Background/importance Cannabinoids are emerging as an alternative pain management option, preliminarily supported by preclinical and clinical studies. Unwanted side effects from oral or inhaled cannabinoids remain, however, a major barrier to widespread use. Peripherally acting cannabinoids (eg, topically applied) may circumvent these side effects while providing localized pain management.

Objective Our purpose was to systematically review the literature on the effectiveness of peripherally acting cannabinoids for pain management.

Evidence review We searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PubMed databases. Included studies examined the effect of topical/peripherally administered cannabinoids on pain ratings in humans, as well as pain-related outcomes in animals (eg, paw withdrawal). Due to a lack of trials, human studies were summarized in a narrative synthesis. Separate meta-analyses were performed for animal studies using radiant tail flick or paw withdrawal outcomes.

Findings Our search yielded 1182 studies following removal of duplicates, with 46 studies (6 human, 40 animal) included. Human studies (one randomized controlled trial and five case studies/series) reported no adverse events to topical cannabinoids and preliminary evidence of decreased pain ratings. Animal studies reporting tail flick (5) (2.81, 95% CI 1.93 to 3.69, p<0.001) and mechanical withdrawal (11) (2.74, 95% CI 1.82 to 3.67, p<0.001) reported prolonged responses (analgesia) in peripheral cannabinoid groups compared with controls.

Conclusions Preclinical animal studies provided low-quality evidence for peripherally administered cannabinoids to provide regional, antinociceptive effects. The scarcity of high-quality human studies underscores the need to translate preclinical evidence into well-controlled human trials.