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Systematic Review on Opioid Treatments for Chronic Pain: Surveillance Reports [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2019 Aug-.
Roger Chou , M.D., FACP, Shelley Selph , M.D., M.P.H., Jesse Wagner , M.A., Azrah Y. Ahmed , B.A., Rebecca Jungbauer , D.Ph., M.P.H, M.A., Kim Mauer , M.D., and Kanaka D. Shetty , M.D., M.S.
Published online: February 2022.
This is the second surveillance report for the 2020 report Opioid Treatments for Chronic Pain 1 (https://effectivehealthcare.ahrq.gov/products/opioids-chronic-pain/research), covering the period October 2021 through November 2021. The 2020 report addressed benefits and harms of opioids in patients with chronic pain, opioid dosing strategies, and risk assessment and risk mitigation strategies. Given the clinical and public health importance of this topic, it is important to identify new evidence that could impact practice or policy. The purpose of this update is to identify new evidence published after September 2021 and to determine how the new evidence impacts findings of the 2020 report and Surveillance Report 1, which added evidence from August 2019 through September 2021 and was published on the Agency for Healthcare Research and Quality (AHRQ) website (https://effectivehealthcare.ahrq.gov/products/opioids-chronicpain/research). A subsequent update is planned for April 2022 (based on evidence published through mid-March 2022).
The effectiveness and comparative effectiveness (benefits and harms, in Key Questions 1 and 2, respectively) of long-term opioid therapy versus placebo, no opioid therapy, or nonopioid therapy.
The comparative effectiveness and harms of various opioid dosing strategies (Key Question 3).The accuracy of instruments for predicting risk for opioid overdose, addiction, abuse, or misuse; the effectiveness of risk prediction instruments; the effectiveness of various risk mitigation strategies; and comparative effectiveness of strategies for managing patients with opioid use disorder (Key Question 4).
The full protocol for the original report, including detailed inclusion criteria using the PICOTS (populations, interventions, comparators, outcomes, timing, settings) framework (https://www.ncbi.nlm.nih.gov/books/NBK556255/table/ch4.tab1) and full Key Questions (https://www.ncbi.nlm.nih.gov/books/n/cer229/ch3/#ch3.s2), are also available on the AHRQ website (https://effectivehealthcare.ahrq.gov/topics/opioids-chronic-pain/protocol) and on the PROSPERO systematic reviews registry (CRD42019127423).
Update searches were conducted to identify evidence published after September 2021 through November 2021. Search strategies from the original report were utilized. 1 In addition, to capture articles not yet indexed in Medline ® , we supplemented the original search strategies with a previously developed 2 optimized (text-word only) search in pre-Medline to identify new studies not yet indexed with Medical Subject Headings (MeSH). As in the original report, searches on electronic databases were supplemented by review of reference lists of relevant articles. Search strategies are available in Appendix A.
As in the original review, one investigator screened citations identified through searches for eligibility for full-text review. (Key Questions and inclusion criteria are available in Appendix B.) In addition, to increase efficiency of abstract review, we utilized a machine learning classifier in conjunction with a second investigator to assist in conducting dual reviews. The machine learning classifier was previously shown to have 100 percent recall for identifying eligible studies in update searches for this review. 2 The machine learning classifier screened all citations; the second investigator performed dual review on all studies that the machine learning classifier did not classify as very low probability. Any citation identified as potentially eligible by either investigator underwent full-text review to determine final eligibility.
We utilized the same methods for data abstraction and quality assessment as for the original report. The decision to update meta-analyses from the original report was based on the number and sample sizes of new studies eligible for meta-analysis (meta-analysis performed if new evidence was large relative to the studies in the original meta-analysis); consistency in findings between the new studies and the original meta-analysis (meta-analysis performed if findings from new evidence appear inconsistent and new studies were appropriate for pooling based on similarity in populations, interventions, and comparisons, in order to determine whether new studies impact conclusions); or whether new evidence could impact the strength of evidence (meta-analysis performed if the strength of evidence based on the original meta-analysis was low or insufficient and new evidence could increase the strength of evidence due to increased precision, high quality, or other factors). The strength of evidence was based on the totality of evidence (evidence in the original report plus new evidence from all surveillance updates) and determined using the methods described in the original report. Changes in the strength of evidence assessments resulting from this current surveillance update are described separately from the findings reported in Surveillance Report 1.
A list of included studies identified for this update is provided in Appendix C. Evidence tables providing data from included studies are available in Appendix D, and quality assessments for each study are shown in Appendix E. A list of articles excluded at full-text review, along with reasons for exclusion, is available in Appendix F.
The search for Surveillance Report 2 from October 2021 through November 2021 yielded 412 citations and identified 1 new eligible study on harms (Figure 1). It is an observational study of patients with rheumatoid arthritis that evaluated the risk of cardiovascular events among tramadol users versus non-users (Appendix D, Table D-2). 3 The study reported estimates adjusted for potential confounders but was rated fair quality, primarily due to unreported attrition and unclear blinding of data analysts to treatments (Appendix E, Table E-2). No new eligible RCTs were identified for Surveillance Report 2.
Literature flow diagram. Note: New studies are those added since the original systematic review and Surveillance Report 1. * Other sources include prior reports, reference lists of relevant articles, systematic reviews, etc.
One new observational study was identified for Surveillance Report 2. It was consistent with the original report in finding an opioid (tramadol) associated with increased risk of all-cause mortality and cardiovascular events versus no opioid.
Table 1 provides the conclusions from the 2020 report and the new findings from studies identified in this and the prior surveillance update report; new findings from Surveillance Report 2 are indicated in the table by bolded and italicized text. Table 1 focuses on Key Questions (KQs) with new evidence since the original report; the full strength of evidence table is available in the full report (https://www.ncbi.nlm.nih.gov/books/NBK556241/bin/appi-et1.docx). New evidence identified for Surveillance Report 1 did not change any of the overall assessments that were included in the original report regarding opioids versus placebo and short-term (KQ 1a) or long-term (KQ 2a) pain or function; harms by dose or duration (KQ 2b); long- versus short-acting opioids (KQ 3b); dose escalation versus dose maintenance (KQ 3f); dose tapering versus no tapering (KQ 3i); different dose tapering strategies (KQ 3j); or buprenorphine/naloxone versus methadone for treatment of opioid use disorder (KQ 4c). For comparisons between mixed-mechanism medications and opioid agonists assessing risk of falls/fracture, hospitalization for adverse events, or cardiovascular adverse events (KQ 2b), there were no studies in the original report. Although Surveillance Report 1 included one new cohort study on this issue, the strength of evidence was insufficient to draw conclusions.
Summary of conclusions and assessments informed by new evidence from surveillance reports.
No new studies were identified for Surveillance Report 2.
The original report included one retrospective cohort study of patients with chronic noncancer pain (n=22,912) that found opioids associated with increased risk of all-cause mortality versus no opioids. 13 The original report also included three observational studies (2 cohort studies [N=449,036] 13 , 14 and 1 case-control study [11,693 cases] 15 ) that found opioids associated with increased risk of cardiovascular events (myocardial infarction in 2 studies and cardiovascular mortality in 1 study) versus no opioid therapy in patients with chronic noncancer pain due to various causes. The strength of evidence was rated low because data were observational, with potential for residual confounding, and two of the studies were rated fair quality 13 , 14 (one case-control study 15 was rated good-quality). One new fair-quality retrospective cohort study identified for Surveillance Report 2 of patients with rheumatoid arthritis (n=1,320) evaluated risk of major cardiovascular events (ischemic heart disease, congestive heart failure, acute ischemic stroke, and intracranial hemorrhage) associated with tramadol use versus no tramadol. 3 It was conducted in Taiwan using a national health insurance database. Consistent with the original report, the new study found tramadol associated with increased risk of cardiovascular events (adjusted hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.08 to 2.72) and mortality (adjusted HR 3.94, 95% CI 1.86 to 8.31) versus no tramadol.
No new studies were identified for Surveillance Report 2.
No new studies were identified for Surveillance Report 2.
One new study of opioids for chronic pain identified for Surveillance Report 2 was consistent with the findings of the original report with regard to increased risk of all-cause mortality and cardiovascular events with opioids versus no opioids. However, the strength of evidence for these outcomes remained low due to methodological limitations (observational studies with some methodological shortcomings). Surveillance Report 2 builds on Surveillance Report 1, which identified new studies on short-term benefits and harms, long-term benefits, risk mitigation strategies, dose-dependent risks of opioids, and management of opioid use disorder, all reporting results consistent with the original report. No new studies on harms of opioid discontinuations or dose reductions were identified for Surveillance Report 2. The next surveillance report is scheduled for April 2022.
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The authors gratefully acknowledge the following individuals for their contributions to this project: research associate and librarian Tracy Dana, M.L.S., research associate Christina Bougatsos, M.P.H., and student research assistant Daniel Oron, B.S., all from Oregon Health & Science University; and Task Order Officer Suchitra Iyer, Ph.D., at the Agency for Healthcare Research and Quality.
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 healthcare in the United States. These reviews provide comprehensive, science-based information on common, costly medical conditions, and new healthcare 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 https://effectivehealthcare.ahrq.gov/about/epc/evidence-synthesis.
This and future quarterly progress reports will provide up-to-date information about the evidence base to inform health plans, providers, purchasers, government programs, and the healthcare system as a whole on the state of the science. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the website (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.
If you have comments on this report, they may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane, Rockville, MD 20857, or by email to vog.shh.qrha@cpe. They will be considered in the next version of the report.
