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Headache Innovations in Headache Management – Recent Advances and Future Perspectives Abraham J Nagy 1 and Alan M Rapoport 2 1. Neurologist, Nevada Headache Institute, Las Vegas, Nevada, US; 2. Clinical Professor of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, US Abstract Since the advent of triptans over two decades ago, progress on new therapeutics for headache management has seemingly slowed as few new lines of care have become available. With major advances in the understanding of headache disorder neurobiology, new therapies are on the horizon. This article will review novel delivery systems of familiar medications and new lines of care with unique therapeutic targets. Promising new therapies like calcitonin gene-related peptide (CGRP) receptor antagonists and 5-hydroxytrypamine (5-HT) 1F receptor agonists are in late-stage development. One neurotoxin has recently been approved for the prevention of chronic migraine. Neuromodulation techniques have rapidly advanced over the last few years. Several new drug targets such as nitric oxide synthase, gap junction modulators, glutamate receptor antagonists, orexin antagonists, transient receptor potential vanilloid 1 (TRPV1) receptor modulators, prostanoid receptors antagonists and pituitary adenylate cyclase 1 (PAC1) receptor antagonists await development. The therapies in the coming decade show great promise for distinctly advancing headache management. Keywords Calcitonin gene-related peptide antagonist, 5-hydroxytrypamine 1F receptor agonist, onabotulinumtoxinA, neuromodulation, sumatriptan, dihydroergotamine Disclosure: Abraham J Nagy is on the advisory board of MAP and is a speaker for Zogenix and Allergan. Alan M Rapoport is on the advisory boards of Allergan, Nautilus Neurosciences, NuPathe, MAP and Winston. He is a speaker for Allergan, Nautilus Neurosciences and Zogenix and is an author of the Phase IIB study on telcagepant. Received: 4 September 2012 Accepted: 29 October 2012 Citation: European Neurological Review Neurology, 2012;7(4):239–43 Correspondence: Abraham J Nagy, Nevada Headache Institute, 8285 West Arby Avenue, Suite 320, Las Vegas, NV 89113, US. E: Migraine is a common, episodic, painful and disabling neurological disorder, with autonomic and gastrointestinal features. 1,2 Many patients require not only acute treatment for attacks but also preventive lines of care. Evolution of headache therapies has been limited by a lack of an effective understanding of migraine pathophysiology. However, recently a number of promising targets for new drug developments have been discovered. In this review, emerging headache treatments and potential new targets for drug development will be discussed. New Approaches with Older Therapies Variations of Triptan Therapy Triptans currently represent the mainstay of current acute migraine therapy. 3 The first triptan to become generic was sumatriptan and this has led to the design of novel delivery mechanisms. Sumatriptan Needle-free Injection Sumavel ® DosePro ® , a needle free sumatriptan injection system, came to the US market in January 2010. Delivering 6 milligram (mg) of sumatriptan subcutaneously propelled through the skin by a burst of nitrogen gas; this system is bioequivalent to the traditional needle based system when injected into the abdomen or thigh. 4 Sumavel is an alternative for patients concerned about needles, patients with nausea and vomiting, and those not adequately managed with oral triptans. © TOUCH MEDICAL MEDIA 2012 Sumatriptan Transdermal Patches One of the most novel approaches to delivering a medication is NP101, Zelrix™, a sumatriptan iontophoretic transdermal patch. The device utilises a small electric current to drive sumatriptan across the skin delivering constant plasma levels more consistently than either oral tablet or nasal preparation, by bypassing the gastrointestinal (GI) tract. 5 Zelrix has been demonstrated to be an effective acute care medication with few of the typical triptan associated side effects. 6 The device has been accepted for filing by the US Food and Drug Administration (FDA) and if approved, may be ideal for patients with nausea and vomiting, patients intolerant to triptan side-effects and those who do not absorb oral medications optimally due to migraine-related gastric stasis. Intranasal Sumatriptan Traditional nasal delivery methods suboptimally deliver sumatriptan causing much of the dose to be swallowed and absorbed slowly via the GI tract. OptiNose is a bidirectional breath-powered device that isolates the nasal cavity from the oropharynx and delivers sumatriptan powder more effectively than current technologies. Early studies of the new device have shown good efficacy and the device is currently undergoing Phase III studies. 7 Zolmitriptan Oral Dissolvable Film Zolmitriptan Rapidfilm ® is a very thin polymeric film strip containing 2.5 and 5 mg zolmitriptan. It is designed to be swallowed with saliva 239