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


Lauren Lipscomb, Mercer University College of Pharmacy


A review of five studies found that the pineal hormone, melatonin, is low in migraine patients. The review suggests that administering melatonin to migraine sufferers relieved pain and decreased headache recurrence. It was also suggested that melatonin may play a role in resynchronizing biological rhythms to lifestyle changes and subsequently relieve migraines. [1]


A review of three studies suggests that there is a pathophysiological relationship between decreased melatonin secretion and migraines. They conclude that melatonin may have a therapeutic benefit in migraines because of this relationship. [2]


The American Headache Society (AHS) and the American Academy of Neurology (AAN) recommend considering amitriptyline for the prevention of episodic migraines. Melatonin is not recommended by the AHS/ANA. [3]

Title: Randomized clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention [4]
Design Randomized, placebo-controlled, double-blinded trial; N= 178
Objective Compare the effect of melatonin, amitriptyline, and placebo on the number of migraine headaches per month
Study Groups Melatonin (n= 60); amitriptyline (n= 59); placebo (n= 59)
Methods The study consisted of a four-week period to established baseline measures followed by a 12-week treatment period. After eligibility had been determined, patients were randomized to treatment groups. Patients meeting eligibility criteria were randomized 1:1:1 to one of the three groups: placebo, melatonin 3 mg or amitriptyline 25 mg, all taken at bedtime.
Duration N/A
Primary Outcome Measure Number of migraine headache days per month at baseline versus last month
Baseline Characteristics Characteristic Placebo (n= 59) Amitriptyline (n= 59) Melatonin (n= 60)
Mean age; y 36.6 37.2 36.9
Female sex; n (%) 45 (76.3) 44 (74.6) 44 (73.3)
Mean migraine attack duration; hr 18.7 16.7 18.1
Migraine frequency; days 7.3 7.2 7.3
Aura; n (%) 9 (15.2) 10 (16.9) 13 (21.7)
Results Primary outcome measure Placebo (n= 59) Amitriptyline (n= 59) Melatonin (n= 60)
Number of migraine headache days (change from baseline)
Baseline 7.3 7.2 7.3
Weeks 1-4 7.0 (0.3) 5.8 (1.4) 5.6 (1.7)
Weeks 5-8 6.6 (0.7) 5.3 (1.9) 5.3 (2.0)
Weeks 9-12 6.2 (1.1) 5.0 (2.2) 4.6 (2.7)
Adverse Events Common Adverse Events: sleepiness: melatonin (18.3%), amitriptyline (40.7%); dizziness: amitriptyline (5%); dry mouth: melatonin (1.6%), amitriptyline (10%); constipation: melatonin (1.6%), amitriptyline (6.7%)
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions Melatonin 3 mg is better than placebo for migraine prevention, and more tolerable than amitriptyline and as effective as amitriptyline 25 mg.


This randomized, double-blinded, placebo-controlled trial found that melatonin was more efficacious at preventing migraines than placebo and more tolerable than amitriptyline. Because this study was blinded, there was potentially less bias between the three study groups. If these results are also found in larger trials, melatonin should be considered for migraine prophylaxis in patients who cannot tolerate the side effects of amitriptyline. Another trial comparing melatonin to other migraine prophylactic medications, such as divalproex or topiramate, is needed to determine if guidelines should be updated to include melatonin. The trial had a relatively small study population. For these results to be applicable to a broader practice setting, a larger trial needs to be completed.



  1. Gagnier JJ. The therapeutic potential of melatonin in migraines and other headache types. Altern Med Rev. 2001;6(4):383-9.
  2. Wilhelmsen M, Amirian I, Reiter RJ, Rosenberg J, Gögenur I. Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies. J Pineal Res. 2011;51(3):270-7.
  3. The American Headache Society and the American Academy of Neurology. The 2012 AHS/AAN Guidelines for Prevention of Episodic Migraine: A Summary and Comparison With Other Recent Clinical Practice Guidelines. http://www.headachejournal.org/SpringboardWebApp/userfiles/headache/file/j_1526-4610_2012_02185_x.pdf. 2012.
  4. 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 Psychiatr. 2016;




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