Melatonin for Migraine Prevention in Children and Adolescents: A Systematic Review of Randomized Controlled Trials
Yara Shaalan1, Shams Albarari2, Rewan Ramadan3, Ainaa A. Alzamari4, Noon Elimam5, Rahaf Mogahed6, Nourhan Elmekkawi7, Arwa Abdelaziz Mostafa8, Eman Fathy9
1Faculty of Medicine, Misr University for Science and Technology, 6th of October City, Egypt, 2Faculty of Medicine, Tbilisi State Medical University, Tbilisi, Georgia, 3Faculty of Pharmacy, Mansoura University, Mansoura, Egypt, 4Palestinian medical complex, Faculty of Medicine, Al-Quds University, Palestine, 5Faculty of Medicine, Bogomolets National Medical University, Kyiv, Ukraine, 6Faculty of Medicine, 6th of October University, 6th of October city, Egypt, 7Zifta General Hospital, Egypt, 8Faculty of Medicine, Mansoura university, Mansoura, Egypt, 9MSc Candidate in the Neuromuscular Disorders and Its Surgeries Department, Faculty of Physical Therapy, Cairo University, Egypt; Physiotherapist, Physical Therapy Department, Damietta General Hospital, Damietta, Egypt
Objective:
To evaluate the efficacy and safety of melatonin for the prevention of migraine in children and adolescents.
Background:
Melatonin is a neurohormone involved in the regulation of circadian rhythms, with proposed migraine preventive mechanisms through its anti-inflammatory, analgesic, antioxidant, and neuroprotective properties. While evidence supports its efficacy in adults, its role in pediatric populations remains less defined.
Design/Methods:
A systematic literature search was conducted across MEDLINE (PubMed), Cochrane Central Register of Controlled Trials, Scopus, and Web of Science until May 2025. Randomized controlled trials (RCTs) of melatonin for migraine prophylaxis in patients aged 2-17 years were included. Exclusion criteria comprised other headache types, combination therapies, and non-trial publications. Two independent reviewers performed the study selection and data extraction.
Results:
Three RCTs (113 participants) met the inclusion criteria. Melatonin was consistently well tolerated, with no serious adverse events reported. In one RCT (n = 42) comparing melatonin with placebo, there was no significant difference in the reduction of monthly headache frequency (mean difference: melatonin -10.3 ± 6.3 vs. placebo -10.0 ± 7.2; p = 0.93). In two RCTs comparing melatonin with amitriptyline, amitriptyline demonstrated significantly greater efficacy, leading to a larger reduction in monthly headache frequency (Study 1: melatonin -7.67 ± 4.8 vs. amitriptyline -11.52 ± 6.9 attacks/month; p < 0.001; Study 2: melatonin -10.44 ± 4.2 vs. amitriptyline -12.54 ± 4.6 attacks/month; p < 0.0001) and a higher rate of ≥50% reduction in headache frequency (“good response”) (Study 1: melatonin 62.5% vs. amitriptyline 82.5%; Study 2: melatonin 66.7% vs. amitriptyline 84.4%; p < 0.04 for both).
Conclusions:
Melatonin is a safe and well-tolerated preventive treatment for pediatric migraine; however, it has not demonstrated superiority to placebo and appears less effective than amitriptyline. These conclusions are based on limited evidence, underscoring the need for larger trials to better define its potential role in therapy.
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