3mg melatonin may aid migraine prevention

Melatonin, which is widely available in North America as an over-the-counter supplement, is more effective than placebo for migraine prevention and has a more favorable adverse effect profile than the tricyclic antidepressant amitriptyline, new research shows.

Results from a multicenter, randomized, double-blind, placebo-controlled trial showed that 3 mg of melatonin was more effective than placebo and had efficacy similar to that of 25 mg of amitriptyline. Furthermore, it was better tolerated than amitriptyline, with lower rates of daytime sleepiness and no weight gain.

"Melatonin 3 mg was significantly better than placebo with no difference compared to amitriptyline with respect to migraine prevention," principal investigator Mario Peres, MD, PhD, told delegates here attending the American Academy of Neurology (AAN) 65th Annual Meeting.

"But if we look at the proportion of responders, then melatonin had better results than amitriptyline," added Dr. Peres, who is director of São Paulo Headache Center, professor of neurology at ABC Medical School, and senior research associate at the Albert Einstein Brain Research Institute, Brazil.

Link to headache, sleep disorders
Produced by the pineal gland, melatonin is a hormone that helps regulate the sleep/wake cycle. It has been available as a supplement in the United States since the 1990s and is often used to aid sleep and attenuate jet lag.

According to Dr. Peres, melatonin's role in regulating circadian rhythm has been linked to cluster headache, hypnic headache, and migraine.

Further, he noted, melatonin plays an important role in sleep regulation, and disruption of melatonin production has been linked to sleep disorders, including sleep apnea, insomnia, and delayed sleep phase syndrome, which, in turn, are linked to headache.

He also noted that there is a bidirectional relationship in which headache can disrupt sleep and lead to insomnia and excessive daytime sleepiness.

Finally, he pointed out that research has linked low levels of melatonin in plasma and urine and altered peak time in melatonin levels to a variety of headache types, including migraine.

According to Dr. Peres, research into melatonin as a potential treatment for headache has included several case reports and open-label studies but only 2 randomized controlled trials: 1 in cluster headache, which was positive, and 1 negative trial in migraine.

The negative migraine trial, he said, had several limitations, including a small sample size and a short duration of only 8 weeks. It also used a slow-release, 2-mg formulation of melatonin, and, although the response rate in the melatonin group was 44%, the placebo group had an exceptionally high response rate of 40%.

Surprise weight-loss finding
To test the efficacy and tolerability of melatonin and amitriptyline vs placebo for migraine prevention, the investigators recruited 178 men and women who met International Headache Society diagnostic criteria for migraine with and without aura and who had 2 to 8 migraine attacks per month.

All patients underwent a 4-week baseline phase during which each participant kept a diary of migraine frequency.

Participants were then randomly assigned to receive 3 mg melatonin (n = 60), 25 mg amitriptyline (n = 59), or placebo (n = 59) for 3 months. Medication was taken between 10 and 11 pm daily.

The study's primary outcome was a reduction in the number of headache days per month. Secondary endpoints included migraine intensity and duration and analgesic use. Tolerability was also measured in all 3 study groups.

The mean reduction in headache frequency was 2.7 in the melatonin group, 2.18 in the amitriptyline group, and 1.18 in the placebo group.

Although migraine frequency did not differ between the 2 active treatment groups, the proportion of responders was greatest in the melatonin group: 54% vs 39.1% for amitriptyline and 20.4% for placebo.

Melatonin was also "very tolerable" and had significantly fewer adverse effects compared with amitriptyline, said Dr. Peres. Daytime sleepiness was the most frequent symptom in all 3 groups but was most pronounced in the amitriptyline group (n = 24).

Although patients gained weight in both the amitriptyline (n = 3) and placebo (n = 1) groups, melatonin was associated with weight loss.

Timing of administration and formulation is also important. Ideally, said Dr. Peres, melatonin should be taken between 10 pm and 11 pm to mimic the physiologic peak. In addition, a fast-acting rather than a slow-release formula should be used.

Overall, said Dr. Peres, the study's findings are promising and warrant further research.

Worth a try?
Commenting on the study, Tobias Kurth, MD, director of research Institut national de la santé et de la recherche médicale (INSERM), University of Bordeaux in France, and associate epidemiologist, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, said the researchers "very convincingly" showed that melatonin was as effective as amitriptyline and both were superior to placebo.

"If this is true, this is great," said Dr. Kurth.

Although the study's findings are preliminary and need to be replicated, Dr. Kurth said that given its favorable adverse effect profile, melatonin may be worth a try.

"I'm not aware of any major side effects associated with melatonin. As long clinicians instruct patients appropriately and emphasize the importance of taking the recommended dose at the same time every day it may be worthwhile," he said.