Tuesday, May 1, 2018

Melatonin for migraine prophylaxis

Interest in using melatonin for headache disorders has been developing for decades. Over the years, several clues have emerged to suggest that melatonin plays a role in a variety of headache disorders, including migraine, cluster, and tension. One of these clues is that melatonin levels are altered in patients suffering from some types of headaches. In patients with migraine headaches, for instance, some research shows that melatonin levels are lower on days when migraines occur compared with the days when they do not. Patients with chronic migraine also appear to have lower melatonin levels than those with episodic migraine.  Nighttime melatonin levels are also lower in patients with migraine compared with those without.

Imaging studies provide additional evidence for melatonin's role in migraine prevention. During migraine attacks, the hypothalamus is activated. Given the presence of melatonin receptors within the suprachiasmatic nucleus of the hypothalamus, it is conceivable that melatonin's binding and action in the hypothalamus could play a role in these headaches.

The role of melatonin in migraine headaches could also be related to its impact on sleep. Melatonin levels are increased at night, inducing the onset of sleep. Lack of sleep can be a migraine trigger, while adequate sleep can reduce migraine attacks.

Melatonin might also affect headaches through direct effects on pain and inflammation.  Animal studies show that melatonin can reduce pain perception in models of inflammation and neuropathic pain, possibly by binding receptors in the spinal cord or through a variety of other pathways.

Clinical research evaluating melatonin in patients with migraine headaches has focused on migraine prophylaxis. Most studies have found beneficial effects from melatonin on headache frequency; however, some of these studies also have serious methodologic limitations. Several uncontrolled studies found that taking melatonin over a period of 2-6 months significantly reduced migraine headache frequency in both adults and children. In these studies, about 62%-78% of patients had a greater than 50% reduction in migraine frequency at the end of the trial compared with at the beginning.

Ebrahimi-Monfared and colleagues  compared melatonin with sodium valproate and placebo in a randomized, double-blind, placebo-controlled trial. In this study, 105 adults with chronic migraine were allocated to receive melatonin 3 mg 30 minutes before bed, sodium valproate 200 mg daily, or placebo for 2 months. All patients also received nortriptyline 25 mg and propranolol 20 mg daily. Melatonin and sodium valproate reduced migraine headache frequency and duration to a similar degree, and each significantly more than placebo (P < .001). Melatonin reduced migraine attack frequency by about 40% and migraine duration by about 56% compared with baseline.

Gonçalves and colleagues conducted the most rigorous trial to date. In this randomized, double-blind, placebo-controlled trial, 196 adults with migraine headaches occurring two to eight times per month were allocated to receive melatonin 3 mg, amitriptyline 25 mg, or placebo at bedtime for 12 weeks. Melatonin reduced the number of migraine headache days by 2.7 compared with 2.2 with amitriptyline (P = .19) and 1.1 with placebo (P = .009). In terms of responder rate, melatonin was significantly more effective than amitriptyline. In the melatonin group, 54.4% of patients had a > 50% reduction in migraine frequency compared with 39.1% in the amitriptyline group (P < .05). Both melatonin and amitriptyline also significantly reduced migraine headache intensity and duration compared with placebo (P < .05).

In all clinical trials, melatonin was well tolerated, with sleepiness being the most commonly reported side effect. Less common side effects included fatigue, dizziness, constipation, stomach upset, and dry mouth. In the placebo-controlled trials, side effects were comparable to those of placebo and less common compared with either amitriptyline or sodium valproate.

Overall, the evidence supporting melatonin for migraine prevention is promising but still preliminary. Nonetheless, given the favorable tolerability and low risk for side effects, melatonin is an option that may be worth considering for reducing migraine frequency, severity, and duration in patients with frequent migraine headaches.

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 Oct;87(10):1127-32.

Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.

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.

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.

Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.

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(4):385-393.


Melatonin is known to be effective in curing migraine.

This study aimed to investigate the therapeutic effect of melatonin versus sodium valproate in the prophylaxis of chronic migraine.

This randomized, double-blind, placebo-controlled clinical trial included patients with chronic migraine who were divided into three equal sized groups, and baseline therapy with nortriptyline (10-25 mg) and propranolol (20-40 mg) was used. Patients in groups A, B, and C were adjunctively treated daily with 3 mg melatonin, 200 mg sodium valproate, and a placebo, respectively. The patients underwent treatment for 2 months and follow-up was done at baseline (baseline), first (I) and second month (II). Attack frequency (AF), attack duration, attack severity, Migraine Disability Assessment (MIDAS) score (within 3 months in two steps), analgesic intake, and drug side effects between the groups and during follow-up were compared.

The mean of monthly AF (melatonin: baseline: 4.2, I: 3.1, II: 2.5, p = 0.018; valproate: baseline: 4.3, I: 3.1, II: 2.3, p = 0.001; placebo: baseline: 4.1, I: 3.8, II: 3.8 p = 0.211), attack duration (hr) (melatonin: baseline: 19.8, I: 10.1, II: 8.7, p < 0.001; valproate: baseline: 19.5, I: 10.2, II: 8.8, p < 0.001; placebo: baseline: 19.6, I: 15.4, II: 14.1, p = 0.271), attack severity (melatonin: baseline: 7.3, I: 5.4, II: 3.5, p < 0.001; valproate: baseline: 7.4, I: 5.3, II: 3.4, p = 0.000; placebo: baseline: 7.3, I: 6.4, II: 6, p = 0.321), and MIDAS score (melatonin: baseline: 15.2, II: 8.9, p = 0.005; valproate: baseline: 16.1, II: 8.3, p = 0.001; placebo: baseline: 16, II: 12.1, p = 0.44), were significantly reduced in the melatonin and sodium valproate groups, but not in the placebo groups. Adverse events were reported in 11 patients (10.47%): 2 (5.71%) during melatonin treatment, 8 (22.85%) during valproate, and 1 (2.85%) during placebo.

The adjuvant treatment with melatonin was found to be superior to the placebo and had the same clinical efficacy as sodium valproate, but with higher tolerability. Melatonin may prove to be an efficient substitute for sodium valproate, as a chronic migraine prophylaxis.

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