PAIN MANAGEMENT AND
THE OPIOID EPIDEMIC
BALANCING SOCIETAL AND INDIVIDUAL
BENEFITS AND RISKS OF PRESCRIPTION
OPIOID USE
Committee on Pain Management and Regulatory Strategies to
Address Prescription Opioid Abuse
Richard J. Bonnie, Morgan A. Ford, and Jonathan K. Phillips, Editors
Board on Health Sciences Policy
Health and Medicine Division
A Consensus Study Report of
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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This activity was supported by Grant No. HHSF223201610015C from the U.S. Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-45954-9
International Standard Book Number-10: 0-309-45954-0
Digital Object Identifier: https://doi.org/10.17226/24781
Library of Congress Control Number: 2017950552
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Copyright 2017 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2017. Pain management and the opioid epidemic: Balancing societal and individual benefits and risks of prescription opioid use. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24781.
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COMMITTEE ON PAIN MANAGEMENT AND REGULATORY STRATEGIES TO ADDRESS PRESCRIPTION OPIOID ABUSE
RICHARD J. BONNIE (Chair), Harrison Foundation Professor of Medicine and Law; Director, Institute of Law, Psychiatry and Public Policy, University of Virginia School of Law, Charlottesville
HORTENSIA DE LOS ANGELES AMARO, Associate Vice Provost for Community Research Initiatives; Dean’s Professor of Social Work and Preventive Medicine, School of Social Work, University of Southern California, Los Angeles
LINDA BURNES BOLTON, System Chief Nurse Executive; Vice President, Nursing; Chief Nursing Officer, Cedars-Sinai Medical Center, Los Angeles, California
JONATHAN P. CAULKINS, H. Guyford Stever Professor of Operations Research and Public Policy, Heinz School of Public Policy and Management, Carnegie Mellon University, Pittsburgh, Pennsylvania
DAVID CLARK, Professor of Anesthesia, Perioperative Pain Medicine and Pain, Stanford University; Director, Veterans Affairs Pain Clinic, Palo Alto, California
ELI ELIAV, Professor and Director, Eastman Institute for Oral Health; Vice Dean for Oral Health, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York
GARRET FITZGERALD, McNeil Professor in Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
TRACI C. GREEN, Deputy Director, Injury Prevention Center, Boston Medical Center, Boston University School of Medicine, Massachusetts; Associate Professor of Emergency Medicine and Epidemiology, The Warren Alpert School of Medicine, Brown University, Providence, Rhode Island
MIGUEL HERNÁN, Kolokotrones Professor of Biostatistics and Epidemiology, Harvard T.H. Chan School of Public Health; Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts
LEE D. HOFFER, Associate Professor, Department of Anthropology, Case Western Reserve University, Cleveland, Ohio
PAUL E. JARRIS, Senior Vice President of Maternal and Child Health Program Impact; Deputy Medical Director, March of Dimes Foundation, Washington, DC
KAROL KALTENBACH, Emeritus Professor of Pediatrics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
AARON S. KESSELHEIM, Associate Professor of Medicine, Harvard Medical School; Director, Program On Regulation, Therapeutics, And Law (PORTAL), Brigham and Women’s Hospital, Boston, Massachusetts
ANNE MARIE McKENZIE-BROWN, Associate Professor of Anesthesiology; Director, Division of Pain Management, Emory University School of Medicine, Atlanta, Georgia
JOSE MORON-CONCEPCION, Associate Professor of Anesthesiology, School of Medicine, Washington University, St. Louis, Missouri
A. DAVID PALTIEL, Professor, Department of Health Policy and Management, School of Public Health, School of Management, Yale University, New Haven, Connecticut
VALERIE REYNA, Professor of Human Development; Director, Human Neuroscience Institute, Cornell University, Ithaca, New York
MARK SCHUMACHER, Chief, Division of Pain Medicine; Professor of Anesthesiology, School of Medicine, University of California, San Francisco
Study Staff
MORGAN A. FORD, Study Director
JONATHAN K. PHILLIPS, Associate Program Officer
ANNE CLAIBORNE, Senior Program Officer
CLARE STROUD, Senior Program Officer (until May 2017)
PAMELA REESE, Senior Program Assistant (until July 2016)
THELMA L. COX, Senior Program Assistant (August 2016–March 2017)
DANIEL FLYNN, Senior Program Assistant (from December 2016)
HILARY BRAGG, Program Coordinator, Board on Health Sciences Policy
CHRISTIE BELL, Financial Officer
ANDREW M. POPE, Director, Board on Health Sciences Policy
Consultants
RONA BRIERE, Consultant Editor
ERIN HAMMERS FORSTAG, Freelance Science Writer
MARGARET FOSTER RILEY, University of Virginia
PATRICIA J. ZETTLER, Georgia State University
Reviewers
This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.
We thank the following individuals for their review of this report:
GEORGES C. BENJAMIN, American Public Health Association
PHILLIP O. COFFIN, San Francisco Department of Public Health
SANDRA COMER, Columbia University
PENNEY COWAN, American Chronic Pain Association
RAYMOND J. DINGLEDINE, Emory University School of Medicine
BARUCH FISCHHOFF, Carnegie Mellon University
PETER BARTON HUTT, Covington & Burling, LLP
SANDRA H. JOHNSON, St. Louis University School of Law
DAVID JULIUS, University of California, San Francisco
ERIN E. KREBS, Minneapolis Veterans Affairs Health Care System
RICHARD LARSON, Massachusetts Institute of Technology
RICHARD C. MOHS, Global Alzheimer’s Platform Foundation
DANIEL RAYMOND, Harm Reduction Coalition
PETER REUTER, University of Maryland
JOSHUA M. SHARFSTEIN, Johns Hopkins Bloomberg School of Public Health
PATRICK TIGHE, University of Florida College of Medicine
SARAH WAKEMAN, Massachusetts General Hospital
ALEC WALKER, Harvard T.H. Chan School of Public Health
CLIFFORD WOOLF, Harvard Medical School
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by KRISTINE M. GEBBIE, Flinders University, and SARA ROSENBAUM, The George Washington University. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.
Preface
Nature and human ingenuity have spawned a class of opioid drugs that alleviate pain and, not coincidentally, induce feelings of well-being. Unfortunately, overprescribing and misuse of these drugs pose serious risks to individuals who consume them and the population at large. Industrial and postindustrial societies have been grappling with the challenge of balancing these benefits and risks for more than 150 years. Alarmingly, rates of opioid use disorder (OUD) and opioid overdose deaths have reached unprecedented levels over the past two decades, and have risen much faster in the United States than in most other countries.
U.S. Department of Health and Human Services data suggest that at least 2 million Americans have an OUD involving prescribed opioids and nearly 600,000 have an OUD involving heroin, with about 90 Americans dying every day from overdoses that involve an opioid. Recognizing the magnitude of the problem, the U.S. Food and Drug Administration (FDA) asked the National Academies of Sciences, Engineering, and Medicine (the National Academies) to characterize the epidemic and to recommend actions that the FDA and other public and private organizations should take to address it, balancing society’s interest in reducing opioid-related harms with the needs of individuals suffering from pain. It was my privilege to chair a committee of talented experts chosen by the National Academies to carry out this important charge.
Few communities have been left untouched by the recent surge of opioid-related deaths. Perhaps at no time in modern history has there been broader public understanding of the nature and consequences of substance use disorder, including OUD. Indeed, the broad reach of the epidemic has
blurred the formerly distinct social boundary between use of prescribed opioids and use of heroin and other illegally manufactured ones. These unfortunate developments may have finally reframed the “cops versus docs” debate that has characterized U.S. drug policy since World War II.
It has become clear (and is well-documented in this Consensus Study Report) that the opioid epidemic will not be controlled without deploying multiple policy tools. Increasing access to treatment for individuals with OUD is imperative, together with a substantial program of research to develop new nonaddictive treatments for pain. The committee urges the FDA to reshape and monitor the legal market for opioids and to facilitate use of safe and effective agents for treating persons with OUD and reducing overdose deaths. In addition, the professional societies, insurers, health care organizations, pharmaceutical manufacturers, and state and federal agencies collectively responsible for shaping prescribing practices should attend to the multiple weaknesses in the nation’s health system that led to this epidemic. Meanwhile, law enforcement agencies will continue to be responsible for curtailing trafficking in illegally manufactured opioids, most recently the low-priced, high-potency fentanyl manufactured in clandestine labs domestically and also streaming into the country from abroad. Although criminal drug law enforcement was beyond the scope of this report, the need for improved tools for tracking the dynamic interaction between the legal and illegal markets is one of its core themes.
The Controlled Substances Act, which provides one of the two prongs of federal statutory regulation of opioids (the other being the Food, Drug, and Cosmetic Act), was enacted by Congress in 1970, as part of an omnibus drug policy bill that also established the National Commission on Marijuana and Drug Abuse, for which I had the honor of serving as Associate Director. The Commission’s second report, issued in 1973, championed strong roles for federal public health agencies, and for federally funded scientific research, in a coordinated national policy for substance use disorder prevention and treatment. Perhaps the tragic effects of the opioid epidemic will reinvigorate federal leadership and provide the impetus for comprehensive and sustained national action.
Richard J. Bonnie, Chair
Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse
Acknowledgments
The National Academies of Sciences, Engineering, and Medicine’s (the National Academies’) Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse and its supporting staff thank the representatives of the study sponsor, the U.S. Food and Drug Administration, including Robert Califf, Sharon Hertz, Joshua Lloyd, and Douglas Throckmorton, who gladly provided the committee with background information, responded to questions, and participated in the committee’s open sessions and workshops. We also thank the many other individuals who shared their expertise and information during the committee’s workshops (see Appendix A for the names of the speakers). Their contributions informed the committee’s deliberations and enhanced the quality of this Consensus Study Report. The study staff, including board director Andrew Pope, study director Morgan Ford, associate program officer Jonathan Phillips, and administrative assistant Thelma Cox, were central in shepherding the report through all its stages. The committee would also like to thank senior program officers Anne Claiborne and Clare Stroud for the guidance they provided throughout the study, as well as science writer Erin Hammers, who helped to draft portions of the report. Special thanks are also due to Rona Briere and Alisa Decatur for their editorial support. We also appreciate the many staff at the National Academies who contributed to the production and review of the report, including Daniel Bearss, Clyde Behney, Christie Bell, Chelsea Frakes, Ellen Kimmel, Janice Mehler, Bettina Ritter, Lauren Shern, and Taryn Young. The committee and staff also extend their gratitude to Greta Gorman, Nicole Joy, Sarah Kelley, An Nguyen-Gia, and Jennifer Walsh for their assistance with report communications and release activities.
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Contents
Study Scope and Emphasis and Report Organization
PART I: PAIN MANAGEMENT AND RESEARCH
2 PAIN MANAGEMENT AND THE INTERSECTION OF PAIN AND OPIOID USE DISORDER
The Scope of the Problem of Pain
Nonopioid Pharmacologic Treatments
Differences in Pain Experiences and Treatment Effectiveness Among Subpopulations
3 PROGRESS AND FUTURE DIRECTIONS IN RESEARCH ON PAIN AND OPIOID USE DISORDER
The Neurobiology of the Reward Pathway and the Intersection of Pain and Opioid Use Disorder
Preclinical and Translational Research
Intersection of Pain and Opioid Use Disorder
PART II: ADDRESSING THE OPIOID EPIDEMIC
4 TRENDS IN OPIOID USE, HARMS, AND TREATMENT
Trends in Prescription Opioid Use and Misuse
Heroin Use and Its Relation to Prescription Opioid Use
The Current State of Surveillance Systems
Recent Developments in Pharmaceutical Treatment of Opioid Use Disorder
Trends in Treatment of Opioid Overdose with Naloxone
5 EVIDENCE ON STRATEGIES FOR ADDRESSING THE OPIOID EPIDEMIC
The Need for a Systems Approach
Strategies for Restricting Supply
Strategies for Influencing Prescribing Practices
Strategies for Reducing Demand
6 OPIOID APPROVAL AND MONITORING BY THE U.S. FOOD AND DRUG ADMINISTRATION
Overview of the FDA’s Regulatory Process for Prescription Drugs and Its Application to Opioids
Public Health Dimensions of FDA Drug Regulation
Key Elements of an Integrated Decision-Making Framework for Opioid Regulation
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Boxes, Figures, and Tables
BOXES
2-1 Universal Precautions in the Use of Pain Medicine for Treatment of Chronic Pain
5-1 Strategies for Addressing the Opioid Epidemic
5-2 An Example of a National Drug Take-Back Program: France’s Cyclamed
5-4 Outcomes Associated with a Harm Reduction Strategy in Portugal
5-5 Harm Reduction Strategies in Huntington, West Virginia
6-1 Approval of Zohydro Extended-Release
6-2 Overarching Recommendation for Development of an Integrated Framework for Regulation of Opioids
6-3 Recommendations for the Clinical Development Stage
6-4 Recommendation for the Approval Stage
6-5 Recommendation for the Post-Approval Monitoring Stage
6-6 Recommendations for Other Regulatory Decisions
A-1 Meeting 1 Open Session Agenda
A-2 Pain Management and Prescription Opioid-Related Harms: Exploring the State of the Evidence
A-3 Regulatory Strategies to Address Prescription Opioid-Related Harms
FIGURES
S-1 Number of overdose deaths from prescription and illicit opioids, United States, 1999–2015
1-2 Number of overdose deaths from prescription and illicit opioids, United States, 1999–2015
4-2 Public health impact of heroin use
4-6 Estimated number of chronic heroin users, 2000–2010 (in millions)
5-1 A systems model of the opioid misuse problem
6-1 Current FDA benefit-risk framework
TABLES
4-1 Characteristics of Medications for the Treatment of Opioid Use Disorder
5-1 States Authorizing Use of PDMP Data, by Selected Professions (as of May 2016)
6-1 Schedules Under the Controlled Substances Act
6-2 Special Biological and Social Characteristics of Opioids and Opioid Derivatives
6-3 The U.S. Food and Drug Administration’s Expedited Drug Development and Approval Pathways
6-4 Example of an Adapted Benefit-Risk Framework for Approval of Opioid Products
Annex 6-1 Extended Release (ER)/Long-Acting (LA) Opioid Post-Marketing Study Requirements
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Acronyms and Abbreviations
ACA |
Patient Protection and Affordable Care Act |
ADAM |
Arrestee Drug Abuse Monitoring |
ADF |
abuse-deterrent formulation |
ADP |
adenosine diphosphate |
ANDA |
Abbreviated New Drug Application |
APAP |
N-Acetyl-p-Aminophenol (acetaminophen) |
ARRIVE |
Animals in Research: Reporting In Vivo Experiments |
ASAM |
American Society of Addiction Medicine |
ASIC |
acid-sensing ion channel |
ATP |
adenosine triphosphate |
BH4 |
tetrahydrobiopterin |
BMT |
buprenorphine maintenance therapy |
CASP6 |
caspase-6 |
CB |
cannabinoid receptor |
CBT |
cognitive behavioral therapy |
CDC |
U.S. Centers for Disease Control and Prevention |
CDSS |
clinical decision support system |
CEWG |
Community Epidemiology Working Group |
CGMP |
Current Good Manufacturing Practice |
CHARM |
Children and Recovering Mothers |
CI |
confidence interval |
CNCP |
chronic noncancer pain |
CNS |
central nervous system |
CoEPE |
Center of Excellence in Pain Education |
COMM |
Current Opioid Misuse Measure |
COX |
cyclooxygenase |
CRPS |
complex regional pain syndrome |
CSA |
Controlled Substances Act |
CSF1 |
colony-stimulating factor 1 |
DA |
dopamine |
DAMP |
damage-associated molecular pattern |
DATA |
Drug Addiction Treatment Act of 2000 |
DAWN |
Drug Abuse Warning Network |
DDD |
defined daily dose |
DEA |
U.S. Drug Enforcement Administration |
DIRE |
Diagnosis, Intractability, Risk, Efficacy tool |
DoD |
U.S. Department of Defense |
DOJ |
U.S. Department of Justice |
DOPR |
delta opioid receptor |
DSM |
Diagnostic and Statistical Manual of Mental Disorders |
DTC |
direct-to-consumer |
DUR |
drug utilization review |
ECHO |
Extension for Community Healthcare Outcomes |
EEG |
electroencephalogram |
EMR |
electronic medical record |
EP3 |
E prostanoid receptor 3 |
EpFA |
epoxy fatty acid |
ER/LA |
extended-release/long-acting |
ERK |
extracellular signal-regulated kinase |
ETASU |
elements to assure safe use |
FAAH |
fatty acid amide hydrolase |
FAERS |
FDA’s Adverse Event Reporting System |
FDA |
U.S. Food and Drug Administration |
FDASIA |
FDA Safety and Innovation Act of 2012 |
FDCA |
Food, Drug, and Cosmetic Act |
FQHC |
federally qualified health center |
GI |
gastrointestinal |
GPR |
G protein-coupled receptor |
GRADE |
Grading of Recommendations, Assessment, Development, and Evaluation |
GTP |
guanosine triphosphate |
HCV |
hepatitis C virus |
HHS |
U.S. Department of Health and Human Services |
HIV |
human immunodeficiency virus |
HMGB1 |
high mobility group box 1 protein |
ICD |
International Classification of Diseases |
IL-6 |
interleukin-6 |
IMMPACT |
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials |
IND |
Investigational New Drug |
IOM |
Institute of Medicine |
IPRCC |
Interagency Pain Research Coordinating Committee |
IR |
immediate-release |
KOPR |
kappa opioid receptor |
MAT |
medication-assisted treatment |
MCH |
maternity care home |
MED |
morphine equivalent dose |
MME |
morphine milligram equivalents |
MOMS |
Maternal Opioid Medical Supports |
MOPR |
mu (µ) opioid receptor |
MPGES |
microsomal prostaglandin E synthase |
NAc |
nucleus accumben |
NAS |
neonatal abstinence syndrome |
NAVIPPRO |
National Addictions Vigilance Intervention and Prevention Program |
NDA |
New Drug Application |
NDEWS |
National Drug Early Warning System |
NeuPSIG |
Neuropathic Pain Special Interest Group |
NFLIS |
National Forensic Laboratory Information System |
NGF |
nerve growth factor |
NIDA |
National Institute on Drug Abuse |
NIH |
National Institutes of Health |
NMDA |
N-Methyl-d-aspartate |
NMPR |
nonmedical pain relief |
NNT |
number needed to treat |
NorBNI |
norbinaltorphimine |
NSAID |
nonsteroidal anti-inflammatory drug |
NSDUH |
National Survey on Drug Use and Health |
OIH |
opioid-induced hyperalgesia |
ONDCP |
Office of National Drug Control Policy |
OPRM1 |
opioid receptor mu1 |
OR |
opioid receptor |
ORT |
Opioid Risk Tool |
OTA |
opioid treatment agreement |
OTC |
over-the-counter |
OUD |
opioid use disorder |
PAMP |
pathogen-associated molecular pattern |
PDMP |
prescription drug monitoring program |
PG |
prostaglandin |
PGE |
prostaglandin E |
PHN |
postherpetic neuralgia |
POATS |
Prescription Opioid Addiction Treatment Study |
POMAQ |
Prescription Opioid Misuse and Abuse Questionnaire |
PPA |
patient–provider agreement |
PPRECISE |
Preclinical Pain Research Consortium for Investigating Safety and Efficacy |
PRR |
pattern recognition receptor |
PVB |
paravertebral block |
PWID |
people who inject drugs |
QALY |
quality-adjusted life year |
QL |
quantity limit |
RA |
rheumatoid arthritis |
RADARS |
Researched Abuse, Diversion, and Addiction-Related Surveillance |
RAGE |
receptor for advanced glycation end products |
RCT |
randomized controlled trial |
REMS |
Risk Evaluation and Mitigation Strategy |
RF |
radiofrequency |
RICO |
Racketeer Influenced and Corrupt Organizations Act |
RMTg |
rostromedial tegmental nucleus |
SA |
short-acting |
SAFE |
Safety, Appropriateness, Fiscal Neutrality, and Effectiveness |
SAMHSA |
Substance Abuse and Mental Health Services Administration |
SCOPE |
Safe and Competent Opioid Prescribing Education |
SCS |
spinal cord stimulation |
sEH |
soluble epoxide hydrolase |
SIF |
safe injection facility |
SIH |
supervised injectable heroin |
SIS |
Spine Intervention Society |
SMB |
state medical board |
SNP |
single-nucleotide polymorphism |
SNRI |
serotonin–norepinephrine reuptake inhibitor |
SOAPP |
Screener and Opioid Assessment for Patients with Pain |
SSRI |
selective serotonin re-uptake inhibitor |
SUD |
substance use disorder |
TCA |
tricyclic antidepressant |
TEDS |
Treatment Episodes Data Set |
THC |
tetrahydrocannabinol |
TIRF |
transmuscosal immediate-release fentanyl |
TLR |
toll-like receptor |
TNF |
tumor necrosis factor |
TPP |
thrombotic thrombocytopenic purpura |
TRPA1 |
transient receptor potential cation channel, member A1 |
TRPV |
transient receptor potential cation channel, subfamily V |
TTX |
tetrodotoxin |
VA |
U.S. Department of Veterans Affairs |
VGSC |
voltage-gated sodium channel |
VHA |
Veterans Health Administration |
VTA |
ventral tegmental area |
WHO |
World Health Organization |
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