Overview

This systematic review and meta-analysis included 104 studies (47 randomised controlled trials [RCTs]), involving a total of 9958 participants (median age 42 years), that compared cannabinoids with placebo or active comparator for the treatment of chronic non-cancer-related pain (CNCP).1 The studies included neuropathic pain, fibromyalgia, rheumatoid arthritis and visceral pain. The interventions included tetrahydrocannabinol (THC), cannabidiol (CBD), combination of THC and CBD; plant-based cannabis and synthetic cannabinoids.

Meta-analysis of eight RCTs found that, across all cannabinoid formulations and types of pain, cannabinoids were more likely than placebo to produce a 30% reduction in pain (pooled odds ratio [OR] 1.46, 95% CI 1.16 to 1.84; n=1734; moderate-quality to very low-quality evidence). This equated to a pooled event rate of 29% of patients treated with cannabinoids reporting a 30% pain reduction compared with 25.9% for placebo, and a number needed to treat (NNT) of 25 (95% CI 15 to 61). Meta-analysis of five RCTs found no evidence for an effect of cannabinoids over placebo for a 50% reduction in pain (moderate-quality to very low-quality evidence).

Meta-analysis of 30 RCTs found that cannabinoids produced a larger reduction in pain intensity than placebo (standardised mean difference −0.14, 95% CI −0.20 to −0.08). This was roughly equivalent to a reduction of 2.9 mm on a 100 mm visual analogue scale of pain intensity, which is well below the 30 mm reduction that is regarded as clinically important. Cannabinoids resulted in more people reporting the outcome of ‘much’ to ‘very much improved’ compared with placebo (18.9% vs 11.8%; NNT 38; pooled OR 1.62, 95% CI 1.34 to 1.96; nine RCTs; low-quality to very low-quality evidence).

Patients who received a cannabinoid for CNCP were more likely to experience adverse events (81.2% vs 66.2%; pooled OR 2.33, 95% CI 1.88 to 2.89), and more likely to withdraw from a trial because of them (pooled OR 3.47, 95% CI 2.64 to 4.56). Adverse effects that were more common with cannabinoids than placebo included dizziness, cognitive disturbance, confusion and disorientation with a number needed to harm (NNH) of 6 (95% CI 5 to 8).

Interpretation of the results was limited by the heterogeneous nature of the trials, of which many were too small to provide robust effect estimates, did not provide detail of cannabinoid doses or were of limited duration with little information about long-term effectiveness or safety of cannabinoid treatment. The highest quality evidence from RCTs was for neuropathic pain and MS-related pain.

The authors concluded that it seems unlikely that cannabinoids are highly effective medicines for CNCP. There was evidence that nabiximols achieved modest pain reductions as adjunctive treatments for MS-related pain. They suggested that cannabinoids are unlikely to be a monotherapy for CNCP.

(Funding was provided by the Commonwealth Department of Health, NSW Government Centre for Medicinal Cannabis Research and Innovation, the Victorian Department of Health and Human Services, and the Queensland Department of Health.)

Context

A recent Cochrane review examined the use of cannabinoids for neuropathic pain and concluded that the potential benefits of cannabis‐based medicines in chronic neuropathic pain might be outweighed by their potential harms.2 The quality of evidence was graded as low to very low and the authors reported that the NNT was 20 for 50% or greater reduction in pain. However, there was an increase in nervous system adverse effects (NNH 3) and psychiatric disorders (NNH 6).

A review of 79 studies (6462 participants) evaluated cannabinoids for a wide range of indications including chronic pain, nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, spasticity in MS, depression, sleep disorder, psychosis and Tourette’s syndrome.3 This review concluded that there was moderate-quality evidence that cannabinoids may be beneficial for the treatment of chronic neuropathic or cancer pain and spasticity due to MS. However, cannabinoids were associated with a greater risk of any adverse event (OR 3.03, 95% CI 2.42 to 3.80), serious adverse events (OR 1.41, 95% CI 1.04 to 1.92) and withdrawals because of adverse events (OR 2.94, 95% CI 2.18 to 3.96).