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Opioid Prescribing: A Systematic Review and Critical Appraisal of Guidelines for Chronic Pain

Teryl K. Nuckols, MD, MSHS; Laura Anderson, MPH; Ioana Popescu, MD, MPH; Allison L. Diamant, MD, MSHS; Brian Doyle, MD; Paul Di Capua, MD; and Roger Chou, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 12 November 2013.

From David Geffen School of Medicine at University of California, Los Angeles, and UCLA Fielding School of Public Health, Los Angeles, California; RAND Corporation, Santa Monica, California; and Oregon Health & Science University, Portland, Oregon.

Financial Support: By the California Department of Industrial Relations and the California Commission on Health and Safety and Workers’ Compensation. Dr. Nuckols was supported by a Mentored Clinical Scientist Career Development Award (K08) from the Agency for Healthcare Research and Quality (grant HS17954).

Potential Conflicts of Interest: Dr. Nuckols: Other: California Commission on Health and Safety and Worker's Compensation, Collaborative Spine Research Foundation. Dr. Chou: Grant: California Commission on Health and Safety and Worker's Compensation, American Pain Society. All other authors have no disclosures. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1193.

Requests for Single Reprints: Teryl K. Nuckols, MD, MSHS, Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at the University of California, Los Angeles, 911 Broxton Avenue, Los Angeles, CA 90095; e-mail, tnuckols@mednet.ucla.edu.

Current Author Addresses: Drs. Nuckols, Popescu, Diamant, Doyle, and Di Capua: Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at the University of California, Los Angeles, 911 Broxton Avenue, Los Angeles, CA 90095.

Ms. Anderson: UCLA Fielding School of Public Health, 650 Charles E. Young Drive South, 16-035 Center for Health Sciences, Los Angeles, CA 90095-1772.

Dr. Chou: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098.

Author Contributions: Conception and design: T.K. Nuckols, A.L. Diamant, R. Chou.

Analysis and interpretation of the data: T.K. Nuckols, L. Anderson, I. Popescu, A.L. Diamant, B. Doyle, P. Di Capua, R. Chou.

Drafting of the article: T.K. Nuckols, I. Popescu, A.L. Diamant, R. Chou.

Critical revision of the article for important intellectual content: T.K. Nuckols, I. Popescu, A.L. Diamant, B. Doyle, R. Chou.

Final approval of the article: T.K. Nuckols, I. Popescu, A.L. Diamant, P. Di Capua, R. Chou.

Provision of study materials or patients: T.K. Nuckols.

Statistical expertise: T.K. Nuckols.

Obtaining of funding: T.K. Nuckols.

Administrative, technical, or logistic support: T.K. Nuckols, L. Anderson.

Collection and assembly of data: T.K. Nuckols, L. Anderson, I. Popescu, A.L. Diamant, B. Doyle, P. Di Capua.

Ann Intern Med. 2014;160(1):38-47. doi:10.7326/0003-4819-160-1-201401070-00732
Text Size: A A A

Background: Deaths due to prescription opioid overdoses have increased dramatically. High-quality guidelines could help clinicians mitigate risks associated with opioid therapy.

Purpose: To evaluate the quality and content of guidelines on the use of opioids for chronic pain.

Data Sources: MEDLINE, National Guideline Clearinghouse, specialty society Web sites, and international guideline clearinghouses (searched in July 2013).

Study Selection: Guidelines published between January 2007 and July 2013 addressing the use of opioids for chronic pain in adults were selected. Guidelines on specific settings, populations, and conditions were excluded.

Data Extraction: Guidelines and associated systematic reviews were evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument and A Measurement Tool to Assess Systematic Reviews (AMSTAR), respectively, and recommendations for mitigating opioid-related risks were compared.

Data Synthesis: Thirteen guidelines met selection criteria. Overall AGREE II scores were 3.00 to 6.20 (on a scale of 1 to 7). The AMSTAR ratings were poor to fair for 10 guidelines. Two received high AGREE II and AMSTAR scores. Most guidelines recommend that clinicians avoid doses greater than 90 to 200 mg of morphine equivalents per day, have additional knowledge to prescribe methadone, recognize risks of fentanyl patches, titrate cautiously, and reduce doses by at least 25% to 50% when switching opioids. Guidelines also agree that opioid risk assessment tools, written treatment agreements, and urine drug testing can mitigate risks. Most recommendations are supported by observational data or expert consensus.

Limitation: Exclusion of non–English-language guidelines and reliance on published information.

Conclusion: Despite limited evidence and variable development methods, recent guidelines on chronic pain agree on several opioid risk mitigation strategies, including upper dosing thresholds; cautions with certain medications; attention to drug–drug and drug–disease interactions; and use of risk assessment tools, treatment agreements, and urine drug testing. Future research should directly examine the effectiveness of opioid risk mitigation strategies.

Primary Funding Source: California Department of Industrial Relations and California Commission on Health and Safety and Workers’ Compensation.


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Appendix Figure.

Summary of evidence search and selection.

AGREE II = Appraisal of Guidelines for Research and Evaluation II; AMSTAR = A Measurement Tool to Assess Systematic Reviews.

* Includes the American Academy of Family Physicians, American Academy of Pain Medicine, American Academy of Physical Medicine and Rehabilitation, American College of Occupational and Environmental Medicine, American College of Physicians, American Geriatrics Society, American Society of Addiction Medicine, American Society of Anesthesiologists, American Society of Interventional Pain Physicians, Association of Military Surgeons of the United States, National Medical Association, and Society of Medical Consultants to the Armed Forces.

† The exact PubMed search terms were “analgesics, opioid”[MeSH], “opioid”[tiab], “opioids”[tiab], “opioid analgesic”[tiab], “opioid analgesics”[tiab], “opiate”[tiab], “opiates”[tiab], “chronic pain”[MeSH], “chronic pain”[tiab], “pain management”[MeSH], and “pain management”[tiab] combined with “guideline”[Publication Type], “guideline*”[tiab], “position statement*”[tiab], “practice parameter*”[tiab], “position paper*”[tiab], and “consensus statement*”[tiab]

‡ Includes the Guidelines International Network; National Institute for Health and Care Excellence; Canadian Medical Association Infobase: Clinical Practice Guidelines; Clinical Practice Guidelines Portal of the Australian Government; Scottish Intercollegiate Guidelines Network; New Zealand Guidelines Group; Biblioteca de Guías de Práctica Clínica del Sistema Nacional de Salud (Library of Clinical Practice Guidelines from the Spanish National Health System); German Agency for Quality in Medicine; German National Disease Management Guidelines Programme: German Disease Management Guidelines; British Columbia Ministry of Health; and Australian Government National Health and Medical Research Council: Guidelines and Publications.§ The American Geriatrics Society updated its guideline in 2009 and stated that the 2002 guideline, which covers slightly different material, was still up to date. When counting guidelines, we considered these to be components of 1 document.

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Submit a Comment/Letter
To the Editor
Posted on December 23, 2013
Laxmaiah Manchikanti, MD, Frank J.E. Falco, MD, Joshua A. Hirsch, MD,
University of Louisville, Temple University, Massachusetts General Hospital
Conflict of Interest: None Declared

The systematic review and critical appraisal of guidelines for opioid prescribing for chronic pain by Nuckols et al (1) is problematic in that it may not meet the criteria of evidence-based medicine and suffers from issues of professionalism. The guidelines authors selected 2 manuscripts (2,3) as outstanding raise concers re: bias, specifically the ones described by American Pain Society (APS)/American Academy of Pain Medicine (AAPM) (2). These manuscripts barely met inclusion criteria because of their publication in 2009, i.e., the literature search ended in October 2008 which makes the articles 5 years old by the time of publication of this manuscript. As we all know, evidence-based medicine is a dynamic subject which continues to change with opioid use and abuse changing more rapidly. We posit that in the rapidly evolving world of opioid use and abuse, 5 years may be too long an inclusion time.  They also have given these guidelines highest score even though Chou and Huffman (4) were the only 2 authors of this original guideline prepared for APS/AAPM. The original guideline consisted of multiple systematic reviews. In a separate manuscript, we highlight concerns regarding perceived conflict of interest in guideline preparation that acknowledged the interplay between academic centers, investigators and societies that may have a pre-conceived notion (and hence bias).  In that case, pharmaceutical companies that manufacture opiates provided funding to APS who then provided funding to the Oregon Health Sciences Center.  We believe this issue of disclosure requirements and conflict of interest to be a real one and simply note that Congress is paying attention to opioid abuse and the role industry funding might play. To drive home this point, the American Pain Foundation closed its doors soon after these investigations were started.

            We believe the authors  have done an injustice to American Society of Interventional Pain Physician (ASIPP) guidelines which have up-to-date literature search, systematic reviews, lack of external funding, and with extensive conflict of interest process identification. In context it is worth noting that the ASIPP guidelines, of which we are authors, provide restrictive use of opioids compared to all other guidelines.

            It is a major service to public to perform systematic reviews with critical appraisal of the literature; however, it would be more appropriate if these are performed without bias.



1.         Nuckols TK, Anderson L, Popescu I, Diamant AL, Doyle B, Di Capua P, Chou R. Opioid Prescribing: A Systematic Review and Critical Appraisal of Guidelines for Chronic Pain. Ann Intern Med. 2013 Nov 12. [Epub ahead of print]

2.         Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, Donovan MI, Fishbain DA, Foley KM, Fudin J, Gilson AM, Kelter A, Mauskop A, O'Connor PG, Passik SD, Pasternak GW, Portenoy RK, Rich BA, Roberts RG, Todd KH, Miaskowski C; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009; 10:113-130.

3.         National Opioids Use Guideline Group (NOUGG). Canadian guidelines for safe and effective use of opioids for chronic non-cancer pain, Version 5.6. April 2010.


4.         Chou R, Huffman L. Guideline for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain: Evidence Review. American Pain Society; Glenview, IL: 2009.



Author's response
Posted on February 20, 2014
Teryl Nuckols, MD, MSHS, Roger Chou, MD
Rand Corporation
Conflict of Interest: None Declared
We appreciate Dr. Manchikanti’s interest but would like to correct some factual inaccuracies in his letter.

First, we applied well-established, pre-specified selection and evaluation criteria consistently across all guidelines. Criteria did not include whether guidelines were “restrictive” in the use of opioids. Both the AGREE and AMSTAR address potential conflicts of interest and funding. In terms of updating, we used a cutoff of five years on the basis of a study that found half of 17 guidelines were out of date by six years. According to the Institute of Medicine, guidelines should be updated when new evidence suggests that key recommendations warrant modification. , We found no indication that recommendations in the APS-AAPM guidelines are considered out of date. To the contrary, more recent guidelines cite the APS-AAPM guideline frequently—including the 2012 ASIPP guideline by Dr. Manchikanti and colleagues.

Second, we have already disclosed all potential conflicts of interest and funding for the current evaluation. The California Commission on Health and Safety and Workers' Compensation funded this study, and a Career Development Award from the Agency for Healthcare Research and Quality also supported the Principal Investigator. No funding was received from other sources. Dr. Chou provided input on content and methods for evaluating guidelines and systematic reviews. As noted in the methods, he did not participate in the evaluation of individual guidelines. Guideline evaluators, based at UCLA, were unaffiliated with guideline developers.

Third, regarding the APS-AAPM guideline, the APS provided funding directly to Oregon Health & Science University (OHSU, not Oregon Health Sciences Center). All potential conflicts of interest and funding sources for the APS-AAPM guideline and its associated systematic review were disclosed in those documents. Pharmaceutical companies did not provide input or have contact with guideline developers. The APS-AAPM guideline has no connection to the American Pain Foundation. Finally, there were more than a dozen other authors of the APS-AAPM guideline in addition to Drs. Chou and Huffman.

Teryl Nuckols, MD, MSHS
Roger Chou, MD
Submit a Comment/Letter

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