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Headache Editorial On the Brink of a New Era in Headache Medicine? Deborah I Friedman, MD, MPH Professor, Neurology & Neurotherapeutics, Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, US Abstract Monoclonal antibodies to calcitonin gene-related peptide, neuromodulation, and new delivery systems portend a bright future for the treatment of migraine and other headache disorders. Keywords Calcitonin gene-related peptide (CGRP), neuromodulation, migraine treatment, cluster headache treatment, monoclonal antibody, vagal nerve stimulation, spenopalatine ganglion stimulation Disclosure: Deborah I Friedman, MD, MPH, is on the speakers bureau for Allergan, has consulted with Avanir, Supernus, and Teva, and has received grant support from Electro- Core and Merck. No funding was received for the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: February 9, 2015 Accepted: February 16, 2015 Citation: US Neurology, 2015;11(1):66–7 Correspondence: Deborah I Friedman, MD, MPH, Professor, Neurology & Neurotherapeutics, Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, MC 9322, Dallas, Texas 75390, US. E: The last major breakthrough in the treatment of migraine and cluster headache (CH) began in the 1980s with the development of subcutaneous sumatriptan, which was introduced to the US market in 1993. Sumatriptan was life-changing for many individuals with migraine, and began what was hailed as the “triptan revolution.” The “revolution” was followed by the “triptan wars” as oral and nasal formulations of various triptans competed for market share. We are now positioned for an equally exciting emergence of new and novel treatments for migraine and other headache disorders. Calcitonin gene-related peptide is a target of interest for migraine therapy, and was initially pursued using small molecule oral agents. The initial studies for acute migraine treatment were promising but, despite efficacy and safety in studies of acute migraine treatment, liver toxicity occurred in subsequent trials for migraine prevention and the compounds were abandoned. 1 Two phase II clinical trials of calcitonin gene-related peptide (CGRP) antibodies were completed and published within the past year. ALD403, given as a single intravenous infusion, showed statistical superiority to placebo in 163 patients with frequent episodic migraine. 2 Although the placebo response was quite high in this trial, 16 patients receiving ALD403 were rendered completely headache free for 12 weeks after the infusion, compared with none in the placebo arm. LY295142, a monoclonal antibody binding to CGRP, was compared with placebo in 217 migraine patients who received biweekly subcutaneous injections for 12 weeks. 3 There was a 20 % therapeutic gain with the active compound, which was safe and well tolerated overall. Additional clinical trials are in progress for migraine and CH. If ultimately successful, the CGRP antibodies 66 will be the first preventive medications that were actually developed for the purpose of treating migraine and CH. Neuromodulation is being studied in the US for migraine and CH, with some devices already available in Europe. External vagal nerve stimulation (gammaCore™, Basking Ridge, New Jersey, US) showed efficacy in European trials of both chronic migraine and chronic CH. The Non-Invasive Vagus Nerve Stimulation for Chronic Migraine Prevention in a Prospective, Randomized, Sham–Controlled Pilot Study (EVENT) study for chronic migraine prevention demonstrated a reduction in headache days in the active stimulation group with additional improvement associated with a longer duration of usage. 4 The same device used for prevention and acute treatment of chronic CH revealed a statistically significant reduction in CH attacks with active stimulation compared with standard care alone, with 37.8 % of participants having at least a 50 % response rate using vagal nerve stimulation compared with 8.3 % of those assigned to standard care and placebo stimulation. 5 As in the migraine study, longer duration of treatment during the study was associated with a continued reduction in CH attacks. There were no serious adverse events associated with treatment. A US study was recently completed and results are pending. The sphenopalatine ganglion (SPG), where sympathetic, parasympathetic, and trigeminal fibers converge, is a target for modulation by stimulation and pharmacologic blockade. An implanted SPG stimulator with a wireless, rechargeable, remote control system is in clinical trials by Autonomic Technologies Inc. (Redwood City, California, US). The device is inserted via transgingival approach by an oromaxillofacial surgeon. Touch ME d ica l ME d ia