Melatonin Compared to Other Treatments for Episodic Migraine: A Systematic Review and Network Meta-Analysis

Migraine is one of the most common neurological diseases, presenting different characteristics among patients. Therefore, there is a need to identify preventive medications that offer more efficacy and fewer adverse effects. Melatonin is a promising therapeutic alternative in this context due to its analgesic, neuromodulatory and cerebral blood flow regulatory mechanism.

This study aims to evaluate the efficacy of melatonin treatment compared to placebo and other drugs in reducing migraine episodes' frequency and secondary outcomes by analyzing randomized clinical trials.

The databases Cochrane, Embase and PubMed were used to search and select relevant studies, according to their specific inclusion criteria. Afterward, the relevant data was extracted, and statistical analysis was conducted with R Studio version 4.3.1, applying appropriate models to maintain heterogeneity within them and produce a combined estimate. Results were interpreted considering potential biases and limitations to form our final statement with the Risk of Bias (RoB 2.0) tool from Cochrane.

A total of nine studies involving 783 patients were included in our analysis. Treatment methods were composed of seven different strategies. The network meta-analysis showed no statistically significant differences related to monthly headache frequency between melatonin and amitriptyline (SD: -1.8; 95% Crl [-5.2, 1.0]); naproxen (SD: -0.98; 95% Crl [-5.5, 3.8]); valproic acid (SD: -0.60; 95% Crl [-5., 3.6]); topiramate (SD: 0.081; 95% Crl [-5.0, 4.7]); propanolol (SD: 1.4; 95% Crl [-3.7, 6.6]) and placebo (SD: 0.49; 95% Crl [-1.6, 2.7]). Other outcomes assessed were the MIDAS score, the mean number of analgesics used and headache duration, in hours, all of which had nonsignificant differences among treatment arms.

This systematic review and network meta-analysis found no substantial support for the efficacy of melatonin treatment in patients with episodic migraine, challenging the assumption of their correlation. Although the results showed no significant association between the disease and melatonin administration, more research is necessary to explore the influence of melatonin in migraine's pathophysiology and further potential indirect mechanisms by which melatonin usage could benefit those who have not responded to conventional therapies.