Melatonin for preventing primary headache: A systematic review

Int J Clin Pract. 2018 Jul;72(7):e13203. doi: 10.1111/ijcp.13203. Epub 2018 May 24.


Background: The aim of this study was to assess the effectiveness and safety of melatonin for primary headache.

Methods: This systematic review following the Cochrane Handbook for Systematic Reviews of Interventions recommendations and PRISMA Statement.

Results: Four randomized controlled trials were included (351 participants). According to the GRADE approach the quality of evidence was very low. The use of melatonin for migraine showed that (i) reduced the number of days with pain and the analgesic consumption when compared with placebo, (ii) no benefits on headache intensity, number of headache days and analgesics consumption when compared with amitriptyline, (iii) reduced the number of analgesic consumption, the attack frequency and the headache intensity when associated with propranolol plus nortriptyline vs placebo plus propranolol plus nortriptyline, and (iv) no difference for any of the interest outcomes when associated with propranolol plus nortriptyline vs sodium valproate plus propranolol plus nortriptyline. The use of melatonin for cluster headache when compared with placebo showed a reduction in the daily number of analgesic consumption and no difference in the number of daily attacks. Adverse events were poorly reported by all of the studies.

Conclusion: This review found that so far there are few clinical trials, with poor methodological quality about melatonin for primary headaches. The available evidence is not sufficient to support the use of melatonin in clinical practice for this population. Further research is still necessary for assess its effects (benefits and harms) for primary headaches patients. Number of Protocol registration in PROSPERO database: CRD42017067105 (available at .

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Acetaminophen / therapeutic use
  • Analgesics / therapeutic use*
  • Aspirin / therapeutic use
  • Central Nervous System Depressants / therapeutic use*
  • Humans
  • Melatonin / therapeutic use*
  • Migraine Disorders / diet therapy*
  • Migraine Disorders / prevention & control
  • Randomized Controlled Trials as Topic
  • Treatment Outcome


  • Analgesics
  • Central Nervous System Depressants
  • Acetaminophen
  • Melatonin
  • Aspirin