Approved in Migraine, CGRP Antagonists Also Promising in Cluster Headache

Cluster headache and migraine are distinct primary headache disorders that are associated with substantial pain and disability.

Cluster headache and migraine are distinct primary headache disorders that are associated with substantial pain and disability. Migraine is characterized by recurrent attacks of unilateral moderate to severe head pain and is frequently associated with nausea, vomiting, photophobia, phonophobia, and sensitivity to odors. Approximately 25% of patients with migraine experience auras, which usually last less than 1 hour, with migraine attacks themselves typically lasting between 4 and 72 hours.1 According to the Migraine Research Foundation, migraine is the third most common disease in the world, affecting 1 billion people globally and 39 million people in the United States, where its prevalence is 14.2%.1,2 Migraine is approximately 3 times more common in women than in men.2 In the World Health Organization’s Global Burden of Disease Study, migraine was identified as the sixth highest cause of years lost because of disability worldwide.3

Cluster headache has been called the most severe pain condition occurring in people, with associated pain described as tearing, stabbing, and burning.4,5 Cluster headache is much rarer than migraine, with an estimated prevalence <0.1%. The disorder is 3 to 7 times more common in men than in women.6 Cluster headaches are characterized by recurrent periods of severe unilateral attacks of excruciating and rapidly escalating pain. These attacks are frequently accompanied by restlessness, agitation, and oculofacial autonomic phenomena such as conjunctival injection, tear secretion, and drooping of the eyelid.7,8 Cluster headaches are often associated with nausea, photophobia, and phonophobia.6 In episodic cluster headache, cluster periods in which patients experience up to 8 headaches a day for 6 to 12 weeks — often during specific months of the year — are followed by periods of remission that can last several months or years. In chronic cluster headache, attacks continue without remission.9,10

Despite their markedly different clinical pictures, cluster headache and migraine share several important characteristics. According to a recent review by Anne Luise Vollesen, MD, and colleagues from the University of Copenhagen, commonalities between the disorders include an array of drug-related and naturally occurring triggers such as stress, sleep, alcohol intake, and weather changes; adequate response to acute treatment with triptans; safety and effectiveness of neuromodulation strategies such as deep brain and occipital nerve stimulation; and effectiveness of anticalcitonin gene-related peptide (CGRP) monoclonal antibodies.6 “The central denominator in both diseases may be the trigeminovascular pathway, alteration in hypothalamic activity, and functional changes in hypothalamic-brainstem connectivity,” noted the review authors.

In 2018, the US Food and Drug Administration approved for migraine prevention 3 new monoclonal antibodies that target CGRP or its receptor: erenumab, fremanezumab, and galcanezumab. CGRP antagonists represent the first class of medications to target specifically the pathophysiologic processes implicated in migraine. Thus far, clinical trial data indicate that these 3 agents have comparable efficacy, are well tolerated, and are not associated with safety issues.11 CGRP is a 37-amino acid neuropeptide that binds to the CGRP receptor complex believed to be responsible for transmitting the pain signals associated with migraine.12 In individuals with migraine, CGRP levels rise at the onset of migraine pain and normalize when migraine pain subsides.13 Accumulating evidence, including a recent placebo-controlled provocation study led by Dr Vollesen, suggests that CGRP is also involved in cluster headache.10 In this study, 37 patients with cluster headache received intravenous infusions of CGRP or placebo. Patients with active-phase episodic cluster headache and chronic cluster headache experienced cluster headache attacks with CGRP infusion; however, this effect was not seen patients with episodic cluster headache in remission. “[CGRP] may exert its cluster headache-inducing abilities in 3 distinctive ways,” the investigators wrote. “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.”

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“We 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,” concluded the review authors. “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 3 trials elucidating this will emerge in coming years.”10 The CGRP antagonists fremanezumab and galcanezumab are currently in late clinical trials for episodic cluster headache prevention.14

Alberto Proietti Cecchini, MD, a senior neurologist at the Fondazione Istituto Nazionale Neurologico Carlo Besta in Milan, Italy, told Clinical Pain Advisor that despite their promise, monoclonal CGRP antibodies may not fully meet the needs of all patients with cluster headache. Dr Cecchini warned against an excessively reductionistic approach, “especially for the difficult-to-treat patient with cluster headache, monoclonal CGRP antibodies may leave room for add-on therapy,” he noted. “We must not neglect the unique history of each individual. That is a main principle in concept of individualized-medicine. To ignore this means to miss the opportunity to fully understand and treat headache.”

Interview was lightly edited for clarity.

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