Novel Intranasal Delivery of Sumatriptan as a Route to Rapid and Sustained Relief in the Acute Treatment of Migraine

US Neurology , 2016;12(2):84–9 DOI:


Migraine remains a common debilitating condition that exerts a high social and economic burden worldwide. Despite the widespread availability of various medications for migraine, many patients are dissatisfied with their treatment. Rapid and effective treatment at an early stage in an attack is vital in migraine to prevent central sensitization leading to attacks that are difficult to treat. Most migraineurs prefer oral medications but this is not always the most rapid or efficient route into the bloodstream. Intranasal administration of migraine treatment provides a rapid, convenient and reliable alternative to oral and other routes. AVP-825 is an intranasal medication delivery system approved by the US Food and Drug Administration in January 2016 as ONZETRA™ Xsail™ (sumatriptan nasal powder [Avanir Pharmaceuticals, Aliso Viejo, CA]) for the acute treatment of migraine with or without aura in adults. AVP-825 contains low dose sumatriptan powder and takes advantage of some unique aspects of the nasal anatomy to confer rapid pain relief in the acute treatment of migraine. In two Phase III trials, AVP-825 was well tolerated and showed significantly faster migraine pain relief and relief from other symptoms including photophobia, phonophobia, and nausea than placebo or oral sumatriptan. This benefit was achieved with substantially lower drug exposure than oral sumatriptan. Additional analyses of data from the Phase III trials show that significantly more patients with migraine receiving AVP-825 reported clinically meaningful relief, sustained relief, pain freedom, lower migraine-related disability and more consistent relief across multiple attacks than those receiving oral sumatriptan. The rapid and sustained action of AVP-825 and its convenience creates the potential for this unique treatment to reduce the burden of migraine in many patients.
Keywords: Intranasal delivery system, sumatriptan, migraine, rapid pain relief
Disclosure: Deborah I Friedman is a consultant for Allergan, Avanir, Supernus, Teva Pharmaceuticals, Eli Lilly, Zosano, and Alder Biopharmaceuticals. She is a speaker for Avanir, Supernus, Teva Pharmaceuticals and has received research support from Merck, Autonomic Technologies, Inc., and Eli Lilly.
Acknowledgments: Medical writing assistance was provided by James Gilbart at Touch Medical Media, London and funded by Avanir.
Received: March 17, 2016 Accepted April 12, 2016
Correspondence: Deborah I Friedman, University of Texas Southwestern, 5323 Harry Hines Blvd, MC 9322, Dallas, Texas, 75390 US. E:
Support: The publication of this article was supported by Avanir Pharmaceuticals. The views and opinions expressed are those of the author and not necessarily those of Avanir.
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.

Migraine is a common and highly debilitating condition that has substantial social and economic burdens.1–4 The condition affects approximately 12% of people in the US and Europe and is most common in women and those aged 30–50 years.5,6 Migraine treatments offering varying degrees of efficacy and differing modes of action have been widely available for many years.7–10 Yet, a proportion of patients remain dissatisfied with their acute therapies because of slow time to pain relief, limited level of pain relief or unreliable effectiveness11–13 Indeed, several studies have reported that most migraineurs would be willing to try an alternative medication.14,15

A substantial unmet medical need remains for more rapid, potent, and consistently reliable acute migraine treatments. Emphasizing this need, research findings demonstrated that suboptimal outcomes following acute intervention represent a significant risk factor for the development of chronic migraine.16,17 In addition to differences in intrinsic pharmacological activity among the various medications used for acute migraine, the route of administration and the drug delivery method can greatly influence effectiveness and tolerability. Selecting the appropriate method is therefore vital to optimize treatment outcomes.

By virtue of the large area of absorptive mucosa with rich vascularization in the posterior nasal cavity, the nose provides an ideal non-invasive route of drug administration for migraine treatment. Despite these potential advantages for drug delivery, oral tablets remain by far the most commonly utilized route, perhaps underscoring patient preferences and/or limitations of current 'non-oral' migraine treatments.

This article discusses the need for rapid pain relief in migraine, limitations of current migraine medications, anatomy of the nasal cavity and its potential advantages as a route for rapid and reliable pain relief in migraine. AVP-825 is an intranasal medication delivery system approved by the US Food and Drug Administration (FDA) in 2016 as ONZETRA Xsail (sumatriptan nasal powder [Avanir Pharmaceuticals, Aliso Viejo, CA, US]) 11 mg for the acute treatment of migraine with or without aura in adults.18 AVP-825 uses the patient’s own breath to propel sumatriptan powder beyond the nasal valve, into the upper posterior nasal cavity, an area conducive to the rapid systemic absorption of medication, while reducing off-target delivery to the front of the nose or the diversion of the drug to the throat and gastrointestinal (GI) tract. The evidence supporting AVP-825 and its potential importance as a new approach to managing migraine is reviewed herein.

The need for rapid pain relief in acute migraine
Both episodic and chronic migraine are generally under-diagnosed and under-treated; patient management is frequently suboptimal and relies primarily on over-the-counter medications or oral triptans.19–21 In the acute treatment of migraine, patients want medications that provide rapid relief, freedom from pain within 2 hours, relief from other symptoms such as photophobia, phonophobia, and nausea, no recurrence or longer times to recurrence, no need for rescue medication, efficacy that is maintained and does not decrease on subsequent attacks, absence of side effects, and oral administration.13,21,22 In order to achieve these goals, ideal patient management should therefore include disease education, avoidance of potential trigger factors and an individually tailored, evidence-based treatment plan that is reassessed at frequent intervals.22,23

In the acute treatment of migraine, rapid delivery of medication at the optimal dose may improve effectiveness and treatment satisfaction by preventing progression of the migraine cycle. Effective treatment should be available for use early in an attack with back-up medications in case of treatment failure, as the response to any treatment cannot be predicted with certainty.23 Multiple formulations of medication delivery should be part of a treatment plan which stratifies use based on the characteristics of the patient’s migraine attack, while considering the presence of significant nausea or vomiting, the patient’s ability to tolerate odors and flavors during a migraine, speed of headache onset, presence of migraine upon awakening, and severity of pain.24

Fast acting treatments provide the best opportunity to treat during the early stages of an attack when it may be terminated fully. If left untreated, second- and third-order trigeminal neurons may become activated leading to central sensitization and allodynia. Once this occurs, the attack is much harder to treat, and triptans may be less effective.25 Nonetheless, fewer than half of patients using triptans to treat their migraines use them early.26 When comparing patients who employed triptans early from those who delayed treatment, the reasons for delaying treatment were: taking over-the-counter medications or a non-triptan first, waiting to be certain that a headache was a migraine, and only taking a triptan if the over-the-counter or non-triptan medication did not work.26 Other factors contributing to treatment delay included concern of running out of triptans, dislike of taking medications, concern about side effects, and cost. By reducing the duration of pain and the other associated symptoms of migraine (e.g., photophobia, phonophobia, nausea, and vomiting), rapid acting therapies may enable an earlier resumption of work/leisure activities and are likely to improve quality of life.27,28

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Keywords: Intranasal delivery system, sumatriptan, migraine, rapid pain relief