Despite an abundance of available options, patients with migraine are often dissatisfied with current abortive therapies. Studies indicate that up to a third of patients do not respond to triptans used as first-line therapies, and many more switch therapies regularly because of adverse effects.1-3 The issues with these treatments are varied, including lack of reliability, unpredictable pharmacokinetics, and poor bioavailability associated with substantial first-pass metabolism of the drugs. Patients also complain of pain at the injection site contributing to resistance to self-injection.1

In a 2018 article, Stapleton reported that, “[a]bout half of migraine patients stop seeking care for their headaches, partly because they are dissatisfied with therapy.”3 He pointed out that patients with migraine are, in fact, among “the most dissatisfied” with their treatment, showing a clear need for new alternatives.

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For some patients, inhaled formulations of known therapies can offer important benefits in terms of rapid onset of action and a lower risk for adverse effects associated with the same drugs given in intravenous (IV), injectable or oral forms.2 Orally inhaled aerosol drug delivery has been used successfully in many therapeutic areas, particularly in pulmonary disease. Inhaled delivery (both nasal and oral) of abortive drugs for migraine have been available for some time, with efficacy comparable to oral formulations, although their use has not been fully adapted as hoped.

“Inhaled migraine therapies are best suited for acute attacks where relief of pain and other migraine symptoms are desired more rapidly than can be accomplished by oral tablets,” Matthew Robbins, MD, a neurologist at Weill Cornell Medicine and New York-Presbyterian Hospital in New York City, told Neurology Advisor. “An inhaled therapy is of particular use for patients who have prominent nausea and vomiting, or have an aversion to swallowing pills during their attacks. In addition, migraine attacks often feature gastroparesis, which means that oral tablets may take longer than usual to work in many patients,” he said. Disadvantages to inhaled therapies include “poor taste, difficulty with absorption, and patient preference to take a more conventional tablet,” he added.

Three main types of agents are available in inhaled forms for migraine, including triptans, dihydroergotamine (DHE) and prochlorperazine.1,2 “Some migraine medications are actually not bioavailable in tablet form, such as [DHE], and are more effective when administered intranasally,” Dr Robbins explained.

Long-used drugs such as sumatriptan and zolmitriptan come in nasal sprays.2 “Inhaled sumatriptan has been limited by poor taste, and zolmitriptan seems to be more tolerable,” said Dr Robbins, noting that recently, a breath-powered intranasal formulation of sumatriptan has been approved as well. This formulation is rapidly absorbed through the nasal mucosa when inhaled, after first exhaling by mouth.1

Ketorolac is a nonsteroid anti-inflammatory drug available as a nasal spray for migraine. In a head-to-head comparison to the sumatriptan nasal spray, ketorolac was found to be superior to placebo and noninferior to sumatriptan.4 Ketorolac, but not sumatriptan, also demonstrated superiority to placebo in maintenance of pain relief at 24 hours. The most common adverse effects were nasal burning and dysgeusia.

DHE is one of the longest treatments for migraine, delivered intravenously during the past decades in the clinical setting for treatment-refractory headache.5,6 Investigation of 4 doses of DHE mesylate (MAP0004) delivered via an inhaler reached comparable concentration to 1 mg IV-DHE at 2 hours, with a 10-fold lower peak plasma level that may be a primary factor in a much greater tolerability.6 Doses of 2 and 4 inhalations both failed to instigate nausea common to IV-DHE, and were not associated with increased risks for cardiovascular and respiratory involvement.6

Prochlorperazine is a phenothiazine dopamine 2 type antipsychotic that demonstrated good efficacy in early studies in migraine.2 Initial phase 1 and 2 trials of an inhaled form of prochlorperazine showed statistically significant improvement in pain relief in 60% to 66% of patients at 3 dosage levels (5 mg, 7.5 mg, and 10 mg) compared with placebo without adverse events. According to a review by Chua and Silberstein,1 further study was discontinued because of possible financial challenges, despite the early promise of this novel abortive therapy.

An inhaled form of another antipsychotic, loxapine, was also investigated for migraine treatment, but further development ceased when trials failed to show sufficient efficacy.6 Although it is not a drug, hyperbaric oxygen could be considered an effective abortive inhaled therapy for migraine. A Cochran review by Bennett et al7 found some evidence of efficacy of hyperbaric oxygen to eliminate acute migraine pain, although the cost and lack of availability are limitations to broad adoption.

Inhaled therapies may be a viable alternative for many patients with migraine who are unable to find relief on other formulations. Unfortunately, their development is largely stalled. In a 2018 editorial, Franco Granella7 described the current frustration with the obstacles to introducing promising inhaled therapies to patients who need them. “[C]linical trials have shown brilliant results in terms of efficacy, rapidity of action and safety. In spite of these potential advantages, inhaled drugs have accounted so far for a tiny part of the market,” he concluded.

References

1. Chua AL, Silberstein S. Inhaled drug therapy development for the treatment of migraine. Expert Opin Pharmacother. 2016;17(13):1733-1743.

2. Thorlund K, Mills EJ, Wu P, et al. Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment comparison meta-analysis. Abstract Cephalalgia. 2014;34(4):258-267.

3. Stapleton KW. Orally inhaled migraine therapy: where are we now? Adv Drug Deliv Rev. 2018;133:131-134.

4. Rao AS, Gelaye B, Kurth T, et al. A randomized trial of ketorolac vs. sumatripan vs. placebo nasal spray (kspn) for acute migraine. Headache. 2016;56(2):331-340.

5. Tepper SJ. Orally inhaled dihydroergotamine: a review. Headache. 2013;(suppl 53)2:43-53.

6. Vandenbussche N, Goadsby PJ. The discovery and development of inhaled therapeutics for migraine. Expert Opin Drug Discov. 2019;14(6):591-599.

7. Bennett MH, French C, Schnabel A, Wasiak J, Kranke P, Weibel S. Normobaric and hyperbaric oxygen therapy for the treatment and prevention of migraine and cluster headache. Cochrane Database Syst Rev. 2015;(12):CD005219.

8. Granella F. Inhaled migraine drug therapy: a start of the art therapeutic strategy or just another gimmick? Expert Opin Pharmacother. 2018;19(16):1743-1745.