CGRP Infusion Shows Efficacy in Cluster Headache Management


After success in migraine treatment, CGRP has now shown a positive effect on acute cluster headache in a randomized clinical trial.

Dr Messoud Ashina

Messoud Ashina, MD, PhD, DMSc, Danish Headache Center and Department of Neurology at the Rigshospitalet and University of Copenhagen, in Denmark

Messoud Ashina, MD, PhD, DMSc

Infusion of calcitonin gene-related peptide (CGRP) has been revealed as a possibly effective treatment for cluster headache management.

In a randomized, double-blind, placebo-controlled, 2-way crossover study, the CGRP infusion was shown to provoke cluster headache attacks in the active phases of episodic and chronic cluster headache but did not do so in the remission phase of episodic cluster headache.1

Conducted by a group of investigators from the Danish Headache Center and Department of Neurology at the Rigshospitalet and University of Copenhagen, in Denmark, including Messoud Ashina, MD, PhD, DMSc, the trial consisted of 37 patients, of which 32 completed the analysis. In total, 28.1% (n = 9) of patients had episodic cluster headache and were included during active phases, while another 28.1% (n = 9) of patients with episodic cluster headache were included during remission phases. Chronic cluster headache was present in 43.8% (n = 14) of patients.

In an accompanying editorial from Amy A. Gelfand, MD, MAS, and Peter J. Goadsby, MD, PhD, it was noted that prior to this study, “it was known that serum CGRP levels are elevated during both spontaneous cluster attacks and those triggered by nitroglycerin infusion” and additionally, effective therapies for cluster headache have been shown to normalize levels of CGRP.2 Although, they noted that “here we learn that infusion of CGRP can also trigger cluster attacks, interestingly only in those patients whose cluster disorder was already active.”

Ashina and colleagues randomized patients to receive either 1.5 µg/min of CGRP or placebo during 20 minutes on 2 study days, with each infusion separated by at least 7 days.

Those with active-phase episodic cluster headache reported a cluster-like attack after CGRP infusion in 8 of 9 cases (mean, 89%; 95% CI, 63 to 100) compared to 1 of 9 cases (mean, 11%; 95% CI, 0 to 37; P = .05) for after receiving placebo. All 8 patients with a cluster-like attack experienced cephalic autonomic symptoms (CAS) or agitation. The mean difference in area under the curve (AUC) from minute 0 to minute 90 when receiving CGRP was 1.903 (95% CI, 0.842 to 2.965) compared to 0.343 (95% CI, 0 to 0.867) when receiving placebo in the same timeframe (P = .04).

During the 90-minute infusion period for those with remission-phase episodic cluster headache, no cluster headaches were reported after infusion of placebo or CGRP. Additionally, none of the 9 patients reported an attack in the subsequent 24 hours. The mean AUC after placebo infusion was 0.019 (95% CI, 0 to 0.062) compared to 0.187 post-CGRP infusion (95% CI, 0 to 0.571; P >.99).

Data on the patients with chronic cluster headache revealed that cluster-like attacks occurred after CGRP infusion in 50% of patients (n = 7; 95% CI, 20 to 80) compared to none after placebo infusion (95% CI, 0; P = .02). During the attacks induced by CGRP, 6 of 7 patients reported CAS. The mean AUC for CGRP was 1.214 (95% CI, 0.395 to 2.033) compared to 0.036 (95% CI, 0 to 0.114) for placebo (P = .01).

According to Ashina and colleagues, in the 30 days prior to the first infusion, the 7 patients with CGRP-induced headache attack reported a median attack frequency of 33, compared to 7.5 for those who did not experience cluster-like headache attack.

“Overall, our findings suggest that (1) CGRP plays a pivotal role in initiation of a single cluster headache attack and (2) that CGRP induces cluster attacks may suggest a possible clinical efficacy of pharmacological interventions that block the effects of CGRP (e.g., specific monoclonal antibodies),” Ashina and colleagues wrote. “In episodic and chronic cluster headache, monoclonal CGRP antibodies are currently being investigated in phase III studies as preventive treatment with study completion expected in 2018.”

Gelfand and Goadsby noted that given the entirety of the evidence about CGRP’s involvement in cluster headache—including this study—there is a reason to be optimistic that these agents could be successful for treating cluster headache.

“An intriguing question now arises as to whether [the] use of CGRP receptor antagonists, gepants, would work immediately,” Gelfand and Goadsby added. They acknowledged that thew CGRP pathway signifies a quantum therapeutics method to treating the headache disorder, with a dual mechanism that includes both immediate and preventive treatment. “We are at the end of truly epoch-making changes for patients who experience what they describe as simply the worst pain there is,” they wrote.


1. Vollesen AL, Snoer A, Beske RP, et al. Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. JAMA Neurol. Published online July 9, 2018.


:10.1001/jamaneurol.2018.1675. Accessed July 10, 2018.

2. Gelfand AA, Goadsby PJ. Cluster Headache and Calcitonin Gene-Related Peptide—More on Quantum Therapeutics in Headache Medicine. JAMA Neurol. Published online July 9, 2018.


:10.1001/jamaneurol.2018.1428. Accessed July 10, 2018.

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