Melatonin for migraine prevention in children and adolescents: A randomized, double-blind, placebo-controlled trial after single-blind placebo lead-in. 2023

Amy A Gelfand, and I Elaine Allen, and Barbara Grimes, and Samantha Irwin, and William Qubty, and Kaitlin Greene, and Maggie Waung, and Scott W Powers, and Christina L Szperka
Child & Adolescent Headache Program, University of California San Francisco, San Francisco, California, USA.

Melatonin is effective for migraine prevention in adults. We hypothesized that melatonin would also be effective for migraine prevention in children and adolescents. This was a randomized, double-blind trial of melatonin (3 mg or 6 mg) versus placebo for migraine prevention in 10-17 year-olds with 4-28/28 headache days at baseline. Participants were recruited from the UCSF Child & Adolescent Headache Program, UCSF child neurology clinic, and social media advertisements. Migraine diagnosis was confirmed by a headache specialist. Participants completed an 8-week single-blind placebo run-in. Those meeting randomization criteria (≥4 headache days and ≥23/28 electronic diary entries during weeks 5-8) were randomized 1:1:1 to placebo:melatonin 3 mg:melatonin 6 mg nightly for 8 weeks. The primary outcome measure was migraine days in weeks 5-8 of randomized treatment between melatonin (combined 6 mg + 3 mg) versus placebo. We aimed to enroll n = 210. The study closed early due to slow enrollment (n = 72). Two participants were in the single-blind phase when the study closed, therefore the meaningful n = 70. Sixteen percent (11/70) were lost to follow-up during the single-blind phase. An additional 21% (15/70) did not meet randomization criteria (<4 headache days: n = 5, <23/28 diary days: n = 7, both: n = 3). Sixty-three percent (44/70) were eligible to randomize, of whom 42 randomized (n = 14 per arm). Taking another preventive at enrollment (OR 8.3, 95% CI 1.01 to 68.9) was the only variable associated with meeting randomization criteria. Of those randomized, 91% (38/42) provided diary data in the final 4-weeks. However, given the amount of missing data, only those with ≥21/28 diary days were analyzed-7/14 (50%) in the placebo group, and 20/28 (71%) in the melatonin groups combined. Median (IQR) migraine/migrainous days in weeks 5-8 of double-blind treatment was 2 (1-7) in the placebo group versus 2 (1-12) in the melatonin groups combined; the difference in medians (95% CI for the difference) was 0 days (-9 to 3). There were no differences in adverse events between groups. When compared to recall at enrollment, headache days decreased across the single-blind placebo phase and the double-blind phase. There was no suggestion of superiority of melatonin; however, given the substantial portion of missing data, numerically higher in the placebo arm, and underpowering, this should not be interpreted as proof of inefficacy. Melatonin was generally well tolerated with no serious adverse events. Future migraine preventive trials in this age group may find this trial helpful for anticipating enrollment needs if using a single-blind placebo run-in. Enriching for those already on a migraine preventive may improve randomization rates in future trials, though would change the generalizability of results.

UI MeSH Term Description Entries
D008550 Melatonin A biogenic amine that is found in animals and plants. In mammals, melatonin is produced by the PINEAL GLAND. Its secretion increases in darkness and decreases during exposure to light. Melatonin is implicated in the regulation of SLEEP, mood, and REPRODUCTION. Melatonin is also an effective antioxidant.
D008881 Migraine Disorders A class of disabling primary headache disorders, characterized by recurrent unilateral pulsatile headaches. The two major subtypes are common migraine (without aura) and classic migraine (with aura or neurological symptoms). (International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004: suppl 1) Acute Confusional Migraine,Headache, Migraine,Status Migrainosus,Abdominal Migraine,Cervical Migraine Syndrome,Hemicrania Migraine,Migraine,Migraine Headache,Migraine Variant,Sick Headache,Abdominal Migraines,Acute Confusional Migraines,Cervical Migraine Syndromes,Disorder, Migraine,Disorders, Migraine,Headache, Sick,Headaches, Migraine,Headaches, Sick,Hemicrania Migraines,Migraine Disorder,Migraine Headaches,Migraine Syndrome, Cervical,Migraine Syndromes, Cervical,Migraine Variants,Migraine, Abdominal,Migraine, Acute Confusional,Migraine, Hemicrania,Migraines,Migraines, Abdominal,Migraines, Acute Confusional,Migraines, Hemicrania,Sick Headaches,Variant, Migraine,Variants, Migraine
D002648 Child A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL. Children
D004311 Double-Blind Method A method of studying a drug or procedure in which both the subjects and investigators are kept unaware of who is actually getting which specific treatment. Double-Masked Study,Double-Blind Study,Double-Masked Method,Double Blind Method,Double Blind Study,Double Masked Method,Double Masked Study,Double-Blind Methods,Double-Blind Studies,Double-Masked Methods,Double-Masked Studies,Method, Double-Blind,Method, Double-Masked,Methods, Double-Blind,Methods, Double-Masked,Studies, Double-Blind,Studies, Double-Masked,Study, Double-Blind,Study, Double-Masked
D006261 Headache The symptom of PAIN in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of HEADACHE DISORDERS. Cephalgia,Hemicrania,Bilateral Headache,Cephalalgia,Cephalodynia,Cranial Pain,Generalized Headache,Head Pain,Ocular Headache,Orthostatic Headache,Periorbital Headache,Retro-Ocular Headache,Sharp Headache,Throbbing Headache,Unilateral Headache,Vertex Headache,Bilateral Headaches,Cephalalgias,Cephalgias,Cephalodynias,Cranial Pains,Generalized Headaches,Head Pains,Headache, Bilateral,Headache, Generalized,Headache, Ocular,Headache, Orthostatic,Headache, Periorbital,Headache, Retro-Ocular,Headache, Sharp,Headache, Throbbing,Headache, Unilateral,Headache, Vertex,Headaches,Headaches, Bilateral,Headaches, Generalized,Headaches, Ocular,Headaches, Orthostatic,Headaches, Periorbital,Headaches, Retro-Ocular,Headaches, Sharp,Headaches, Throbbing,Headaches, Unilateral,Headaches, Vertex,Ocular Headaches,Orthostatic Headaches,Pain, Cranial,Pain, Head,Pains, Cranial,Pains, Head,Periorbital Headaches,Retro Ocular Headache,Retro-Ocular Headaches,Sharp Headaches,Throbbing Headaches,Unilateral Headaches,Vertex Headaches
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000293 Adolescent A person 13 to 18 years of age. Adolescence,Youth,Adolescents,Adolescents, Female,Adolescents, Male,Teenagers,Teens,Adolescent, Female,Adolescent, Male,Female Adolescent,Female Adolescents,Male Adolescent,Male Adolescents,Teen,Teenager,Youths
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D016037 Single-Blind Method A method in which either the observer(s) or the subject(s) is kept ignorant of the group to which the subjects are assigned. Single-Masked Study,Single-Blind Study,Single-Masked Method,Method, Single-Blind,Method, Single-Masked,Methods, Single-Blind,Methods, Single-Masked,Single Blind Method,Single Blind Study,Single Masked Method,Single Masked Study,Single-Blind Methods,Single-Blind Studies,Single-Masked Methods,Single-Masked Studies,Studies, Single-Blind,Studies, Single-Masked,Study, Single-Blind,Study, Single-Masked
D016896 Treatment Outcome Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series. Rehabilitation Outcome,Treatment Effectiveness,Clinical Effectiveness,Clinical Efficacy,Patient-Relevant Outcome,Treatment Efficacy,Effectiveness, Clinical,Effectiveness, Treatment,Efficacy, Clinical,Efficacy, Treatment,Outcome, Patient-Relevant,Outcome, Rehabilitation,Outcome, Treatment,Outcomes, Patient-Relevant,Patient Relevant Outcome,Patient-Relevant Outcomes

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