Melatonin for Migraine Headache Prophylaxis

Question

Is melatonin effective for reducing the frequency of migraine headaches?

Response from Philip J. Gregory, PharmD Drug Information Consultant

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.^[1] Nighttime melatonin levels are also lower in patients with migraine compared with those without.^[1,2]

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.^[1]

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.^[1]

Melatonin might also affect headaches through direct effects on pain and inflammation.^[1] 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.^[3]

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.^[4,5,6,7,8]

Three placebo-controlled clinical trials assessing the use of melatonin for migraine prevention have been published.

Alstadhaug and colleagues^[9] compared extended-release melatonin 2 mg 1 hour before bed versus placebo in a crossover trial with 46 adults who experienced two to seven migraine headaches per month. After a 4-week run-in phase, participants were randomly assigned to receive melatonin or placebo for 8 weeks. Treatments were switched following a 6-week washout period. No significant difference was detected between melatonin and placebo for migraine headache frequency.

Ebrahimi-Monfared and colleagues^[10] 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^[11] 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 (

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.^[9,10,11]

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.

https://wb.md/2I52dbG