Objectives: To update the evidence on benefits and harms of cannabinoids and similar plant-based compounds to treat chronic pain using a living systematic review approach.
Data sources: Ovid® MEDLINE®, PsycINFO®, Embase®, the Cochrane Library, and SCOPUS® databases; reference lists of included studies; and submissions received after Federal Register request were searched to April 4, 2022.
Review methods: Using dual review, we screened search results for randomized controlled trials (RCTs) and observational studies of patients with chronic pain evaluating cannabis, kratom, and similar compounds with any comparison group and at least 1 month of treatment or followup. Dual review was used to abstract study data, assess study-level risk of bias, and rate the strength of evidence (SOE). Prioritized outcomes included pain, overall function, and adverse events. We grouped studies that assessed tetrahydrocannabinol (THC) and/or cannabidiol (CBD) based on their THC to CBD ratio and categorized them as comparable THC to CBD ratio, high-THC to CBD ratio, and low-THC to CBD ratio. We also grouped studies by whether the product was a whole-plant product (cannabis), cannabinoids extracted or purified from a whole plant, or a synthetic product. We conducted meta-analyses using the profile likelihood random effects model and assessed between-study heterogeneity using Cochran’s Q statistic chi square test and the I2 statistic. Magnitude of benefit was categorized as no effect or small, moderate, and large effects.
Results: From 3,283 abstracts, 21 RCTs (N=1,905) and 8 observational studies (N=13,769) assessing different cannabinoids were included; none evaluated kratom. Studies were primarily short term, and 59 percent enrolled patients with neuropathic pain. Comparators were primarily placebo or usual care. The SOE was low unless otherwise noted. Compared with placebo, comparable THC to CBD ratio oral spray was associated with a small benefit in change in pain severity (7 RCTs, N=632, 0 to10 scale, mean difference [MD] −0.54, 95% confidence interval [CI] −0.95 to −0.19, I2=39%; SOE: moderate) and overall function (6 RCTs, N=616, 0 to 10 scale, MD −0.42, 95% CI −0.73 to −0.16, I2=32%). 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% vs. 7.5%, RR 1.79, 95% CI 1.19 to 2.77, I2=0%). Synthetic products with high-THC to CBD ratios were associated with a moderate improvement in pain severity, a moderate increase in sedation, and a large increase in nausea (pain: 6 RCTs, N=390, 0 to 10 scale, MD −1.15, 95% CI −1.99 to −0.54, I2=48%; sedation: 3 RCTs, N=335, 19% vs. 10%, RR 1.73, 95% CI 1.03 to 4.63, I2=28%; nausea: 2 RCTs, N=302, 12.3% vs. 6.1%, RR 2.19, 95% CI 0.77 to 5.39; I²=0%). We also found moderate SOE for a large increased risk of dizziness (2 RCTs, 32% vs. 11%, RR 2.74, 95% CI 1.47 to 6.86, I2=40%). Extracted whole-plant products with high-THC to CBD ratios (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. We observed a moderate improvement in pain severity when combining all studies of high-THC to CBD ratio (8 RCTs, N=684, MD −1.25, 95% CI −2.09 to −0.71, I2=58%; SOE: moderate). Evidence (including observational studies) on whole-plant cannabis, topical or oral CBD, low-THC to CBD, other cannabinoids, comparisons with active products or between cannabis-related products, and impact on use of opioids was insufficient to draw conclusions. Other important harms (psychosis, cannabis use disorder, and cognitive effects) were not reported.
Conclusions: Low to moderate strength evidence suggests small to moderate 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 during short-term treatment (1 to 6 months); high-THC to CBD ratio products were also associated with increased risk of withdrawal due to adverse events. Evidence for whole-plant cannabis and other comparisons, outcomes, and plant-based compounds was unavailable or insufficient to draw conclusions. Small sample sizes, lack of evidence for moderate and long-term use and other key outcomes, such as other adverse events and impact on use of opioids during treatment, indicate that more research is needed.