A bidirectional relationship appears to connect tension-type headache (TTH) and circadian dysregulation. The present systematic review examined the published evidence for melatonin (MT) supplementation in the prophylaxis of TTH. Initially, we reviewed case-control studies investigating nocturnal MT or 6-sulphatoxymelatonin (aMT6s, a urine-discarded metabolite) in TTH individuals and healthy controls (HC). Secondly, we reviewed studies appraising the use of MT in the prevention of TTH.

The search strategy involved MEDLINE EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar and OpenGrey. Case-control studies were appraised according to the Newcastle-Ottawa-Scale, whereas randomised controlled trials were assessed based on the risk-of-bias Cochrane tool. Infrequent, as well as frequent, episodic, and chronic TTH patients were evaluated separately in children and adults.

Our search strategy yielded two case-control studies. One (high-quality) did not reveal any difference in morning salivary MT concentration between children with frequent episodic TTH and HC. The second (moderate-quality) was indicative of a disturbed nocturnal secretion pattern in adults with chronic TTH. For the second part, five uncontrolled studies were retrieved. In total, 94 adults with chronic TTH were assessed and results were suggestive of a beneficial effect of MT on headache frequency, intensity, induced disability, and induced analgesic consumption. However, the uncontrolled-unblinded designs may have induced an important placebo effect. Non-adult populations and frequent TTH were substantially understudied.

There are not enough studies to designate the role of MT in the prevention of TTH. Given the disease's background, additional relevant research is warranted for chronic TTH.