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Original Investigation
October 2018

Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial

Author Affiliations
  • 1Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 2Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
JAMA Neurol. 2018;75(10):1187-1197. doi:10.1001/jamaneurol.2018.1675
Key Points

Question  Does calcitonin gene-related peptide play a role in initiating cluster headache attacks in patients with episodic cluster headache in active phase, episodic cluster headache in remission, and chronic cluster headache?

Findings  In this randomized cross-over trial of 32 patients with cluster headache, Calcitonin gene-related peptide provoked cluster headache attacks in patients with episodic cluster headache exclusively during active phase, not in remission phase, and provokes attacks in chronic cluster headache.

Meaning  Calcitonin gene-related peptide plays a pivotal role in initiation of cluster headache attacks, possibly indicating efficacy of calcitonin gene-related peptide antagonism in the treatment of cluster headache.

Abstract

Importance  Signaling molecule calcitonin gene-related peptide (CGRP) induces migraine attacks and anti-CGRP medications abort and prevent migraine attacks. Whether CGRP provokes cluster headache attacks is unknown.

Objective  To determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in remission phase, and chronic cluster headache.

Design, Setting, and Participants  A randomized, double-blind, placebo-controlled, 2-way crossover study set at the Danish Headache Center, Rigshospitalet Glostrup, in Denmark. Analyses were intent to treat. Inclusion took place from December 2015 to April 2017. Inclusion criteria were diagnosis of episodic/chronic cluster headache, patients aged 18 to 65 years, and safe contraception in women. Exclusion criteria were a history of other primary headache (except episodic tension-type headache <5 days/mo), individuals who were pregnant or nursing; cardiovascular, cerebrovascular, or psychiatric disease; and drug misuse.

Interventions  Thirty-seven patients with cluster headaches received intravenous infusion of 1.5 μg/min of CGRP or placebo over 20 minutes on 2 study days.

Main Outcomes and Measures  Difference in incidence of cluster headache–like attacks, difference in area under the curve (AUC) for headache intensity scores (0 to 90 minutes), and difference in time to peak headache between CGRP and placebo in the 3 groups.

Results  Of 91 patients assessed for eligibility, 32 patients (35.2%) were included in the analysis. The mean (SD) age was 36 (10.7) years (range, 19-60 years), and the mean weight was 78 kg (range, 53-100 kg). Twenty-seven men (84.4%) completed the study. Calcitonin gene-related peptide induced cluster headache attacks in 8 of 9 patients in the active phase (mean, 89%; 95% CI, 63-100) compared with 1 of 9 in the placebo group (mean, 11%; 95% CI, 0-37) (P = .05). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo. Calcitonin gene-related peptide–induced attacks occurred in 7 of 14 patients with chronic cluster headaches (mean, 50%; 95% CI, 20-80) compared with none after placebo (P = .02). In patients with episodic active phase, the mean AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes for the placebo group was 0.343 (95% CI, 0-0.867) (P = .04). In patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for the placebo group was 0.036 (95% CI, 0-0.114) (P = .01). In the remission phase, the mean AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and the mean AUC from 0 to 90 minutes for placebo was 0.019 (95% CI, 0-0.062) (P > .99).

Conclusions and Relevance  Calcitonin gene-related peptide provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. These results suggest anti-CGRP drugs may be effective in cluster headache management.

Trial Registration  ClinicalTrials.gov (NCT02466334).

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