Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention
Open accessAbstract
INTRODUCTION: Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use. METHODS: A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18-65 years, with migraine with or without aura, experiencing 2-8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups. RESULTS: Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users. CONCLUSIONS: Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.
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Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency.
“Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency, and melatonin was better tolerated than amitriptyline.”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [109]
Melatonin was better tolerated than amitriptyline.
“Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency, and melatonin was better tolerated than amitriptyline.”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [109]
In a randomized, multi-center, parallel-group design, a 3 mg dose of melatonin reduced migraine frequency, demonstrating the same effectiveness as amitriptyline in the primary endpoint of the frequency of migraine headaches per month.
“A randomized, multi-center, parallel-group design was conducted in which melatonin was compared with amitriptyline and placebo for twelve weeks. A 3 mg dose of melatonin reduced migraine frequency, demonstrating the same effectiveness as amitriptyline in the primary endpoint of the frequency of migraine headaches per month [109].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [109]
Melatonin has also been reported as an effective treatment for primary headache disorders.
“It has also been reported as an effective treatment for primary headache disorders [109].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [109]
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- Authors
- Gonçalves, A. L., Martini Ferreira, A., Ribeiro, R. T., Zukerman, E., Cipolla-Neto, J., & Peres, M. F. P.
- Affiliations
- Faculdade de Medicina do ABC (BR)
- Hospital Israelita Albert Einstein (BR)
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2016-05-10
- Volume
- 87
- Issue
- 10
- Pages
- 1127-1132
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- PMC
- PMC5036209
- OpenAlex
- W2347737266
- Cited by
- 169
- References
- 25
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 28 · 2023: 16 · 2022: 23 · 2021: 17 · 2020: 20 · 2019: 12 · 2018: 13 · 2017: 12 · 2016: 3
- FWCI
- 11.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (0854258-0)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Migraine and Headache Studies
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Health Professions › Complementary and Manual Therapy › Temporomandibular Joint Disorders
- Keywords
- melatonin, amitriptyline, migraine prophylaxis, migraine with or without aura, headache frequency, drug tolerability, weight gain, analgesic use, migraine intensity
- MeSH terms
- Adolescent, Adult, Aged, Amitriptyline, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Melatonin, Middle Aged, Migraine Disorders, Young Adult
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