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Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain: 2023 Update
Comparative Effectiveness Review, No. 250
Investigators: Roger Chou, M.D., FACP, Azrah Y. Ahmed, B.A., Benjamin J. Morasco, Ph.D., Christina Bougatsos, M.P.H., Tracy Dana, M.L.S., Rongwei Fu, Ph.D., and Terran Gilbreath, M.P.H.
Structured Abstract
Objectives:
To update the evidence on benefits and harms of cannabinoids and other plant-based compounds to treat subacute and chronic pain in adults and adolescents using a living systematic review approach.
Data sources:
Ovid® MEDLINE®, PsycINFO®, Embase®, the Cochrane Library, and SCOPUS® databases, and reference lists of included studies were searched to April 23, 2023.
Review methods:
An updated protocol with expanded inclusion criteria (addition of sub-acute [4 to 12 weeks’ duration] pain and adolescents) was posted on the PROSPERO registry. We grouped studies based on their tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio and by product type, i.e. whole-plant (extracted or purified) or synthetic. We conducted random effects meta-analyses and categorized magnitude of benefit (large, moderate, small, or no effect [less than small]).
Results:
Two new randomized controlled trials (RCTs) (n=115 and 15) and two new observational studies (N=2,071) were added for this annual update; no study addressed subacute pain or adolescents. One new RCT compared high and low THC to CBD ratio products versus placebo; the other new RCT evaluated was very small and had methodological limitations. Since the inception of this living review, from 5,228 total abstracts identified, 23 RCTs (N=2,035) and 10 observational studies (N=15,840) assessing different cannabinoids were included; no study evaluated kratom. Studies were primarily short term, and 58 percent enrolled patients with neuropathic pain. Comparators were primarily placebo or usual care. Strength of evidence (SOE) was low unless indicated otherwise.
Compared with placebo, plant-extracted comparable ratio THC to CBD oral spray was associated with a small decrease in pain severity (7 RCTs, N=632, 0 to 10 scale, mean difference [MD] −0.54, 95% confidence interval [CI] −0.95 to −0.19, I2=39%; SOE: moderate) and a small decrease in overall function (6 RCTs, N=616, 0 to 10 scale, MD −0.42, 95% CI −0.73 to −0.16, I2=32%; SOE: moderate) versus placebo. There was no effect on study withdrawals due to adverse events. There was a large increased risk of dizziness and sedation, and a moderate increased risk of nausea (dizziness: 6 RCTs, N=866, 31.0% vs. 8.0%, relative risk [RR] 3.57, 95% CI 2.42 to 5.60, I2=0%; sedation: 6 RCTs, N=866, 8.0% vs. 1.2%, RR 5.04, 95% CI 2.10 to 11.89, I2=0%; and nausea: 6 RCTs, N=866, 13.9% vs. 7.5%, RR 1.79, 95% CI 1.19 to 2.77, I2=0%).
Synthetic high-THC to CBD ratio products were associated with a small improvement in pain severity, a moderate increase in sedation, and a large increase in risk of nausea following the addition of one new RCT (pain: 7 RCTs, N=448, 0 to 10 scale, MD −0.95, 95% CI −1.81 to −0.25, I2=60%; sedation: 4 RCTs, N=386, 19.5% vs. 11.5%, RR 1.60, 95% CI 1.01 to 2.95, I2=8%; nausea: 3 RCTs, N=353, 11.1% vs. 5.2%, RR 2.22, 95% CI 0.90 to 5.05; I2=0%). There was also moderate SOE for a large increased risk of dizziness (3 RCTs, N=353, 28.9% vs. 11.0%, RR 2.52, 95% CI 1.20 to 4.82, I2=41%). Extracted whole-plant high-THC to CBD ratio products (oral) were associated with a large increased risk of study withdrawal due to adverse events (1 RCT, 13.9% vs. 5.7%, RR 3.12, 95% CI 1.54 to 6.33) and dizziness (1 RCT, 62.2% vs. 7.5%, RR 8.34, 95% CI 4.53 to 15.34); outcomes assessing benefit were not reported or insufficient.
Evidence (including observational studies) on whole-plant cannabis, topical or oral CBD, low-THC to CBD ratio products (2 new RCTs), other cannabinoids, comparisons with active non-cannabis treatments or between cannabis-related products, and impact on use of opioids also remained insufficient. Evidence was not available on important harms such as psychosis, cannabis use disorder, and cognitive effects.
Conclusions:
Low to moderate strength evidence suggests small improvements in pain (mostly neuropathic), and moderate to large increases in common adverse events (dizziness, sedation, nausea) with high and comparable THC to CBD ratio extracted cannabinoids and synthetic products versus placebo during short-term treatment (1 to 6 months) in adults with chronic pain. Evidence for low-THC to CBD ratio products, whole-plant cannabis, and other comparisons, outcomes, and plant-based compounds was unavailable or insufficient to draw conclusions.
Contents
- Preface
- Acknowledgments
- Technical Expert Panel
- Peer Reviewers
- Executive Summary
- Introduction
- Methods
- Results
- Description of Included Evidence
- KQ 1 and KQ 2. In adults or adolescents with chronic or subacute pain, what are the benefits (KQ 1) and harms (KQ 2) of cannabinoids for treatment of chronic or subacute pain?
- KQ 3 and KQ 4. In adults or adolescents with chronic or subacute pain, what are the benefits (KQ 3) and harms (KQ 4) of kratom or other plant-based substances for treatment of chronic or subacute pain?
- Discussion
- References
- Abbreviations and Acronyms
- Appendixes
- Appendix A. Literature Search Strategies
- Appendix B. Methods
- Appendix C. Included Studies List
- Appendix D. Results – Study Level Summary Tables and Meta-Analyses
- Appendix E. Evidence Tables
- Appendix F. Risk of Bias Assessment
- Appendix G. Details on Strength of Evidence
- Appendix H. Excluded Studies List
- Appendix I. Funnel Plot of High-THC Ratio Studies Included in Meta-Analysis for Pain Severity
Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, 5600 Fishers Lane, Rockville, MD 20857; www.ahrq.gov
Contract No. 75Q80120D00006
Prepared by: Pacific Northwest Evidence-based Practice Center, Portland, OR
Suggested citation:
Chou R, Ahmed AY, Morasco BJ, Bougatsos C, Dana T, Fu R, Gilbreath T. Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain: 2023 Update. Comparative Effectiveness Review No. 250. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 75Q80120D00006.) AHRQ Publication No. 23-EHC031. Rockville, MD: Agency for Healthcare Research and Quality; August 2023. doi: https://doi.org/10.23970/AHRQEPCCER250UPDATE2023. Posted final reports are located on the Effective Health Care Program search page.
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. 75Q80120D00006). 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.
None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report.
The information in this report is intended to help healthcare decision makers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of healthcare 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 is made available to the public under the terms of a licensing agreement between the author and the Agency for Healthcare Research and Quality. Most AHRQ documents are publicly available to use for noncommercial purposes (research, clinical or patient education, quality improvement projects) in the United States, and do not need specific permission to be reprinted and used unless they contain material that is copyrighted by others. Specific written permission is needed for commercial use (reprinting for sale, incorporation into software, incorporation into for-profit training courses) or for use outside of the U.S. If organizational policies require permission to adapt or use these materials, AHRQ will provide such permission in writing.
AHRQ or U.S. Department of Health and Human Services endorsement of any derivative products that may be developed from this report, such as clinical practice guidelines, other quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied.
A representative from AHRQ served as a Contracting Officer’s Representative and reviewed the contract deliverables for adherence to contract requirements and quality. AHRQ did not directly participate in the literature search, determination of study eligibility criteria, data analysis, interpretation of data, or preparation or drafting of this report.
AHRQ appreciates appropriate acknowledgment and citation of its work. Suggested language for acknowledgment: This work was based on an evidence report, Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain: 2023 Update, by the Evidence-based Practice Center Program at the Agency for Healthcare Research and Quality (AHRQ).
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