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.
As a family physician, this is useful to know.
Living systematic review of an important topic that is continually updated - this is great work. In terms of practice change, nothing special here. The evidence base continues to be low, effectiveness essentially "meh". Side effects present including dizziness and nausea. Gaps in terms of the range of marijuana products examined, including no good data on low THC:CBD ratio products or CBD-only products. Not practice changing for me.
As a family physician, I think it is interesting to know the evidence of the efficacy and side effects of THC derivatives for treating pain. Although it does not bring major changes in what is already known so far, I recommend reading it.