Efficacy and Safety of Melatonin as Prophylaxis for Migraine in Adults: A Meta-analysis

Aims: To evaluate the efficacy and safety of melatonin for migraine prophylaxis in adults. Methods: After a comprehensive literature search in the MEDLINE, Cochrane Database, and International Clinical Trial Registry Platform databases, reviewers extracted data from three relevant articles. PRISMA guidelines were followed in the selection, analysis, and reporting of the findings. Quality assessment was performed using the Cochrane risk of bias assessment tool. A random-effects model was used to estimate the effect size, and meta-regression was performed for variables with a likely influence on effect size. Subgroup analysis was performed based on the comparison used in the included studies. Results: Melatonin therapy in migraine was associated with a significantly higher responder rate when compared to both placebo and standard therapy (OR = 1.84; 95% CI: 1.08 to 3.14; P = .03). The results of the meta-analyses indicated that melatonin can achieve a significant reduction in frequency of migraine attacks (MD = 1.00; 95% CI: 0.02 to 1.98; P = .04), migraine attack duration (MD = 5.02; 95% CI: 0. 91 to 9.13; P = .02), use of analgesics (MD = 1.43; 95% CI: 0.38 to 2.48; P = .008), and migraine severity (MD = 1.93; 95% CI: 1.23 to 2.63; P < .0001) over placebo, but had no significant effects in comparison to amitriptyline or valproate. There was no significant difference in the occurrence of common adverse drug reactions, such as drowsiness and fatigue, between the melatonin group and the comparison groups. Conclusions: Melatonin showed a beneficial prophylactic role in migraine, with a better responder rate in comparison to placebo in reducing migraine severity, mean attack duration, mean attack frequency, and analgesic use, but did not show significant effects in comparison to amitriptyline or valproate.

frequency of migraine attacks; melatonin; meta-analysis; migraine; migraine attack duration; migraine severity; prophylaxis; responder rate

1. Puledda F, Messina R, Goadsby PJ. An update on migraine: Current understanding and future directions. J Neurol 2017;264:2031–2039.

2. Gonçalves AL, Martini Ferreira A, Ribeiro RT, Zukerman E, Cipolla-Neto J, Peres MF. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry 2016;87:1127–1132.

3. Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry 2010;81:428–432.

4. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:343–349.

5. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1337–1345.

6. Stewart WF, Shechter A, Lipton RB. Migraine heterogeneity. Disability, pain intensity, and attack frequency and duration. Neurology. 1994;44(6 Suppl 4):S24–S39.

7. Piccinni C, Cevoli S, Ronconi G, et al. A real-world study on unmet medical needs in triptan-treated migraine: Prevalence, preventive therapies and triptan use modification from a large Italian population along two years. J Headache Pain 2019;20:74.

8. Kumar A, Kadian R. Migraine Prophylaxis. Treasure Island: StatPearls, 2020.

9. Bettahi I, Pozo D, Osuna C, Reiter RJ, Acuña-Castroviejo D, Guerrero JM. Melatonin reduces nitric oxide synthase activity in rat hypothalamus. J Pineal Res 1996;20:205–210.

10. Danilov A, Kurganova J. Melatonin in chronic pain syndromes. Pain Ther 2016;5:1–17.

11. Zisapel N. Melatonin-dopamine interactions: From basic neurochemistry to a clinical setting. Cell Mol Neurobiol 2001;21:605–616.

12. Ramadan NM. The link between glutamate and migraine. CNS Spectr 2003;8:446–449.

13. Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA. Potential therapeutic use of melatonin in mi-graine and other headache disorders. Expert Opin Investig Drugs 2006;15:367–375.

14. Vogler B, Rapoport AM, Tepper SJ, Sheftell F, Bigal ME. Role of melatonin in the pathophysiology of migraine: Implications for treatment. CNS Drugs 2006;20:343–350.

15. Gagnier JJ. The therapeutic potential of melatonin in migraines and other headache types. Altern Med Rev 2001;6:383–389.

16. Leite Pacheco R, de Oliveira Cruz Latorraca C, Adriano Leal Freitas da Costa A, Luiza Cabrera Martimbianco A, Vianna Pachito D, Riera R. Melatonin for preventing primary headache: A systematic review. Int J Clin Pract 2018;72:e13203.

17. Chen IJ, Yang CP, Lin SH, Lai CM, Wong CS. The circadian hormone melatonin inhibits morphine-induced tolerance and inflammation via the activation of antioxidative enzymes. Antioxidants (Basel). 2020;9:780.

18. Fakhri S, Ahmadpour Y, Rezaei H, et al. The antinociceptive mechanisms of melatonin: Role of L-arginine/nitric oxide/cyclic GMP/KATP channel signaling pathway. Behav Pharmacol 2020;31:728–737.

19. Zhu S, McGeeney B. When indomethacin fails: Additional treatment options for “indomethacin responsive headaches”. Curr Pain Headache Rep 2015;19:7.

20. Ebrahimi-Monfared M, Sharafkhah M, Abdolrazaghnejad A, Mohammadbeigi A, Faraji F. Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial. Restor Neurol Neurosci 2017;35:385–393.

21. Alstadhaug KB, Odeh F, Salvesen R, Bekkelund SI. Prophylaxis of migraine with melatonin: A randomized controlled trial. Neurology 2010;75:1527–1532.

22. Long R, Zhu Y, Zhou S. Therapeutic role of melatonin in migraine prophylaxis: A systematic review. Medicine (Baltimore). 2019;98:e14099.

23. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1.

24. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.

25. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: A new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev 2019;10:ED000142.

26. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1:9–160.

27. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808.

28. Tassorelli C, Diener HC, Dodick DW, et al. Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine in adults. Cephalalgia 2018;38:815–832.

29. Review Manager. Version 3.5. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

30. R: A Language and Environment for Statistical Computing. Version 3.4. Vienna: R Foundation for Statistical Computing, 2013.

31. GRADEpro Guideline Development Tool. Hamilton, Ontario, Canada: McMaster University, Evidence Prime, 2015.

32. Fallah R, Fazelishoroki F, Sekhavat L. A randomized clinical trial comparing the efficacy of melatonin and amitripty-line in migraine prophylaxis of children. Iran J Child Neurol 2018;12:47–54.

33. Fallah R, Shoroki FF, Ferdosian F. Safety and efficacy of melatonin in pediatric migraine prophylaxis. Curr Drug Saf 2015;10:132–135.

34. Gelfand AA, Qubty W, Patniyot I, et al. Home-based trials in adolescent migraine: A randomized clinical trial. JAMA Neurol 2017;74:744–745.

35. Peres MF, Zukerman E, da Cunha Tanuri F, Moreira MF, Cipolla-Nieto J. Melatonin, 3 mg, is effective for migraine pre-vention. Neurology 2004;63:757.

36. Bougea A, Spantideas N, Lyras V, Avramidis T, Thomaidis T. Melatonin 4 mg as prophylactic therapy for primary headaches: A pilot study. Funct Neurol 2016;31:33–37.

37. Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX. Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci 2000;917:376–386.

38. Gurunathan S, Kang MH, Kim JH. Role and therapeutic potential of melatonin in the central nervous system and cancers. Cancers (Basel). 2020;12:1567.

39. Singh M, Jadhav HR. Melatonin: Functions and ligands. Drug Discov Today 2014;19:1410–1418.