Neurol Sci (2013) 34 (Suppl 1):S101–S108 DOI 10.1007/s10072-013-1396-7 TREATMENT Update on future headache treatments Abraham J. Nagy • Alan M. Rapoport Ó Springer-Verlag Italia 2013 Abstract Headache disorders are common and heterog- nitric oxide (NO) antagonists, gap junction modulators, enous neurologic entities. The complexities of management glutamate receptor antagonists, orexin receptor antagonists are further encumbered by the relatively few effective and prostanoid receptor antagonists. Therapies developing choices for acute and preventive therapies available to the over the next several years will be welcome additions to the headache specialist to treat these diverse disorders. As headache specialist’s armamentarium. advances have been made in uncovering headache patho- physiology, new therapies have surfaced and others are Keywords Acute migraine treatment Á CGRP antagonist Á forthcoming. This article will highlight new lines of care in Dihydroergotamine Á Headache therapy pipeline development. There are several novel delivery mechanisms of familiar medications which bypass the limitations of current delivery systems, including the sumatriptan ionto- Introduction phoretic patch Zecuity, the intranasal sumatriptan Opti- Nose system, the zolmitriptan Rapidfilm orally dissolvable Migraine is a common, episodic and chronic neurological film and the orally inhaled dihydroergotamine Levadex disorder, involving the peripheral and central connections system. New lines of care based upon recently discovered of the trigeminal nerve and the vasculature, and charac- therapeutic targets will also be discussed including calci- terized by its severity and disability. Nearly 20 % of the tonin gene-related peptide (CGRP) receptor antagonists, population of Western countries affected by migraine, serotonin receptor agonists, and sphenopalatine ganglion probably migraine and chronic migraine, currently avail- (SPG) intermittent stimulation. Finally, emerging targets able therapeutic options seem to be remarkably limited. for future therapeutics will be explored including transient The most recent major advance in acute treatments avail- receptor potential vanilloid (TRPV1) receptor modulators, able for patients occurred over two decades ago with the advent of triptans. Although onabotulinumtoxinA has been recently approved for chronic migraine, the progress with A. J. Nagy (&) Á A. M. Rapoport new alternatives for preventive medications seems to have Nevada Headache Institute, 8205 W Warm Springs Rd, slowed. Two beta blockers and two antiepileptics have Suite 210, Las Vegas, NV 89113, USA remained the only FDA approved migraine preventives for e-mail: [email protected]; [email protected] many years. Cluster headache, considered as one of the A. M. Rapoport most severe of the primary headache disorders, also has e-mail: [email protected] limited options for both prevention and acute care. Despite, A. J. Nagy the fact that few new therapeutic options have come to K | E Centers for Advanced Medicine, LLC, market, there has been a rapid evolution in the under- Las Vegas, NV, USA standing of headache pathophysiology. Advances in imaging techniques, new animal models and innovative A. M. Rapoport The International Headache Society, The David Geffen School signaling molecules have opened the door to unique and of Medicine at UCLA, Los Angeles, CA, USA exciting prospects for headache therapies. In this review, 123 S102 Neurol Sci (2013) 34 (Suppl 1):S101–S108 emerging treatments and new promising targets for drug as Zecuity in association with its January 2013 approval development will be discussed. by the FDA. It is expected to be available in the US in the fourth quarter of 2013. • Intranasal sumatriptan via the Optinose intranasal Innovations of older therapies apparatus: Current delivery systems for intranasal sumatriptan deliver suboptimal doses of sumatriptan Triptan variations because much of the dose tends to be swallowed and absorbed slowly via the GI tract. OptiNose, is a Injectable sumatriptan first was the first triptan launched in bi-directional, breath-actuated device that delivers Europe in 1991 and the US in 1993. Today, there are seven sumatriptan powder more effectively than current triptans available in various formulations including tablets, technologies. Consisting of a mouthpiece and a nozzle injections, orally disintegrating tablets and nasal sprays. which forms a seal when placed in one nostril, the Although triptans currently represent the mainstay of acute device is activated by blowing into it. Upon actuation, migraine therapy [1], over one-third of the patients do not the soft palate rises, isolating the nasal cavity from the respond well to triptans and well over half of them are oropharynx, and a fine powder of sumatriptan is willing to try other treatments [2]. The main limitations of deposited across the entire nasal mucosa on one side current triptans cited are slow speed of effect, recurrence of and then passes through to the other nostril. Because of pain, poor tolerability, inadequate absorption of tablets and the improved deposition of the drug, a phase I study need for a second dose. Since sumatriptan has become was able to demonstrate that more sumatriptan is generic, attempts at addressing these shortcomings have led absorbed across the nasal cavity than traditional nasal to the design of several novel delivery mechanisms. delivery methods [6]. A phase II study was designed to evaluate the efficacy and safety of a single dose of 10 or • Sumatriptan transdermal patch (Zecuity): One of the 20 mg of a powder formulation of sumatriptan deliv- most novel approaches to delivering a medication, ered with the OptiNose device in comparison with which may address the unmet need of acute treatment placebo [7]. In terms of efficacy, a greater proportion of in the setting of nausea and vomiting or poor absorption subjects who received sumatriptan 10/20 mg were pain- due to migraine related gastric stasis, is the sumatriptan free at 2 h compared with those who received placebo patch. NP101, is an iontophoretic transdermal patch (54/57 % vs. 25 %, p \ 0.05). Pain relief at 2 h for the that utilizes a small electric current to drive sumatriptan two doses was significantly better than placebo (84/ across the skin delivering a constant plasma level of 80 % vs. 44 %, p \ 0.001). Pain relief was noted as 10 ng/ml throughout the 4 h dosing period more early as 60 min (73/74 % vs. 38 %, p \ 0.01) and at consistently than either the 100 mg oral tablet or 48 h, sustained pain-free results were also notable (47/ 20 mg nasal preparation by bypassing the GI tract [3]. 49 % vs. 27 %, p \ 0.05). The most common adverse The microprocessor within the device continuously effect was dysgeusia or metallic taste in 10 % of monitors skins resistance and adjusts drug delivery to subjects receiving the 10 mg dose and 13 % receiving maintain a consistent dose of 6.5 mg of sumatriptan. the 20 mg dose. No significant adverse events or triptan The device has been demonstrated to be an effective sensations occurred, including chest discomfort, pares- acute care medication with few of the typical triptan thesia or asthenia. The device is currently undergoing associated side effects [4, 5]. The 2 h pain relief was 53 phase III investigations. vs. 29 % placebo (p = 0.0001) and the 2 h pain free • Zolmitriptan orally dissolvable film: Orally dissolvable rate (primary endpoint) was 16 vs. 8 % for placebo. formulations of triptans appeal to migraine sufferers The sustained pain relief rate from 2 to 24 h was 34 % who have nausea and difficulty in ingesting conven- for the drug and 21 % for placebo. The drug device also tional tablets. Zolmitriptan Rapidfilm advances this achieved significance over placebo with regard to concept one step further and is a very thin polymeric nausea freedom, photophobia freedom and phonopho- film strip containing 2.5 and 5 mg zolmitriptan. It bia freedom. The most common adverse event was averts the need for water and is design to be swallowed application site-related pruritus, which was generally with saliva. Approved in early 2012 in Europe for acute mild and resolved without treatment. With good 2 h migraine therapy, it is currently in the approval process pain relief, relief of associated symptoms, few adverse by the FDA for North American distribution. events and the ability to bypass the GI tract and first pass metabolism, this is an attractive alternative to Orally inhaled dihydroergotamine (DHE): DHE is an ergot standard oral treatment. NP101 was formerly called that has been available in various formulations for over the last Zelrix but prior to launch has been rebranded in the US 50 years. While intravenous DHE is the mainstay of headache 123 Neurol Sci (2013) 34 (Suppl 1):S101–S108 S103 inpatient management, it is limited in use for outpatient care. neurotransmission of meningeal trigeminovascular afferents DHE administered via currently available nasal preparations as well as brain stem pain signaling [12]. CGRP receptors are has a slow onset of action, low bioavailability of about 40 %, compelling targets for acute migraine therapy and CGRP and is less effective than nasal and subcutaneous sumatriptan receptor antagonists may be the next most promising advance [8]. Intramuscular and subcutaneous dihydroergotamine is in migraine management. The first effective CGRP receptor more effective, but produces somewhat more adverse effects antagonist was intravenous BIBN4096, olcegepant. Although and the mode of administration is less convenient. A new oral it was reported in early clinical studies to produce headache DHE inhalation device, Levadex, has been demonstrated to relief in 66 % of subjects compared to 27 % of controls, the provide similar onset of action and efficacy comparable to further development of the drug was terminated possibly intravenous DHE. The device delivers DHE deep into the lung because of low oral bioavailability and/or other unknown automatically after breath actuation. A phase I study of DHE factors [13]. MK-0974, telcagepant, is the first reported oral delivered by the inhaler vs. 1 mg of IV DHE was performed CGRP antagonist to complete 2 phase III trials.