PAIN+ CPN

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 June 30, 2024. Review methods. We grouped studies based on their tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio and by product type: synthetic, purified (plant-derived product consisting of a single cannabinoid, e.g. dronabinol or CBD), or extracted (from whole plant, containing multiple cannabinoids). We conducted random effects meta-analyses and categorized magnitude of benefit (large, moderate, small, or no effect [less than small]). Results. Three new randomized controlled trials (RCTs) in four publications (n=134, 86, and 60) and two new observational studies (N=296 and 32,332) were added for this annual update; no study addressed subacute pain or adolescents. One new RCT compared high THC, low THC, and combination THC to CBD ratio products versus placebo in patients with neuropathic pain; one new RCT evaluated oral CBD plus paracetamol versus paracetamol alone for knee osteoarthritis; and one new RCT evaluated a topical (intraoral) THC to CBD product versus placebo for temporomandibular disorders. Since the inception of this living review, from 5,894 total abstracts identified, 26 RCTs (in 27 publications) (N=2,315) and 12 observational studies (N=48,468) assessing different cannabinoids have been included; no study evaluated kratom. Studies were primarily short term, and 53 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, extracted, comparable ratio THC to CBD oral spray was associated with a small decrease in pain severity (7 RCTs, N=878, 0 to 10 scale, mean difference [MD] -0.54, 95% confidence interval [CI] -0.95 to -0.19, I2 =39%; SOE: moderate); improvement in overall function favored the cannabis product but was slightly below the threshold for small (negative values for function indicate improved 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 (WAEs). There was a large increased risk of dizziness and sedation, and a moderate increased risk of nausea (dizziness: 6 RCTs, N=866, relative risk [RR] 3.57, 95% CI 2.42 to 5.60, I2=0%; sedation: 6 RCTs, N=866, RR 5.04, 95% CI 2.10 to 11.89, I2=0%; and nausea: 6 RCTs, N=866, RR 1.79, 95% CI 1.19 to 2.77, I2=0%). Synthetic and purified high THC to CBD ratio products were associated with a small improvement in pain severity, with no effect on overall function or disability. There was a moderate increase in risk of WAEs, a moderate increase in sedation, and a large increase in risk of nausea (pain: 8 RCTs, N=507, 0 to 10 scale, MD -0.78, 95% CI -1.59 to -0.08, I2=64%; WAEs: 6 RCTs, N=487, RR 1.92, 95% CI 1.10 to 4.80, I2=0%; sedation: 5 RCTs, N=458, RR 1.57, 95% CI 1.11 to 2.29, I2=0%; nausea: 4 RCTs, N=425, RR 2.12, 95% CI 1.09 to 3.96; I²=0%). There was also moderate SOE for a large increased risk of dizziness (4 RCTs, N=425, RR 2.30, 95% CI 1.53 to 3.52, I2=22%). Synthetic or purified oral CBD alone was not associated with decreased pain intensity (4 RCTs, N=334, 0 to 10 scale, MD 0.40, 95% CI -0.14 to 1.00, I2=20%; SOE: moderate), greater likelihood of pain response (4 RCTs, N=334, RR 0.84, 95% CI 0.62 to 1.10; I2 =0%; SOE: moderate), or improved function (3 RCTs, N=272, standardized mean difference [SMD] 0.11, 95% CI -0.14 to 0.41, I2=0%; SOE: moderate) versus placebo, and combined oral THC plus CBD (~1:2 ratio) was not associated with decreased pain intensity (2 RCTs, N=123, 0 to 10 scale, MD 0.12, 95% CI -0.71 to 0.93, I2=0%), greater likelihood of experiencing >=30 percent improvement in pain (2 RCTs, N=123, RR 1.07, 95% CI 0.73 to 1.57, I2=0%), or improved function (1 RCT, n=60, SMD 0.29, 95% CI -0.21 to 0.80) versus placebo. Evidence (including observational studies) on whole-plant cannabis, topical CBD, other cannabinoids, comparisons with active noncannabis treatments or between cannabis-related products, and impact on use of opioids 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 extracted, comparable THC to CBD ratio and synthetic or purified high THC to CBD ratio products versus placebo during short-term treatment (1 to 6 months). Low- to moderate-strength evidence suggests that low THC to CBD ratio products may not be associa

Discipline Area	Relevance to Practice	Is this News?	Score
Physician

Physician rater

Well conducted review and important for the field.

Physician rater

As a U.S. hospitalist, I have never prescribed cannabis. I do, however, see a number of patients who come in with cannabis hyperemesis syndrome. Given its new legality and the new restrictions on opioids, I am seeing far more patients use this. This guideline suggests minimal benefit and significant harm with cannabis in RCTs, which is helpful in my advising patients.

Physician rater

It is interesting to note that it seems it's the THC component that confers a small, if any, pain benefit (and more adverse events) rather than the CBD component of the cannabis products.

Physician rater

As an ambulatory specialist, updated evidence-based information on this topic is critical. This living update reinforces the rather narrow range of conditions that cannabis “may” benefit to a small degree. The persistence and relative high incidence of side effects makes this a discussion, not a blanket endorsement as many patients seem to think. The summary is great but may even overestimate the benefit as many studies had an elevated risk of bias. Additionally, the size of the document will force most to rely solely on this summary.

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