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For Your Patients-Cluster Headache

CGRP Implicated in Cluster Headache Attacks

Shaw, Gina

doi: 10.1097/01.NT.0000546218.20488.67
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Researchers reported that calcitonin gene-related peptide (CGRP) provoked cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. The study suggests that anti-CGRP drugs may effectively help manage cluster headache.

Calcitonin gene-related peptide (CGRP) provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache, although not in remission-phase episodic cluster headache, according to a report in the July 9 online edition of JAMA Neurology. These results come more than two months after the Food and Drug Administration approved the first anti-CGRP agent erenumab (Aimovig) for the treatment of migraine headache and suggest that the incipient new class of anti-CGRP drugs may be effective in the management of cluster headache as well.

The researchers, led by Messoud Ashina, MD, PhD, DMSc, of the Danish Headache Center and department of neurology at Rigshospitalet Glostrup at the University of Copenhagen, randomized 37 adult patients with cluster headache to receive an intravenous infusion of 1.5 μg/min of CGRP or placebo over 20 minutes on two study days. CGRP induced cluster headaches in eight of nine patients in the active phase, compared with one of nine in the placebo group (p=.05). CGRP-induced attacks occurred in seven of 14 patients with chronic cluster headaches compared with none after placebo (p =.02). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo.

“Our results demonstrated that CGRP provokes cluster headache attacks in patients with cluster headache exclusively during active phase in episodic cluster headache and in chronic cluster headache,” the authors wrote. “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.”

CGRP may precipitate cluster headaches in three distinctive ways, the authors suggested. “First, this may happen via vascular effects of CGRP, likely involving neurogenic inflammation. Second, CGRP receptor components are also found in the human trigeminal ganglion, which has been suggested as the possible site of action for the CGRP receptor antagonists in migraine treatment. Third, neurons in sphenopalatine ganglion express CGRP and its receptor components. Efferent outflow from sphenopalatine ganglia is suggested as initiating mechanism of cluster headache attacks, and on-demand sphenopalatine ganglia stimulation is an effective novel therapy for individuals with cluster headache with dual effects, acute pain relief, and attack prevention.”

Because of their rarity — cluster headaches affect one in 1000 adults, according to the World Health Organization — they are often misdiagnosed as migraine or sinus headaches, and once they finally are properly diagnosed, are among the most difficult to treat. The American Headache Society's 2016 guidelines for the management of cluster headache include only two Level A recommendations for acute treatment: high flow oxygen and subcutaneous injections of sumatriptan. While inhaled oxygen is highly effective in aborting attacks, the Centers for Medicare and Medicaid Services do not cover it under either Medicare or Medicaid, so its accessibility is limited. Subcutaneous sumatriptan, the gold-standard treatment, is contraindicated in patients with cardiovascular risk factors.

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Jennifer Bickel, MD, FAAN, medical director of the headache program at Children's Mercy Hospital and Clinics in Kansas City, MO, praised the design of the study. “They only had 32 patients, and yet it was so well designed that the outcomes are meaningful and clinically relevant. Studies like this not only advance the treatment of cluster headache, but also our understanding of its pathophysiology.”

“As we look for other options for a disorder like cluster headache, which is so disabling, these are very interesting and exciting data,” said Bert Vargas, MD, FAAN, associate professor of neurology at UT Southwestern in Dallas who specializes in concussion, headache, and facial pain. “Now, when we take someone who is in phase for cluster headache who potentially is going to have multiple attacks during the day, it's hard to tell if they would have happened anyway or are truly related to the infusion. That said, the investigators do document a pretty close temporal relationship between the infusions and onset of attacks, which lends support to the idea that there is a direct relationship.”

But the fact that CGRP did not produce headaches in patients not in phase and produced them less reliably in chronic cluster patients suggests that other as yet unidentified mechanisms are in play, Dr. Vargas cautioned. “I do think we need to avoid oversimplifying primary headaches like cluster and migraine, and not think of CGRP as a panacea. We know the role of CGRP in migraine, and yet there is not a 100 percent response to these agents in those headaches. I can imagine it would be the same for cluster headache. However, there is clearly the potential for CGRP antagonists to play a role in cluster prevention and acute treatment.”

Erenumab and any other anti-CGRP antagonists approved in the future should only be used in patients who have failed to respond or cannot tolerate other treatment options, said Robert Cowan, MD, FAAN, Higgins Family Professor of Neurology and director of the Headache Program at Stanford University.





“There's a lot we still don't know about the impact on the body of blocking a molecule that is so ubiquitous in the system and that has so many different roles,” he said. “I want to see 800,000 people safely on this medication before I'm really comfortable with it. This many people with completely or nearly completely blocked CGRP makes me nervous. CGRP floods the brain in head trauma, which we know is neuroprotective, but what happens if there is also an antibody blocking it? What happens to wound healing when the inflammatory process is interfered with. Or bone layering? There are a lot of questions about the class as a whole, and until we have a lot more patients who have done well with these agents, I'm still going to be concerned about it.”

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•. Vollesen ALH, Snoer A, Beske RP, et al Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: A randomized clinical trial JAMA Neurol 2018; Epub 2018 Jul 9.
    © 2018 American Academy of Neurology