Table Of ContentEvidence 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
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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
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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
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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
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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.
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