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Evidence Report/Technology Assessment Number 218 The Effectiveness and of Risks Long-Term Opioid Treatment of Chronic Pain Evidence-Based Practice Evidence Report/Technology Assessment Number 218 The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-2012-00014-I Prepared by: Pacific Northwest Evidence-based Practice Center Oregon Health and Science University, Portland, OR University of Washington, Seattle, WA Investigators: Roger Chou, M.D., FACP Rick Deyo, M.D., M.P.H. Beth Devine, Pharm.D., Ph.D., M.B.A. Ryan Hansen, Pharm.D., Ph.D. Sean Sullivan, Ph.D. Jeffrey G. Jarvik, M.D., M.P.H. Ian Blazina, M.P.H. Tracy Dana, M.L.S. Christina Bougatsos, M.P.H. Judy Turner, Ph.D. AHRQ Publication No. 14-E005-EF September 2014 This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2012-00014-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. This report may periodically be assessed for the urgency to update. If an assessment is done, the resulting surveillance report describing the methodology and findings will be found on the Effective Health Care Program Web site at: www.effectivehealthcare.ahrq.gov. Search on the title of the report. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials that are clearly noted in the document. Further reproduction of those copyrighted materials is prohibited without the specific permission of the copyright holder. Persons using assistive technology may not be able to fully access information in this report. For assistance contact [email protected]. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. Suggested citation: Chou R, Deyo R, Devine B, Hansen R, Sullivan S, Jarvik JG, Blazina I, Dana T, Bougatsos C, Turner J. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evidence Report/Technology Assessment No. 218. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2014. www.effectivehealthcare.ahrq.gov/reports/final.cfm. ii Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. These reviews provide comprehensive, science-based information on common, costly medical conditions, and new health care technologies and strategies. Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews can help clarify whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about AHRQ EPC systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm. AHRQ expects that these systematic reviews will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an email list to learn about new program products and opportunities for input. We welcome comments on this systematic review. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by email to [email protected]. Richard G. Kronick, Ph.D. Yen-pin Chiang, Ph.D. Director Acting Deputy Director Agency for Healthcare Research and Quality Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality Stephanie Chang, M.D., M.P.H. Suchitra Iyer, Ph.D. Director, EPC Program Task Order Officer Center for Evidence and Practice Improvement Center for Evidence and Practice Agency for Healthcare Research and Quality Improvement Agency for Healthcare Research and Quality iii Acknowledgments The authors gratefully acknowledge the following individuals for their contributions to this project: Suchitra Iyer, Ph.D., Task Order Officer; David Reuben, M.D., National Institutes of Health Working Group Chair; and the National Institutes of Health Working Group. Key Informants This topic was nominated to AHRQ from the National Institutes of Health. Therefore, in place of Key Informants, a National Institutes of Health Working Group Planning Meeting was conducted to provide input into the key questions and the scope of the report. Technical Expert Panel In designing the review questions and methodology at the outset of this report, the EPC consulted several technical and content experts, reflecting a variety of viewpoints relevant to this topic. Technical experts consulted are expected to have divergent and possibly conflicting opinions. This diversity is helpful in achieving a well-rounded report. The study questions, design, methodological approaches, and/or conclusions do not necessarily represent the views of individual technical and content experts. Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified. The list of Technical Experts who participated in developing this report follows: Matthew Bair, M.D., M.S. Associate Professor of Medicine, Indiana University School of Medicine Research Scientist, Indiana University Center for Health Services and Outcomes Research Research Scientist, Center for Health Services Research Regenstrief Institute, Inc. Core Investigator, VA HSR&D Center for Health Information and Communication Indianapolis, IN Gilbert Fanciullo, M.D., M.S. Director, Pain Management Center Dartmouth-Hitchcock Medical Center Lebanon, NH Gary Franklin, M.D., M.P.H. Research Professor Environmental and Occupational Health Sciences Adjunct Research Professor, Health Services University of Washington Seattle, WA iv Charles Inturrisi, Ph.D. Professor of Pharmacology Weill Cornell Medical College New York, NY Robert Jamison, Ph.D. Professor of Anaesthesia Harvard Medical School Psychologist Brigham and Women’s Hospital Boston, MA Erin E. Krebs, M.D., M.P.H. Core Investigator, Center for Chronic Disease Outcomes Research Minneapolis VA Health Care System Associate Professor of Medicine, University of Minnesota Minneapolis, MN Leonard Paulozzi, M.D., M.P.H. Medical Epidemiologist Division of Unintentional Injury Prevention National Center for Injury Prevention and Control Centers for Disease Control and Prevention Atlanta, GA Mark Wallace, M.D. Chair, Division of Pain Management University of California, San Diego San Diego, CA Lonnie Zeltzer, M.D. Director, Children's Pain and Comfort Care Program Mattel Children's Hospital UCLA Distinguished Professor of Pediatrics, Anesthesiology, Psychiatry and Biobehavioral Sciences David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA v Peer Reviewers Prior to publication of the final evidence report, EPCs sought input from independent Peer Reviewers without financial conflicts of interest. However, the conclusions and synthesis of the scientific literature presented in this report does not necessarily represent the views of individual reviewers. Peer Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential non-financial conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential non-financial conflicts of interest identified. The list of Peer Reviewers follows: Matthew Bair, M.D., M.S. Associate Professor of Medicine, Indiana University School of Medicine Research Scientist, Indiana University Center for Health Services and Outcomes Research Research Scientist, Center for Health Services Research, Regenstrief Institute, Inc. Core Investigator, VA HSR&D Center for Health Information and Communication Indianapolis, IN Daniel Carr, M.D., M.A. Professor of Public Health and Community Medicine Program Director, Pain, Research Education & Policy Tufts University School of Medicine Boston, MA Gary Franklin, M.D., M.P.H. Research Professor, Environmental and Occupational Health Sciences Adjunct Research Professor, Health Services University of Washington Seattle, WA Aaron M. Gilson, M.S., M.S.S.W., Ph.D. Research Program Manager/Senior Scientist Pain & Policy Studies Group Carbone Cancer Center University of Wisconsin-Madison Madison, WI vi Douglas Gourlay M.D., M.Sc., FRCP(c), FASAM Former Director, Pain and Chemical Dependency Division Wasser Pain Center Toronto, Ontario, Canada Charles Inturrisi, Ph.D. Professor of Pharmacology Weill Cornell Medical College New York, NY Robert Jamison, Ph.D. Professor of Anaesthesia, Harvard Medical School Psychologist, Brigham and Women’s Hospital Boston, MA Erin E. Krebs, M.D., M.P.H. Core Investigator, Center for Chronic Disease Outcomes Research Minneapolis VA Health Care System Associate Professor of Medicine, University of Minnesota Minneapolis, MN Leonard Paulozzi, M.D., M.P.H. Medical Epidemiologist Division of Unintentional Injury Prevention National Center for Injury Prevention and Control Centers for Disease Control and Prevention Atlanta, GA Dennis Turk, Ph.D. Professor, Department of Anesthesiology & Pain Medicine University of Washington Seattle, WA Mark Wallace, M.D. Chair, Division of Pain Management University of California, San Diego San Diego, CA Lonnie Zeltzer, M.D. Director, Children’s Pain and Comfort Care Program Mattel Children’s Hospital UCLA Distinguished Professor of Pediatrics, Anesthesiology, Psychiatry and Biobehavioral Sciences David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA vii The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain Structured Abstract Objectives. Chronic pain is common and use of long-term opioid therapy for chronic pain has increased dramatically. This report reviews the current evidence on effectiveness and harms of opioid therapy for chronic pain, focusing on long-term (>1 year) outcomes. Data sources. A prior systematic review (searches through October 2008), electronic databases (Ovid MEDLINE, Scopus, and the Cochrane Libraries January 2008 to August 2014), reference lists, and clinical trials registries. Review methods. Using predefined criteria, we selected randomized trials and comparative observational studies of patients with cancer or noncancer chronic pain being considered for or prescribed long-term opioid therapy that addressed effectiveness or harms versus placebo, no opioid use, or nonopioid therapies; different opioid dosing methods; or risk mitigation strategies. We also included uncontrolled studies >1 year that reported rates of abuse, addiction, or misuse, and studies on the accuracy of risk prediction instruments for predicting subsequent opioid abuse or misuse. The quality of included studies was assessed, data were extracted, and results were summarized qualitatively. Results. Of the 4,209 citations identified at the title and abstract level, a total of 39 studies were included. For a number of Key Questions, we identified no studies meeting inclusion criteria. Where studies were available, the strength of evidence was rated no higher than low, due to imprecision and methodological shortcomings, with the exception of buccal or intranasal fentanyl for pain relief outcomes within 2 hours after dosing (strength of evidence: moderate). No study evaluated effects of long-term opioid therapy versus no opioid therapy. In 10 uncontrolled studies, rates of opioid abuse were 0.6 percent to 8 percent and rates of dependence were 3.1 percent to 26 percent in primary care settings, but studies varied in methods used to define and ascertain outcomes. Rates of aberrant drug-related behaviors ranged from 5.7 percent to 37.1 percent. Compared with nonuse, long-term opioid therapy was associated with increased risk of abuse (one cohort study), overdose (one cohort study), fracture (two observational studies), myocardial infarction (two observational studies), and markers of sexual dysfunction (one cross-sectional study), with several studies showing a dose-dependent association. One randomized trial found no difference between a more liberal opioid dose escalation strategy and maintenance of current dose in pain or function, but differences between groups in daily opioid doses at the end of the trial were small. One cohort study found methadone associated with lower risk of mortality than long-acting morphine in a Veterans Affairs population in a propensity adjusted analysis (adjusted HR 0.56, 95 percent CI 0.51 to 0.62). Estimates of diagnostic accuracy for the Opioid Risk Tool were extremely inconsistent and other risk assessment instruments were evaluated in only one or two studies. No study evaluated the effectiveness of risk mitigation strategies on outcomes related to overdose, addiction, abuse, or misuse. Evidence was insufficient to evaluate benefits and harms of long-term opioid therapy in high-risk patients or in other subgroups. viii Conclusions. Evidence on long-term opioid therapy for chronic pain is very limited but suggests an increased risk of serious harms that appears to be dose-dependent. More research is needed to understand long-term benefits, risk of abuse and related outcomes, and effectiveness of different opioid prescribing methods and risk mitigation strategies. ix