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Table of contents :
Contents......Page 6
Contributors......Page 10
Dedication......Page 14
Foreword......Page 16
Introduction......Page 18
1 Opioid Dependence in America: HISTORY AND OVERVIEW......Page 20
2 Experience With Buprenorphine in the United States, 2002–2008......Page 46
3 General Opioid Pharmacology......Page 64
4 Efficacy and Safety of Buprenorphine......Page 78
5 Patient Assessment......Page 98
6 Clinical Use of Buprenorphine......Page 114
CASE 1......Page 135
7 Clinical Management I: BUPRENORPHINE TREATMENT IN OFFICE-BASED SETTINGS......Page 138
CASE 2......Page 164
8 Clinical Management II: PSYCHOSOCIAL AND SUPPORTIVE TREATMENT......Page 166
CASE 4......Page 180
CASE 5......Page 181
9 Psychiatric Comorbidity......Page 184
CASE 6......Page 206
CASE 8......Page 207
10 Medical Management......Page 210
CASE 9......Page 226
11 Management of Acute and Chronic Pain......Page 232
CASE 10......Page 242
12 Opioid Use by Adolescents......Page 246
CASE 11......Page 268
13 Logistics of Office-Based Buprenorphine Treatment......Page 272
14 Comments on the Case Vignettes......Page 294
Appendix 1 USEFUL WEB SITES AND RECOMMENDED READINGS......Page 304
Appendix 2 STUDY QUESTIONS AND ANSWER GUIDE......Page 310
A......Page 342
B......Page 343
C......Page 344
D......Page 346
E......Page 347
H......Page 348
I......Page 349
M......Page 350
N......Page 351
O......Page 352
P......Page 353
S......Page 355
U......Page 357
X......Page 358
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HANDBOOK OF

Office-Based Buprenorphine Treatment OF OPIOID DEPENDENCE

This page intentionally left blank

HANDBOOK OF

Office-Based Buprenorphine Treatment OF OPIOID DEPENDENCE Edited by

John A. Renner Jr., M.D. Petros Levounis, M.D., M.A.

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. Copyright © 2011 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 14 13 12 11 10 5 4 3 2 1 First Edition Typeset in Adobe’s ACaslon and Eurostile American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Handbook of office-based buprenorphine treatment of opioid dependence / edited by John A. Renner Jr., Petros Levounis. — 1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-58562-369-3 (pbk. : alk. paper) 1. Opioid abuse—Chemotherapy. 2. Buprenorphine—Therapeutic use. I. Renner, John A., 1938– II. Levounis, Petros. [DNLM: 1. Opioid-Related Disorders—drug therapy. 2. Buprenorphine— therapeutic use. WM 284] RC568.O45H36 2010 615'.7822—dc22 2010026314 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

Contents Contributors . . . . . . . . . . . . . . . . . . ix Dedication . . . . . . . . . . . . . . . . . . . . xiii Foreword . . . . . . . . . . . . . . . . . . . . xv Frank J. Vocci, Ph.D.

Introduction. . . . . . . . . . . . . . . . . . xvii

1

Opioid Dependence in America HISTORY AND OVERVIEW . . . . . . . . . . . . . 1 John A. Renner Jr., M.D.

2

Experience With Buprenorphine in the United States, 2002–2008 . . 27 David A. Fiellin, M.D.

3

General Opioid Pharmacology . . . . . . 45 John T. Pichot, M.D.

4

Efficacy and Safety of Buprenorphine . . . . . . . . . 59 Eric C. Strain, M.D.

5

Patient Assessment . . . . . . . . . . . . 79 Petros Levounis, M.D., M.A.

6

Clinical Use of Buprenorphine . . . . . . 95 Ricardo Restrepo, M.D., M.P.H. Petros Levounis, M.D., M.A. CASE 1 ............................................116

7

Clinical Management I BUPRENORPHINE TREATMENT IN OFFICE-BASED SETTINGS . . . . . . . . . . . . 119 Jeffrey D. Baxter, M.D. CASE 2 ............................................145

8

Clinical Management II PSYCHOSOCIAL AND SUPPORTIVE TREATMENT . . . . . . . . . . . . 147 Peter D. Friedmann, M.D., M.P.H. Patricia A. Cioe, M.S., R.N.P. CASE 3 ............................................161 CASE 4 (CONTINED IN CHAPTER 11) ............161 CASE 5 (CONTINUED IN CHAPTER 9) ............162

9

Psychiatric Comorbidity. . . . . . . . . 165 Elinore F. McCance-Katz, M.D., Ph.D. CASE CASE CASE CASE

10

5 (CONTINUED FROM CHAPTER 8) ........ 187 6 ........................................... 187 7 ........................................... 188 8 ........................................... 188

Medical Management . . . . . . . . . . 191 Jeanette M. Tetrault, M.D. Lynn E. Sullivan, M.D. David A. Fiellin, M.D. CASE 9 ........................................... 207

11

Management of Acute and Chronic Pain . . . . . . . . . 213 Daniel P. Alford, M.D., M.P.H., F.A.C.P. CASE 4 (CONTINUED FROM CHAPTER 8) ........ 223 CASE 10 ......................................... 223

12

Opioid Use by Adolescents . . . . . . . 227 Ximena Sanchez-Samper, M.D. Sharon Levy, M.D., M.P.H. CASE 11 ......................................... 249

13

Logistics of Office-Based Buprenorphine Treatment . . . . . . . 253 Joji Suzuki, M.D.

14

Comments on the Case Vignettes . . 275 John A. Renner Jr., M.D. Gregory Acampora, M.D.

Appendix 1 USEFUL WEB SITES AND RECOMMENDED READINGS . . . . . . . . 285 Appendix 2 STUDY QUESTIONS

AND

ANSWER GUIDE . . . 291

Index . . . . . . . . . . . . . . . . . . . . . . 323

Contributors Gregory Acampora, M.D. Teaching Fellow/Resident, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts Daniel P. Alford, M.D., M.P.H., F.A.C.P. Associate Professor of Medicine, Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts Jeffrey D. Baxter, M.D. Assistant Professor, Department of Family Medicine and Community Health, University of Massachusetts Medical School, Worcester, Massachusetts Patricia A. Cioe, M.S., R.N.P. Staff Nurse Practitioner, Division of General Internal Medicine, Rhode Island Hospital, Providence, Rhode Island David A. Fiellin, M.D. Associate Professor, Departments of Internal Medicine and Investigative Medicine, Yale University School of Medicine, New Haven, Connecticut Peter D. Friedmann, M.D., M.P.H. Professor of Medicine and Community Health, Alpert Medical School of Brown University; Director, Center on Systems, Outcomes and Quality in Chronic Disease and Rehabilitation, Providence Veterans Affairs Medical Center; Director, Research Section, Division of General Internal Medicine, Rhode Island Hospital, Providence, Rhode Island Petros Levounis, M.D., M.A. Director, The Addiction Institute of New York; Chief, Division of Addiction Psychiatry, The St. Luke’s and Roosevelt Hospitals; Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York

ix

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Sharon Levy, M.D., M.P.H. Assistant Professor of Pediatrics, Harvard Medical School; Medical Director of the Adolescent Substance Abuse Program, Children’s Hospital, Boston, Massachusetts Elinore F. McCance-Katz, M.D., Ph.D. Professor of Psychiatry, University of California, San Francisco, School of Medicine, San Francisco, California John T. Pichot, M.D. Private Practice, General Psychiatry and Addiction Psychiatry; South Texas Veterans Healthcare System, San Antonio, Texas John A. Renner Jr., M.D. Associate Professor of Psychiatry, Boston University School of Medicine, VA Boston Healthcare System, Boston, Massachusetts Ricardo Restrepo, M.D., M.P.H. Assistant Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons; Director, Addiction Psychopharmacology Clinic, The Addiction Institute of New York at St. Luke’s and Roosevelt Hospitals; Attending Psychiatrist, Adult Outpatient Clinic, St. Luke’s and Roosevelt Hospitals, New York, New York Ximena Sanchez-Samper, M.D. Instructor, Harvard Medical School; Addiction Psychiatrist, Adolescent Substance Abuse Program, Children’s Hospital, Boston, Massachusetts Eric C. Strain, M.D. Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland Lynn E. Sullivan, M.D. Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut Joji Suzuki, M.D. Medical Director of Addictions, Department of Psychiatry, Brigham and Women’s Hospital; Instructor in Psychiatry, Harvard Medical School, Boston, Massachusetts Jeanette M. Tetrault, M.D. Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut

Disclosures of Interest

xi

Disclosures of Interest The following contributors to this book have indicated a financial interest in or other affiliation with a commercial supporter, a manufacturer of a commercial product, a provider of a commercial service, a nongovernmental organization, and/or a government agency, as listed below: Peter D. Friedmann, M.D., M.P.H. Speakers’ Bureau: Reckitt Benckiser Petros Levounis, M.D., M.A. Speakers’ Bureau: AstraZeneca, Cephalon, Forest Pharmaceuticals, Pfizer, Takeda John A. Renner Jr., M.D. Speakers’ Bureau: Forest Labs (acamprosate); Stock Ownership: Johnson & Johnson Eric C. Strain, M.D. In the past 12 months, I have provided consulting services or received other forms of support (e.g., travel, research) from the following companies: Abbott Laboratories, Reckitt Benckiser Pharmaceuticals, Shire Pharmaceuticals*, The Oak Group*, Titan Pharmaceuticals. *No direct connection with the contents of the chapter. In the past 12 months, I have also received forms of support (e.g., honoraria, research grants) from the following federal agencies or from contract agencies used by these agencies: The Center for Substance Abuse Treatment (CSAT); The National Institute on Drug Abuse (NIDA). The following contributors to this book have indicated no competing interests to disclose during the year preceding manuscript submission: Gregory Acampora, M.D.; Daniel P. Alford, M.D., M.P.H., F.A.C.P.; Jeffrey D. Baxter, M.D.; Patricia A. Cioe, M.S., R.N.P.; Sharon Levy, M.D., M.P.H.; Elinore F. McCance-Katz, M.D., Ph.D.; John T. Pichot, M.D.; Ricardo Restrepo, M.D., M.P.H.; Lynn E. Sullivan, M.D.; Joji Suzuki, M.D.; Jeanette M. Tetrault, M.D.

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Dedication PEOPLE SOMETIMES ASK US, “Why do you do this work?” The assumption is that caring for addicts is frustrating and depressing; these patients don’t get better and are manipulative, ungrateful, or worse. These ideas have always seemed strange and more than a little sad to us—and very foreign to our actual experience as clinicians. The introduction of buprenorphine in the United States coincided with the crystal methamphetamine epidemic in the gay community and the first wave of young veterans returning from conflicts in the Middle East. Our work with buprenorphine has been affected profoundly by these events. Early in the crystal methamphetamine epidemic, I started treating gay men who were addicted not only to crystal meth but also to opioids, alcohol, and nicotine; sometimes sexual compulsions further complicated the clinical picture. As director of the Addiction Institute of New York, I enlisted the support of the city of New York in creating a multifaceted treatment program specifically designed for gay men who struggle with addictive substances and behaviors. The work and collaboration of great colleagues, the use of sublingual buprenorphine, and the techniques of motivational interviewing have been the key ingredients in the project’s enormous success. Gay men from all walks of life—from the famous executive who helplessly saw his empire crumble under his meth use, to the 19-year-old musician who just arrived in New York only to find himself in the midst of prostitution and heroin addiction— now come to a “safe space” to discuss addiction, sexuality, and living as gay men in a primarily homophobic world. Every day I’m inspired by the courage of these men who fight addiction, battle discrimination, and pursue their individual paths to healing and happiness—quite often in the face of nothing less but ostracism by family and society. I am profoundly grateful to my patients who have trusted me to be a partner in their recovery and would like to dedicate this book to them. Petros Levounis, M.D., M.A. xiii

xiv Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

As part of my work in the addiction program at the VA Boston Healthcare System, I decided to start a buprenorphine therapy group for returning veterans. They easily bonded as combat veterans and as recovering addicts, and buprenorphine very quickly enabled most of them to gain control over their opioid use problem. The core issue for the “BUP Group” became their struggle to regain self-respect and confidence for a meaningful future. How do you square your image as a tough combat veteran—responsible for the survival of your squad— with the conning, lies, and degradation of addicted behavior? What do you do with the terror and guilt that haunts your dreams when you know that opioids will provide instant relief? The BUP Group taught me the meaning of true courage—honestly facing the worse in your past and finding the strength both to forgive yourself and to move forward. For some of these men, recovery has come with little or no support or trust from family, friends, and even other members of 12-step groups. The unique bond within this remarkable group of combat veterans has been a powerful source of understanding, respect, and caring. It has been my good fortune to be a part of the buprenorphine story, to see recovery become possible where before there was little hope and much despair. I have learned that we don’t cure addiction, but we can manage it successfully and that recovery is real. This book is dedicated to all the patients who have used buprenorphine to reclaim their hope and their lives, but most especially to the veterans in my BUP Group. With my love, respect, and admiration, it has been my privilege to share this road with you. John A. Renner Jr., M.D.

Foreword THE NATIONAL INSTITUTE on Drug Abuse (NIDA) had an interest in the development of buprenorphine as a treatment for opioid dependence in the late 1970s. Although a previous licensing agreement with Norwich Eaton Pharmaceuticals prevented Reckitt & Colman (now Reckitt Benckiser) from codeveloping buprenorphine for opioid dependence with NIDA, they provided NIDA with buprenorphine to perform clinical studies in the 1980s. Following clinical pharmacology studies that pointed to the sublingual route as the preferred route of drug delivery, Drs. Ed Johnson, Jerry Jaffe, and Paul Fudala of the NIDA Intramural Research Program performed a clinical trial of buprenorphine that provided the first evidence of its effectiveness for the treatment of opioid dependence (Johnson et al. 1992). I believe this compelling evidence was crucial in Reckitt & Colman’s decision to develop buprenorphine for the treatment of opioid dependence. NIDA negotiated a Cooperative Research and Development Agreement (CRADA) with Charles O’Keeffe, Reckitt & Colman’s U.S. president in 1993–1994. NIDA collaborated with Reckitt & Colman on a liquid dosage form and, subsequently, on the solid dosage forms that are today known as Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone). NIDA’s grantees and contractors performed the pharmacokinetics studies, clinical pharmacology studies (to determine the ratio of buprenorphine to naloxone for the Suboxone formulation), and multicenter clinical trials (with the Department of Veterans Affairs Cooperative Studies Program) that were necessary for the U.S. Food and Drug Administration approval of Subutex and Suboxone, which occurred in October 2002. Successful partnerships require groups of competent, effective people working toward a common goal. Improving the treatment of opioid dependence was the common goal that propelled the CRADA between NIDA and Reckitt Benckiser. Subutex and Suboxone were launched in January 2003. Since that time, thousands of physicians have become registered to prescribe buprenorphine and hundreds of thousands of patients are receiving this medication, alone or in combination with naloxone. By July 2009, the 16,700 physicians who were xv

xvi Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

registered to prescribe Subutex or Suboxone treated over 1 million people with these medications. This is a testament to the successful partnership between NIDA and Reckitt Benckiser and the adoption by the treatment community of Subutex and Suboxone as first-line products for managing opioid dependence. This book is a continuation of the collaborative spirit that sustained the NIDA–Reckitt Benckiser CRADA. May you use the information contained herein to improve the lives of the patients you treat with Subutex and Suboxone. Frank J. Vocci, Ph.D. President, Friends Research Institute Baltimore, Maryland July 2009

References Johnson RE, Jaffe JH, Fudala P: A controlled trial of buprenorphine treatment for opioid dependence. JAMA 267:2750–2755, 1992

Introduction Background Between 2002 and 2010, a group of American Psychiatric Association (APA) members and staff devoted considerable time and effort to the presentation of more than 100 buprenorphine training courses across the United States. Under the supervision of the former APA Council on Addiction Psychiatry, this was part of a larger training effort that also included the American Academy of Addiction Psychiatry, the American Society of Addiction Medicine, and the American Osteopathic Association of Addiction Medicine. To date, more than 23,000 physicians have completed the training required to quality for the Drug Enforcement Administration (DEA) waiver to prescribe buprenorphine in an office-based setting, and the Council on Addiction Psychiatry (hereafter, “the Council”) made significant progress toward its goal of expanding the number of psychiatrists trained to treat opioid-dependent patients. The bulk of the funding for the buprenorphine training courses was provided by Reckitt Benckiser, the manufacturer of Suboxone (the sublingual buprenorphine-naloxone tablet), in the form of unrestricted educational grants to the various professional societies. In anticipation of the end of its exclusivity rights to the drug, Reckitt Benckiser eliminated the majority of these training grants in 2008. The leadership of the Council recognized that the end of commercial funding presented a major challenge for the APA to develop new options for training physicians. The inspiration for this manual came primarily from Beatrice Eld, Associate Director, APA’s Department of Quality Improvement and Psychiatric Services. She is the APA’s primary staff support for the Council and the individual most responsible for organizing all of the APA buprenorphine courses. Ms. Eld opened discussions about this book with American Psychiatric Publishing and encouraged us to take on this project as a compliment to other APA buprenorphine training activities. We are sincerely grateful for her support and enthusiasm—none of the APA’s success with buprenorphine training would have been possible without her dedication and hard work. xvii

xviii Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

How to Use This Manual Although it is our intention that this manual will serve as a general resource for anyone interested in the problem of opioid dependence—and in particular the role of buprenorphine in office-based treatment—the core of the manual is designed to mirror the content of the face-to-face buprenorphine training courses. It is intended to cover all of the basic information needed to care for buprenorphine patients. The print format permitted us to provide a depth of information not possible in the face-to-face courses, and particularly to expand on topics such as counseling approaches and the treatment of adolescents, which were rarely included in the original courses. One of the most successful elements of the courses was the small group case discussions. We have therefore included a number of brief case vignettes throughout the manual (in Chapters 6–12). The cases were chosen to illustrate important clinical or administrative issues, and each is followed by a series of questions that will focus the reader’s attention on specific aspects of the cases. We recommend that readers review the cases after reading the relevant chapters and that they then check the case discussions at the end of the manual (Chapter 14, “Comments on the Case Vignettes”) to be sure that they correctly understand the material that has been presented. The chapter authors are all expert clinicians and most of them regularly participated as faculty in buprenorphine training programs. This volume, therefore, draws on a wealth of clinical and educational expertise. We have endeavored to present the information in a manner that is both practical and accessible. Two useful appendixes also are provided for readers: Appendix 1, “Useful Web Sites and Recommended Readings,” provides a listing of resources that clinicians will find valuable in the practice of office-based buprenorphine treatment. In addition, questions are included in Appendix 2, “Study Questions and Answer Guide,” to help readers assess their knowledge of the material presented and to ensure their understanding of the major points in the text.

1 Opioid Dependence in America HISTORY

AND

OVERVIEW

John A. Renner Jr., M.D.

OPIOID ABUSE and dependence have been a serious problem in the United States since before the Civil War. This chapter traces the evolution of this problem from the era of opium-laced patent medicines, through the problems with injectable morphine after the Civil War, to the heroin epidemics of the twentieth century, and finally to the current epidemic of opioid pharmaceutical abuse that began in the 1990s. I emphasize the history of medical efforts to manage opioid dependence and recurrent conflicts with a public policy approach that has emphasized criminal justice solutions to the problem. The introduction of office-based buprenorphine treatment is best understood as an effort to restore a medical treatment model and a more coherent public health approach to what has become an intractable medical, legal, and social problem.

Opioid Dependence 1830–1995 OPIATE ABUSE

IN THE

NINETEENTH CENTURY

In eighteenth-century America, opium extracts such as laudanum, which contained alcohol, and black drop opium, which contained no alcohol, were common 1

2

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

ingredients in a wide range of prescriptions and patent medicines. These medications were used to treat food poisoning and other gastrointestinal problems, and were valued for their sedating and calming effects. The first apparent opioid problem in the United States occurred in the early nineteenth century when patent medicines laced with tincture of opium were readily available from apothecaries or door-to-door peddlers. Because the drugs were cheap, individuals with mild states of dependence had no problem maintaining medication supplies and had relatively little functional disability. The typical abuser at that time was a white, middle-class farm housewife who became addicted while self-medicating a wide range of physical and psychological ailments. Although some individuals were more impaired by their dependency, there was no association with criminal behavior. At worse, the addict was perceived as “sickly” or neurasthenic (Musto 1999). Physicians and the public associated the risks for dependence with the lower social classes. The risks for dependence were noted, but they were thought to be minimal and to be balanced by the medicinal benefits of opium. Some physicians even claimed that opiates could improve the functioning of strong-willed individuals (Wood 1868). Advances in technology in the early nineteenth century permitted the isolation of specific alkaloids from crude opium and led to the identification of morphine as a potent agent with significant physiological and psychological effects. Commercial morphine production began in the United States in 1832. The invention of the hypodermic syringe permitted the direct injection of this powerful and habit-forming substance and opened the door to both more effective pain treatment and increased risks for opioid dependence. A second and more visible group of nineteenth-century addicts were Civil War veterans who became addicted to intramuscular morphine after being treated for combat injuries. By 1870, some physicians began to recognize the habit-forming risk of morphine injections, though they were thought to present less of a dependence risk than oral opium preparations (Allbutt 1870). In the decades following the Civil War, it became common medical practice for physicians to give patients morphine as long-term therapy to manage chronic pain. This morphine dependence syndrome was called soldier’s disease, a reflection of both the origin of the disorder, the relatively acceptable social status of the patient, and the medical paradigm that guided society’s understanding of the condition. During the late nineteenth century, rates of morphine dependence in the United States far exceeded those of other Western industrialized nations. Although this was commonly attributed to the aftermath of Civil War injuries, other major European nations also experienced wars and extensive use of morphine without having comparable rates of dependence (Musto 1999). The reasons for the high levels of U.S. opium consumption and the unique vulnerability to opioid dependence in this country have never been adequately explained. In the United States, social attitudes regarding the long-term use of opiates began to shift with the increased immigration of Chinese laborers and growing

Opioid Dependence in America

3

public concern about the devastating effect that opium abuse had on China. This, along with the growth of the Temperance Movement, led to a fear of opium addiction as a dangerous, foreign, “un-American” problem that needed to be eradicated. These attitudes led to a decline in the per capita consumption of crude opium, as was first noted in 1887. (The misperception of opioid abuse as un-American remains a common attitude, despite data that suggest that compared with other advanced European nations, U.S. citizens have an unusual propensity to abuse opioids.) By the end of the nineteenth century, the conceptual paradigm for opioid dependence had shifted from a medical model to a moral and criminal justice model—a conceptual ambiguity that continued throughout the twentieth century. Although the medical value of the drug was not questioned, physicians gradually came to recognize the dangers associated with the overprescription of morphine. There was a perception that the risks of addiction were most prevalent in immigrant groups such as the Chinese and in the lower social classes. Unlike with alcohol, there was no evidence that opiates destroyed body tissues. Therefore, it was presumed that the social deterioration associated with chronic opiate use was a reflection of the user’s weak character and lack of morals. Very gradual dose reduction, or detoxification, was thought to be the cure, though it was recognized that successful treatment requires a high level of motivation. In Germany, there were reports of high relapse rates following attempts to wean patients from morphine, and it was hypothesized that regular use of morphine would induce predictable physiological changes that would make anyone an addict (Levinstein 1878). These observations contrasted with the dominant opinion in England and in the United States, and supported the notion that the moral deterioration associated with addiction was a consequence of the disorder and not the cause. By 1900, there were an estimated 250,000 opiate addicts in the United States. In many cities, efforts to manage the problem shifted from the individual physician’s office to a system of morphine clinics, where groups of addicts were given daily morphine injections. In some cities these clinics were administered by law enforcement authorities, a further reflection of the confusion between the medical and criminal justice paradigms. Opiate dependence, along with alcoholism and syphilis, were lumped together as vices, social afflictions that were difficult to cure, that predominantly impacted the lower classes, and that led to eventual physical, moral, and social deterioration. With the gradual development of modern treatments for many common medical conditions, the value of opiates as all-purpose medications for a wide range of physical and psychological conditions became identified with a form of backward and unscientific medical practice. This shift in practice made it much easier to support the need to closely regulate this aspect of medicine. Beyond modest tariffs, no restrictions on the importation of opium and opium products existed during the nineteenth century. The unregulated use of

4

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inexpensive patent medicines, often with opiates or cocaine as their primary active ingredient, reached a peak in the late nineteenth century. Attempts by individual states to regulate the sale of opiate products were largely ineffective, although some states and cities began to require that morphine could only be ordered with a physician’s prescription. There was no requirement for accurate labels on patent medicines involved in interstate commerce until the passage of the Pure Food and Drug Act in 1906. In 1909, the importation of smoking opium was prohibited. None of these measures was successful in eliminating the opiate abuse problem.

THE HARRISON ACT AND THE PROHIBITION OF ADDICTION TREATMENT The control of opioid medications changed dramatically in 1914 with the passage of the Harrison Narcotics Tax Act, which established the U.S. Food and Drug Administration (FDA) and a federal system for the regulation of drug manufacturers, pharmacies, and physician prescribing. The Harrison Act made it illegal to prescribe opioids for the maintenance or treatment of addiction. This led to the closing of the existing 44 morphine maintenance clinics, and ultimately the jailing of more than 3,000 physicians who refused to stop prescribing opioids for their patients. After the Supreme Court upheld the Harrison Act in 1919, organized medicine abandoned all support for the treatment of addicts, and management of the opioid addiction problem was conclusively shifted to the criminal justice system. Ultimately, the criminal justice model proved ineffective as a strategy for handling the opioid addiction problem. In the late nineteenth century, a process had been discovered for converting morphine into heroin (diacetylmorphine). The commercial availability of heroin in 1898 introduced a new, potent, and highly reinforcing opioid that insured the perpetuation of the opioid dependence problem. Regulation of patent medicine production and the elimination of any legitimate medical treatment for opioid addiction ushered in the era of the heroin black market. Despite efforts to eliminate the problem, there were major heroin epidemics in the United States following World War I, World War II, and the Vietnam War. Chronic heroin users were stigmatized as a deviant and criminal minority. For most of the twentieth century, the lifetime risk for heroin dependence was assumed to be relatively low and to range from 0.4% to 0.7% (Compton et al. 2007; Grant 1996; Kessler et al. 1994; Regier et al. 1990). At any one time, there were an estimated 1,000,000 active heroin addicts in the United States. The typical addict in this era was a white, urban, working class male; the largest and most visible segment of the addicted population was localized in New York City.

Opioid Dependence in America

5

In the 1960s Vincent Dole, an internist at The Rockefeller Institute (now The Rockefeller University), was approached by New York law enforcement authorities and was asked to explore a medical approach for managing opioid addiction. In 1965, Dole and his wife Marie Nyswander published their landmark paper on the efficacy of methadone maintenance (Dole and Nyswander 1965). The legalization of methadone maintenance treatment occurred in 1972 when the FDA issued the initial federal methadone regulations (37 Federal Register 26790–26807, Vol. 37, No. 242, December 15, 1972), which reversed elements of the Harrison Act. While this change reflected the failure of the prohibitionist criminal justice model, the FDA regulations established a heavily regulated methadone clinic system that typically operated outside of mainstream medical practice. Dole and Nyswander stressed the importance of adequate methadone doses to block the euphoria caused by heroin; the need for long-term, if not indefinite, maintenance treatment; and the importance of counseling and other ancillary psychosocial services. Over the next 30 years, there were rarely more than 100,000 addicts in methadone maintenance treatment at any one time, generally less than 10% of the population in need of treatment. Despite evidence of its efficacy (Ball and Ross 1991), methadone maintenance treatment was never welcomed by the majority of addicts or by most communities. There is little evidence of efficacy for most of the other treatments available for opioid dependence. Short-term detoxification, even when followed by outpatient counseling, is generally associated with a 95% relapse rate. Although the therapeutic community movement attracted some measure of public support, therapeutic community programs have never been particularly effective in retaining participants. Rarely do more than 10% of voluntarily admitted patients complete treatment. However, among those individuals who complete a 9- to 18-month therapeutic community program, about 80% achieve longterm recovery (Hubbard et al. 1997). Today most of these programs primarily work with court-referred individuals, though retention in treatment still remains a problem. The most comprehensive review of the long-term course of opioid dependence is the work of Hser et al. (2001), who conducted a 33-year follow-up of 581 male heroin addicts treated in the California Civil Addict Program from 1962 to 1964 (Figure 1–1). By 1996–1997, at the time of the 33-year followup, 284 individuals (48% of the original sample) had died. Among the 242 surviving subjects who were interviewed, 40.5% had used heroin within the past year, 20.7% tested positive for heroin, 9.5% refused to be tested, and 4% were incarcerated. Also, 22.1% were daily alcohol drinkers and many others reported other illicit drug use (35.5%, marijuana; 19.4%, cocaine; 10.3%, crack; and 11.6%, amphetamines). Only 22% were abstinent and another 6% were in methadone maintenance treatment. Overall this study demonstrates the lethal-

6

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

ity of heroin addiction; the relatively low rate of recovery, even with enforced treatment; and the long-term stable pattern of heroin use for the majority of addicts. Heroin addiction was demonstrated to be a chronic lifetime disorder with severe health and social consequences (Hser et al. 2001).

HEROIN ABUSE IN THE POST–WORLD WAR II/VIETNAM ERA From World War II to the early 1990s, heroin abuse was the predominant opioid problem in the United States. Annual estimates of drug use have been available from the Monitoring the Future survey since 1975 and the National Survey on Drug Use and Health (NSDUH; formerly called the National Household Survey on Drug Abuse) since the early 1990s, but information on drug use disorders has rarely been collected. Data from the 2006 NSDUH indicate that the annual number of new users of heroin ranged from 28,000 to 80,000 between 1984 and 1994. This increased to an average of 100,000 from 1995 to 2001, but then declined slightly to 91,000 in 2006 (Substance Abuse and Mental Health Services Administration 2007). As a percentage of the total U.S. population, the annual number of new heroin users was relatively unchanged from 1965. NSDUH 2006 data estimated that 3.79 million Americans had used heroin at least once in their lifetime; 323,000, or less than 10% of that group, were classified with either heroin abuse or dependence (Substance Abuse and Mental Health Services Administration 2007).

Prevalence of Substance Use Disorders The 2006 NSDUH data are consistent with earlier studies that estimated that 10%–15% of individuals who use licit or illicit opioids are at risk for developing dependence or abuse. The risk is presumed to be significantly higher in individuals with co-occurring psychiatric disorders, particularly depressive disorder). The most recent major national survey on substance use disorders, the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), collected specific data on the use and abuse of both illicit drugs and prescribed medications. This was the first national survey that separated data on opioids from data on other drugs of abuse, and the first to separate data on heroin from data on the abuse of prescription pain relievers. NESARC data indicated that prevalence rates of 12-month and lifetime drug dependence were 0.6% and 2.6%, respectively; the corresponding rates for drug abuse were 1.4% and 7.7%. Higher rates of abuse and dependence were re-

Abstinence

90

Methadone maintenance

80

Sample, %

70

Occasional use

22% 2% 6% 7% 4%

60 Daily narcotic use

50

Opioid Dependence in America

100

40 30

48%

Incarcerated Deceased

20 10 Unknown

12%

0 ‘56 ‘58 ‘60 ‘62 ‘64 ‘66 ‘68 ‘70 ‘72 ‘74 ‘76 ‘78 ‘80 ‘82 ‘84 ‘86 ‘88 ‘90 ‘92 ‘94 ‘96

1956 through 1996

FIGURE 1–1. The natural history of narcotics addiction among a male sample (N=581) [follow-up of the California Civil

7

Addict Program]. Source. Reprinted from Hser YI, Hoffman V, Grella CE, et al: “A 33-year follow-up of narcotic addicts.” Archives of General Psychiatry 58:503–508, 2001. Copyright © 2001 American Medical Association. All rights reserved.

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

ported in men versus women, and in American Indians versus whites. The mean age of onset for opioid dependence or abuse was 22.8 years. Data for the nonmedical use of prescription opioids indicated a 4.7% lifetime prevalence of use, compared with a lifetime prevalence of 1.4% for nonmedical opioid drug use disorders. These findings suggest that there is at least a 30% risk for developing a drug use disorder among users of prescription pain relievers, which is between two and three times the risk reported for the development of drug use disorders among users of heroin. The most recent national survey, NSDUH 2008, reported that 1.7 million individuals age 12 or older met criteria for dependence or abuse of pain relievers in the past year; this number has been stable for the last 4 years (Substance Abuse and Mental Health Services Administration 2009b). Despite the growing number of individuals with opioid use disorders, fewer than one-third of individuals in this group have ever received treatment. NESARC data showed a lag of 3.4 years between the mean age of onset of an opioid use disorder (22.8 years) and the mean age of first treatment (26.2 years) (Compton et al. 2007).

The New Epidemic of Abuse of Pain Relievers For most of the twentieth century, the illicit use of pain relievers was assumed to be a relatively small part of the U.S. drug problem. Physicians thought that there was minimal risk for dependence among individuals treated for acute or chronic pain. The introduction of pentazocine (Talwin) in the 1960s was associated with a brief period of abuse after addicts discovered that they could induce a potent sense of euphoria by injecting a combination of Talwin and amphetamines (“Ts and blues”). This problem was resolved after the FDA ordered a reformulation of the drug as a combination tablet of Talwin and naloxone (Talwin Nx). The abuse of opioid pharmaceuticals remained at a low level until more potent pain medications were introduced to the U.S. market in the 1990s. From 1970 to 1995, the annual number of new nonmedical users of pain relievers was reported to range from 700,000 to 1,000,000 (Substance Abuse and Mental Health Services Administration 2005a). As the medical community became comfortable with the use of these new opioid pharmaceuticals for the treatment of severe pain, there was interest in the development of more potent medications with low abuse potential and with a longer duration of action that would permit pain patients to sleep through the night. Although oxycodone showed promise because of its potency, the sustained-release technology that had been successful in the development of a long-acting formulation of morphine, morphine sulfate (MS Contin), could

Opioid Dependence in America

9

not be successfully adapted for oxycodone. In 1996, Purdue Pharma resolved this problem with the introduction of OxyContin, an acrylic-coated formulation of oxycodone that dissolves slowly and provides 12 hours of pain relief. Doses ranging from 10 mg to 160 mg can be delivered with this formulation, far exceeding the 30-mg maximum dose of oxycodone tablets. Neither the FDA nor Purdue anticipated a significant abuse problem with such a slowrelease formulation, and Purdue was permitted to market OxyContin as a firstline medication for the treatment of nonmalignant pain with less abuse potential than other comparable pain relievers. The drug proved highly successful and rapidly gained a significant share of the U.S. market for pain medications (Meier 2003). Within 2–3 years of the introduction of OxyContin, physicians in rural Maine and Virginia reported that young adults were crushing the tablets and injecting or snorting the drug. With these methods of ingestion, users were exposed to very high doses of oxycodone. The experience was extremely euphoric and reinforcing, and many of the users rapidly became addicted. Correspondingly, the number of opioid overdose deaths reported nationally began to increase dramatically. It gradually became apparent that the reports of addictive behavior and the growing number of overdose deaths did not just involve individuals using the drug illicitly. Physicians began to report that patients being treated for legitimate pain problems were becoming addicted to OxyContin and that some of them were finding it impossible to stop using the drug (Meier 2003). Over the next few years, NSDUH data showed a dramatic increase in the number of nonmedical abusers of opioid pharmaceuticals. Physicians eventually realized that very little data existed to support the notion that there is a minimal risk for iatrogenic addiction when opioids are used to treat chronic pain. Most of the published reports describing a low risk for iatrogenic addiction dealt only with the treatment of acute pain. There was no credible published research on the risks for addiction with newer, long-acting, and high-potency drugs such as OxyContin, when prescribed for either acute or chronic pain. By 2000, the number of new abusers of pain relievers tripled to 2,500,000 (Figure 1–2) (Substance Abuse and Mental Health Services Administration 2003). While this change corresponded with the introduction of OxyContin to the U.S. market, it also reflected the widespread illicit use of drugs such as Vicodin (hydrocodone-acetaminophen) and Percocet (oxycodone-acetaminophen). Since that time there has been a significant shift from the abuse of heroin to the abuse of opioid pharmaceuticals as the dominant opioid abuse problem in the United States. In 2007, 5.2 million Americans—2.1% of individuals age 12 or older—reported using prescription pain relievers nonmedically in the past month. This rate did not differ significantly from the rate in 2002. However, the rate among males in this group increased from 2.0% to 2.6% during the same period. In 2007, there were 2,147,000 new initiates to

10

Pain relievers

New users (thousands)

2,500 2,000 1,500

Tranquilizers

1,000

Stimulants 500 Sedatives 0 1965

FIGURE 1–2. Source.

1970

1975

1980

1985

1990

1995

2000

Annual numbers of new nonmedical users of psychotherapeutics: 1965–2001. Substance Abuse and Mental Health Services Administration 2003.

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

3,000

Opioid Dependence in America

11

the abuse of pain relievers, surpassing even marijuana as the most common drug of abuse; in comparison, there were only 106,000 new users of heroin in 2007 (Figure 1–3) (Substance Abuse and Mental Health Services Administration 2008, 2009a). These numbers were comparable in 2008, when the NSDUH reported 2.176 million new initiates to the abuse of pain relievers compared with 2.2 million new initiates to marijuana use (Substance Abuse and Mental Health Services Administration 2009b). Of note is the decline in new initiates of OxyContin abuse from 615,000 in 2004 to 478,000 in 2008 (Substance Abuse and Mental Health Services Administration 2009b). The mean age for first use among new initiates to the abuse of pain relievers in 2007 was 21.2 years (Substance Abuse and Mental Health Services Administration 2008). This new group of drug abusers tends to be younger, better educated, and less antisocial than the typical heroin addict (Table 1–1). They initially use the drug orally or snort it, and are much less likely to use drugs intravenously. They are also more likely to have psychiatric problems such as depression or anxiety.

Buprenorphine and the Return to Office-Based Treatment More than 55.7% of people age 12 or older who abuse pain relievers are given their drugs for free by friends or relatives and another 14.8% buy or take the drugs from friends or relatives, whereas fewer than 4% purchase their drugs from a dealer or stranger (Figure 1–4) (Substance Abuse and Mental Health Services Administration 2007). Another 19.1% report they got the drug from just one physician. Although many in this group are able to control their use and remain occasional social users, a significant number become dependent. It has been estimated that 10%–30% of individuals exposed to licit and illicit opioids may develop symptoms of dependence or abuse. Rates may be significantly higher in individuals with a family history of drug or alcohol dependence, or in individuals with co-occurring psychiatric disorders, particularly individuals with attention-deficit/hyperactivity disorder or those exposed to combat trauma or sexual abuse. As users’ habits progress, they start purchasing drugs from illicit sources and often switch to heroin once they recognize that it is less expensive than pain relievers. At this point, some users, though not all, also switch from snorting to injecting heroin or other opioids. This transition is often associated with a rapid deterioration in social functioning and an increase in antisocial behavior. Although the total number of Americans with substance dependence or abuse has remained stable, ranging from 22.0 million in 2002 to 22.2 million

12

Past-year initiates (thousands)

2,147

2,090

2,000

1,500 1,232

1,000

906 781

775 642

500 270

198 106

58

0 Marijuana Cocaine Inhalants LSD Heroin Pain relievers Tranquilizers Ecstasy Stimulants Sedatives

FIGURE 1–3.

Past-year initiates for specific illicit drugs among persons age 12 or older: 2007. LSD=lysergic acid diethylamide; PCP=phencyclidine. Source. Substance Abuse and Mental Health Services Administration 2008.

PCP

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

2,500

13

Opioid Dependence in America

TABLE 1–1.

Comparison of heroin users with abusers of pain relievers

Characteristics

Pre-1995

Post-1995

Drug of choice

Heroin

Prescription pain relievers

Age

Older

Younger

Drug source

Dealer

Free from friends

Use pattern

Intravenous

Oral/snorting

Medical problems

Hepatitis C; HIV infection

None or pain issues

Legal problems

Common

Rare

Education

High school dropouts

Some college

in 2008, there has been an increase in the number of individuals abusing pain relievers, which now rank second to marijuana among significant illicit drugs of abuse in the United States. The current prevalence of nonmedical opioid use disorders is almost three times the level of prior estimates of heroin use disorders. Among young adults ages 18–25, the rate for current illicit use of prescription pain relievers increased from 4.1% in 2002 to 4.6% in 2007; among adults age 26 and older, the rate increased from 1.3% in 2002 to 1.6% in 2007 (Substance Abuse and Mental Health Services Administration 2009a). The incidence of past-year abuse of or dependence on pain relievers among persons 12 years old or older was stable at 1.7 million in both 2007 and 2008 (Substance Abuse and Mental Health Services Administration 2009b), although this is more than eight times the incidence of abuse or dependence involving heroin (Substance Abuse and Mental Health Services Administration 2008). NSDUH data estimated that 23.2 million persons age 12 or older needed treatment for an illicit drug or alcohol problem in 2007, of whom only 2.4 million received treatment at a specialty substance abuse treatment facility. Among the individuals in this group, 558,000 sought treatment for problems related to the abuse of pain relievers compared with 335,000 who sought treatment for heroin-related problems. More than 20.8 million individuals needed, but did not receive, substance abuse treatment. Among those who sought treatment, more than 30% were unable to access care because of lack of health insurance coverage or financial resources and another 15% either could not find treatment or lacked transportation (Substance Abuse and Mental Health Services Administration 2008). The increase in addiction to pain relievers has also fueled a secondary increase in heroin dependence. From 1984 to 1994 the number of new heroin us-

14

Drug dealer/ stranger More than 3.9% one doctor 1.6% One doctor 19.1%

Bought on Internet 0.1%

Other a 4.9%

Source where friend/relative obtained

Free from friend/relative 55.7% One doctor 80.7%

Bought/took from friend/relative 14.8% Just one doctor 80.7%

FIGURE 1–4.

More than one doctor 3.3% Free from friend/relative 7.3% Bought/took from friend/relative 4.9%

Othera 2.2%

Drug dealer/ stranger 1.6%

Where pain relievers were obtained for most recent nonmedical use among past-year users age 12 or older: 2006. Totals may not sum to 100% because of rounding or because suppressed estimates are not shown. aThe Other category includes these sources: “Wrote fake prescription,” “Stole from doctor’s office/clinic/hospital/pharmacy,” and “Some other way.” Source. Substance Abuse and Mental Health Services Administration 2007.

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Source where respondent obtained

Opioid Dependence in America

15

ers each year ranged from 28,000 to 80,000. The number averaged over 100,000 per year from 1995 to 2001, but dropped to 94,000 in 2007. In 2006, NSDUH data estimated that 3.79 million Americans had used heroin at least once in their lifetime; of that group 323,000 were classified with either heroin dependence or abuse, and 250,000 were estimated to be in methadone maintenance treatment (Substance Abuse and Mental Health Services Administration 2007). Concerns about the legal and clinical constraints mandated for methadone maintenance treatment and its relatively low level of appeal to most heroin addicts led to a search for a safer yet clinically effective alternative treatment. This problem became even more acute in the mid-1990s when the rapid increase in the number of individuals abusing opioid pharmaceuticals far outstripped the capacity of the addiction treatment system. Buprenorphine was identified as a target medication to develop for treating opioid dependence after early studies suggested clinical efficacy, a strong safety profile, and less abuse potential than methadone (see Chapter 4, “Efficacy and Safety of Buprenorphine”). Its very favorable safety profile suggested that buprenorphine could be prescribed safely in office-based clinical settings, thus avoiding the legal constraints of the methadone clinic system that were felt to discourage addicts from participating in treatment. Indeed, heroin addicts typically delay participation in methadone maintenance treatment for 4–5 years beyond the point when treatment is warranted. This delay typically translates into more severe social, behavioral, and medical deterioration, thus guaranteeing a more treatment-resistant and complicated condition. Before 2002, only methadone and LAAM (L-α-acetylmethadol) were approved as opioid agonist treatments and both medications could only be dispensed in heavily regulated opioid treatment programs (OTPs). When buprenorphine was approved by the FDA in 2002 for the treatment of opioid dependence in office-based settings, it was estimated that fewer than 1 in 10 heroin addicts were receiving any type of effective treatment. Detoxification treatment was still the most common form of treatment provided, despite little evidence of efficacy. Because of buprenorphine’s wider availability in less stigmatized, office-based settings, it was hoped that this new treatment option would both fill the gap in treatment resources and lead to earlier participation in treatment. The primary goal was to expand treatment options by returning opioid addiction treatment to mainstream medical practice and to train a much larger group of physicians to effectively care for these patients. It was hoped that better-educated physicians would encourage patients to shift to more effective long-term treatment models and to avoid repeated episodes of shortterm detoxification.

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Drug Addiction Treatment Act of 2000 Implementing this change required an amendment to the federal Controlled Substances Act, the Drug Addiction Treatment Act of 2000 (P.L. 106-310; DATA 2000). This law authorized practitioners to prescribe FDA-approved narcotic drugs in Schedules III, IV, and V, or combinations of such drugs, for maintenance or detoxification treatment of opioid dependence. The law placed no limit on the quantities of drugs that could be prescribed for unsupervised use, unless the drugs have been subject to an adverse determination. In essence, this meant that physicians could prescribe up to a month’s supply of medication, with refills, as deemed appropriate. DATA 2000 specified that the drugs utilized and the prescribing physicians (practitioners) must meet certain requirements. Practitioners had to be deemed qualifying physicians, which was defined as having the capacity to refer patients for appropriate counseling and ancillary services. There was no legal requirement that the physician personally provide drug counseling or other ancillary services. The intent of the law was to require that the physician provide the more traditional and relatively limited medical role of monitoring medication use. It was hoped that this would encourage physicians who were not specialists in addiction psychiatry or addiction medicine to expand their practice to include the management of opioid agonist treatment.

QUALIFYING PHYSICIANS Qualifying physicians were initially limited to no more than 30 patients at one time for an individual practice or a group practice. The 30-patient limit was intended to avoid the development of large buprenorphine practices, similar to the “methadone mills” seen in the 1970s, and to thus ensure more individualized and appropriate care for all buprenorphine patients. It was quickly realized that limiting group practices (which in many cases meant very large health care systems) to 30 patients was unrealistic and defeated the purpose of expanding access to addiction treatment. In 2006, DATA 2000 was amended to eliminate the 30-patient limit for group practices and to permit individual physicians to request approval to expand their practice to 100 patients after 1 year’s experience using buprenorphine. DATA 2000 defined seven possible routes through which a licensed physician could be recognized as qualifying under the requirements of the legislation: 1. Being board-certified in addiction psychiatry by the American Board of Psychiatry and Neurology

Opioid Dependence in America

17

2. Being certified in addiction medicine by the American Society of Addiction Medicine (ASAM) 3. Being certified in addiction medicine by the American Osteopathic Association (AOA) 4. Experience as an investigator in buprenorphine clinical trials 5. Having completed 8 hours of training provided by the American Psychiatric Association, the American Academy of Addiction Psychiatry, ASAM, the American Medical Association, AOA, or other organizations that may be designated by the secretary of the U.S. Department of Health and Human Services (DHHS) 6. Training or experience as determined by a state medical licensing board 7. Other criteria as established by the secretary of DHHS. To date, DHHS has not designated any other organization to provide training, and the American Medical Association has chosen not to offer buprenorphine addiction treatment training courses. No state medical licensing board has designated other specific training or experience as required for prescribing buprenorphine, nor has the secretary of DHHS established any other criteria. To obtain the waiver necessary to prescribe buprenorphine, a physician must notify the secretary of DHHS in writing by mail, by fax, or online at www.buprenorphine.samhsa.gov, giving his or her name and U.S. Drug Enforcement Administration (DEA) registration number, identifying the category under which he or she meets the criteria to become a qualifying physician (of the seven listed above), and certifying that that he or she will comply with the requirements of the law. The Substance Abuse and Mental Health Services Administration (SAMHSA) has developed a Waiver Notification Form (SMA-167), which is available online (www.buprenorphine.samhsa.gov/ howto.html) and which can be used to submit the required information. DHHS has 45 days to review the physician’s application to determine whether the physician meets the requirements of DATA 2000. Once a positive determination is made, DHHS notifies DEA, which then assigns a new DEA identification number to the practitioner. This number comprises the physician’s original DEA number, but the first letter is substituted with an X. DEA is also required to issue this X number if DHHS has not completed its review within the 45-day period. Once the practitioner has received his or her X number, the practitioner may begin to prescribe buprenorphine for the treatment of opioid dependence. Whenever physicians write a prescription under the requirements of DATA 2000, they must list both their primary DEA number and their X number on the prescription. Should a physician decide to prescribe sublingual buprenorphine for an unapproved indication—for a condition other than opioid dependence, such as for pain—he or she should not use the X number. Despite the fact that the X number is to be used only when prescribing bu-

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

prenorphine for the treatment of opioid dependence, it is important that practitioners recognize that any violation of federal or state prescribing regulations or narcotics laws puts both their X number and their primary DEA number at risk. The most common circumstance that has led to revocation of DEA registration is violation of the 30-patient or 100-patient limit.

PHYSICIAN LOCATOR The Waiver Notification Form also asks whether the applicant wants to be listed as a provider of buprenorphine treatment on the physician locator page of SAMHSA’s Web site (http://buprenorphine.samhsa.gov/bwns_locator). If the physician indicates his or her willingness to be listed, the physician’s name, address, and telephone number are posted on the Web site. Because prospective patients use this information to contact the physician, it is important that office contact information and not home numbers be provided. Physicians can choose to be listed on the physician locator page at any time and can also request that their information be removed at any time.

FDA APPROVAL

OF

BUPRENORPHINE

The second principal element of DATA 2000 is the specification that the authorization to treat opioid dependence in an office-based setting only applies to narcotic drugs that have been approved by the FDA for the maintenance or detoxification treatment of opioid dependence. The law applies to drugs, or combinations of drugs, in Schedules III, IV, or V. Sublingual buprenorphine and the combination sublingual formulation of buprenorphine-naloxone are the only drugs currently approved by the FDA for this purpose under DATA 2000. When the FDA approved these two sublingual formulations of buprenorphine, all of the available formulations of buprenorphine were rescheduled to Schedule III. Previously, the only FDA-approved formulations of buprenorphine were the intramuscular and intravenous formulations, marketed as Buprenex. Those formulations are only approved for the treatment of pain and were previously in Schedule V. Before the approval of sublingual buprenorphine, many hospitals had been using Buprenex outside of its approved labeling, for the inpatient detoxification of opioid dependence. It is important to understand that DEA considers such off-label use of Buprenex to be illegal and that practitioners risk sanctions if they continue this practice. There are no restrictions or special authorizations required for the use of sublingual buprenorphine in an inpatient setting for opioid detoxification, because in that setting the drug is dispensed and not prescribed. The buprenorphine waiver and X number are only required for the prescription of buprenorphine in the outpatient setting.

Opioid Dependence in America

19

DATA 2000 also permits the dispensing of sublingual buprenorphine in OTPs with a methadone program registration. There is no limit on the number of buprenorphine patients that can be treated in the OTP setting. However, the same regulations that apply to the dispensing of methadone also apply to the dispensing of buprenorphine in this setting. For the first 90 days, patients must be seen 6 days a week and are permitted only one take-home dose per week. After 90 days, if they have demonstrated good treatment compliance and there is no evidence of continued illicit drug use as demonstrated by urine toxicology, take-home medication may be increased to 2 days per week. Following standard OTP regulations, it would take a minimum of 2 years of proven treatment success before a patient would achieve monthly take-home medication privileges. These limitations on take-home privileges have significantly limited the use of buprenorphine in OTPs. In June 2009, the secretary of DHHS proposed a modification of OTP regulations to remove the restrictions on take-home use for buprenorphine dispensed in the OTP setting (74 Federal Register 29153– 29158, 42 CFR Part 8.12[i]). If implemented, this change will likely expand the use of buprenorphine in OTPs. In addition to providing closer supervision and monitoring than office-based treatment, the OTP setting also has the advantage of providing a higher level of on-site ancillary services. OTPs are a more appropriate setting for the treatment of complicated patients who require close monitoring and high levels of counseling and other services. OTPs are particularly appropriate for patients at high risk for diversion or for unstable individuals who are not at the stage where they can successfully comply with the requirements of office-based treatment. SAMHSA was mandated by DATA 2000 to publish a Treatment Improvement Protocol (TIP) that provides clinical guidance for the use of buprenorphine. This is TIP 40, “Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction,” which was published in 2004. The TIP Series has been an invaluable resource for clinicians treating patients with alcohol- and drug-related problems. Of particular interest are TIP 42, “Substance Abuse Treatment for Persons With Co-Occurring Disorders,” and TIP 43, “Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs.” All of the TIPs are available free of charge from SAMHSA and can be ordered from their Web site, www.kap.samhsa.gov/products/manuals/tips/ index.htm. Other useful sources of information and support are the Federation of State Medical Boards Web site, www.fsmb.org/pdf/2002_grpol_opioid_ addiction_treatment.pdf, and the National Alliance of Advocates for Buprenorphine Treatment, www.naabt.org. A particularly useful free mentoring system is the Physician Clinical Support System (PCSS), www.pcssmentor.org (see also Chapter 2, “Experience With Buprenorphine in the United States, 2002–2008”). PCSS is administered by ASAM under a contract from SAMHSA’s Center for Substance

20

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Abuse Treatment and in cooperation with the other DATA-approved training organizations (the American Psychiatric Association, the American Academy of Addiction Psychiatry, and AOA). Any physician with the buprenorphine waiver is eligible to join PCSS. He or she is then assigned to a buprenorphine expert clinician in the physician’s area, who acts as an ongoing mentor and supervisor. Mentors are readily available by telephone and e-mail and are also willing to have their mentees visit their offices for direct observation of patient care. PCSS has proved to be a particularly valuable resource for clinicians with little prior experience treating opioid- and heroin-dependent patients.

Evaluation of DATA 2000 DATA 2000 required that there be an evaluation of the results of this legislation during the first 3 years following FDA approval of buprenorphine. DHHS was mandated to assess the clinical efficacy of the drug, including whether the treatment has been effective in the office setting, whether access to treatment has improved, and whether there have been any adverse consequences for the public health. DEA was mandated to evaluate safety issues, including the extent of violations of the 30-patient limit, physician recordkeeping and security measures related to on-site drug storage, data related to emergency room drug mentions, and the risks of overdose (Substance Abuse and Mental Health Services Administration 2006b). In compliance with this mandate, DEA inspected two buprenorphine practitioners in each DEA district every 18 months. On the basis of these evaluation results, DHHS and DEA could decide whether the provisions of DATA 2000 should remain in effect. The law would cease to be in effect 60 days after an adverse evaluation was published; thus, additional legislative action was not required to repeal the law. Should difficulties such as significant misuse or drug diversion become a major problem, it would be relatively easy for these government agencies to terminate office-based treatment for opioid dependence with buprenorphine. In 2010, DEA began systematic inspections of all DATA-waivered practitioners, primarily to monitor compliance with the 30- to 100-patient limit. In March 2006, the secretary of DHHS issued a formal Determinations Report on the evaluation of DATA 2000 that indicated that the buprenorphine waiver program had expanded access to treatment and had produced effective treatment outcomes without producing negative public health issues (Substance Abuse and Mental Health Services Administration 2006a). As of May 2010, it was estimated that 1–2 million patients in the United States have been treated with buprenorphine. Regarding accessibility to treatment, DHHS determined that 31% of patients taking buprenorphine were new to any type of substance abuse treatment and 60% were new to medication-assisted treatment

Opioid Dependence in America

21

(Figure 1–5). Only 9% were transferred from methadone to buprenorphine treatment. Of equal importance was the finding that 60% of buprenorphine patients had been addicted to nonheroin opioids, a population that has historically avoided participation in methadone treatment. Indeed, patients treated under the buprenorphine waiver have much more accurately reflected the population of illicit drug users in the community, as compared with patients in methadone treatment. In community samples of individuals abusing opioids, only 4% of the population were using heroin, whereas 96% were using nonheroin opioids (Figure 1–6). Patients entering methadone treatment have primarily been addicted to heroin (83%, vs. 17% addicted to nonheroin opioids or the combination of heroin and nonheroin opioids) compared with the 40% addicted to nonheroin opioids who have entered buprenorphine treatment. There have also been significant demographic differences between methadone and buprenorphine patients. Buprenorphine treatment populations have had higher percentages of women than methadone treatment populations as well as higher percentages of whites and employed individuals, and more than three times as many individuals with some postsecondary education (Figure 1–7) (Stanton et al. 2006; Substance Abuse and Mental Health Services Administration 2005b).

Conclusion Opioid dependence has been a long-standing problem in the United States. Although medical management of chronic opioid dependence was common practice in the nineteenth century, it was made illegal under the Harrison Narcotics Tax Act in 1914 and most contemporary physicians have no experience treating the opioid use disorders. Heroin abuse remained endemic throughout the twentieth century despite ongoing efforts to eliminate supplies and incarcerate users. A new epidemic of the abuse of pain relievers began in the mid-1990s and opioid pharmaceuticals quickly replaced heroin as the dominant opioid problem among young adults, almost surpassing the prevalence of marijuana abuse in this population. As compared with heroin abuse, the use of these more potent opioid pharmaceuticals is associated with a higher risk of opioid dependence disorder, even among legitimate pain treatment patients, and a more rapid progression of the addiction syndrome. This new addict population is younger, better educated, and less antisocial than typical heroin addicts, though there is a high incidence of co-occurring depression and anxiety disorders. The legalization of methadone maintenance treatment in 1972 represented a return to a medical management model, but few addicts were willing to attend heavily regulated methadone clinics and this approach had minimal impact on the incidence of heroin abuse. The limitations of the methadone clinic

80% 60%

60% 40%

31%

20%

9%

0% New to substance abuse treatment

FIGURE 1–5.

60%

New to medicationassisted treatment

Transitioned from methadone

Characteristics of respondents in buprenorphine patient study. patient study, drug of abuse. Source. Substance Abuse and Mental Health Services Administration 2005b. aIn

Addicted to nonheroin opioidsa

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Percentage of patients treated

22

100%

Methadone treatment

Treatment under the BUP waiver

NSDUH past month use 2002

TEDS 2002 admissions involving methadone treatment

Patient study BUP evaluation 2005

96% Nonheroin only

4,549,570 reported opioid abuse

Heroin only

40% Nonheroin only

83% Heroin only

111,885 admissions involved methadone treatment

Nonheroin opioids only

Opioid Dependence in America

Opioid abuse

434 patients recruited from 132 sites

Heroin and nonheroin opioids

FIGURE 1–6. Discrepancy between populations abusing opioids and populations treated. BUP=buprenorphine; NSDUH=National Survey on Drug Use and Health; TEDS =Treatment Episode Data Set. Source. Substance Abuse and Mental Health Services Administration 2005b. 23

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Percentage of patients treated

24

100% 80% 60% 40% 20% 0%

Female

White

Methadone admissions to TEDS sites Buprenorphine patient study

Employed

Some postsecondary education

FIGURE 1–7. Methadone patients and buprenorphine patient study sample: demographic differences. The Treatment Episode Data Set (TEDS) reports primarily on admissions to facilities receiving public funding. Admissions to private facilities are underrepresented. Source. Substance Abuse and Mental Health Services Administration 2005b. system led authorities to consider other medications that might be safely utilized in more general medical practice settings. Buprenorphine, a partial opioid agonist, was identified as both an effective and a safe medication for use in office-based settings. With the approval of sublingual buprenorphine in 2002, there has been a significant increase in available treatment options. In early 2010, it was estimated that there were 300,000 individuals currently in buprenorphine treatment, compared with an estimated 275,000 individuals in methadone treatment. Although the abuse of both heroin and opioid pharmaceuticals continues to be a significant problem, office-based buprenorphine treatment has been proved to be an effective public health approach to containing the epidemic (Sullivan et al. 2005). And although the recent leveling off of nonmedical use of prescription pain relievers among young people ages 12 and older is promising, it is premature to assume that buprenorphine treatment has effectively curbed the problem of opioid dependence in the United States. It is clear, however, that large numbers of addicts have found life-saving treatment and have been able to become functioning and contributing members of society. For the first time, an effective medical treatment has had a significant impact on this chronic public health problem.

Opioid Dependence in America

25

References 74 Federal Register 29153–29158/Vol 74, No 117/Friday, June 19, 2009/Proposed Rules: Opioid drugs in maintenance and detoxification treatment of opiate addiction; buprenorphine and buprenorphine combination; approved opioid treatment medications use. Department of Health and Human Services, 42 CFR Part 8, RIN 0930-AA14. Available at: http://buprenorphine.samhsa.gov/NPRM-06-192009.pdf. Accessed May 5, 2010. Allbutt TC: On the abuse of hypodermic injections of morphia. Practitioner 5:327–331, 1870 Ball JC, Ross A: The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome. New York, Springer-Verlag, 1991 Compton WM, Thomas YF, Stinson FS, et al: Prevalence, correlates, disability, and comorbidity of DSM-IV drug abuse and dependence in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry 64:566–576, 2007 Dole VP, Nyswander M: A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 193:646–650, 1965 Drug Addiction Treatment Act of 2000, Pub. L. No. 106-310. Available at: http:// buprenorphine.samhsa.gov/fulllaw.html. Accessed April 22, 2010. Grant BF: Prevalence and correlates of drug use and DSM-IV drug dependence in the United States: results of the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abus 8:195–210, 1996 Hser YI, Hoffman V, Grella CE, et al: A 33-year follow-up of narcotics addicts. Arch Gen Psychiatry 58:503–508, 2001 Hubbard RL, Craddock SG, Flynn PM, et al: Overview of 1-year follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). Psychology of Addictive Behaviors 11:261–278, 1997 Kessler RC, McGonagle KA, Zhao S, et al: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8–19, 1994 Levinstein E: Morbid Craving for Morphia. Translated by Harrer C. London, Smith, Elder, 1878 Meier B: Pain Killer: A “Wonder” Drug’s Trail of Addiction and Death. Emmaus, PA, Rodale, 2003 Musto DF: The American Disease: Origins of Narcotic Control, 3rd Edition. New York, Oxford University Press, 1999 Regier DA, Farmer ME, Rae DS, et al: Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 264:2511–2518, 1990 Stanton A, McLeod C, Luckey B, et al: SAMHSA/CSAT evaluation of the buprenorphine waiver program. Paper presented at the annual meeting of the American Society of Addiction Medicine, San Diego, CA, May 2006 Substance Abuse and Mental Health Services Administration: Results From the 2002 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NHSDA Series H-22, DHHS Publ No SMA 03–3836). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2003. Available at: http://www.oas.samhsa.gov/nhsda/2k2nsduh/results/2k2Results.htm. Accessed April 29, 2010.

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Substance Abuse and Mental Health Services Administration: Results From the 2004 National Survey on Drug Use and Health: National Findings. (Office of Applied Studies, NSDUH Series H-28, DHHS Publ No SMA 05-4062). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2005a. Available at: http://www.oas.samhsa.gov/NSDUH/2k4NSDUH/2k4results/2k4results.htm. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: Evaluation of the Buprenorphine Waiver Program: Results From SAMHSA/CSAT’s Evaluation of the Buprenorphine Waiver Program, June 20, 2005b. Available at: http:// www.buprenorphine.samhsa.gov/findings.pdf. Accessed May 31, 2010. Substance Abuse and Mental Health Services Administration: The Determinations Report: A Report on the Physician Waiver Program Established by the Drug Addiction Treatment Act of 2000 (“DATA”), March 30, 2006a. Available at: http:// www.buprenorphine.samhsa.gov/SAMHSA_Determinations_Report.pdf. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: The SAMHSA Evaluation of the Impact of the DATA Waiver Program: Summary Report, Task Order 277-00-6111, March 30, 2006b. Available at: http://www.buprenorphine.samhsa. gov/FOR_FINAL_summaryreport_colorized.pdf. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: Results From the 2006 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-32, DHHS Publ No SMA 07-4293). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2007. Available at: http://www.oas.samhsa.gov/NSDUH/2k6NSDUH/2k6results.cfm. Accessed June 29, 2008. Substance Abuse and Mental Health Services Administration: Results From the 2007 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-34, DHHS Publ No SMA 087-4343). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2008. Available at: http://www.oas.samhsa.gov/NSDUH/2k7NSDUH/2k7results.cfm. Accessed November 14, 2008. Substance Abuse and Mental Health Services Administration: The NSDUH Report: Trends in Nonmedical Use of Prescription Pain Relievers: 2002 to 2007 (Office of Applied Studies), February 5, 2009a. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2009a. Available at: http://www.oas.samhsa.gov/ 2k9/painRelievers/nonmedicalTrends.cfm. Accessed April 29, 2010. Substance Abuse and Mental Health Services Administration: Results From the 2008 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-36, DHHS Publ No SMA 09-4434). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2009b. Available at: http://www.oas.samhsa.gov/nsduh/2k8nsduh/2k8Results.cfm. Accessed April 29, 2010. Sullivan LE, Chawarski M, O’Connor PG, et al: The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering treatment? Drug Alcohol Depend 79:113–116, 2005 Wood GB: A Treatise on Therapeutics, and Pharmacology, or Materia Medica, 3rd Edition (two volumes). Philadelphia, PA, JB Lippincott, 1856

2 Experience With Buprenorphine in the United States, 2002–2008 David A. Fiellin, M.D.

Creating a New Treatment Paradigm The implementation of buprenorphine treatment in the United States represented a new treatment paradigm and a collaborative effort between researchers, government, industry, medical societies, and physicians. In this chapter, I review the legislative and regulatory changes that permitted the use of buprenorphine for the treatment of opioid dependence, and present an overview of the experience in the United States since the initiation of this new treatment paradigm. Research in the 1970s through the 1990s funded by the National Institute on Drug Abuse (NIDA) led to the development of buprenorphine and the U.S. Food and Drug Administration’s (FDA’s) approval in 2002 as a treatment for opioid dependence. The approval of buprenorphine in the United

This chapter is adapted with permission from Fiellin DA: “The First Three Years of Buprenorphine in the United States: Experience to Date and Future Directions.” Journal of Addiction Medicine 1:62–67, 2007. 27

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States followed licensing, research, and its use as a treatment for opioid dependence in the 1990s, most notably in France and Australia. Since the Harrison Narcotics Tax Act of 1914, U.S. physicians were not allowed to provide opioid agonist medication to patients for the sole purpose of treating opioid dependence. As the prevalence of opioid dependence increased (see Chapter 1, “Opioid Dependence in America”) and a new treatment was emerging, U.S. government agencies considered mechanisms to broaden treatment access. The policy argument put forth in support of an amendment to the Controlled Substances Act—to allow for an expansion of access to agonist medications for the treatment of opioid dependence—included specific reference to the efficacy of these treatments and their limited availability vis-à-vis the treatment need. Regulatory changes were put in place to expand methadone treatment services to standard medical settings (Clark 2006) and to loosen the restrictions on take-home doses for those receiving this treatment (Fiellin and O’Connor 2002), but these changes did not amount to widespread expansion of methadone treatment. Greater effort was directed toward the use of physician prescription of medications with less abuse and diversion potential (i.e., Schedule III vs. Schedule II medications), such as buprenorphine, because this was seen as a more plausible paradigm for widespread treatment of opioid dependence. Congress passed modifications to the Controlled Substances Act, termed the Drug Addiction Treatment Act of 2000 (P.L. 106-310; DATA 2000), and in October of 2002 the FDA approved buprenorphine and the buprenorphine-naloxone combination for the treatment of opioid dependence in office-based settings. At almost the same time as FDA approval, the U.S. Drug Enforcement Administration (DEA) changed the schedule of all buprenorphine products from Schedule V to Schedule III, a move that preserved DEA’s role according to DATA 2000. The implementation of this new paradigm required efforts to train and support physicians (Gordon et al. 2008).

Implementing the New Paradigm PHYSICIAN TRAINING Between November 1, 2001, and January 1, 2009, approximately 20,000 physicians (Table 2–1) received training in the treatment of opioid dependence from one of the five medical societies that are named in DATA 2000 as capable of providing this type of training. These trainings were provided in a face-to-face format, via the Internet, or on CD-ROM. Of note, DATA 2000 provides for the future approval of other medications in Schedules III through V and does not mandate that the trainings focus specifically on the use of buprenorphine, but rather requires that they be generically applicable to treatment and management

29

Experience With Buprenorphine in the United States, 2002–2008

TABLE 2–1.

Physician training and certification according to the stipulations in DATA 2000, as of January 2009 Total trainees

In-person training

Web-based training

Physicians who have received training

20,235

14,504

5,731

Waiver notification forms received by CSAT

17,623

NA

NA

Waiver notifications certified by CSAT

16,183

NA

NA

115

NA

NA

Waiver notifications denied by CSAT

Note. CSAT=Center for Substance Abuse Treatment; DATA 2000=Drug Addiction Treatment Act of 2000; NA=data not available. Source. N. Reuter, Center for Substance Abuse Treatment, personal communication.

of opioid-dependent patients. The initial training materials were developed in 2000 as a standard curriculum through funding to medical societies from the federal Center for Substance Abuse Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration (SAMHSA). This curriculum consists of a large set of standard slides and has been updated once, in 2003. In late 2008, discussions were under way at CSAT regarding the need to produce another update to the curriculum to incorporate new evidence and clinical experience. Before the approval of buprenorphine and buprenorphine-naloxone for the treatment of opioid dependence in 2002, CSAT provided funds for the majority of physician training. From 2002 through 2008, the burden of training physicians fell primarily on the medication’s manufacturer, provided through unrestricted educational grants to medical societies. As of early 2010, the funding for future face-to-face trainings is unclear, although the Web-based and CD-ROM–based options still exist. A number of training paradigms have been developed for the face-to-face courses; most rely on a mixture of didactics and case discussions. One model provides for 4 hours of training (half of the 8-hour training requirement) to be conducted online before the face-to-face course (Gunderson et al. 2006). The quality and outcomes of training have never been fully investigated, although most anecdotal reports and evaluations are positive regarding the organization and content. In addition, organizations have performed faculty development to help improve quality (Wong et al. 2005). One concern has been that approxi-

30

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

mately 10% of trainees apparently do not go on to notify CSAT and DEA of their intent to prescribe under DATA 2000 (Table 2–1). In one published instance, despite high satisfaction with the training, only 6 of 29 trainees went on to seek certification and only 2 indicated that they were prescribing buprenorphine or buprenorphine-naloxone (Gordon et al. 2008). It is known that some of the perceived barriers to utilization of the medication (e.g., induction logistics, access to mental health services) become less important over time and with experience prescribing buprenorphine (Netherland et al. 2009).

PHYSICIAN SUPPORT The uniqueness of this new practice in U.S. medicine may deter some physicians from seeking training or the appropriate registration to provide buprenorphine. In one survey of 235 Massachusetts physicians with the ability to prescribe buprenorphine, 66% indicated that they were in fact prescribing (Walley et al. 2008). Being a primary care physician compared with a psychiatrist (adjusted odds ratio [AOR], 3.02; 95% confidence interval [CI], 1.48– 6.18) and having a solo practice only compared with having a group practice (AOR, 3.01; 95% CI, 1.23–7.35) were associated with prescribing, whereas reporting low patient demand (AOR, 0.043; 95% CI, 0.009–0.21) and insufficient institutional support (AOR, 0.37; 95% CI, 0.15–0.89) were associated with not prescribing (Walley et al. 2008). In response to concerns that physicians might need additional assistance beyond initial training in implementing buprenorphine treatment in officebased practice, SAMHSA in 2004 provided financial support to create a Physician Clinical Support System (PCSS) that is designed to support physicians who are considering or currently treating opioid-dependent patients with buprenorphine. PCSS (www.pcssmentor.org) is a collaborative effort between the American Society of Addiction Medicine (ASAM), the American Psychiatric Association, the American Osteopathic Association (AOA), the American Academy of Addiction Psychiatry, and 25 other primary care, addiction, pain, and HIV specialty societies. In late 2008, PCSS had 87 physicians who served as mentors and provided support to over 3,600 participants in all 50 states and Puerto Rico. Services are provided via e-mail, telephone, and visits to the mentor’s place of care. The most common services provided by PCSS include information on induction timing and procedures, medication management, patient scheduling, payment for services, and paperwork. Also in 2004, the HIV/AIDS Bureau of the Health Resources and Services Administration funded an initiative through its Special Projects of National Significance branch to develop and evaluate programs that integrate HIV infection primary care and buprenorphine treatment for opioid dependence. This program was designed to address the specific issues that relate to the integra-

Experience With Buprenorphine in the United States, 2002–2008

31

tion of buprenorphine into HIV infection clinical care (Sullivan et al. 2006a, 2006b). The 10 sites involved in this project received training and support from a centralized Evaluation and Support Center (www.bhives.org) and began enrolling patients in mid-2005. As of late 2008, the sites had enrolled more than 321 HIV-positive opioid-dependent patients into care with buprenorphine. A pilot study from one site demonstrated promising results (Sullivan et al. 2006c). The U.S. Department of Veterans Affairs (VA) has created efforts to support physician prescription of buprenorphine. This process helps areas of the country in which VA facilities do not have methadone services for veterans with opioid dependence. The VA Substance Use Disorders Quality Enhancement Research Initiative has developed a service that provides consultation to VAbased physicians to improve their capacity to provide buprenorphine. The service consists of clinical experts, a resource guide regarding implementing buprenorphine treatment, and a monthly newsletter. As of late 2007, all 14 registered VA sites have used the service (Gordon et al. 2007). Other programs have developed around the country to assist with the implementation of buprenorphine therapy. Various state and local entities have engaged in efforts to help support the implementation of office-based treatment with buprenorphine (Baltimore City Health Department 2007). These efforts have ranged from organized team trainings to formalized state-based support systems (McCarty et al. 2004). One such effort is based on a nurse or nurse practitioner model and exemplifies the potential role of nonphysician staff in the care of opioid-dependent patients (Labelle 2008).

Evaluating the Impact of the New Paradigm PHYSICIAN REGISTRATION As of early 2009, over 16,000 physicians had notified the federal government of their intention to prescribe under the auspices of DATA 2000 (Table 2–1). California and New York led the nation with approximately 1,800 such physicians each. Included in these numbers are those who meet the legislation’s requirements based on either completing the 8-hour training or another criterion such as being certified in addiction psychiatry by the American Board of Psychiatry and Neurology, in addiction medicine by AOA, or in addiction medicine by ASAM. It is perhaps important to note that among the physicians who have received a DEA registration number to prescribe buprenorphine (noted by the first alphanumeric of the applicant’s existing registration number replaced with an X), the majority are eligible due to completion of the training outlined in the legislation, whereas a minority meet criteria based on their specialty certification.

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Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

PHYSICIAN PRESCRIBING There is no central registry of physician prescribing of buprenorphine in the United States. Prescribing behavior can be extrapolated from information maintained on controlled substances by the DEA, Office of Diversion Control. This information, assembled in the Automation of Reports and Consolidated Orders System, shows that in 2006 the distribution of buprenorphine increased from 58,291 grams in the first quarter to 85,418 grams in the fourth quarter. Overall 287,101 grams of buprenorphine were distributed during 2006, with 93% distributed to 28,430 pharmacies nationwide. This represented an increase over the 98 grams in 2002. States receiving the largest supplies include California, Florida, Massachusetts, New York, and Pennsylvania. States receiving the smallest supplies include Arkansas, Nebraska, North Dakota, South Dakota, and Wyoming. The states with the largest number of grams distributed on a per capita basis were Vermont, Maine, Massachusetts, Rhode Island, and Connecticut. Those with the fewest grams distributed per capita were South Dakota, Iowa, Arkansas, Nebraska, and Kansas. Additional information regarding physician prescribing can be deduced from the congressionally mandated 3-year evaluation (see the following section, “Congressionally Mandated Evaluation”). An early survey indicated that approximately 105,000 patients in the United States had received treatment with buprenorphine (Substance Abuse and Mental Health Services Administration 2005). Of these, only 10%–15% transitioned from methadone treatment. Information from a national prescription database demonstrates an increase in the number of prescriptions of buprenorphine-naloxone from 39,000 in 2003 to 1,719,000 in 2007, an average annual growth rate of 113% (Mark et al. 2009). Twenty-eight percent of prescriptions were written by psychiatrists. In a separate study of psychiatrists (Thomas et al. 2008), nearly 90% of addiction specialists surveyed had the appropriate DEA registration to prescribe buprenorphine and two-thirds had treated patients with the medication. However, fewer than 10% of non–addiction specialist psychiatrists had prescribed buprenorphine. Information from the medication’s manufacturer estimates that 15,603,273 daily doses or 42,749 patient-years of buprenorphine and/or buprenorphine-naloxone were provided in 2006, assuming an average daily dose of 16 mg. For the 3-year period between January 2003 and December 2006, an estimated 300,000 patients were treated with buprenorphine and/or buprenorphine-naloxone. In the last quarter of 2006, prescriptions were written for buprenorphine and/or buprenorphine-naloxone by 4,641 physicians with special DEA registration. The most recent information, from the third quarter of 2008, indicates that approximately 326,000 individuals had received treatment over a 90-day period and that 225,600 were receiving treatment at a single point in time. Of those

Experience With Buprenorphine in the United States, 2002–2008

33

225,600 patients, an estimated 95% were receiving the buprenorphine-naloxone combination product instead of the buprenorphine-alone formulation and 76% were engaged in ongoing maintenance therapy in contrast to a planned short-term medication taper (E. Johnson, personal communications, September 2007 and December 2008).

CONGRESSIONALLY MANDATED EVALUATION DATA 2000 includes a stipulation that allows the secretary of the U.S. Department of Health and Human Services “to make a determination of whether treatments provided under waivers...have been effective forms of maintenance treatment and detoxification treatment in clinical settings...[;] whether such waivers have significantly increased (relative to the beginning of such period) the availability of maintenance treatment and detoxification treatment; and...whether such waivers have adverse consequences for the public health.” To this end, SAMHSA’s CSAT commissioned a series of surveys designed to assess the impact of the introduction of buprenorphine on the treatment system. The Addiction Physician Survey (Quarter 4, 2003) was sent to a sample of approximately 1,000 physician addiction specialists. The Waivered Physician Survey (Quarter 1, 2005) was sent to a sample of approximately 1,800 physicians, all of whom had waivers to prescribe buprenorphine, to learn more about physicians’ experience treating with buprenorphine once it had been available for at least 1 year. Finally, the patient survey (Kissin et al. 2006) collected data by telephone interview from a cohort of about 400 buprenorphine patients to assess their response to and satisfaction with buprenorphine therapy. Although the complete final findings have not yet been published, presentations by federal officials provide insight into the initial findings (Table 2–2).

BUPRENORPHINE DIVERSION There is evidence of buprenorphine diversion, although few reports indicate that this diversion is for abuse or euphoria. The primary use of diverted doses appears to be for “paraprescribing” or “unobserved treatment” in which an opioid-dependent person takes a dose of the medication that was not prescribed for him or her for the purpose of avoiding opioid withdrawal or using illicit opioids. A U.S. survey of 1,000 patients seeking treatment for prescription opioid abuse at 100 drug treatment programs around the country showed that 20%– 35% had misused buprenorphine “to get high” in the past 30 days, but that fewer than 3% were primarily addicted to buprenorphine (Cicero et al. 2007b). A November 2006 report from CSAT concluded that buprenorphine diversion and abuse were concentrated in specific geographic areas (JBS International 2006). A report based on a network of drug abuse experts noted that there was

34

Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

TABLE 2–2.

Major findings from SAMHSA CSAT surveys on DATA 2000

Physician survey The number of states, and number of sites within states, providing medication-assisted treatment for opioid dependence increased in the year following the introduction of buprenorphine. 53% of waivered physicians had no prior experience providing medicationassisted treatment. 56% of waivered physicians were not addiction specialists. The largest proportion of waivered physicians reported that they practiced in individual practices. The smallest proportion of waivered physicians practiced in opioid treatment programs and/or specialty substance abuse treatment clinics. The majority of physicians reported providing induction for ≤100 patients. 21% of physicians reported providing detoxification only, whereas 79% reported providing detoxification and maintenance treatment. The proportion of physicians who described buprenorphine treatment as “very effective” was 32% for those who provided the medication to patients for 1 month. 217 of 47,664 patients (0.5%) experienced severe adverse reactions, nearly half of which were described as “withdrawal.” The top five challenges to physician prescribing were cost, patient’s resistance to counseling, patient’s use of other drugs, patient compliance/retention, and the 30-patient limit. The most common patient census counts per physician were 1–5 (27%) and 30 (20%). Patient survey 60% of patients were dependent on nonheroin opioids. 60% of patients were new to medication-assisted treatment. 63% of patients reported one or two visits to the physician during the first 30 days of treatment. 41% of patients reported no counseling sessions in the first 30 days of treatment. 65% of patients reported nonopioid illicit drug use or binge alcohol use in the past 30 days.

Experience With Buprenorphine in the United States, 2002–2008

TABLE 2–2.

35

Major findings from SAMHSA CSAT surveys on DATA 2000 (continued)

32% of patients reported a lifetime diagnosis of chronic pain. 95% of patients indicated that buprenorphine was very or extremely helpful. 60% of patients reported retention in treatment at 6 months. 64% and 65% of patients indicated that it is harder to buy buprenorphine on the street than methadone or OxyContin (oxycodone), respectively. Note. CSAT=Center for Substance Abuse Treatment; DATA 2000=Drug Addiction Treatment Act of 2000; SAMHSA=Substance Abuse and Mental Health Services Administration. Source. Kissin et al. 2006.

no difference in the frequency of reports of buprenorphine abuse versus tramadol abuse and that each was much lower than the frequency of abuse reported for oxycodone or methadone (Cicero and Inciardi 2005). In this study, more than 33% of those who had abused buprenorphine reported that they took the medication as an attempt at self-medication. A further study conducted with 501 heroin-using subjects in New York City determined that only one subject had abused buprenorphine or buprenorphine-naloxone (Davis and Johnson 2008). The Drug Abuse Warning Network presents national estimates of drugrelated visits to hospital emergency departments (Substance Abuse and Mental Health Services Administration 2008). In 2006, there were an estimated 247,669 (95% CI, 214,160–281,177) emergency department visits for nonmedical use of prescription medications, of which 4,440 (95% CI, 823–8,057) were reports of nonmedical use of buprenorphine and or buprenorphine-naloxone. During the same time, there were no reports of buprenorphine associated with suicide attempts (Substance Abuse and Mental Health Services Administration 2008, Table 16). Another study looked at reports to 18 regional poison control centers around the United States and noted that the average quarterly ratio of abuse cases per 1,000 prescriptions dispensed was 0.08 (SD ±0.09) for buprenorphine, and 0.16 (SD±0.08) for buprenorphine-naloxone (Smith et al. 2007). Research using reports from a key informant network at 233 substance abuse treatment centers in the United States demonstrated that buprenorphine, compared with other prescription opioids, had the lowest number of unique recipients of dispensed drug (individuals for whom prescriptions were written) and was among the drugs with the lowest numbers of cases of abuse per 100,000 population (approximately 0.2), but was among those with the highest numbers of reports of abuse per unique recipient of dispensed drug (Cicero et al. 2007a). One interpretation of these data is that buprenorphine has

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little value as a drug that produces euphoria, yet is more likely to be shared by those to whom it is prescribed.

DRUG ENFORCEMENT ADMINISTRATION ACTION DATA 2000 indicates that “the Attorney General may make a determination of the extent to which there have been violations of the numerical limitations” of patients who are treated by physicians. Initially the legislation set the limit at 30 patients per individual physician and/or group practice as defined by the Social Security Act. This was subsequently changed to 30 patients per individual physician, irrespective of their affiliation with a group practice. DEA has been responsible for monitoring physician practice involving buprenorphine since FDA approval of the medication in late 2002. This monitoring has included 425 individual physician investigations that were conducted by field agents during the period between October 2003 and January 2008. Of these investigations, 253 (59.5%) cited no problems or revealed that the physicians had yet to begin a practice using buprenorphine. Of the 74 investigations that cited problems or actions taken by investigators (involving 0.006% of all registered physicians), 35 manifested as verbal warnings (e.g., record-keeping or dispensing violations), 23 manifested as letters of admonition (e.g., recordkeeping, dispensing, and security violations), 8 manifested as surrender of DEA registrations for cause, 2 manifested as show cause proceedings, 1 led to a civil action, and 5 were still undergoing active investigation (Curry 2008).

LEGISLATIVE CHANGES AND REGULATORY CONCERNS Congress has acted twice to modify DATA 2000 since the original legislation. The first modification occurred in January 2005 and changed the 30-patient limit such that it applied to an individual physician and not a group practice. This allowed individual physicians to care for up to 30 patients with medications such as buprenorphine even if they were practicing within a group practice in which other physicians were providing the same type of treatment. In December 2006, Congress again modified the legislation, to allow physicians who had possessed a registration for at least 1 year and who had applied to the secretary of the Department of Health and Human Services for a waiver to treat up to 100 patients with medications such as buprenorphine. As of early 2009, 2,729 physicians had notified CSAT of their intent to treat up to 100 patients. In summary, the modifications by Congress were designed to expand the number of patients that physicians could care for under the provisions of DATA 2000 and the Controlled Substances Act.

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In addition to funding the congressionally mandated waiver evaluation and PCSS, CSAT has effected regulatory action and provided guidance. CSAT moved in May 2003 to add buprenorphine to the list of medications that could be provided by federally regulated opioid treatment programs (68 Federal Register 27937–27939). Opioid treatment programs were not subject to the same numerical limits that apply when individual physicians prescribe buprenorphine but rather were subject to the regulations (e.g., patient-counselor ratios, frequency of take-home medications) that cover the provision of all opioid agonist treatments in these facilities. In April 2006, CSAT issued a “Dear Colleague” letter expressing concerns over pharmacies that were compounding buprenorphine and buprenorphinenaloxone in “various strengths, colors and flavors,” indicating that this practice presented potentially serious public health and safety issues (Clark 2006). Specific concerns were expressed regarding the possibility of degradation of compounded buprenorphine and naloxone into toxic substances via moisture and oxidation. In addition, concern was expressed regarding the unknown pharmacokinetics of compounded products.

FUNDING In the spring of 2003, the National Association of State Alcohol and Drug Abuse Directors conducted a survey of the directors of all state agencies on alcohol and other drugs (AOD agencies), and the AOD agency directors of the District of Columbia and five U.S. territories (National Association of State Alcohol and Drug Abuse Directors 2004). The survey included responses from 94% (n=47) of the state AOD agency directors and 33% (n=2) of the U.S. territorial AOD agencies. Forty-nine percent of the respondents indicated that their state did not plan to expend Substance Abuse Prevention and Treatment (SAPT) Block Grant monies or other monies controlled by the state AOD agency in support of appropriate services for patients receiving buprenorphine. Fifty-nine percent of states did not plan to expend SAPT Block Grant monies or other monies controlled by the state AOD agency to cover the cost of buprenorphine for patients in the public AOD system. Forty-nine percent of state respondents indicated that they did not anticipate their state would include buprenorphine on their state’s Medicaid formulary. Finally, only 47% of state respondents indicated that their state’s Medicaid benefits would cover physician and medication costs associated with office-based buprenorphine treatment for eligible clients. A 2004 working paper prepared for CSAT outlined the complex environment in which reimbursement for buprenorphine and related services must occur. The report highlighted that given the complicated processes, restricted coverage for substance abuse care, and multiple funding streams, treatment with

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buprenorphine would not occur to any great degree unless the payment systems, organized care systems, and public funders were willing to reimburse physicians, therapists, pharmacists, and the medication’s manufacturer and distributor for their services and product (Avisa Group 2005). Over time, it appears that coverage from public and private insurers has increased, although this is not universal. Legislative changes, including legislation that addresses parity between mental health and medical disorders, may provide further expansion. Finally, the potential introduction of generic versions of the medication following the manufacturer’s period of exclusivity could portend reduced medication-related fees.

Improving the New Paradigm ONGOING RESEARCH Federal databases reveal approximately 60 research projects involving buprenorphine funded by the National Institutes of Health. The research covers a wide range of topics including counseling, pregnancy, HIV infection, incarceration, and adoption by health maintenance organizations. In addition, the NIDA Clinical Trials Network has recently completed studies on the use of buprenorphine for detoxification and in the treatment of adolescent patients (Woody et al. 2008) and has ongoing trials investigating the use of buprenorphine in patients addicted to prescription opioids and comparing its effects on hepatic transaminases with those of methadone.

UNDERINVESTIGATED AREAS Despite the importance of this ongoing work, the U.S. experience thus far indicates some important areas for further investigation for clinical and policy guidance (Table 2–3). The clinical areas reflect issues that are frequently identified in physician discussions of buprenorphine and/or those that are highlighted in the existing evaluations. To date there has been a dearth of research, observational or experimental, on the use of the buprenorphine-naloxone combination in the doses available in the United States for the treatment of patients with isolated pain disorders or pain syndromes that are comorbid with opioid dependence. Likewise, the current investigations provide a snapshot into what clinical practice is like; however, there is no current mechanism for collecting detailed information regarding the quality of care that is provided by physicians. Some of the clinical issues are not unique to the U.S. implementation of buprenorphine use (Auriacombe et al. 2004; Carrieri et al. 2006). Many of the barriers articulated by U.S. physicians mirror those cited regarding programs in other countries (Lintzeris et al. 2004). Other barriers are unique to the implementation

Experience With Buprenorphine in the United States, 2002–2008

TABLE 2–3.

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Clinical and policy areas for further investigation

Clinical 1. The appropriate use of buprenorphine-naloxone for pain 2. The need for and appropriate use of alternate formulations of buprenorphine-naloxone 3. The integration of buprenorphine into programs that traditionally do not provide medication 4. The quality of care received by patients in office-based practices (e.g., number of physician and counseling visits, medication dosage and duration) 5. The appropriate level, type, and delivery strategy for counseling for patient subgroups 6. Strategies to assist physicians in addressing the barriers of medication cost, patient’s use of counseling, patient retention, patient’s use of other drugs, induction, medication management, patient scheduling, and payment 7. The need for additional physician training regarding record keeping Policy 1. How best to engage larger numbers of non–addiction physicians in the provision of buprenorphine treatment 2. How best to train and support physicians and practices for the provision of buprenorphine treatment 3. The appropriate role of governmental and pharmaceutical entities in providing physician education and support 4. How best to address the geographic variation in access to buprenorphine treatment 5. The role of prescribing by nonphysicians with DEA registrations 6. Strategies to encourage the use of buprenorphine in specialty and opioid treatment programs 7. Strategies to ensure payment for medication, physician services, and ancillary services 8. The need for ongoing evaluation of the impact of DATA 2000 on access, care, and public health given the potential expansion of practices enabled by legislative changes 9. Surveillance of physicians’ charging practices for services 10. Surveillance for diversion, especially findings that indicate injection misuse of buprenorphine and buprenorphine-naloxone Note. DATA 2000=Drug Addiction Treatment Act of 2000; DEA=U.S. Drug Enforcement Administration.

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in the United States. For instance, issues regarding medication cost and physician payment are not as pertinent in countries with a single payer system. The policy issues center on training and support, expansion of access, and ongoing monitoring of the impact of buprenorphine therapy implementation. The available data suggest that more than half of the physicians who have received a DEA registration number that allows them to prescribe under DATA 2000 have limited to no experience providing this type of medication or practicing in the field of addiction treatment. This is to be expected given the restrictions on this type of practice in the United States before 2003. In addition, greater physician involvement in the care of opioid-dependent patients and an effort to expand access to treatment were the intent of those who drafted DATA 2000. Training and supporting physicians in this new practice of medicine have been a challenge for the specialty medical societies, CSAT, and the medication’s manufacturer. The rapid growth in the use of the medication, the apparent benefits realized by patients, and the lack of evidence of adverse effects on the public health provide reassurance that the training and support efforts to date have been successful, or at least not detrimental. The scope and nature of, and payment for, future training and support services will likely have a profound effect on the ability of this treatment to reach larger groups of patients. Payment for buprenorphine-related treatment services is likely to have an even greater effect on their expansion. In 2003 commercial and public funding systems were not in place to provide reimbursement for the provision of opioid agonist therapy by physicians. Although formal cost-effectiveness studies of buprenorphine therapy have been conducted (Schackman et al. 2006), there is evidence that large health care providers may see the provision of methadone, instead of buprenorphine, as a viable alternative for their patients (Avisa Group 2005).

Conclusion Office-based buprenorphine treatment has introduced a significant new paradigm for the treatment of opioid dependence in the United States. Effective strategies to improve the geographic distribution of treatment services and to engage a larger number of providers in the use of buprenorphine have been elusive. The treatment of addictive disorders by mainstream medical providers will likely continue to expand, with medications available for the treatment of nicotine, alcohol, and opioid addiction. It is likely that time combined with growing experience by physicians who adopt the practice early on will serve to establish buprenorphine as a mainstream medication. Efforts to increase education at the resident physician level should help in this regard. Many practices have incorporated the use of nurses, nurse practitioners, and physician assistants into the provision of buprenorphine treatment. In some states, nurse practitioners and

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physician assistants have DEA registrations that allow them to prescribe controlled substances (e.g., opioid pain medications) and consideration should be given to expanding DATA 2000 to include these health professionals. Finally, given the importance of the problem of untreated opioid dependence and recent legislative changes that will allow practices to expand dramatically, the findings from the federal evaluation of DATA 2000 and ongoing evaluation beyond the 3-year congressional mandate will be essential to help guide further policies and programs. Future iterations of the surveys will be needed to help address some of the areas outlined above and in Table 2–3. This information will provide evidence to gauge both the negative and positive effects of this new practice of medicine in the United States and allow for improved care of patients addicted to opioids.

References 68 Federal Register 27937–27939/Vol 68, No 99/Thursday, May 22, 2003/Rules and Regulations: Opioid drugs in maintenance and detoxification treatment of opiate addiction; addition of buprenorphine and buprenorphine combination to list of approved opioid treatment medications. Department of Health and Human Services, 42 CFR Part 8, RIN 0910-AA52. Available at: http://www.buprenorphine.samhsa. gov/bwns/InterimFinalRule-05-22-2003.pdf. Accessed August 20, 2009. Auriacombe M, Fatséas M, Dubernet J, et al: French field experience with buprenorphine. Am J Addict 13 (suppl 1):S17–S28, 2004 Avisa Group: Evaluation of the Buprenorphine Waiver Program: Buprenorphine Reimbursement and Availability Tracking Study. September 2005. Available at: http:// www.avisagroup.com/images/Final_Report_of_Tracking_Study.pdf. Accessed August 21, 2009. Baltimore City Health Department: Baltimore Buprenorphine Initiative: Interim Progress Report, July 2007. Available at: http://www.baltimorehealth.org/ buprenorphine.html. Accessed August 11, 2009. Carrieri MP, Amass L, Lucas GM, et al: Buprenorphine use: the international experience. Clin Infect Dis 43 (suppl 4):S197–S215, 2006 Cicero TJ, Inciardi JA: Potential for abuse of buprenorphine in office-based treatment of opioid dependence. N Engl J Med 353:1863–1865, 2005 Cicero TJ, Surratt H, Inciardi JA, et al: Relationship between therapeutic use and abuse of opioid analgesics in rural, suburban, and urban locations in the United States (see comment). Pharmacoepidemiol Drug Saf 16:827–840, 2007a Cicero TJ, Surratt HL, Inciardi J: Use and misuse of buprenorphine in the management of opioid addiction. J Opioid Manag 3:302–308, 2007b Clark HW: Dear Colleague letter. Rockville, MD, Center for Substance Abuse Treatment, April 3, 2006. Available at: www.buprenorphine.samhsa.gov/ CompoundingandSellingBuprenorphine.pdf. Accessed August 10, 2009. Curry D: Drug Enforcement Administration Report. Buprenorphine Summit, Center for Substance Abuse Treatment, Washington, DC, February 21–22, 2008. Available at: http://buprenorphine.samhsa.gov/presentations/Buprenorphine_Summit.02. 21.08.v2.ppt. Accessed August 12, 2009.

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Davis WR, Johnson BD: Prescription opioid use, misuse, and diversion among street drug users in New York City. Drug Alcohol Depend 92:267–276, 2008 Drug Addiction Treatment Act of 2000, Pub. L. No. 106-310. Available at: http:// buprenorphine.samhsa.gov/fulllaw.html. Accessed April 22, 2010. Fiellin DA, O’Connor PG: New federal initiatives to enhance the medical treatment of opioid dependence. Ann Intern Med 137:688–692, 2002 Gordon AJ, Trafton JA, Saxon AJ, et al: Implementation of buprenorphine in the Department of Veterans Affairs: results of the first three years. Drug Alcohol Depend 90:292–296, 2007 Gordon AJ, Liberto J, Granda S, et al: Outcomes of DATA 2000 certification trainings for the provision of buprenorphine treatment in the Veterans Health Administration. Am J Addict 17:459–462, 2008 Gunderson EW, Fiellin DA, Levin FR, et al: Evaluation of a combined online and in person training in the use of buprenorphine. Subst Abuse 27:39–45, 2006 JBS International: Diversion and Abuse of Buprenorphine: A Brief Assessment of Emerging Indicators. Final report, November 30, 2006. Available at: http:// buprenorphine.samhsa.gov/Buprenorphine_FinalReport_12.6.06.pdf. Accessed August 11, 2009. Kissin W, McLeod C, Sonnefeld J, et al: Experiences of a national sample of qualified addiction specialists who have and have not prescribed buprenorphine for opioid dependence. J Addict Dis 25:91–103, 2006 Labelle C: Nurse Care Manager Model. Buprenorphine Summit, Center for Substance Abuse Treatment, February 21–22, 2008, Washington, DC. Available at: http:// www.buprenorphine.samhsa.gov/presentations/LaBelle.pdf. Accessed January 26, 2009. Lintzeris N, Ritter A, Panjari M, et al: Implementing buprenorphine treatment in community settings in Australia: experiences from the Buprenorphine Implementation Trial. Am J Addict 13 (suppl 1):S29–S41, 2004 Mark TL, Kassed CA, Vandivort-Warren R, et al: Alcohol and opioid dependence medications: prescription trends, overall and by physician specialty. Drug Alcohol Depend 99:345–349, 2009 McCarty D, Rieckmann T, Green C, et al: Training rural practitioners to use buprenorphine; using The Change Book to facilitate technology transfer. J Subst Abuse Treat 26:203–208, 2004 National Association of State Alcohol and Drug Abuse Directors: States’ Perspectives on Buprenorphine and Office Based Medication Assisted Dependency Treatment. June 14, 2004. Available at: http://www.nasadad.org/resource.php?base_id=83. Accessed August 10, 2009. Netherland J, Botsko M, Egan JE, et al; BHIVES Collaborative: Factors affecting willingness to provide buprenorphine treatment. J Subst Abuse Treat 36:244–251, 2009 Schackman BR, Merrill JO, McCarty D, et al: Overcoming policy and financial barriers to integrated buprenorphine and HIV primary care. Clin Infect Dis 43 (suppl 4):S247–S253, 2006 Smith MY, Bailey JE, Woody GE, et al: Abuse of buprenorphine in the United States: 2003–2005 (see comment). J Addict Dis 26:107–111, 2007 Substance Abuse and Mental Health Services Administration: Evaluation of the Buprenorphine Waiver Program: Results From SAMHSA/CSAT’s Evaluation of the Buprenorphine Waiver Program, June 20, 2005. Available at: http:// www.buprenorphine.samhsa.gov/findings.pdf. Accessed May 31, 2010.

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Substance Abuse and Mental Health Services Administration: Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits (Office of Applied Studies, DAWN Series D-30, DHHS Publ No SMA 08-4339). Rockville, MD, 2008. Available at: http://dawninfo.samhsa.gov/files/ ED2006/DAWN2k6ED.htm. Accessed January 26, 2009. Sullivan LE, Barry D, Moore BA, et al: A trial of integrated buprenorphine-naloxone and HIV clinical care. Clin Infect Dis 43 (suppl 4):S184–S190, 2006a Sullivan LE, Bruce RD, Haltiwanger D, et al: Initial strategies for integrating buprenorphine into HIV care settings in the United States. Clin Infect Dis 43 (suppl 4):S191–S96, 2006b Sullivan LE, Tetrault J, Bangalore D, et al: Training HIV physicians to prescribe buprenorphine for opioid dependence. Subst Abuse 27:13–18, 2006c Thomas CP, Reif S, Haq S, et al: Use of buprenorphine for addiction treatment: perspectives of addiction specialists and general psychiatrists. Psychiatr Serv 59:909– 916, 2008 Walley AY, Alperen JK, Cheng DM, et al: Office-based management of opioid dependence with buprenorphine: clinical practices and barriers. J Gen Intern Med 23:1393–1398, 2008 Wong JG, Holmboe ES, Jara GB, et al: Faculty development in small-group teaching skills associated with a training course on office-based treatment of opioid dependence. Subst Abuse 25:35–40, 2005 Woody GE, Poole SA, Subramaniam G, et al: Extended vs short-term buprenorphinenaloxone for treatment of opioid-addicted youths: a randomized trial. JAMA 300:2003–2011, 2008

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3 General Opioid Pharmacology John T. Pichot, M.D.

OPIOIDS HAVE PLAYED a significant role in the human experience for more than five millennia. Evidence found at Neolithic Period dig sites located in present-day Switzerland indicates cultivation of Papaver somniferum seeds and pods and suggests that the first organized human farming included the intentional growing of the opium poppy (Booth 1999). The earliest historical record began with the Sumerian civilization located along the banks of the Tigris-Euphrates river system of lower Mesopotamia in what is now southern Iraq. Clay tablets from around 3,400 B.C. include the oldest-known medical writings and represent the opium poppy by the ideograms Hul and Gil, which translate to the “joy plant” (Booth 1999). For thousands of years, opioids have been used to control coughing, diarrhea, and pain, and to induce euphoria, primarily by oral ingestion of opium. In the 1600s, opium smoking also became prevalent and spread around the world from Asia to Europe and the American colonies, primarily through British-controlled trade routes (Booth 1999). In the nineteenth century, a number of scientific and technical developments set the stage for the modern era of opioid use and abuse. In 1806, a German publication described the first isolation of a component of opium, named morphium after Morpheus, the Greek god of dreams and sleep. By the 1820s, morphine was commercially available around the world. The develop45

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ment of the syringe in the mid-1800s, perfected by Dr. Alexander Wood of Edinburgh in 1853, allowed efficient parenteral delivery of morphine. The first semisynthetic opioid, heroin, was discovered in 1874 by pharmacist C.R. Wright in London’s St. Mary’s Hospital. The first completely synthetic opioid was designed as a replacement for morphine by German scientists during World War II when the Allied blockade prevented access to opium (Booth 1999). In this chapter, I will review key features of the opioids and their interactions with opioid receptors. I will then focus on buprenorphine interactions with opioid receptors. Finally, I will turn our attention to pharmacological issues with clinical relevance for using buprenorphine in the treatment of opioid addiction, including the treatment of withdrawal and its use as a maintenance medication for opioid dependence disorder.

Opioid Key Features Opioid is the broad term for the entire group of compounds that have agonist effect on the µ opioid receptors. This term opioid includes three basic subgroups (Booth 1999): 1. Opiates—the naturally occurring substances present within raw opium. Examples of these naturally occurring compounds isolated from raw opium include morphine, codeine, and thebaine. 2. Semisynthetic opioids—these do not occur in nature but are derived by modification of a naturally occurring opiate. Examples of semisynthetic opioids include heroin, developed from the opiate morphine, and oxycodone and buprenorphine, each developed from the opiate thebaine. 3. Synthetic opioids—these neither occur in nature nor are developed from opiates, but are fully synthetic compounds designed to act as opioid receptor agonists. Methadone and fentanyl are examples of synthetic opioids, as are many of the other opioid prescription medications in common clinical use. There are several pharmacological characteristics of drugs that increase abuse potential as demonstrated in animal experimental models and in human behavior. Three primary factors that all result in a more rapid onset of opioid pharmacological effects are relevant to this increase in abuse potential: 1) drugs with a faster route of administration have greater abuse potential—that is, injecting and smoking a drug give it greater abuse potential than oral ingestion; 2) drugs with a shorter half-life have greater abuse potential, such as short-acting heroin versus long-acting methadone; and 3) drugs with greater lipophilic properties, which allow for more rapid transport across the blood-brain barrier, are associated with greater abuse potential. For example, heroin (diacetylmor-

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TABLE 3–1.

Opioid agonist effects

Acute use effects

Chronic use effects

Overdose effects

Euphoria Emesis Constricted pupils Slowed respirations Drowsiness Analgesia Decreased awareness Altered consciousness

Physical dependence Psychological dependence Variable energy changes Constipation

Nonresponsive Pinpoint pupils or “blown” pupils Bradycardia Hypotension Skin cyanotic Muscles flaccid Pulmonary edema Slowed respirations

Source. American Psychiatric Association 2000; Booth 1999; Center for Substance Abuse Treatment 2004.

phine) rapidly crosses the blood-brain barrier, even faster than morphine, due to the presence of two extra acetyl groups. These factors help explain why heroin is so euphorigenic, is so addictive, and is at the center of a multibillion dollar, worldwide illegal market—and has been for many decades (Booth 1999; Center for Substance Abuse Treatment 2004).

Opioid Receptors There are three main types of opioid receptors: µ, κ, and δ receptors. The µ opioid receptor is the primary receptor relevant to the use of buprenorphine in the treatment of opioid-dependent patients, and is therefore the focus of the rest of this clinically oriented chapter. For those interested in a more through discussion of buprenorphine’s potential interactions with other receptors, Cowan and Lewis (1995) published a textbook reviewing several decades of research on buprenorphine. Cowan recently published a paper updating some of these topics (Cowan 2007). The µ opioid receptor was named mu specifically because it was found to be the binding site for morphine. Mu receptors are widely distributed throughout the human nervous system. Agonist binding and activation of these receptors results in the actions listed in Table 3–1 (Center for Substance Abuse Treatment 2004; Reckitt Benckiser Healthcare 2006). A substance’s action, once it binds to the µ opioid receptor, can be very different depending on some key pharmacological properties. These differences are demonstrated in Figure 3–1 (Center for Substance Abuse Treatment 2004). In this figure, moving up the vertical axis represents an increasing opioid effect and moving to the right on the horizontal axis represents an increasing dose of the medication.

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Opioid effect

Full agonist (methadone)

Partial agonist (buprenorphine)

Antagonist (naloxone) Log dose

FIGURE 3–1. Conceptual representation of opioid effect versus log dose. Conceptual representation only; not to be used for dosing purposes. Source. Center for Substance Abuse Treatment 2004. Full agonists of the µ receptor include morphine, heroin, and methadone, as well as most of the prescription opioids. Full agonist binding is highly reinforcing in animal models of addiction and in human beings; full agonists are clearly the most widely abused type of opioid. This is demonstrated in Figure 3–1 by the squares labeled “Full agonist (methadone).” The illustration demonstrates how the level of opioid effect steadily increases (vertical axis) as the dose of the full agonist increases (horizontal axis). If the full agonist dose is too high then the opioid effect may become too great, and the individual is at risk of dying from respiratory depression. Partial agonists of the µ receptor bind the receptors but have a ceiling to the level of agonist activity that results from the receptor binding. Buprenorphine is an example of a partial agonist of the µ receptor. When it binds to the µ receptor, opioid agonist effects as listed in Table 3–1 may be experienced, or if the person is in opioid withdrawal, withdrawal symptoms may be relieved, but these effects are limited in degree. It is clear that buprenorphine’s ability to induce euphoria and respiratory depression has a ceiling effect even at high doses.

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This is demonstrated in Figure 3–1 by the circles labeled “Partial agonist (buprenorphine).” As the dose of the partial agonist increases (horizontal axis), the level of opioid effect steadily increases (vertical axis) until a ceiling is reached and no additional opioid effect is added even if the dose continues to increase. Even if the dose is very high, the opioid effect is limited and the risk of opioid overdose is minimal. Antagonists of the µ receptor are also shown in Figure 3–1, represented by the triangles labeled “Antagonist (naloxone)” demonstrating that they, too, bind the receptor but they provide no opioid effect at all regardless of the dose. Two examples of opioid antagonists are naltrexone and naloxone. Naltrexone is an oral medication with a half-life of sufficient duration to allow for once-daily dosing, or even alternate-day dosing, and is also approved by the U.S. Food and Drug Administration as a treatment for opioid dependence disorder. It works primarily by blocking agonists from binding to the µ receptor. It has not proven to be as effective a treatment for opioid dependence disorder as medications with agonist action, primarily because of the lack of any agonist effects and the absence of significant reduction in craving to use opioids (Center for Substance Abuse Treatment 2004). Naloxone is also an antagonist medication, but one that has to be given parenterally. Its primary clinical role has been to treat acute opioid overdose emergently by reversing the opioid effects including respiratory depression, by displacing opioid agonists off the µ receptors. Naloxone triggers a full opioid withdrawal disorder in individuals who are physically tolerant and dependent. Naloxone also has a clinical role in preventing diversion of buprenorphine as an integrated component of one sublingual product that combines buprenorphine and naloxone in a single tablet. This product is discussed in greater detail later in this chapter (see “Buprenorphine: Clinical Use Issues”). In summary, buprenorphine functions as a partial agonist with a ceiling effect for both opioid-induced euphoria and opioid-induced respiratory depression, and therefore clearly has an improved safety margin over all full opioid agonists. This is the primary reason that buprenorphine has been proven to be a clinically effective and safe treatment for opioid dependence disorder and has FDA approval for use in office-based settings (Center for Substance Abuse Treatment 2004). What is less clear is whether buprenorphine acts as a partial agonist regarding its analgesic effects. Cowan suggests in his recent paper (2007) that buprenorphine’s analgesic effect has not been clearly demonstrated to have a ceiling. He also reports that buprenorphine’s agonist actions at the opioid receptor-like-1 (ORL-1) receptor may have a role in explaining some of the analgesic effect of buprenorphine (Cowan 2007). The ORL-1 receptor was identified as a G protein-coupled receptor that is structurally very similar to opioid receptors. Subsequently the ORL-1 receptor’s endogenous ligand nociceptin (orphanin FQ) was discovered. This ligand-receptor system is the focus of

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ongoing research regarding its role in pain and analgesia. Fioravanti and Vanderah’s article (2008) provides a review that is beyond the scope of this chapter.

Opioid Withdrawal Issues When opioids are repeatedly dosed within a relatively short period of time, physical tolerance develops. Tolerance manifests as either a need for increased amounts of opioids to obtain the desired effect or a markedly diminished effect with continued use of the same amount of opioid (American Psychiatric Association 2000). Once physical tolerance and physical dependence on opioids have been established, opioid withdrawal is often experienced. Opioid withdrawal disorder is a specific mental disorder defined in the current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) and criteria include key signs and symptoms: 1) dysphoric mood, 2) nausea or vomiting, 3) muscle aches, 4) lacrimation or rhinorrhea, 5) pupillary dilation, piloerection, or sweating, 6) diarrhea, 7) yawning, 8) fever, and 9) insomnia. This DSM-IV-TR definition also accounts for the two main types of opioid withdrawal that are important to understand in the clinical use of buprenorphine, spontaneous withdrawal and precipitated withdrawal: •



Spontaneous withdrawal occurs when the usual opioid dosage is significantly reduced or when opioids are suddenly discontinued. For patients who are tolerant to short-acting opioids, such as hydrocodone or heroin, the onset of spontaneous withdrawal is within 24 hours of stopping opioid use and often begins within 8 hours after last use. In the case of long-acting opioids, such as methadone, spontaneous withdrawal does not develop for 24 hours or more after opioid use has ended. Precipitated withdrawal can occur when full agonists are displaced from the µ opioid receptor by substances that have greater affinity for receptor binding and have less agonist action; therefore, displacement by either an antagonist or a partial agonist rapidly reduces the level of agonist effect. If the person is opioid tolerant this will likely trigger the opioid withdrawal disorder, often suddenly and with a strong intensity.

Affinity and dissociation are two characteristics of µ opioid receptor binding that are important to understanding buprenorphine’s pharmacological actions. The affinity for a receptor refers to the strength to which the substance binds the receptor regardless of its action once bound. Buprenorphine has very strong affinity for the µ receptor, so much so that it displaces any full agonist that may be occupying the µ receptor. That is why the patient must wait until

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Opioid effect

Full agonist (methadone)

Partial agonist (buprenorphine)

Antagonist (naloxone) Log dose

FIGURE 3–2. Precipitated withdrawal if buprenorphine displaces full opioid agonist. Conceptual representation only; not to be used for dosing purposes. Source. Center for Substance Abuse Treatment 2004. all full opioid agonists are off the receptors before taking buprenorphine, so that buprenorphine will not displace the full agonists and precipitate opioid withdrawal. Naloxone and naltrexone also have strong µ receptor affinity, and displace full agonists and trigger full opioid withdrawal disorder (Center for Substance Abuse Treatment 2004). Figure 3–2 demonstrates this concept by the downward arrow representing the clinically significant sudden displacement of full agonists from the µ receptor by buprenorphine and the resultant decrease in the full agonist opioid effect in the central nervous system to a much reduced level, represented by the ceiling effect of the partial agonist. This rapid relative reduction to the partial agonist ceiling level results in opioid withdrawal symptoms even though some opioid agonist effect is still present from buprenorphine’s binding. If an antagonist is given and displaces the full agonist from the µ receptors, the point of the arrow will drop all the way to the horizontal axis, where no opioid agonist effect is present and full opioid withdrawal disorder will be experienced.

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Dissociation from a receptor refers to how easily the drug uncouples from the receptor when it is already bound. Buprenorphine dissociates very slowly from the µ receptor and, once bound, stays tightly attached—so tightly that full opioid agonists given after buprenorphine has attached to the µ receptors cannot displace it. This has two important clinical implications: 1. If the physician accidentally precipitates withdrawal in a person by displacing full agonists with buprenorphine, do not then give full agonists to treat the precipitated opioid withdrawal disorder because they will not displace the buprenorphine. 2. Once buprenorphine has successfully been inducted and the person continues to take it, taking another opioid will not produce any additional opioid effects and most likely the person will feel no effect. Even the injection of heroin will not displace buprenorphine off the µ receptors; thus the drug’s slow dissociation from the receptors has an added therapeutic advantage. This also has potential implications for giving opioids for analgesia if a buprenorphine patient needs acute pain management, but there are several options to address pain management in these circumstances (see Chapter 11, “Management of Acute and Chronic Pain”). The specifics of spontaneous and precipitated withdrawal are relevant for buprenorphine induction and in explaining to patients the importance of having stopped taking all opioids prior to induction, how long they must wait for initial buprenorphine dosing, and that they must be experiencing the opioid withdrawal disorder before the first dose of buprenorphine may be given. The details of induction are covered in Chapter 6 (“Clinical Use of Buprenorphine”).

Buprenorphine PHARMACOKINETICS Buprenorphine is approximately 96% protein bound in the plasma and undergoes N-dealkylation via the cytochrome P450 (CYP450) 3A4 enzyme system to produce an active metabolite, norbuprenorphine. Both buprenorphine and norbuprenorphine also undergo glucuronidation in the liver. Thirty percent of the drug is eliminated in urine and 70% in feces. Buprenorphine has a mean elimination half-life from plasma of 37 hours (Center for Substance Abuse Treatment 2004; Reckitt Benckiser Healthcare 2006). Buprenorphine’s metabolism by the CYP450 3A4 enzyme means that inhibitors of 3A4 or other substrates metabolized by the 3A4 enzyme could raise buprenorphine levels

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and that 3A4 inducers could lower buprenorphine levels. Table 3–2 shows a partial list of medications interacting with the CYP450 3A4 enzyme system. With the exception of interactions with some antiretroviral medications, it appears that most of these interactions are not clinically significant (see also Chapter 6, section “Drug-Drug Interactions,” and Chapter 9, “Psychiatric Comorbidity,” section “Drug Interactions With Buprenorphine”). Deaths have been associated with injecting buprenorphine with benzodiazepines and/or other central nervous system depressants (Reynaud et al. 1998a, 1998b). Therefore the use of sedative-hypnotics (benzodiazepines, barbiturates, and others) is a relative contraindication to treatment with buprenorphine, because the combination of buprenorphine and sedative-hypnotics may increase depression of the central nervous system. If treatment with buprenorphine and sedative hypnotics is necessary, the doses of both medications may need to be lowered (Center for Substance Abuse Treatment 2004). Side effects of buprenorphine can include constipation, nausea, and emesis but the frequency and intensity of these side effects are much lower than with full opioid agonists (Center for Substance Abuse Treatment 2004). Patients maintained with buprenorphine show no clinically significant disruption in cognitive and psychomotor performance on formal testing (Walsh et al. 1994). Elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported in patients taking buprenorphine (Lange et al. 1990; Petry et al. 2000). Petry et al. (2000) reported mild elevations in liver enzyme levels in patients who received sublingual buprenorphine for more than 40 days and who were treated with various dosages (2, 4, or 8 mg/70 kg/day). They found that patients with a history of viral hepatitis were significantly more likely to have enzyme level increases shown on their liver function tests compared with those without a history of hepatitis. This study had 72 patients with a history of hepatitis who had a median increase in ALT of 8.5 (range, −12 to 54) and a median increase in AST of 9.5 (range, −8 to 32); and 48 patients without a history of hepatitis who had a median ALT increase of 0 (range, −7 to 8) and a median AST increase of 1 (range, −6 to 4.5). The likelihood of seeing an increase in AST level varied as a function of buprenorphine dosage. It is important to note that these increases, while statistically significant, were quite small and of questionable clinical significance (Petry et al. 2000). There are reports of very high transaminase elevations (13–50 times normal levels) associated with intravenous buprenorphine use in patients infected with the hepatitis C virus. The proposed mechanism is inhibition of hepatic mitochondrial function by very high buprenorphine concentrations associated with injection, but not with sublingual dosing (Berson et al. 2001; Johnson et al. 2003).

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TABLE 3–2. Inhibitorsb Amiodarone Clarithromycin Delavirdine Erythromycin Fluconazole Fluoxetine Fluvoxamine Grapefruit juice Indinavir Itraconazole Ketoconazole Metronidazole Miconazole Nefazodone Nelfinavir Nicardipine Norfloxacin Omeprazole Paroxetine Ritonavir Saquinavir Sertraline Verapamil Zafirlukast Zileuton

aFor

Medications metabolized by cytochrome P450 3A4 (partial list)a Substrates Alprazolam Amlodipine Astemizole Atorvastatin Carbamazepine Cisapride Clindamycin Clonazepam Cyclobenzaprine Cyclosporine Dapsone Delavirdine Dexamethasone Diazepam Diltiazem Disopyramide Doxorubicin Erythromycin Estrogens Etoposide Felodipine Fentanyl Fexofenadine Glyburide Ifosfamide Indinavir Ketoconazole Lansoprazole Lidocaine

Loratadine Losartan Lovastatin Miconazole Midazolam Nefazodone Nelfinavir Nicardipine Nifedipine Nimodipine Ondansetron Oral contraceptives Paclitaxel Prednisone Progestins Quinidine Rifampin Ritonavir R-warfarin Saquinavir Sertraline Simvastatin Tacrolimus Tamoxifen Verapamil Vinblastine Vinorelbine Zileuton

Inducers c Carbamazepine Dexamethasone Efavirenz Ethosuximide Nevirapine Phenobarbital Phenytoin Primidone Rifampin

a continuously updated list of cytochrome P450 3A4 drug interactions, visit http://medicine.iupui.edu/clinpharm/ddis. bPotentially increasing blood levels of buprenorphine. cPotentially decreasing blood levels of buprenorphine. Source. Center for Substance Abuse Treatment 2004.

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CLINICAL USE ISSUES Three different clinical formulations of buprenorphine are available in U.S. pharmacies as of this writing in 2010. One is FDA approved for use as a parenteral analgesic and two sublingual forms are FDA approved for use in the treatment of opioid withdrawal disorder and opioid dependence disorder.

Parenteral Analgesic Parenteral buprenorphine hydrochloride (HCl) is a formulation that is available as a solution for intramuscular or intravenous use and has been approved by the FDA as an analgesic. Parenteral buprenorphine HCl is available in a solution with a concentration of 0.3 mg/mL, and recommended dosing for moderate to severe pain is 0.3 mg intramuscularly or intravenously. This initial dose may be repeated once after 30–60 minutes, then every 6–8 hours as needed for pain control (Ben Venue Laboratories 2004). It is important to understand that it is against U.S. federal laws for any prescriptions to be written for parenteral buprenorphine for the treatment of either opioid withdrawal disorder or opioid dependence disorder. It is not just beyond the FDA-approved uses to prescribe parenteral buprenorphine HCl for these opioid disorders, it is against the law and puts the physician at risk for federal prosecution and punishment.

Sublingual Forms Sublingual buprenorphine is available in the United States in two forms. One is Suboxone, referred to as the combo product, which combines buprenorphine and naloxone in a homogenous compressed tablet; the other is Subutex, referred to as the mono product, a tablet that contains only buprenorphine. Both are FDA approved for the treatment of opioid dependence, which applies to DSM-IV-TR diagnoses of opioid withdrawal disorder and opioid dependence disorder. The combo product combines buprenorphine and naloxone in a 4-to-1 ratio in two dose sizes, either 8 mg buprenorphine with 2 mg naloxone or 2 mg buprenorphine with 0.5 mg naloxone. The mono product contains only buprenorphine in two dose sizes, either 8 mg buprenorphine or 2 mg buprenorphine. The target clinical dosage range for both the combo and mono product is 8–16 mg of buprenorphine per day, with a maximum recommend dosage of 32 mg/day. As Table 3–3 shows, sublingual buprenorphine has poor oral availability. Swallowing these tablets results in no clinically significant effects. Buprenorphine tablets dissolved sublingually, as designed, allow the buprenorphine to be absorbed and to be clinically effective. In the case of the combo product, the buprenorphine is absorbed when dissolved sublingually but the naloxone is not significantly absorbed and has no clinical effect. However, if the combo prod-

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TABLE 3–3.

Bioavailability of buprenorphine Buprenorphine bioavailability relative to route of administration

Route of administration

Intravenous

Intramuscular

Sublingual solution

100%





Intramuscular

70%

100%



Sublingual solution

49%

70%

Sublingual tablet

29%

Intravenous

42%

100% 50%–70%

Source. Brewster et al. 1981; Kuhlman et al. 1996; Lloyd-Jones et al. 1980; Nath et al. 1999; Schuh and Johanson 1999; Strain and Stitzer 1999; Weinberg et al. 1988. Adapted from Center for Substance Abuse Treatment 2004.

uct is dissolved into solution and injected, then naloxone is clinically active and binds to the µ receptors and its antagonist effect predominates, blocking much of the opioid effect. Naloxone also triggers opioid withdrawal disorder if the individual who injects it is opioid dependent. When the mono product is injected, buprenorphine can produce significant levels of euphoria, clearly can be abused for its euphoric effect, and is subject to diversion for misuse. The only reason naloxone is an added component of the combo tablet is to prevent dissolving and injecting the tablet for euphoric effect, thus minimizing the risk of diversion (Center for Substance Abuse Treatment 2004; Stoller et al. 2001).

Conclusion Humans have used opiates for medicinal and euphorigenic purposes for thousands of years. The recent development of opioid antagonists and partial agonists has expanded our therapeutic options and, with buprenorphine, has added a unique agent for the treatment of opioid dependence. Because of its high affinity for opioid receptors, its long duration of action, and the ceiling effect on respiratory depression, it has proved to be an unusually safe and effective medication for managing opioid addiction. Dosing is relatively straightforward, though clinicians must be careful to avoid precipitating opioid withdrawal when initiating buprenorphine treatment in individuals who have recently used other opioids. The presence of naloxone in the buprenorphine combo tablet is an added safety feature that reduces the potential for abuse and diversion and further enhances the drug’s clinical utility.

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Clinical Pearls • Opioids are more likely to be abused if they 1. Have a faster route of administration, 2. Have a shorter half-life, and 3. Are more lipophilic, which allows them to pass through the blood-brain barrier more easily. • Buprenorphine, a µ opioid receptor partial agonist, binds tightly to opioid receptors but only partially activates them. Thus, buprenorphine's ability to produce euphoria and respiratory depression is limited, even at high doses. • Patients who are physically dependent on opioids can develop a precipitated withdrawal with buprenorphine; therefore, patients need to be in opioid withdrawal before receiving the initial dose of buprenorphine. • Buprenorphine is metabolized by the CYP450 3A4 system, but most drug-drug interactions do not appear to be clinically significant. • The buprenorphine-naloxone combination is the preferred form of the medication in order to diminish the likelihood of diversion to injected use.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Ben Venue Laboratories: Buprenorphine hydrochloride injection: prescribing information. Bedford, OH, Ben Venue Laboratories, August 2004. Available at: http:// www.bedfordlabs.com/BedfordLabsWeb/products/inserts/Div-BUP-P00.pdf. Accessed June 15, 2010. Berson A, Gervais A, Cazals D, et al: Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol 34:346–350, 2001 Booth M: Opium: A History. New York, St Martin’s Griffin, 1999 Brewster D, Humphrey MJ, Mcleavy MA: The systemic bioavailability of buprenorphine by various routes of administration. J Pharm Pharmacol 33:500–506, 1981 Center for Substance Abuse Treatment: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publ No (SMA) 04-3939. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2004. Available at: http:// www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hssamhsatip& part=A72248. Accessed April 29, 2010.

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Cowan A: Buprenorphine: the basic pharmacology revisited. J Addict Med 1:68–72, 2007 Cowan A, Lewis JW (eds): Buprenorphine: Combatting Drug Abuse with a Unique Opioid. New York, Wiley-Liss, 1995 Fioravanti B, Vanderah TW: The ORL-1 receptor system: are there opportunities for antagonists in pain therapy? Curr Top Med Chem 8:1442–1451, 2008 Johnson RE, Strain EC, Amass L: Buprenorphine: how to use it right. Drug Alcohol Depend 79:S59–S77, 2003 Kuhlman JJ, Lalani S, Magluilo J, et al: Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol 20:369–378, 1996 Lange WR, Fudala PJ, Dax EM, et al: Safety and side-effects of buprenorphine in the clinical management of heroin addiction. Drug Alcohol Depend 26:19–28, 1990 Lloyd-Jones JG, Robinson P, Henson R, et al: Plasma concentration and disposition of buprenorphine after intravenous and intramuscular doses to baboons. Eur J Drug Metab Pharmacokinet 5:233–239, 1980 Nath RP, Upton RA, Everhart ET, et al: Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol 39:619– 623, 1999 Petry NM, Bickel WK, Piasecki D, et al: Elevated liver enzyme levels in opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict 9:265–269, 2000 Reckitt Benckiser Healthcare: Buprenorphine hydrochloride and naloxone hydrochloride dihydrate sublingual tablets (Suboxone) and buprenorphine hydrochloride sublingual tablets (Subutex): prescribing information. Hull, United Kingdom, Reckitt Benckiser Healthcare, September 2006 Reynaud M, Petit G, Potard D, et al: Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Addiction 93:1385–1392, 1998a Reynaud M, Tracqui A, Petit G, et al: Six deaths linked to misuse of buprenorphinebenzodiazepine combinations. Am J Psychiatry 155:448–449, 1998b Schuh KJ, Johanson CE: Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet. Drug Alcohol Depend 56:55–60, 1999 Stoller KB, Bigelow GE, Walsh SL, et al: Effects of buprenorphine/naloxone in opioiddependent humans. Psychopharmacology (Berl) 154:230–242, 2001 Strain EC, Stitzer ML (eds): Methadone Treatment for Opioid Dependence. Baltimore, MD, Johns Hopkins University Press, 1999 Walsh SL, Preston KL, Stitzer ML, et al: Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 55:569–580, 1994 Weinberg DS, Inturrisi CE, Reidenberg B, et al: Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther 44:335–342, 1988

4 Efficacy and Safety of Buprenorphine Eric C. Strain, M.D.

History and Rationale for the Development of Buprenorphine for Treatment of Opioid Dependence This chapter provides a review of the history of buprenorphine from its initial development as an analgesic to its current use as a treatment for opioid dependence. The discussion includes an overview of the safety and efficacy trials that established its value as a medication for maintenance treatment and for the management of opioid withdrawal. Buprenorphine was first synthesized in the late 1960s and was initially developed and marketed throughout the world as an analgesic. In the United States it was sold under the brand name Buprenex and outside the United States as Temgesic. In the United States, it was only available in a parenteral form for the treatment of pain. However, a sublingual analgesic form was marketed in other countries (e.g., New Zealand). Although buprenorphine was initially marketed for the treatment of pain, it was quickly recognized that buprenorphine might have value as a medication that could be used for the treatment of opioid dependence. A paper published by Jasinski and coworkers (1978) described the pharmacological profile of buprenorphine in humans under a variety of experimental conditions and concluded that the medication had characteristics that might make it particularly useful and effective for the treatment of opioid dependence. 59

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PHARMACOLOGICAL FEATURES Of its pharmacological characteristics, three primary features of buprenorphine are particularly relevant to its use as an opioid dependence treatment medication. Two of these may be seen as advantageous, whereas the third is a relatively minor detriment to its use. Although it is beyond the scope of this chapter to address each in detail, these three characteristics are reviewed here because they have direct clinical implications. 1. Buprenorphine acts as an agonist at the µ opioid receptor. It has been long recognized that it is a partial agonist at the µ receptor. Partial agonist medications produce effects that are very similar to full agonist medications at the lower end of a dose-response curve, but as the dose of a partial agonist increases, the effect of the medication plateaus, such that there is less of a maximal effect compared with a full agonist medication. The common medications that are contrasted with buprenorphine are full µ opioid receptor agonists such as methadone and morphine, which generally have the capacity to produce greater effects than buprenorphine at higher doses. Notably, the relative degree of maximal effect of a partial agonist relative to a full agonist can vary as a function of the outcome measure being considered (e.g., in the case of opioids, respiratory depression vs. gastrointestinal motility vs. analgesia). The fact that buprenorphine acts at the µ opioid receptor is important for several reasons. Agonism at the µ receptor means that buprenorphine can suppress spontaneous opioid withdrawal, ensuring that patients who are in opioid withdrawal at the time they take their first dose of buprenorphine will have suppression of those withdrawal symptoms. In addition, occupancy at the µ receptor provides blockade, so a subsequently administered dose of another µ opioid receptor agonist (such as heroin) is not experienced to the same degree as would occur if no buprenorphine were present. Finally, opioids that act at the µ receptor generally decrease craving for illicit opioids in persons who are physically dependent on opioids and who receive maintenance therapy with a µ agonist. 2. Buprenorphine has a bell-shaped dose-response curve. That is, as the dose of buprenorphine increases, there is an increase in a measured effect (e.g., analgesia, respiratory depression) until a maximal effect is achieved, then the measured effect decreases at even higher doses. Notably, this bell-shaped dose-response curve has only been shown in animal models (i.e., no human studies to date have shown it). However, in animals buprenorphine’s bellshaped curve has been shown for several measures, including analgesia, gastrointestinal motility (i.e., constipation), and respiratory depression.

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The reason for the decrease in effects at higher doses was originally thought to be related to a second opioid receptor effect of buprenorphine— antagonism at the κ receptor. (This combination of partial agonism at the µ receptor and antagonism at the κ receptor is the reason buprenorphine is sometimes called an opioid mixed agonist-antagonist. There are several other marketed opioid mixed agonist-antagonist analgesics, such as pentazocine and butorphanol.) However, more recent preclinical data suggest that the descending limb of buprenorphine’s dose-response curve can be attributed to an alternative pharmacological action of this medication—a nonopioid action at the opioid receptor-like-1 (ORL-1) receptor. That is, buprenorphine acts as an agonist at the ORL-1 receptor. Animal studies suggest that when ORL-1 receptors are not present, buprenorphine produces effects that look like those of a full agonist opioid (i.e., no descending limb to the dose-response curve). These two pharmacological effects translate to clinical advantages. Mu receptor agonism means that buprenorphine suppresses withdrawal, blocks the effects of other opioids, and decreases craving. The bell-shaped doseresponse curve, combined with the lower maximal effect as a partial µ agonist, means that there is a lower risk of respiratory depression associated with an overdose of the drug. However, the third feature of the drug is not a particularly advantageous characteristic (although it is not a marked disadvantage, either). 3. Buprenorphine has poor oral bioavailability. The most common delivery route for medications taken on an outpatient basis is swallowing, and although other routes can be used (e.g., the injection of insulin, topical administration of nicotine with a patch), they are less common routes of administration. Buprenorphine has fair sublingual bioavailability and a sublingual form was developed for the treatment of opioid dependence. Although this route of administration is relatively uncommon for medications that are self-administered, it has been accepted by patients. Because a sublingual tablet needs to be water soluble, a concern with this formulation was that it could be relatively easy to dissolve in water and inject. Given that the sublingual bioavailability is only fair compared with parenteral bioavailability, sublingual doses are relatively high compared with typical parenteral analgesic doses (8–16 mg vs. 0.2–0.3 mg, respectively). Thus, a water-soluble sublingual tablet has the potential to be relatively easy to dissolve and inject with the subsequent delivery of a relatively high dose of the drug. These aspects of administration route and relative bioavailability could impact the risk of diversion and parenteral misuse of a sublingual buprenorphine tablet. To address this potential, tablets that contain naloxone

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were developed. Although a full description of the scientific basis for a buprenorphine-naloxone tablet is not provided here, the logic of this combination is based on three observations. First, naloxone has very poor sublingual bioavailability. Second, injected naloxone precipitates an opioid withdrawal syndrome in persons with opioid dependence. And third, opioid withdrawal is distressing but rarely life threatening. Thus, when a combined buprenorphine-naloxone tablet is taken via the intended therapeutic route (sublingually), the desired therapeutic effect is achieved. However, if the tablet is dissolved and injected (by an opioid-dependent person), then the naloxone effect occurs and the person experiences the opioid withdrawal syndrome. (However, note that this would only be the case for a person who is opioid dependent.) Although the withdrawal syndrome is distressing, it is generally tolerable and not a medical emergency. These pharmacological features of buprenorphine suggested that it could be a useful agent for the treatment of opioid dependence, and furthermore that it would be pharmacologically different from traditional full µ opioid receptor agonist medications (i.e., methadone and L-α-acetylmethadol [LAAM]). As these features came to be appreciated, there was recognition that it might be possible for buprenorphine to be used outside the traditional methadone clinic delivery system. In order to appreciate this aspect of buprenorphine’s development, the context of medications development needs to be appreciated, in particular the approval and use of LAAM in the United States.

U.S. APPROVAL AND USE OF LAAM AND ITS IMPACT ON BUPRENORPHINE DEVELOPMENT During the 1990s, when buprenorphine was being intensively studied as a potential treatment for opioid dependence, another opioid treatment medication was also being studied and eventually approved for use in the United States— LAAM. Although LAAM had been identified as a possible treatment for opioid dependence in the 1970s, it had languished for years until the National Institute on Drug Abuse (NIDA) took the initiative to obtain U.S. Food and Drug Administration (FDA) approval for this medication, which then occurred in 1993. However, LAAM needed to be dispensed through the opioid treatment program (OTP) system—that is, methadone clinics. Despite the availability of this new alternative medication that had good efficacy, there was very limited use of LAAM and essentially no expansion of the treatment system was associated with the availability of LAAM. Although subsequent concerns arose regarding potential cardiac effects of LAAM, its eventual withdrawal from the U.S. market was due to low sales rather than its cardiac effects.

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The experience with LAAM impacted planning for the eventual approval and use of buprenorphine. LAAM could only be provided through the OTP system, and had not expanded treatment capacity. In order to avoid a similar experience with buprenorphine in the United States, federal legislative changes were enacted that permitted the use of certain types of medications in officebased practices for the treatment of opioid dependence. This law, the Drug Addiction Treatment Act of 2000, identified potential medications for officebased treatment as being on Schedule III, IV, or V (i.e., having less abuse potential than Schedule II medications, such as methadone). Although this legislation did not specify buprenorphine, it was clearly designed with buprenorphine in mind. Because buprenorphine was approved as a Schedule III medication (based on its pharmacological characteristics suggesting it has lower abuse potential), it could then be used in office-based practices. This increased the likelihood that buprenorphine would not be another LAAM.

SUMMARY Although buprenorphine was initially developed for use as an analgesic, it is interesting that buprenorphine’s major clinical impact has occurred as a treatment for opioid dependence. As has been noted repeatedly over the years, the pharmacological effects of buprenorphine are unique, and these unique features— such as its partial agonist effects and the bell-shaped dose-response curve— make it particularly suited for the treatment of opioid addiction. Because of these features, buprenorphine was well positioned to be used outside of the traditional OTP system, which in turn made it a medication that has helped to expand the treatment of opioid dependence.

Controlled Trials Assessing Buprenorphine’s Efficacy for Maintenance Treatment of Opioid Dependence Clinical studies testing the efficacy of buprenorphine have included both inpatient (or residential) human laboratory studies and outpatient clinical trials. The former have tended to be smaller studies with a within-subject design (i.e., in which volunteers serve as their own control subject over the course of the study). There have been an extensive number of these studies, and reviewing all of them is beyond the scope of this chapter. The results from these studies provided critical information about buprenorphine, although direct translation to clinical use

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of the medication was not always the purpose of the studies. Outpatient clinical trials, on the other hand, provide important data that are more representative of and relevant to clinical use. These generally have been group comparison studies, and two primary comparisons have been used to test buprenorphine’s efficacy in outpatient clinical trials—studies that compared it with placebo, and those that compared it with methadone. Although most of these studies were conducted in the 1990s, before buprenorphine’s approval in the United States, there continue to be outpatient clinical trials testing its efficacy.

HUMAN LABORATORY STUDIES Multiple human laboratory studies have tested the blockade efficacy of buprenorphine under different experimental conditions. In general, these studies enroll opioid-dependent volunteers, maintain the subjects with buprenorphine or buprenorphine-naloxone (either buprenorphine solution or, in later studies, the tablet formulation), and then test whether opioid agonist–like effects are produced when subjects receive a prototypic µ opioid receptor agonist such as morphine, heroin, or hydromorphone. The subject might be challenged directly with the drug (Bickel et al. 1988; Strain et al. 1997, 2002) and assessed for the drug’s effects, or be allowed to self-administer the drug to determine whether the drug’s relative reinforcing effects are diminished by buprenorphine treatment (Comer et al. 2001, 2005; Mello and Mendelson 1980). One difficulty with these human laboratory studies is that the ideal control condition—a period of time when the subject is maintained with placebo and challenged with an opioid or allowed to self-administer an opioid—is not included in the studies. A placebo maintenance period would permit the efficacy of buprenorphine to be more accurately characterized. However, it is not practical to conduct such a study, even if conducted under the controlled conditions of an inpatient ward as is typical for these projects. Participants would need to be fully withdrawn from opioids, making blinding of buprenorphine versus placebo maintenance conditions problematic. Alternatively, a separate group of subjects who do not have active opioid dependence could be used as a comparison group, although groups need to be matched to ensure that other factors do not account for differences that might be noted. Given these qualifications, studies have typically compared the relative efficacy of different doses of buprenorphine, with the idea that greater attenuation of opioid effect or less selfadministration for a higher dose of buprenorphine (vs. a lower dose) provides evidence of efficacy. When buprenorphine is studied in the human laboratory, dose-related blockade is generally demonstrated. That is, volunteers maintained on buprenorphine (or buprenorphine-naloxone) report lower ratings of opioid agonist–like effects with higher doses of buprenorphine, and self-administer less

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of a µ opioid receptor agonist at the higher doses. Dosages of either 2 or 4 mg of buprenorphine per day (or the equivalent of buprenorphine-naloxone) produce significantly less blockade of opioid effects and less self-administration of an opioid, compared with dosages of 8–32 mg of buprenorphine per day (or the equivalent of buprenorphine-naloxone). These effects have been shown both with direct challenge sessions and in self-administration studies. Some evidence suggests that 16 mg may be more effective than 8 mg of buprenorphine daily, although not all studies have shown a distinction. However, this should not be interpreted to mean that daily doses of greater than 8 mg of buprenorphine are not more effective than 8 mg/day, and clearly there are some subjects in studies (and some patients in clinical practice) who have better outcomes with daily doses greater than 8 mg. There can be considerable variability in the responses of individual subjects in a human laboratory study. Results from these studies also show that there is often incomplete blockade or suppression of self-administration of a µ opioid receptor agonist when a person is maintained with buprenorphine—especially if a sufficiently high dosage of the µ agonist is employed in the study. Although these studies provide critical data relevant to the demonstration of buprenorphine’s efficacy, they also highlight that the medication alone is not a magic bullet that fully addresses all of the factors that can lead to use of illicit opioids by a person with opioid addiction. Although maintenance with buprenorphine—probably at a dosage of at least 8 mg/day for most patients—can be very effective at decreasing the subjective effects of opioids and the likelihood of taking these drugs, optimal outcomes are achieved when buprenorphine is taken by a motivated patient who is engaged in other treatment services that concurrently address drug use (see Chapter 8, “Clinical Management II,” and Chapter 9, “Psychiatric Comorbidity”).

OUTPATIENT GROUP COMPARISON CLINICAL TRIALS Human laboratory studies provide data from highly controlled experimental conditions that allow characterization of buprenorphine’s efficacy when confounding factors (e.g., other drug use, presence of a comorbid condition) are controlled for or excluded from study participants. Outpatient clinical trials, on the other hand, provide data that can be viewed as more reflective of “real life.” Such studies, although closer to clinical practice than residential studies, often employ design features that distinguish these trials as significantly different from routine care (e.g., double-blind dosing, random assignment to treatment conditions, intensive collection of standard outcome measures). It is worth noting that the goal of a controlled clinical trial is not to model exactly how a medication will be used by clinicians, but to provide a scientific basis for answering

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specific questions about the efficacy and/or safety of the medication under the particular experimental conditions utilized. There are advantages to both outpatient clinical trials and inpatient/residential laboratory study approaches, and they should be seen as complementary with each being relevant to the drug development process. The next two sections describe findings from outpatient clinical trials of buprenorphine’s efficacy compared with placebo and compared with methadone.

Buprenorphine Compared With Placebo Relatively few studies have tested the efficacy of buprenorphine compared with a true placebo condition. In part, this is related to the inherent difficulty in blinding placebo medication use for a person who is opioid dependent. It is very likely that the blind would be immediately broken if an opioid-dependent person were to directly start taking placebo, because the person would readily detect the lack of withdrawal suppression and subjective opioid agonist effects, and the resulting classic opioid withdrawal symptoms. However, strategies have been employed to provide true placebo control conditions; probably the most common such approach has been to have participants who have been assigned to a placebo condition undergo a period of active treatment medication that includes gradual withdrawal and transfer onto placebo doses of buprenorphine. In alternative methods to this approach, one study used a low-dose buprenorphine condition as a placebo-like control condition (Ling et al. 1998), and another used a novel choice procedure that allowed volunteers to switch from placebo to active medication (Johnson et al. 1995). Controlled outpatient clinical trials that have tested the efficacy of buprenorphine compared with placebo have consistently shown that buprenorphine is more effective than placebo for primary outcome measures of treatment retention and illicit opioid use (Fudala et al. 2003; Johnson et al. 1995; Kakko et al. 2003; Krook et al. 2002; Ling et al. 1998). Cross-study comparisons are somewhat difficult, given the use of different dosages of buprenorphine, different durations of treatment, and different outcome assessments. In general, however, dosages of 8–16 mg of sublingual buprenorphine per day (or the equivalent of buprenorphine-naloxone) have typically been compared with 0 mg (or in one case, a 1-mg placebo-like control condition) and shown to be superior. Although dosages greater than 16 mg/day have been tested, the relative efficacy of higher dosages compared with 8–16 mg/day has not been a primary outcome assessed. Such higher dosages (up to 32 mg/day) may be clinically indicated for some patients, and there is clearly variability in the optimal dosage needed for some patients. Although it is difficult to compare outcomes from these studies, it is worth noting that retention of buprenorphine-treated patients is consistently superior

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to retention of patients treated with placebo. Indeed, placebo-treated participants in these studies generally drop out. For example, after 16 weeks of treatment in one study, the retention rate for patients treated with 16 mg of buprenorphine per day was 61% versus 40% for the 1-mg (placebo-like) condition (Ling et al. 1998). In a study of 1 year’s duration, 75% of participants treated with 16 mg of sublingual buprenorphine per day remained in treatment at 1 year, compared with none of the participants who underwent double-blind buprenorphine withdrawal followed by placebo treatment (Kakko et al. 2003). In summary, these rigorously conducted, controlled clinical trials show that daily sublingual buprenorphine is superior to placebo in the outpatient treatment of opioid dependence. A final point regarding these studies, and the clinical trials comparing buprenorphine versus methadone that are summarized in the next section, is worth noting. The goal of these studies was to test the efficacy of buprenorphine. However, optimal clinical outcomes for the treatment of opioid dependence (and other addictions) occur when pharmacotherapies are combined with nonpharmacological treatments (Amato et al. 2004). Thus, if the interested clinician reader reviews these papers and studies, it is important to keep in mind that it is likely the reported outcomes can be considerably improved when buprenorphine is used outside the constraints of a clinical trial, and with the concurrent care of committed clinicians.

Buprenorphine Compared With Methadone Although the number of studies that have tested buprenorphine’s efficacy compared with placebo is relatively small, many more outpatient studies have compared buprenorphine with methadone treatment (Mattick et al. 2008). The general conclusions drawn here are based on well-conducted clinical trials. Studies that were not double-blind, did not randomize participants to dose conditions, or had other methodological features that make interpretation of findings problematic are generally not factored in when considering buprenorphine’s efficacy relative to methadone’s efficacy in this section. (Such studies can provide supportive evidence, but confounds in design or execution make interpretation of findings problematic.) Despite the use of good clinical trial methods, features of these studies can differ considerably—for example, in the dosages of buprenorphine and methadone used, the frequency of buprenorphine dosing, whether the doses of each medication are fixed or flexible, and the primary outcome assessments and the frequency of collection for these primary outcome assessments. Despite these differences, several general conclusions regarding buprenorphine’s efficacy compared with methadone’s can be made. Outcomes with buprenorphine treatment are generally similar to those achieved with methadone, with methadone dosages of up to about 60 mg/day. When methadone dosages

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of greater than 60 mg/day are used, it appears that methadone provides better outcomes (treatment retention and some measure of illicit opioid use—selfreported use and/or urine testing results—are typically used as primary outcome measures in most studies). However, it is worth noting that most clinical trials have been conservative with buprenorphine dosing (despite the apparent safety of this medication at high doses), that no studies have tested the efficacy of dosages greater than 32 mg of sublingual buprenorphine per day, and that few have tested doses even that high. It is useful to elaborate on this point. Recall that buprenorphine has a bell-shaped dose-response curve. Theoretically, it is possible that at higher doses a decrease in some effects might occur, but that greater degrees of opioid blockade might still be achieved. Thus it is interesting that despite the apparent safety of high doses of buprenorphine, no controlled clinical trials have tested dosages greater than 32 mg/day. Indeed, there has been little research in humans that has examined the effects of daily doses greater than 32 mg under any experimental conditions, such as human laboratory studies. It appears that dosages of about 8–24 mg of buprenorphine per day produce outcomes similar to those seen with moderate dosages of methadone (i.e., up to 60 mg/day). Most of the studies that have compared buprenorphine versus methadone were conducted in methadone treatment clinics (OTPs), and it is important to note that the circumstances under which buprenorphine is used in the United States—in an office-based setting that is physician based—are very different from the treatment provided at an OTP. Although there has been research looking at the efficacy of buprenorphine in office-based settings (Fiellin et al. 2006), this work is more limited and generally has not compared office-based buprenorphine to traditional OTP-delivered methadone treatment. Although findings from controlled clinical trials comparing daily sublingual buprenorphine with methadone suggest that outcomes achieved with methadone may be better at higher methadone doses, this should not be interpreted to suggest that buprenorphine is not a treatment option for patients with higher levels of opioid physical dependence. There can be considerable variability in the response that different patients have to a medication. Indeed, it has been shown that the bioavailability of buprenorphine can vary twofold between different subjects treated with the same dose, suggesting that conclusions based on the dose delivered may obscure differences related to blood levels (Strain et al. 2004). And, the impact of nonpharmacological aspects of treatment (e.g., intensity of counseling services), the particular circumstances of the patient (e.g., his or her level of motivation), and the features of the setting of treatment (e.g., ready access to office-based treatment) can impact the efficacy of buprenorphine. Perhaps the most important conclusion that can be drawn from the controlled clinical trials that have compared buprenorphine and methadone is that both medications are efficacious, and that a patient who

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is not responding well to one—when all aspects of the treatment have been optimized (e.g., dosage, level of counseling, involvement of significant others)— should be considered for treatment with the other. Both are excellent options for the treatment of opioid dependence.

Controlled Trials Assessing Buprenorphine’s Efficacy for Opioid Withdrawal Treatment When buprenorphine first became available for the treatment of opioid dependence in the United States, a considerable proportion of its use was for the treatment of opioid withdrawal. Indeed, before the approval of the sublingual tablet it was very common for clinicians to report that they used the parenteral form of buprenorphine to treat opioid withdrawal. Although the current relative proportion of buprenorphine use for withdrawal versus maintenance treatment is not known, it appears that the growth of buprenorphine use in the United States in recent years has been greater for maintenance than for withdrawal treatment. Before the use of buprenorphine for the treatment of opioid withdrawal, a common pharmacological treatment used to alleviate opioid withdrawal, especially in inpatient settings, was clonidine. An early study that directly compared buprenorphine with clonidine found that buprenorphine had an overall better profile of efficacy and safety than clonidine (Cheskin et al. 1994), and subsequent studies have had similar findings (Gowing et al. 2004; Ling et al. 2005; Ziedonis et al. 2009). Although situations in which clonidine would be preferred for the treatment of opioid withdrawal in a particular patient can be imagined, in general clonidine is no longer a first-line agent for this indication—especially on an inpatient basis, where dosing can be supervised and risk of diversion or misuse of buprenorphine is quite low. On an outpatient basis, methadone or buprenorphine may be used to treat opioid withdrawal. Studies that have directly compared buprenorphine with methadone for the outpatient treatment of withdrawal have been uncommon, and those that have done so have tended to involve either small samples, special groups such as adolescents, or subjects who were treated concurrently with other medications, making interpretation of findings more difficult (Ebner et al. 2004; Gowing et al. 2004; Seifert et al. 2002). Studying the efficacy of buprenorphine versus methadone in the outpatient treatment of opioid withdrawal in the United States is further confounded by the two very different mechanisms under which each medication can be provided. Virtually all methadone treatment in the United States for opioid dependence treatment is pro-

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vided through OTPs, a centralized and regulated system of care that has limited availability and often strict rules that emphasize treatment adherence in a very standardized form for patients at a particular clinic. This is a markedly different system of care compared with buprenorphine’s availability via officebased practices, where treatment is decentralized, can be more individualized, has a higher degree of medical involvement, and may involve fewer counseling services and behavioral interventions than an OTP. Some general conclusions regarding the use of buprenorphine for the treatment of opioid withdrawal can be made: • •



Longer periods of withdrawal (at least 30 days) are probably more effective than shorter withdrawal periods (Amass et al. 1994; Katz et al. 2009). Buprenorphine is superior to clonidine (and is approved for the treatment of opioid dependence in the United States, whereas clonidine is not), and should be the medication of choice when considering which of these two medications to use. Lofexidine, an α2-adrenergic agonist like clonidine, is available for treating opioid withdrawal in the United Kingdom, but is not available in the United States. A few studies have compared buprenorphine with lofexidine for the treatment of opioid withdrawal, but firm conclusions about the relative efficacy of the two medications are probably premature at this time. The efficacy of buprenorphine compared with that of methadone has not been well characterized, and this is a topic that needs to be addressed—both with respect to office-based methadone (vs. buprenorphine) treatment and with respect to OTP-delivered buprenorphine (vs. methadone) treatment.

Buprenorphine’s Safety and Side Effects Buprenorphine is a safe medication with a relatively unremarkable side-effect profile. Several areas of potential concern have been identified in recent years regarding medications used to treat opioid dependence. Each of these topics is addressed in this section as it relates to buprenorphine, followed by a section that summarizes the side effects associated with buprenorphine treatment. It is important to stress that in general, buprenorphine is a medication that is safe and effective for the overwhelming majority of patients who take it.

LIVER FUNCTION A few case reports have shown that very high doses of buprenorphine delivered by intravenous injection can produce an acute change in liver function test re-

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sults. Before buprenorphine’s approval in the United States, a retrospective evaluation of patients treated with sublingual buprenorphine found that there were slight increases in liver enzyme levels (serum transaminase levels) when patients with a history of hepatitis C infection were treated with buprenorphine (Petry et al. 2000). Subsequently, the FDA-approved labeling for buprenorphine included a caution regarding liver function and buprenorphine use. However, clinical experience has generally not supported a particular concern about this potential adverse event. At present, the NIDA Clinical Trials Network is conducting a study looking at buprenorphine’s possible effects on liver function. Pending the results from that study, there are no specific recommendations regarding monitoring of buprenorphine’s effects on liver function, although it would seem prudent to monitor liver enzyme levels in a patient who may be at particularly high risk for liver problems.

CARDIAC CONDUCTION The opioid agonist medication LAAM was briefly marketed in the United States and Europe for the treatment of opioid dependence. However, it was withdrawn from the European market due to concerns about cardiac conduction effects, especially prolongation of the QTc interval and the risk of torsades de pointes (a potentially fatal arrhythmia). It was also withdrawn from the U.S. market, but at the initiative of the manufacturer, apparently due to poor sales. These experiences with LAAM led to a reappraisal of the potential cardiac effects of other µ opioid receptor agonists. Various reports have examined both methadone and buprenorphine to see whether there is evidence of QTc interval prolongation associated with either of these medications. This is currently a controversial topic with respect to methadone, with some reports suggesting there may be QTc prolongation with very high doses of methadone (although the full clinical meaning of such prolongation is debated). However, of more relevance to this chapter, assessments of buprenorphine have not found evidence that it is associated with prolongation of the QTc interval (Fanoe et al. 2007; Wedam et al. 2007).

PRECIPITATED W ITHDRAWAL A potential adverse effect of buprenorphine is precipitated opioid withdrawal associated with the first dose of sublingual buprenorphine. Buprenorphine’s partial agonist effects at the µ receptor, as reviewed earlier in this chapter (in “Pharmacological Features”), may produce less effect than a full opioid agonist. Under the right circumstances, an acute dose of buprenorphine can precipitate an opioid withdrawal syndrome. It is important to note that this is an effect produced by buprenorphine itself, and that this phenomenon differs from the

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precipitated withdrawal produced by the injection of naloxone when a buprenorphine-naloxone tablet is injected (Stoller et al. 2001). Buprenorphinerelated precipitated withdrawal can occur in opioid-dependent persons and is associated with the first sublingual dose of the medication. It generally increases in likelihood if the first dose of buprenorphine is high (e.g., ≥ 8 mg sublingual buprenorphine), if the patient has a high level of physical dependence on opioids (e.g., the equivalent of ≥60 mg of oral methadone per day), and/or if there is a short time interval between the last dose of a full opioid agonist and the first dose of buprenorphine (e.g., ≤2 hours since the last dose of the full agonist). Thus, longer time intervals since the last dose of agonist, lower first doses of buprenorphine, and lower levels of physical dependence decrease the risk of buprenorphine-related precipitated withdrawal. For patients who are thought to be at higher risk for buprenorphine-related precipitated withdrawal (e.g., a patient maintained with 100 mg of oral methadone per day), it may be useful to give small (e.g., 2-mg) repeated doses of buprenorphine (or buprenorphine-naloxone) every 2 hours rather than a single larger first dose (Rosado et al. 2007). Ideally, the patient should show some evidence of early spontaneous opioid withdrawal before the first dose of buprenorphine, to minimize the risk of precipitating withdrawal. Finally, the risk of buprenorphine-related precipitated withdrawal is associated with the first dose of the medication—once the patient is regularly taking buprenorphine, there is no risk of buprenorphine precipitating withdrawal.

OVERDOSE Although patients have overdosed with buprenorphine, there does not appear to be the same risk of respiratory depression as seen with overdoses of full opioid agonists (e.g., heroin). The exception to this is when a patient overdoses with buprenorphine along with a sedative such as a benzodiazepine. Shortly after buprenorphine became available in France, there were reports of patient deaths associated with injection of buprenorphine tablets along with a benzodiazepine such as flunitrazepam, an injectable benzodiazepine not available in the United States (Reynaud et al. 1998; Tracqui et al. 1998). However, overdose of buprenorphine alone does not seem to carry the same risk of death. The U.S. label for buprenorphine notes there should be caution when buprenorphine is used concurrently with a benzodiazepine. This should be viewed as a relative rather than an absolute contraindication, because oral benzodiazepines were used by many patients enrolled in clinical trials with buprenorphine before its approval, and there were no deaths noted in those studies. The risk for death associated with a buprenorphine-benzodiazepine combination may be greatest when higher doses of both medications are injected.

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OTHER SIDE EFFECTS In addition to the safety and side effects points noted above, five other topics should be briefly addressed when considering buprenorphine: headache, constipation, erectile dysfunction, cognitive functioning/performance, and sweating. According to the FDA-approved labeling for buprenorphine, in a 4-week study that compared buprenorphine alone or in combination with naloxone versus placebo, the most common side effect noted by patients treated with buprenorphine was headache and the rate of headaches was higher in the buprenorphinenaloxone (36.4%) and buprenorphine (29.1%) groups than in the placebo group (22.4%). Similarly, rates of reported constipation were higher in buprenorphine-naloxone recipients (12.1%) and buprenorphine recipients (7.8%) than in placebo recipients (2.8%). However, for both headache and constipation, comparisons with placebo tell only part of the story, because it would be helpful to know how buprenorphine compares with another opioid treatment medication such as methadone. There are limited data reporting on such comparisons, although it appears that in terms of these side effects buprenorphine and methadone are generally not markedly different (Lofwall et al. 2005). Some evidence suggests that there may be higher rates of erectile dysfunction in patients treated with methadone than in those treated with buprenorphine (Hallinan et al. 2008; Quaglio et al. 2008). However, it is important to note that studies to date have been based on patients in treatment who have received the medications under nonblinded conditions, and potential confounding features to such analyses make interpretation of findings somewhat difficult. Studies of buprenorphine suggest that the doses typically used in the treatment of opioid dependence do not produce impairment in cognitive functioning or performance (Mintzer et al. 2004; Soyka et al. 2001), although there is some evidence that patients with opioid dependence may do less well than normal control subjects on such measures (Soyka et al. 2008). Finally, some clinicians have noted patient reports of increased sweating while receiving buprenorphine maintenance therapy. Interestingly, this side effect has been noted with methadone maintenance therapy as well.

SUMMARY Based on the studies and reports published to date, buprenorphine appears to be a safe medication with no significant or critical side effects. Initial concerns about possible liver effects have not been well supported, although data from the NIDA Clinical Trials Network study will help to address this question. Other effects, such as constipation, headache, and sweating, are not uncommon for patients treated with opioids, and do not appear to be severe. There

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appears to be a lack of effects in notable areas, including measures of cognition and performance, erectile dysfunction, and cardiac conduction. Although other side effects may be yet identified, the extensive use of buprenorphine to date suggests that if major adverse effects or significant side effects were to occur, then they should have been noted by now. The conscientious clinician should remain aware of possible effects noted in this section, but should also be reassured that buprenorphine has an overall mild side-effect profile.

Future Directions for Buprenorphine Treatment of Opioid Dependence Buprenorphine has been a highly successful addition to the interventions clinicians can use for the treatment of opioid dependence. There are three future directions regarding buprenorphine use to briefly mention here: •





Development of alternative, novel formulations of buprenorphine: There has been considerable interest in developing an injectable or implantable, sustained-release form of buprenorphine that could be delivered monthly or even every several months. At least two such formulations have been tested, although an approved product that could be marketed is still probably a year or two away. In addition, a patch form of buprenorphine and a buccal soluble film form have been tested in humans. Use of higher doses: At present, studies have generally tested maximum daily doses of 32 mg. Given the dose-response curve for buprenorphine and its safety at higher doses, it is somewhat surprising that the efficacy (and safety) of dosages higher than 32 mg/day have not been tested. Transition off buprenorphine: Given the success of this medication, it is probable that some proportion of patients maintained with buprenorphine could transition off it (e.g., take the sustained-release form of naltrexone instead). How this can be optimally done needs to be determined—especially for the clinician in an office-based practice.

These three areas—novel formulations, the use of higher doses, and the transition off buprenorphine—should be areas of research as this medication becomes more firmly established in clinical use.

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Conclusion Buprenorphine is a novel opioid. Its unique profile of effects makes it very well suited for the treatment of opioid dependence, and research has confirmed its clinical efficacy and safety for the treatment of opioid dependence. Studies have demonstrated that it is superior to placebo treatment and that its efficacy is comparable to that of moderate doses of methadone (with the qualification noted that higher doses of buprenorphine have not been systematically tested for efficacy and safety). In addition to demonstrated efficacy, it is also a safe medication with no substantial adverse effects or significant side effects. This profile of effects makes it well suited for use in office-based treatment, where it has been able to make a substantial impact.

Clinical Pearls • Buprenorphine (and buprenorphine-naloxone) is a safe and effective medication for the treatment of opioid dependence. • Buprenorphine (and buprenorphine-naloxone) is more effective than placebo and is at least as effective as moderate doses of methadone (about 60 mg of daily methadone). High doses of buprenorphine (>32 mg/day) for the treatment of opioid dependence have not been rigorously studied in human clinical trials. • Buprenorphine (and buprenorphine-naloxone) has a good safety profile with a side-effect profile that is similar to that seen with other opioids. The most common side effects are headache, constipation, and increased sweating. • There do not appear to be increases in the QTc interval associated with buprenorphine use.

References Amass L, Bickel WK, Higgins ST, et al: A preliminary investigation of outcome following gradual or rapid buprenorphine detoxification. J Addict Dis 13:33–45, 1994 Amato L, Minozzi S, Davoli M, et al: Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004147. DOI: 10.1002/14651858.CD004147.pub3. Bickel WK, Stitzer ML, Bigelow GE, et al: Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther 247:47–53, 1988

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Cheskin LJ, Fudala PJ, Johnson RE: A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. Drug Alcohol Depend 36:115– 121, 1994 Comer SD, Collins ED, Fischman MW: Buprenorphine sublingual tablets: effects on IV heroin self-administration by humans. Psychopharmacology (Berl) 154:28–37, 2001 Comer SD, Walker EA, Collins ED: Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers. Psychopharmacology (Berl) 181:664–675, 2005 Ebner R, Schreiber W, Zierer C: Buprenorphine or methadone for detoxification of young opioid addicts? [in German] Psychiatr Prax 31 (suppl 1):S108–S110, 2004 Fanoe S, Hvidt C, Ege P, et al: Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 93:1051– 1055, 2007 Fiellin DA, Pantalon MV, Chawarski MC, et al: Counseling plus buprenorphinenaloxone maintenance therapy for opioid dependence. N Engl J Med 355:365– 374, 2006 Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 349:949–958, 2003 Gowing L, Ali R, White J: Buprenorphine for the management of opioid withdrawal. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD002025. DOI: 10.1002/14651858.CD002025.pub4. Hallinan R, Byrne A, Agho K, et al: Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med 5:684–692, 2008 Jasinski DR, Pevnick JS, Griffith JD: Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 35:501–516, 1978 Johnson RE, Eissenberg T, Stitzer ML, et al: A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Depend 40:17– 25, 1995 Kakko J, Svanborg KD, Kreek MJ, et al: 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet 361:662–668, 2003 Katz EC, Schwartz RP, King S, et al: Brief vs. extended buprenorphine detoxification in a community treatment program: engagement and short-term outcomes. Am J Drug Alcohol Abuse 35:63–67, 2009 Krook AL, Brors O, Dahlberg J, et al: A placebo-controlled study of high dose buprenorphine in opiate dependents waiting for medication-assisted rehabilitation in Oslo, Norway. Addiction 97:533–542, 2002 Ling W, Charuvastra C, Collins JF, et al: Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction 93:475–486, 1998 Ling W, Amass L, Shoptaw S, et al: A multicenter randomized trial of buprenorphinenaloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction 100:1090–1100, 2005 Lofwall MR, Stitzer ML, Bigelow GE, et al: Comparative safety and side effect profiles of buprenorphine and methadone in the outpatient treatment of opioid dependence. Addiction Disorders and Their Treatment 4:49–64, 2005

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Mattick RP, Kimber J, Breen C, et al: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD002207. DOI: 10.1002/14651858.CD002207. pub3. Mello NK, Mendelson JH: Buprenorphine suppresses heroin use by heroin addicts. Science 207:657–659, 1980 Mintzer MZ, Correia CJ, Strain EC: A dose-effect study of repeated administration of buprenorphine/naloxone on performance in opioid-dependent volunteers. Drug Alcohol Depend 74:205–209, 2004 Petry NM, Bickel WK, Piasecki D, et al: Elevated liver enzyme levels in opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict 9:265–269, 2000 Quaglio G, Lugoboni F, Pattaro C, et al: Erectile dysfunction in male heroin users, receiving methadone and buprenorphine maintenance treatment. Drug Alcohol Depend 94:12–18, 2008 Reynaud M, Petit G, Potard D, et al: Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Addiction 93:1385–1392, 1998 Rosado J, Walsh SL, Bigelow GE, et al: Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100mg of daily methadone. Drug Alcohol Depend 90:261–269, 2007 Seifert J, Metzner C, Paetzold W, et al: Detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs. methadone. Pharmacopsychiatry 35:159–164, 2002 Soyka M, Horak M, Dittert S, et al: Less driving impairment on buprenorphine than methadone in drug-dependent patients? J Neuropsychiatry Clin Neurosci 13:527– 528, 2001 Soyka M, Lieb M, Kagerer S, et al: Cognitive functioning during methadone and buprenorphine treatment: results of a randomized clinical trial. J Clin Psychopharmacol 28:699–703, 2008 Stoller KB, Bigelow GE, Walsh SL, et al: Effects of buprenorphine/naloxone in opioiddependent humans. Psychopharmacology (Berl) 154:230–242, 2001 Strain EC, Walsh SL, Preston KL, et al: The effects of buprenorphine in buprenorphine-maintained volunteers. Psychopharmacology (Berl) 129:329–338, 1997 Strain EC, Walsh SL, Bigelow GE: Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine. Psychopharmacology (Berl) 159:161–166, 2002 Strain EC, Moody DE, Stoller KB, et al: Relative bioavailability of different buprenorphine formulations under chronic dosing conditions. Drug Alcohol Depend 74:37–43, 2004 Tracqui A, Kintz P, Ludes B: Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. J Anal Toxicol 22:430–434, 1998 Wedam EF, Bigelow GE, Johnson RE, et al: QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med 167: 2469–2475, 2007 Ziedonis DM, Amass L, Steinberg M, et al: Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence. Drug Alcohol Depend 99:28–36, 2009

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5 Patient Assessment Petros Levounis, M.D., M.A.

THE ASSESSMENT of a patient for buprenorphine treatment is essentially the same as the assessment of any patient who has an addiction. In this chapter, I describe the complete evaluation of a patient and cover a broad range of issues that may impact addiction treatment. Everyday clinical practice often dictates a symptom-focused evaluation, and treating patients with buprenorphine is not an exception. For example, I include a brief discussion of physical examination as part of a complete patient assessment. However, the majority of psychiatrists do not routinely conduct physical examinations; typically they collaborate with internists and other primary care physicians who cover this aspect of the patient’s medical care. Treating patients with buprenorphine should not change your way of evaluating your patients and managing your practice.

Establishing a Relationship When the clinician is interviewing a patient who is opioid dependent, a matter-of-fact, nonjudgmental, and respectful approach works best. Many patients have been discriminated against or mistreated because of their substance use disorder. Understandably, they may be mistrustful of physicians and may not be eager to talk about events and activities that are embarrassing and often illegal. Open the interview by asking about the patient’s level of comfort. For example, 79

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you may want to say, “How are you feeling?” “Are you feeling any withdrawal symptoms?” “When was the last time you used any opioids?” This approach helps to establish you as considerate and compassionate and may influence how likely the patient will be to retain information you give—as well as how likely he or she will be to open up about sensitive problems and to return to your office. Establishing a trusting and secure relationship is one of the most powerful elements of successful addiction treatment and is critical in the management of any chronic relapsing disorder (Najavits and Weiss 1994). Recognize that some information is difficult to talk about and acknowledge the patient’s discomfort. For example, at some point you may say: “You seemed to get quiet when I asked that.” Assure confidentiality and tell the patient that you are asking because you are concerned for his or her health. I have found that being genuinely interested and curious about your patient’s life provides the most powerful means of smoothing out awkward feelings and allowing your patient to open up about his or her drug history. Using curiosity as your primary approach to the patient also helps you persist in getting full answers to difficult questions and following up on qualified answers. For example, if the answer to the question “Have you ever injected heroin?” is “Not really,” you may then ask the patient to tell you all about the last time he or she injected. In some cases, it may be easier to lead with assumptive questions, such as “When was the last time you injected heroin?”

Taking a History of Drug Use THE BASICS Patients who use heroin and/or prescription opioids often use other substances as well. When taking a drug history, inquire about both legal and illegal substances. Asking specifically about each class of drugs, as well as about each possible source such as dealers, friends and family, prescriptions, the Internet, herbal stores, and over-the-counter medications can give surprising and valuable results. For each drug, you should gather information about 1) frequency of use, 2) amount used, 3) route of administration, 4) acute response to the effects of the drug, and 5) changes in use over time. Typically, start with questions about legal drugs (nicotine, alcohol, prescription pills) and then progress to illegal drugs (e.g., cannabis, heroin, hallucinogens, cocaine, and crystal methamphetamine). Patients are less likely to be defensive when describing their use of legal drugs, and the discussion may then progress more easily into areas associated with illegal drugs and illegal activities. Another way of obtaining the drug history is to start with the first psychoactive agent used and work chronologically through the patient’s experience with substances of abuse. Either way, information about the most recent use, including use in the weeks and

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TABLE 5–1.

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Commonly abused opioids

Diacetylmorphine (heroin) Codeine Oxycodone (OxyContin, Percodan, Percocet, Tylox) Hydrocodone (Vicodin, Lortab) Morphine (MS Contin, Oramorph) Hydromorphone (Dilaudid) Meperidine (Demerol) Fentanyl (Sublimaze, Actiq) Propoxyphene (Darvon) Methadone (Dolophine) Opium days just before the assessment, is likely to be the most helpful in evaluating the patient for buprenorphine treatment. In general, assumptive, open-ended questions generate more detailed and productive information. For example, you may ask, “How are things at home since you started drinking regularly?” or “What has been going on in your life since you lost your job?” Opioids are abused by all routes of administration including intravenous, oral, inhalation (snorting), smoking, subcutaneous (skin “popping”), and intramuscular. Heroin is often used intravenously, but in recent years more and more people inhale heroin. This shift in the pattern of use may be due to the AIDS epidemic and the associated danger of infection from contaminated needles. It may also be due to the increase in the purity of heroin, which is now potent enough to give the user an adequate “high” even if it is inhaled and not injected. Prescription opioids are typically taken orally but may also be snorted, chewed, or crushed and injected. Pills are crushed to circumvent the mechanism that delays the release of the active ingredients in long-acting formulations such as OxyContin (an acryliccoated formulation of oxycodone). Please see Table 5–1 for a list of the most commonly abused opioids and Table 5–2 for other commonly abused substances. Family participation in the evaluation is ideal but often not an option. Patients have often been cut off from contact with their loved ones because of the illness of addiction. However, when family members come to the office, they tend to offer very useful information and insights into the patient’s illness. They can also become great allies in carrying out the patient’s treatment plan, helping him or her both logistically and emotionally, and can act as your liaison in the patient’s home.

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TABLE 5–2.

Other commonly abused substances

Nicotine Alcohol Benzodiazepines Cocaine Methamphetamine (crystal meth) Cannabis Phencyclidine (PCP) “Club drugs” (ecstasy, ketamine, γ-hydroxybutyrate) Noncontrolled substances (e.g., clonidine, dextromethorphan)

THE CONSEQUENCES Almost all patients who abuse opioids have experienced opioid withdrawal at some point in their lives. Although they are very familiar with the actual symptoms and consequences of intoxication and withdrawal, they may not be familiar with the medical terms, and these should be explained. It may also be necessary to explain to the patient what is meant by tolerance; that is, that with time greater amounts of the drug are needed to achieve the same effect, or there is a diminished effect from the same amount of the drug. Asking the patient about the different consequences of his or her use is useful in two ways. First, it helps paint a multidimensional picture of the patient’s life and thus establish past and current levels of psychosocial functioning. Second and perhaps more important, it helps the patient identify losses in his or her life, which may increase motivation for change. I often review five areas of consequences of drug use: 1. Medical consequences may include hepatitis C, HIV infection, and other infections (e.g., endocarditis, abscesses), as well as injuries from falls and burns secondary to intoxication. Medical comorbidities are discussed further in Chapter 10 (“Medical Management”). 2. Psychiatric consequences may include opioid-induced depression, sexual dysfunction, and sleep disorders. Although opioids are less likely to result in symptoms of mental illness than are most other drugs of abuse, differentiating between substance-induced and independent psychiatric disorders can be challenging. This topic is discussed further in Chapter 9, “Psychiatric Comorbidity.” 3. Interpersonal and family consequences may include separation or divorce and estrangement from parents, siblings, and children.

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4. Financial and employment consequences can include bankruptcy, loss of job, and loss of a professional license. 5. Legal consequences may include arrests for driving under the influence (DUI) or driving while intoxicated (DWI), incarceration, parole or probation, and loss of custody of children.

PREVIOUS TREATMENTS

AND

RECOVERY EFFORTS

Before getting into the patient’s previous medical treatments, the clinician needs to know whether the patient has tried to stop using by himself or herself. Frequently people who are addicted to opioids have tried to quit on their own, either with the help of home products and over-the-counter medications such as antidiarrheal agents and sleeping aids, or with no pharmacological help at all, that is, going “cold turkey.” (The expression cold turkey comes from the piloerection and characteristic clammy appearance of the skin during opioid withdrawal.) If this is the case, ask what happened. Ask about the severity and duration of any withdrawal symptoms, and how the patient expects to feel differently with medical treatment. Some patients may also have a history of involvement with mutual help groups, which are sometimes called self-help groups or 12-step groups, like Alcoholics Anonymous and Narcotics Anonymous. Finding out how long the patient has been attending meetings and how many meetings he or she attends each week can give you an indication of the patient’s motivation for treatment. If the patient has been attending mutual help meetings consistently, has formally joined a group, and has a sponsor, then he or she is more likely to be committed to the recovery process. Reviewing with the patient previous medical treatments typically involves the following four areas: 1. Detoxification, which includes inpatient hospital admissions and outpatient community-based programs 2. Rehabilitation in 28-day or other residential treatment facilities 3. Outpatient counseling or psychotherapy 4. Long-term pharmacotherapy, which includes maintenance with methadone (a µ opioid receptor agonist), maintenance with buprenorphine (a µ opioid receptor partial agonist), or treatment with naltrexone (a µ opioid receptor antagonist). You may also ask the patient about his or her longest period of abstinence, how it was attained, and what worked to sustain it. Inquiring about drug cravings and triggers to relapse (including emotions, people, places, and things) helps the patient remember the major obstacles to sobriety. The review of trig-

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gers signals to the patient that serious effort will be required to identify, avoid, and cope with these powerful culprits of drug relapse. It also alerts the clinician to the patient’s specific vulnerabilities that will need to be addressed in a comprehensive treatment plan (see Chapter 7, “Clinical Management I”).

SUMMARY MNEMONIC One way to keep in mind the different elements of taking a history of drug use is by remembering the acronym TRAPPED (Welsh 2003), which stands for the following: 1. Treatment history (inpatient, outpatient; methadone, buprenorphine, naltrexone) 2. Route of administration (intravenous, intranasal, intramuscular) 3. Amount (in dollars, “bags,” or milligrams) 4. Pattern of use (changes over time) 5. Prior abstinence (with or without medical help) 6. Effects (medical, psychiatric, psychosocial) 7. Duration of use (including most recent use).

MEDICAL, PSYCHIATRIC, FAMILY, PSYCHOSOCIAL HISTORY

AND

Apart from the direct medical consequences of drug use discussed earlier in this chapter, the medical history also includes significant acute and chronic medical illnesses as well as operations, allergies, and current medications. The inventory of current medications should list not only medications prescribed to the patient but also medications prescribed to others (often family members or friends) that the patient may be taking from others’ medicine cabinets, and prescription medications that the patient may be buying on the street. This list should also include over-the-counter preparations, dietary supplements, and herbal pills. The psychiatric history consists of the review of psychiatric hospitalizations, outpatient treatments, and psychiatric medications. Be sure to inquire about treatment delivered by nonpsychiatrists, such as a primary care physician who prescribes an antidepressant or a psychologist who provides psychotherapy. Chapter 9 discusses psychiatric assessment in detail. It is well established that both addiction and other psychiatric conditions, like depression, schizophrenia, and bipolar disorder, have significant genetic components. A detailed family history therefore contributes valuable information to aid in our understanding of the patient’s vulnerabilities and helps us dis-

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TABLE 5–3.

Stages of change

1.

Precontemplation—“I don’t want to ever quit.”

2.

Contemplation—“Someday, I may want to think about quitting.”

3.

Preparation (determination)—“I’m seriously planning to quit in the next few weeks.”

4.

Action—“I have just stopped using and work hard to stay clean.”

5.

Maintenance—“I have been sober for several months.”

tinguish between a primary psychiatric disorder and a substance-induced psychiatric condition (Pickens and Svikis 1988). The psychosocial history, sometimes also referred to as personal history, completes the comprehensive history portion of the patient assessment. It consists of gathering information about the patient’s childhood development; education; employment; military service; physical or sexual abuse; run-ins with the law; spouse or partner; children; housing and living situation; and religion and spirituality. Several elements of the psychosocial history have already been covered in this chapter, given that addiction tends to interfere with—and often destroy—many aspects of a person’s life.

MOTIVATION

FOR

CHANGE

Based on the Transtheoretical Model of Change developed by Prochaska and DiClemente (1982), patients have different levels of motivation for changing their substance use. The five stages of change are listed in Table 5–3. Although many patients seem to progress sequentially through the stages of change from precontemplation to maintenance, clinicians often treat patients who skip stages or sometimes go back to an earlier stage despite considerable early gains toward motivation for sobriety. For example, a patient may be working hard on the action stage of change, during which he or she may be attending meetings and taking medication; however, a slip with heroin use may severely disappoint and discourage the patient, who may then experience a setback and return to the contemplation stage: “Do I really want to stop using? Maybe I’m meant to be a heroin addict and I should just accept it.” Most patients are ambivalent about change, but exploring this ambivalence is a critical element in enhancing their motivation. An additional stage of change is relapse. With addiction being a chronic relapsing illness, it is reasonable to expect that some patients will relapse. Relapse is part of the natural history of the illness and of the recovery process, and as such plays a significant role in the progression of a person through the change

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cycle. Patients who relapse typically reenter the stages of change at the contemplation level and may progress more rapidly during subsequent treatment (Levounis and Arnaout 2010).

Physical Examination The physical examination is particularly helpful in identifying and caring for the intravenous drug user. Needle marks and sclerosed veins (track marks) on the upper extremities, secondary to chronic heroin injecting, can be easily concealed by long-sleeved shirts but become apparent on physical examination. Skin infections can lead to cellulitis and abscesses that, unless they are discovered and treated in a timely fashion, may progress to even more serious conditions. Furthermore, the physical examination is essential in the medical treatment of the patient who also has hepatitis C and/or HIV infection. Physical examination is also helpful in identifying the presence and severity of opioid intoxication (e.g., constricted pupils) and opioid withdrawal (e.g., dilated pupils). Sinusitis and chronic cough are also consistent with chronic opioid use. Chapter 10 discusses the basic assessment and management of the patient with opioid dependence and co-occurring medical illnesses.

Laboratory Examination Certain laboratory test results can raise our level of suspicion for alcohol and drug abuse. Abnormal liver function test results (especially an elevated aspartate aminotransferase to alanine aminotransferase ratio and an elevated γglutamyltransferase level), elevated red blood cell mean corpuscular volume, and carbohydrate-deficient transferrin are all associated with alcohol abuse and dependence. Antibodies to HIV, hepatitis B virus, and hepatitis C virus may indicate intravenous drug use. Urine toxicology examinations (UTs) are helpful in the evaluation (and often the treatment) of the substance-abusing patient. Heroin and codeine metabolize into morphine, which is the substance detected in urine. Codeine metabolizes into morphine slowly, so it can be present either as codeine or morphine (or both) in urine. However, heroin (diacetylmorphine) is never found in urine because it hydrolyzes very quickly to morphine. Occasionally, the intermediate product in this hydrolysis, 6-monoacetylmorphine (6-MAM), is transiently detected in urine and the test for this is sometimes used in forensic settings. If urine is positive for 6-MAM, the patient certainly used heroin; however, if 6-MAM detection is negative, then the test gives no information about heroin use. Routine UTs for opioids typically test only for morphine and codeine, so tests for semisynthetic opioids like oxycodone, hydrocodone, and

Patient Assessment

TABLE 5–4.

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DSM-IV-TR criteria for substance abuse

A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period: (1) recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household) (2) recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use) (3) recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct) (4) continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights) B. The symptoms have never met the criteria for substance dependence for this class of substance. Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. Copyright © 2000 American Psychiatric Association. Used with permission.

hydromorphone often have to be ordered separately. UTs also test for cocaine, benzodiazepines, and cannabis, but, if the patient uses such substances sporadically, he or she may not have used near the time of sample collection and the result may be negative (see Chapter 7). Detecting drugs in hair, saliva, and sweat samples has attracted great attention as alternatives to UTs. However, the current clinical usefulness of these methods is limited, and they are used primarily in experimental settings.

Diagnosis The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR; American Psychiatric Association 2000) provides detailed criteria for establishing the diagnosis of substance abuse (Table 5–4) and substance dependence (Table 5–5). Please note that substance dependence and substance addiction are identical terms. Although American psychiatrists are still

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TABLE 5–5.

DSM-IV-TR criteria for substance dependence

A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period: (1) tolerance, as defined by either of the following: (a) a need for markedly increased amounts of the substance to achieve intoxication or desired effect (b) markedly diminished effect with continued use of the same amount of the substance (2) withdrawal, as manifested by either of the following: (a) the characteristic withdrawal syndrome for the substance (refer to Criteria A and B of the criteria sets for withdrawal from the specific substances) (b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms (3) the substance is often taken in larger amounts or over a longer period than was intended (4) there is a persistent desire or unsuccessful efforts to cut down or control substance use (5) a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chain-smoking), or recover from its effects (6) important social, occupational, or recreational activities are given up or reduced because of substance use (7) the substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer was made worse by alcohol consumption) Specify if: With Physiological Dependence: evidence of tolerance or withdrawal (i.e., either Item 1 or 2 is present) Without Physiological Dependence: no evidence of tolerance or withdrawal (i.e., neither Item 1 nor 2 is present)

Patient Assessment

TABLE 5–5.

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DSM-IV-TR criteria for substance dependence (continued)

Course specifiers: Early Full Remission Early Partial Remission Sustained Full Remission Sustained Partial Remission On Agonist Therapy In a Controlled Environment Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. Copyright © 2000 American Psychiatric Association. Used with permission.

struggling to reach consensus about which is the better name for the disorder, there is little disagreement about the illness itself; the two terms, dependence and addiction, are used interchangeably throughout the scientific and clinical literature, including the present volume. Given that the U.S. Food and Drug Administration has approved sublingual buprenorphine specifically for the treatment of opioid dependence, it is necessary that patient assessment clearly document that the patient meets DSM-IV-TR criteria for this disorder. It is also helpful to specify whether the diagnosis is “with physiological dependence” (if there is evidence of tolerance or withdrawal) or “without physiological dependence.”

Buprenorphine Versus Methadone: Regulatory Criteria and Limitations The regulatory criteria for the use of buprenorphine differ from the criteria for methadone use in the treatment of opioid dependence. Although buprenorphine can be prescribed to anyone age 16 years and older who currently meets DSM-IVTR criteria for opioid dependence, methadone treatment requires that patients be at least 18 years old; currently meet DSM-IV-TR criteria for opioid dependence; and have been addicted for at least 1 year before admission to treatment. Buprenorphine for the treatment of opioid dependence can be prescribed at the office or clinic of any physician who has a valid waiver from the U.S. Drug Enforcement Administration. In comparison, methadone for the treat-

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ment of opioid dependence can only be administered at a federally approved and regulated clinic, an opioid treatment program (OTP) facility. This difference gives buprenorphine a tremendous practical and social advantage. Physicians can now provide mainstream treatment for opioid addiction as part of their everyday practice, and patients can address their substance use problems within the privacy and comfort of the patient-physician relationship. On the other hand, methadone treatment in an OTP facility, which requires daily attendance at least for the first several months of treatment, may be best for patients who require a highly structured environment. For example, patients who have polysubstance dependence and/or other psychiatric conditions that require more comprehensive care usually benefit from the daily encounters, monitoring, services, and routines of an OTP (Schottenfeld et al. 2005). In general, patients who are less stable and less motivated, with a lower level of functioning and a higher need for psychosocial supports, may be more appropriate for methadone treatment in an OTP than for buprenorphine in an office-based treatment practice. Table 5–6 summarizes the selection considerations for selecting office-based buprenorphine treatment versus OTP-based methadone treatment. Another option that has recently become more widely available is buprenorphine treatment provided in an OTP. This may be the best choice for a patient who prefers buprenorphine to methadone, yet may not have the stability required for office-based buprenorphine treatment. Some patients are most successful when they begin buprenorphine treatment in the highly structured environment of an OTP, and then move to an office-based clinic or private office when they are psychiatrically, socially, and medically ready for the transition.

Appropriateness for Office-Based Buprenorphine Treatment The majority of patients who are opioid dependent should be considered for treatment with buprenorphine. Specifically, the risks and benefits of buprenorphine therapy should be balanced against the alternatives of nontreatment or other forms of treatment (Fishman et al. 2010). Although several pharmacological and nonpharmacological interventions have been shown to be useful (methadone and naltrexone, cognitive-behavioral therapy, and 12-step facilitation; see Chapter 8, “Clinical Management II”), the efficacy, safety, and tolerability profile of buprenorphine recommends this medication as a first-line treatment of opioid dependence (see Chapter 4, “Efficacy and Safety of Buprenorphine”). As summarized by Gordon et al. (2007), a patient should be considered an appropriate candidate for treatment with buprenorphine if he or she:

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TABLE 5–6.

Selection considerations: buprenorphine versus methadone

Selection considerations

Buprenorphinea

Methadoneb

Criteria

Current DSM-IV-TR diagnosis of opioid dependence

Current DSM-IV-TR diagnosis of opioid dependence 1-year history of addiction

Age

≥ 16 years

≥18 years

Reliability

Higher

Lower

Motivation

Higher

Lower

Social needs

Lower

Higher

Level of function

Higher

Lower

aOffice-based bOpioid

• • • •

treatment. treatment program.

Meets DSM-IV-TR criteria for the diagnosis of opioid dependence Is interested in office-based treatment of his or her illness Understands the risks and benefits (as well as the induction requirements) of the medication Demonstrates motivation for change.

This being said, treatment outcomes are considerably better when patients also engage in nonpharmacological therapies and receive psychosocial support. Multiple studies have shown that buprenorphine treatment is successful in a wide variety of office practices and clinics (Barry et al. 2009; Fiellin et al. 2008). The decision to initiate buprenorphine treatment for a patient at your setting also depends on how well your resources match the patient’s needs. For example, a patient who has multiple and significant medical problems may be better served in a medical office that offers buprenorphine treatment than in a private psychiatric office. Conversely, a patient who has borderline personality disorder may not be treated as successfully by a physician who is not trained in psychiatry. If the patient has a significant chronic pain syndrome as well as opioid dependence, then medication management may be best addressed in a pain management specialist’s office. And if the patient’s severity of addiction requires a higher level of care, such as an intensive outpatient program or partial hospitalization, then referral to an addiction treatment center or an OTP (as discussed in the previous section, “Buprenorphine Versus Methadone: Regulatory Criteria and Limitations”) may be indicated.

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Conclusion Several factors improve the chances for successful office-based treatment. The ideal buprenorphine candidate adheres to the treatment plans; is medically and psychiatrically healthy; lives in a stable and supportive psychosocial environment; attends mutual help meetings regularly; does not use alcohol or other drugs; and does not have a history of multiple previous treatments and relapses. However, the question the physician should be asking is not whether one patient is a better buprenorphine candidate than another patient, but whether a particular individual will be better off with buprenorphine or without buprenorphine treatment. If your practice is suitable for the patient and you have access to additional resources (e.g., a medical specialist or an intensive outpatient program), then office-based buprenorphine treatment is one of the very best options you can offer to your opioid-dependent patient.

Clinical Pearls • Assess your patients for buprenorphine therapy the same way you assess all your patients. • Explore the patient’s motivation and identify his or her stage of change. • Establish the diagnosis of opioid dependence using the DSM-IVTR criteria. Specify whether the diagnosis is with or without physiological dependence. • Regard buprenorphine as your first-line treatment of opioid dependence, but also consider other pharmacological and nonpharmacological options.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Barry DT, Irwin KS, Jones ES, et al: Integrating buprenorphine treatment into officebased practice: a qualitative study. J Gen Intern Med 24:218–225, 2009 Fiellin DA, Moore BA, Sullivan LE, et al: Long-term treatment with buprenorphine/ naloxone in primary care: results at 2–5 years. Am J Addict 17:116–120, 2008 Fishman MJ, Shulman GR, Mee-Lee D, et al: ASAM Patient Placement Criteria: Supplement on Pharmacotherapies for Alcohol Use Disorders. Baltimore, MD, Lippincott Williams & Wilkins, 2010

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Gordon AJ, Trafton JA, Saxon AJ, et al; for the Buprenorphine Work Group of the Substance Use Disorders Quality Enhancement Research Initiative: Implementation of buprenorphine in the Veterans Health Administration: results of the first 3 years. Drug Alcohol Depend 90:292–296, 2007 Levounis P, Arnaout B (eds): Handbook of Motivation and Change: A Practical Guide for Clinicians. Washington, DC, American Psychiatric Publishing, 2010 Najavits LM, Weiss RD: Variations in therapist effectiveness in the treatment of patients with substance abuse disorders: an empirical review. Addiction 89:679–688, 1994 Pickens RW, Svikis DS (eds): Biological Vulnerability to Drug Abuse. National Institute on Drug Abuse Research Monograph 89 (DHHS Publ No ADM 90-1590). Rockville, MD, National Institute on Drug Abuse, 1988. Available at: http:// archives.drugabuse.gov/pdf/monographs/89.pdf. Accessed July 1, 2010. Prochaska JO, DiClemente CC: Transtheoretical therapy: towards a more integrative model of change. Psychotherapy: Theory, Research and Practice 19:276–288, 1982 Schottenfeld RS, Chawarski MC, Pakes JR, et al: Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. Am J Psychiatry 162:340–349, 2005 Welsh CJ: “Trapped": a mnemonic for taking a substance use history (letter). Acad Psychiatry 27:289, 2003

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6 Clinical Use of Buprenorphine Ricardo Restrepo, M.D., M.P.H. Petros Levounis, M.D., M.A.

IN THIS CHAPTER, we review the clinical use of buprenorphine in the treatment of opioid dependence. This is a “how to” chapter. We first present a brief overview of the pharmacology of buprenorphine and some general considerations in setting up the treatment, then describe in detail the practical aspects of buprenorphine induction, stabilization, and maintenance therapy. We also briefly describe the option of using buprenorphine for opioid detoxification, although this approach has considerable limitations and drawbacks as discussed in Chapter 4 (“Efficacy and Safety of Buprenorphine”). We hope that this chapter will be used as a quick reference to the nuts and bolts of treating the opioiddependent patient with buprenorphine. A case is presented at the end of this chapter, including related questions for additional consideration. For discussion of this case, please see Chapter 14, “Comments on the Case Vignettes.”

Buprenorphine Formulations The formulations approved for the treatment of opioid dependence by the U.S. Food and Drug Administration (FDA) are 1) buprenorphine (Subutex), often 95

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FIGURE 6–1.

The 2-mg buprenorphine tablet (the 2-mg mono product, 2-mg Subutex). Photography by Henry B. Lee.

FIGURE 6–2.

The 8-mg buprenorphine tablet (the 8-mg mono product, 8-mg Subutex). Photography by Henry B. Lee.

referred to as the mono product; and 2) a buprenorphine-naloxone combination tablet in a 4:1 ratio (Suboxone), the combo product. The mono product is available in doses of 2 mg (Figure 6–1) and 8 mg (Figure 6–2) of buprenorphine; the combo product is available in doses of 2 mg buprenorphine/0.5 mg naloxone (Figure 6–3) or 8 mg buprenorphine/2 mg naloxone (Figure 6–4). For practical purposes, when physicians refer to the combo product as “8 mg of bup” or “2 mg of bup,” it is understood that what they mean is 8 mg of buprenorphine with 2 mg of naloxone or 2 mg of buprenorphine with 0.5 mg of naloxone, respectively. Another buprenorphine formulation that is available for pain management—but is not approved for the treatment of opioid dependence in the United States—is injectable buprenorphine (Buprenex).

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FIGURE 6–3.

The 2-mg buprenorphine/0.5-mg naloxone tablet (the 2-mg combo product, 2-mg Suboxone). Photography by Henry B. Lee.

FIGURE 6–4.

The 8-mg buprenorphine/2-mg naloxone tablet (the 8-mg combo product, 8-mg Suboxone). Photography by Henry B. Lee.

Pharmacology Overview Buprenorphine is a long-acting partial agonist at the µ opioid receptor. The medication has high affinity, slow dissociation, and low intrinsic activity at the µ receptor. The partial agonist effects of buprenorphine on the µ receptor increase linearly with increasing doses of the drug, until moderate doses result in a plateau of pharmacological effects and further increases in doses result in no additional

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effect. The advantage of this ceiling effect is that buprenorphine carries a lower risk of abuse, addiction, and serious side effects (e.g., respiratory depression) compared with full opioid agonists. On the other hand, buprenorphine can precipitate opioid withdrawal in a person who is physiologically dependent on a full opioid agonist (see Chapter 3, “General Opioid Pharmacology”), so patients need to be monitored during induction therapy in order to avoid such precipitated withdrawal. Buprenorphine has poor oral bioavailability, which is the main reason the sublingual tablet was developed. In addition, the buprenorphine-naloxone combination formulation was developed to discourage diversion for intravenous use. The sublingual buprenorphine-naloxone tablet, taken as indicated, has an almost exclusively buprenorphine effect—naloxone absorbed by the sublingual route does not precipitate withdrawal because it has minimal sublingual bioavailability. However, if a patient attempts to get “high” by crushing and injecting the combination tablet, naloxone will precipitate opioid withdrawal because it has excellent intravenous bioavailability (Chapter 3). An expert panel convened by the Center for Substance Abuse Treatment (part of the federal Substance Abuse and Mental Health Services Administration) recommended that the buprenorphine-naloxone combination tablets be used for all treatment purposes—including induction, stabilization, and maintenance—with the exception of use in pregnant patients. For pregnant women, even the minute amounts of naloxone that become bioavailable through the sublingual route can be detrimental to the fetus and the mono product is therefore preferred (see Chapter 10, “Medical Management”). For the rest of this chapter, we use the term buprenorphine to refer to the buprenorphine-naloxone combination tablet unless otherwise specified.

Buprenorphine Induction The goal of buprenorphine induction and stabilization is to find the lowest dosage of buprenorphine at which the patient 1) discontinues or markedly reduces use of other opioids; 2) experiences no cravings for opioids of abuse; 3) has no opioid withdrawal symptoms; 4) has minimal or no side effects from the medication; and 5) starts feeling that his or her life is no longer out of control. Buprenorphine induction must be managed carefully because withdrawal symptoms can arise from either too little or too much medication, resulting in spontaneous or precipitated withdrawal, respectively. Undermedication will not treat the patient’s opioid withdrawal symptoms adequately, and overmedication may bring on the very symptoms from which the patient is seeking relief (Center for Substance Abuse Treatment 2004). Furthermore, underdosing buprenorphine may lead the patient to try to self-medicate withdrawal symptoms

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with other opioids, alcohol, or benzodiazepines. Overdosing buprenorphine during the induction phase may result in potentially significant respiratory depression in individuals who are also using other central nervous system (CNS) depressants. After buprenorphine induction and the patient has been stabilized with an appropriate dosage of the medication, buprenorphine maintenance is usually the preferred treatment, but some patients may elect to undergo detoxification. One of the most significant advantages of buprenorphine is that the patient does not have to make this decision at the start of therapy, a time when typically he or she is in the midst of a crisis. Instead, the decision can be made several weeks later, when the patient’s condition has stabilized. Whether the patient ultimately decides to continue taking the medication or discontinue taking it, the initial steps are the same: induction and stabilization.

PHYSICIAN CHOICES Getting the Pills Physicians have the option of either a) keeping a supply of medication in the office for the induction, or b) instructing the patient to fill a prescription for the first doses in a pharmacy and then to bring the medication to the office, where it will be administered. Either way, secure access to the medication by establishing a list of pharmacies in your area that are familiar with the medication. If the first option is followed and a supply of buprenorphine tablets is kept in the office, the physician and the institution must keep detailed records as required by federal and state laws. These laws mandate specific conditions for maintaining supplies of controlled substances for administration or dispensing (see Chapter 13, “Logistics of Office-Based Buprenorphine Treatment”). Unless you work in a hospital or other institution with adequate on-site pharmacy resources, the option whereby the physician gives the patient a prescription for the first day’s dosage may be preferable. However, asking the patient to fill the prescription and bring the medication back to the office implies a delay with the first day’s dosing and a risk that the patient may not return with the filled prescription. Another option is to fax the prescription to the pharmacy and then have it delivered to your office.

Deciding Between Mono and Combo Tablets In most circumstances, induction can begin with the buprenorphine-naloxone combination tablet. As previously mentioned (in “Pharmacology Overview”), there is essentially no naloxone bioavailability by the sublingual route, so the patient will not experience precipitated withdrawal from the naloxone con-

100 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

tained in a first dose of buprenorphine-naloxone. Induction with buprenorphine mono tablets should generally be avoided. It can be done in very limited circumstances, such as in a hospital-based detoxification or in pregnant patients who are not candidates for methadone use. If the buprenorphine mono formulation is used for induction in nonpregnant patients, we recommend switching to buprenorphine-naloxone as soon as possible to reduce the risk of diversion of the medication.

Choosing the Day of the Week Monday through Wednesday, in the morning, is the ideal time to start the induction. An early morning appointment decreases the risk of opioid use before the office visit and starting early in the week allows more opportunities for follow-up assessment visits. Avoid induction during the weekend, unless your work setting has the personnel and infrastructure needed to treat patients at that time.

Selecting the Setting National clinical guidelines recommend observing the initial buprenorphine induction directly in the physician’s office and monitoring the patient’s progress by regular office visits during the stabilization and maintenance phases of the patient’s treatment. A new treatment setting for the induction has recently been suggested. It is defined as a home buprenorphine induction, in which the patient initiates the medication off-site after the initial assessment is completed and instructions are given by the clinician (Lee et al. 2009). However, more clinical data are needed before recommending this alternative as a routine procedure. Whatever approach you choose, it is helpful to partner with a colleague who is also certified to prescribe buprenorphine and can cover your practice when necessary.

PATIENT INSTRUCTIONS Preparing for the Induction Following assessment of the patient and the decision to initiate buprenorphine treatment (see Chapter 5, “Patient Assessment”), you need to give your patient instructions in preparation for induction to buprenorphine treatment. The most important direction is that the patient needs to arrive at the office in the state of withdrawal. Explain that withdrawal depends on many factors, such as

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level of tolerance, amount of use, and the type of opioid(s) abused. Ask your patient not to take any opioids for symptomatic relief while preparing for the induction; list opioids for the patient using both common and street names of the drugs to avoid confusion.

Taking the Pills Explain to the patient that buprenorphine is a sublingual tablet, which takes about 5–10 minutes to dissolve. While dissolving the tablet under the tongue, the patient should 1) not talk, 2) not drink, and 3) not chew the tablet or swallow the medication until the entire tablet has dissolved. Absorption improves with a moist mouth. Taking more than one tablet at the same time can be uncomfortable and may result in a paste-like mass with poor absorption. Advise the patient to take one pill at a time until he or she completes the full dosage for the day.

LEVEL

OF

WITHDRAWAL

The patient should experience mild to moderate withdrawal before taking the first buprenorphine sublingual dose. As a general rule, the longer the physician can delay the first dose of buprenorphine, the easier and less complicated the induction will be (Casadonte 2009). In order to reliably assess withdrawal symptoms, we recommend that the clinician use the Clinical Opiate Withdrawal Scale (COWS; Figure 6–5). COWS items include both signs (objective items such as resting pulse, pupil size, tremor, runny nose or tearing, yawning, sweating, and gooseflesh skin) and symptoms (subjective items such as anxiety or irritability, restlessness, bone or joint aches, and gastrointestinal upset). Each item is scored from 0–4 or 0– 5, and the total score is interpreted as follows (Wesson and Ling 2003): 5–12

Mild withdrawal

13–24

Moderate withdrawal

25–36

Moderately severe withdrawal

>36

Severe withdrawal

In addition to COWS, the clinician can provide the patient with a subjective scale, the Subjective Opiate Withdrawal Scale (SOWS; Figure 6–6). The symptoms are rated by the patient on a scale score of 0 (not at all present) to 4 (an extreme feeling) (Handelsman et al. 1987). The patient may complete this form in the waiting room and thus easily provide the clinician with a quick first estimate of the level of opioid withdrawal.

102 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Patient’s name:___________________________ Date: ______________ Buprenorphine induction: Enter scores at time zero, 30 minutes after first dose, 2 hours after first dose, etc. Times: ____ ____ ____ ____ Resting pulse rate: (record beats per minute) Measured after patient has been sitting or lying for 1 minute. 0 pulse rate 80 or below 1 pulse rate 81–100 2 pulse rate 101–120 4 pulse rate >120 Sweating: over past half-hour not accounted for by room temperature or patient activity. 0 no report of chills or flushing 1 subjective report of chills or flushing 2 flushed or observable moistness on face 3 beads of sweat on brow or face 4 sweat streaming off face Restlessness: observation during assessment. 0 able to sit still 1 reports difficulty sitting still, but is able to do so 3 frequent shifting or extraneous movements of legs/arms 5 unable to sit still for more than a few seconds Pupil size: 0 pupils pinned or normal size for room light 1 pupils possibly larger than normal for room light 2 pupils moderately dilated 5 pupils so dilated that only the rim of the iris is visible FIGURE 6–5.

Clinical Opiate Withdrawal Scale.

Clinical Use of Buprenorphine

Bone or joint aches: if patient was having pain previously, only the additional component attributed to opiate withdrawal is scored. 0 not present 1 mild diffuse discomfort 2 patient reports severe diffuse aching of joints/ muscles 4 patient is rubbing joints or muscles and is unable to sit still because of discomfort Runny nose or tearing: not accounted for by cold symptoms or allergies. 0 not present 1 nasal stuffiness or unusually moist eyes 2 nose running or tearing 4 nose constantly running or tears streaming down cheeks Gastrointestinal (GI) upset: over last half-hour. 0 no GI symptoms 1 stomach cramps 2 nausea or loose stool 3 vomiting or diarrhea 5 multiple episodes of diarrhea or vomiting Tremor: observation of outstretched hands. 0 No tremor 1 tremor can be felt, but not observed 2 slight tremor observable 4 gross tremor or muscle twitching Yawning: observation during assessment. 0 no yawning 1 yawning once or twice during assessment 2 yawning three or more times during assessment 4 yawning several times/minute FIGURE 6–5.

Clinical Opiate Withdrawal Scale. (continued)

103

104 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Anxiety or irritability: 0 none 1 patient reports increasing irritability or anxiousness 2 patient obviously irritable anxious 4 patient so irritable or anxious that participation in the assessment is difficult Gooseflesh skin: 0 skin is smooth 3 piloerection of skin can be felt or hairs standing up on arms 5 prominent piloerection Total scores with observer’s initials: Score: 5–12=mild 13–24 =moderate 25–36 =moderately severe >36= severe withdrawal FIGURE 6–5.

Clinical Opiate Withdrawal Scale. (continued)

Flow sheet for measuring symptoms over a period of time during buprenorphine induction. For each item, write in the number that best describes the patient’s sign or symptom. Rate it on just its apparent relationship to opiate withdrawal. For example, if heart rate is increased because the patients was jogging just before assessment, the increased pulse rate would not be added to the score. Source. Template from the American Society of Addiction Medicine.

INDUCTION W ITH PATIENTS DEPENDENT ON SHORT-ACTING OPIOIDS In general, the patient can begin buprenorphine therapy 12–16 hours after the last use of a short-acting opioid (e.g., heroin, hydrocodone, immediate-release oxycodone). Before receiving the first dose of buprenorphine, the patient needs to exhibit objective opioid withdrawal symptoms (a COWS score of > 12). If there is no or little clinical evidence of mild to moderate opioid withdrawal, reassess the last use of opioids and consider asking the patient to either 1) return another day, or 2) wait in the office until evidence of withdrawal is clear. A third option, allowing the patient to leave the office and return later that day, with clear instructions to not take any opioids while he or she is away from the office, is not recommended because there is the possibility that the patient will use more opioids and/or not return.

105

Clinical Use of Buprenorphine

Please score each of the 16 items below according to how you feel now (circle one number). Scale:

0=not at all 1=a little 2=moderately 3=quite a bit 4=extremely

Date: Time:

Symptom

Score

1 I feel anxious

0

1

2

3

4

2 I feel like yawning

0

1

2

3

4

3 I am perspiring

0

1

2

3

4

4 My eyes are teary

0

1

2

3

4

5 My nose is running

0

1

2

3

4

6 I have goose bumps

0

1

2

3

4

7 I am shaking

0

1

2

3

4

8 I have hot flushes

0

1

2

3

4

9 I have cold flushes

0

1

2

3

4

10 My bones and muscles ache

0

1

2

3

4

11 I feel restless

0

1

2

3

4

12 I feel nauseous

0

1

2

3

4

13 I feel like vomiting

0

1

2

3

4

14 My muscles twitch

0

1

2

3

4

15 I have stomach cramps

0

1

2

3

4

16 I feel like using now

0

1

2

3

4

TOTAL (range 0–64):

FIGURE 6–6. Source.

Subjective Opiate Withdrawal Scale. Handelsman et al. 1987.

106 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

Once mild to moderate withdrawal is established, the patient is given 2–4 mg of buprenorphine. After the initial dose, it is recommended that the clinician monitor the patient in the office for 2 hours to confirm that opioid withdrawal symptoms subside and do not reemerge. The length of time the patient is monitored in the office varies depending on the clinician’s familiarity with the patient and experience with the medication. Relief of opioid withdrawal symptoms should begin within 30–45 minutes after the first dose. If symptoms start to subside, a second dose of 2–4 mg is typically administered, and frequently, the patient is instructed to take additional buprenorphine at home as needed for symptom relief. The maximum amount of buprenorphine at the end of the first day of induction ranges from 8 to 16 mg (Sullivan and Fiellin 2008). If symptoms of opioid withdrawal worsen or reemerge after the first dose of buprenorphine, precipitated withdrawal is a likely explanation (see “Managing Precipitated Withdrawal” below). Advise your patient to avoid driving or operating other machinery until he or she is familiar with the effects of the medication.

INDUCTION W ITH PATIENTS DEPENDENT ON INTERMEDIATE- AND LONG-ACTING OPIOIDS In general, patients who are using intermediate-acting opioids (e.g., sustainedrelease oxycodone) should first be given buprenorphine 18–24 hours after their last use of the intermediate-acting opioid; for patients using long-acting opioids (e.g., methadone) we recommend waiting 36–48 hours after last use of the full agonist. If the patient attends a methadone program, confirm his or her dosage, management, and the rationale for switching from methadone to buprenorphine with both the patient and the patient’s counselor. Methadone has a very long duration of action and accumulates in tissue stores, resulting in an increased risk of precipitated withdrawal during buprenorphine induction. Current clinical practice recommends that patients first taper—slowly—their methadone use to no more than 30 mg/day (or its equivalent, if taking another long-acting opioid or an intermediate-acting opioid). We then recommend holding the dosage of methadone to 30 mg/day for a minimum of 1 week in order to establish a steady state. Then discontinue methadone use and evaluate the patient frequently, possibly daily for 2–3 days, until mild to moderate signs and symptoms of opioid withdrawal develop (a COWS score of >12). At that point, you can safely administer the first buprenorphine dose of 2–4 mg and proceed with the induction as described above under “Induction With Patients Dependent on Short-Acting Opioids.” If the patient does not tolerate a methadone taper to 30 mg/day, it is still possible to start buprenorphine use; however, in this case the judgment of the clinician will guide the induction process. As described above, the first dose of

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buprenorphine should not be given until there is clear evidence of opioid withdrawal, and the patient may require very close monitoring to avoid or manage any precipitated withdrawal (see the next section, “Managing Precipitated Withdrawal”). The scientific literature on this topic is limited, with few guidelines on how to safely switch patients from methadone dosages higher than 30 mg/day to buprenorphine treatment (Glasper et al. 2005).

MANAGING PRECIPITATED WITHDRAWAL If opioid withdrawal worsens or reemerges shortly after the first dose of buprenorphine, the medication has most likely precipitated a withdrawal syndrome due to its high affinity for the µ receptor and resultant displacement of the full opioid agonist from the receptor. Precipitated withdrawal is not a medical emergency but can be very uncomfortable. The preferred strategy in the management of precipitated withdrawal is to administer additional doses of buprenorphine, 2 mg every 1–2 hours, attempting to provide enough agonist effect to suppress the withdrawal. Increasing the dosage of the medication responsible for the adverse effect may seem counterintuitive, especially to the affected patient, but it makes both pharmacological and clinical sense. Once buprenorphine has precipitated withdrawal, the medication cannot be taken back—therefore, pushing the dosage to achieve an agonist response is the best alternative. In rare circumstances when the induction needs to be stopped, as in the case of a patient who refuses to take any more buprenorphine, supportive treatments for the patient’s withdrawal symptoms are necessary. The following medications can be used: clonidine, 0.1 mg every 8 hours (or lofexidine outside the United States) to reduce autonomic withdrawal symptoms while monitoring the patient’s blood pressure; antiemetics for nausea; dicyclomine for abdominal cramps; hydroxyzine for agitation; loperamide for diarrhea; trazodone for insomnia; and nonsteroidal anti-inflammatory agents such as ibuprofen for myalgias and arthralgias. Ask the patient to return to the office the next day for a follow-up visit and possibly a new buprenorphine induction attempt.

SECOND DAY

OF INDUCTION

After the first day of buprenorphine induction, the procedures for patients dependent on short-, intermediate-, or long-acting opioids are the same. A review of the patient’s subjective experience on the first day of buprenorphine induction, a COWS score check, and a clinical evaluation may be used to determine the need for dosage adjustment, depending on the withdrawal or overmedication symptoms experienced by the patient. If the patient continues to experience withdrawal symptoms, he or she should receive the total dose used on the first day and additional 2- to 4-mg increments of buprenorphine until a total dose of 12–16 mg is achieved

108 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

on the second day of induction. If the patient feels sedated and overmedicated at the end of the first day, lower the daily dose by 2–4 mg. If neither withdrawal nor overmedication symptoms are observed on the second day, repeat the total dose from the first day. A good night’s sleep is a good measure of adequate coverage. Sometimes the induction takes more than 2 days. You may ask the patient to come back to the office for further dose adjustments, or you may review the clinical status over the telephone or by e-mail and adjust as needed. Dose adjustments follow the same principles as above: raise the dosage if withdrawal symptoms continue and/or cravings for opioids occur, and lower the dosage if adverse effects occur. Whereas the maximum daily dose is 32 mg of buprenorphine by the end of the first week, the majority of patients stabilize with 8–16 mg/day. Do not assume that the patient has not used any other opioids since the first day of induction—ask your patient if he or she has used any opioids since leaving the office. Suspect active opioid use if the patient continues experiencing opioid withdrawal symptoms and/or difficulties with medication adherence. A urine toxicology examination for drugs of abuse may be indicated to guide clinical interventions.

SPECIAL CASES Pregnancy At the present time, methadone (a pregnancy category C medication) is the only FDA-approved medication for opioid-dependent pregnant women. Pregnant patients should be offered methadone maintenance therapy when available. If buprenorphine (also a pregnancy category C medication) is indicated (e.g., a pregnant patient refuses to take methadone and buprenorphine’s benefits outweigh its risks, or there is no methadone treatment available in your community), use the mono formulation of buprenorphine only. Mono buprenorphine does not contain naloxone, which can cause fetal and maternal hormonal changes. It also reduces the potential that the medication could result in maternal and fetal withdrawal symptoms if the patient tries to use the drug intravenously (see also Chapter 10).

Opioid Dependence Without Physiological Dependence People who have opioid dependence but are not currently physically dependent can also benefit from treatment with buprenorphine. For example, someone who has been addicted to heroin for many years but has not used for the past 6 months while incarcerated is at high risk for relapse on release from prison. Also, patients who binge on opioids but do not meet criteria for physiological dependence (tol-

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erance or withdrawal) may still meet criteria for opioid dependence according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) due to severe psychosocial deterioration. Reinduction with buprenorphine may also be appropriate for a patient who recently completed detoxification treatment but has begun to use opioids occasionally. In this case, there would be no reason to delay treatment until the patient has resumed daily use and is again physically dependent. Buprenorphine treatment can address such patients’ cravings and keep them safe. Buprenorphine induction for patients who are not physiologically dependent on opioids starts with 2–4 mg of buprenorphine. Raise the dose by 2-mg increments during the following days until the patient is comfortable and cravings abate. You may repeat a target dose of buprenorphine that was successful during past stabilization and maintenance phases.

Buprenorphine Stabilization The stabilization phase lasts 1–2 months. During this period, patients are seen regularly, every 1–3 weeks, in order to find a homeostatic state in the opioid system. Adjust the dosage of buprenorphine, if needed, to determine the minimum dosage necessary to eliminate withdrawal symptoms, markedly decrease cravings, and minimize side effects. Once you achieve initial control of withdrawal symptoms and craving, further dose increases should be approached in a very conservative manner. Because of the drug’s long half-life (24–60 hours, mean elimination half-life of 37 hours) it may take 10–14 days to achieve the full benefit of an increased dosage. More frequent increases may therefore result in unnecessary and excessive doses. The average daily dose is 8–16 mg of buprenorphine but some patients require as much as 32 mg/day. If a patient continues to have significant cravings and/or withdrawal symptoms at 32 mg/day, consider discontinuing buprenorphine and treating the patient with methadone. During the stabilization phase, discuss with the patient the possibility of engaging in psychosocial treatments and 12-step programs (see Chapter 8, “Clinical Management II”). This is an appropriate point at which to reinforce the message that the patient should not expect buprenorphine to eliminate all of his or her problems, and that the most successful outcomes are seen in patients who combine medication with psychosocial treatment and other recovery efforts.

Buprenorphine Maintenance Buprenorphine maintenance lasts several months or years depending on the patient’s individual needs. Many opioid-dependent patients require treatment

110 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

with buprenorphine indefinitely, not unlike patients with diabetes requiring insulin treatment or bipolar patients needing lithium maintenance. During this time, continue to review the benefits and adverse effects of buprenorphine; periodically run liver function tests; and counsel the patient on relapse prevention, physical well-being, and mental health (see also Chapter 8). After completion of the stabilization phase, most patients continue with the same dosage, typically 8–16 mg/day. However, several medical and psychosocial factors may dictate a change in dosage. Medical factors include significant weight increase or decrease, progression of liver disease, changes in other prescription medications, and pregnancy or menopause. As patients stabilize further and feel healthy, their life circumstances get better, finances recover, relationships blossom, and coping skills improve. As a result, patients may have fewer opioid cravings, have a lower risk of relapse, and need less medication. Even if complete detoxification is not the goal of treatment, discuss with your patient the possibility of working toward a lower dosage of buprenorphine as long as he or she still feels comfortable and safe from relapse. Reassure the patient that he or she can always return to the maintenance dosage if needed (see also Chapter 7, “Clinical Management I”).

DOSING STRATEGIES Once the patient is stable and the buprenorphine maintenance daily dose is established, he or she may switch to a less-than-daily dosing schedule (Johnson et al. 2003). Buprenorphine can be taken sublingually safely and effectively on an alternate-day dosing schedule (every 48 hours) by doubling the maintenance dose (e.g., if the patient is taking 8 mg/day, switch to 16–16–24 mg/day on Monday, Wednesday, Friday, respectively) (Amass et al. 1994). Alternative schedules include dosing every 72 hours by tripling the maintenance dose (Bickel et al. 1999); or dosing every 96 hours by quadrupling the maintenance dose (Petry et al. 2000). The efficacy of thrice-weekly dosing has been well documented; however, more data are needed before these other dosing schedules can be recommended. Although daily dosing is generally recommended to improve medication adherence, less-than-daily dosing regimens are also clinically useful for several reasons: 1. Alternate-day dosing schedules have been shown to be preferred by some patients to daily dosing. 2. Thrice-weekly dosing has been shown to be safe and effective. 3. In an opioid treatment program (OTP), these dosing schedules decrease the risk of diversion, because they reduce the need for take-home medication. In addition, monitoring and ensuring compliance with medication can be done at the clinic if diversion is suspected.

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4. Less-than-daily dosing schedules may be an incentive to patients contingent on abstinence from illicit drugs and compliance with treatment, as with methadone. It is likely that the benefits of less-than-daily dosing schedules with buprenorphine will be more advantageous when prescribed in an OTP facility, but these schedules may also be considered for buprenorphine treatment in an officebased setting (Marsch et al. 2005). On the other hand, although once-daily dosing is an effective treatment to block opioid craving and relapse, in some cases more frequent dosing may be advised. Some patients report that buprenorphine works well through the morning but experience a recurrence of thoughts and urges to use late in the afternoon or early in the evening. One effective strategy is to keep the same daily dose but to have the patient divide the tablet and the dosing—that is, change from one 8-mg tablet every morning to a half-tablet (4 mg) every morning and another half-tablet (4 mg) in the mid- or late afternoon. It has been suggested that the recurrence of thoughts and urges to use is a psychological effect in individuals who have been using short-acting opioids with multiple doses every day for many years. In other words, twice-daily dosing is a way for patients to feel better psychologically about buprenorphine’s effectiveness by mirroring their long-term drug use pattern. However, it is possible that there is also a pharmacological explanation for this complaint—as in the case of pain management, when it is usually necessary to recommend divided daily doses.

DRUG-DRUG INTERACTIONS Buprenorphine is metabolized to norbuprenorphine by the cytochrome P450 3A4 (CYP3A4) isoenzyme. Buprenorphine is primarily a substrate of CYP3A4. Medications that can inhibit or induce the CYP3A4 isoenzyme may increase or decrease, respectively, the plasma concentrations of buprenorphine. Inhibitors of the CYP3A4 isoenzyme include macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., ketoconazole), antidepressants (e.g., fluoxetine, fluvoxamine, sertraline), and HIV protease inhibitors (e.g., ritonavir, saquinavir, indinavir). CYP3A4 isoenzyme substrates can also raise buprenorphine levels, including alprazolam, diazepam, buspirone, trazodone, zolpidem, caffeine, haloperidol, pimozide, erythromycin, and oral contraceptives. Based on buprenorphine’s ceiling effect (see “Pharmacology Overview” earlier in this chapter), the increase in plasma concentrations of buprenorphine do not result in clinical complications unless buprenorphine is used with other CNS depressants (see below). Inducers of the CYP3A4 isoenzyme include carbamazepine, phenytoin, phenobarbital, reverse transcriptase inhibitors (e.g., zidovudine), nonnucleoside

112 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

reverse transcriptase inhibitors (e.g., efavirenz), and rifampin. Reduction in plasma concentrations of buprenorphine might induce withdrawal if the buprenorphine does not provide sufficient µ receptor coverage. However, buprenorphine has an active metabolite, norbuprenorphine, which is also a µ opioid agonist and thus helps reduce the risk of a buprenorphine–CYP3A4 inducer interaction resulting in withdrawal. With the exception of interactions with the retroviral drugs atazanavir and ritonavir, it is not clear that any of these theoretical interactions has any practical clinical implications. For further discussion of the interaction between buprenorphine and the CYP3A4 system, please see “Drug Interactions With Buprenorphine” in Chapter 9, “Psychiatric Comorbidity.” In Chapter 3, Table 3–2 provides a partial list of medications metabolized by CYP3A4 and may be a helpful reference. Buprenorphine has such high affinity for the µ opioid receptor that it will displace most full opioid agonists and may thus precipitate withdrawal. Although this concept has been reviewed multiple times in buprenorphine training curricula (including this book), the likelihood of buprenorphine-precipitated withdrawal is low, and even when it does occur it is mild in intensity and short in duration. For a detailed discussion of the interaction of buprenorphine with full opioid agonists, please see Chapter 3 and Chapter 11 (“Management of Acute and Chronic Pain”). The opioid antagonist naltrexone is approved by the FDA for the treatment of opioid dependence and alcohol dependence but should not be combined with buprenorphine. Naltrexone has adequate oral bioavailability and could potentially precipitate withdrawal in a patient who is taking buprenorphine. There is a potential synergistic effect in combining CNS depressants with buprenorphine, especially when taken intravenously. In a study conducted with rats (Nielsen and Taylor 2005), the ceiling effect of buprenorphine disappeared when buprenorphine was combined with high doses of benzodiazepines. The combination of buprenorphine and diazepam resulted in respiratory depression similar to the effect of full agonists. Although the combination of buprenorphine and benzodiazepines or other CNS depressants is not contraindicated, patients taking buprenorphine who also take sedatives (either prescribed by a physician or purchased illegally) are at increased risk of respiratory depression. A medical advisory published by Reckitt Benckiser (2009), the manufacturer of Suboxone and Subutex, advises the following: • • • •

Consider reducing the dosage of either buprenorphine or the benzodiazepine or both. Educate the patient about the potential danger. Treat co-occurring psychiatric disorders, such as depression and/or anxiety. Avoid prescribing benzodiazepines whenever possible.

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For a detailed discussion of the interaction of buprenorphine with benzodiazepines and other sedating agents, please see also the section “Overdose” in Chapter 4.

Detoxification With Buprenorphine The treatment of opioid withdrawal by administering a medication taper and eventually discontinuing it is sometimes called medical withdrawal and sometimes detoxification. Strictly speaking, the term detoxification is a misnomer because opioids are not in themselves neurotoxic (as compared with alcohol, for example, which is directly toxic to the nervous system), but the term detoxification has prevailed both in the medical literature and the community. Buprenorphine can be used for detoxification from opioids safely and effectively in both inpatient and outpatient settings. Studies support that buprenorphine is more effective and is better tolerated than clonidine for the treatment of opioid withdrawal (Ziedonis et al. 2009). Before the FDA approval of sublingual buprenorphine in the United States, the analgesic formulation was administered by injection and used for opioid withdrawal. At the present time, the injectable formulation is not recommended, based on the clinical advantages of the sublingual preparation (American Psychiatric Association 2007). Since the approval of sublingual buprenorphine for the treatment of opioid dependence, the FDA has specifically stated that the parenteral formulation should no longer be used for this purpose. Both buprenorphine and methadone have long action and proven effectiveness in detoxification. Buprenorphine has the additional advantage of being very safe because of its ceiling effect. However, well-designed studies comparing buprenorphine and methadone for opioid withdrawal are limited (Polydorou and Kleber 2008). The management of opioid withdrawal can be divided into three scenarios: 1) rapid detoxification in 3 or fewer days, 2) detoxification in 4–30 days, and 3) detoxification in more than 30 days. All approaches require that patients experience mild to moderate opioid withdrawal (a COWS score of >12) before the first dose of 2–4 mg of buprenorphine is administered. Equally important is that all approaches recommend that patients engage in some form of psychosocial treatment and support after completion of detoxification. The average daily dose of buprenorphine on the first and second days of rapid detoxification ranges between 8 and 12 mg; on the third day the patient is given 6 mg of buprenorphine; then the medication is discontinued (Cheskin et al. 1994). Alternatively, the buprenorphine dosage can be decreased in decrements of 2 mg/day over the following days if necessary (Horspool et al.

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2008). Two 5-day protocols have been shown to be safe and efficacious in treating acute withdrawal, with the higher-dosage buprenorphine schedule (8–8–8– 4–2 mg/day on days 1–5) demonstrating moderate superiority over the lowerdosage protocol (2–4–8–4–2 mg/day on days 1–5) (Oreskovich et al. 2005). Information on the long-term efficacy of these interventions is limited. The moderate-length detoxification approach allows patients to undergo induction and stabilization before medication tapering begins. Patients first stabilize with an adequate buprenorphine dosage according to their withdrawal severity, cravings, adverse effects, and other drug use. The average daily dose of buprenorphine on a moderate detoxification schedule is 8 mg. The Clinical Trials Network (CTN), a project sponsored by the National Institute on Drug Abuse, has used a 13-day detoxification dosing schedule that is suitable for inpatient and outpatient settings (Table 6–1). On the first day, 4 mg of buprenorphine and an additional 4 mg, if needed, are administered; on the second day 8 mg and on the third day 16 mg are given. For the next 4 days (day 4 through day 7), buprenorphine dosages are decreased in decrements of 2 mg/day, reaching 8 mg on the seventh day of detoxification. Then the daily dose is decreased gradually by 2 mg every 2 days. During the last 2 days (days 12 and 13 ) of the CTN protocol, the patient takes 2 mg of the medication per day (Ling et al. 2005). However, this CTN protocol is only one of the detoxification schedules using buprenorphine sublingual tablets that are suggested in the literature, and the comparative effectiveness of the approaches is largely unknown. A study of 364 patients with opioid dependence (Katz et al. 2009) compared a brief, 5-day buprenorphine detoxification protocol with an extended, 30-day protocol. The results suggest that longer detoxification schedules improve treatment engagement, increase the chances for successful completion of detoxification, and facilitate transition to long-term addiction treatment. Withdrawal symptoms associated with a more gradual reduction in buprenorphine dosage, over a period longer than 30 days, are less severe than they are with shorter detoxification protocols. The medical literature reports less illicit opioid use and greater treatment retention with longer detoxification schedules (Horspool et al. 2008; Sullivan and Fiellin 2008). As previously mentioned, the clinician can also use additional, nonopioid medications for symptomatic relief of opioid withdrawal during the detoxification with buprenorphine, if clinically indicated (see “Managing Precipitated Withdrawal”). Clinical evidence of insomnia, anxiety, restlessness, nausea, vomiting, diarrhea, and muscle cramps has justified the use of ancillary medications.

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TABLE 6–1.

National Institute on Drug Abuse Clinical Trials Network buprenorphine withdrawal protocol

Study day

1

2

6

7

8

9 10 11 12 13

Combinationa daily dose (mg)

4b

8 16 14 12 10

8

6

6

3

4

5

4

4

2

2

aBuprenorphine-naloxone. bPlus

additional 4 mg, as needed. Source. Ling et al. 2005.

Buprenorphine Taper Sometimes both patients and physicians plan to discontinue buprenorphine after a period of stabilization. It is unclear whether tapering a stable buprenorphine dosage is best accomplished with a short- or long-term discontinuation schedule. A study of 516 patients taking buprenorphine found a modest advantage of a 7-day taper versus a 28-day taper, with 44% versus 30% of patients having opioid-free urine specimens, respectively, at the end of the taper (Ling et al. 2009). It is important to underscore that discontinuation of buprenorphine is frequently an ineffective treatment of opioid dependence; in a study by Ling et al. (2009), only 12% (with a 7-day taper) to 13% (with a 28-day taper) of the subjects remained opioid free at the 3-month follow-up.

Conclusion Treating opioid dependence with buprenorphine is technically simple and straightforward. The treatment has three phases: induction, stabilization, and maintenance. During induction, the patient works closely with the physician to avoid withdrawal symptoms (spontaneous or precipitated) and ensure a smooth transition. Maximizing symptom relief and minimizing adverse effects is the balancing act of the stabilization phase. During the maintenance phase, the focus shifts from dose adjustments to promotion of a healthy lifestyle, investment in various psychosocial treatments, and fulfillment of the patient’s personal goals. The majority of patients feel mild to moderate discomfort for a few hours during the first day of induction, but this is quickly followed by profound relief and gratitude once they experience the beneficial effects of the medication. For physicians, effecting this dramatic transformation can be one of the most rewarding and gratifying aspects of medical practice.

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Clinical Pearls • Always use the buprenorphine-naloxone formulation except in pregnant patients (who may receive the mono buprenorphine formulation if necessary). • If the patient is physiologically dependent on opioids, make sure that he or she is in mild to moderate withdrawal before starting the induction. The longer you can delay the first dose of buprenorphine, the easier and less complicated the induction will be. • Start the induction with 2–4 mg of buprenorphine and raise the dosage over the first couple of days of induction to a target daily dose of 8–16 mg; the maximum dosage is 32 mg/day. • Stabilize the patient over 1–3 weeks. If further dose adjustments are needed, a) increase the dosage to manage cravings or withdrawal symptoms, or b) lower the dosage, as tolerated, to reduce side effects or for patient preference. Because of buprenorphine’s long half-life, dose increases should occur no more frequently than once a week. • Avoid using other opioid agonists or opioid antagonists while the patient is taking buprenorphine. Drug-drug interactions with most other classes of drugs can be managed with dose adjustments. • If you decide to use buprenorphine for detoxification, keep in mind that the longer the taper, the greater the chance of success.

CASE 1 Sally is a 21-year-old sophomore at a local college. She makes an appointment after seeing your name on the Internet buprenorphine physician locator list. In the office, she is taciturn and makes little eye contact. You learn that she started occasional use of pain pills in high school when “everyone was doing it on the weekends.” Three months ago, a friend gave her “Oxys.” She is worried now because she uses them almost daily. She says: “I feel lousy if I don’t get them.” She recently failed two exams and has stopped her daily jogging routine. She admits to occasional marijuana use and has a few drinks on weekends but denies use of other drugs. “I tried to stop, but I can’t. My parents are going to kill me....”

1. Does Sally demonstrate DSM-IV-TR criteria for opioid dependence? 2. Does Sally demonstrate DSM-IV-TR criteria for opioid abuse? 3. Does she meet legal criteria for opioid agonist therapy? Is her age an issue?

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4. Is she a candidate for office-based buprenorphine treatment, or should she be referred to an OTP?

♦ ♦





♦ ♦



You conduct a thorough evaluation and decide that Sally would benefit from office-based buprenorphine therapy. She reports that she has been recently using “two 80s a day” (i.e., two 80-mg tablets of OxyContin daily). She makes it clear that she doesn’t want to stay on buprenorphine “forever.”

1. What would you consider “adequate education” before starting treatment? 2. Would you feel comfortable writing a prescription for her to bring buprenorphine back to the office? 3. Is a urine toxicology examination indicated? 4. What initial buprenorphine dosage would you prescribe? 5. How would you determine your initial target dosage for this patient? 6. If she experiences precipitated withdrawal in your office what would you do next? 7. When would you give the next dose if she is able to tolerate the initial dose? 8. What are your treatment goals? (Brief taper with drug-free counseling? Gradual taper? Long-term maintenance?) How necessary is counseling in this case?

References Amass L, Bickel WK, Higgins ST, et al: Alternate-day dosing during buprenorphine treatment of opioid dependence. Life Sci 54:1215–1228, 1994 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 American Psychiatric Association: Practice guideline for the treatment of patients with substance use disorders, 2nd edition. Am J Psychiatry 164(4 Suppl):5–123, 2007. Available at: http://www.psychiatryonline.com/pracGuide/pracGuideTopic_5. aspx. Accessed April 23, 2010. Bickel WK, Amass L, Crean JP, et al: Buprenorphine dosing every 1–3 days in opioiddependent patients. Psychopharmacology 146:111–118, 1999 Casadonte PP: Buprenorphine induction, in Physicians Clinical Support System–Buprenorphine (PCSS-B), Clinical Guidance. October 27, 2009. Available at: http:// www.pcssbuprenorphine.org/pcss/documents2/PCSS_BuprenorphineInduction_ 050308.pdf. Accessed May 7, 2010. Center for Substance Abuse Treatment: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publ No (SMA) 04-3939. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2004. Available at: http:// www.kap.samhsa.gov/products/manuals/index.htm. Accessed April 29, 2010.

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Cheskin LJ, Fudala PJ, Johnson RE, et al: A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. Drug Alcohol Depend 36:115–121, 1994 Glasper A, Reed LJ, de Wet CJ, et al: Induction of patients with moderately severe methadone dependence onto buprenorphine. Addict Biol 10:149–155, 2005 Handelsman L, Cochrane KJ, Aronson MJ, et al: Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 13:293–308, 1987 Horspool MJ, Seivewright N, Armitage CJ, et al: Post-treatment outcomes of buprenorphine detoxification in community settings: a systematic review. Eur Addict Res 14:179–185, 2008 Johnson RE, Strain EC, Amass L: Buprenorphine: how to use it right. Drug Alcohol Depend 70 (suppl 1): 59–77, 2003 Katz EC, Schwartz RP, King S, et al: Brief vs. extended buprenorphine detoxification in a community treatment program: engagement and short-term outcomes. Am J Drug Alcohol Abuse 35:63–67, 2009 Lee JD, Grossman E, DiRocco D, et al: Home buprenorphine/naloxone induction in primary care. J Gen Intern Med 24:226–232, 2009 Ling W, Amass L, Shoptaw S, et al: Buprenorphine Study Protocol Group: A multicenter randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction 100:1090–1100, 2005 Ling W, Hillhouse M, Domier C, et al: Buprenorphine tapering schedule and illicit opioid use. Addiction 104:256–265, 2009 Marsch LA, Bickel WK, Badger GJ, et al: Buprenorphine treatment for opioid dependence: the relative efficacy of daily, twice and thrice weekly dosing. Drug Alcohol Depend 77:195–204, 2005 Nielsen S, Taylor DA: The effect of buprenorphine and benzodiazepines on respiration in the rat. Drug Alcohol Depend 79:95–101, 2005. Epub 2005 Feb 17 Oreskovich MR, Saxon AJ, Ellis ML, et al: A double-blind, double-dummy, randomized, prospective pilot study of the partial mu opiate agonist, buprenorphine, for acute detoxification from heroin. Drug Alcohol Depend 77:71–79, 2005 Petry NM, Bickel WK, Badger GJ: A comparison of four buprenorphine dosing regimens using open-dosing procedures: is twice-weekly dosing possible? Addiction 95:1069–1077, 2000 Polydorou S, Kleber HD: Detoxification of opioids, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition. Edited by Galanter M, Kleber HD. Washington, DC, American Psychiatric Publishing, 2008, pp 265–287 Reckitt Benckiser: Medical Advisory & Best-Practices Update. Richmond, VA, Reckitt Benckiser Pharmaceuticals, May 2008. Available at: http://www.suboxone.com/ pdfs/MedicalAdvisory.pdf. Accessed June 8, 2010. Sullivan LE, Fiellin DA: Narrative review: buprenorphine for opioid-dependent patients in office practice. Ann Intern Med 148:662–670, 2008 Wesson DR, Ling W: The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 35:253–259, 2003 Ziedonis DM, Amass L, Steinberg M, et al: Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence. Drug Alcohol Depend 99:28–36, 2009

7 Clinical Management I BUPRENORPHINE TREATMENT IN OFFICE-BASED SETTINGS Jeffrey D. Baxter, M.D.

ADOPTING A NEW treatment modality can be challenging, especially in outpatient office settings where providers and staff may feel their resources are stretched to meet the needs of the patient population they already are serving. But, as has been described in earlier chapters of this book, the need to expand treatment services is urgent, and the potential to improve the lives of patients hurt by the disease of opioid addiction is great. Most providers have found that buprenorphine treatment integrates easily into their outpatient office practices, and that patients greatly appreciate the opportunity to receive treatment. The purpose of this chapter is to offer some suggestions for managing patients in office-based buprenorphine treatment. It is my hope that the procedures outlined below will provide a foundation for organizing treatment in a way that will be rewarding both for providers and for the patients seeking treatment. 119

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A case is presented at the end of this chapter, including related questions for additional consideration. For discussion of this case, please see Chapter 14, “Comments on the Case Vignettes.”

Organizing Your Office to Support Buprenorphine Treatment A number of steps can be taken to help prepare an office for providing buprenorphine treatment. Begin by establishing administrative and clinical procedures for each stage of the treatment, including screening, induction, and ongoing treatment. Important elements include managing referrals and inquiries, staff education and training, and communication and coordination with other treatment providers. Also, because drug addiction shares many of the features of chronic medical illness (McLellan et al. 2000), providers should consider adapting office systems already in place for managing other chronic diseases for office-based buprenorphine treatment (Saitz et al. 2008). The care management models described below are effective ways to implement this treatment approach.

MANAGING REFERRALS

AND INQUIRIES

How will referrals for treatment, either self-referral from patients or referrals from outside providers, be managed? If you are participating in one of the available online treatment referral resources, such as the treatment finder supported by the Substance Abuse and Mental Health Services Administration, your office will receive calls from patients and providers, from both within and outside your local area (see Chapter 13, “Logistics of Office-Based Buprenorphine Treatment”). It is important to identify the phone number these callers will use and how their calls will be managed. Will office staff answer those calls, or will patients and providers be asked to leave a message? Who will return those calls? Some offices have designated nonphysician providers to manage the initial communication and screening with patients, to ensure that patients are appropriate and eligible for care in the office before any physician time is invested. It may be useful to develop an initial screening tool that outlines any inclusion or exclusion criteria that may be specific to your office.

STAFF EDUCATION

AND

TRAINING

Because the treatment of addiction has been managed outside of medical and psychiatric office settings for most of the last century, it is important to provide

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education and informational resources for support staff. Nurses, office staff, and even many medical providers may hold deep-seated beliefs about the causes or treatment of addiction, many of which are not at all evidence based. Common misconceptions include beliefs that addiction is a sign of character flaws or moral weakness and that medical treatment doesn’t work for such conditions. Some staff may object to the idea of opioid agonist treatment, believing that buprenorphine treatment involves substituting one addiction for another. Finally, some individuals may have personal experience with addiction, either themselves or with close family members, and these experiences may influence their feelings or behaviors toward others with an addictive illness. Any investment made in educating staff about the natural history and treatment of opioid dependence will provide immediate value in the clinical setting. The National Institute on Drug Abuse–sponsored Web site Buprenorphine (Suboxone) Training and Practice Tools (www.buppractice.com) contains links to training guides and courses specifically designed for clinical and administrative staff.

CARE MANAGEMENT MODEL Any office providing buprenorphine treatment should be able to provide either well-coordinated or fully integrated medical, psychiatric, and behavioral treatment. To facilitate this comprehensive care, some medical offices utilize care management models for buprenorphine treatment similar to those used for diabetes and other chronic medical illnesses. In these models, a nurse, a clinical social worker, or another nonphysician provider takes a leadership role in monitoring patients under the direction of the physician. Although nonphysician providers may not prescribe buprenorphine under the current authorizing legislation, they may provide many of the components of care, including the initial screening, management of the induction and early stabilization periods, ongoing adherence and recovery monitoring, communication with outside providers, and other coordination of care (Bodenheimer et al. 2002a, 2002b; Saitz et al. 2008). Similarly, psychiatrists often work in close collaboration with behavioral treatment providers who provide screening, assessment, and ongoing clinical services. Collaboration with a behavioral treatment provider offers the additional benefit of integrating evidence-based individual and/or group counseling services into the care process. The ability to establish care management or other more advanced collaborative models varies, depending on what resources are available locally, the quality of communication among members of the treatment team, and what nonphysician services are reimbursable under patients’ insurance plans. In any shared model, physicians need to ensure that the amount of physician supervision and contact is safe, appropriate, and consistent with clinical guidelines. For a discussion of other models of care, see Chapter 13.

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COMMUNICATION AND COORDINATION WITH OTHER TREATMENT PROVIDERS Communication with other providers involved in each patient’s care is essential for safe and effective office-based buprenorphine treatment. Most buprenorphine providers require that patients identify all treatment providers involved in their care, and that patients sign information release forms compliant with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) to allow communication with the other providers, before starting treatment. Buprenorphine providers may choose to mandate that other providers or consultants be active participants in a patient’s care, or that patients engage in certain types of treatment. The most common situation is for buprenorphine providers to require participation in some form of group or individual counseling and/or 12-step recovery program. Other examples include psychiatrists who may require that a patient have a primary care physician, or medical care providers who may require ongoing treatment with a psychiatrist. Establishing collaboration and referral agreements among providers of different types of services will assist patients in accessing these treatments and will facilitate communication and documentation. Making connections with specialty substance abuse treatment providers such as those who work at detoxification centers and in methadone maintenance programs is particularly important in case patients do not do well with office-based treatment and ultimately need more intensive or more highly structured care. For buprenorphine providers who do not have formal collaborative relationships, monitoring adherence to other treatment and coordinating care with other providers may pose a significant challenge. For busy providers, taking time to communicate with other providers may not seem to be a priority compared with other issues that have to be managed during a visit. Completing the required release forms to allow a more formal exchange of protected information is also time consuming. Finally, patients may resist treatment providers’ efforts to communicate with each other, because of either embarrassment, fear that disclosure of an addiction diagnosis may affect the quality of the care provided, or a desire to obtain medications from other providers that may not be safe or appropriate in combination with buprenorphine. Some techniques to facilitate communication include the following: 1. Create a letter that identifies the patient as a participant in buprenorphine treatment and provides basic information about the medication and contact information for you and your office. Have every patient sign releases so that this letter may be sent to each provider involved in a patient’s care. Consider requesting that a copy of the documentation from patients’ visits with other treatment providers be copied formally to you following each appointment.

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2. Create a communication form for patients to give to consultants and other providers that requests a quick summary of their office visit along with information about how that provider can be contacted in case you have questions. Keep it short, because no provider appreciates additional paperwork. This form could also include a request for the consultant to acknowledge that he or she is aware that the patient is currently enrolled in a buprenorphine treatment program. 3. If possible, include HIPAA-compliant release of information statements on these forms for patients to sign, so that all necessary documentation is included as part of a single-page document. See Chapter 13 for a sample release of information form. 4. Have the patient be responsible for transporting these forms or other types of documentation between providers, and include this responsibility in the list of activities required for buprenorphine treatment. You need to consider what responses you will take if providers refuse communication, if patients report that outside appointments are canceled or changed, or if, for some other reason, patients do not return paperwork to your office.

Establishing a Therapeutic Environment After a patient has been screened, assessed, and found to be appropriate for treatment with buprenorphine within your clinical setting, a number of additional steps are recommended before induction to help establish a safe and effective therapeutic environment, as summarized below.

INFORMED CONSENT Patients must be able to provide informed consent for participation in buprenorphine treatment. As for any treatment, obtaining informed consent involves reviewing the nature of the proposed treatment and making sure that the patient understands the potential benefits and risks of treatment, not only for themselves but also for the people around them. Informed consent procedures for buprenorphine treatment usually include reviewing the following: • • •

That buprenorphine is an opioid that causes physical dependence The goals of opioid substitution therapy, such as relieving withdrawal symptoms and eliminating drug abuse Alternative treatment options, such as inpatient detoxification or methadone maintenance

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Potential medication interactions and side effects, including opioid withdrawal symptoms.

Obtaining informed consent is different from reviewing a treatment agreement or contract, which focuses more on office procedures and expected behaviors (see the next section, “Treatment Agreements”). Informed consent should be obtained before starting treatment, and renewed on a periodic basis during treatment. Obtaining informed consent is challenging in many ways. Providers must be able to communicate the risks and benefits of treatment to patients who usually have no medical training and may have low literacy levels or limited English proficiency. Patients with an opioid addiction may be desperate for treatment and may rush through a review of the risks and alternative treatment options in order to obtain treatment. Some providers may request that a patient’s spouse or other family member participate in the informed consent process, both to help ensure that the patient understands the information presented, and to educate family members so they can better support patients entering treatment. Figure 7–1 shows a model informed consent form adapted from the tools used in my office. This document includes information that pertains specifically to one office setting and is in no way perfect or exhaustive; it is meant only to model the process and provide a foundation for other providers initiating buprenorphine treatment.

TREATMENT AGREEMENTS Traditional treatment agreements, known as contracts, have focused mostly on what is expected of the patient during treatment, such as behavioral codes, office procedures, and treatment components with which patients are expected to comply. Patients have often perceived these contracts as a set of rules being imposed by one party (the provider) onto another (the patient). Providers have often considered any deviation from these contracts as a violation or breach that could result in the discontinuation of treatment. More recently, treatment contracts have been replaced by the concept of the treatment agreement. The goal of a treatment agreement is to establish a mutually agreed-on understanding of what is expected of the patient, the provider, and the provider’s office staff during treatment. As in agreements or contracts in business settings, these documents are designed to outline the expectations and responsibilities of all of the parties signing the agreement. The hope is that clear, written parameters established up front will help avoid conflict and confusion during the course of treatment. Each provider needs to develop an agreement that reflects the unique needs within the clinical setting in which he or she works. A sample treatment agreement is included in Figure 7–2. Please note again that this is only an example, and that the components listed may or may not apply to your treatment setting.

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I, __________________________, have read and understand the following (initial each line as it is reviewed): _____Buprenorphine is a medication used to treat people with addiction to opioids, such as heroin, oxycodone, or hydrocodone. Buprenorphine is an opioid that can be used to replace the drugs you are abusing, to prevent the withdrawal sickness and help you stop abusing drugs. Like other opioids, after taking buprenorphine for a while, you will feel withdrawal sickness if you stop taking it suddenly. _____Buprenorphine is used to treat opioid addiction, and does not directly help with abuse of alcohol or other drugs such as cocaine or amphetamines. _____Buprenorphine treatment is lexible and can last as long as is needed to help prevent relapse to drug use. Each patient will plan how long to be in treatment with the doctor. When a patient and doctor agree that it is time to decrease the medication, the dose will be decreased slowly to help prevent withdrawal sickness. _____Buprenorphine lasts a long time in the body and should be taken only once per day, unless otherwise instructed by the physician or member of the treatment team. _____Buprenorphine treatment is a tool to help patients recover from opioid addiction, but taking this medication alone is not considered enough treatment to help patients get better, and patients will be required to participate in other forms of treatment such as counseling or 12-step programs. _____Buprenorphine is available in a tablet called Suboxone, which is buprenorphine mixed with a medicine called naloxone. his tablet will work only if you leave it under your tongue and let it completely dissolve. Even though it may have a bad taste, you cannot eat or drink while taking the medicine, because if you swallow it, it will not work. _____Buprenorphine may make you constipated, or feel tired or sleepy. You may not be able to drive a car or operate machinery while taking this medicine. If you are having any side efects from the medicine, you must notify the doctor immediately. _____ his medicine may hurt the liver. Blood tests will be done to make sure you do not have liver problems from the medicine.

FIGURE 7–1. ment.

Sample informed consent form for buprenorphine treat-

126 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

_____ If you take this medicine with alcohol or any medicine or drug that causes sleepiness, you could become very sick or die. Taking sedatives such as Klonopin, Valium, or Xanax (or any benzodiazepine) can be dangerous for people taking buprenorphine and should never be done without the permission of your doctor. _____ If other people take buprenorphine when it is not prescribed for them, they could become very sick or even die, especially children. To participate in buprenorphine treatment, patients must be able to keep this medication locked up, in a cabinet or a lock box, so children cannot get to it. If a child or other person takes your medication, you must call 911 immediately. _____ Taking lower doses of the medication will decrease the chances of having side efects or other problems with buprenorphine. Patients should always work with the doctor to ind the lowest dose of the medicine that helps. _____If you take buprenorphine while you have other opioid medications such as oxycodone, hydrocodone, or methadone in your body, you may sufer severe withdrawal sickness. All patients must tell the doctor if they are taking any other opioid drugs or medications. _____ his medicine will block the efect of opioid pain medications, including medicines given in emergencies and after surgery. Notify all physicians that you are taking this medication. Notify your physician immediately if you need to have surgery or any medical or dental procedure so you can plan ahead for pain medication. Other doctors may not know about this medicine, so carry the buprenorphine treatment information card† at all times. _____ his medicine is not currently approved for use in women who are pregnant. Women who are pregnant require diferent medications and special treatment services to protect the woman and the baby. If you are pregnant, or considering getting pregnant, please notify the doctor immediately. _____ Buprenorphine treatment is not right for everyone. Some patients may have problems with their physical or mental health that make them ineligible for treatment. Other patients may need more intensive treatment to get better. If the doctor decides that buprenorphine treatment is not safe or appropriate for you, he or she will help you get into another type of treatment program.

FIGURE 7–1. Sample informed consent form for buprenorphine treatment. (continued) †Available

from the drug manufacturer.

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Some patients feel that buprenorphine treatment is too risky for them, or that they do not want to do some of the things being asked of them in order to participate in treatment. If you do not qualify for or do not want buprenorphine treatment, we can help refer you to other forms of treatment, including: • Methadone maintenance, where patients go to a program and get methadone every day to help prevent withdrawal sickness and drug abuse • Inpatient detoxiication, where patients are admitted to a hospital or treatment program and receive treatment for the withdrawal sickness for a few days • Outpatient treatment, where patients go for counseling but do not typically receive medications to treat withdrawal sickness • Residential treatment, where patients work on recovery skills while living away from home with other patients recovering from addiction.

I have read this form and discussed it with a medical care provider. I have had the opportunity to ask questions and would like to: _____ start buprenorphine treatment. _____ be referred to another treatment instead of buprenorphine. ____________________________________ Patient signature

_______________ Date

Provider statement: I have reviewed the above information with this patient and believe they understand what buprenorphine treatment involves, including potential risks and beneits. _____________________ Provider signature

_____________________ Provider name

________________ Date

FIGURE 7–1. Sample informed consent form for buprenorphine treatment. (continued)

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I, ___________________________as a participant in buprenorphine treatment at____________________________ understand and voluntarily agree that (initial each statement after reviewing): _____ I will keep (and be on time for) all my scheduled appointments with the doctor and other members of the treatment team. _____ I will participate in group or individual counseling, 12-step recovery programs, or other types of treatment that I am asked to participate in. _____ I will keep the medicine safe, secure, and out of the reach of children. If the medicine is lost or stolen, I understand it will not be replaced until my next appointment. _____ I will take my medication as instructed and not change the way I take it without irst talking to the doctor or another member of the treatment team. _____ I will tell the doctor or another member of the treatment team if I stop my treatment for any reason. I understand that I will need to plan ahead for any surgery or other medical procedures for which I may need medicines for pain. _____ I will not call between appointments, or at night or on the weekends looking for reills. I understand that prescriptions will be illed only during scheduled oice visits with the treatment team. _____ I will make sure I have an appointment for reills. If I am having trouble making an appointment, I will tell a member of the treatment team immediately. _____ I will treat the staf at the oice respectfully at all times. I understand that if I am disrespectful to staf or disrupt the care of other patients my treatment will be stopped. _____ I will not sell this medicine or share it with others. I understand that if I do, my treatment will be stopped. _____ I will sign a release form to let the doctor speak to all other doctors and counselors that I see. _____ I will tell the doctor about all other medicines that I take, and let him or her know right away if I have a prescription for a new medicine. _____ I will use only one pharmacy to get all of my medicines: Pharmacy name/phone # _____ I will not get any opioid pain medicines or other medicines that can be addictive such as benzodiazepines (Klonopin, Xanax, Valium) or stimlulants (Ritalin, amphetamines) without telling a member of the treatment team before I ill that prescription. I understand that the only exception to this is if I need pain medicine for an emergency at night or on the weekends. _____ I will not use illegal drugs such as cocaine, marijuana, or amphetamines while taking buprenorphine. I understand that if I do, my treatment may be stopped. _____I will not take any prescribed medication that can be addictive, such as benzodiazepines, stimulants, or opioid pain medicines, without the approval of the physician prescribing buprenorphine.

FIGURE 7–2.

Sample buprenorphine treatment agreement with program statement.

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_____ I will come in for drug testing and counting of my pills within 24 hours of being called. I understand that I must make sure the oice has current contact information in order to reach me, and that any missed tests will be considered positive for drug use. _____ I will keep up to date with any bills from the oice and tell the doctor or a member of the treatment team immediately if I lose my insurance or can’t pay for the treatment anymore. _____ I understand that I may lose my right to treatment in this oice if I break any part of this agreement. Buprenorphine Treatment Program Statement We here at _____________________ are making a commitment to work with you in your eforts get better. To help you in this work, we agree that: • We will help you schedule regular appointments for medicine reills. If we have to cancel or change your appointment for any reason, we will make sure you have enough medication to last until your next appointment. • We will make sure that this treatment is as safe as possible. We will check regularly to make sure you are not having bad side efects. • We will keep track of your prescriptions and test for drug use regularly to help you feel like you are being monitored well. • We will help connect you with counseling, 12-step programs, and other forms of treatment to help you with your recovery work. • We will help you set treatment goals and monitor your progress in achieving those goals. • We will work with any other doctors you are seeing and provide education and information to them about buprenorphine so that they can treat you safely and efectively. • We will include anyone from your family in your treatment if you want them to participate and feel that it would be helpful to have them be a part of it. • We will work with you to make sure you get safe and appropriate pain treatment when needed. • We will work with you to help you stop using other drugs, such as cigarettes, alcohol, and cocaine. • We will work with your medical insurance providers to make sure you do not go without medicine because of paperwork or other things they may ask for. • When it is time to decrease the dose of the medicine, we will work with you to decrease it slowly so that you do not feel a lot of withdrawal symptoms and to help make sure you do not start to use drugs again. If for some reason you can’t stay on buprenorphine treatment, we will help you ind other treatment and, as best we can, work to make sure you do not get sick from stopping the medicine. __________________________ Patient signature __________________________ Provider signature

FIGURE 7–2.

_________________________ Patient name _________________________ Provider name

__________ Date __________ Date

Sample buprenorphine treatment agreement with program statement. (continued)

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ESTABLISHING TREATMENT GOALS/ TREATMENT PLANNING Formal, structured treatment planning is a central component of most behavioral and substance abuse treatment modalities. For medical providers, treatment planning occurs more informally in the context of the office visit, and is incorporated into the plan section of a progress note. Regardless of the approach, there are a few general principles of treatment planning that, when utilized, help both patients and providers monitor treatment progress. Providers should begin by helping patients identify the goals of treatment. Most patients quickly identify cessation of drug use and improvements in their financial or legal situations as immediate goals. Be sure to explore areas that patients may not have considered, such as the potential for improvement in medical and psychiatric conditions, employment, family and interpersonal relationships, education, and housing. It is important to work with patients to identify specific goals and actions to be taken, and help set a timeline for achieving those goals. The provider must be sure to set reasonable expectations about what can be achieved in a set amount of time, and to monitor and measure progress. Establishing unrealistic goals or timelines risks reinforcing feelings of failure and a patient’s belief that he or she is unable to make lasting positive change. Goals (and the types of actions needed to meet those goals) will change across time as patients progress in treatment, making it important to review and update treatment goals with every visit. Discussing the length of opioid agonist treatment is particularly important. Contrary to popular belief, very few patients enter medication-assisted treatment hoping to continue treatment indefinitely. Most patients, through their own wishes or under pressure from their families or others in our society, only want short-term treatment. Patients must recognize that although treatment is voluntary and they may leave at any time, studies have shown that ongoing maintenance treatment with an opioid agonist results in the best outcomes (National Consensus Development Panel 1998; Sees et al. 2000) and that patients with opioid dependence who leave opioid agonist treatment return to drug use more than 80% of the time (Magura and Rosenblum 2001) and have a high rate of death by overdose (Zanis and Woody 1998). Overall, the longer the treatment the better the outcome, and for many patients indefinite treatment may be needed to sustain abstinence and continue to make progress on other treatment goals. One of the most critical aspects of treatment planning is to link patients’ goals to the duration of treatment. What do patients want to achieve, and how long will it take to accomplish their goals? After months or years of enduring the consequences of opioid addiction, why rush through treatment? Encourage patients to have patience—to give themselves enough

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time to meet their treatment goals and enjoy the benefits of the investment they have made by engaging in treatment.

Clinical Philosophy: The Chronic Disease Paradigm McLellan et al. (2000) offered a clinical paradigm for drug addiction that is very helpful in approaching patients with addictive diseases. These authors suggested that drug addiction shares many characteristics with other common chronic medical illnesses, such as diabetes, asthma, and hypertension: 1. 2. 3. 4. 5.

Genetic heritability A role for personal responsibility Well-defined pathophysiology Good response to treatment Similar rates of noncompliance with treatment.

Like those medical conditions, and similar to many chronic psychiatric conditions, drug addiction involves a complex interplay of genetic, environmental, and behavioral factors that must all be addressed in order to maintain good health and support recovery.

SHORT-TERM VERSUS LONG-TERM TREATMENT It is helpful to conceptualize opioid addiction as a brain disease, in which repeated exposure to drugs leads to alterations of neurotransmitter levels and receptor function in the brain (Dole 1988). When these neurochemical changes are coupled with the subjective “high” provided by the drug and the behaviors associated with drug use, the brain’s internal reward system is functionally hijacked. The experience of the drug becomes the brain’s primary reward, resulting in compulsive drug use, the inability to cut down or discontinue use, and the ongoing use of drugs despite suffering negative consequences—the core manifestations of the disease of addiction. More important, these neurochemical and behavioral changes are not easily reversible. The purpose of opioid agonist treatment with buprenorphine (or methadone) is to stabilize these neurochemical changes in order to allow patients to engage in the longer-term work of recovery. These medications are not sufficient in themselves for patients to sustain recovery, but they are often essential for helping patients regain control of their lives and begin the recovery process. To many people, considering drug addiction as a medical disease needing medical treatment may seem misguided. Each individual has the choice

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whether or not to take a drug, and if he or she stops taking the drug, most of the problems associated with addiction will be resolved. Many people have used drugs in their lifetime but have not developed addiction. Others have developed problems but resolved them on their own or with minimal intervention. We do not usually consider it to be the person’s fault if a person develops a chronic disease. So, if it’s not the person’s fault that he or she developed a chronic addiction, how can we hold the individual responsible for working to improve the condition? As suggested by McLellan et al. (2000), addiction results from a complex interaction between an individual’s genetics, social and family contexts, and personal choices. I believe it is important to acknowledge up front for patients, their families, and other members of society that patients’ personal choices are instrumental not only in the development of drug addiction, but in achieving recovery as well. In my office, the take-home message for patients is: “It may not be 100% your fault that you became addicted, but it will be 100% your responsibility to achieve recovery. And we are here to help.” It is helpful to remember that personal choices similarly affect the development and course of medical diseases such as diabetes, hypertension, and asthma. Yet the responses from our society and the medical profession to people with addiction have been very different than the responses to patients with these other chronic medical illnesses. For example, who would suggest that patients with diabetes who go through a 5-day sugar detoxification program would be cured of their diabetes? Or that a patient with diabetes or hypertension should be discharged from care for noncompliance when they stop taking a medication or “relapse” to eating fast food or dessert again? In addition, a common characteristic of individuals with more severe and persistent forms of addiction is the presence of a co-occurring psychiatric disorder. These individuals are the least likely to achieve sobriety on their own, and typically require long-term comprehensive treatment for both their substance use disorder and their other psychiatric problems (see Chapter 9, “Psychiatric Comorbidity”). But, would a 30-day residential treatment program effectively prevent a patient from ever having problems with depression or schizophrenia in the future? As is the case with other chronic illnesses, short intensive treatments may be necessary at times, but when provided alone they usually have very little lasting impact on the course of addictive diseases. Patients will require ongoing care, and will cycle through periods in which control of their addiction improves or worsens. Therefore, managing addiction in the office setting requires the same ongoing monitoring and care needed for managing any other chronic medical or psychiatric condition. Fortunately, all of the steps that providers and staff usually take to help a patient get a chronic illness back under control, also help patients with poorly controlled addiction.

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CHRONIC DISEASE MANAGEMENT PRINCIPLES Following the induction and early stabilization phases of treatment, the principles used in managing chronic medical diseases are applicable to buprenorphine treatment: 1. Providers should schedule regular appointments, with visit intervals determined by how well the disease is controlled. Patients struggling to meet treatment goals need to be seen more often, whereas patients who have achieved long-term stability may be seen less often. 2. As with any medication for any condition, most visits begin with the process of reconciling the medication record and updating dosing information for all medications being prescribed. This is followed by reviewing the patient’s use of the medication to evaluate for compliance, effectiveness, safety, and side effects. Is the medication successfully suppressing withdrawal symptoms and craving? How often is the patient taking the medication during the day? Some providers allow patients to dose the medication at whatever interval they prefer as long as they do not exceed a designated daily dose. Other providers insist on once-daily dosing out of concern that multiple daily dosing may simulate drug abuse behaviors and may not be conducive to achieving recovery. Also ask whether there have been any days when the patient has gone without the medication or taken an extra dose. Is the patient experiencing any toxicity that would require an immediate intervention, such as sedation or cognitive impairment? Are there less serious side effects, such as constipation or sweating? And is the patient taking any medication that may interact with buprenorphine or put the patient at risk of impairment or overdose when taken in combination with buprenorphine? 3. The next step is to review to what degree each patient is meeting his or her treatment goals. In diabetes, a provider might review a blood glucose monitoring record or the most recent hemoglobin A1c level. In buprenorphine treatment, drug testing results provide an objective measure of the success of treatment. Abstinence is an essential component, but certainly not the only component of a patient’s recovery. Achieving stable employment, pursuing educational or vocational training opportunities, improving fulfillment of role responsibilities, improving interpersonal relationships, and resolving financial and legal issues all represent some of the important nonmedical outcomes of successful treatment. Improvements in comorbid conditions may also be critically important signs of treatment progress. For patients with co-occurring medical and/or psychiatric conditions, the stabilization of drug abuse may be the first essential step needed to facilitate the treatment of other coexisting conditions (see Chapter 9; Chapter 10,

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“Medical Management”; and Chapter 11, “Management of Acute and Chronic Pain”). As patients and providers integrate treatment for co-occurring disorders into the treatment goals, monitoring for progress in addiction treatment broadens to include monitoring for improvements in other related medical and psychiatric conditions. 4. As with any chronic condition, relapses should be anticipated and do not mean that the patient has failed or that the treatment is ineffective. Providers should pay careful attention to the language used to discuss relapse because patients can become very discouraged when relapse occurs. When providers remain optimistic about the potential for recovery it is much more likely that patients will as well. It is very useful to reframe the relapse episode as a learning opportunity, a chance to identify previously unrecognized high-risk situations or to expose weak elements in the treatment plan. Many patients in early sobriety fail to appreciate the range of changes and the intensity of effort needed to sustain true recovery. It may only be through brief lapses or relapses that patients are able to develop a truly effective recovery plan. It is often helpful for clinicians to point out at the beginning that lapses or relapses “may” occur and to stress the importance of a quick return to treatment while reinforcing the message that patients are always welcome to return despite a relapse. Patients need to learn that being honest about their struggle for recovery will be met with added support and respect and not rejection or disappointment. 5. Participation in nonpharmacological treatment modalities is a critical element in the recovery process. Few medical providers would consider treatment for diabetes or hypertension to be complete if it did not include regular attention to diet, exercise, and other behavioral changes that would positively affect the disease course. Most mental health clinicians recognize that medications are only one component of a comprehensive treatment plan for conditions such as depression or anxiety. Similarly, participation in behavioral treatment modalities is considered essential by most buprenorphine providers, and reviewing a patient’s participation in counseling and/ or 12-step recovery programs is a part of every visit. 6. Motivation enhancement techniques should be an essential component of every visit (see Chapter 8, “Clinical Management II”). In short, motivation enhancement therapy is a way of communicating with patients that helps to increase their motivation to make positive changes and reinforces to patients that they can effectively make those changes in their lives. As medical providers we often focus on what is wrong: abnormal laboratory test results, poorly controlled conditions, and the lack of improvement in patients’ conditions. This information is important, but patients often leave visits discouraged and with little hope or confidence that things will ever

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get better. The motivation enhancement approach reminds providers to recognize and highlight areas where patients have succeeded in making positive changes and to review how those changes were achieved. By reiterating and reinforcing what is working well, it becomes more likely that patients will repeat those productive behaviors. Other unique elements of monitoring buprenorphine treatment that warrant mentioning include dosing technique, dosage tapering, and maintaining safety of medication supplies; these topics are reviewed below.

DOSING TECHNIQUE When reviewing a patient’s buprenorphine dosage, it is important to carefully review the patient’s technique for taking the sublingual tablet. It is especially important to review dosing technique when patients request dose increases or complain that the medication “wears off ” or that the dose “just doesn’t hold me.” Patients unfamiliar with the unique sublingual dosing of buprenorphine, or who for other reasons end up swallowing the tablets or the liquid that forms in the mouth when the tablets first dissolve, receive only a fraction of the medication dose due to first-pass hepatic metabolism. When questioned carefully, patients may reveal that they swallow the sublingual tablets outright or take them with coffee or another beverage to dilute the bitter orange taste. Patients swallowing the sublingual tablets receive only a fraction of the sublingual dose; improving dosing technique may increase serum buprenorphine levels and eliminate the need for an increase in dosage.

TAPERING

THE

DOSAGE

Strategies for tapering buprenorphine doses are covered in Chapter 6, “Clinical Use of Buprenorphine.” In general, dosing levels and tapering plans should be a regular part of treatment planning, even though complete detoxification may not be the goal for many patients. Patients should be encouraged to work toward the lowest dosage that prevents withdrawal symptoms and relapse to drug use. As patients progress in treatment and gain greater degrees of psychosocial stability, it should be expected that they will need less medication to support their sobriety. This approach helps to minimize side effects, maximize cost-effectiveness at each stage of treatment, and encourage patients to actively pursue the skills and support networks they need to maintain recovery. Patients are more willing to attempt dose reductions if they understand that the schedule and amount of any dosage taper is under their control, and that they will have the opportunity to consider returning to the previous dosage should they experience difficulty at a lower dosage.

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MAINTAINING SAFETY

OF

MEDICATION SUPPLIES

As the number of patients receiving buprenorphine has expanded, so has the number of poisoning events due to accidental ingestion of the medication. Even though only a fraction of the medication is absorbed when chewed or swallowed, individuals without preexisting opioid tolerance can experience significant toxicity with oral administration, such as respiratory depression. Children are at particular risk for buprenorphine overdose because the tablets look and smell like orange candy, and children may suck on or hold tablets in their mouths, thus increasing the amount of medication absorbed. All patients should be reminded regularly to keep their medications out of the reach of children, preferably in a locked container or a safe.

Managing Problem Behaviors Time invested in reviewing treatment agreements, establishing strong therapeutic relationships, and developing clear treatment plans will prevent many problem behaviors. That being said, it is helpful to plan ahead and prepare providers and support staff to provide clear, consistent responses when problems do occur. In all situations, safety is the most important priority. Providers must respond immediately to any behavior that seriously compromises the safety of patients or those around them. For example, threatening behavior against other patients or staff, or criminal behavior such as selling drugs or forging prescriptions, would usually result in immediate dismissal. Short of serious safety concerns, however, it is important to remember that change is a process that happens gradually and often involves both steps forward and steps backward in order to make progress. Prompt, graded responses to less serious behaviors, coupled with motivation enhancement, will maintain safety and retain patients in treatment. Minimal problems, such as a missed counseling visit, may be easily managed by a focused discussion with the treating physician. A brief relapse may require a temporary increase in the frequency of monitoring visits and urine screens, and possibly a dosage adjustment. A more serious relapse may indicate the need for a major review of the treatment plan, with the addition of more counseling services and/or a significant increase in participation in mutual support groups, as described below. Problem behaviors fall into five general categories: 1. Violations of office policies, including inappropriate interactions with office staff, noncompliance with financial responsibilities associated with treatment, calling in to report lost or stolen medications, calls for early refills, and nonemergency calls after office hours

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2. Noncompliance with treatment plans, including unapproved increases in buprenorphine dosing, missed office appointments or missed visits with consultants, declining to allow communication with other treatment providers, failing to provide urine samples for drug screening, and failing to participate in behavioral treatment as requested 3. Continued use of opioids, including unapproved use of opioid pain medications 4. Abuse of nonopioid illegal drugs such as marijuana or cocaine, problem alcohol use, and unapproved use of other medications with abuse potential 5. Criminal behavior such as alteration of prescriptions, diversion of prescribed buprenorphine, selling or sharing other medications or illegal drugs, and theft. When problem behaviors arise that do not cause immediate safety concerns, it is important to verify and document the behavior, and review this information with the patient. Many clinicians begin by reviewing the details of the problematic behavior along with the treatment agreement and the most recent treatment plan to make sure that all parties have the same expectations and goals. Patients should also have the opportunity to tell their side of the story. In specialty behavioral and substance abuse treatment settings, it is common to implement a written behavior contract, which identifies the problem behavior, the expected remedy, the time period in which it is expected that the situation will be remedied, and the consequences if insufficient action is taken. In physicians’ offices where this formal process may be too time consuming, or with less serious problems, a verbal review of similar information documented in the progress note may be more practical. As with chronic illnesses such as diabetes or depression, when patients are nonadherent or not meeting treatment goals the most common responses are to increase monitoring and increase the intensity of treatment. Patients might be seen once or twice a week for a time, with more frequent drug screens and limited medication supplies. Providers can mandate participation in 12-step programs or other formal behavioral or psychiatric treatment. For patients struggling to stabilize substance abuse or mental health symptoms, participation in structured intensive outpatient programs or inpatient hospitalization may be required. It is important to explain that any increase in the intensity and requirements of treatment is not punitive and is primarily to ensure the patient’s ultimate success in treatment. Occasional opioid use during the first week or two of treatment is not unusual and may require a dosage adjustment, but it rarely implies a serious treatment problem. However, ongoing use of opioids should prompt a careful review of adherence to buprenorphine dosing, the adequacy of that dose, med-

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ication dosing technique, and the adequacy of counseling or other recovery activities. Relapses to opioid use after a period of stability typically occur in response to some unexpected stressor. A review of the circumstances may reveal some previously unidentified risk factors and suggest some needed improvements to the treatment plan. A temporary intensification of treatment services may be adequate to help the patient restore his or her previous level of functioning. Behavior associated with buprenorphine diversion should lead to increased frequency of visits and screening tests to monitor drug use, shortinterval prescriptions, and random callbacks to count the number of pills left in the patient’s bottle. It is not uncommon for some patients to stop all use of opioids (other than buprenorphine) but then present evidence of a new or intensified problem with alcohol or other drugs. These problems are best managed by counseling and participation in a 12-step program. Patients should be told that sobriety from all drugs of abuse is the goal of treatment and that the ongoing use or abuse of alcohol and other drugs is likely to undermine the success of their buprenorphine treatment program. That being said, occasional social drinking or marijuana use should not be grounds for the termination of buprenorphine treatment. Some patients may take months or even years to establish complete sobriety. The clinician should look for signs of progress toward full recovery and sobriety, but recognize that progress may be slow and occur at different rates with different substances. Unfortunately, ongoing problematic use of alcohol and benzodiazepines poses the additional risk of respiratory suppression, overdose, withdrawal, and seizures. Patients with problematic alcohol and/or benzodiazepine use may require referral for detoxification services. Failure to resolve problems with ongoing dependence on alcohol or other classes of drugs may require a review of the patient’s basic suitability for buprenorphine therapy or for office-based treatment. Ultimately, providers will need to weigh the risks and benefits of officebased treatment with buprenorphine for each patient and determine whether it is both safe and appropriate to continue. Except in the most unusual or extreme circumstances, termination of office-based buprenorphine treatment should be the last response to behavioral problems. However, providers must be realistic about the complexity of problems that they can manage in their office setting. Patients who cannot take or store buprenorphine safely, or who are engaged in criminal behavior, should be referred immediately to a higher level of care. Patients who, after a series of interventions to intensify treatment and monitoring, are unable to meet treatment goals or adhere to treatment expectations should also be referred to a higher level of care. Most commonly, patients doing poorly in office-based buprenorphine treatment are referred to higher-intensity specialty substance abuse services, such as inpatient detoxification centers,

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methadone maintenance treatment, and/or residential treatment programs. Continued buprenorphine treatment within the structure of a methadone program or a residential therapeutic community may also be an option for some patients. Questions often arise about how to transition patients to higher levels of care. Programs may have long waiting periods, and patients may be reluctant to change treatment modalities. Except in cases where there are serious safety concerns or criminal activity, it is important to avoid abruptly stopping treatment. The current standard of care is to provide patients, in writing, with the reasons why you are recommending the change in treatment, a warning about the potential for withdrawal symptoms and the risks associated with relapse to drug use, contact information for local substance abuse treatment centers, and a transitional supply of medication to cover the patient for a reasonable period of time while he or she is seeking other treatment. Alternatively, the medication can be tapered over the course of a few weeks and then discontinued. If a patient becomes unstable, admission to a detoxification center or other inpatient unit may be needed to ensure the patient’s safety and facilitate the beginning of another form of treatment. Patients should always be reminded to seek emergency care in case of crisis.

Screening for Drugs of Abuse Regular screening for opioids and other drugs of abuse is an essential component of office-based buprenorphine treatment. Although some patients may complain that drug screening feels like an invasion of privacy, others express appreciation for the monitoring and request that it be performed regularly. The manner in which drug screening is presented may impact how well it is accepted by patients. Include drug testing expectations in the initial treatment agreement, and use language that normalizes this testing as a standard part of monitoring for the safety and effectiveness of buprenorphine treatment. If concerns arise, comparisons to the management of other medical conditions may also help. No patient would have confidence in a physician’s care if he or she prescribed insulin without regularly checking blood glucose measurements and hemoglobin A 1c levels, or lithium without measuring serum lithium levels. Similarly, it would be irresponsible and unsafe to provide addiction treatment without monitoring for ongoing drug abuse.

BASIC DRUG SCREENING TECHNIQUES The two most commonly utilized methods for drug screening are immunoassays and gas chromatography–mass spectrometry (GC-MS) (Moeller et al. 2008). Drug screening in office-based buprenorphine treatment is most often

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performed using urine samples, although oral swabs for saliva testing are becoming more popular. Immunoassays work in the same way that dipstick pregnancy tests and rapid strep screens do. An antibody to the drug metabolite is linked to a color indicator and then bonded to elution paper. When the paper absorbs a liquid that contains drug metabolites, these metabolites bind to the antibodies and cause the indicator to change color, which represents a positive result. There are many benefits to this type of testing. Immunoassays are inexpensive, easy to perform, and can be used in many clinical settings including physicians’ offices and other outpatient treatment program settings. Specific tests have been developed for a number of opioids, including oxycodone, methadone, and buprenorphine.

INTERPRETING DRUG TEST RESULTS There are, however, a number of limitations to immunoassay drug testing. First, immunoassays are qualitative tests, providing only a positive or negative result. They provide no information about the level of drug metabolite in a sample, and only read positive when the amount of drug metabolite in the fluid tested reaches a certain threshold level, or cutoff. The cutoff for opioid metabolites is set quite high in many standard screens, meaning that a patient may demonstrate a false-negative result when lower levels of metabolite are present. Table 7–1 shows the threshold levels for drug metabolites used in U.S. Department of Transportation testing, and the average time it takes after drug use for the metabolites to be detected in urine. Cutoffs vary for commercial drug testing kits that are not used for testing under federal guidelines. Note that the cutoff levels for opioid metabolites are set quite high to prevent false-positive screening results from opiates found in low levels in some foods (e.g., poppy seeds). It is also possible to have false-positive results due to the presence of other substances and medications that cross-react with the components of the immunoassay. Table 7–2 lists some common substances that may cause false-positive immunoassay screening results. This list is not exhaustive; please see Manchikanti et al. 2008 and Moeller et al. 2008 for more detailed information. Providers should note that although many agents cross-react with the amphetamine screen, the metabolite for cocaine, benzoylecgonine, is unique. Only cocaine and medications that contain cocaine, and not other topical anesthetics, should cause a positive result. Most buprenorphine providers have mechanisms in place to follow up any questionable positive results by confirming or clearing them with GC-MS testing. Finally, it is important to recognize that standard opiate immunoassay screens detect only morphine and drugs that are metabolized to morphine: heroin, codeine, and all morphine products. Semisynthetic opioids such as the

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TABLE 7–1.

Federal workplace drug testing cutoff valuesa and detection time in urine Initial cutoff level Confirmatory Typical detection by immunoassay level by GC-MS time in urine (days) (ng/mL) (ng/mL)

Opioid metabolites (morphine, heroin) Cocaine metabolite (benzoylecgonine) Marijuana metabolite (∆-9-THC) Amphetamines Phencyclidine

2,000

2,000

2–3

300

150

2–4

50

15

3–30

1,000

500

2

25

25

8

Note. GC-MS=gas chromatography–mass spectrometry; ∆-9-THC=∆-9-tetrahydrocannabinol. aValues used in U.S. Department of Transportation testing. Source. Adapted from Moeller et al. 2008.

commonly abused pharmaceutical opioids oxycodone and hydrocodone occasionally, but not reliably, cross-react and give a positive opiate screening result. Specific testing should be done to detect semisynthetic opioids. Fully synthetic opioids, such as methadone and fentanyl, are not detected by standard opiate screens, and also require testing specifically for these agents. Similarly, buprenorphine is not detected in opiate screens. Providers should consider regular testing for buprenorphine but must order buprenorphine testing specifically and be sure to test for the buprenorphine metabolite norbuprenorphine to provide some objective evidence that patients are taking the medication on a regular basis. Table 7–3 lists the most prevalent metabolites of the most common opioid agents. These metabolites are noted specifically only if GC-MS testing is performed. Urine drug testing also presents a number of logistical issues that buprenorphine providers must consider: • • • •

Will testing be done on-site or at a referral laboratory? If testing is done on-site, will patients be observed while providing the samples to prevent substitution? Will other quality control measures such as urine temperature, specific gravity, and creatinine levels be available? By what mechanism, and in what circumstances, will screening immunoassays be sent for GC-MS confirmation?

Common substances and medications that may cause false-positive immunoassay results

Opiates

Benzodiazepines

Marijuana

Amphetamines

Phencyclidine

Dextromethorphan

Oxaprozin

Dronabinol

Bupropion

Dextromethorphan

Diphenhydraminea

Sertraline

Efavirenz

Chlorpromazine

Diphenhydramine

Quinine

Hemp-containing foods

Ephedrine

Doxylamine

Quinolones

NSAIDs

Phenylephrine

Ibuprofen

Rifampin

Proton pump inhibitors

Phenylpropanolamine

Imipramine

Verapamila

Riboflavin

Pseudoephedrine

Ketamine

Promethazine

Meperidine

Ranitidine

Tramadol

Selegiline

Venlafaxine

Trazodone Note. NSAIDs=nonsteroidal anti-inflammatory drugs. aFalse-positive result on methadone screen only. Source. Adapted from Moeller et al. 2008.

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TABLE 7–2.

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TABLE 7–3.

Common opioids and their most prevalent metabolites

Drug

Metabolites

Morphine

Morphine, morphine glucuronides

Heroin (diacetylmorphine)

6-Monoacetylmorphine, morphine

Codeine

Norcodeine, morphine

Oxycodone

Noroxycodone, oxymorphone, oxycodol

Hydrocodone

Norhydrocodone, hydromorphone, hydrocodol

Hydromorphone

Hydromorphone glucuronides

Buprenorphine

Norbuprenorphine, buprenorphine glucuronides

Methadone

EDDP

Meperidine

Normeperidine

Propoxyphene

Norpropoxyphene

Fentanyl

Norfentanyl

Note. EDDP=2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. Source. Adapted from Manchikanti et al. 2008; Nagar and Raffa 2008.

• • •

Will testing be done randomly, or only at the time of office visits? What will happen if the patient is found to have substituted a urine sample? How will patients pay for this monitoring if they are uninsured, or if their insurance does not pay for this service?

In any circumstance, it is helpful to develop relationships with a referral laboratory, preferably one with some experience in drug testing. Providers with links to hospital labs may be able to call on the hospital lab staff with questions. In many areas, there are private drug testing companies with professional toxicologists that will manage the entire testing process. Providers should monitor testing procedures, however, because many labs charge per item tested, and the cost of each screening can get quite high.

TESTING

FOR

BUPRENORPHINE

Testing procedures for buprenorphine deserve a quick final comment. Immunoassays that detect buprenorphine are available commercially, and have the same limitations as immunoassays for other substances. These tests can be managed in the office, but false-positive results are possible due to cross-reactivity with other

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substances, and false-negative results are possible if the level in the patient’s urine falls below the cutoff point. Many providers are using GC-MS testing to measure levels of buprenorphine and its primary metabolite, norbuprenorphine. Patients initiating buprenorphine treatment show higher levels of the parent compound buprenorphine, but patients who are taking the medication steadily should have levels of norbuprenorphine well above that of the parent compound. Very high levels of the unchanged parent compound with very low or absent levels of the metabolite may indicate that a patient has dissolved a tablet into the urine sample. Unfortunately, urine buprenorphine levels vary widely and there is no reliable way to determine how much buprenorphine a person is taking by looking at drug levels. This testing may be most helpful to identify patients who have no buprenorphine in their system, or to provide additional information in the evaluation of patients who are not meeting treatment goals or who complain of inadequate dosing.

Conclusion Treatment with buprenorphine in office-based settings is safe and effective, and has greatly expanded the availability of agonist treatment for opioid addiction at a time of critical need for additional treatment resources in this country. Most providers find that, with a bit of preparation, buprenorphine treatment integrates well into any office setting that is experienced in managing other chronic medical or psychiatric conditions. The tools and guidelines provided in this chapter are intended to help providers cultivate a therapeutic environment for treating opioid addiction that minimizes problem behaviors and optimizes treatment outcomes. Although offering this new treatment modality does require some additional effort and resources, I believe providers will find it well worth the effort to have such a positive impact on the lives of patients, families, and communities experiencing the consequences of opioid addiction.

Clinical Pearls • Opioid addiction shares many features with other chronic medical and psychiatric conditions and the principles used in managing chronic diseases in office-based settings are applicable to buprenorphine treatment. • Time invested in reviewing informed consent and treatment agreements, establishing strong therapeutic relationships, and developing clear treatment plans will prevent many problems. • We all learn from our mistakes—relapse is a part of the natural history of any chronic disease and should be considered as an

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opportunity to intensify treatment, review treatment goals, and develop new strategies for working toward sustained recovery. • Prompt, graded responses to problem behaviors coupled with motivation enhancement strategies and other behavioral treatment modalities will maintain safety and retain patients in treatment. • Regular screening for opioids and other drugs of abuse is an essential component of office-based buprenorphine treatment, but providers must consider the limitations of the different testing techniques when reviewing test results.

CASE 2 Mark is a married 45-year-old postal worker who comes to your office saying: “Someone told me you write for BUP.” He has been receiving methadone treatment for the last 5 years but has a new postal route and tells you: “I can’t make it to the clinic and keep my job. I’ve been on 120 mg of methadone and have been clean for the last 3 years.” He says you can call the clinic to verify that he has been compliant. “I have to be on time for work!” he adds. He does not attend Alcoholics Anonymous, Narcotics Anonymous, or any other supportive group meetings.

1. What steps are recommended to convert someone from methadone treatment to buprenorphine treatment? 2. If this patient recently converted to buprenorphine treatment under the care of a different physician but complains of the other prescriber’s “requirements,” would you feel comfortable prescribing buprenorphine? 3. What are your requirements (ancillary therapy/support in and out of your office), if any, of someone for whom you are prescribing buprenorphine?

♦ ♦





♦ ♦



Mark has been coming to your “BUP group” fairly consistently for the past 3 months. He had a positive test result for cocaine on his urine toxicology screen 2 weeks ago. He also missed coming to his group meeting last week.

1. Did you ask Mark to sign a treatment agreement when you took over his case? 2. Did you delineate your limits for exclusion from your practice? 3. Is this a rule violation? 4. Is this a clinical problem? 5. What will be your next step?

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References Bodenheimer T, Wagner EH, Grumbach K: Improving primary care for patients with chronic illness. JAMA 288:1775–1779, 2002a Bodenheimer T, Wagner EH, Grumbach K: Improving primary care for patients with chronic illness: the chronic care model, Part 2. JAMA. 288:1909–1914, 2002b Dole VP: Implications of methadone maintenance for theories of narcotic addiction. JAMA 260:3025–3029, 1988 Magura S, Rosenblum A: Leaving methadone treatment: lessons learned, lessons forgotten, lessons ignored. Mt Sinai J Med 68:62–74, 2001 Manchikanti L, Atluri S, Trescot AM, et al: Monitoring opioid adherence in chronic pain patients: tools, techniques, and utility. Pain Physician 11 (suppl):s155–s180, 2008 McLellan AT, Lewis DC, O’Brien CP, et al: Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284:1689–1695, 2000 Moeller KE, Lee KC, Kissack JC: Urine drug screening: practical guide for clinicians. Mayo Clin Proc 83:66–76, 2008 Nagar S, Raffa RB: Looking beyond the administered drug: metabolites of opioid analgesics. Current Clinical Practice 57 (suppl):s1–s8, 2008 National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction: Effective medical treatment of opiate addiction. JAMA 280:1936– 1943, 1998 Saitz R, Larson MJ, Labelle C, et al: The Case for Chronic Disease Management for Addiction. J Addict Med 2:55–65, 2008 Sees KL, Delucchi KL, Masson C, et al: Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA 283:1303–1310, 2000 Zanis DA, Woody GE: One-year mortality rates following methadone treatment discharge. Drug Alcohol Depend 52:257–260, 1998

8 Clinical Management II PSYCHOSOCIAL AND SUPPORTIVE TREATMENT Peter D. Friedmann, M.D., M.P.H. Patricia A. Cioe, M.S., R.N.P.

OPIOID DEPENDENCE is a complex behavioral disorder that affects multiple dimensions of a person’s life, so it is no surprise that its treatment is a complex, multidimensional intervention. Long-term recovery requires a level of commitment and effort that goes far beyond simple compliance with buprenorphine treatment, and experienced buprenorphine providers have learned that psychosocial counseling is an essential part of office-based treatment. Patients should be educated that buprenorphine alone is not enough, and that patients who participate in counseling have the best outcomes (Stein et al. 2005). The most successful patients typically invest in a range of therapeutic activities that include individual and/or group counseling and participation in self-help recovery programs. In this chapter, we give an overview of treatment options for ambulatory patients who receive office-based buprenorphine therapy. Counseling can take several forms; not all are equally effective, and even 147

148 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

evidence-based treatments are not effective for all patients at all times. So trial and error and multiple “doses of treatment” over a long period of time are often necessary to facilitate lasting behavioral change. A basic understanding of the available treatment options is essential to assist patients in achieving the most favorable outcomes. Cases are presented at the end of this chapter, including related questions for additional consideration. For discussion of these cases, please see Chapter 14, “Comments on the Case Vignettes.”

Professional Counseling Improves Outcome Research on the efficacy of psychosocial counseling for patients receiving methadone maintenance therapy first identified the relationship between treatment improvement and professional counseling (McLellan 1993). Patients who met with skilled professional counselors were shown to have better outcomes then those who met with untrained drug counselors. It was eventually determined that confrontational counseling, nonspecific drug counseling, and nonspecific psychotherapy are ineffective, whereas cognitive-behavioral therapy (CBT), contingency management, and other manual-guided behavioral therapies such as motivation enhancement therapy (MET), 12-step facilitation (TSF), and behavioral marital therapy are associated with significant improvements in treatment (Miller and Wilbourne 2002; O’Farrell and Fals-Stewart 2002). The largest and most scientifically rigorous random assignment trial comparing the effect of different types of psychosocial treatments in substance use disorders was Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity), funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Although this study focused on individuals with alcohol dependence and not opioid dependence, its findings are commonly accepted as relevant across the addictive disorders. Individuals in Project MATCH were randomly assigned to manual-guided individual CBT, MET, or TSF therapy. All of the subjects showed significant improvement, and the three counseling approaches were thought to be equally effective. Among buprenorphine-naloxone patients, receipt of any counseling has been associated with better treatment retention (Stein et al. 2005). However, the intensity of counseling might not matter. In a study of three levels of counseling intensity, patients randomly assigned to 40 minutes weekly did no better than those who received 20 minutes weekly (Fiellin et al. 2006), and those receiving less intensive counseling were more satisfied (Barry et al. 2007). Al-

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though counseling must be available to buprenorphine patients, 40% or more patients do not attend formal counseling (Finch et al. 2007), and many choose self-help groups only. Although existing research has not identified any one counseling approach as being the most effective, it supports the efficacy of a variety of manual-guided individual and group therapies as delivered by professionally trained therapists. We describe a number of these approaches below.

ASSESSMENT

FOR

PROFESSIONAL TREATMENT

Many treatment programs use the American Society of Addiction Medicine Patient Placement Criteria to determine the appropriate intensity of treatment services. These criteria assess patients’ severity of illness in six dimensions: 1. 2. 3. 4. 5. 6.

Acute intoxication/withdrawal potential Medical condition that may distract from or complicate recovery Comorbid emotional/behavioral problems Treatment acceptance and resistance (insight/compliance) Relapse potential (craving/history of relapses) Recovery environment (structured/supportive).

Arguably the most important dimensions for deciding on the setting and intensity of rehabilitative services are the comorbid emotional/behavioral problems and recovery environment. Comorbid emotional/behavioral problems, whether or not they fulfill the criteria for a psychiatric disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000), are endemic among substance-using patients. Recovery environment refers to whether the individual has a supportive place to live (i.e., a drug-free environment) and a structured daily routine (e.g., a job, school, or even attending daily Alcoholics Anonymous [AA] meetings). Often, patients with co-occurring disorders or unstable recovery environments require more intensive treatment settings such as intensive outpatient treatment/partial hospitalization (9–25 hours/week) or residential treatment. Patients with limited emotional/behavioral comorbidity, a structured daily routine, and a supportive environment can usually receive outpatient treatment (10 mm, or >5 mm in HIVpositive patients, at 48–72 hours after PPD skin testing) should be further tested for signs of active pulmonary or extrapulmonary infection and, if results are negative, should be considered or referred for treatment for LTBI. For patients exposed to bacillus Calmette-Guérin (BCV) vaccination, the test should be performed and

204 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

TABLE 10–2.

Medications used for treatment of HIV infection Medication

Class

Generic name

Other namesa

NNRTIs

delavirdine efavirenz etravirine nevirapine rilpivirine abacavir abacavir+lamivudine abacavir+lamivudine+zidovudine didanosine emtricitabine lamivudine lamivudine+zidovudine stavudine tenofovir DF tenofovir DF+emtricitabine zalcitabine zidovudine amprenavir atazanavir darunavir fosamprenavir indinavir lopinavir+ritonavir nelfinavir ritonavir saquinavir tipranavir enfuvirtide maraviroc

Rescriptor, DLV Sustiva, EFV Intelence, TMC125 Viramune, NVP TMC278 Ziagen, ABC Epzicom Trizivir Videx, Videx EC, ddI Emtriva, FTC Epivir, 3TC Combivir Zerit, d4T Viread, TDF Truvada Hivid, ddC Retrovir, AZT, ZDV Agenerase, APV Reyataz, ATV Prezista, DRV Lexiva, FPV Crixivan, IDV Kaletra, LPV/r Viracept, NFV Norvir, RTV Invirase, SQV Aptivus Fuzeon, T20 Selzentry, UK-427,857 SCH417690

NRTIs

Protease inhibitors

Entry inhibitors

vicriviroc Integrase inhibitors elvitegravir raltegravir Maturation inhibitor bevirimat Combination tenofovir DF+emtricitabine (NRTIs)+efavirenz (an NNRTI)

GS-9137 Isentress, MK-0518 PA-457 Atripla

Note. AZT=azidothymidine; ddC=dideoxycytidine; NNRTIs=nonnucleoside reverse transcriptase inhibitors; NRTIs=nucleoside reverse transcriptase inhibitors; tenofovir DF=tenofovir disoproxil fumarate; Videx EC=Videx enteric-coated (extended-release) capsules. aTrade

names, abbreviations, code designations.

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interpreted as it is for unvaccinated persons. For those with chest X-ray findings or other findings consistent with active infection, specialty referral to a pulmonologist and possible hospitalization need to occur as soon as possible. The goal of LTBI treatment is to prevent development or reactivation of active infection. Treatment of LTBI requires 9 months of administration of isoniazid (isonicotinic acid hydrazide; INH) 300 mg/day coupled with pyridoxine 10–50 mg/day to prevent the potential side effect of neuropathy. Patients should be followed throughout treatment for signs or symptoms of hepatotoxicity. If a patient’s liver function test results show enzyme levels increased to three times the upper limit of normal, therapy should be discontinued. Adherence to treatment is a common concern and directly observed therapy can be instituted as a means to increase treatment adherence. Methadone programs have been effective for linking opioid agonist treatment to INH chemoprophylaxis and increasing medication adherence (Batki et al. 2002; O’Connor et al. 1999). Though INH may decrease serum methadone levels, this interaction does not appear to be clinically significant (Raistrick et al. 1996). There are no published reports to date regarding buprenorphine treatment coupled with INH therapy for the treatment of LTBI.

Buprenorphine Treatment in Special Populations ADOLESCENT PATIENTS Limited data have been published on the use of buprenorphine in adolescent patients, and treatment protocols have mostly mimicked those protocols used in adults. Adolescent patients are often funneled into detoxification protocols rather than programs with longer-term maintenance strategies. However, a recent report has shown that adolescent patients receiving longer-term treatment (12 weeks) had improved outcomes compared with subjects randomly assigned to a 14-day detoxification strategy (Woody et al. 2008). Another issue to consider in this patient population is the involvement of parents in the overall treatment approach. In general, it is important to review state laws on parental consent before treatment of adolescent patients. Often, the approach should be individualized with regard to supervised dosing, parental involvement in doctor visits, and so on (see Chapter 12, “Opioid Use by Adolescents”).

GERIATRIC PATIENTS To date, there are no published data on the use of buprenorphine for the treatment of opioid dependence in patients over age 65 years. In fact, there is little

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known about the use of illicit substances in this population. Pain control in the elderly is an emerging area of study, and there is concern over appropriately defining prescription opioid misuse in this population. If buprenorphine treatment is considered, gradual dose escalation and monitoring for medication interactions and for transaminase elevations should be undertaken.

PREGNANT WOMEN In the United States, roughly 5,000–10,000 infants are born to opioid-dependent mothers annually. One major clinical concern is the development of neonatal abstinence syndrome, which occurs in 40%–95% of infants exposed to opioids in utero (Doberczak et al. 1991). There is substantial experience treating opioid-dependent pregnant patients with methadone and for this reason methadone remains the standard of care. The role of buprenorphine in the treatment of this population continues to emerge. Both methadone and buprenorphine are pregnancy category C drugs. Infants exposed to buprenorphine in utero seem to experience milder neonatal abstinence syndrome (Johnson et al. 2001). Because of the potential teratogenicity associated with naloxone, patients who become pregnant while receiving buprenorphinenaloxone treatment should be switched to either methadone or to the buprenorphine-only tablet during pregnancy. Pregnant, opioid-dependent patients should be comanaged with an obstetrician who has experience treating opioid-dependent patients (see “Buprenorphine and Pregnant Patients” in Chapter 12).

OTHER SPECIAL POPULATIONS In patients with renal insufficiency, buprenorphine levels are not altered and at present no dose adjustment is recommended (Elkader and Sproule 2005; Filitz et al. 2006). In patients with significant liver disease and transaminase levels greater than five times the upper limit of normal, the clinician should consider decreasing the dosage of buprenorphine or discontinuing its use and should refer the patient to a liver specialist (Saxon 2005). Cardiac arrhythmias have been noted in patients maintained with methadone and L -α-acetylmethadol (LAAM); however, there is no evidence to support that QTc interval prolongation occurs in patients taking buprenorphine (Baker et al. 2006).

Conclusion Patients with opioid dependence frequently have comorbid medical conditions, especially infectious diseases. Screening for and treatment of these comorbid conditions is of paramount importance in order to provide the best possible

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care for this patient population. Knowledge of these potential comorbid conditions is important for any clinician treating patients with opioid agonists. Office-based buprenorphine treatment allows for linkage of substance abuse treatment with comprehensive medical care. Use of buprenorphine to treat opioid dependence may need to be individualized in certain populations.

Clinical Pearls • Patients accepted for buprenorphine treatment should have a comprehensive history taken and a targeted physical examination as well as evaluation of urine toxicology and baseline liver function tests. • Clinicians treating patients with opioid agonist treatment should consider screening patients for HIV infection, hepatitis B, hepatitis C, tuberculosis, and syphilis, as well as offering immunizations against hepatitis A and B viruses, influenza, pneumonia, and tetanus, if appropriate. • Treatment modalities for hepatitis B, hepatitis C, and HIV infection are complex and continue to emerge. Physicians caring for patients with these comorbid conditions should have an understanding of potential treatment options and their potential interactions with buprenorphine. • Hepatitis B, hepatitis C, and HIV infection are not contraindications to office-based treatment with buprenorphine. • Adolescent, geriatric, and pregnant patients with opioid dependence may require an individualized treatment approach, and further guidance identifying proper strategies for the care of these special populations will likely emerge over time.

CASE 9 Ellie is a 56-year-old homeless woman who has been receiving buprenorphine therapy in your mental health clinic for the past 2 years. She had a “hard life on the streets” and was diagnosed with HCV infection 10 years ago. She has not considered doing anything about it because “nobody offered.” Her AST and ALT levels have been running at 1½ times the high-normal values. She says that she always has one drink a day and smokes one pack of cigarettes a day. She calls and says, “My eyes look kind of yellow, and I don’t feel so great....” You obtain lab test results that reveal AST and ALT levels are five times the highnormal value, with an AST:ALT ratio of greater than 1 and a total bilirubin level of 3 mg/dL (normal range, 0.3–1.9 mg/dL).

208 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

1. What are the possible causes of her jaundice? Is this likely to be related to her buprenorphine treatment? 2. Should you stop the buprenorphine treatment? 3. Would she be an appropriate candidate for interferon and ribavirin therapy? What is your mechanism for referral to a gastroenterologist?

References Advisory Committee on Immunization Practices: Recommended adult immunization schedule: United States, 2009. Ann Intern Med 150:40–44, 2009 American Thoracic Society: Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 49:1–51, 2000 Baker JR, Best AM, Pade PA, et al: Effect of buprenorphine and antiretroviral agents on the QT interval in opioid-dependent patients. Ann Pharmacother 40:392–396, 2006 Bartlett JG, Branson BM, Fenton K, et al: Opt-out testing for human immunodeficiency virus in the United States: progress and challenges. JAMA 300:945–951, 2008 Batki SL, Grube VA, Bradley JM, et al: A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users. Drug Alcohol Depend 66:283–293, 2002 Berson A, Fau D, Fornacciari R, et al: Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation (see comment). J Hepatol 34:261–269, 2001a Berson A, Gervais A, Cazals D, et al: Hepatitis after intravenous buprenorphine misuse in heroin addicts (see comment). J Hepatol 34:346–350, 2001b Bruce RD, Altice FL: Case series on the safe use of buprenorphine/naloxone in individuals with acute hepatitis C infection and abnormal hepatic liver transaminases. Am J Drug Alcohol Abuse 33:869–874, 2007 Carrieri MP, Vlahov D, Dellamonica P, et al: Use of buprenorphine in HIV-infected injection drug users: negligible impact on virologic response to HAART: the Manif2000 Study Group. Drug Alcohol Depend 60:51–54, 2000 Centers for Disease Control and Prevention: Guidelines for Viral Hepatitis Surveillance and Case Management. Atlanta, GA, Centers for Disease Control and Prevention, 2005. Available at: http://www.cdc.gov/hepatitis/SurveillanceGuidelines. htm. Accessed July 6, 2010. Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report: Cases of HIV Infection and AIDS in the United States and Dependent Areas, 2007. Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2007report/ default.htm. Accessed May 30, 2010. Centers for Disease Control and Prevention: False-positive oral fluid rapid HIV tests— New York City, 2005–2008. MMWR Morb Mortal Wkly Rep 57:660–665, 2008a Centers for Disease Control and Prevention: Hepatitis C Information for Health Professionals, July 8, 2008b. Available at: http://www.cdc.gov/hepatitis/HCV/ index.htm. Accessed January 8, 2009. Centers for Disease Control and Prevention: HIV Incidence, September 11, 2008c. Available at: http://www.cdc.gov/HIV/topics/surveillance/incidence.htm. Accessed May 30, 2010.

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Davis GL: Hepatitis B: diagnosis and treatment. South Med J 90:866–870; quiz 871, 1997 Dienstag JL: Hepatitis B virus infection (see comment). N Engl J Med 359:1486–1500, 2008 Doberczak TM, Kandall SR, Wilets I: Neonatal opiate abstinence syndrome in term and preterm infants. J Pediatr 118:933–937, 1991 Elkader A, Sproule B: Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet 44:661–680, 2005 Fattovich G, Brollo L, Giustina G, et al: Natural history and prognostic factors for chronic hepatitis type B. Gut 32:294–298, 1991 Fattovich G, Giustina G, Degos F, et al: Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients (see comment). Gastroenterology 112:463–472, 1997 Fiellin DA, O’Connor PG: Clinical practice: office-based treatment of opioid-dependent patients (see comment). N Engl J Med 347:817–823, 2002 Filitz J, Griessinger N, Sittl R, et al: Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine. Eur J Pain 10:743–748, 2006 Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975–982, 2002 Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone (see comment). N Engl J Med 349:949–958, 2003 Ganem D, Prince AM: Hepatitis B virus infection—natural history and clinical consequences (see comment; erratum). N Engl J Med 350:1118–1129, 2004 Garfein RS, Vlahov D, Galai N, et al: Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health 86:655–661, 1996 Gourevitch MN, Friedland GH: Interactions between methadone and medications used to treat HIV infection: a review. Mt Sinai J Med 67:429–436, 2000 Gowing LR, Farrell M, Bornemann R, et al: Brief report: methadone treatment of injecting opioid users for prevention of HIV infection. J Gen Intern Med 21:193– 195, 2006 Imperial JC: Natural history of chronic hepatitis B and C. J Gastroenterol Hepatol 14(suppl):S1–S5, 1999 Inglesby TV, Rai R, Astemborski J, et al: A prospective, community-based evaluation of liver enzymes in individuals with hepatitis C after drug use. Hepatology 29:590– 596, 1999 Johnson RE, Jones HE, Jasinski DR, et al: Buprenorphine treatment of pregnant opioid-dependent women: maternal and neonatal outcomes. Drug Alcohol Depend 63:97–103, 2001 Kuehn B: CDC recommends vaccine for smoking. JAMA 300:2713–2714, 2008 Lauer GM, Walker BD: Hepatitis C virus infection (see comment). N Engl J Med 345:41–52, 2001 Lee WM: Acute liver failure (see comment; erratum). N Engl J Med 329:1862–1872, 1993 Malik AH, Lee WM: Chronic hepatitis B virus infection: treatment strategies for the next millennium. Ann Intern Med 132:723–731, 2000 Manns MP, McHutchison JG, Gordon SC, et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958–965, 2001

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Mauss S, Berger F, Goelz J, et al: A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance. Hepatology 40:120–124, 2004 McCance-Katz EF, Moody DE, Morse GD, et al: Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend 91:269–278, 2007 Moatti JP, Carrieri MP, Spire B, et al: Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment: the Manif 2000 study group. AIDS 14:151–155, 2000 O’Connor PG, Shi JM, Henry S, et al: Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture for drug users in methadone maintenance. Addiction 94:1071–1075, 1999 Petry NM, Bickel WK, Piasecki D, et al: Elevated liver enzyme levels in opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict 9:265–269, 2000 Protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep 39:1–26, 1990 Raistrick D, Hay A, Wolff K: Methadone maintenance and tuberculosis treatment (see comment). BMJ 313:925–926, 1996 Recommendations from the National Institutes of Health consensus development conference statement: management of hepatitis C: 2002. Hepatology 36:1039, 2002 Saxon AJ: Monitoring of liver function tests and hepatitis in patients receiving buprenorphine/naloxone, in Physicians Clinical Support System–Buprenorphine (PCSS-B), Clinical Guidance. November 22, 2005. Available at: http:// www.pcssbuprenorphine.org/pcss/documents2/PCSS_Hepatitis_052307.pdf. Accessed May 7, 2010.] Sulkowski MS: Management of treatment-naive chronic HCV patients (online only), in Clinical Care Options (http://www.clinicaloptions.com/Hepatitis.aspx). Reston, VA, Clinical Care Options, May 18, 2007 Sullivan LE, Fiellin DA: Buprenorphine: its role in preventing HIV transmission and improving the care of HIV-infected patients with opioid dependence. Clin Infect Dis 41:891–896, 2005 Sullivan LE, Metzger DS, Fudala PJ, et al: Decreasing international HIV transmission: the role of expanding access to opioid agonist therapies for injection drug users. Addiction 100:150–158, 2005 Sullivan LE, Barry D, Moore BA, et al: A trial of integrated buprenorphine/naloxone and HIV clinical care. Clin Infect Dis 43 (suppl 4):S184–S190, 2006 Sullivan LE, Moore BA, Chawarski MC, et al:. Buprenorphine/naloxone treatment in primary care is associated with decreased human immunodeficiency virus risk behaviors. J Subst Abuse Treat 35:87–92, 2008 Sylvestre DL: Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend 67:117–123, 2002 Sylvestre DL, Clements BJ: Adherence to hepatitis C treatment in recovering heroin users maintained on methadone. Eur J Gastroenterol Hepatol 19:741–747, 2007 Walensky RP, Arbelaez C, Reichmann WM, et al: Revising expectations from rapid HIV tests in the emergency department (see comment; summary for patients). Ann Intern Med 149:153–160, 2008 Wasley A, Grytdal S, Gallagher K: Surveillance for acute viral hepatitis—United States, 2006. MMWR Surveill Summ 57:1–24, 2008

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Woody GE, Poole SA, Subramaniam G, et al: Extended vs short-term buprenorphinenaloxone for treatment of opioid-addicted youth: a randomized trial (see comment). JAMA 300:2003–2011, 2008 Younossi ZM: Viral hepatitis guide for practicing physicians: Cleveland Clinic of Medicine. Cleve Clin J Med 67 (suppl 1):SI6–SI45, 2000

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11 Management of Acute and Chronic Pain Daniel P. Alford, M.D., M.P.H., F.A.C.P.

ADEQUATE TREATMENT of pain is recognized as an essential dimension of quality medical care. Managing pain is complex when patients also have a history of addiction. Treatment of pain can be particularly challenging in a patient with opioid dependence who is receiving opioid agonist therapy (OAT) (i.e., methadone or buprenorphine) (Alford et al. 2006). Whereas nonopioid analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] and acetaminophen) are recommended for treating most pain, moderate to severe pain often requires the use of opioid analgesics. Some of the most often cited reasons for physicians not prescribing opioid analgesics are fear of causing cognitive and psychomotor side effects, fear of causing iatrogenic drug addiction, concerns about prescription drug diversion (Savage 1999), and concerns about regulatory scrutiny (Gallagher 2004). In this chapter, buprenorphine refers to either buprenorphine or to the buprenorphine-naloxone combination tablet unless otherwise specified. A common concern is that the use of opioid analgesics in patients receiving OAT may result in relapse to active drug use. There is no evidence that exposure to opioid analgesics in the presence of pain increases relapse in OAT pa213

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tients. A small retrospective study of methadone-maintained postsurgical patients who received opioid analgesics found no difference in relapse indicators when compared with matched methadone patients (Kantor et al. 1980). Similarly, no evidence of relapse was noted in six methadone-maintained patients treated with opioid analgesics for cancer pain (Manfredi et al. 2001). In fact, relapse prevention theories would suggest that the stress associated with unrelieved pain is more likely to be a trigger for relapse than adequate analgesia. This is supported by a study in which methadone maintenance patients stated that pain played a substantial role in their initiating and continuing illicit opioid use (Karasz et al. 2004). Physicians also express concerns regarding opioid analgesics causing severe respiratory or central nervous system (CNS) depression in patients maintained with OAT. Tolerance to the respiratory and CNS depressant effects of opioids occurs rapidly and reliably (Gutstein and Akil 2006). Cancer patients with worsening pain who require dose escalations typically do not exhibit respiratory and CNS depressant effects with the administration of additional opioids (Manfredi et al. 2001). It has been suggested that acute pain serves as a natural antagonist to opioid-associated respiratory and CNS depression (Eriator 1998). Therefore, the concern about severe drug toxicity with opioid analgesics in patients maintained with OAT is not supported by clinical or empirical experience. Not uncommonly, patients dependent on opioids are perceived by health care providers to be demanding when hospitalized with acute pain. This scenario develops in part because of the patients’ distrust of the medical community, concern about being stigmatized, and fears that their pain will be undertreated or that their OAT may be altered or discontinued (Merrill et al. 2002). Patients’ anxiety related to these concerns, which can be profound and well founded, can complicate provision of adequate pain relief. Physicians’ concern that they are being manipulated by drug-seeking patients is difficult to quantify and is emotion laden. Pain is always subjective, making assessment of its presence and severity difficult. During an initial assessment it is difficult, if not impossible, to differentiate between inappropriate drug-seeking and appropriate pain relief–seeking behaviors. A careful clinical assessment for objective evidence of pain decreases the chance of being manipulated by a drug-seeking patient, and supports the use of opioid analgesics in patients with a history of opioid dependence. It is important to remember that patients maintained with OAT are typically receiving opioid maintenance doses that block the euphoric effects of coadministered opioids, theoretically decreasing the likelihood of opioid analgesic abuse. Complicating the use of opioids in managing pain is the confusing and often misunderstood terminology used in pain management and addiction medicine. Physical dependence and tolerance are typical and predictable physiological

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consequences of opioid exposure. These terms, in and of themselves, do not indicate maladaptive behaviors and do not meet the diagnostic criteria of substance dependence in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) without, for example, loss of control or continued use despite harm. Pain medicine specialists and addiction treatment providers commonly operate in separate spheres without much communication or collaboration. The well-described interplay between addiction and pain calls into question this artificial separation. In this chapter, I cover the epidemiology and neurobiology of pain in patients with opioid dependence. I also discuss buprenorphine analgesic pharmacology and review acute and chronic pain management in patients on buprenorphine maintenance therapy. Cases are presented at the end of this chapter, including related questions for additional consideration. For discussion of these cases, please see Chapter 14, “Comments on the Case Vignettes.”

Epidemiology and Neurobiology Pain is common in patients with opioid dependence and those maintained with OAT. One survey reported that 52% of 228 treatment-seeking, opioid-dependent veterans complained of moderate to very severe pain lasting more than 30 days (Trafton et al. 2004). Two cross-sectional surveys suggest that among patients receiving methadone maintenance therapy, the prevalence of chronic pain ranges from 37% to 61% (Jamison et al. 2000; Rosenblum et al. 2003). There are no comparable data for patients receiving buprenorphine maintenance therapy. The clinical conditions of pain and opioid dependence are not unrelated phenomena. Martin and Inglis observed over 40 years ago that self-medicating patients with opioid addiction have “an abnormally low tolerance for painful stimuli” (Martin and Inglis 1965). Opioids, whether administered with analgesic or addictive intent, activate opioid receptors, which provide both analgesia and reward (Compton and Gebhart 2003). The presence of one condition appears to influence the expression of the other. Clinical examples of this include 1) how the presence of acute pain appears to decrease the euphorigenic (pleasurable) qualities of the opioid, and 2) how the presence of addictive disease appears to worsen the experience of pain (Zacny et al. 1996). Regarding the latter, researchers identified over a decade ago that persons with addiction and pain have a “syndrome of pain facilitation” (Savage and Schofferman 1995). Their pain experience is worsened by subtle withdrawal syndromes, intoxication, withdrawal-related sympathetic nervous system arousal, sleep disturbances, and affective changes, all consequences of addictive disease. Supporting a negative effect of addiction on pain tolerance, both stimulant and

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opioid abusers have been shown to be less pain tolerant than peers in remission (Compton 1994).

Buprenorphine Pharmacology Since the 1970s, buprenorphine has been available worldwide as a parenteral and sublingual analgesic. Buprenorphine is a partial opioid agonist at the µ receptor, resulting in supraspinal analgesia, euphoria, miosis, respiratory depression, and decreased gastrointestinal motility. It is also an antagonist at the κ receptor, resulting in limited spinal analgesia, sedation, and dysphoria. Although a ceiling effect on respiratory depression has been demonstrated, there are conflicting data on whether an analgesic ceiling effect exists in animal models, and there are no published data indicating an analgesic ceiling in humans (Cowan 2007). This is in contrast to full opioid agonists (e.g., morphine, oxycodone, methadone), which have no analgesic or respiratory ceiling effect. Buprenorphine’s high affinity at the µ receptor makes it difficult to displace. This effectively blocks the analgesic properties of other coadministered opioid analgesics and also risks displacement of previously administered opioid analgesics. Buprenorphine’s slow dissociation from the µ receptor gives it a relatively long serum half-life and induces a more mild withdrawal. In opioid-naive individuals, sublingual buprenorphine doses of 0.2–0.6 mg provide effective analgesia for postoperative pain, lasting 6–8 hours (Johnson et al. 2005). For opioiddependent and thus tolerant individuals, it is unclear what degree of analgesia is obtained from sublingual buprenorphine and what the optimal dosage for acute pain would be. Pharmacological explanations account for why opioid-dependent patients do not receive adequate analgesia from maintenance buprenorphine therapy prescribed for addiction treatment. Not only do the analgesic and addiction treatment profiles of buprenorphine differ, the neuroplastic changes associated with chronic opioid exposure (i.e., tolerance) may effectively diminish its analgesic effectiveness (White 2004). Buprenorphine’s duration of action for analgesia (6–8 hours) is substantially shorter than its suppression of opioid withdrawal and craving (24–48 hours) (Johnson et al. 2005). Because buprenorphine is usually dosed every 24 hours, the period of even partial pain relief with this medication is small. Tolerance is another factor why these patients derive little analgesia from maintenance buprenorphine therapy. Analgesic tolerance develops for different medications within the opioid class, a phenomenon referred to as cross-tolerance (Collett 1998). Doverty and colleagues (2001) found patients receiving methadone maintenance therapy to be cross-tolerant to the analgesic effects of morphine, and when analgesia was obtained its duration was shorter than expected. Therefore, cross-tolerance between the opi-

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oids used for maintenance therapy and other opioids used for analgesia may explain why patients maintained with OAT often require higher and more frequent doses of opioid analgesics to achieve adequate pain control.

Pain Assessment Because of the complex interplay between pain and addiction, a comprehensive clinical approach to patients with dependence disorders is needed. As with all patients, self-reporting remains the gold standard for assessing pain. Although a number of clinical pain assessment measures exist, none have been validated specifically in patients with addiction disorders, in which anxiety, fear, past experiences, and other psychological elements may impact pain ratings. Simple scales provide estimates of an individual’s intensity of pain cross-sectionally and can be used longitudinally to measure the impact of interventions targeting pain. On a 10-point scale mild pain is typically considered equivalent to a selfreported level of 1–3, moderate pain is in the range of 4–7, and severe pain is anything greater than that (Turk and Melzack 2001). To understand the impact of chronic pain on function, measures such as the Brief Pain Inventory can be used (Tan et al. 2004). In addition, physicians should obtain information and results from prior pain evaluations, including imaging and other testing, treatments tried, past psychiatric therapy, and the impact of these prior interventions on pain and functional abilities.

Acute Pain Management The appropriate treatment of acute pain in patients receiving OAT (i.e., methadone, buprenorphine) includes uninterrupted OAT equivalence to address the patient’s baseline opioid requirement for addiction treatment and aggressive pain management. As with all patients with chronic pain, nonpharmacological and nonopioid pain treatments should be aggressively implemented. However, moderate to severe acute pain often requires opioid analgesics. Literature suggests that undertreating acute pain may lead to decreased responsiveness to opioid analgesics, thus making subsequent pain control more difficult (Mao et al. 1995). To decrease the total amount of opioid given to these patients, multimodal analgesia (e.g., NSAIDs, acetaminophen) and adjuvant analgesics (e.g., antidepressants, anticonvulsants) that enhance opioid effects may be coadministered (Kehlet and Dahl 1993). Continuing the patient’s baseline opioid requirements avoids worsening pain symptoms due to the increased pain sensitivity associated with opioid withdrawal. Thus daily opioid treatment requirements, or the patient’s opioid debt, must be met before attempting to achieve analgesia (Peng et al. 2005). To decrease patients’ anxiety, clinicians should re-

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assure them that their opioid addiction treatment will continue and that their pain will be aggressively treated. Considering the increased pain sensitivity and cross-tolerance with OAT, adequate pain control generally necessitates higher opioid doses at shorter dosing intervals. Analgesic dosing should be continuous or scheduled rather than on an as-needed basis. Allowing pain to reemerge before administering the next dose causes unnecessary suffering and anxiety, and increases tension between the patient and treatment team. Empirical data on the use of patient-controlled analgesia in patients with substance dependence and acute pain are limited. Paige and colleagues (1994) reported that although women receiving methadone maintenance therapy had higher pain scores after cesarean section surgery, there was no statistically significant difference in opioid analgesic usage compared with control subjects. Clinical experience supports consideration of using patient-controlled analgesia in patients receiving OAT; increased patient control over analgesia minimizes patient anxiety over pain management. The pharmacological properties of opioids must be considered when selecting an opioid analgesic for a patient receiving OAT. Although opioids bind to multiple subtypes of opioid receptors in the CNS, binding to the µ receptor subtype is primarily responsible for the analgesic effect. Mixed agonist-antagonist opioid analgesics such as pentazocine (Talwin), nalbuphine (Nubain), and butorphanol (Stadol) must be avoided because they are likely to displace the maintenance opioid from the µ receptor, thus precipitating acute opioid withdrawal in patients receiving OAT (Scimeca et al. 2000). Opioid analgesic combination products containing fixed doses of acetaminophen and an opioid (e.g., Percocet, Vicodin) should be limited to situations not requiring large doses so as to avoid acetaminophen-induced hepatic toxicity. Alternatively, one could prescribe each medication individually at appropriate doses to achieve the desired analgesic effect and avoid hepatic damage. Clinical experience treating acute pain in patients maintained with buprenorphine is limited. Pain treatment with concurrent opioid analgesics is complicated by buprenorphine’s high affinity for the µ receptor. This high affinity risks displacement of, or competition with, full opioid agonist analgesics when administered concurrently or sequentially. However, animal studies have demonstrated additive analgesic effects when combining a full opioid agonist (e.g., morphine, oxycodone) with buprenorphine (Kogel et al. 2005). Several possible approaches exist for treating acute pain requiring opioid analgesia in patients receiving buprenorphine therapy. With such limited clinical experience, the following treatment approaches are based on the available literature, pharmacological principles, and published recommendations (Alford et al. 2006). The most effective approach will be elucidated with increased clinical experience. In all cases, due to highly variable rates of buprenorphine dissociation from the µ receptor, the opioid antagonist naloxone should be

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available, and the level of consciousness and respiration should be monitored frequently. 1. Continue buprenorphine maintenance therapy and titrate a short-acting opioid analgesic to effect. Because higher doses of full opioid agonist analgesics may be required to compete with buprenorphine at the µ receptor, caution should be taken if the patient’s buprenorphine maintenance therapy is abruptly discontinued. Increased sensitivity to the full opioid agonist with respect to CNS and respiratory depression could occur. 2. Divide the buprenorphine daily dose and administer every 6–8 hours to take advantage of its analgesic properties. For example, for buprenorphine 24 mg daily, the split dose would be 8 mg every 8 hours. Because of the apparent lack of analgesic ceiling effect and the presence of a respiratory depression ceiling effect, it is possible to safely administer additional buprenorphine (i.e., parenterally or sublingually) to the patient’s maintenance dose to treat acute pain. One case report described analgesic benefit of time-limited supplemental doses of sublingual buprenorphine of up to 72 mg for acute pain (Book et al. 2007). 3. Discontinue buprenorphine and treat with scheduled full opioid agonist analgesics by titrating to effect to avoid withdrawal and then to achieve analgesia (e.g., sustained-release and immediate-release morphine). With resolution of the acute pain, discontinue the full opioid agonist analgesics, and resume buprenorphine maintenance using an induction protocol. 4. If the patient is hospitalized in acute pain, the patient’s baseline opioid requirement can be managed and thus opioid withdrawal prevented by converting buprenorphine therapy to methadone 30–40 mg daily. Methadone at this dosage will prevent acute withdrawal in most patients, and compared with buprenorphine, binds less tightly to the µ receptor. Thus, responses to additional opioid agonist analgesics will be as expected (i.e., increasing doses will provide increased analgesia). It is recommended that short-acting opioid analgesics be used for easy titration. If opioid withdrawal persists, subsequent daily methadone doses can be increased in 5to 10-mg increments. This method allows titration of opioid agonist analgesics for pain control in the absence of opioid withdrawal. When the acute pain resolves, discontinue the opioid agonist analgesics and methadone, and resume buprenorphine maintenance using an induction protocol. If hospital discharge occurs while opioid agonist analgesics are still required, then discontinue methadone and treat as stated in the third buprenorphine approach above. If buprenorphine therapy needs to be restarted following acute pain management (i.e., third and fourth approaches), it is important to keep in mind that

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buprenorphine induction can precipitate opioid withdrawal. Thus, in a patient receiving a full opioid agonist regularly, the patient should be in mild opioid withdrawal before restarting buprenorphine therapy.

Chronic Pain Management The management of chronic pain in patients receiving OAT is complex. Outcomes in chronic pain management are frequently expressed in terms of improved quality of life and function. Improvements in physical capabilities, social interactions, and health care utilization have been variously used as indicators of good chronic pain management. Similarly, management of chronic pain in patients receiving OAT should be reflected by improved functionality in these domains. It is in the context of well-treated addiction that good pain management outcomes can be expected. Of note, interventions known to improve chronic pain are similar to those effective in managing addiction (e.g., cognitive therapy, behavior modification, involvement of family, treatment of concurrent psychological or psychiatric problems, stress management, and group support). The positive effects of various types of interventions on both chronic pain and addiction suggest that exposure to these types of interventions in either context would yield improvements in the other. Patients maintained with buprenorphine can be managed using nonpharmacological interventions (e.g., acupuncture, cognitive-behavioral therapy, massage, relaxation, physical therapy) and/or nonopioid medications (e.g., acetaminophen, NSAIDs, antidepressants, anticonvulsants). Although methadone-maintained patients with chronic pain may benefit from concurrent treatment with sustained-release opioid analgesics, this approach is not possible with buprenorphine treatment. Buprenorphine’s high µ receptor affinity makes it difficult, if not impossible, to manage chronic pain with concurrent full opioid agonist analgesics. However, due to its inherent analgesic properties, buprenorphine could be dosed every 6–8 hours to treat both opioid dependence (an onlabel indication—i.e., one that is within U.S. Food and Drug Administration– approved drug labeling) and pain (an off-label indication). Malinoff and colleagues (2005) reported that 86% of patients treated with divided doses of sublingual buprenorphine (mean dosage, 8 mg/day) had moderate to substantial pain relief along with improved mood and function. If a patient receiving buprenorphine maintenance therapy requires a full opioid agonist for adequate treatment of chronic pain, the patient must discontinue buprenorphine maintenance treatment. Before taking this step, the physician and patient together need to weigh the risks and benefits of this approach: 1) the risks of prescription medication abuse and potential relapse to drug use without buprenorphine versus 2) the potential improvements in pain and function that might be

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gained from treatment with a full opioid agonist. Alternatively, the patient could be transferred to an opioid treatment program (OTP) for methadone maintenance treatment of his or her addiction, which would allow the patient to receive concurrent opioid analgesic treatment of his or her chronic pain.

Conclusion Addiction elicits neurophysiological, behavioral, and social responses that worsen the pain experience and complicate the provision of adequate analgesia. Treating acute and chronic pain in patients receiving OAT (i.e., methadone, buprenorphine) can be clinically challenging. Patients with a history of opioid dependence most likely experience acute and chronic pain differently than other patients. Moreover, OAT with the drug taken once a day does not provide analgesia to patients in acute or chronic pain. Because of opioid cross-tolerance and increased pain sensitivity in these patients, opioid analgesics often need to be administered in higher doses and at shortened intervals. In treating acute pain in patients receiving buprenorphine maintenance therapy, the clinician should provide 1) reassurance regarding uninterrupted OAT equivalence in order to avoid opioid withdrawal and 2) reassurance regarding aggressive pain management, including patient-controlled analgesia to mitigate patient anxiety and facilitate successful treatment of pain. For patients maintained with buprenorphine who have chronic pain, nonopioid analgesics and nonpharmacological approaches should be tried. If chronic opioid use is required, splitting the buprenorphine dose or transferring the patient to an OTP so the patient can receive methadone maintenance therapy with conconcurrent opioid analgesics may be required.

Clinical Pearls Acute pain management • Reassure the patient that his or her addiction history will not prevent adequate pain management. • Continue the usual or equivalent dose of OAT to avoid opioid withdrawal. • Relieve patient anxiety by discussing, in a nonjudgmental manner, the plan for pain management. •

Try nonopioids and nonpharmacological strategies.

If opioids analgesics are required: • Cross-tolerance will necessitate higher doses at shorter intervals.

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• Prescribe continuous scheduled dosing rather than writing “prn” orders. • Avoid using mixed agonist-antagonist opioids because they will precipitate an acute withdrawal syndrome. Option 1 • Continue buprenorphine maintenance therapy. • Use concurrent short-acting opioid analgesics. Option 2 • Divide the buprenorphine daily dose to take advantage of the drug’s analgesic properties. • You may increase the usual maintenance dosage to achieve increased analgesia. • Return to the usual daily maintenance dosage when pain resolves. Option 3 • Discontinue buprenorphine and treat the patient with scheduled full opioid agonist analgesics by titrating to effect to avoid withdrawal and then to achieve analgesia. • Convert therapy back to buprenorphine when acute pain resolves. Option 4 (if patient is hospitalized) • Convert therapy from buprenorphine to methadone (30– 40 mg/day) to treat opioid dependence. • Use concurrent short-acting opioid analgesics. • Naloxone (Narcan) at bedside. • Convert therapy back to buprenorphine before discharge. Chronic pain management • Try nonopioids and nonpharmacological strategies. If opioid analgesics are required: Option 1 • Divide the daily buprenorphine dose to use every 6- to 8-hour dosing. Option 2 • Refer the patient to an OTP for methadone maintenance therapy to treat opioid dependence and treat chronic pain with sustained-release opioid analgesics.

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CHAPTER 8)

Martha, the 35-year-old woman who had trouble reconciling her 12-step program and taking buprenorphine, eventually found them mutually inclusive; she has continued as an active member of Alcoholics Anonymous and is taking 16 mg of buprenorphine per day. She now needs her gallbladder removed; her surgeon calls asking for help managing her medication during the perioperative period. He expects her to be hospitalized for 2 days and to have pain for a week to 10 days.

1. What are the recommendations for the perioperative pain management of a patient taking buprenorphine? 2. Do you have to taper doses until the buprenorphine is completely discontinued? 3. If you taper down to completely discontinue buprenorphine, how do you cross over to another opioid? 4. How do you use methadone in the perioperative period? 5. If the patient is pregnant, what are the recommendations about buprenorphine and pregnancy? (See Chapter 10, “Medical Management,” section “Pregnant Women.”)

CASE 10 Fred is a 44-year-old senior noncommissioned officer who was injured in Iraq by an improvised explosive device 4 years ago and has residual chronic lower extremity and low back pain. He was treated through pain management services at a Veterans Administration medical center with a complicated course that included trials of opioid, nonopioid, regional block, and physical treatments. During the course of treatment, he became addicted to opioids and was eventually referred for buprenorphine treatment. He has achieved excellent control of his opioid problem and “tolerable” control of his pain with sublingual buprenorphine 8 mg/naloxone 2 mg three times a day. He is now successfully pursuing a master of business administration degree. He calls from the emergency department (ED) and tells you that he fell and reinjured his leg. The ED physician wants to prescribe some additional pain medication.

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

What would be the strategies for addressing acute pain in this client? What are the available nonopioid therapies? What are the available nonpharmacological therapies? When do you seek collaboration with other specialists? Does buprenorphine provide adequate pain relief? Compare and contrast strategies for treating pain in the context of agonist maintenance treatment.

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References Alford DP, Compton P, Samet JH: Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 144:127– 134, 2006 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Book SW, Myrick H, Malcolm R, et al: Buprenorphine for postoperative pain following general surgery in a buprenorphine-maintained patient (letter). Am J Psychiatry 164:979, 2007 Collett BJ: Opioid tolerance: the clinical perspective. Br J Anaesth 81:58–68, 1998 Compton MA: Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. J Pain Symptom Manage 9:462–473, 1994 Compton P, Gebhart G: The neurophysiology and pain and addiction, in Principles of Addiction, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Annapolis, MD, American Society of Addiction Medicine, 2003, pp 1385– 1404 Cowan A: Buprenorphine: the basic pharmacology revisited. J Addict Med 1:68–72, 2007 Doverty M, White JM, Somogyi AA, et al: Hyperalgesic responses in methadone maintenance patients. Pain 90:91–96, 2001 Eriator I: Narcotic analgesics for chronic pain management. Curr Pain Headache Rep 2:193–200, 1998 Gallagher R: Opioids in chronic pain management: navigating the clinical and regulatory challenges. J Fam Pract 53:S23–S32, 2004 Gutstein HB, Akil H: Opioid analgesics, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th Edition. Edited by Brunton LL, Lazo JS, Parker KL. New York, McGraw-Hill, 2006, pp 547–590 Jamison RN, Kauffman J, Katz NP: Characteristics of methadone maintenance patients with chronic pain. J Pain Symptom Manage 19:53–62, 2000 Johnson RE, Fudala PJ, Payne R: Buprenorphine: considerations for pain management. J Pain Symptom Manage 29:297–326, 2005 Kantor TG, Cantor R, Tom E: A study of hospitalized surgical patients on methadone maintenance. Drug Alcohol Depend 6:163–173, 1980 Karasz A, Zallman L, Berg K, et al: The experience of chronic severe pain in patients undergoing methadone maintenance treatment. J Pain Symptom Manage 28:517– 525, 2004 Kehlet H, Dahl JB: The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 77:1048–1056, 1993 Kogel B, Christoph T, Strabburger W, et al: Interaction of the µ-opioid receptor agonist and antagonists with the analgesic effect of buprenorphine in mice. Eur J Pain 9:599–611, 2005 Malinoff HL, Barkin RL, Wilson G: Sublingual buprenorphine is effective in the treatment of chronic pain syndrome. Am J Ther 12:379–384, 2005 Manfredi PL, Gonzales GR, Cheville AL, et al: Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy. J Pain Symptom Manage 21:169–174, 2001

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Mao J, Price DD, Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 62:259–274, 1995 Martin JE, Inglis J: Pain tolerance and narcotic addiction. Br J Soc Clin Psychol 4:224– 229, 1965 Merrill JO, Rhodes LA, Deyo RA, et al: Mutual mistrust in the medical care of drug users: the keys to the “narc” cabinet. J Gen Intern Med 17:327–333, 2002 Paige D, Proble L, Watrous G, et al: PCA use in cocaine using patients: a pilot study. American Journal of Pain Management 4:101–105, 1994 Peng PW, Tumber PS, Gourlay D: Review article: perioperative pain management of patients on methadone therapy. Can J Anaesth 52:513–523, 2005 Rosenblum A, Joseph H, Fong C, et al: Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 289:2370–2378, 2003 Savage SR: Opioid use in the management of chronic pain. Med Clin North Am 83:761–786, 1999 Savage SR, Schofferman J: Pharmacological therapies of pain in drug and alcohol addictions, in Pharmacological Therapies for Drug and Alcohol Addictions. Edited by Miller N, Gold M. New York, Marcel Dekker, 1995, pp 373–409 Scimeca MM, Savage SR, Portenoy R, et al: Treatment of pain in methadone-maintained patients. Mt Sinai J Med 67:412–422, 2000 Tan G, Jensen MP, Thornby JI, et al: Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain 5:133–137, 2004 Trafton JA, Oliva EM, Horst DA, et al: Treatment needs associated with pain in substance use disorder patients: implications for concurrent treatment. Drug Alcohol Depend 73:23–31, 2004 Turk DC, Melzack R (eds): Handbook on Pain Assessment, 2nd Edition. New York, Guilford, 2001 White JM: Pleasure into pain: the consequences of long-term opioid use. Addict Behav 29:1311–1324, 2004 Zacny JP, McKay MA, Toledano AY, et al: The effects of a cold-water immersion stressor on the reinforcing and subjective effects of fentanyl in healthy volunteers. Drug Alcohol Depend 42:133–142, 1996

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12 Opioid Use by Adolescents Ximena Sanchez-Samper, M.D. Sharon Levy, M.D., M.P.H.

SCREENING FOR ALCOHOL abuse and illicit drug use needs to be a standard procedure in any practice that cares for adolescents and young adults. Recent national surveys indicate that prescription pain relievers have replaced marijuana as the most common entry drugs for adolescents beginning to experiment with drugs. In this chapter, we review appropriate screening tools and management approaches for use in this population. We cover standard treatment options with a focus on the treatment of adolescents dependent on heroin or opioid pharmaceuticals and the promising role of buprenorphine in the treatment of this high-risk population. A case is presented at the end of this chapter, including related questions for additional consideration. For discussion of this case, please see Chapter 14, “Comments on the Case Vignettes.”

Epidemiology Opioid abuse among adolescents is a growing problem in the United States. According to data from the National Institute on Drug Abuse’s Monitoring the 227

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Future study, use of “narcotics other than heroin” has doubled among high school students since the year 2000, with marked increases in the use of longacting oxycodone tablets and hydrocodone-acetaminophen combination tablets. In 2007, the annual prevalence for oxycodone and hydrocodone use reached its highest level since these data have been collected, with 1.8%, 3.9%, and 5.2% of eighth, tenth, and twelfth graders, respectively, reporting oxycodone use in the past year and 2.7%, 7.2%, and 9.6% of them, respectively, reporting hydrocodone use in the past year (Johnston et al. 2007). Past-year heroin use without a needle also increased among high school seniors, rising from 0.6% in 2006 to 1.0% in 2007. Survey results also indicate an increased perception of availability, decreased social disapproval, and a decreased perception of risk associated with using opioids; all of these factors suggest that opioid misuse continues to be on the rise (Boyd et al. 2006; Johnston et al. 2007). These reports likely underestimate actual prevalence because data are collected only from teenagers in school on the day of the survey; teens with high rates of absenteeism and those who drop out of school are an even higher-risk group. Teenagers may not fully appreciate the risks of misusing prescription opioids because these drugs are legal and easily accessible (Boyd et al. 2006). Many adolescents who misuse opioids to get high may quickly become addicted and transition to heroin use when they can no longer afford the street price of opioid medications. A decrease in the price of heroin has increased accessibility to teens, and an increase in purity has allowed for nonintravenous administration, which has made the drug more attractive to adolescents (Hopfer et al. 2003). As a result, use of heroin by adolescents has increased substantially and is currently at its highest level since the heroin epidemic of the 1960s (Hughes and Rieche 1995; Johnston et al. 2009). Heroin-related emergency department visits among youths ages 12–17 underwent a fourfold increase between 1991 and 1996 (Greenblatt 1997), and approximately 27% of those reporting first-time heroin use in the year 2000 were under age 18. Although all adolescents are at risk, heroin use is more common among teens with early-onset substance use or those who have developed polysubstance dependence. Boys account for 53%–68% of users (Hopfer et al. 2002) and approximately 80%–97% of users are white. Intravenous use accounts for 45%–57% of all heroin use by adolescents, which raises a significant public health concern due to an increased risk of contracting and spreading HIV infection, hepatitis, and other infectious diseases (Marsch 2005).

Risk and Protective Factors Individual, peer, family, and community factors all impact the likelihood of drug use and the likelihood of progressing to substance use disorders (Oetting

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and Beauvais 1987; Weinberg 2001). Healthy parental attitudes and role modeling decrease the likelihood that teens will try drugs or affiliate with peers who use drugs. Conversely, conflicted parent-child relationships, parental ineffectiveness, insufficient parental monitoring, inconsistent discipline, deprived socioeconomic status, and parental alcohol or drug use have all been robustly correlated with adolescent opioid use (Teichman and Kefir 2000). Lower levels of parental education are also correlated with heroin use by teens, with rates highest among those whose parents did not complete grade school (Catalano et al. 1992). Early-onset substance use predicts a rapid progression to substance use disorders. Early use of nicotine and alcohol increases the risk of developing substance use disorders later in life, including cannabis, stimulant, opioid, and/or alcohol dependence (Hopfer et al. 2002). Teens diagnosed with substance dependence are also more likely than their peers to continue substance use into adulthood (Hingson et al. 2006). Legal problems and co-occurring childhood psychopathology are also risk factors for progression from opioid use to opioid disorders, especially among adolescent females. The most frequently identified antecedent psychiatric disorders include behavioral disorders (conduct disorder, attention-deficit/hyperactivity disorder [ADHD]), mood disorders, anxiety disorders, and learning disabilities (Currie et al. 2005; Goodwin et al. 2002; Wilens et al. 2003).

Substance Use and Co-Occurring Disorders Substance use disorders frequently co-occur with other mental health disorders, and opioid dependence is no exception. The most common comorbidities include mood and anxiety disorders, conduct disorder, oppositional defiant disorder, and ADHD (Currie et al. 2005; Goodwin et al. 2002; Wilens et al. 2004). Adolescents with substance use disorders are also more likely to have been victims of physical or sexual abuse than their peers (Jaycox et al. 2004). Substances of abuse can induce, mimic, or exacerbate underlying mental illness. Opioid-dependent adolescents with comorbid mental health disorders are more likely to require inpatient hospitalization, are less likely to be compliant with medications, are more likely to drop out of treatment, and are at higher risk of relapse. Despite these poor outcomes, simultaneous treatment of the co-occurring mental health disorder helps to alleviate the substance use. Therefore, all adolescents with opioid dependence should be evaluated for cooccurring mental health disorders and should be treated for both disorders simultaneously.

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Screening and Assessment Screening for drug use, including opioids, should occur as part of routine adolescent medical care. Screening is a two-step process—it begins with opening questions about drug use, such as: “During the past 12 months (or since your last appointment), did you drink any alcohol (more than a few sips)? Smoke any marijuana? Use anything else to get high? By ‘anything else’ I mean illegal drugs, over-the-counter and prescription drugs, and things that you sniff or huff ” (Knight et al. 1999). Since 2007, more teens have reported drug initiation with opioid pharmaceuticals than any other class of drugs, including marijuana, making opioids a new gateway drug. Because of this phenomenon, it is important to specifically mention opioids in the opening questions (Johnston et al. 2007). Teens who answer yes to one or more of the opening questions should be further screened with a standardized, developmentally appropriate tool that can distinguish low- versus high-risk substance use. Work by Wilson et al. (2004) has demonstrated that even experienced clinicians significantly underestimate substance use disorders when relying on clinical impressions alone. Several screening tools are available, including the CRAFFT questionnaire (with CRAFFT being a mnemonic for six key terms within the questions: car, relax, alone, forget, family or friends, trouble; Figure 12–1), which has been extensively validated (Knight et al. 1999, 2002) and is recommended by the American Academy of Pediatrics. Every adolescent should receive a brief intervention appropriate to their level of use based on screening results. Readers are referred to the review article “Screening, Brief Intervention, and Referral to Treatment for Adolescents” (Levy and Knight 2008) for a general approach to office-based screening and intervention. Beyond screening, substance use should be considered in the differential diagnosis of any teen who presents with new-onset behavioral, emotional, or school problems, or when an adult suspects substance use because a teen has appeared intoxicated or has been in possession of drugs or paraphernalia. Recognition of the physical and behavioral manifestations of common drugs of abuse can aid in focusing screening questions, testing, and prompt intervention. Physician and family understanding of risk and protective factors may be the single most important element for identifying at-risk youths and intervening early. Adolescents who report any use of opioids (other than as prescribed by a physician) should receive further assessment to determine the motivation and pattern of use, associated problems, attempts at quitting, and previous treatment in order to determine the stage of use and whether a substance use disorder is present. Opioid use occurs on a continuum from misuse to dependence as

231

Opioid Use by Adolescents

The CRAFFT Screening Questions

Please answer all questions honestly; your answers will be kept confidential.

Part A During the PAST 12 MONTHS, did you:

No

1. Drink any alcohol (more than a few sips)?

  

2. Smoke any marijuana or hashish? 3. Use anything else to get high?

Yes If you answered NO to ALL (A1, A2, A3) answer only B1

  

If you answered YES to ANY (A1 to A3) answer B1 to B6

“anything else” includes illegal drugs, over-the-counter and prescription drugs, and things that you sniff or “huff”

Part B

No

Yes

1. Have you ever ridden in a CAR driven by someone (including yourself) who was “high” or had been using alcohol or drugs?





2. Do you ever use alcohol or drugs to RELAX, feel better about yourself, or fit in?





3. Do you ever use alcohol or drugs while you are by yourself, or ALONE?





4. Do you ever FORGET things you did while using alcohol or drugs?





5. Do your FAMILY or FRIENDS ever tell you that you should cut down on your drinking or drug use?





6. Have you ever gotten into TROUBLE while you were using alcohol or drugs?





CONFIDENTIALITY NOTICE: The information on this page may be protected by special federal confidentiality rules (42 CFR Part 2), which prohibit disclosure of this information unless authorized by specific written consent. A general authorization for release of medical information is NOT sufficient.

FIGURE 12–1. CRAFFT screening questionnaire. Source. Reprinted with permission from the Center for Adolescent Substance Abuse Research, CeASAR, Children’s Hospital, Boston, Massachusetts. Copyright © 2009 Children’s Hospital Boston.

232 Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence

described below. Treatment strategies are most effective when targeted to the stage of use. Opioid misuse is characterized by oral use of opioids without a prescription exclusively for pain relief. Because of the highly addictive nature of opioids, teens using these medications without medical supervision may develop opioid addiction. Problematic opioid use is defined by the occurrence of a single adverse consequence as a result of use, use for reasons other than relief of pain (e.g., to become intoxicated), or use by any route other than oral (e.g., insufflated or injected). Substance-related problems may include decreased school performance, suspensions, relationship problems with parents or peers, motor vehicle accidents, injuries, emergency department visits, physical or sexual assaults, and legal problems. These may be accompanied by significant changes in dress, behavior, and peer group. Opioid abuse refers to continued opioid use in the context of significant problems or impairment in functioning. It is defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association 2000) as a maladaptive pattern of use that causes impairment in social or school functioning, recurrent physical risk or legal problems, and continued use despite harm occurring over a 12-month period, with no diagnosis of dependence. Opioid dependence or addiction refers to loss of control over drug use and is characterized by a maladaptive pattern of compulsive opioid use, preoccupation, and associated negative consequences. Tolerance and withdrawal are nearly universal. Clinical manifestations typically include continual use of substances when available, solitary use, disrupted family relationships, and loss of outside supports. Formal diagnostic criteria are specified in DSM-IV-TR. If a teen denies drug use in the context of substantial evidence to the contrary, the clinician should conduct a confidential interview and ask for an explanation of the reported observations (e.g., “Why is your mother so worried that you are using drugs?” or “Why were you carrying pills in your pocketbook?”). Urine drug testing for opioids may also be a useful part of an assessment, but the procedure has significant limitations. A drug test may be negative in the context of drug use if the window of detection (