Efficacy and effectiveness of melatonin for the management of musculoskeletal pain: a systematic review and meta-analysis of placebo and active controlled trials

ABSTRACT: Melatonin may provide benefits for managing musculoskeletal (MSK) pain, and this review evaluated its efficacy and effectiveness on pain intensity and sleep quality. We searched 6 databases from inception to April 2025 and included randomized controlled trials in people with chronic or postoperative MSK pain reporting pain or sleep outcomes. Comparators included placebo or active controls (eg, analgesics). Random-effects meta-analyses were performed using mean differences with 95% confidence intervals. Subgroup analyses were conducted by comparator type. Sensitivity analyses included only low-risk studies. Certainty of evidence was assessed using GRADE. Twenty-three studies (2028 participants) were included. For people with chronic MSK pain, melatonin was not superior to placebo in reducing pain (mean difference [MD]: -6.76/100, 95% confidence interval [CI]: -15.89 to 2.36) but was superior to active controls (MD: -11.21/100, 95% CI: -14.29 to -8.13); in sensitivity analysis, melatonin was superior to placebo (MD: -10.04, 95% CI: -17.68 to -2.39). For people with postoperative pain, melatonin was superior to placebo, with effects similar to active controls. Sleep quality favoured melatonin in people with chronic MSK pain but not in those with postoperative pain. Adverse events were mild and transient. Melatonin may provide modest benefits for pain in people with chronic MSK pain, while evidence in postoperative pain remains limited. Although treatment effect estimates were comparable with conventional analgesics, most did not reach minimal clinically important difference thresholds and the certainty of evidence was low to moderate. Melatonin may be considered as a potential adjunct rather than a primary treatment, pending randomized controlled trials with standardised dosing and longer follow-ups.