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Calcitonin gene-related peptide linked to cluster headache attacks

Calcitonin gene-related peptide, the molecule that causes migraines, also caused cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache, according to findings recently published in JAMA Neurology.

“Elucidating the role of [calcitonin gene-related peptide] in cluster headache attack induction will provide novel insights to mechanisms underlying the disease. A role of [calcitonin gene-related peptide] in attack generation would provide novel opportunities for targeted treatment of this severely disabling disease,” Anne Luise H. Vollesen, MD, of Danish Headache Center in Copenhagen, Denmark, and colleagues wrote.

Researchers studied the difference in incidence of cluster headache–like attacks, difference in area under the curve (AUC) for headache intensity scores, and difference in time to peak headache in 27 patients (mean age, 36 years) receiving either 1.5 µg/min of calcitonin gene-related peptide or placebo during the course of 20 minutes on 2 days.

Vollesen and colleagues found that calcitonin gene-related peptide induced cluster headache attacks in eight of nine patients in the active phase vs. one in the patient who received placebo. In the remission phase, no patient with an episodic cluster headache reported an attack after placebo or calcitonin gene-related peptide. Calcitonin gene-related peptide led to attacks in half of the 14 patients with chronic cluster headaches vs. none of the patients after receiving placebo (P = .02).

Researchers also wrote that in those patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for those who received calcitonin gene-related peptide was 1.214 (95% CI, 0.395-2.033) vs. 0.036 (95% CI, 0-0.114) for those receiving placebo. In the remission phase, the mean AUC from 0 to 90 minutes for those receiving calcitonin gene-related peptide was 0.187 (95% CI, 0-0.571) compared to 0.019 (95% CI, 0-0.062) for those receiving placebo. In patients in the episodic active phase, the mean AUC from 0 to 90 minutes for those receiving calcitonin gene-related peptide was 1.903 (95% CI, 0.842-2.965) and 0.343 (95% CI, 0-0.867) for those receiving placebo.

“We demonstrated that [calcitonin gene-related peptide] 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,” Vollesen and colleagues wrote.

“Our results also cautiously suggest efficacy of [calcitonin gene-related peptide] antagonism in the treatment of cluster headache and current phase 3 trials elucidating this will emerge in coming years,” they added.

Amy A. Gelfand, MD, MAS and Peter J. Goadsby, MD, PhD, of the department of neurology at the University of California, San Francisco suggested there should be guarded optimism for the thousands of patients impacted by cluster headaches in an accompanying editorial.

“Given the totality of the evidence, including the current study, that [calcitonin gene-related peptide] antagonism is involved in cluster headache, there is reason for optimism that these agents could also prove fruitful for cluster headache treatment. In fact, a phase 3 study of one of the anti-[calcitonin gene-related peptide] antagonism monoclonal antibodies for episodic cluster headache has reportedly hit its primary end point, although another trial for patients with chronic cluster headaches reportedly did not,” they wrote.

“An intriguing question now arises as to whether use of [calcitonin gene-related peptide] antagonism receptor antagonists, gepants, would work immediately. The [calcitonin gene-related peptide] antagonism pathway represents a quantum therapeutics approach to migraine, having a duality of mechanism: immediate and preventive treatment, which is resolved when appropriately measured. We are at the end of truly epoch-making changes for patients who experience what they describe as simply the worst pain there is,” Gelfand and Goadsby concluded. – by Janel Miller

Disclosures: Vollesen reports no relevant financial disclosures. Please see the study and editorial for all other authors’ relevant financial disclosures.