EC Clinical and Medical Case Reports

Migraine is a global chronic disorder. According to World Health Organization (WHO) estimation, the worldwide prevalence of current migraine to be 10% and the lifetime prevalence to be 14%. Several classes of drugs such beta blocker, antiseizure drugs, amitriptyline and nortriptyline, serotonin-norepinephrine reuptake inhibitors, calcitonin gene-related peptide (CGRP) antibodies, NSAIDS, antihypertensive drugs, botulinum toxin type A are used to prevent migraine. While these drugs are effective to prevent headache the adverse effects sometimes become intolerable for many patients. Therefore, there is a need for a preventative therapy with less or no adverse effect profile. Melatonin, which is a pleiotropic hormone synthesized and secreted mainly by the pineal gland in vertebrates, can be a good option as it significantly minimizes the adverse effect. Melatonin is an endogenous regulator of circadian and seasonal rhythms. Melatonin is involved in many physiological and pathophysiological processes demonstrating antioxidant, antineoplastic, anti-inflammatory and immunomodulatory properties. Accumulating evidence has revealed that melatonin plays an important role in pain modulation through multiple mechanisms. Melatonin is also available in multiple dosage forms and can be administered through various routes of administration, including oral, sublingual, trans-buccal, topical and intramuscular. It can be used by pediatric patients, geriatric patients with sleep disorder eliminating all the adverse effects caused by other drugs. In this review article we discuss the results of the clinical studies that demonstrated melatonin as an effective and more tolerable preventive agent for migraine with fewer side effects.

Keywords: Melatonin; Migraine Prevention; Endogenous Hormone; Headache; Chronic Migraine

1. Bigal ME., et al. “The epidemiology and impact of migraine”. Current Neurology and Neuroscience Reports2 (2004): 98-104.
2. Lipton RB., et al. “Migraine prevalence, disease burden, and the need for preventive therapy”. Neurology5 (2007): 343-349.
3. Buse DC., et al. “Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers”. Journal of Neurology, Neurosurgery, and Psychiatry 4 (2010): 428-432.
4. Silberstein SD., et al. “Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. 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”. Neurology17 (2012): 1337-1345.
5. Modi S and Lowder DM. Medications for Migraine Prophylaxis Brody School of Medicine at East Carolina University, Greenville, North Carolina.
6. Kazi F., et al. Second-line interventions for migraine in the emergency department: A narrative review Headache Current (2021).
7. Galletti F., et al. “Pathophysiological basis of migraine prophylaxis”. Progress in Neurobiology 2 (2009): 176-192.
8. Glaser A. CGRP for migraine: what it is, why it matters, and how to get it (2019).
9. Melatonin Monograph. In: Clinical Pharmacology. Tampa, FL: Gold Standard, Inc. Online Database.
10. Monograph. Alternative Medicine Review 10 (2005): 326-336.
11. In: Natural Medicines. Somerville, MA: Therapeutic Research Center. Online database.
12. Melatonin (Natural Products Database). In: Lexicomp Online. Hudson, OH: Lexi-Comp.
13. Tordjman S., et al. “Melatonin: Pharmacology, Functions and Therapeutic Benefits”. Current Neuropharmacology 3 (2017): 434-443.
14. Dubocovich ML. “Melatonin receptors: are there multiple subtypes?” Trends in Pharmacological Sciences 2 (1995): 50-56.
15. Ebisawa T., et al. “Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores”. Proceedings of the National Academy of Sciences of the United States of America 13 (1994): 6133-6137.
16. Cardinali DP., et al. “Melatonin site and mechanism of action: single or multiple?” Journal of Pineal Research 1 (1997): 32-39.
17. Hattori A., et al. “Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates”. Biochemistry and Molecular Biology International 3 (1995): 627-634.
18. Claustrat B., et al. “Nocturnal plasma melatonin levels in migraine: a preliminary report”. Headache 4 (1989): 242-245.
19. Peres MFP. “Melatonin, the pineal gland and their implications for headache disorders”. The International Classification of Headache6 (2005): 403-411.
20. Masruha MR., et al. “Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities”. Headache3 (2010): 413-419.
21. Masruha MR., et al. “Low urinary 6-sulphatoxymelatonin concentrations in acute migraine”. The Journal of Headache and Pain 4 (2008): 221-224.
22. Claustrat B., et al. “Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus”. Cephalalgia: an International Journal of Headache 4 (1997): 511-517.
23. Peres MFP., et al. “Potential therapeutic use of melatonin in migraine and other headache disorders”. Expert Opinion on Investigational Drugs 4 (2006): 367-375.
24. Peres M., et al. “Chronobiological features in episodic and chronic migraine”. Cephalalgia 7 (2003): 9600.
25. Peres MF., et al. “Hypothalamic involvement in chronic migraine”. Journal of Neurology, Neurosurgery, and Psychiatry 6 (2001): 747-751.
26. Bruera O., et al. “Plasma melatonin pattern in chronic and episodic headaches: evaluation during sleep and waking”. Functional Neurology 2 (2008): 77-81.
27. Tanuri FC., et al. “Melatonin treatment decreases c-fos expression in a headache model induced by capsaicin”. Journal of Pineal Research 2 (2009): 105-110.
28. Mantovani M., et al. “Mechanisms involved in the antinociception caused by melatonin in mice”. Journal of Pineal Research 4 (2006): 382-389.
29. Vogler B., et al. “Role of melatonin in the pathophysiology of migraine: implications for treatment”. CNS Drugs 5 (2006): 343-350.
30. Gagnier JJ. “The therapeutic potential of melatonin in migraines and other headache types”. Alternative Medicine Review: a Journal of Clinical Therapeutic 4 (2001): 383-389.
31. Peres MFP., et al. “Melatonin, 3 mg, is effective for migraine prevention”. Neurology 4 (200 4): 757.
32. Nagtegaal JE., et al. “Melatonin-responsive headache in delayed sleep phase syndrome: preliminary observations”. Headache4 (1998): 303-307.
33. Miano S., et al. “Melatonin to prevent migraine or tension-type headache in children”. Neurological Society and of the Italian Society of Clinical Neurophysiology 4 (2008): 285-287.
34. Alstadhaug KB., et al. “Prophylaxis of migraine with melatonin: a randomized controlled trial”. Neurology17 (2010): 1527-1532.
35. Anastasia Bougea., et al. “Melatonin 4 mg as prophylactic therapy for primary headaches: a pilot study”. Functional Neurology 1 (2016): 33-37.
36. Fallah R., et al. “Safety and efficacy of melatonin in pediatric migraine prophylaxis”. Current Drug Safety 2 (2015): 132-135.
37. Gonçalves AL., et al. “Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention”. Journal of Neurology, Neurosurgery, and Psychiatry 10 (2016): 1127-1132.
38. Amy A Gelfand., et al. “Home-Based Trials in Adolescent Migraine: A Randomized Clinical Trial”. JAMA Neurology6 (2017): 744-745.
39. Gelfand A. “Melatonin for Adolescent Migraine Prevention Study (The MAP Study)”. Clinical Trials (2021).
40. Alstadhaug KB., et al. “Prophylaxis of migraine with melatonin: a randomized controlled trial”. Neurology 17 (2010): 1527-1532.
41. Kelley NE and Tepper DE. “Rescue therapy for acute migraine, part 2: neuroleptics, antihistamines, and others”. Headache 52 (2012): 292.
42. Rizzoli PB. “Acute and preventive treatment of migraine”. Continuum 18 (2012): 764.
43. Friedman BW., et al. “Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine”. Neurology 82 (2014): 976.
44. Orr SL., et al. “Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings”. Cephalalgia 35 (2015): 271.
45. Marmura MJ., et al. “The acute treatment of migraine in adults: the American headache society evidence assessment of migraine pharmacotherapies”. Headache 55 (2015): 3.
46. Melatonin Monograph. In: MicroMedex 2.0. Ann Arbor, MI: Truven Health Analytics. Online Database (2022).
47. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/beta-blockers/art-20044522
48. General side effects and challenges associated with anti-epilepsy medication: A review of related literature, African Journal of Primary Health Care and Family Medicine (2020).
49. Adverse Drug Effects, Compliance, and Initial Doses of Antihypertensive Drugs Recommended by the Joint National Committee vs the Physicians' Desk Reference) (2001).
50. Onabotulinumtoxin A: Generic, Uses, Side Effects, Dosages, Interactions, Warnings (rxlist.com).
51. Colmenero MD., et al. “Melatonin administration during pregnancy retards sexual maturation of female offspring in the rat”. Journal of Pineal Research 1 (1991): 23-27.
52. Jahnke G., et al. “Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats”. Basic and Clinical Pharmacology and Toxicology 2 (1999): 271-279.
53. Voordouw BC., et al. “Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation”. The Journal of Clinical Endocrinology and Metabolism 1 (1992): 108-117.
54. Cavallo A and Ritschel WA. “Pharmacokinetics of melatonin in human sexual maturation”. The Journal of Clinical Endocrinology and Metabolism 5 (1996): 1882-1886.
55. Commentz JC., et al. “Melatonin and 6-hydroxymelatonin sulfate excretion is inversely correlated with gonadal development in children”. Hormone Research in Paediatrics 3 (1997): 97-101.
56. Carman JS., et al. “Negative effects of melatonin on depression”. The American Journal of Psychiatry 10 (1976): 1181-1186.
57. Wirtz PH., et al. “Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men”. Journal of Pineal Research 2 (2008): 127-133.
58. Cagnacci A., et al. “Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women”. Clinical Endocrinology 3 (2001): 339-346.
59. Sandyk R., et al. “Melatonin as a proconvulsive hormone in humans”. International Journal of Neuroscience 1-2 (1992): 125-135.
60. Sheldon SH. “Pro-convulsant effects of oral melatonin in neurologically disabled children”. Lancet 9111 (1998): 1254.
61. pdf (2022).
62. Lusardi P., et al. “Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study”. British Journal of Clinical Pharmacology 5 (2000): 423-427.
63. Weekley LB. “Melatonin-induced relaxation of rat aorta: interaction with adrenergic agonists”. Journal of Pineal Research 1 (1991): 28-34.
64. Härtter S., et al. “Increased bioavailability of oral melatonin after fluvoxamine coadministration”. Clinical Pharmacology and Therapeutics 1 (2000): 1-6.
65. Von Bahr C., et al. “Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin”. European Journal of Clinical Pharmacology 2 (2000): 123-127.