Calcitonin Gene-Related Peptide Provokes Cluster Headache Attacks

woman with headache
woman with headache
The role of calcitonin gene-related peptide may play a role in triggering cluster headache attacks in patients with episodic cluster headache in active phase.

Calcitonin gene-related peptide (CGRP) provoked cluster headache in patients with chronic cluster headache and active-phase episodic cluster headache but did not do so in remission-phase episodic cluster headache, according to a study published in JAMA Neurology.

This double-blind, randomized, 2-way crossover, placebo-controlled study sought to determine whether the infusion of CGRP would provoke cluster headache attacks in patients with active episodic cluster headache, episodic cluster headache in remission, and chronic cluster headache.

Ninety-one patients from the Danish Headache Center were assessed for the study, and 32 were included for analysis. Patients were randomly assigned to receive intravenous infusion of CGRP 1.5 μg/min or placebo continuously for 20 minutes on 2 separate study days, with at least 7 days between testing. The dosing for CGRP was identical to that used in previous migraine provocation studies. Patients were made aware that the infusion may cause headaches, but no further details were discussed. Headache intensity was reported by patients at baseline, then every 10 minutes thereafter for 90 minutes. If headache did occur, patients remained on-site for another 30 minutes to ensure the full experience of the attack was recorded.

Eight of the 9 participants with active cluster headache experienced a cluster headache attack within the 90-minutes after initiation of CGRP infusion (mean, 89%; 95% CI, 63%-100%) in comparison to 1 of 9 after placebo infusion (mean, 11%; 95% CI, 0%-37%) (P =.05). None of the 9 participants in a remission phase of episodic cluster headache experienced cluster headache attacks after CGRP or placebo infusion. Seven of 14 participants with chronic cluster headache experienced cluster headache attacks after CGRP infusion (mean, 50%; 95% CI, 20%-80%) in comparison to 0 of 14 after placebo infusion (P =.02).

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Study investigators conclude that “CGRP provokes cluster headache attacks in patients with cluster headache exclusively during active phase in episodic cluster headache and in chronic cluster headache. We hypothesize that this difference hails from the hypothalamus modulating the provocability threshold of the system allowing a peripheral trigger to set off attacks. Our results also cautiously suggest efficacy of CGRP antagonism in the treatment of cluster headache and current phase III trials elucidating this will emerge in coming years.”


Vollesen ALH, Snoer A, Beske RP, et al. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial [published online July 9, 2018]. JAMA Neurol. doi: 10.1001/jamaneurol.2018.1675