Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study

Headache. 2002 Sep;42(8):787-92. doi: 10.1046/j.1526-4610.2002.02181.x.


Background: The periodicity of cluster headache suggests involvement of the suprachiasmatic nucleus of the hypothalamus, the biological clock. The secretion of melatonin, a hormone produced by the pineal gland and regulated by the suprachiasmatic nucleus, is altered in patients with cluster headache. Melatonin shifts circadian rhythms. A previous study of melatonin for primary prophylaxis of cluster headache demonstrated a 50% response rate.

Objective: To evaluate the use of melatonin as adjunctive therapy in patients with cluster headache who have incomplete relief of their headaches on conventional therapy.

Methods: Nine patients participated in the study, six with chronic cluster headache and three with episodic cluster headache. Patients with chronic cluster headache completed a baseline diary for 1 month, followed by 1 month of melatonin treatment, then 1 month of placebo. Patients with episodic cluster headache received placebo for 1 month, then melatonin for 1 month. Patients continued their usual prophylactic and abortive treatments during the study. Headache frequency, intensity, and use of analgesics were recorded. The primary endpoint of the study was the mean number of headaches per day, with mean daily analgesic consumption and percentage of mild, moderate, and severe headaches as secondary endpoints.

Results: There were no significant differences between means on analysis of variance and t testing for the melatonin, placebo, and baseline months for all primary and secondary endpoints. There were no side effects reported.

Conclusions: Patients with chronic cluster headache or patients with episodic cluster headache whose headaches are uncontrolled on conventional therapy do not appear to gain therapeutically from the addition of melatonin to their usual treatment regimens. It is perhaps the phase-shifting properties of melatonin that mediate its effect in patients with episodic cluster headache, and it may be necessary to treat from the beginning of the cluster bout to reset the circadian pacemaker, thus producing a more positive outcome.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial

MeSH terms

  • Adjuvants, Immunologic / therapeutic use*
  • Adolescent
  • Aged
  • Analgesics / therapeutic use
  • Chronic Disease
  • Circadian Rhythm
  • Cluster Headache / classification
  • Cluster Headache / drug therapy*
  • Cluster Headache / physiopathology
  • Delayed-Action Preparations
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Melatonin / therapeutic use*
  • Middle Aged
  • Pilot Projects
  • Single-Blind Method
  • Treatment Outcome


  • Adjuvants, Immunologic
  • Analgesics
  • Delayed-Action Preparations
  • Melatonin