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Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain: 2024 Update

Draft Comments Apr 2, 2024

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 January 15, 2024.

Review methods. We grouped studies based on their tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio and by product type: synthetic, plant-purified (plant-derived product consisting of a single cannabinoid, e.g. dronabinol or CBD), or plant-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. Two new randomized controlled trials (RCTs) in three publications (n=134 and 86) 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:CBD ratio products versus placebo in patients with neuropathic pain; the other new RCT evaluated oral CBD plus paracetamol versus paracetamol alone for knee osteoarthritis. Since the inception of this living review, from 5,644 total abstracts identified, 25 RCTs (in 26 publications) (N=2,255) and 12 observational studies (N=48,468) assessing different cannabinoids have been included; no study evaluated kratom. Studies were primarily short term, and 54 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 (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 plant-purified high-THC to CBD ratio products were associated with a small improvement in pain severity, 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 plant-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, 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% 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 non-cannabis 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 plant-extracted comparable THC to CBD ratio and synthetic or plant-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 associated with improved outcomes versus placebo. Evidence for whole-plant cannabis and other comparisons, outcomes, and plant-based compounds was unavailable or insufficient to draw conclusions.

This is the third annual update of a living systematic review addressing the effectiveness and harms of plant-based treatments for chronic and subacute pain in adults and adolescents. The first systematic review was published in October of 2021, and the first and second updates were published in September of 2022 and August of 2023, respectively. As this review is "living," it uses methods to identify and synthesize recently published literature and adapt its scope on an ongoing basis. Included plant-based compounds are those that have potential analgesic effects as well as the potential for addiction, misuse, and serious adverse effects.

Studies of cannabis-related products were grouped based on their tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio using the following categories: comparable THC to CBD, high-THC to CBD (including THC only), and low-THC to CBD (including CBD only). Since the second annual update of the systematic review published in August 2023, two new placebo-controlled randomized controlled trials (RCTs) in three publications and two new observational studies were added, for a total of 25 RCTs (in 26 publications) and 12 observational studies. One of the new RCTs evaluated oral plant-purified THC (dronabinol), synthetic CBD, or both and the other new RCT evaluated plant-purified CBD; the new observational studies evaluated various (low, comparable, or high-THC to CBD ratio) products. In patients with chronic (mainly neuropathic) pain with short-term treatment (4 weeks to <6 months):

  • Plant-extracted comparable-THC to CBD ratio oral spray is probably associated with small improvements in pain severity (strength of evidence [SOE]: moderate) and overall function versus placebo (SOE: moderate). There may be no increase in risk of serious adverse events (SAEs) (SOE: low) or withdrawal due to adverse events (WAEs) (SOE: low). There may be a large increased risk of dizziness (SOE: low) and sedation and a moderate increased risk of nausea (SOE: low).
  • Synthetic and plant-purified THC (high THC to CBD) may be associated with small improvement in pain severity (SOE: low), but with increased risk of WAEs (SOE: low), sedation (SOE: low), and nausea (SOE: low) versus placebo. Synthetic and plant-purified THC is probably associated with a large increased risk of dizziness (SOE: moderate).
  • Low-THC to CBD ratio oral products (synthetic or plant-purified CBD alone, or combined plant-purified THC plus synthetic CBD in ratio ~1:2) may not be associated with improved pain and function versus placebo (SOE: moderate for CBD alone and low for THC/CBD). THC plus CBD is probably associated with large increased risk of nausea (SOE: moderate).
  • Other key adverse event outcomes (psychosis, cannabis use disorder, cognitive deficits) and outcomes on the impact on opioid use were not reported or evidence was insufficient to draw conclusions.
  • No evidence on other plant-based compounds such as kratom met criteria for this review.

 

Project Timeline

Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain

Oct 28, 2020
Topic Initiated
Nov 3, 2020
Jan 4, 2024
Apr 2, 2024
Draft Comments
Apr 2, 2024 - Apr 30, 2024
Page last reviewed April 2024
Page originally created March 2024

Internet Citation: Draft Comments: Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain: 2024 Update. Content last reviewed April 2024. Effective Health Care Program, Agency for Healthcare Research and Quality, Rockville, MD.
https://effectivehealthcare.ahrq.gov/products/plant-based-chronic-pain-treatment/living-review-update

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