero 2008). A person’s preference for a particular treatment was the reason many GPs treating people with back pain gave for non-adherence to the guidelines (Schers et al. 2000; Schers et al. 2001). Finding better ways to implement clinical guidelines, while addressing individual preferences in treatment, in the context of personalised medicine and active involvement of the person in pain, remains a challenge (Koes et al. 2010).

Costs of poor pain management One of the major consequences of inadequate pain management is the financial cost, which impacts on health budgets across the world. Even in Australia, with a relatively small population of 23 million, costs of pain were estimated in 2007 as $34 billion (Access Economics 2007). In Switzerland, direct costs of low back pain were estimated at €2.6 billion (Wieser et al. 2011); in Ireland the cost of chronic pain was estimated to be €5.34 billion (Raftery et al. 2012); in the Netherlands, the total cost of back pain was estimated to be €3.5 billion (Lambeek et al. 2011); in Sweden the total cost of low back pain was €1860 million (Ekman et al. 2005). Disease burden costs are also measured in the collateral epidemic of iatrogenic opioid addiction and death (Bruehl et al.

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2013; Tedeschi 2006), as well as the serious and potentially fatal side-effects of the more ‘benign’ drugs such as NSAIDs, with the cardiac, renal, and gastrointestinal bleeding risks they pose, especially in the elderly and with polypharmacy (Bandolier 2007a; Jones et al. 2008).

How does the person in pain feel? While much of pain research is focused on understanding the epidemiology, physiology, and psychology of pain, there is relatively little research into how a person feels about their experience of the pain management process. Studies in this area suggest a deep level of dissatisfaction stemming from a mismatch between the person’s expectations and his or her lived experience within ‘the medical system’ (McKinnon et al. 1997; Upshur et al. 2006; Upshur et al. 2010). People perceiving caring, empathy, and genuine concern by doctors about their pain responded positively (Ong et al. 1995). This translated to improved wellbeing with important clinical consequences. They were less likely to adhere to their treatment regime if they felt dissatisfaction with the consultation (Kenny 2004; Ong et al. 1995; Rao et al. 2007). They also experienced greater relief of symptoms when they perceived that the consultation centred on them. This emphasises the importance of empathy as a therapeutic tool that is able to contribute to better emotional health and to fewer diagnostic tests and referrals, with concomitant reduced costs (Matthias and Bair 2010; Stewart et al. 2000). Indeed, the emotional context was an important predictor of outcomes of treatment, positively and negatively, as the person’s emotional response to the doctor was the strongest preditor of successful pain management (Tai-Seale et al. 2011). People also appreciated absence of suspicion about whether they were overusing drugs. Importantly, they valued their potential to provide input about their pain medication and to be actively involved in decision-making about their pain management, including decisions about medications (Upshur et al. 2010). However, doctors often underestimated how much a person in pain wanted to be actively involved in decision-making about their treatment (Cox et al. 2007). As a corollary, absence of empathy and a mismatch between what the person expects and how the doctor responds can result in stigmatisation of people in pain (Slade et al. 2009). This can apply as much to administrative staff as to the GP, as the person perceiving a lack of empathy at any level then feels that they are a burden to everyone (Upshur et al. 2010). In fact, Cohen suggests that education of doctors involved in pain management must extend beyond pathophysiology to development of insights into their own potential and often inadvertent contribution to stigmatisation of the person in pain (Cohen et al. 2011).



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Person-centred care To address the disconnect between expectations and the reality of care, and to improve overall quality of health care, there has been a policy goal of patient-centred care in both the United States and the United Kingdom. This is defined by the Institute of Medicine (IOM) as ‘care that is respectful of, and responsive to, individual patient preferences, needs and values, which is personalized care that gives patients the opportunity to exercise the degree of control they choose to have over their health care decisions’ (Committee on Quality of Health Care in America 2001). In a similar vein, the British National Health Service (NHS) defines personalised care as ‘compassionate, dignified and respectful care’, though the stated goal is to make care safer and more effective rather than to base it on the intrinsic value of the person. The language and concepts of patient-centred care are those of morality, rather than ‘evidence-based’ medicine and the guidelines that flow from that evidence. The concept of patient-centred care applied in the context of pain management is central to and recognised by the Australian NPS (National Pain Summit of Australia 2010), which goes further and describes an ‘empowered patient’ who becomes an active participant in, not just a passive receiver of, care as a partner in the effective management of pain. Empowerment of people in pain should enable them to take more responsibility for their health, in particular in the management of their pain (Pulvirenti et al. 2012). The challenge is for the GP to balance the individual’s preferences and expectations against professional knowledge, guidelines, and evidence-based medicine, which may be at odds with each other (McClimans et al. 2011). Nevertheless, McClimans and colleagues (2011) believe that even decisions that do not adhere to guidelines or are not in line with the evidence base ought to be honoured. Several studies have demonstrated that GPs are effective in balancing expectations with evidence-based guidelines in a person-centred model of care (Heath et al. 2009; Verheij 2011).

Complementary and alternative medicine Not all people are willing to accept the limitations of conventional medicine and the current evidence-based guidelines (Vincent and Furnham 1996). This has led to an international trend where people seek complementary and alternative medicine (CAM) therapies for pain relief, most commonly concurrently with conventional medicine. A cross-sectional survey of people with chronic pain in primary care clinics in the United States reported that 52% sought pain relief with CAM therapies (Rosenberg et al. 2008). A similar study in the United Kingdom reported that 84% of people surveyed in general practice had used at least one CAM treatment in the previous year, most commonly glucosamine and fish oils (Artus et al. 2007). In Israel, 6–10% of

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people reported using CAM therapies (Niskar et al. 2007), with a cross-sectional study of those attending specialised CAM clinics reporting that almost 50% sought pain relief, most frequently with acupuncture (Peleg et al. 2011). Interestingly, medical practitioners referred one-third of this study population. The impetus for people seeking CAM therapies often relates to dissatisfaction with their conventional medicine experience and concern about the invasive nature of the approach, as well as to side-effects of medication (Peleg et al. 2011; Vincent and Furnham 1996). However, dissatisfaction with conventional medicine is not always the main driver for seeking CAM treatments (Bishop et al. 2010; Ndao-Brumblay and Green 2010). A perception that CAM treatments were less authoritarian, and enabled greater autonomy as well as more personal control of health, were predictors of use, but not in all studies. A cross-sectional study of people using CAM demonstrated a philosophical view that these therapies were more holistic, using integrated mind/body theories, and that this was the most significant factor for almost 50% of those choosing CAM therapies (Astin 1998). Moreover, in some countries, such as Singapore, culturally specific views about CAM treatments such as traditional Chinese medicine, influenced how people used therapies, such as acupuncture, together with conventional treatments (Tan et al. 2013). In general, higher education levels were one of the most significant predictors of use of CAM, but only a very small minority used CAM treatments exclusively. So how do GPs and other specialists respond to people’s use of CAM, given the limited evidence of efficacy for many of the treatments used? From a clinical perspective, many doctors are not even aware that people are using CAM therapies. A study in the United Kingdom identified that up to 77% of people did not mention their CAM use to their doctors (Robinson and McGrail 2004; Saydah and Eberhardt 2006). Reasons for this centred on their assumption of negative reactions from their doctor. This is not unreasonable, given that a study showing doctors’ views on CAM cover a spectrum from enthusiasts to skeptics, with a largely negative attitude based on a perceived lack of evidence (Maha and Shaw 2007). Nevertheless, the dissonance between the academic view and the GP front line, at least in the United Kingdom, is reinforced by a study where 83% of GPs referred people in pain for CAM treatments where conventional therapies had failed. The most common CAM recommendation was for acupuncture, though referrals have decreased in the last decade (Perry et al. 2013; van Haselen et al. 2004). In the van Haselen study, while 70% of the doctors surveyed felt that use of CAM could lead to cost savings, particularly for referrals involving pain, there was also concern that costs could increase. Given the polarity of views within medicine, the relevance of what the person in pain wants becomes dominant. This may mean that an individual’s choice should be respected (McClimans et al. 2011) even if it involves use of CAM therapies (Robinson and McGrail 2004). At the very least this will facilitate continuing dialogue with the person in pain.



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Conclusion The reality for the person in pain is that their first engagement with the healthcare system most commonly is with the GP. It is also the GP to whom they return after a consultation with a specialist or following a hospital admission, and with whom they experience ongoing care. As set out in the NPS, the skills of GPs in building links with other clinicians need to be stronger and ongoing to have more efficient consultative interaction with pain specialists and other clinicians. The importance of these interactions and consultations and the role of telemedicine is expanded in Chapter 18. General practice will continue to remain central to primary care for people in pain. The unique quality of longitudinal care in general practice, and the care of a person and his or her family over years, offers the potential for much improved quality of life for the individual, as well as reduction in the costs of pain management to the community. As treatment and understanding of pain improves, and with more focused GP education in pain management, general practice should remain the cornerstone for managing pain.

Chapter 2

Understanding the pathophysiology of pain Philip J Siddall

Introduction Much as we may not like the experience of pain, it is a sensory process that is crucial to our survival. Not only is pain fundamental to our existence, it is extremely complex and cannot simply be regarded as a sensation. A nociceptive stimulus sets in train a whole range of pathophysiological effects from the periphery to the brain that overflows to behaviour and social interactions. It is difficult to deal with all of these events and interactions in a chapter such as this. The focus here will be on the pathophysiological processes that underlie the experience of pain. However, it is important to remember that these processes occur within a psychological and social milieu that will influence and be influenced by these same processes. From a biological point of view, it has been proposed that pain be divided into two entities: physiological pain and pathophysiological pain (Woolf 1989). Physiological pain describes the situation in which an acute noxious stimulus activates peripheral nociceptors, which then transmit sensory information through several relays until it reaches the brain and is recognised as a potentially harmful stimulus. More commonly, the insult to the body, which produces pain, also results in tissue injury with accompanying inflammation. These initial responses in the periphery can be followed by a large number of secondary changes in the central nervous system, either in response to injury and increased afferent input, or in response to deafferentation and loss of afferent input, including cellular and molecular changes and signalling (see Chapter 15). These secondary processes that occur following tissue injury result in a stimulus– response relationship that differs from that seen following physiological pain, and such pain has been termed pathophysiological. 16



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The term pathophysiological recognises that the nervous system is not a static entity but is malleable and responds to both increased and decreased inputs. These multitudinous nervous system alterations are now increasingly well-characterised and are often labelled as ‘neuroplasticity’. Although this term is used in various ways, it refers to the secondary changes within the nervous system that occur in response to changes in sensory input in the presence or absence of injury. While this term lacks the negative connotations of pathophysiology, such changes often appear maladaptive rather than adaptive and therefore can be considered pathophysiological (Flor et al. 2006). The focus of this chapter will be on pain pathophysiology. Although the chapter will briefly review the pathways and mechanisms underlying the transduction, transmission, and perception of acute pain, it will have a stronger focus on the plastic changes in the nervous system that occur in the presence of pain. Not only has basic science given us fascinating glimpses into these secondary changes, but also ultimately they are extremely relevant to our understanding of the experience of pain. In addition, for those who have a clinical perspective, the understanding of these processes is crucial for the adequate assessment and treatment of pain.

Pain types Before looking at pathophysiological mechanisms, it may be helpful to briefly review pain from a clinical perspective, since this provides a framework for considering these mechanisms. Pain is commonly divided into two types depending on the system of the body that is affected and believed to be underlying the experience of pain. These two types can be defined as nociceptive and neuropathic (Scholz et al. 2009). From a pathophysiological point of view, these two types of pain have fairly distinct underlying pathophysiological mechanisms. The most recent International Association for the Study of Pain (IASP) definition of nociceptive pain is ‘Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors’ (Taxonomy Committee of the International Association for the Study of Pain 2012). In essence, in this definition nociceptive pain is pain due to the stimulation of receptors by an adequate stimulus in a normally functioning nervous system. This is different from pain that may arise from damage to the nervous system itself. In contrast, neuropathic pain is defined as ‘Pain caused by a lesion or disease of the somatosensory nervous system’ (Taxonomy Committee of the International Association for the Study of Pain 2012). This newer and more restrictive definition of neuropathic pain omits the word dysfunction which was present in previous versions (Merskey and Bogduk 1994). Although this change has not met with universal support, it removes some of the ambiguity

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and confusion surrounding some pain conditions that were not believed to be associated with tissue trauma, but were believed to be due to dysfunction within the nervous system. It is also recognised that a large component of the pain experience is neither nociceptive nor neuropathic but arises from neuroplastic changes themselves (Coderre et al. 1993; Melzack et al. 2001). These neuroplastic processes, although secondary to the initiating event, are a hugely influential component of the pain experience. In fact, some pain conditions are believed to be more dependent on these neuroplastic changes than on nociceptive or neuropathic inputs and are described below. These issues regarding how pain is conceptualised are complex but have a fundamental and hugely important influence on how practitioners and other health professionals, family, and friends relate to people with pain. The health professional’s conceptual view of pain pathophysiology is at the heart of how pain is investigated, assessed, labelled, and treated, and even how the health professional empathises with the person in pain. This chapter will therefore explore the nature of these nociceptive, neuropathic, and neuroplastic components of pain and how they operate and interact. It will then briefly discuss the clinical implications of this framework for the assessment and treatment of pain.

Pain mechanisms The periphery The stimulus Nociceptive stimuli fall into three main groups: chemical, thermal, and mechanical. At least at the beginning, these stimuli need to be at a level sufficient to activate the specific receptors that are present to detect any stimulus that may be threatening. Therefore, this mechanism of peripheral detection serves us well to detect and respond appropriately to a potentially damaging stimulus (Hucho and Levine 2007). The peripheral receptor A group of highly developed and specialised receptors that detect noxious stimuli have now been recognised (Woolf and Ma 2007). These receptors, which in this context are termed nociceptors, are widespread in skin, muscle, connective tissues, blood vessels, and thoracic and abdominal viscera. Depending on the response characteristics of the nociceptor, stimulation results in propagation of impulses along the primary afferent fibre towards the spinal cord. Afferent fibres involved in nociception can be broadly divided into two main classes: myelinated and unmyelinated (Figure 2.1). Approximately 10% of cutaneous myelinated fibres and 90% of unmyelinated fibres are



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Primary afferent nociceptors C fibre nociceptor unmyelinated polymodal – responds to thermal, mechanical, chemical stimuli

STIMULUS A delta fibre nociceptor small myelinated high threshold mechanoreceptors mechanothermal receptors

Figure 2.1  The two main primary afferent fibre types involved in nociception.

nociceptive. The smallest diameter, thinly myelinated Aδ mechanothermal nociceptors have axonal diameters of 2–5 µm and conduction velocities of 6–30 m/s, and are involved in short-lasting, pricking-type pain. Unmyelinated C fibre polymodal nociceptors are less than 2 µm in diameter and have a conduction velocity of 0.5–2 m/s and are involved in dull, poorly localised, burning type pain. The receptors involved in nocieption are located in somatic regions, such as skin, as well as the viscera, and therefore may be involved in the perception of superficial, deep somatic or visceral pain. Visceral receptors display different response properties and in general respond well to chemical stimuli but poorly to mechanical stimuli other than stretch. The nerve cell bodies of the somatic sensory fibres are located in dorsal root ganglia, and together with the sympathetic or parasympathetic axons form the peripheral nerves. The number of afferent fibres is variable according to the area innervated, being relatively high in areas such as the lips or fingertips, but overall is low compared with the surface that is innervated, suggesting that pain will be poorly localised. Visceral afferents converge onto second order dorsal horn cells, which also receive cutaneous input. Convergence gives rise to the phenomenon of referred pain in dermatomal segments corresponding to their cutaneous innervations (Cervero and Belmonte 1996). Peripheral sensitisation The first pathophysiological change in the process of nociception is peripheral sensitisation (Hucho and Levine 2007). Almost any time a stimulus is strong enough to activate nociceptors, it also induces the process of inflammation. Even a relatively benign noxious stimulus such as a scratch to the skin initiates an inflammatory process in the periphery, and this then changes the response to subsequent sensory stimuli. The inflammatory response

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results in release of chemicals such as substance P, neurokinin A, and CGRP from the peripheral terminals of nociceptive afferent fibres. Release of these peptides results in a changed excitability of sensory and sympathetic nerve fibres, vasodilatation and extravasation of plasma proteins, as well as action on inflammatory cells to release chemical mediators. These interactions result in release of a ‘soup’ of inflammatory mediators such as potassium, serotonin, bradykinin, histamine, cytokines, nitric oxide, and products from the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism (Plate 1). These chemicals then act to sensitise high threshold nociceptors, which results in the phenomenon of peripheral sensitisation. The end result of these processes is a lowered threshold to stimulation and therefore sensitisation of the primary afferent fibre. Peripheral sensitisation is then a feature of nociceptive pain, and can also be present with nerve injury. It is almost always present when nociception occurs, and it contributes to the strength of the signal that will be transmitted towards the spinal cord. (See also Chapter 15.) Damage to the primary afferent Damage to primary afferents is a common cause of neuropathic pain. Causes include conditions such as postherpetic neuralgia, diabetic neuropathy, and other peripheral neuropathies. Trauma or disease involving peripheral nerves, the spinal cord, and brain all result in local changes that are believed to give rise to neuropathic pain. Local pathophysiological changes include upregulation of ion channels close to the site of injury and the dorsal root ganglion, and expression and release of neurochemicals such as neurotrophins (Plate 2). Upregulation of ion channels results in increased neuronal responsiveness, generation of ectopic activity, and increased glutamate release from the nerve terminal in the spinal cord (Campbell and Meyer 2006; Costigan et al. 2009; Zhuo 2007). Neurotrophin expression regulates the structure and function of the nerve, and the nerve may even undergo a phenotypic switch with large fibres expressing peptides found in nociceptive afferents (Pezet and McMahon 2006). All of these changes contribute to generation of signals that are then transmitted towards the brain (Rogawski and Loscher 2004). The link between nerve damage and neuroplasticity is so close that it is difficult to identify a form of neuropathic pain that does not involve neuroplastic changes (Navarro et al. 2007). Neuroplastic changes aimed at maintaining sensory input may occur at peripheral and spinal levels. At a peripheral level, nerve fibres undergo morphological and physiological changes. The damaged end of the nerve fibre sprouts and may produce a spontaneously firing neuroma (Plate 3). It may also demonstrate changed properties in response to various stimuli. These properties include sensitivity to mechanical stimuli, spontaneous firing, and sensitivity to noradrenaline. Similar changes occur within the cell body of the afferent nociceptor, the dorsal root ganglion. Reduction in blood supply to myelinated fibres results



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in demyelination and production of ectopic impulses. These impulses may give rise to the perception of sharp, shooting, or burning pain in conditions such as diabetic neuropathy. The spinal cord The dorsal horn Small myelinated Aδ fibres terminate principally in the superficial dorsal horn (lamina I) and in lamina V of the deeper dorsal horn. Unmyelinated C fibres and autonomic post ganglionic fibres terminate principally in lamina II. Some small diameter fibres also ascend and descend several segments in Lissauer’s tract before synapsing with neurons that project to higher centres. Within the dorsal horn, there is a complex interaction among afferent fibres, local intrinsic spinal neurons, and the endings of descending pathways from the brain. Two main classes of second order dorsal horn neurons are associated with sensory processing. The first class of neurons is termed nociceptive specific or high threshold. The second class of neurons is termed wide dynamic range (WDR) or convergent. These two classes of neurons have different response properties to afferent input and are located in different regions of the dorsal horn. Nociceptive responsive neurons are located within the superficial laminae of the dorsal horn and respond selectively to noxious stimuli. WDR neurons are generally located in deeper laminae and respond to both noxious and nonnoxious input. WDR neurons increase their firing rate in proportion to the intensity of the stimulus. Pharmacological studies have been important in identifying the many neurotransmitters and neuromodulators that are involved in pain processes in the dorsal horn. The excitatory amino acids glutamate and aspartate have a major role in nociceptive transmission in the dorsal horn. The excitatory amino acids act at NMDA, non-NMDA receptors such as AMPA , kainate and metabotropic glutamate receptors. A number of peptides that can also act as neurotransmitters are released by primary afferents and have a role in nociception. These include substance P, neurokinin A, and CGRP. Substance P and neurokinin A act on neurokinin receptors. There are many other receptors that are also involved in nociceptive transmission or modulation. These include the µ, κ and δ opioid receptors, and α adrenergic, GABA, serotonin (5HT), and adenosine receptors. (See also Chapter 12.) Neuroplasticity in the dorsal horn: central sensitisation High levels of nociceptive input result in an increased responsiveness of dorsal horn neurons (Mendell 1966). Therefore, in most clinical situations where there is prolonged nociceptive input, the high level of input leads to a ‘wind-up’ of spinal cord neuronal astrocytic and microglial activity and increased responsiveness. WDR neurons normally do not signal pain in response to a tactile stimulus at a non-noxious level, but if they become

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sensitised and hyper-responsive they may discharge at a high rate following an innocuous tactile stimulus. If the activity of the WDR neuron exceeds a threshold level following this stimulus, then the non-noxious tactile stimulus will be perceived as painful and give rise to the phenomenon of allodynia (Drew et al. 2001). It appears that non-NMDA receptors such as the AMPA receptor may mediate responses in the ‘physiological’ processing of sensory information. However, with prolonged release of glutamate or activation of neurokinin receptors, a secondary process occurs that appears to be crucial in the development of abnormal ‘pathophysiological’ responses to further sensory stimuli. This sustained activation of non-NMDA or neurokinin receptors primes the NMDA receptor so that it is in a state ready for activation. Activation of NMDA receptors appears to set in train a cascade of secondary events in the activated neuron. These events lead to changes within the cell that increase the responsiveness of the nociceptive system and lead to some of the phenomena described above. The NMDA receptor channel in its resting state is ‘blocked’ by a magnesium ‘plug’. Priming of the NMDA receptor by co-release of glutamate and the peptides acting on the neurokinin receptors leads to removal of the magnesium plug and subsequent calcium influx into the cell. This then leads to secondary events such as oncogene induction, production of pro-inflammatory molecules including nitric oxide (NO), and activation or production of a number of second messengers including phospholipases, cGMP, ecosanoids, and protein kinase C. These second messengers then act directly to change the excitability of the neuron or induce the production of oncogenes, which may result in long-term alterations in the responsivity of the cell (Plate 4). Demonstration of the phenomenon of wind-up has had a major impact on the current conceptualisation of pain (Ren 1994; Woolf 2010), but several caveats must be made in relation to its clinical relevance and application. First, wind-up in its original form was an electrophysiological laboratory phenomenon that was demonstrated using a controlled electrical stimulus (Mendell 1966). This does not mean that correlates have not been demonstrated in humans and that it is not relevant, but it is almost certainly different (ArendtNielsen and Petersen-Felix 1995). Also, wind-up is not the only process contributing to central sensitisation. Long-term potentiation (LTP) is an important physiological process involved in memory, and it may also be a contributor to pain. It has been demonstrated to occur in the spinal cord and there is reasonably strong evidence to support its involvement in nociception (Sandkühler and Liu 1998; Sandkühler 2000; Ji et al. 2003). LTP may not only be involved in nociception but may be more important clinically than wind-up because of its much longer duration of effect. Several other changes have been noted to occur in the dorsal horn with central sensitisation. First, there is an expansion in receptive field size ‘like ripples from a pebble in a pond’, so that a spinal neuron will respond to



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stimuli outside the region to which it would normally respond. Second, there is an increase in the magnitude and duration of the response to stimuli that are above the normal threshold. Third, there can be a reduction in threshold so that stimuli that are not normally noxious activate neurons that normally transmit nociceptive information. These changes may be important in acute pain states such as postoperative pain (see also Chapter 5) and in development of chronic pain. The recognition of wind-up has led to a surge of interest in approaches such as pre-emptive analgesia (Dahl 1994). Much of the philosophy and rationale behind pre-emptive analgesia lies in an attempt to reduce the development of ‘sub-acute’ or chronic pain by abolishing or reducing acute pain, thus preventing the changes associated with wind-up (Woolf and Chong 1993). Having said that, results in the clinic have not lived up to the theoretical rationale and there is still much debate about the clinical usefulness of pre-emptive analgesic approaches (Moiniche et al. 2002). It has also been demonstrated that morphological changes occur within the dorsal horn following peripheral nerve injury. Peripheral nerve injury results in a redistribution of central terminals of myelinated afferents with sprouting of these terminals from lamina IV to lamina II (Woolf et al. 1992). If functional contact is made between these terminals, which normally transmit non-noxious information, and neurons that normally receive nociceptive input, this may provide a framework for the pain and hypersensitivity to light touch (allodynia) that is seen following nerve injury. Regional and global hyperexcitability Central sensitisation usually leads to an increased responsiveness to subsequent inputs from the same region. For example, surgery will result in hyperalgesia in the surrounding area, or a person with an osteoarthritic knee may have increased pain with movement. However, there is also evidence that hyperexcitability related to central sensitisation may be regional or even generalised. For example, in complex regional pain syndrome, a whole limb is affected and there is an increased tone across multiple modalities including autonomic, somatomotor, and somatosensory (Wasner et al. 2003). There is also evidence that hyperexcitability may be generalised, with a global reduction in sensory thresholds (Lidbeck 2002). The reason for the global change in excitability is not known but may be due to genetic factors that set the general level of inhibitory tone. It can also be influenced by cognitive and emotional factors, which again modulate global levels of inhibition and excitation through descending modulatory pathways. Does spinal neuroplasticity become independent of pain? Sometimes wind-up is referred to with the idea that it becomes an independent or at least a very sustained process that continues to maintain pain after healing has occurred and the stimulus has been removed.

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There is little evidence to support this. The bulk of evidence suggests that central sensitisation reverses once inputs are reduced to their normal levels. Wind up is dependent on ongoing inputs. When the inputs stop, the responsiveness decreases to its original state within minutes (Mendell 1966). Most clinical evidence supports this observation. For example, in most situations, people who have a total hip replacement have relief of their pain following surgery. This is despite the fact that ongoing inputs from the hip, sometimes for many years, have presumably resulted in wind-up and sensitisation of dorsal horn neurons. The situation may be different in neuropathic pain where nerve injury results in direct and local, or indirect and distant, long-term plastic changes. In these circumstances, it may be justifiable to assert that neuroplastic changes occur that act as long-term generators of pain. However, in nociceptive pain conditions, there is little evidence to support the concept that the pain can be ‘centralised’ and therefore completely independent of peripheral inputs. Ascending spinal pathways Second-order projection neurons in the dorsal horn, as well as some in the ventral horn and region adjacent to the central canal region, project to supraspinal structures. Fibres may ascend one or two segments from their point of origin before crossing in the dorsal commissure. They then ascend predominantly in the contralateral anterolateral quadrant (ventrolateral funiculus) of the spinal cord, but a significant proportion travel ipsilaterally. Damage to the spinal cord Damage to the spinal cord through trauma or disease can also result in plastic changes that contribute to development of neuropathic pain. Direct damage at the site of spinal cord injury results in disruption of local inhibitory networks (Drew et al. 2004). Damage to the spinal cord can also result in enhanced microglial activity (Hains and Waxman 2006). These changes result in increased responsiveness and excitability of projection neurons and even abnormal spontaneous activity of neurons at higher levels. The brain Brain pathways Second-order neurons projecting from the dorsal horn along the spinal cord terminate in the thalamus and other structures such as the brainstem. These projections target brain regions that are involved in a variety of physiological processes. Some of these are relatively simple reflexes such as brainstem control of heart rate, blood pressure, and breathing. Others are more complex, such as coordinated midbrain responses that involve integrated somatomotor, vasomotor, and sudomotor responses to a perceived threat. Projections to the thalamus also connect with other neurons that relay to a complex network of regions that comprise the pain ‘matrix’ (Lee and Tracey



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2010; Tracey 2008). These regions are variably activated by different inputs that come together to comprise the complex discriminatory, evaluative, and affective perceptual experience that we know as pain. In addition to this perceptual experience, it is also important to remember that activation of brain regions results in a motor response that become enmeshed within the pain experience and result in observable behaviours. These include cognitive, emotional, and somatomotor responses that underlie how a person thinks, feels, and acts in response to nociceptive signals. The roles of different brain regions The effect of cortical stimulation and lesions on pain perception is confusing and intriguing. It has been known for many years that people who have had a complete hemispherectomy can have almost normal pain sensation. In the awake human, stimulation of the primary somatosensory cortex typically evokes non-painful sensations and it is very difficult to elicit sensations of pain. Neurosurgical lesions of cortical regions produce varying effects depending on the region ablated. Lesions of the frontal lobe and cingulate cortex result in a condition in which pain perception remains. However, the suffering component of pain appears to be reduced. The person with a lesion in these areas only reports pain when queried, and spontaneous requests for analgesia are reduced. Functional imaging techniques such as PET and fMRI have been helpful in elucidating supraspinal mechanisms of pain processing (Lee and Tracey 2010) (See also Chapter 7). However, there is a wide variation in the pattern of brain activation in response to a noxious stimulus, variation that may be due to the different stimuli used in different studies. Using both PET and fMRI techniques, painful stimuli result in activation of sensory, motor, premotor, parietal, frontal, occipital, insular and anterior cingulate regions of the cortex. While it is by no means clear, it has been suggested on the basis of functional brain imaging findings that the somatosensory region of the cortex is involved in evaluating the nature and location of the stimulus, posterior parietal regions of the cortex are involved in recognition of the potentially harmful nature of the stimulus, while the frontal and anterior cingulate cortices are involved in the emotional and cognitive response to pain including attention and response selection (Plate 5). This is in line with the division of higher neural centres involved in pain processing into those that are involved in the sensory-discriminative (somatosensory cortex) and the affective (cingulate cortex, prefrontal cortex, insular cortex, and parietal cortex) components of pain perception. Damage to the brain Damage to the brain can result in neuropathic pain. The classic example of this is central post-stroke pain. This usually occurs when a vascular episode results in damage to the thalamus or other regions and produces ongoing

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pain (Vestergaard et al. 1995). Mechanisms underlying central post-stroke pain are likely similar to mechanisms causing pain following spinal cord injury, with damage to local inhibitory circuits in the thalamus resulting in abnormal spontaneous activity and increased excitability of neurons involved in pain processing. Thalamic and cortical neuroplasticity Increased nociceptive input also results in changes at the brain level. These have been best demonstrated in the thalamus and somatomotor cortex. In the thalamus, very much like the spinal cord, increased inputs lead to an increased excitability and sensitisation of thalamic neurons (Anderson et al. 2006; Burstein et al. 2010). Again, thalamic neurons are under the control of local and distant inhibitory inputs, so that disruption to the inhibitory inputs can indirectly contribute to sensitisation of thalamic neurons. Increased nociceptive inputs also result in changes in the structure, organisation, and representation of cortical regions (Seifert and Maihofner 2011). Increased inputs appear to result in an increase in the cortical representation of the region that is pain. For example, in people with low back pain, there is an expansion of the cortical region representing the low back area (Flor et al. 1997). It has also been demonstrated that pain is linked to a decrease in grey matter volume due to neuronal loss in regions such as the thalamus and prefrontal cortex (Apkarian et al. 2004). The significance of this reduction in volume is uncertain but it may represent a reduction in local inhibition. Importantly for our understanding of neuroplasticity, this decrease in thalamic grey matter volume appears to reverse with a reduction in pain (Gwilym et al. 2010). Loss of afferent input as a result of nervous system injury leads to rapid and sometimes dramatic changes in the brain that are quite different from those seen with nociceptive pain (Seifert and Maihofner 2011). One of the earliest and best-known studies investigated the way the brain functions following amputation (Flor et al. 1995). Normally, the somatosensory cortex is tightly organised in the sensory homunculus. The sensory homunculus is organised so that the region of the somatosensory cortex responding to inputs from the feet is located close to the midline of the brain. Moving from the midline laterally, other parts of the somatosensory cortex in sequence respond to stimulation of the legs, torso, hands, and face. Following amputation, it has been demonstrated that the sensory homunculus reorganises so that regions of the cortex that normally respond to sensation from the missing hand now respond to inputs from the lip. The extent of reorganisation corresponds to the presence of pain and has also been demonstrated following spinal cord injury (Wrigley et al. 2009). This link between pain and brain reorganisation has led to use of the term maladaptive plasticity to describe what appears to be an unhelpful and possibly harmful neural response to nervous system damage (Flor et al. 1995; Knecht et al. 1998; Wrigley et al. 2009).



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Brain neuroplasticity: cause or consequence? One of the uncertainties regarding brain neuroplastic changes is whether they are independent contributors or simply a consequence of the pain. There is certainly emerging evidence that some brain changes seen in association with pain are reversed when the pain is removed. As mentioned above, the decrease in grey matter volume in the thalamus that is evidenced in people with osteoarthritis of the hip reverses following successful hip replacement (Gwilym et al. 2010). Also, the cortical reorganisation seen with amputation and loss of inputs appears to be reversible with a technique that stimulates the stump (Flor et al. 2001). Therefore, brain changes appear reversible and linked to pain, and may accompany rather than be a contributor to central sensitisation. Pain modulation For a century, considerable interest has focused on the presence of descending influences that modulate sensory and motor input (Sherrington and Sowton 1915). This concept was further developed by Melzack and Wall (1965) with the proposal of the ‘gate theory’. It is now known that there are powerful inhibitory (and facilitatory) influences on nociceptive transmission acting at many levels of the neuraxis. (See also Chapter 13.) Afferent impulses arriving in the dorsal horn initiate both inhibitory and facilitatory mechanisms that modulate the effect of subsequent impulses. Inhibition occurs through the effect of local inhibitory interneurons and descending pathways from the brain. In the dorsal horn, incoming nociceptive messages are modulated by endogenous and exogenous agents that act on opioid, α-adrenergic, GABA, and glycine receptors located at both preand postsynaptic sites. Both GABA and glycine are involved in tonic inhibition of nociceptive input, and loss of their inhibitory action can result in features of neuropathic pain such as allodynia (Drew et al. 2004). Although both GABAA and GABAB receptors have been implicated at both pre- and postsynaptic sites, it has been demonstrated that GABAA-receptor-mediated inhibition occurs through largely postsynaptic mechanisms (Persohn et al. 1991). In contrast, GABAB mechanisms may be preferentially involved in presynaptic inhibition through suppression of excitatory amino acid release from primary afferent terminals (Buritova et al. 1996). Descending inhibition from the brain may be activated by external factors such as stress, or by other manipulations such as acupuncture and spinal cord stimulation (Meyerson and Linderoth 2006; Sandkühler 2000). Descending influences arise from a number of supraspinal structures including the hypothalamus, periaqueductal grey (PAG), locus coeruleus, nucleus raphe magnus, and nucleus paragigantocellularis lateralis. They descend in the spinal cord in the dorsolateral funiculus (Fields and Basbaum 1994) (Plate 6). This descending modulation involves the action of a number of neurotransmitters.

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Serotonin and noradrenaline are released in the dorsal horn and, although there is some debate about the role of serotonin, both appear to have an important role in such descending modulation. Other transmitters that appear to be important are substance P, cholecystokinin, GABA, thyrotropin-releasing hormone (TRH), somatostatin, and enkephalin. Although the role of descending systems has been emphasised, there is also evidence for the modulation of ‘higher’ structures. For example, stimulation in the PAG can produce inhibition of the responses of neurons in the medial thalamus (Nandi et al. 2002). Although it is possible that this inhibition may occur through the activation of descending pathways, it indicates that there are multiple interactions at many levels of the nervous system.

Implications for the assessment of pain Pathology, pain, and neuroplasticity A number of studies show that there is a very poor relationship between routinely available pathology techniques and pain intensity. For example, in conditions such as low back pain there is a poor correlation between pain intensity and radiological findings (Jensen et al. 1994), and in conditions such as fibromyalgia it is difficult to identify peripheral pathology (Lidbeck 2002). These findings are sometimes translated to mean that peripheral pathology is not a significant contributor to pain in these situations and that therefore finding or treating a peripheral nociceptive generator is unhelpful. Even worse, people may revert to a more dualistic approach that in effect regards the pain in these situations as psychological rather than physical. Our understanding of neuroplasticity goes against both of these views. Pain is due to the interaction of peripheral inputs with the levels of central sensitisation that are present. This means that people who have features of nociceptive pain, but with only limited evidence of peripheral pathology that does not correspond with the level of reported pain, may still have a nociceptive generator. However, the level of central sensitisation may be such that it is producing amplification of the peripheral signal. This accounts for the variable relationship between identifiable peripheral pathology and pain report, but without leading to a disregard for identifying and treating a peripheral generator. It also reduces the propensity to label the pain as purely psychological. Therefore, assessment and treatment need to be directed at identifying and treating both factors rather than assuming that one is not present, or that its absence signifies some sort of ‘psychological’ and somehow unphysiological process. Assessing central sensitisation Despite the importance of central sensitisation, we currently lack simple objective methods of assessing it. This raises several questions. Are there



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objective measures that can provide an accurate indication of levels of central sensitisation? Are there clinical features, such as a heightened startle reflex or heightened deep tendon reflexes, that indicate increased generalised responsiveness and therefore global central sensitisation? Should objective measures such as quantitative sensory testing be used more frequently to assess sensory thresholds as a marker of regional or global sensitisation? Will spinal cord or brain imaging provide a tool for identification of functional changes that are linked to the presence of central sensitisation? It is also difficult to assess with any certainty the levels of emotional and cognitive factors that may be contributing to central sensitisation through alterations in descending controls. Possible future refinement in psychological assessment, central nervous system imaging, or use of other tools, may help unravel the basis of these changes. Whatever the answer, it is becoming increasingly clear that, particularly with persistent pain, the ability to accurately assess levels of central sensitisation in individuals is a crucial need that will aid our understanding of a person’s experience of pain and lead to better treatment. Assessing neuropathic pain Assessing neuropathic pain and trying to link clinical assessment to pathophysiological mechanisms has been an area of interest over recent years. Pain ‘phenotyping’ has been suggested as a method of identifying specific patterns of sensory signs and symptoms that may indicate specific pathophysiology. This approach is based on the premise that the mechanisms underlying a particular condition may relate more to the specific pattern or cluster of symptoms and signs than to the aetiology of the problem (Jensen and Baron 2003; Woolf 2004a). For example, it is known that people with diabetic neuropathy present with varying patterns of sensory symptoms, with thermal and mechanical hyperaesthesia and hypoaesthesia. Very careful assessment using quantitative sensory testing to identify sensory thresholds in many individuals has found these people can be grouped according to the symptom and sign profile (Baron et al. 2009). These patterns may hold clues in identifying particular mechanisms in individual subjects. This ‘mechanismsbased’ approach seeks to identify specific mechanisms in the hope that these mechanisms will respond to particular treatments (Woolf 2004a). Psychological processes and neuroplasticity Evaluation of psychological contributors is an extremely important component of pain assessment. Our psychological state has a major influence on central sensitisation and therefore on the experience of pain. This influence occurs through activation of descending controls from the brain that increase or decrease central sensitisation. Therefore, these descending influences ‘set the gain’ on the amount of amplification that occurs in the spinal cord (Price et al. 2006). These descending pathways are modulated by higher brain

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centres involved in cognitions and lower brain centres involved in mood. This directly links our cognitions and emotions that influence the strength and direction of descending controls and the level of amplification of incoming signals. This link between cognition and pain pathways/central sensitisation has strong implications for our assessment and treatment of pain. Identifying the presence and severity of cognitive and emotional factors that influence central sensitisation is an important part of assessment that enables clinicians to understand the interplay and relative mix of factors that may be involved in a person’s experience of pain. This understanding then leads to treatment, which can be directed according to the mix of peripheral and central factors that may be operating.

Putting it all together The concepts outlined above provide a model for the assessment of pain that is more aligned to underlying pathophysiological mechanisms than to the underlying clinical condition or even a division between nociceptive and neuropathic. Pain is seen to be driven by three interrelated and almost universally present factors: a peripheral signal (from a nociceptive or neuropathic generator), an amplifier (central sensitisation), and a gain-setter (descending controls) (Plate 7). If these factors are important for understanding and treating pain, then it is important to identify these different components. In practice, this means, first, identifying the likely nociceptive or neuropathic generator. Second, it is important to assess the levels of central sensitisation. This is likely to account for apparent differences between the signal from the generator and the final output. Third, it is important to assess the level of gain produced by descending controls. Psychological state is a strong determinant of the direction and strength of descending controls, and therefore careful psychological assessment that identifies and assesses levels of psychological factors known to influence descending controls, such as anxiety, catastrophising, and hypervigilance, will be important ingredients of pain evaluation. These steps are not without difficulties. We have no reliable method of objectively measuring the signal from the generator. In many people with chronic pain, non-neural tissue pathology can appear minor or undetectable using currently available investigative tools. Also, as mentioned above, we do not have reliable and objective measures of central sensitisation. Although we have tools to assess cognitive and emotional factors, we still have no accurate way of linking these to an individual’s experience of pain. It is to be hoped that we can make progress in all of these areas. Future diagnostic approaches may detect pathology that we are currently unable to detect. Also, it is possible and indeed likely that detection and quantification of central sensitisation and its relationship with psychological factors will



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greatly enhance our ability to unravel the complex experience of pain and provide better guidance for treatment. (See also Chapter 7.) Implications for the treatment of pain Several principles of treatment may arise from this approach. First, if present, we should treat nociceptive and neuropathic generators. Second, if central sensitisation is an important component, we should consider treatment directed at this process. Third, any psychological factors that are contributing to a change in the levels of amplification need to be addressed using interventions. In addition, the approach raises other points for consideration. First, treatment should address all of these factors, rarely one in isolation. Pain treatment requires a multifactorial approach that aims to reduce the signal, a reduction in central sensitisation and therefore the level of amplification, and a change in gain-setting through altering descending controls. Second, it means neither ignoring nor placing all hope in eliminating the peripheral generator. Peripheral generators are not irrelevant, but neither is it always possible to eliminate them entirely, and they need to be seen and treated in the context of central sensitisation. Third, psychological factors are hugely influential in the experience of pain as they can determine the level of gain. Strategies and treatments that change mood and cognitions, such as cognitive behavioural treatment, therefore can be powerful tools to change pain intensity. In fact, offering these treatments with pain reduction as a potential primary outcome may help enhance motivation and adherence.

Summary The experience of pain has multiple components that contribute in different ways. Although it may be stating the obvious, pain is not due to what is happening in the periphery or in the central nervous system; it is a mixture of nociception, neurological, and psychological factors. In addition, pathophysiological or ‘neuroplastic’ mechanisms are integral and hugely influential components of the pain experience that need to be taken into account. It is helpful to address the neuroplastic changes that occur in association with neuropathic or nociceptive inputs as well as the influence of descending controls on these changes. Consideration of all of these factors has the potential to provide a more balanced, more comprehensive, and therefore more successful approach to the treatment of pain.

Recommended reading Costigan M, Scholz J, Woolf CJ (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annual Review of Neuroscience 32, 1–32.

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Flor H, Nikolajsen L,Staehelin Jensen T (2006) Phantom limb pain: a case of maladaptive CNS plasticity? Nature Reviews Neuroscience 7, 873–881. Ji RR, Kohno T, Moore KA, Woolf CJ (2003) Central sensitization and LTP: do pain and memory share similar mechanisms? Trends in Neurosciences 26, 696–705. Sandkühler J (2000) Learning and memory in pain pathways Pain 88, 113–118. Taxonomy Committee of the International Association for the Study of Pain (2012) Pain Definitions. www.iasp-pain.org/Content/NavigationMenu/ GeneralResourceLinks/PainDefinitions/default.htm. Woolf CJ (2010) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15.

Chapter 3

Myofascial pain Peter T Dorsher

Introduction This chapter begins by introducing and defining the concept of myofascial pain and follows with a brief history of myofascial pain going back 2000 years. The traditional trigger point concept/model of myofascial pain is discussed, and how its findings mirror those of the acupuncture tradition. A neurogenic model of myofascial pain that incorporates the concept of neurogenic inflammation is then presented which correlates better with the clinical and physiological underpinnings of myofascial pain syndrome. The chapter also covers the relevance of metabolic considerations, exercise regimes, and other treatments for myofascial pain syndrome.

What is myofascial pain? Although the term myofascial pain syndrome (MPS) derives from the terms myo (muscle) and fascial (fascia), and by definition syndrome, it is a constellation of symptoms with no proven underlying aetiology. No single specific cause of MPS has been defined. Perhaps this is not surprising as there are over 600 muscles in the human body and many subtypes. Muscles, as part of the body’s musculoskeletal system, are the main agents of locomotor activity. They are also essential in glucose homeostasis (Sinacore and Gulve 1993), maintaining pH (Juel et al. 2003), and serve as an amino acid reservoir for protein synthesis and hepatic gluconeogenesis (Wolfe 2006). Muscles represent approximately 40% of total body weight, consume 54 kJ/kg/day of energy at rest (18% of body total) (Heymsfield et al. 2002), and use



33

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Section 1 – The person

approximately 15% of the cardiac output at rest, which may increase to 88% during maximal exercise (Hänninen and Ataly 1998). Myofascial pain is a symptom commonly seen in clinical practice and affects up to 85% of the general population (Simons 1996). One universitybased primary care clinic found that nearly a third of patients presented to their practitioner with pain, and of those 30% met the criteria for MPS (including having spontaneous pain, tender points in muscles with typical referred pain patterns for those muscles, and exacerbation of patients’ typical pain with examination of those trigger points) (Skootsky et al. 1989). In the United States alone, 100 million individuals were affected by chronic pain, with an economic impact conservatively estimated to be as high as US$635 billion per year, with half of that relating to loss of work productivity (Gaskin and Richard 2012). This expenditure exceeds the yearly costs for cancer, heart disease, or diabetes (Gaskin and Richard 2012). In Canada in 2005, myofascial trigger point (MTrP) injections were reported to be the second most common procedure after epidurals performed by anaesthesiologists treating chronic pain (Peng and Castano 2005). Thus, MPS is commonly seen in clinical practice and has major impact in terms of healthcare costs and morbidity to those individuals affected.

Historical perspectives The diagnosis and treatment of myofascial pain had been documented for thousands of years in texts such as The Yellow Emperor’s Classic of Internal Medicine (Neijing Suwen), published in approximately 200 BCE. (Zhu 2001). Based on at least 2000 years of clinical experience, it describes the causes of muscular pain: ‘Wind, cold, and dampness settle in the flesh and compress the flesh, making the fluids coagulate to become froth. The froth is affected by cold and condenses. The condensation extrudes the textures of the muscles to make them split. The splitting causes pain. The pain makes the blood converge. The convergence of the blood produces heat (inflammation). This is how the pains occur’ (Zhu 2001). Fast-forward to the mid-1800s in Germany, when Froriep first described MPS as ‘muscle calluses’ (Froriep 1843). By the 1930s, Lewis and Kellgren (1939) proposed that pain originating in a muscle could lead to the perception of pain at a point distant from the muscle. This is the first description of ‘referred’ muscle pain. In 1983, Travell and Simons published the first volume of Myofascial Pain and Dysfunction: The Trigger Point Manual, which systematically compiled various muscles’ common trigger points and their referred pain patterns (Plate 8) (Travell and Simons 1983). Travell and Simons (1983) defined a trigger point as ‘a hyperirritable spot, usually within a taut band of skeletal muscle or in the muscle’s fascia, that is painful on compression and that can give rise to characteristic referred pain, tenderness, and autonomic phenomena.’ Almost all of the approximately 250 common MTrPs described



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in Myofascial Pain and Dysfunction are used to treat pain conditions, with the only exceptions being the ‘cardiac arrhythmia,’ ‘belch button,’ and ‘causes diarrhea’ points (Travell and Simons 1983). Cutaneous, fascial, ligamentous, and periosteal trigger points can also develop in addition to those in muscles. Travell and Simons’ texts document, however, that except for a trigger point associated with the lateral collateral ligament of the knee, the common trigger points are all associated with muscles (Travell and Simons 1983; Travell and Simons 1993). Clinically, MTrPs are considered ‘active’ if they are producing pain, while ‘latent’ trigger points do not cause pain but may cause dysfunction (e.g. limited shoulder motion in frozen shoulder produced by subscapularis muscle shortening due to trigger points) (Travell and Simons 1983). MTrPs may be associated with a variety of autonomic effects including vasoconstriction, pilomotor response, ptosis, and hypersecretion (Travell and Simons 1983). Palpation of MTrPs can also sometimes result in referred autonomic phenomena (e.g. trapezius trigger points) and distortion of proprioception. Approximately a quarter of the common trigger points described by Travell and Simons (1983; 1993) also have somatovisceral effects. These include a sternocleidomastoid trigger point associated with chronic cough and an abdominal oblique trigger point associated with hiccups. Inherent in the definition of trigger points is that their symptoms can be reproduced via trigger point palpation or needling techniques applied to the affected muscles, and relieved with therapy (stretches, massage, injections, etc.) directed to those muscles. Although the presence of a local twitch response elicited through snapping palpation or needling was described as a diagnostic criterion, the lack of reproducibility of this clinical finding has generally led to the twitch response being considered non-diagnostic (Hsieh et al. 2000). While proper training in palpatory technique does increase the reproducibility of trigger point localisation between examiners (Gerwin et al. 1997), it otherwise shows fair to poor inter-examiner reliability (Hsieh et al. 2000). The difficulty in obtaining reliable diagnostic signs or tests for MTrP have made interpretation of the myofascial pain literature difficult and caused some experts to question the existence of MPS (Bohr 1995). Trigger point needling The practice of needle insertion to relieve pain was described by William Osler, the ‘father’ of modern medicine in his Principles and Practice of Medicine in 1905 (Osler 2009). Osler advocated use of ‘dry needling’ to treat back pain: ‘For lumbago acupuncture is, in acute cases, the most efficient treatment. Needles of from three to four inches [7.5–10 cm] in length (ordinary bonnetneedles, sterilized, will do) are thrust into the lumbar muscles at the seat of the pain and withdrawn after five to ten minutes. In many instances the relief is immediate and I can corroborate fully the statements of Ringer, who taught me this practice, as to its extraordinary and prompt efficacy in many instances.’

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The practice of deactivating MTrPs by dry needling or injections of local anaesthetics is long-standing and has many proponents. Travell and Simons (1983) consider that dry needling is as effective as injecting the points with local anaesthetic with or without corticosteroids. Some practitioners also inject homeopathic anti-inflammatories (e.g. Traumeel) or neurolytic agents (e.g. Sarapin) in trigger points, though there is no adequate clinical trial evidence to support their use (Reisner 2004). Travell and Simons (1983) endorsed dry needling for treatment of MTrP, and this treatment modality is increasingly incorporated into evolving physical therapy practice standards in the United States (Dommerholt et al. 2006). Some clinicians claim that dry needling is essentially the equivalent of acupuncture’s treatment of ah shi (‘that’s it’) tender points; others reject this view (Dommerholt et al. 2006). Acupuncture has also been shown to be efficacious in large controlled trials for treating chronic neck and back pain (Haake et al. 2007; Witt et al. 2006), and a recent study showed similar efficacy of acupuncture compared to trigger point injections with local anaesthetic in the treatment of MTrP (Gazi et al. 2011). Our group (Dorsher et al.) has documented that the common MTrPs described by Travell and Simons (1983; 1993) have essentially complete overlap with classical acupuncture points in terms of their anatomic locations, their clinical uses in pain and non-pain conditions, and the correspondences of myofascial referred pain patterns to acupuncture meridians (Dorsher and Fleckenstein 2008a; Dorsher and Fleckenstein 2008b; Dorsher and Fleckenstein 2009). Indeed, the MPS-referred pain patterns as described by Travell and Simons validate the concept of acupuncture ‘meridians’ (Dorsher 2009). The anatomic reason for the similarities of the two traditions is shown in Figure 3.1: whether one enters a muscle with a needle to reach a trigger point,

injection needle

target area for needle acupuncture needle

Figure 3.1  Mechanism of similarity of trigger point and acupuncture therapies for myofascial pain.



3 – Myofascial pain

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or reaches an acupuncture point by inserting a needle between muscle/fascial planes, the needle is likely to end up in the same anatomic location, at the neurovascular bundle coursing between muscle layers. The MTrP twitch response then could easily be explained as mechanical stimulation of an axon by a needle to produce a fasciculation (twitch) (Dorsher and Fleckenstein 2008a; Dorsher and Fleckenstein 2008b).

Current concepts and theories There are two theories proposed regarding the pathogenesis of MPS: the ‘integrated hypothesis of trigger point formation’ (Gerwin et al. 2004), and the neurogenic model. Integrated hypothesis of trigger point formation Myofascial pain theorists postulate that overstress of muscle produces muscle fibre damage and local hyper-contractility in the muscle. A resulting localised capillary constriction, accentuated by local sympathetic hyperactivity, produces muscle hypoperfusion. This in turn causes local muscle hypoxia, ischaemia and increase in pH, inhibiting local acetylcholinesterase activity. In combination with local muscle damage, such changes cause local release of pro-inflammatory mediators including substance P, CGRP, potassium, serotonin, cytokines, and bradykinin, which increase motor endplate activity and sensitise muscle nociceptors. Thus, profound alteration of motor endplate activity and activity/sensitivity of muscle nociceptors results in local muscle hyper-contractility (taut band) and tenderness/pain. The continuing peripheral afferent nociceptive input to the dorsal horn neurons and beyond can result in central sensitisation and subsequent wide dynamic range (WDR) neuron wind-up, leading to hypersensitivity, allodynia, and the referred pain phenomenon seen in active trigger points (Gerwin et al. 2004). There are several problems with this concept. Biopsies of MTrPs from patients with chronic myofascial pain have not demonstrated any consistent muscle pathology or inflammatory cells (Yunus et al. 1986). Though some authors have reported ‘contraction knots’ in trigger point histology (Simons and Stolov 1976; Pongratz and Späth 1997), this does not clarify if the local contraction is the cause or the effect of the pathophysiology. The hypothesis also does not clarify why clinically some trigger points become ‘active’ rather than ‘latent’, and suggests that MTrPs should occur anywhere in muscles. The anatomic locations of many common trigger point locations described by Travell and Simons (1983; 1993) have been replicated by multiple, independent researchers, which suggests trigger points seen in clinical practice are not randomly distributed throughout muscles. Finally, Shah and colleagues (2008) studied the biochemical milieu of MTrPs in the upper trapezius muscle and demonstrated marked elevated levels of pro-inflammatory mediators in

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active trigger points there when compared to normal controls. These mediators include bradykinin, substance P, CGRP, TNFα, IL1β, IL6, IL8, serotonin, and norepinephrine. An unexpected result, however, was the finding of lesser elevations of these pro-inflammatory mediators in their subjects’ clinically uninvolved gastrocnemius muscles (Shah et al. 2008). This suggests central sensitisation is occurring even in subjects with localised chronic myofascial pain. Neurogenic model of MPS The neurogenic model of MPS is consistent with the clinical and laboratory findings in MPS (and also fibromyalgia), and resolves the inconsistencies of the integrated hypothesis of trigger point formation. Central to this neurogenic model is the concept of ‘neurogenic inflammation’ (McDonald et al. 1996). Noxious peripheral stimulation of sensory fibres not only produces afferent information to the spinal cord, but efferent neural stimulation (axonal or dorsal root reflexes) through those same sensory fibres that produce local release of inflammatory mediators such as substance P and CGRP (McDonald et al. 1996). This release of bioactive substances in the periphery acts on mast cells, immune cells, and vascular smooth muscle there, resulting in local redness and warmth (due to vasodilation), swelling (due to plasma extravasation), and hypersensitivity – thus producing ‘neurogenic inflammation’. Thus, in the neurogenic model of chronic myofascial pain, excessive efferent output from the spinal cord segmentally from the ventral roots produces local muscle hyper-contractility (taut band), while segmental dorsal root and axonal reflexes produce efferent release of pro-inflammatory mediators there (‘neurogenic inflammation’) that cause local swelling, warmth, and hypersensitivity (Levine et al. 1985). There are many levels of evidence to support this model. First, a trigger point cannot exist in a muscle if its nerve supply (mixed sensory and motor) is transected – the resulting interruption of the nerve action potentials transmitted from the spinal cord anterior horn cells to the muscle’s neuromuscular junction prevents contraction of that muscle. An example: if the sciatic nerve is cut, the muscles it supplies become atrophic, atonic, insensate, and cannot develop MTrPs. Second, the neurogenic model of MPS explains why medications that have efficacy for treating neuropathic pain conditions such as anti-epileptics (gabapentin, pregabalin), tricyclic agents (amitriptyline), and SNRI medications (duloxitene, milnacipran) are more effective for treating chronic MPS symptoms than drugs that are highly efficacious for treating nociceptive (visceral and somatic) pain conditions, such as nonsteroidal anti-inflammatory agents and opioids. Third, the neurogenic model would also explain why Shah and colleagues (2008) found elevated levels of pro-inflammatory mediators in the gastrocnemius muscles far distant from the active trigger points in the trapezius mus-



3 – Myofascial pain

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cles of their subjects, as this demonstrates that subclinical central sensitisation producing mild neurogenic inflammation is occurring in distant, clinically uninvolved muscles in those patients. Patients having latent trigger points then experience only segmental spinal sensitisation without activation of ascending pain pathways (no pain perception) or WDR neurons (no adjacent spinal segment or central/brain sensitization). The excessive efferent outflow from the spinal cord at that spinal level activates the muscle fibres to produce a focal continuous muscle contraction (taut band) that in turn produces clinical symptoms of latent trigger points such as stiffness or restricted joint range of motion. Active trigger points would represent greater segmental sensitisation with not only the segmental muscle taut band but also activation of ascending pain pathways (pain perception) and WDR neurons to potentially produce spread of sensitisation to adjacent spinal segments and CNS/brain. The segmental sensory system involvement leads to neurogenic inflammation at the site of the trigger point. Fibromyalgia, then, can be viewed as widespread spinal and brain (limbic system) sensitisation producing widespread neurogenic inflammation that clinically results in widespread tenderness, muscle pain, organ sensitisation (endometriosis, interstitial cystitis, Raynaud’s like phenomenon, as examples), and limbic system sensitisation that produces sleep impairment, lower pain threshold, appetite changes, and mood changes. This central nervous system/limbic system hyperactivity has been confirmed on functional magnetic resonance imaging (fMRI). Fourth, the neurogenic model further explains why there are no inflammatory cells or macroscopic muscle abnormalities demonstrable in trigger point biopsies in chronic MPS. Finally, this model explains why the common trigger points as described by Travell and Simons (1983; 1993) and confirmed by other researchers occur independently: these common trigger points are postulated to exist at the sites of neuromuscular junctions of the skeletal muscles (where their efferent motor nerves terminate).

Diagnostic and other considerations in chronic myofascial pain Autoimmune and neoplastic considerations It is important to exclude serious medical illnesses that may present as regional or widespread pain. Autoimmune and neoplastic disorders must be considered in chronic regional or widespread pain, especially if clinical deterioration is progressive over time or pain is worse with recumbency. Autoimmune disorders such as polymyalgia rheumatica (PMR) may present with widespread muscle aching and stiffness (Schmidt 2009). PMR is associated with giant cell arteritis which can produce blindness if untreated, so early diagnosis is essential. Inflammatory markers, including erythrocyte

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sedimentation rate and C-reactive protein (CRP), are elevated, indicating systemic inflammation, and initiation of corticosteroid and prompt referral to a rheumatologist is indicated. Polymyositis or other inflammatory myopathies may also present with regional or widespread muscle pain (Schulze et al. 2009). Polymyositis may also be a paraneoplastic syndrome associated with undiscovered cancer. Elevated serum muscle enzymes (creatine phosphokinase, aldolase) and sedimentation rate/CRP with muscle weakness and tenderness are typical clinical findings. Beyond muscle pain from paraneoplastic syndromes as described above, widespread metastatic disease, or blood dyscrasias, such as multiple myeloma, can present with widespread muscle pain. Clinical symptoms often include unexplained fevers, recurrent infections, unexplained weight loss, and/or pain with recumbency, especially at night, along with progressive worsening of symptoms despite appropriate medical management. Thyroid abnormalities, especially hypothyroidism, can also present with muscle pain, though it is usually widespread rather than regional pain (Gerwin 2005). Hyperthyroidism can also present with muscle pain and weakness (Duyff et al. 2000). Fatigue, unexplained weight loss or gain, and depression or anxiety may be clinical symptoms, and appropriate pathology tests including thyroid hormone assays (thyroid stimulating hormone, T4, T3) can help establish this diagnosis. Parathyroid hormone abnormalities, especially as seen in haemodialysis patients (Golan et al. 2009), are associated with chronic pain including muscle pain. Low serum calcium levels are associated with muscle cramps. Abnormal serum calcium levels can help establish this as a potential contributing cause to the muscle pain. Rarely, chronic infections such as in Lyme disease, babesiosis, ehrlichiosis, toxoplasmosis, and hepatitis C may produce widespread or regional pain including myalgias and/or arthralgias (Gerwin 2005). Clinical suspicion and failure to respond to usual therapies for myofascial pain should make the clinician consider these entities in the differential diagnosis. Nutrition and vitamin deficiencies A variety of nutritional deficiencies have been implicated in the persistence of chronic myofascial pain. Vitamin D deficiency is associated with musculoskeletal pain among multiple other deleterious bodily effects, and a recent study of over 900 patients with neurologic disorders including chronic myofascial pain found 80% to be moderately to severely vitamin D deficient, with deficiencies more profound in females (Mohnot et al. 2012). Vitamin D deficiency may contribute to impaired neuromuscular functioning among patients with chronic pain, as well as contributing to poor physical performance and reduced exercise tolerance (Houston et al. 2011; Turner et al. 2008). Other vitamin deficiency states associated with chronic myofascial pain include B12 deficiency, which may be present in up to 20% of individuals over age 6 (Baik and Russell 1999).



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Deficiency of bodily iron stores (ferritin levels 90%) compared with gabapentin (bioavailability 35–60%). Pregabalin also has a slightly longer half-life, requiring 12-hour dose intervals rather than the 8-hour intervals required for gabapentin. Their role in treating neuropathic pain has led to interest in their possible use for acute pain management and in the possible prevention of chronic post-surgical pain. Gabapentinoids have been studied widely in the perioperative setting, but most of the individual studies have been small in numbers and doses used have been variable. This makes it difficult to draw conclusions about efficacy and optimal dosing regimens. Consistent findings when pregabalin or gabapentin are used perioperatively have been a reduction in opioid dose requirements and improved pain scores (Tiippana et al. 2007; Zhang et al. 2011). Other findings included a reduction in nausea and vomiting (possibly related to opioid sparing), but also an increase in visual disturbances or dizziness. When given as a single dose prior to surgery, typical doses are 900–1200 mg for gabapentin and 300 mg for pregabalin. In a meta-analysis of long-term outcomes, there was a modest benefit in reduction of chronic pain at 3–6 months following surgery with perioperative gabapentin (OR 0.52; 95% CI 0.27–0.98) and also pregabalin (OR 0.09; 95% CI 0.02–0.52) (Clarke et al. 2012). However, the results of this analysis have been questioned (Chelly 2013).

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α2 agonists Clonidine (parenteral/oral) is an α2 adrenergic receptor agonist that has weak analgesic properties in addition to local vasoconstrictor effects. Clonidine acts centrally as an antihypertensive agent and is a mild sedative and anxiolytic. For these latter effects it is often given orally as a premedicant prior to neurosurgery. Given intraoperatively, 100 mcg results in mild postoperative sedation and anxiolysis but it has minimal effects on analgesic requirements (Hidalgo et al. 2005). Its role systemically then is as a supplement to other more potent agents, but care is advised because of its contributory sedative effects. Another role for clonidine is as a supplement to prolong single-shot spinal anaesthesia or in addition to local anaesthetics in epidural infusions (Elia et al. 2008). Clonidine added to low-dose epidural bupivacaine improved movement-related pain relief after hysterectomy but was associated with mild systemic hypotension (Mogensen et al. 1992). Typical concentrations in epidural infusion solutions would be 2–5 mcg/mL. Clonidine has a similar effect to adrenaline when added to local anaesthetics for peripheral nerve blocks in prolonging their duration, however some benefits in anxiolysis may also be seen from systemic absorption. Dexmedetomidine (parenteral) is a potent α2 adrenergic receptor agonist with a relatively short duration of action (T1/2 approximately 9 minutes) and thus it needs to be given by intravenous infusion. It has similar properties to clonidine, but its main role is to induce mild sedation, as its analgesic efficacy is weak (Chrysostomou and Schmitt 2008). Adrenaline (epinephrine) has been used as an additive to local anaesthetics in epidural infusions at concentrations typically of 2 mcg/mL (Niemi and Breivik 2002; Niemi and Breivik 2003). When added to bupivacaine and fentanyl, a minimum concentration of 1.5 mcg/mL achieved improved block density and movement-associated analgesia compared with lower doses (Niemi and Breivik 2002; Niemi and Breivik 2003). The mechanism of action is likely to be similar to the spinal effects of clonidine without the centrally induced hypotension or drowsiness. This makes adrenaline a useful additive to epidural infusions. Local anaesthetic-based techniques Local anaesthetics form the basis of many analgesic strategies following major limb, trunk, or skeletal surgery. This is because local anaesthetic blocks or infusions can provide a targeted intense analgesia with minimal systemic side-effects. However, it should be recognised that effective regional analgesia requires skill to administer and maintain, and carries risks of its own. Neuraxial analgesia Spinal anaesthesia with a local anaesthetic will provide postoperative analgesia for the duration of the residual block, which typically is 4–6 hours following a single dose of intrathecal bupivacaine. Analgesia can be prolonged up



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to 18 hours by the addition of small doses of opioids, especially morphine (see above). However, for most major procedures, supplemental analgesic strategies are needed, such as IV opioid PCA or an ongoing epidural or perineural local anaesthetic-based infusion. Epidural analgesia provides superior acute pain relief for all types of procedures compared with IV PCA opioids (Block et al. 2003). Epidural local anaesthetic infusions reduce pulmonary infections and complications compared with parenteral opioids (Ballantyne et al. 1998; Pöpping et al. 2008), and because thoracic epidural analgesia improves bowel recovery and mobility after abdominal surgery it is a recommended part of the enhanced recovery protocols associated with colorectal surgery (Kehlet 2008). Epidural analgesia is usually maintained for 2–4 days using an indwelling catheter sited to the appropriate dermatomes. Thus, for thoracic surgery, the T5 to T7 vertebral level is used, whereas for orthopaedic surgery a lumbar level of placement is appropriate. The use of low concentrations of local anaesthetics (e.g. ropivacaine 0.2%) combined with opioids (e.g. fentanyl, see opioids above) results in the most effective analgesia (Scott et al. 1999). For the benefits of epidural analgesia to be realised, experienced nursing care overseen by qualified personnel (e.g. an APS or anaesthetist) is required. The quality of analgesia and level of block must be assessed regularly and the infusion adjusted as required. Despite its efficacy, complications of epidural analgesia cause great concern, especially those relating to spinal cord injury due to compression from an epidural abscess or haematoma. The risk of these events is extremely low (Cameron et al. 2007) – epidural haematoma being less than 1 : 5000 in non-obstetric patients and abscess less than 1 : 3000 (Moen et al. 2004). The keys to safe management are awareness and control of anticoagulation during catheter insertion, manipulation, and removal, meticulous asepsis during insertion and with dressing changes, and vigilant patient assessment with early intervention to diagnose and treat if required (Horlocker et al. 2010b). Any unexpected persistence or increase in motor blockade should be treated with suspicion, as should the presence of back pain or lower-limb neurological signs. Pyrexia coupled with a significant insertion site infection is also a cause of concern. In planning the most effective analgesia, risks versus benefits in the individual patient need to be borne in mind; however, consideration should likewise be given to the risks of alternative techniques, such as risk of OIVI with opioid PCA. Peripheral nerve and plexus blockade The use of perineural local anaesthetic blockade is increasing due to many factors, including the rise in short-stay patient admissions needing effective analgesia at discharge following relatively painful procedures (e.g. shoulder surgery), and the advent of ultrasound guidance, which facilitates accurate needle placement and decreases the risk of damage to adjacent structures (Abrahams et al. 2009; Cowlishaw et al. 2012). Perineural blockade is

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associated with a very low incidence of complications (Barrington and Snyder 2011) and, when patients are followed up systematically and rigorously, most neurological injuries relate to non-anaesthetic factors, with only 3 of 6069 patients having block-related nerve injury (Barrington et al. 2009; Borgeat et al. 2001). There is evidence that continuous perineural local anaesthetic infusions, regardless of catheter location, provided superior postoperative analgesia and fewer opioid-related side-effects (e.g. nausea and vomiting or pruritus) compared with parenteral opioid analgesia (Richman et al. 2006). Interscalene and supraclavicular brachial plexus blocks provide effective postoperative pain relief after shoulder or arm surgery. Suprascapular nerve block is also effective for less extensive procedures such as shoulder joint arthroscopy. A single-injection arm block will provide 8 hours or more of analgesia, and this may persist up to 24 hours. Patients can be disconcerted by arm weakness and numbness, and appropriate steps should be taken to protect the limb. Interscalene catheters can be used for either bolus dose ‘top-ups’ or infusions of local anaesthetic agents for up to 48 hours (Kean et al. 2006). Paravertebral blocks and catheter infusions provide effective analgesia following thoracic or breast surgery and are an alternative to epidural analgesia (Joshi et al. 2008; Kotze et al. 2009). They have the advantage of avoiding the neuraxis and causing less sympathetic blockade and thus less hypotension. Transversus abdominus plane (TAP) blocks provide a relatively low-risk option for analgesia following abdominal surgery, especially where the incision is unilateral and in the lower abdomen. Analgesia is not as effective as epidural infusions; however, it can be supplemented with other analgesics. TAP catheters can even be placed bilaterally. Femoral nerve catheters and sciatic nerve blocks are widely used for analgesia following knee joint arthroplasty or reconstruction. A femoral nerve catheter infusion with dilute local anaesthetic (e.g. 0.2% ropivacaine) can be usefully run for up to 48 hours after the surgery (Dauri et al. 2009). Femoral nerve block has been shown to provide comparable analgesia to epidural infusions following major knee surgery (Fowler et al. 2008). The major concern is motor blockade of the quadriceps muscles, which limits ambulation and rehabilitation. Provided that low concentrations of local anaesthetic are used from the beginning, and infusion rates are not high (e.g. M

Primary stabbing headache

–

–

–

any

V1

very severe

stabbing

F>M

Trigeminal neuralgia

?

–

–

1–3/night

15–30 min

generalised

moderate

throbbing

M=F

Hypnic headache

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8 – Migraine and other primary headache disorders

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Preventive treatments The options for preventive treatment in cluster headache depend on the bout length of a person’s cluster headache. Most experts would now favour verapamil as the first-line preventive treatment when their bout is prolonged, or if they have a chronic cluster headache, whereas limited courses of oral corticosteroids or methysergide can be very useful strategies for them when the bout is relatively short (May et al. 2006). Verapamil has been suggested as a useful option for the last decade and compares favourably with lithium. What has clearly emerged from clinical practice is the need to use higher doses than had initially been considered, and certainly higher than those used in cardiological indications. Although most people will start on doses as low as 40–80 mg twice daily, doses up to 960 mg daily and beyond are now employed. Side-effects, such as constipation and leg swelling, can be a problem, but more difficult is the issue of cardiovascular safety. Verapamil can cause heart block by slowing conduction in the atrioventricular node, as demonstrated by prolongation of the A-H interval clinically manifest as PR interval prolongation. It seems appropriate to do a baseline ECG and then repeat the ECG 10 days after a dose change, usually 80 mg increments, when doses exceed 240 mg daily. It is clear that the cardiac slowing effect can even be seen on a stable high dose of verapamil, so that checking the PR interval every 6 months while on therapy is appropriate (Cohen et al. 2007). Acute attack treatment In people with cluster headache, their attacks often peak rapidly and require a treatment with quick onset. Many people with acute cluster headache respond very well to treatment with oxygen inhalation. This should be given as 100% oxygen at 10–15 L/min for 15–20 minutes (Cohen et al. 2009). It is important to have a high flow and high oxygen content. Injectable sumatriptan 6 mg has been a boon for many patients with cluster headache (Ekbom and The Sumatriptan Cluster Headache Study Group 1991). It is effective, rapid in onset, and with no evidence of tachyphylaxis. Sumatriptan 20 mg (van Vliet et al. 2003) or zolmitriptan 5 mg (Cittadini et al. 2006) nasal sprays are effective in acute cluster headache, and offer useful options for people who may not wish to self-inject daily. Sumatriptan is not effective when given preemptively as 100 mg orally three times daily (Monstad et al. 1995), and there is no evidence that it is useful when used orally in the acute treatment of a person’s cluster headache. Medically intractable chronic cluster headache In recent years, neuromodulation approaches to this group of highly disabled people have been devised. The functional imaging (fMRI) finding of thalamic change in patients with chronic migraine treated with occipital nerve stimulation (ONS) led to its study in cluster headache (Matharu et al. 2004). Initial

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open-label experience suggests that two-thirds of otherwise medically intractable patients will have substantial improvement with ONS (Burns et al. 2007; Burns et al. 2009). Similarly, fMRI changes in cluster headache (Plate 11) lead to trials of deep brain stimulation that have also seen up to three-quarters of people with otherwise intractable headache respond positively (Leone 2006). Most recently, sphenopalatine ganglion stimulation has been studied (Schoenen et al. 2013) and seems promising, as does transcutaneous vagal nerve stimulation (Nesbitt et al. 2013). Neuromodulation is an area of active exploration for the treatment of people with medically refractory cluster headache (Nesbitt and Goadsby 2012).

Trigeminal-autonomic cephalalgias II – paroxysmal hemicrania Sjaastad first reported eight cases of a frequent unilateral severe but shortlasting headache without remission, coining the term chronic paroxysmal hemicrania (CPH) (Sjaastad and Dale 1974). A large series of 31 cases demonstrated a mean duration of attack of 17 minutes and a daily attack frequency of 11 (Cittadini et al. 2008). By analogy with cluster headache, the patients with remission have been referred to as having episodic paroxysmal hemicrania (Kudrow et al. 1987), about 20% of our series, and those with the nonremitting form are described as having chronic paroxysmal hemicrania. The overall syndrome can be simply called paroxysmal hemicrania (PH). The essential features of paroxysmal hemicrania are: • • • •

short-lasting attacks averaging about 20 minutes very frequent attacks, typically 10 or more per day marked cranial autonomic features ipsilateral to the pain robust, quick (less than 72 hour), excellent response to indomethacin.

The therapy of PH is complicated by gastrointestinal side-effects seen with indomethacin, although thus far there is no reliable option. By analogy with cluster headache, verapamil has been used in PH although the response is not spectacular; higher doses require exploration. We have seen topiramate be very helpful. PH can coexist with trigeminal neuralgia, PH-tic syndrome, just as in cluster-tic syndrome, and each component requires separate treatment. Secondary PH has been reported with lesions in the region of the sella turcica, an arteriovenous malformation, cavernous sinus meningioma, and a parotid epidermoid. Secondary PH is more likely if the patient requires high doses (> 200 mg/day) of indomethacin, and raised CSF pressure should be suspected in apparent bilateral PH. It is worth noting that indomethacin reduces CSF pressure by an unknown mechanism. It is appropriate to image patients, with MRI when practical, when a diagnosis of PH is being considered, looking particularly for pituitary gland changes, and to carry out tests of pituitary function (Levy et al. 2005).



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Trigeminal-autonomic cephalalgias III – SUNCT/SUNA SUNCT/SUNA are shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features. Sjaastad and colleagues (1989) reported three male patients whose brief attacks of pain in and around one eye were associated with sudden conjunctival injection and other autonomic features of cluster headache. The attacks lasted only 15–60 seconds and recurred 5–30 times per hour, and could be precipitated by chewing or eating certain foods, such as citrus fruits. They were not abolished by indomethacin. The paroxysms of pain usually last between 5 and 250 seconds, although longer duller interictal pains are recognised, as are longer attacks. The conjunctival injection seen with SUNCT is often the most prominent autonomic feature, and tearing may be very obvious. When both features are not present, the term SUNA has been proposed. SUNCT has been thought of as being difficult to treat, although in a large case series two-thirds of patients responded to lamotrigine and almost all patients respond acutely to intravenous lidocaine (Cohen et al. 2006). The essential features of SUNCT/SUNA are: • short-lasting attacks of pain typically lasting seconds • triggering of pain by cutaneous stimuli, such as touching, chewing, or the wind • no refractory period to pain triggering when present • prominent cranial autonomic features. Secondary SUNCT/SUNA and the differential diagnosis with trigeminal neuralgia The differential diagnosis turns around the degree of cranial autonomic activation, which may be seen to some degree in trigeminal neuralgia but is very prominent in SUNCT, and the lack of a refractory period to pain triggering in SUNCT/SUNA, whereas a refractory period is typical in trigeminal neuralgia.

Trigeminal-autonomic cephalalgias IV – hemicrania continua Hemicrania continua (HC) will join the TACs in the third edition of the International Classification of Headache Disorders based on the accumulation of clinical and neuroimaging data in recent years. Two patients were initially reported with this syndrome, a woman aged 63 years and a man of 53. They developed unilateral headache without obvious cause. One patient noticed redness, lacrimation, and sensitivity to light in the eye on the affected side. Both patients were relieved completely by indomethacin while other NSAIDs were of little or no benefit. As with the other TACs, HC can have remitting

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and unremitting forms. The essential features of hemicrania continua are (Cittadini and Goadsby 2010): • strictly lateralised continuous pain • fluctuations of pain that can be severe and are similarly lateralised • pain exacerbations that may be associated with cranial autonomic features in more than 90% of cases • complete resolution of pain with indomethacin. Indomethacin can be administered by injection. This can be blinded with an alternate injection of saline for the placebo-controlled indomethacin test, which is a safe and effective way to diagnose hemicrania continua. The alternative is a trial of oral indomethacin, initially 25 mg three times daily, then 50 mg three times daily, and then 75 mg three times daily. One should allow up to 2 weeks for any dose to have a useful effect. Acute treatment with sumatriptan is of no clear benefit in HC.

Chronic daily headache Each of the preceding primary headache forms can occur very frequently. When a patient experiences headache on 15 days or more a month, one can apply the broad diagnosis of chronic daily headache (CDH). CDH is not one thing but a collection of very different problems with different management strategies. Crucially, not all daily headache is simply tension-type headache (Table 8.4). This is a common clinical misconception in headache that confuses the clinical phenotype with the headache biotype. It should be said that population-based studies bear out clinical practice in that a large group of refractory daily headache patients overuse various over-the-counter preparations (Bigal et al. 2008). Chronic daily headache and migraine While it is widely accepted that some of the primary headaches, tension-type headache, cluster headache, and paroxysmal hemicrania, have chronic varieties, this question became unnecessarily troublesome for migraine from the 1940s through much of the twentieth century. Chronic (or frequent) migraine is simply the most troublesome and disabling end of the migraine spectrum, often associated with medication overuse. It seems not in question that the syndrome exists; the only argument concerns its prevalence. In the author’s clinical experience, in both the United Kingdom and the United States, it is the most common problem that is sent to headache clinics. The International Headache Society mandates 8 clear days of migraine or days treated with a triptan out of at least 15 days of headache to make the diagnosis (Olesen et al. 2006). From a pragmatic viewpoint, given the advice is no different in lifestyle or reduction in medication overuse, a simple



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Table 8.4  Classification of chronic daily headache Primary > 4 h daily Chronic

migrainea

< 4 h daily Chronic cluster

Secondary headacheb

Post-traumatic • head injury • iatrogenic Post-infectious

Chronic tension-type headachea

Chronic paroxysmal hemicrania

Inflammatory, such as • Giant cell arteritis • Sarcoidosis • Behçets syndrome

Hemicrania continuaa

SUNCT/SUNA

Chronic CNS infection

New daily persistent headachea

Hypnic headache

Substance abuse headache

a May be complicated by analgesic overuse. In the case of substance abuse headache, the headache is completely resolved after the substance abuse is controlled (Headache Classification Committee of The International Headache Society 2004). Clinical experience suggests that many patients continue to have headache even after cessation of analgesic use. The residual headache probably represents the underlying headache biology. b Chronic cluster headache patients may have more than 4 h per day of headache. The inclusion of the syndrome here is to emphasise that, by and large, the attacks themselves are less than 4 h duration.

approach is to diagnose chronic migraine in patients with 15 days or more of headache when there are any migrainous features, throbbing, lateralisation, photophobia, phonophobia, or movement aggravation. Management of CDH The management of CDH can be very rewarding. Most patients with medication overuse respond very sensibly when the problem is explained. The keys to managing daily headache are: • exclude treatable causes (Table 8.4) • obtain a clear medication use history • make a diagnosis of the primary headache type involved. Management of medication overuse – outpatients It is essential that analgesic use be reduced and eliminated. Patients can reduce their use either by, as an example, 10% every week or two, depending on their circumstances, or if they wish, and there is no contraindication, by immediate cessation of use. Either approach can be facilitated by first keeping a careful diary over a month or two to be sure of the size of the problem. A small dose of an NSAID, such as naproxen 500 mg twice daily if tolerated, will take the edge off the pain as the analgesic use is reduced. It is a useful aside that longer-acting NSAID use on a regular basis does not seem a reliable cause of daily headache (Bahra et al. 2003). When the patient has reduced their analgesic use substantially, a preventive is usually introduced. It must

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be emphasised that preventives generally do not work in the presence of medication overuse, so the patient must reduce the analgesics or the entire use of the preventive is a wasted effort. Naturally, some patients still respond (Diener et al. 2007). The most common cause of intractability to treatment is the use of a preventive when analgesics continue to be used regularly, and pragmatically one could adduce that in a patient who has failed more than three preventives, dosed adequately, and has medication overuse, there is a more than chance link. For some patients this is very difficult, and often one must be blunt that some degree of pain is inevitable in the first instance if the problem is to be controlled. Management of medication overuse – inpatient Some patients will require admission for detoxification. This is broadly two groups, those who fail outpatient withdrawal, and those who have a significant complicating medical indication, such as brittle diabetes mellitus or epilepsy, where withdrawal may be problematic as an outpatient. When such patients are admitted, acute medications are withdrawn completely on the first day, unless there is some contraindication. Anti-emetics that are nonsedative are preferred, specifically domperidone, oral or suppositories, 5-HT3 receptor antagonists, ondansetron or granesitron or aprepitant (Chou and Goadsby 2013), and fluids are administered as required to ensure adequate hydration, as well as clonidine for opioid withdrawal symptoms. For acute intolerable pain during the waking hours, intravenous aspirin (1 g intravenously) is useful, and at night chlorpromazine by injection (Weatherall et al. 2010). Most patients will then benefit from a 5-day course of intravenous dihydroergotamine (DHE) (Nagy et al. 2011). DHE is indispensable in this setting. Positive predictors of a good outcome are dose – more is better – and control of nausea, so each of the medications above should be employed. Preventive treatments Preventive treatment is entirely dependent on the underlying clinical problem. It is essential to make a diagnosis, such as chronic migraine or chronic cluster headache, and then use the preventive suitable to the patient and aimed at the underlying primary headache type.

New daily persistent headache New daily persistent headache (NDPH) is a clinically distinct syndrome with a range of important possible causes (Box 8.5). From a nosological point of view, all that is mentioned here could be placed variously in the International Headache Society classification; however, the term serves both patients and clinicians by highlighting a group of conditions some of which are curable. NDPH can have both primary and secondary forms (Box 8.5). The revised



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Box 8.5  Differential diagnosis of new daily persistent headache

Primary • Migrainous-type • Featureless (tension-type)

Secondary • • • • •

Sub-arachnoid haemorrhage Low CSF volume headache Raised CSF pressure headache Post-traumatic headache* Chronic meningitis

* includes post-infective forms

third edition of the International Classification of Headache Disorders improves on the second edition by allowing the most common primary phenotype – NDPH of a migrainous type. The extension here of the term for secondary headaches is clinically pragmatic. Clinical presentation NDPH patients present with a history of headache on most if not all days. The onset of headache is abrupt, often moment-to-moment, but in less than a few days, with three suggested as an upper limit. The classical history, if that term is yet appropriate, will be for the patient to recall the exact day and circumstances, so from one moment to the next a headache develops that never leaves them. This presentation triggers certain key questions about the onset and behaviour of the pain. The important issues arise from considering the differential diagnosis, particularly of the secondary headache forms. Although subarachnoid haemorrhage is listed for some logical consistency, as the headache may certainly come on from one moment to the next, it is not likely to produce diagnostic confusion in this group of patients. However, subarachnoid haemorrhage is so important that it must always pass by the diagnostic formulation, if only to be excluded, either by history or appropriate investigation. The issue of secondary NDPH has been covered elsewhere recently (Goadsby 2011). Primary NDPH Initial descriptions of primary NDPH recognised it to occur in both males and females. Migrainous features were common, with unilateral headache in about one-third and throbbing pain in about one-third. Nausea was reported in about half the patients, as was photophobia and phonophobia observed in about half. A number of these patients have a history of migraine, but not

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more than one might expect given the population prevalence of migraine. It is remarkable that the initial report noted that 86% of patients were headachefree at 24 months. It is general experience among those interested in headache management that primary NDPH is perhaps the most intractable and least therapeutically rewarding form of headache. In general, one can classify the dominant phenotype, migraine or tension-type headache, and treat with preventives according to that sub-classification, as for patients with chronic daily headache. Primary NDPH with a tension-type headache phenotype is very unresponsive to treatment.

Recommended reading Lance JW, Goadsby PJ (2005) Mechanism and Management of Headache. Elsevier, New York. Lipton RB, Bigal M (2006) Migraine and Other Headache Disorders. Marcel Dekker, New York. Olesen J, Tfelt-Hansen P, Ramadan N, et al. (2005) The Headaches. Lippincott, Williams & Wilkins, Philadelphia, PA.

Chapter 9

Neuropathic pain Philip J Siddall

Introduction Neuropathic pain often occurs following damage to the nervous system and may be a component of both acute and chronic pain conditions. Although the presentation of neuropathic pain does overlap with nociceptive pain, there are distinctive features that give clues to the presence of a neuropathic component. These differences in presentation suggest that damage to the nervous system results in specific pathophysiological changes. The reason for attempting to distinguish neuropathic pain in the clinic is that, traditionally, different treatment approaches are applied according to the clinical features presenting as neuropathic pain. These approaches are aimed at addressing the specific mechanisms underlying neuropathic pain. Although there appears to be increasing overlap in treatment approaches to nociceptive and neuropathic pain, some treatments appear to have greater specificity and efficacy for pain following damage to the nervous system. Therefore, an understanding of underlying mechanisms, alongside a systematic approach to identification and treatment of neuropathic pain, should result in an effective approach to management and hopefully provide best possible outcomes for people with neuropathic pain. This chapter will explore the concept of neuropathic pain, what makes it different from nociceptive pain, current understanding of the underlying mechanisms, methods of assessment, and current approaches to treatment.

Definition The International Association for the Study of Pain (IASP) previously defined neuropathic pain as pain initiated or caused by a primary lesion or

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dysfunction in the nervous system (Merskey and Bogduk 1994). This widely accepted definition includes conditions such as post-herpetic neuralgia, trigeminal neuralgia, central post-stroke pain, pain following spinal cord injury (SCI), and pain associated with diabetes mellitus. There is, however, some confusion in identifying whether conditions are nociceptive or neuropathic. The conditions listed above clearly fall into the neuropathic pain category and most people would agree that pains associated with appendicitis, renal colic, and osteoarthritis are nociceptive rather than neuropathic. However, although conditions such as fibromyalgia, irritable bowel syndrome, and complex regional pain syndrome (CRPS) type I are not the result of nerve injury, they exhibit features such as allodynia and hyperalgesia in which the person’s pain perception appears to be out of proportion to the stimulus. Therefore, it is generally considered that there must be a component of CNS dysfunction contributing to the pain. Clinical features such as hyperalgesia and allodynia that are suggestive of CNS dysfunction often lead to classification of pain as neuropathic. There are two problems with this approach. The first is that a person’s apparent disproportionate perception of pain to the stimulus may be attributed to CNS dysfunction and therefore labelled as neuropathic; the second is that if pathophysiological CNS changes are included as dysfunction, then nearly all persistent pain states would have to be included within this definition. In an attempt to resolve this issue, it was proposed that the term ‘neuropathic pain’ be confined to those conditions in which pain is initiated or caused by a primary injury to the nervous system (Max 2002). This more restricted definition has gained increasing acceptance. Its greater specificity does make it easier to apply in practice, and it may be more helpful from a diagnostic and treatment point of view in trying to group together conditions that share common pathologies (Treede et al. 2008). The IASP has now adopted the following definition of neuropathic pain: ‘Pain caused by a lesion or disease of the somatosensory nervous system’ (Jensen et al. 2011).

Clinical features and assessment The diagnosis of neuropathic pain relies on descriptors and signs, as well as techniques including quantitative sensory testing, nerve conduction studies, and imaging. Several questionnaires have also been developed to aid in the diagnosis and assessment of neuropathic pain, such as the Neuropathic Pain Scale (Galer and Jensen 1997), the Neuropathic Pain Questionnaire (Krause and Backonja 2003), the pain DETECT questionnaire (Freynhagen et al. 2006), the DN4 (Bouhassira et al. 2005), and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) (Bennett 2001). More invasive techniques such as nerve and skin biopsy may be useful in directly assessing the nature of nerve pathology (Lauria and Lombardi 2012).



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While traditionally neuropathic pain has been classified on the basis of aetiology, for example diabetic neuropathic pain, trigeminal neuralgia, postherpetic neuralgia, classification on this basis may not be the most helpful approach for determining effective treatment. Symptoms (spontaneous or evoked pain, paraesthesia, etc.) and signs (mechanical allodynia, thermal hyperalgesia, etc.) that may relate more closely to mechanisms may be more helpful in identifying appropriate treatment (Woolf et al. 1998). Symptoms and history The person with neuropathic pain typically describes spontaneous pain that can be divided into broad types. The first of these is a constant burning pain. The second is an intermittent shooting or electric pain. In addition, positive symptoms of paraesthesia and the presence of dysaesthesiae such as itching, crawling, and tingling are highly suggestive of a neuropathic component. Negative symptoms such as numbness suggest a nervous system lesion and are also a feature of neuropathic conditions typically occurring in or adjacent to a region of sensory disturbance, and may begin weeks, months, or even years following the initial insult to the nervous system. As well as these spontaneous symptoms, evoked symptoms of increased sensitivity to touch, clothing, wind, and temperature suggest the presence of neuropathic pain. This distinction between stimulus-evoked and stimulusindependent (spontaneous) pains may be useful in identifying different contributing mechanisms. As with nociceptive pain, nerve injury may be associated with a hyperreflexic or hypertonic state that involves not only alterations in sensory function but somatomotor and autonomic functions (Wasner et al. 2003). This condition commonly affects, but is not restricted to, a single limb with characteristic spontaneous pain, allodynia, changes in sweating (both increases and decreases), changes in skin colour (mottled, blue, red), changes in temperature (hot and cold), oedema, and tremor. Some people may progress with hair loss, muscle wasting, osteoporosis, and nail changes. If these changes are associated with nervous system injury, this constellation of somatosensory, somatomotor, and autonomic changes is referred to as CRPS type II (Stanton-Hicks et al. 1995), replacing the term ‘causalgia’. CRPS type I is defined when there is no evidence of nervous system injury. Although suggestive, there are no definitive diagnostic descriptors for a diagnosis of neuropathic pain (Rasmussen et al. 2004). For example, many nociceptive pain conditions also give rise to shooting and stabbing pain and pain with a burning quality. The diagnosis is strengthened by additional features of a nerve lesion such as numbness, paraesthesiae, and dysaesthesiae. Signs and physical examination Standard neurological examination, such as sensory, motor, and tendon reflex testing will identify negative signs suggestive of a neurological lesion. In addition, positive signs, such as mechanical and thermal allodynia and

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hyperalgesia, can be identified using examination aids such as cotton wool, brushes, a tuning fork, and tubes filled with cold and warm water. Once again, although positive features such as allodynia and hyperalgesia are present in neuropathic pain conditions, they are also present in nociceptive pain conditions and these features alone are not diagnostic of neuropathic pain (Backonja et al. 2013). Careful neurological examination of the person with neuropathic pain will often reveal selective loss of nerve fibre function, for example a loss of sensation to pin prick and cool but preserved or enhanced sensitivity to light touch. In people with incomplete nervous system injuries, sensory loss is commonly, although not always, confined to damage to ‘spinothalamic’ functions of pin prick and heat sensation. It has also been suggested that spinothalamic tract damage is necessary, although not sufficient, for development of neuropathic pain (Defrin et al. 2001). Other investigations Further assessment of a person with suspected neuropathic pain relies on other investigations that may enable the clinician to quantify sensory changes and determine the nature and location of the nervous system lesion. These include quantitative sensory testing, nerve conduction studies, somatosensory evoked potentials, computerised tomography and magnetic resonance imaging, and questionnaires, as mentioned above.

Aetiology Neuropathic pain due to a primary lesion to the nervous system can arise from a number of broad aetiologies, including trauma, infection, ischaemia, toxic damage, irradiation, inflammation, metabolic changes, immune-mediated effects, and compression (Box 9.1). Neuropathic pain is also subdivided on the basis of the site of pathology. That associated with damage to the peripheral nervous system is referred to as peripheral neuropathic pain, while damage associated with spinal cord and brain is often referred to as central neuropathic pain.

Prevalence While there is comparatively little information available regarding the overall prevalence of neuropathic pain, studies that have documented the prevalence of pain in conditions such as diabetic neuropathy (Ziegler et al. 1992), Herpes zoster (Haanpää et al. 1999), and SCI pain (Siddall et al. 2003), have found that between one-quarter and one-half of people with these conditions will experience chronic neuropathic pain, with a lower incidence of central post-stroke pain (8%) (Andersen et al. 1995) and a higher incidence of



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Box 9.1  Some clinical conditions in which neuropathic pain may be a feature

Peripheral nerve lesions • • • • • • • •

Neuroma (amputation, nerve transection) Nerve compression (tumours, entrapment) Nerve crush, stretching, incomplete section (trauma) Mononeuropathies (diabetes, irradiation, ischaemia) Polyneuropathies (diabetes, alcohol, amyloid, toxic) Compression (disc, tumour, scar tissue) Root avulsion (e.g. brachial plexus avulsion) Inflammation (e.g. post-herpetic neuralgia)

Spinal cord lesions • Contusion • Tumour • Hemisection

Brainstem, thalamus, cortex lesions • Infarction (stroke) • Tumour • Trauma

phantom limb pain (60–80%) (Nikolajsen and Jensen 2001). Other conditions not always associated with neuropathic pain have a relatively high prevalence, including multiple sclerosis (22%) (Osterberg et al. 1994), Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy (CIDP) (33%) (Moulin et al. 1997). It is also increasingly recognised that chronic pain frequently occurs postoperatively following mastectomy (Kroner et al. 1992), hernia repair (Callesen et al. 1999), and caesarean section (Nikolajsen et al. 2004), with most studies reporting an incidence of 10–20% (Perkins and Kehlet 2000). Although it is not always possible to demonstrate definitively, it is presumed that most, if not all, of these pains have a neuropathic basis. There is still uncertainty as to why some people develop neuropathic pain following nerve injury and others do not. Although some of the variability may be due to physical factors, such as the degree of scarring around the nerve and fibrosis, there is also increasing evidence that the development of neuropathic pain may be related to genetic factors (Inbal et al. 1980; Tegeder et al. 2006).

Mechanisms and pathophysiology Although neuropathic pain is referred to as a pain type, possibly suggesting a single contributing mechanism, a number of contributing mechanisms

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have been identified (Dworkin et al. 2003; Navarro et al. 2007; Woolf 2004a) at peripheral, spinal, and supraspinal levels. However, the relative importance of the contribution of these sites is the matter of some debate. In central neuropathic pain states, such as below-level neuropathic spinal cord injury pain and central post-stroke pain, peripheral mechanisms may play a previously under-reported role. Peripheral mechanisms Injury to peripheral nerves results in a number of changes that may contribute to the development of pain. These include: • Release of peptides such as substance P and calcitonin gene-related peptide from the distal end of damaged primary afferent nerves. Release of inflammatory mediators and cytokines may also sensitise nerve terminals, leading to peripheral sensitisation of adjacent primary afferents with increased inputs from these fibres. See also Chapter 15. • Alterations in the expression of neurotrophins that regulate the structure and function of the nerve (Pezet and McMahon 2006). These changes can alter the way that the damaged nerve responds to stimuli and communicates with other nerves. The nerve may even undergo a phenotypic switch and large fibres may begin to express peptides found in nociceptive afferents. For example, following sciatic nerve injury, there is increased expression of brain-derived neurotrophic factor (BDNF) in large primary afferent fibres that appears to be related to the development of neuropathic pain (Zhou et al. 1999a). • Upregulation and reorganisation of sodium channels in damaged primary afferents close to the site of injury as well as in the nerve cell bodies within the dorsal root ganglion (DRG). This can result in increased firing and the generation of ectopic activity and impulses that travel towards the spinal cord, and result in the transmission of signals towards the brain (Figure 9.1) (Rogawski and Loscher 2004). sodium channel expression

Dorsal horn

Figure 9.1  Ectopic activity generates signals at the damaged end of the primary afferent nerves and at the dorsal root ganglion



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Ca2+ Na Na Ca2+

Na

Ca2+

glutamate

Ca2+

Na

Figure 9.2  Nerve injury induces the expression of sodium and calcium channels (from Rogawski and Loscher 2004).

• Upregulation of voltage-gated calcium channels located on the DRG neuronal cell bodies and their satellite cells. Activation of the channels results in increases in calcium entry into the neuron, with a resulting increased release of glutamate within the neuronal cell bodies and satellite cells within the DRG and from the nerve ending (Figure 9.2) (Rogawski and Loscher 2004). • Expression of α adrenoceptors at the site of damage and in the DRG cell bodies and satellite cells (Hanani 2010a; Hanani 2010b) may contribute to the development of autonomic features that are a component of CRPS (Wasner et al. 2003). This may result in pathological coupling of sympathetic and primary afferent nerve activity (McLachlan et al. 1993; Zhou et al. 1999b). Receptors on the damaged nerve are responsive to circulating catecholamines and an increase in sympathetic activity may result in enhanced activity in primary afferent fibres. Spinal mechanisms Changes may also occur at a spinal cord level as a result of direct damage or secondary to peripheral changes. These include a reduction in local inhibition, central sensitisation, structural changes, and glial activation. Changes in inhibition A reduction in local inhibition may occur due to direct spinal cord damage, loss of neighbouring inputs, or secondary dysfunction of inhibitory processes in the spinal cord (Knabl et al. 2008). Under normal conditions sensory inputs are subject to inhibition from neighbouring inputs. This ‘surround inhibition’ mediated primarily through GABA inhibitory mechanisms acts to dampen activity in neighbouring regions and is similar in concept to the gate control theory. Damage to peripheral nerves and the spinal cord has been shown to

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result in changes in GABA content and receptors in the dorsal horn and thalamus. Loss of inputs or ‘deafferentation’ results in a loss of inhibition and increased responsiveness in adjacent receptive fields. This may explain the allodynia and hyperalgesia that is commonly observed adjacent to the region of sensory loss. Loss of inhibition may also result in spontaneous activity of sensory neurons. This means that loss of inputs may result in spontaneous activity of transmission neurons that is experienced as spontaneous pain in the region where sensation is now absent. Central sensitisation Central sensitisation may occur as a result of both increased inputs and reduction in inhibition or an increase in facilitation. Release of glutamate from the terminals of primary afferents will result in activation of AMPA receptors. Sustained release of glutamate and depolarisation of the cell membrane will remove the magnesium plug from NMDA receptors and allow influx of calcium ions. Release of substance P will activate neurokinin 1 receptors, which will indirectly increase intracellular calcium. With the increase in intracellular calcium comes a cascade of events, such as increased production of nitric oxide and activation of protein kinase C, which will phosphorylate the NMDA receptor and further increase its excitability. All of these changes contribute to the development of central sensitisation and an increased responsiveness of second-order neurons to further inputs. This process may underlie the allodynia and hyperalgesia evident on clinical examination. Central sensitisation is largely a function of the combination of inputs and the direction and extent of modulation of those inputs. Thus, conditions in which there are strong nociceptive inputs and/or facilitation of inputs will result in central sensitisation, and central sensitisation may occur with neuropathic pain but is not specific to it. Structural changes Structural changes, including nerve fibre sprouting and synaptic remodelling that is closely interlinked with functional changes, including increased responsiveness, may occur as a result of altered neurotrophin release following nerve injury, and may contribute to the development of neuropathic pain. Although there has been recent debate about the relevance of the finding for the clinical situation, animal studies have demonstrated that damage to primary afferent nerves results in sprouting of large fibres transmitting touch simulation into regions of the dorsal horn that transmit pain (Woolf et al. 1992). This abnormal connection between fibres transmitting touch and central nerve pathways that transmit painful stimuli to the brain has been hypothesised to present a mechanism underlying allodynia. Altered neurotrophin production and release may also result in changes in receptor and neurotransmitter expression and function and alter the responsiveness of sensory neurons (Gardell et al. 2003).



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Glial cell

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Release of: Proinflammatory cytokines e.g. interleukin 1 beta Glutamate Nitric oxide ATP

glutamate neurotrophins Presynaptic

Postsynaptic

Figure 9.3  Glial cell activation results in the release of chemicals contributing to neuronal sensitisation.

Glial activation Glial activation – which includes activation of neuroglia such as the astrocytes and the resident microglia of haemopoietic origin – may result in the release of proinflammatory cytokines such as IL1β and other neurochemicals, such as glutamate, nitric oxide, and adenosine triphosphate (Figure 9.3). Release of these molecules from glial cells in the spinal cord and thalamus may contribute to central sensitisation and amplify signals going from the periphery to the brain (Hains and Waxman 2006). Supraspinal mechanisms As well as changes at a peripheral and spinal level, there is evidence that changes at a supraspinal level may contribute to neuropathic pain. Loss of descending inhibition following damage to descending inhibitory pathways may lead to increased responsiveness of spinal neurons. Under normal conditions, sensory inputs are subject to inhibition from descending pathways from the brain. These descending pathways arise from the brainstem and involve transmitters, such as noradrenaline and serotonin (5HT), and make connections in the dorsal horn that modulate the amount of information transmitted to the brain. Activation of descending facilitation may also contribute to neuropathic pain (Suzuki et al. 2004b). Descending pathways can produce facilitation of inputs at a spinal level as well as inhibition. It is believed that with some neuropathic pain conditions there is a ‘switching on’ of descending facilitatory pathways that results in amplification of inputs at a spinal or supraspinal level. Hyperexcitability of neurons in supraspinal pathways may alter the way that the brain processes incoming information from the periphery. For example, functional imaging studies demonstrate a decrease in activity in the thalamus of people with neuropathic pain (Hsieh et al. 1995), with loss of inhibitory chemicals such as GABA (Ralston et al. 2000) and increased responsiveness of cells to touch (Gerke et al. 2003). These findings suggest that brain

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regions upstream of the injury are altered in response to nerve injury signalling and may contribute to the presence of pain. Synaptic remodelling occurs following nerve injury. As well as changes in the function of cells in the brain, the brain is plastic and attempts to reorganise rapidly within minutes following loss of inputs (Calford and Tweedale 1988) to compensate for the loss of inputs. However, functional brain imaging such as magnetoencephalography (MEG) and fMRI studies suggest that this reorganisation may be maladaptive and there may be a link between the extent of reorganisation and the development of pain (Flor et al. 1995; Wrigley et al. 2009).

Treatment A range of treatments are used in the management of neuropathic pain but obtaining effective long-term relief is notoriously difficult (Attal et al. 2006; Dworkin et al. 2003; Haanpää et al. 2011). Interestingly, a review by Finnerup and colleagues (Finnerup et al. 2010) found a large increase in the number of trials but little gain in terms of efficacy when compared with a review they had done in 2005 (Finnerup et al. 2005). Treatments that are effective in reducing nociceptive pain, such as simple analgesics, opioids, and NSAIDs, have traditionally been regarded as ineffective in the treatment of neuropathic pain. Pharmacological treatment of neuropathic pain has relied more on the use of so-called ‘adjuvant medications’. These include tricyclic antidepressants, anticonvulsants, local anaesthetics, NMDA antagonists, and α adrenergic agonists. Unfortunately, controlled studies demonstrate that the best of these drugs will only produce a positive response (around 50% relief of pain) in about one-third to one-half of people with a persistent neuropathic pain condition (Finnerup et al. 2010). Often these drugs are used in combination because they have different modes of action. Apart from medications, other approaches, such as stimulation techniques, spinal drug administration, and ablative techniques, are used. The recent evidence on brain reorganisation has also opened exploration of other techniques using physical and psychological approaches. There are no drug treatments currently available that consistently provide effective relief in the treatment of CRPS type II (Kingery 1997). The pharmacological treatment of CRPS type II largely relies on the use of drugs generally used in the treatment of neuropathic pain as described below (Wasner et al. 2003). Several other treatments have been demonstrated to have efficacy specifically in the management of CRPS, including oral glucocorticoids and intravenous bisphosphonates. Topical preparations A number of topical preparations are also used in the treatment of neuropathic pain. The evidence in support of these ranges from a positive result



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with a randomised controlled trial (RCT) of lignocaine (lidocaine) patches in the treatment of post-herpetic neuralgia (Rowbotham et al. 1996) to mixed results – some positive but some negative RCTs – with capsaicin and clonidine patch. Some compounding pharmacists make up creams containing mixtures of agents such as ketamine, amitriptyline, and gabapentin. While the rationale for systemic use of these agents is clear, the usefulness of these agents applied topically is uncertain. Opioids It is often stated that opioids are ineffective in the treatment of neuropathic pain. This view has shifted and most regard opioids as relatively ineffective. There is certainly good evidence that systemic opioids are effective in relieving a range of neuropathic pain conditions if high enough doses are given (Rowbotham et al. 1991). It is more difficult to obtain effective long-term relief with oral opioids. However, once again it is often stated that it is possible with high enough doses, and morphine and oxycodone have been shown to be effective in reducing pain associated with post-herpetic neuralgia and diabetic neuropathy. However, it may be difficult to obtain satisfactory relief without significant side-effects, and tolerance develops over the long term. See also Chapter 12. Methadone has some NMDA antagonist action and this has been suggested as a rationale for its use in neuropathic pain. Oxycodone appears to act on specific opioid receptors that are formed following nerve injury, and this may be an explanation for its increased effectiveness. Tramadol may also have increased effectiveness because of its serotonergic and noradrenergic actions. It has been demonstrated to be effective in the treatment of diabetic neuropathic pain (Harati et al. 1998) and post-herpetic neuralgia (Boureau et al. 2003). Tramadol can have side-effects, such as headache, dizziness, nausea, and drowsiness, and caution must be exercised in administering it in conjunction with other drugs that increase serotonergic activity, such as tricyclic antidepressants or SSRIs, as serotonergic syndrome can occur. If opioids are used for treatment of chronic pain, the preference is for long-acting formulations. NMDA antagonists NMDA antagonists have been used widely in the treatment of neuropathic pain (Sang 2000). The NMDA antagonist that is used most widely is ketamine. Generally, this is only used parenterally, but intravenous and subcutaneous administration has been shown to be effective in a range of neuropathic pain conditions, including neuropathic SCI pain, post-herpetic neuralgia, and phantom limb pain (Hocking and Cousins 2003). Side-effects of dysphoria limit its use. A limited number of NMDA antagonists are available orally. Dextromethorphan has been used most widely, but results are generally disappointing, and it may produce side-effects, such as cognitive impairment, ataxia, and sedation. Although a positive response was obtained in a study of

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people with diabetic neuropathy and pain (Nelson et al. 1997), two other studies in central post-stroke pain and post-herpetic neuralgia were negative (Sang et al. 2002). Memantine (Sang et al. 2002) and amantadine are newer NMDA antagonists that have been used but with limited evidence of efficacy. Local anaesthetics Parenteral (intravenous or subcutaneous infusion) lignocaine (lidocaine) has been used for the treatment of a number of neuropathic pain conditions with positive results in RCTs: post-herpetic neuralgia, diabetic neuropathy, central post-stroke pain, and neuropathic SCI pain. As mentioned above, a local anaesthetic (lidocaine) patch has also been developed and has been demonstrated to result in good relief of pain in people with post-herpetic neuralgia (Rowbotham et al. 1996). Unfortunately, there are no good oral forms of these agents. Mexiletine is a local anaesthetic related drug but has been used with generally poor results in clinical trials. An RCT in people with diabetic neuropathy was positive, but studies in people with central post-stroke pain and neuropathic spinal cord injury pain (Chiou Tan et al. 1996) were negative. Antidepressants Tricyclic antidepressants, such as amitriptyline, imipramine, and nortriptyline, have been widely used in the treatment of neuropathic pain. There is evidence of efficacy in the treatment of diabetic neuropathic pain, post-herpetic neuralgia, and nerve injury pain, and numbers needed to treat are among the lowest of all agents used in the treatment of neuropathic pain (around 2–2.5) (Fishbain 2000; McQuay et al. 1996). Their pain-relieving effect is separate from their mood-altering effect, and they are used at lower doses (10–75 mg/day) for treating pain. It is believed that they primarily work through an increase in availability of central noradrenaline and serotonin, but they have a number of other actions that may contribute to their analgesic effect. However, the mixture of serotonergic and noradrenergic effects appears to be important for analgesic efficacy, as SSRIs are less effective in relieving pain. Unfortunately, their wide-ranging action results in sideeffects, such as dry mouth, constipation, blurred vision, sedation, and weight gain, which may limit their use. More recently, selective serotonin and noradrenaline reuptake inhibitors, including venlafaxine and duloxetine, have been developed and show promise in a number of neuropathic pain states, including diabetic neuropathy (Goldstein et al. 2005). These mixed reuptake inhibitors appear to have better efficacy than the SSRIs. Anticonvulsants Anticonvulsant medications have also been used extensively in the treatment of neuropathic pain (Tremont-Lukats et al. 2000). These include the ‘older’ anticonvulsants, such as phenytoin, sodium valproate, and carbamazepine,



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and ‘newer’ anticonvulsants, such as gabapentin, lamotrigine, pregabalin, and topiramate. Anticonvulsants have a wide variety of actions, including sodium channel blockade (lamotrigine, phenytoin and carbamazepine), inhibition of glutamate release (lamotrigine), increasing the availability of GABA (valproate), and block of voltage-gated calcium channels (gabapentin and pregabalin) (Rogawski and Loscher 2004). The older anticonvulsants are associated with a high incidence of drowsiness and dizziness and can affect liver function (carbamazepine, valproate). The newer anticonvulsants have provided a slight improvement in efficacy. Their suggested advantage is an improved side-effect profile. However, they still result in unacceptable drowsiness and dizziness in some people, and lamotrigine can produce a severe rash. In terms of efficacy, the best evidence is for carbamazepine (trigeminal neuralgia, diabetic neuropathy), gabapentin (diabetic neuropathy, post-herpetic neuralgia, phantom limb pain, Guillain-Barré syndrome, neuropathic SCI pain), lamotrigine (HIV neuropathy, trigeminal neuralgia, diabetic neuropathy, central post-stroke pain) and pregabalin (postherpetic neuralgia, diabetic neuropathy, neuropathic SCI pain). Other agents include oxcarbazepine, which has been shown to be efficacious in diabetic neuropathic pain, and topiramate, for which there is little evidence and which has been shown to be ineffective in treating diabetic neuropathic pain. α adrenergic agonists α adrenergic agonists are primarily administered centrally either by the epidural or intrathecal route, although there is some evidence that they may be effective either topically or systemically. The main drug in this class is clonidine, although tizanidine is another agent that is available in some countries. Spinal clonidine may also be administered in combination with opioids such as morphine and appears to have an additive or synergistic action that improves efficacy. Epidural clonidine may also provide relief in some people with CRPS. Cannabinoids Some people state that recreational drug use with marijuana relieves neuropathic pain. However, studies examining the effectiveness of cannabinoids have been disappointing. A few studies found a modest effect in people with multiple sclerosis (Rog et al. 2005; Svendsen et al. 2004; Novotna et al. 2011), and another found a small effect in peripheral neuropathic pain (Selvarajah et al. 2010). Neural blockade techniques Injection of local anaesthetic and steroid around peripheral nerves, nerve roots, and plexi may be beneficial, particularly where there is a relatively short-term inflammatory process. However, the benefit of nerve blockade in well-established neuropathic pain conditions is limited.

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For many years, treatment of CRPS relied on sympathetic blockade by blockade of sympathetic ganglia or by regional intravenous administration of agents that deplete noradrenaline, such as guanethidine, reserpine, or bretylium. However, poor long-term response, particularly in chronic cases, has resulted in decreasing reliance on these interventional approaches. Stimulation techniques Stimulation techniques, such as transcutaneous electrical nerve stimulation (TENS), peripheral nerve stimulation, acupuncture, spinal cord stimulation, deep brain stimulation, and motor cortex stimulation may benefit some people. Although many of these techniques are widely used, the evidence for all of these approaches is limited. TENS is non-invasive and simple to apply, but outcomes from clinical trials in the treatment of neuropathic pain are mostly disappointing. Acupuncture has been used for a number of neuropathic pain conditions with some success. Spinal cord stimulation is more invasive but evidence mostly from case series suggest it is effective in some people with neuropathic pain particularly affecting the limbs (Kumar et al. 1991), and there is increasing evidence that it may provide symptomatic relief in people with CRPS. Deep brain stimulation is very invasive with potential for major morbidity, and is used infrequently (Kumar et al. 1997). Motor cortex stimulation has been used in various forms to treat neuropathic pain (Brown and Barbaro 2003). Epidural stimulation has been reported to be helpful but is very invasive. There has been more recent interest in two forms of non-invasive stimulation, repetitive transcranial magnetic stimulation and transcranial direct current stimulation. There is evidence that both of these forms of cortical stimulation result in pain relief, although the evidence for a long-term effect is still lacking (Rosen et al. 2009). Spinal drug administration As mentioned above, failure of oral administration of drugs may lead to consideration of spinal administration. There is some evidence that spinal administration of morphine and clonidine may be effective in some people with neuropathic pain (Siddall et al. 2000). However, consideration also needs to be given to the side-effects and issues associated with long-term spinal administration of opioids, including dose escalation and hormonal effects. Ablative techniques Ablative techniques have often been proposed as a solution for people suffering from neuropathic pain. These include removal of a neuroma, dorsal rhizotomy, neurectomy, spinothalamic tractotomy, cordectomy, and destruction of various brain regions. The rationale is sometimes based on the false premise that severing a nerve or tract will stop inputs and provide longterm relief of pain. However, almost always, relief is temporary. Regrowth



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of a neuroma and other plastic changes within the nervous system mean that pain usually recurs with 6–12 months. Therefore, ablative techniques are usually reserved for situations in which the expected life-span of the patient is relatively short. The main exception is dorsal root entry zone (DREZ) lesions (Sindou et al. 2001). This procedure ablates the region where primary afferent fibres enter the dorsal horn, and good relief can sometimes be obtained in people with neuropathic pain associated with brachial plexus lesions. Psychological and functional approaches As with other types of chronic pain, neuropathic pain has a strong impact on physical, emotional, and social functioning (Haythornthwaite and BenrudLarson 2000). The demonstration of a link between CNS reorganisation and neuropathic pain and the reversibility of the reorganisation has led to an interest in the use of functional programs that aim to restore normal inputs to the brain. This can include sensory stimulation or even ‘tricking’ the brain into believing there are inputs by use of techniques such as a mirror box or visual illusions (Moseley 2007). Although interesting and potentially useful, the evidence for such techniques is still limited. Psychological techniques such as distraction and desensitisation may be useful. For CRPS, the best functional outcomes appear to be obtained by using approaches that alleviate symptoms in combination with physical therapies applied in a functional rehabilitation program. Despite the large number of approaches that are used in the treatment of neuropathic pain, there is still no treatment that will provide reliable, adequate, and sustained relief of pain. Therefore, approaches that improve the ability of the person to manage and cope with their pain are useful. Gains are usually confined to functional outcomes, such as improvement in mood and activity levels, rather than pain relief. However, cognitive behavioural treatment programs may assist in the development of improved strategies for managing persistent pain. See also chapters 16 and 17.

Recommended reading Calford MB, Tweedale R (1988) Immediate and chronic changes in responses of somatosensory cortex in adult flying-fox after digit amputation. Nature 332, 446–448. Campbell JN, Meyer RA (2006) Mechanisms of neuropathic pain. Neuron 52 (1), 77–92. Dworkin RH, Backonja M, Rowbotham MC, et al. (2003) Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Archives of Neurology 60, 1524–1534.

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Finnerup NB, Sindrup SH, Jensen TS (2010) The evidence for pharmacological treatment of neuropathic pain. Pain 150 (3), 573–581. Flor H, Elbert T, Knecht S, et al. (1995) Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 375, 482–484. Treede RD, Jensen TS, Campbell JN, et al. (2008) Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70 (18), 1630–1635. Woolf C, Shortland P, Coggeshall RE (1992) Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 355, 75–78.

Chapter 10

Pain management in cancer patients Muhammad Salman Siddiqi and Paul Glare

Introduction It is estimated that approximately 5% of Americans have cancer, and this figure is likely to be similar in Australia and other developed countries. Approximately half of the people with cancer will die from their disease, making it the second leading cause of mortality in Americans. Not only is cancer a life-threatening diagnosis, but the suffering it causes is exacerbated by the fact that most people with cancer will experience pain. Irrespective of the cancer stage, one-third of people with cancer grade their pain as moderate or severe (Daut and Cleeland 1982; van den Beuken-van Everdingen et al. 2007). Unfortunately, their pain becomes more prevalent as the disease progresses. Therefore, it is not surprising that pain is greatly feared by people with cancer and their families (Ferrell et al. 1991). Suboptimal pain control can be very debilitating, and it may impede the healing process. Severe pain can interfere with physical rehabilitation, mobility, and proper nutrition, and a significant number of people with cancer are subsequently diagnosed with depression (Massie and Holland 1992; McMillan et al. 2008). Treating cancer pain is clearly a priority, with the goals of optimising comfort and function while avoiding unnecessary adverse effects from medications. Fortunately, prompt, effective pain control is available and this can prevent needless suffering of people with cancer and may significantly improve the quality of their lives. High-quality pain relief is elusive for many people with cancer, however. In a survey taken some 20 years ago, it was estimated that less than half of people with cancer had received adequate pain relief, and 25% died with their pain poorly controlled. This is despite the fact that the pain endured by 90% of them could have been well managed with relatively simple

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interventions. As a result of these data, intensive educational efforts to improve people’s pain management have been provided over the past two decades; unfortunately, though, it seems little has changed. A recent large study found that people with common cancers (breast, prostate, colon, and lung) from 38 institutions across the United States, at any point during their care, who were treated on an outpatient basis at either an academic medical centre or community clinic, found that pain was still a problem for them (Fisch et al. 2012). More than 3000 of these people were identified to be at risk for pain, and more than 2000 reported having pain or requiring analgesics at initial assessment; of these 2000 people, one-third were receiving inadequate analgesic prescribing. Twenty per cent of those who reported feeling severe pain were not receiving any analgesics. Of more than 400 people who were under-treated at an initial assessment, fewer than one-third had received appropriate treatment by the follow-up visit. While no discrepancy for age or gender was noted, minorities were only half as likely to have adequate pain relief. Why is adequate cancer pain relief so difficult to achieve? Many barriers to it exist, and a complicating factor is that most cancer care is now provided as part of ambulatory care. While people who are hospitalised with significant pain may be evaluated by pain specialists, those treated on an outpatient basis are typically managed by their oncologist, who is pressed for time and is not an expert in assessing and treating complicated pain problems. Pain is a subjective feeling that has not to date been easily and universally quantified. People with similar cancer types may experience different intensities of pain and may respond to the same analgesic in different ways. They may also exhibit varying sensitivities to adverse effects from many of the drugs used. Because pain is multifaceted, a single analgesic may not be sufficient to alleviate all aspects of pain that the person is experiencing, thus complicating their pharmacological regimen. Depending on the type and extent of the cancer, administration routes may be limited for some people, and more innovative methods of drug delivery may need to be utilised. For example, as cancer progresses, oral administration may not deliver the appropriate level of analgesia desired due to waning level of consciousness or failure of gastrointestinal absorption. In addition, some people experience persistent nausea and vomiting during the course of chemotherapy, and this will interfere with oral administration of analgesics. Society has also placed limitations on pain control because of renewed concerns about addiction or opioid abuse. Patients and their families or caregiver must be educated about the pain process, the medications used, and the side-effects they can realistically expect. They also need to know that there are many options available to the pain specialist, pharmacological and surgical, and that pain management can be seen as a multidisciplinary activity requiring the expertise of physicians, nurses, pharmacists, dietitians, and other clinicians. Another challenge to the treatment of a person’s cancer pain is the paucity of good clinical trials providing objective data that can be extrapolated to the



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individual. Some limitations with the clinical trials found in the literature today include the heterogeneity of cancer pain types, the limited number of people enrolled, the spectrum of available analgesics and doses used for optimal pain control, the lack of a single objective pain scale, and the variable duration of treatment provided in different textbooks or guidelines. The current approach to pain control should be individualised for every person. This will require knowledge of the cancer type, the drugs available on the market, and the person’s individual metabolism, drug tolerances, and even genetic morphology. Periodical re-evaluation of their medication regimen is essential to finely tune analgesia and to minimise exposure to potentially dangerous adverse effects. The aim of this chapter is to help the non-specialist better understand how to evaluate and manage a person’s cancer pain and to recognise when they should seek assistance from an expert.

Epidemiology of pain in people with cancer Although pain is one of the most feared consequences for people with cancer and from their treatment, it is important to remember that pain and cancer are not synonymous. The incidence of pain varies with the primary site, affecting more than 80% of people with primaries of bone, cervix, or head and neck, but less than 20% of those with leukaemia or lymphoma (Twycross and Lack 1983). People with common cancers, such as lung, colon, breast, and prostate, frequently experience significant pain, especially in the advanced stages of their disease (Daut and Cleeland 1982). The prevalence of their pain during the time course of a cancer illness has been compared to a roller coaster, with pain being common at time of initial diagnosis and treatment, but then resolving, prior to appearing again when there is recurrent disease. Surveys have found that approximately one-third of those who remain ambulatory but receiving chemotherapy have pain (Cleeland et al. 1994, Jacox et al. 1994). In people whose cancer progresses to advanced cancer, pain occurs in two out of three, and in up to 90% of people with terminal cancer (Twycross and Lack 1983). The prevalence of pain in disease-free cancer survivors has been estimated at more than 40% (Green et al. 2010).

Classification of cancer pain It is clinically important not to think of pain as a single entity in the person with cancer. Multiple different pains often occur concurrently – in one survey of those with advanced cancer, only 20% had only one pain, while one-third had four or more pains (Twycross and Lack 1990) – and each person needs to be evaluated separately. It is also clinically helpful to classify their cancer pain to expedite initiation of effective treatment, as different types of pain may require different therapies.

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There are four different aspects of a person’s cancer pain that need to be considered when attempting to classify it: pain intensity, the pathophysiology of the pain, onset and duration, and aetiology. Pain intensity Pain in the cancer patient may be mild, moderate, or severe. Pain intensity is important because it directs the potency of analgesics that are appropriate, as illustrated by the analgesic ladder of the World Health Organization (www. who.int/cancer/palliative/painladder/en). Pain intensity is also an important metric of the outcome of management. Pain intensity has been shown to be highly correlated with pain interference with function, other symptoms, mood, and quality of life (Cleeland 1991). There are different ways of scoring a person’s pain intensity, including using categories like mild, moderate, and severe, using a numerical score such as a 0–10 scale, or using graded symbols such as facial expressions. Numerical rating scales are preferred, and a score of 1–4 is equivalent to ‘mild’, 5–6 is ‘moderate’, and 7–10 is ‘severe’. A two-point reduction in the pain score from baseline is considered clinically significant. Pain pathophysiology The pathophysiological classification of a person’s pain has traditionally distinguished nociceptive pain, which features normal transmission of noxious stimuli from somatic tissues or viscera to the brain via an intact nervous system, from neuropathic pain, which arises from nerve damage without the need of any peripheral noxious stimulus (Besson 1999; Portenoy 1992). This simple classification has proven clinically useful with regard to initiating a person’s pharmacotherapy, as nociceptive pain tends to be more opioid responsive, but this paradigm is being challenged in two ways. First, nociceptive pain due to peripheral inflammation may develop a central neuropathic component, due to changes in the dorsal horn of the spinal cord, called central sensitisation (Dickenson 1995). Second, animal models of cancer pain reveal unique pain syndromes not seen in people with non-malignant pain, for example, cancer-induced bone pain and chemotherapy-induced peripheral neuropathy (Honore et al. 2000; Mantyh et al. 2002; Shimoyama et al. 2002). Onset and duration of the pain As with non-malignant pain, a person’s cancer-related pain may be classified as acute or chronic pain. Acute cancer pain is an important clinical entity as it may be amenable to specific treatment of the underlying problem. This is especially the case if a person’s acute pain crises are due to sudden onset of a serious cancer-associated complication, such as a pulmonary embolus, haemorrhagic brain metastases, pathological fracture, or an acute abdomen. More commonly, acute pain in a person with cancer is secondary to an invasive diagnostic procedure (e.g. bone marrow biopsy, post-lumbar puncture headache) or therapeutic procedure (e.g. post-incisional pain after surgery, mucositis pain post-transplant). These pains should be self-limited and managed like



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Table 10.1  Prevalence of cancer pain by aetiology, in different settings(Foley 1993; Twycross and Fairfield 1982) Tumourrelated (%)

Treatmentrelated (%)

Debilityrelated (%)

Unrelated (%)

MSKCC outpatient, 1989 (Foley 1993)

62

25

–

10

MSKCC outpatient, 2009

67

20

5

10

MSKCC hospitalised, 1989 (Foley 1993)

78

19

–

3

British inpatient hospice (Twycross and Fairfield 1982)

67

5

6

22

Setting

other acute pain. Infections such as shingles are also common in people with cancer and can present as acute pain. It is obviously important to diagnose such pain promptly. In practice, however, this simple acute/chronic dichotomy is not very useful, as a person with chronic cancer pain frequently has intermittent flares of pain intensity, called breakthrough pain (BTP), because their pain ‘breaks through’ the regularly scheduled treatment of the chronic pain. The assessment and management of BTP is discussed in more detail below. Pain aetiology Unlike chronic non-malignant pain, there is almost always an underlying structural basis for pain in people with cancer. The work-up should aim at eliciting the cause. While tumour is the most common cause (see Table 10.1), this cannot be presumed to be the case every time. Other aetiologies always need to be considered, and to be ruled out as part of the work-up. Pain may be a side-effect of a person’s cancer treatment, including surgery, radiation therapy, and chemotherapy, the newer targeted therapies being no exception to this rule (Paice 2010). Pain may be due to cancer-related debility. It may also be caused by an unrelated comorbidity, such as degenerative disc disease, osteoporosis, diabetic neuropathy, and so on. The prevalence of each varies with the clinical setting (Foley 1993; Twycross and Fairfield 1982), with tumour-related pain being more common in those who are hospitalised, and more common in other aetiologies in the ambulatory setting.

Clinical assessment of cancer pain A comprehensive assessment of a person’s pain is the key to optimal cancer pain treatment. A poor assessment of a person’s pain has been identified as a major barrier to effective pain management (Von Roenn et al. 1993). The aim of the cancer pain assessment is to obtain information from the person’s history, physical examination, and data review that enables the aetiology,

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mechanism, intensity, and periodicity of each pain that the person complains of to be precisely determined, so that an effective, appropriate treatment plan can be developed. A pain scale should be used to document their pain intensity. Reconciliation of the home medicine list is another integral piece of the overall pain assessment. Information regarding their past and present pain medicines, their doses, regimen, duration of treatment (and reason for discontinuing an agent, if applicable), should be obtained and is an important part of their assessment. A formal psychosocial evaluation of each person should also be performed, as psychological distress will lower their pain threshold. Anxiety, depression, and other distress are more common for people with cancer than for the general population, so psychosocial assessment is very important and should emphasise the effect of pain on the person and their families or caregiver, and should address the cognitive (meaning of the pain), emotional (affective and existential), and social (personal history and environmental) factors that are influencing the person’s pain experience. It is important to identify when anxiety or depression reaches a pathological level that requires specific treatment. An affirmative substance abuse history further complicates pain assessment and therapy (see below). Unlike the person with chronic non-malignant pain, a physical basis for pain can usually be identified in a person with cancer. The clinician needs to be familiar with the lists of common cancer pain syndromes (e.g. epidural disease, plexopathies) to facilitate identification of the cause, so that treatment can be initiated and morbidity (e.g. paraplegia due to cord compression) prevented or minimised. Identification of a treatable cause of pain is only relevant in a person amenable to further anti-cancer therapy. This may not be as important in people with far advanced cancer on best supportive care or hospice. Each painful area should be carefully examined to determine if palpation or manipulation of the site produces pain. The neurological aspect of their physical examination is emphasised so that syndromes such as spinal cord compression or base of skull metastases are not overlooked (Elliott and Foley 1989). Common sites of pain referral (e.g. shoulder pain from subdiaphragmatic lesions) should be kept in mind when performing the examination. Appropriate diagnostic tests should be performed to determine the cause of a person’s pain and extent of disease, and to correlate this information with the findings on their history and physical exam, to ensure that the appropriate areas of the body have been imaged, and that the abnormalities found do in fact explain the person’s pain. As the pain may be the harbinger of progression of their tumour, imaging may need to be repeated. Assessment of BTP Approximately one-half to two-thirds of people with chronic cancer-related pain experience episodes of BTP (Portenoy and Hagen 1990; Portenoy et al. 1999). BTP is associated with more severe and frequent baseline pain, more pain-related functional impairment, and worse mood. Two types of BTP are



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described: incident pain and end-of-dosage failure pain. Incident BTP breaks through otherwise-adequate analgesia any time during the dosing interval. Incident pain can be frequent or rare, and can be predictable or unpredictable. It is usually somatic (e.g. movement-related bone pain), but can also be visceral or neuropathic. End-of-dosage failure BTP emerges towards the end of the dosing interval, usually in a consistent and predictable pattern. The characteristics of BTP vary from person to person, including the duration of the breakthrough episode and possible causes. Generally, BTP is transient, lasting seconds to minutes, but may occasionally be present for hours, and often occurs several times a day. BTP can happen unexpectedly, for no obvious reason, or it may be triggered by a specific activity, like coughing, moving, or going to the bathroom. Importantly, the cause of the BTP may not be the same as that of the baseline chronic pain. For all these reasons, BTP needs as thorough a clinical evaluation (proportional to prognosis) as the baseline pain it relates to: site, radiation, intensity, aggravating/relieving factors; physical exam; investigations. Pharmacological management is the mainstay of treatment, but as this usually involves taking stronger opioids, often multiple times throughout the day, the inconvenience and toxicity of extra doses means that treatment of the underlying cause (e.g. radiotherapy, surgery) should be aggressively pursued, if treatment is available and the prognosis is appropriate. Subsequent assessment Subsequent assessment is also required and should evaluate the effectiveness of any therapeutic manoeuvres that have been implemented. If pain is not controlled, one needs to determine whether the cause is related to the progression of disease, a new cause of pain, or a side-effect of the treatment. The eight steps of the initial assessment should be repeated with each new report of pain. Because of the complexity of the evaluation, it may take an extended period of time to determine all these issues as more information about the person and their disease comes to light. A checklist such as that shown in Box 10.1 may assist with the complex task of a person’s cancer pain assessment, but it needs to be remembered that Box 10.1  Eight-step approach to cancer pain management 1. Believe the patient’s pain complaints. 2. Take a detailed pain history and assess the severity of the pain. 3. Include a substance abuse history. 4. Perform a careful physical examination. 5. Order and personally review any diagnostic tests. 6. Consider pharmacological and non-pharmacological approaches to pain syndromes. 7. Assess the psychological state of the patient. 8. Assess the level of pain control afterwards.

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their extreme suffering and anguish may present as uncontrollable pain. A ‘narrative’ approach to the cancer pain history will be needed to enable the physician to better understand the link between nociception, pain behaviour, and coping styles, and suffering in the individual patient (Lickiss 2001). Ideally, anti-cancer therapy (surgery, radiation, or chemotherapy) with either curative or palliative intent will be possible and will remove the noxious stimulus and eliminate the cause of the pain. Of course, analgesia should not be withheld while the full assessment is being completed and disease-controlling therapies administered. Indeed, it will be much easier to investigate the cause of the pain when the person is receiving adequate analgesia. In many cases, however, their pain is due to advanced, progressive disease and there are no further treatment options. Analgesia then becomes the main goal of treatment.

Treatment of people with cancer pain Once the cause of the person’s pain and the psychosocial factors contributing to their pain-related distress and behaviour are identified, an individualised, multimodal treatment plan should be developed. Analgesics are the cornerstone of cancer pain management. Non-pharmacological interventions, such as physical therapy, TENS, cognitive behavioural therapies, acupuncture, and other complementary and alternative therapies, may also have a role in treating cancer pain (Menefee and Monti 2005) and are discussed further below. Analgesic medicines fall into three groups: non-opioids, including aspirin, NSAIDs, and acetaminophen (paracetamol); weak opioids, such as codeine, hydrocodone, tramadol, and tapentadol; and the strong opioids, such as morphine, hydromorphone, oxycodone, fentanyl, and methadone (see also chapters 4, 5, 11 and 12). The sequential use of analgesics of increasing potency according to the severity of the pain was proposed in the early 1980s by the WHO, so is often referred to as the WHO analgesic ladder. According to this approach, a trial of opioid therapy should be given to all cancer patients with pain of moderate or greater severity. Some 30 years on, authorities continue to widely endorse the guiding principle behind the ladder, that analgesic selection should be primarily determined by severity of pain (Benedetti et al. 2000; Hanks et al. 2001; Hanks et al. 2004), even if the evidence is insufficient to estimate the efficacy of the ladder (Jadad and Browman 1995; Marinangeli et al. 2004). Non-opioids The WHO recommendation on NSAIDs for mild pain conflicts with the US National Comprehensive Cancer Network (NCCN) Practice Guidelines for Adult Cancer Pain, which states that the haematologic, renal, hepatic, and cardiovascular toxicities of chemotherapy may be increased by the concomitant prescription of NSAIDs, and that opioids are a safe and effective alternative (Swarm et al. 2010; see also www.NCCN.org). A risk–benefit analysis is required



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in each cancer patient before prescribing NSAIDs. If NSAIDs are to be used, start with one that the patient has found effective and has tolerated well in the past. Otherwise, use ibuprofen up to 400 mg t.i.d. Blood pressure, CBC, and biochemistry should be monitored at baseline and repeated every 3 months. A proton pump inhibitor should be co-prescribed if patients give a history of NSAID-related gastrointestinal bleeding. If the patient does not tolerate two sequential NSAIDs, another approach should be used. Topical NSAIDs may be effective in these cases. Intravenous (IV) ketorolac 15–30 mg every 6 hours PRN for a maximum of 5 days is often effective in a pain crisis, even in patients on high-dose opioids. Acetaminophen is safe and effective for most cancer patients (Stockler et al. 2004). It lacks many of the toxicities of the NSAIDs, but may cause hepatoxicity at doses over 4 g per day, particularly in those with liver disease or a history of alcoholism. Acetaminophen is as effective as aspirin as an analgesic but will not be as effective for pain that is inflammatory or bone in origin. Weak opioids Weak opioids comprise the second step of the WHO analgesic ladder and are recommended for pain, or mild cancer pain, that is not responsive to ibuprofen or acetaminophen. The need for the second step of the ladder is controversial because low-dose formulations of strong opioids pain have been shown to be more effective than weak opioids for moderate intensity cancer pain (Marinangeli et al. 2004). Consequently, many experts advocate skipping the second step of the ladder and going straight to a strong opioid for all cancer pain of moderate intensity or greater (Benedetti et al. 2000; Cleary 2000; Hanks et al. 2001; Walsh 2000), although the current NCCN cancer pain guideline does not weigh in on this issue (visit www.NCCN.org for the latest updates). There has also been controversy about whether weak opioids (alone or in combination with non-opioids) are more effective than non-opioids alone. At therapeutic doses, there is no evidence of superiority for one opioid for mild to moderate pain over another (De Conno et al. 1991). If a weak opioid is to be used, the traditional options included codeine, hydrocodone, propoxyphene, and meperidine (pethidine). Meperidine and propoxyphene are no longer recommended, while several newer options are now available. Tramadol is a weak opioid with additional effects on the monaminergic system. At therapeutic doses in combination with a non-opioid, its analgesic effect for mild to moderate pain is similar to that of an opioid (Leppart 2001; Wilder-Smith et al. 1994). The extent to which the dose can be titrated is limited, as at doses just above the normal therapeutic dose (400 mg/ day), tramadol can cause CNS toxicities, including headache, convulsions, and serious psychiatric reactions in some patients. The opioid agonist effect of tramadol requires its metabolism via the CYP2D6 isozyme of cytochrome P450, which is lacked by 5–15% patients. Tapentadol is a new variation on tramadol that does not require CYP2D6 metabolism to have opioid agonist activity. In chronic pain patients, tapentadol has been shown to be equivalent to low dose of oxycodone with less gastrointestinal toxicity. It has recently

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been studied in cancer patients and appeared to be effective in a Phase 2 study (Mercadante et al. 2012). Strong opioids Strong opioids are the mainstay of management of moderate to severe cancer pain. While opioids have been used as analgesics for centuries, it is only recently that a systematic review has concluded that oral morphine is effective for cancer pain (Wiffen and McQuay 2007). In the United States, numerous strong opioids are approved by the Food and Drug Administration (FDA) for cancer pain management, with each developed country having its own organisation for drug approval, such as the Therapeutic Goods Administration (TGA) in Australia. Morphine remains the drug of first choice (Vignaroli et al. 2012) for various reasons, which include: the majority of patients tolerate morphine well; it is effective in most cases; a wide variety of oral formulations are available, allowing flexibility of dosing intervals; and it is inexpensive. Alternative strong opioids to morphine available in the United States include hydromorphone, oxycodone, fentanyl, methadone, oxymorphone, and levorphanol. These should be considered when titration of morphine results in doselimiting side-effects. The ten principles for the correct use of morphine are shown in Box 10.2, and are based on the NCCN cancer pain and other published guidelines (Hanks et al. 2001; Swarm et al. 2010; see also www.NCCN.org). Traditionally, mixed agonist-antagonists, such as pentazocine and butorphanol, have not been recommended for cancer pain because of their limited usefulness and the risk of precipitating a withdrawal when an opioiddependent patient is switched from a full agonist to one of these agents. Buprenorphine is a new agent in this class that is considered to have some role for cancer pain management, especially as it is available in a transdermal preparation (Pergolizzi et al. 2009). Buprenorphine is a semi-synthetic derivative of thebaine that is 25–100 times more potent than morphine, resulting in Box 10.2  10 principles for the correct use of morphine in chronic cancer pain 1. 2. 3. 4. 5. 6. 7. 8.

Administer by mouth. Administer around the clock, not PRN. Start with immediate-release morphine and titrate up dose. Change to sustained-release morphine when the does is stable. Continue immediate-release morphine for rescue dosing (BTP). Anticipate and prevent side-effects, especially constipation. Know that the oral-to-parenteral equipotency ratio is 3:1. Reduce the dose in people with renal failure because they accumulate the active metabolite morphine-6-glucuronide. 9. Know how and when to use opioid rotation. 10. Educate both patient and family about morphine.



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an estimated conversion ratio of 1 : 110–1 : 115 to provide an equal degree of analgesia. However, it is only a partial µ opioid receptor agonist, being also a κ and δ opioid receptor antagonist. TD buprenorphine has been licensed in Europe since 2002, where the registered dose range is 35–140 mcg/h, considered adequate to achieve sufficient pain relief for most cancer patients. Currently, TD buprenorphine is commercially available in the United States only in strength of 5, 10, and 20 mcg/h, applied for 7 days, so it included here with the weak opioids as a treatment for mild–moderate pain. It has a valuable role in the treatment of chronic cancer pain because of its efficacy and good safety and tolerability profile, including a low risk of respiratory depression, a lack of immunosuppression, and a lack of accumulation in patients with impaired renal function, and a lack of development of tolerance.

Initiating treatment with strong opioids In patients with continuous chronic cancer pain, oral morphine should be given on a regularly scheduled basis, around the clock, to keep the pain under control and to prevent the peaks and valleys in blood levels that occur with PRN dosing. The starting dose of oral morphine depends on the intensity of the pain, and whether or not the patient is opioid naive (taking less than 60 mg morphine/day or equivalent), or is progressing from a weak opioid. • In naive patients having a pain crisis due to an oncological emergency, or patients who are very distressed by non-emergency severe pain (≥ 7 on a scale of 0–10), parenteral morphine should be used with bolus of IV morphine preferable. –– The NCCN guideline recommends 2.5 mg IVPB repeated every 15 minutes until pain is controlled –– If there is no improvement (pain score remains ≥ 7), each dose should be increased 50–100% –– If there is no improvement after three doses, the situation needs to be reassessed and a different agent, for example hydromorphone, considered. • In tolerant patients, the initial bolus should be 10–20% of the TDD in IV equivalents, given on the same IVPB regimen as for naive patients • In naive patients with moderate–severe pain ( intensity ≥ 4/10 who are less distressed), oral morphine can be used for titration. –– It has been shown to be as effective as parenteral morphine, although more drug needs to be given by mouth (approximately triple the IV dose) because oral morphine undergoes extensive first pass metabolism in the liver –– It has a slower onset of action, peak effect being achieved at 60 minutes vs. 15 minutes of IV –– Opioid-naive patients should be started on 5 mg of immediate release (IR) morphine and tolerant patients on 10 mg, given every 4 hours plus PRN

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–– The dose is titrated up in 50–100% increments every 12–24 hours until the pain is controlled. If it has not improved at all after two or three increments, a different opioid should be considered, along with a change to the IV route –– Even lower starting doses such as 2.5 mg every 4 hours should be considered in the frail elderly. The titration should be on the lower end and slower side of the range in the elderly. • In tolerant patients with moderate–severe pain, the initial bolus should be 10–20% of the TDD in oral equivalents, given on the same regimen as naive patients. Once the pain is controlled, the immediate release (IR) formulation should be converted to a sustained release (SR) oral morphine formulation in the case of moderate pain, or a patient-controlled analgesia (PCA) in the case of a hospitalised patient with severe pain. Most patients can be managed in the ambulatory setting with oral SR morphine. The starting dose is derived by calculating the TDD of IR morphine (regularly scheduled plus rescues) and divided by the dosing regimen (one to three times per day, depending on the formulation). The SR morphine dose needs to be reviewed regularly and may need titration up if there is increasing pain from progression of disease. This approach is very safe and respiratory depression and excessive sedation almost never occurs. A supply of IR medication is need for rescue doses to treat breakthrough pain. This should normally also be IR morphine. The rescue dose for IR morphine is usually one-twelfth to one-sixth of the total daily SR dose. When prescribing PCA, guidelines suggest a 25% increase in the baseline rate for mild–moderate pain and a 50% increase for moderate–severe pain, but in general the increase should be based on the number of rescues taken. When converting from oral to IV, the IV dose is reduced to one-third of the oral dose, expressed as an hourly rate (e.g. 30 mg oral morphine every 4 hours becomes 2.5 mg IV morphine/hour). Guidelines suggest to start with an IV rescue dose of half-hourly IV basal every 15–20 minutes or an oral rescue of 10–15% of the total daily opioid dose every 1–2 hours. In managing a pain crisis in an opioidtolerant patient, double that IV dose is administered as a bolus, repeating same dose in 20 minutes if no relief is obtained. If the pain persists at a level of more than 6/10, with no side-effects, increase the IV dose by 50% and continue to administer a dose every 20 minutes until benefit is achieved or side-effects are experienced. Once relief is obtained and PCA is to be started, the total amount of opioid the patient used in the past 24 hours is converted into an IV dose equivalent for the past 24 hours and converted into an hourly dose for the PCA basal rate, then rescues are ordered. For opioid-naive patients in a pain crisis, morphine sulfate is given in 5–15 mg IV boluses until the pain is relieved, and the starting basal rate for PCA is 1–3 mg/h. When utilising PCA, staff need individual instruction on how to assess the readings on the PCA pump and perform other functions. PCA is suitable in



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cognitively intact elderly people provided they have sufficient manual dexterity to press the button, but it is contraindicated in patients who are confused. In those cases, the PRN ‘rescue’ button should not be used and can be removed from the pump. Family members should be instructed NOT to push the PRN ‘rescue’ button; only the patient should administer the PRN ‘rescue’ dose. Clinician-activated bolus (CAB) is a larger rescue dose (typically double the hourly rate), only administered by a nurse or physician. CABs are useful to allow patients who can’t tolerate lying down to have an MRI or radiation therapy. CABs can also be used for a pain crisis, severe incidental BTP, or other painful episodes. PCA can also be delivered at home, for example with the support of an infusion company. While life-threatening respiratory depression and sedation almost never occur when morphine is titrated using this approach, it is important to anticipate and prevent the side-effects that do occur commonly, especially constipation, nausea, and drowsiness. • Laxatives should be prescribed prophylactically unless the patient has preexisting diarrhoea. There is minimal evidence-base to recommend a firstline laxative (Miles et al. 2006), but clinical experience recommends avoiding bulking agents such as fibre in the patient with advanced cancer and instead to rely on softeners (e.g. docusate), stimulants (e.g. senna), and osmotic agents (e.g. lactulose or polyethylene glycol). A combination of senna and docusate was recently recommended by a majority of experts convened by the International Association for Hospice and Palliative Care (Vignaroli et al. 2012). • The same experts recommend metoclopramide as the first-line anti-emetic for opioid-induced nausea, but they failed to agree if its administration should be ‘regular’ or ‘as needed’. As nausea is less common than constipation and is usually self-limiting, we suggest that prophylactic anti-emetics are not usually needed. • Stimulant drugs, such as methylphenidate 5–10 mg bid initially, may be tried to overcome opioid-induced sedation, but caution is required in the elderly and in younger patients with a cardiac history, altered mental status, or extreme anxiety. More serious neurotoxicity with hallucinations and myoclonus occasionally occurs when higher doses are needed, but this usually resolves with opioid rotation (Essandoh et al. 2010). The last, but by no means least important, step in the initiation of opioid therapy for cancer pain is patient and family education. Their fears and concerns, such as tolerance, dependence, addiction, side-effects, and proximity to death all need to be anticipated and addressed (Wells et al. 1998). Not only do these perceptions lead to under-treatment of cancer pain (Potter et al. 2003), but failure to fill or adhere to pain medicine prescriptions has been shown to be the strongest risk factor for readmission in cancer patients (Kangovi et al. 2012). All these fears are misconceptions.

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• If the dose increases, it is because of more pain, not the development of tolerance. As there is no ceiling to strong opioid doses, initiation of therapy should not be saved for ‘later’. • Physical dependence is likely to occur with chronic use of strong opioids, but if they are no longer needed, schedules for safely and effectively tapering opioid doses are available. • Addiction is very unlikely to arise de novo in cancer patients who have not had problems with substance abuse previously; if problems do arise, effective management programs for addiction are available. • Pain medicine will not make the cancer patient a zombie, and, despite what the package insert says, will not cause respiratory depression or suicidality. The common side-effects are constipation, drowsiness, and nausea. These can be effectively managed in most cases. • Being started on pain medicine does not mean the patient is dying. These days, analgesics are offered to anyone with moderate–severe pain. Pain and cancer are not synonymous, and increasing pain does not necessarily mean the cancer is progressing. Cancer pain is a roller-coaster and the pain medicine will be stopped again if the pain resolves. It is also important to be sensitive to cost issues for people in pain with regard to choice of drug. This should take into account the person’s medical insurance or if the drug is subsidised by government.

After effective treatment with morphine has been initiated Problems in subsequent cancer pain management Some of these can be managed by the oncologist or other primary treating physician. In more complex situations, collaboration or consultation with a pain specialist or palliative care specialist is recommended. When a change to parenteral opioids is required In many patients with advanced cancer, parenteral opioids are needed at some stage in the course of their illness either because of a pain crisis or they become unable to swallow. If patients are hospitalised with uncontrolled pain, the IV route is used, as discussed previously. In hospice patients, the subcutaneous (SC) route is used. Intramuscular injections should be avoided. IV morphine is usually given by continuous infusion, with rescue doses administered on demand by clinicians (CAB) or self-administered by the patient if using PCA. Hospitals will have their own IV therapy guidelines on how to prescribe and administer IV opioids. Generally speaking, morphine and hydromorphone can run simultaneously with other solutions, including antibiotics. This is not the case with fentanyl or methadone, for which a separate line is required. If the pain is well controlled, and there is loss of the oral route due to the patient being NPO or having problems with nausea and



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vomiting, transdermal opioids, such as fentanyl or buprenorphine, are a good option, but then issues of opioid rotation come up (see below). When side-effects are preventing escalation of the dose to an effective level Morphine works well in the majority of patients. In the Cochrane review, only 4% of patients withdrew from clinical trials because of adverse events (Wiffen and McQuay 2007), but in practice some 10–30% develop intolerable side-effects which prevent titrating the morphine dose up to the effective level (Cherny et al. 2001). In this situation, there are six strategies to consider, depending on pain intensity and other aspects of the clinical situation: • If the pain is only mild (intensity score of 1–3), do not increase the dose further and even consider reducing it by 25% • If the pain is moderate–severe (intensity score ≥ 4): –– Continue morphine and treat the side-effects with adjuvant medications (e.g. more aggressive laxatives, anti-emetics, psychostimulants) –– Continue with morphine but add a co-analgesic drug that will be opioid sparing and allow the morphine dose to be reduced. Commonly used co-analgesics include acetaminophen or an NSAID for bone pain or other somatic pain, or an antidepressant or anticonvulsant in the case of neuropathic pain. –– Change to an alternative strong opioid, a practice referred to as opioid rotation. –– Utilise more invasive techniques, such as spinal opioids, or anaesthetic procedures, such as a nerve blocks. –– Redouble non-pharmacological approaches, such as complementary therapies.

Reducing the dose If the noxious stimulus is greatly reduced or eliminated after treatment of a painful oncologic emergency or other effective intervention, the dose may need to be reduced (Broadbent and Glare 2005; Hanks et al. 1981). A typical tapering regimen is a 25–50% dose reduction every 2–3 days. When tapering, the patient should be educated about possible withdrawal symptoms and given suggestions for abating those symptoms (a useful guide to opioid tapering is available at http://pain-topics.org/pdf/Safely_Tapering_Opioids.pdf). The dose also needs to be reduced if renal failure occurs, as the active metabolite morphine-6-glucuronide accumulates, presenting with respiratory depression and/or neurotoxicity: drowsiness, confusion, myoclonic twitching (Hagen et al. 1991; Osborn et al. 1986). It is recommended that morphine should be avoided in renal failure/dialysis patients. In this situation, rotation to an alternative strong opioid is recommended (see below). Fentanyl

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and methadone are the safest to use (Dean 2004), although hydromorphone and oxycodone may be used with caution and close monitoring. Dose adjustments may also be required in patients with very advanced liver disease. This is an area that is less well studied than renal failure, but in general the opioids that undergo oxidative metabolism via cytochrome P450 are more likely to be affected (Hanna 2011).

More aggressive management of side-effects If opioid-induced nausea persists despite metoclopramide, the symptoms should be re-evaluated and other options, such as haloperidol, olanzapine, or a serotonin antagonist, may be tried.(Glare et al. 2011). If sedation remains troublesome, methylphenidate can be titrated up to 60 mg/day, monitoring for cardiac stimulatory toxicity (hypertension, tachycardia, palpitations). If these become problematic, modafinil is another stimulant with less pronounced cardiac effects. For patients in whom opioid-induced constipation (OIC) persists despite maximal doses of conventional laxatives and the addition of suppositories or enemas, a third step is needed. Rotation to a lessconstipating opioid, such as tramadol, tapentadol, fentanyl, or methadone can be tried. Prokinetic agents could also be tried. Metoclopramide (10–20 mg by mouth every 6 hours) may be effective, although it only has prokinetic effects on the proximal small bowel. Cisapride is no longer available because of cardiac toxicity. Newer agents include prucalopride that has colonic stimulatory effects but is not yet FDA-approved, and lubiprostone, which is a chloride channel activator used in irritable bowel syndrome that has been shown to be effective for OIC (Camilleri 2011). If the patient’s constipation fails to respond to these measures, an opioid antagonist can be tried, although a peripherally restricted one such as methylnaltrexone should be used. At a once-daily dosage of 0.15 mg/kg subcutaneously, methylnaltrexone will produce laxation in most cases of OIC (Thomas et al. 2008). A bowel obstruction must be excluded before commencing methylnaltrexone. Centrally acting opioid antagonists such as naloxone should be avoided because of the risk of reversing analgesia, although oxycodone/naloxone combination tablets (not FDA-approved) have recently been shown to be safe and effective for improving constipation without compromising analgesia, in doses up to 120 mg/day of oxycodone (Ahmedzai et al. 2012).

Addition of co-analgesic agents Co-analgesics are agents given to enhance pain relief provided by an opioid. Some are pain medicines in their own right (e.g. NSAIDs, acetaminophen, local anaesthetics), but most are primarily used for some other purpose. The



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list of potential co-analgesic drugs is long and may include antidepressants, anti­convulsants, benzodiazepines, skeletal and smooth muscle relaxers, corticosteroids, and antibiotics (see Table 10.2). The rationale behind prescribing co-analgesics is that some types of pain appear to be less responsive to opioids than others, and much higher doses of opioids – associated with a higher incidence of side-effects – are needed if these pains are managed with ‘single agent’ opioids alone. However, prescribing co-analgesic drugs contributes to polypharmacy with its attendant problems of drug interactions, toxicity, inconvenience, and cost. Neuropathic pain is the most common example of cancer pain for which co-analgesics are used, and antidepressants or anticonvulsants are the usual agents of choice. Occasionally, co-analgesics are used as first line options (e.g. for a treatment-related neuropathic pain such as chemotherapy-related peripheral neuropathy), but most neuropathic pain in cancer is due to a tumour mass compressing adjacent neural structures and an opioid is already being prescribed. The antidepressants and anticonvulsants are reasonably effective, with a number needed to treat (NNT) of 3–4, although this figure has been derived from studies of non-malignant neuropathic pain (diabetic neuropathy and post-herpetic neuralgia). The NNT is the number of patients that need to be treated for one to benefit compared with a control in a clinical trial, and the higher the NNT, the less effective is the treatment. Most pain medicines have a NNT of 2–6. It was once taught that the neuropathic pain descriptors directed co-analgesic choice – antidepressants for burning, differentiation-type pain, anticonvulsants for shooting/lancinating neuralgic-type pain – but this no longer appears to be clinically relevant. Choice of drug will be dictated by toxicity, drug interactions, and coexisting conditions. For example, SSRI antidepressants can be problematic in combination with fentanyl due to development of the serotonin syndrome, and they may also inactivate tamoxifen (Kelly et al. 2010). Among the antidepressants, the TCAs are the most extensively studied and are effective, but their anticholinergic side-effects are poorly tolerated by elderly cancer patients, and they are difficult to recommend as first-line choices in this patient population. Most of the common serotonin reuptake inhibitors, such as escitalopram, are not effective for neuropathic pain, but serotonin-norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine, are proving to be effective, although less so than TCAs (with NNT around 5). Gabapentin and pregabalin are the main two anticonvulsants used nowadays in cancer patients, because of their superior side-effect and drug interaction profile when compared to older agents like carbamazepine. Although they may be slightly less effective (NNT 4–5) than the antidepressants, they are usually better tolerated, drowsiness, dizziness, and pedal oedema being the main side-effects. Both work via the same mechanism of action (voltagegated calcium channels in the spinal cord), but pregabalin has some

50, dose dependent

100

100

90–100

Diclofenac

Ibuprofen

Ketorolac

Naproxen

High

45

50 (35–82)

Nortriptyline

Venlafaxine

Duloxetine

33–60

>90

Gabapentin

Pregabalin

Anticonvulsants

30–60

Amitriptyline

Antidepressants

20–40

50, dose dependent

60–70 oral 30–40 rectal

Celecoxib

Aspirin

Acetaminophen

Acetaminophen and NSAIDs

Bio-availability (%)

Nil

90

99

20

99

100

97

50–70

Negligible at therapeutic doses

Protein binding (%)

Table 10.2  Pharmacokinetic parameters of selected co-analgesic agents

Nil

Nil

CYP2D6 and CYP1A2

CYP2D6

CYP2D6

CYP2D6; also CYP1A2, CYP2C19, CYP3A4. Active metabolites

CYP2C9

Glucuronidation;