Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention

Abstract

IntroductionMelatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.MethodsA 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.ResultsMean 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.ConclusionsMelatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.

The Role of Melatonin in the Treatment of Primary Headache Disorders

“…The observed reduction in headache frequency at 3 months was: 2.7 in those treated with melatonin, 2.2 for amitriptyline ( P = .19), and 1.2 for placebo ( P = .009). The tolerability of melatonin was comparable to placebo and better than amitriptyline . In contrast, in a smaller randomized, double‐blind cross‐over design study of 46 subjects, 2 mg of sustained release melatonin was not different from placebo for migraine prevention after 8 weeks of treatment .…”

“…Melatonin's comparatively favorable side effect profile compared to indomethacin makes it a desirable treatment candidate. The side effects of melatonin are generally few and mild, even at high dosages; daytime tiredness and dizziness are possible …”

“…For migraine, 3 mg appears to be the minimum effective dose in adults, and uncontrolled data suggest a slightly higher dose of 4 mg may also be helpful . Further work is needed to determine whether there is a dose‐response.…”

“…It is often not explicitly stated whether immediate release or prolonged release melatonin is being used in treatment trials, though when not specified it is probably more likely to be immediate release melatonin. In migraine, the positive RCT used immediate release melatonin and the underpowered negative study used sustained release melatonin and also a lower dose . Hence, currently immediate release melatonin appears preferable in the treatment of migraine.…”

Biology of Neuropeptides: Orexinergic Involvement in Primary Headache Disorders

“…This altered functional connectivity highlights a key role for the hypothalamus in the earliest phase of the attack and demonstrates a significant unmet need to identify which hypothalamic networks (anatomical and pharmacological) may be involved in attack initiation. While several candidate neuropeptide systems have been proposed including dopamine, oxytocin, neuropeptide Y, and melatonin, the current review will focus on the hypothalamic specific orexin (hypocretin) system and its potential role in primary headaches.…”