A new Australian-led review triggers media attention but experts say melatonin for chronic MSK pain has no justification at present.
Researchers say melatonin could emerge as a useful adjunct for managing chronic musculoskeletal pain, with a new systematic review finding the hormone produces modest improvements in pain and sleep quality while maintaining a favourable safety profile.
The review caught the attention of the mainstream media, with the Australian Financial Review, the ABC’s Health Report, Sky News Australia, The Sydney Morning Herald, The Herald Sunand The Conversation all picking up on a release from The University of Sydney.
However, the researchers cautioned that the benefits were relatively small and supported by low-to-moderate certainty evidence, meaning melatonin should complement rather than replace established therapies.
“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,” they wrote.
“Melatonin may be considered as a potential adjunct rather than a primary treatment, pending randomised controlled trials with standardised dosing and longer follow-ups.”
Melbourne rheumatologist Professor Rachelle Buchbinder AO, NHMRC investigator fellow, and VC Distinguished Professor and head of the Musculoskeletal Health Unit and Wiser Health Care Group at Monash University’s School of Public Health and Preventive Medicine, agreed with the authors’ caution.
She said she wasn’t convinced by the findings of this review and thought high-quality placebo-controlled trials for specific types of musculoskeletal conditions would be needed to definitively determine whether melatonin has any benefits in people with conditions that cause chronic musculoskeletal pain.
“Based on a qualitative review of people with shoulder pain, if a patient has better pain control they have better sleep,” Professor Buchbinder told Rheumatology Republic.
“There is no justification at present to recommend melatonin be used for people with chronic musculoskeletal pain.”
The University of Sydney-led review, published in Pain, analysed 23 randomised controlled trials involving 2028 participants with either chronic musculoskeletal pain or postoperative musculoskeletal pain.
The researchers said it was the first review to separately evaluate melatonin’s efficacy against placebo and its effectiveness compared with active treatments, including analgesics and antidepressants.
Across nine trials involving chronic musculoskeletal conditions such as osteoarthritis, rheumatoid arthritis, chronic low back pain, fibromyalgia, temporomandibular disorders, and neuropathic pain, melatonin reduced pain when compared with all treatment groups combined.
When analysed against placebo alone, however, the reduction did not initially reach statistical significance.
That changed when the researchers restricted the analysis to studies judged to have a low risk of bias. In those higher-quality trials, melatonin produced a statistically significant reduction in pain compared with placebo, strengthening confidence that the treatment has genuine analgesic effects in chronic musculoskeletal conditions.
Melatonin also outperformed active comparators including diclofenac, fluoxetine, and amitriptyline in several studies, although the researchers urged caution because few high-quality head-to-head trials were available.
Sleep quality also improved significantly in people with chronic musculoskeletal pain. Seven studies showed melatonin produced clinically meaningful improvements on validated sleep measures, supporting growing evidence that targeting sleep disturbance may also help reduce chronic pain.
The researchers said melatonin’s effects could extend beyond its well-known role in regulating sleep, noting that clinical guidelines generally did not recommend it as a first-line treatment for insomnia.
They said laboratory and clinical evidence suggested melatonin influences multiple pain pathways through activation of MT2 receptors, modulation of opioid and GABA signalling, antioxidant activity, and suppression of inflammatory mediators. Improved sleep quality, reduced anxiety, and restoration of circadian rhythms may also contribute indirectly to lower pain levels.
The findings were less convincing in postoperative patients.
Fourteen trials examined melatonin after orthopaedic procedures including hip and knee arthroplasty, spinal surgery, fracture repair, and rib fractures. Although melatonin reduced postoperative pain compared with placebo, its overall effects were no better than those achieved with conventional analgesics or other active medications.
The reduction in pain also failed to reach the accepted threshold for a clinically important improvement in acute postoperative pain. Similarly, melatonin did not significantly improve postoperative sleep quality.
Treatment regimens varied substantially across studies. Chronic pain trials generally used oral doses between 3mg and 10mg daily for periods ranging from four weeks to three months.
Postoperative studies used doses from 1mg to 10mg, often administered only once before surgery. Exploratory analyses found no evidence that higher doses produced greater pain relief. Instead, longer treatment duration appeared more closely associated with improved outcomes in chronic musculoskeletal pain.
The review also highlighted melatonin’s safety profile. Fourteen studies reported adverse events, with nausea, dizziness, headache, and drowsiness the most commonly observed side effects.
These were generally mild and transient, with no serious safety concerns identified. The researchers noted that previous reviews had similarly found no evidence that long-term or high-dose melatonin caused dependence or major adverse effects.
The researchers also compared melatonin’s effect size with those reported for NSAIDs, finding broadly similar estimates for pain reduction in chronic musculoskeletal conditions. However, they stressed this should not be interpreted as therapeutic equivalence.
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While some pooled results were statistically significant, many failed to exceed the accepted minimal clinically important difference of around 11-14 points on a 100-point pain scale.
Combined with the low certainty of evidence and relatively small sample sizes, that limited confidence in recommending melatonin as a frontline analgesic, the researchers said.
“In summary, melatonin seems to offer benefits for reducing pain and improving sleep in people with chronic MSK pain,” they concluded.
“These pain effects are comparable in magnitude with those of conventional analgesics (e.g., NSAIDs), although the similarity in estimate magnitude does not indicate therapeutic equivalence.
“For people with postoperative pain, melatonin is more effective than placebo and shows similar effects to analgesic and non-analgesic medications.
“Given the current evidence, melatonin may be considered as an adjunct option, with modest effects and low-to-moderate certainty.
“Further high-quality RCTs with standardised dosing and longer follow-up are needed to better inform melatonin’s clinical use.”
Lead author and University of Sydney PhD student Kangchao Wu from the Musculoskeletal Research Hub at the Charles Perkins Centre and the School of Health Sciences, said the low-cost, readily available option showed exciting promise.
“For many patients, pain doesn’t exist in isolation and is closely tied to poor sleep,” he said.
“Melatonin appears to target both, which makes it particularly useful for people managing chronic pain.”
Co-author Professor Paulo Ferreira, Director of the Musculoskeletal Research Hub, said the research highlighted the growing potential of drug repurposing – using existing treatments in new ways to deliver faster, more accessible health benefits.
“We’re taking a medication we already understand and applying it to a problem that affects a huge proportion of the global population,” Professor Ferreira said.
