Headaches are one of the most common and frustrating presenting symptoms. The question of how best to treat this incapacitating condition has plagued physicians since 3000 BC. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is localized to the C and Aᵟ sensory fibers. These fibers play a role in nociception or pain perception.
In a 1990 study, Goadsby et al. identified an association between CGRP and migraine attacks, leading to the evaluation of CGRP antagonists in the treatment of migraine. Monoclonal antibodies that target either CGRP or its receptor have shown promise. In the 2017 STRIVE trial, the human monoclonal antibody erenumab significantly reduced migraine effects and frequency. Similar results were reported for the monoclonal antibody galcanezumab in the prevention of episodic migraine in the EVOLVE-1 trial.
The success of monoclonal antibodies in the treatment of migraine headache led investigators to explore whether similar efficacy could be achieved in the treatment of cluster headaches — another debilitating primary headache disorder. In a multicenter randomized trial published in the NEJM, Goadsby and colleagues now report that the monoclonal antibody galcanezumab reduced weekly frequency of cluster headache attacks, as compared with placebo.
The following NEJM Journal Watch summary explains the study in more detail.
Galcanezumab for Treating Episodic Cluster Headaches
Nauman Tariq, MD reviewing Goadsby PJ et al. N Engl J Med 2019 Jul 11
The FDA has approved the first anti–calcitonin gene–related peptide antibody for episodic cluster headache.
Cluster headaches are typically sharp, one-sided headaches lasting 15 to 180 minutes, often accompanied by red, watery eyes and nasal congestion. Less common than migraine, their severity is far worse. Investigators conducted a double-blind, randomized, placebo-controlled 8-week study to assess the safety and efficacy of subcutaneous galcanezumab injections for these headaches.
The treatment group had a mean reduction of almost 9 fewer weekly attacks in the first 3 weeks compared with 5 fewer in the placebo group (P=0.04; confidence interval, 0.2–6.7); 71% of galcanezumab recipients and 53% of placebo recipients experienced a reduction of at least 50% in headache frequency at week 3. Both groups had a continued reduction in cluster attacks from week 4 to 8, with no clinically significant difference, which could suggest spontaneous remission occurring in both groups. Injection-site pain was the most common adverse effect in the galcanezumab recipients (8%).
Comment: This study was limited by a small sample size. The intervention group received three 100-mg galcanezumab injections on day 1 and again at 4 weeks — a higher dose than the standard regimen currently given to migraine patients (a 240-mg initial injection followed by 120 mg monthly). In migraine trials, half of galcanezumab recipients had a 50% reduction in migraine days after 3 months, whereas in this study, the outcome measure was achieved much faster, a difference perhaps explained by the higher dose. Episodic cluster headaches transform into chronic form in up to 15% of patients. It would be interesting to know whether this drug could decrease that percentage in future. Of note, galcanezumab failed to reach its primary end point in a chronic cluster headache trial.
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Krista is a 2019-2020 editorial fellow at the New England Journal of Medicine. She is from Nassau, Bahamas where she is training in general surgery at the University of the West Indies.