Transdermal Sumitriptan Acts Rapidly on Migraine Symptoms and Provides Sustained Relief

Daniel M. Keller, PhD

September 17, 2009

September 17, 2009 (Philadelphia, Pennsylvania) — A novel, single-use transdermal patch that transports sumatriptan into the skin using a mild electric current (Zelrix, NuPathe) overcomes some of the problems of oral triptans for the treatment of migraine headache, a new study suggests.

In about 30% of patients, migraine-associated nausea and vomiting may interfere with oral delivery of triptans, and gastroparesis may limit drug absorption. Nasal triptan formulations may have problems of unpleasant taste and inconsistent bioavailability. The iontophorectic system examined in this study controls the rate and amount of drug delivered, so more consistent plasma levels are achieved and unpleasant side effects may be avoided.

Jerome Goldstein, MD, director of the San Francisco Clinical Research Center and Headache Clinic, presented the results of a multicenter, randomized, double-blind, placebo-controlled phase 3 trial during the 14th International Headache Congress here. The trial tested the iontophoretic transdermal delivery device to treat a single moderate to severe migraine attack.

Increased Freedom From Headache

Compared with placebo (n = 228), patients using the active device (n = 234) experienced significantly increased freedom from headache pain, photophobia, phonophobia, and nausea. These patients also had significantly better sustained pain relief and used less rescue medication. Adverse events occurred slightly more frequently among the patients using the device and were mostly mild application site reactions that resolved within 2 days.

The 2 groups of the trial were well balanced. Patients had a mean age of 41 years in both groups, women made up 84% to 86% of the groups, about 82% of participants were white, and the mean body mass index of the patients was about 27 kg/m2. History of sumatriptan use in the active drug and placebo groups was equivalent (oral, 94% and 96%; nasal spray, 22% and 23%; subcutaneous, 27% and 31%, respectively).

Patients with fewer than 2 or more than 6 migraines per month or more than 15 headache days per month in the 3 months before the trial were excluded. The trial originally randomized 530 patients, but 61 of them (31 in the active treatment group and 30 in the placebo group) did not experience a migraine attack within the 2-month cut-off period and were excluded.

The active device, containing the drug, a battery, and a microprocessor, delivered sumatriptan during a 4-hour period. A similar placebo device delivered sodium. Patients rated their migraine pain during an attack on a 4-point scale (0 – 3) and were instructed to use a patch only if they rated the pain as 2 or 3 (moderate to severe). They were not allowed any analgesic or antiemetic medication within the 8 hours before or 2 hours after activating the device.

The primary efficacy endpoint of the trial was the proportion of patients who were headache-pain-free at 2 hours after activating the patch. Efficacy analyses were based on the intention-to-treat population.

The active device was significantly superior to placebo in freedom from headache pain at all time points out to 12 hours. It was also superior to placebo out to 12 hours in relieving pain, nausea, photophobia, and phonophobia.

Outcomes With Active Device vs Placebo Device (Proportion of Patients)

Outcome Active Device Placebo Device P Value
Migraine-free at 2 hours (%) 16 8 .0135
Pain-free at 2 hours (%) 19 9 .009
Pain relief at 2 hours (%) 53 29 <.001
Pain relief at 1 hours (%) 29 19 .0135
Nausea-free at 2 hours (%) 84 63 <.001
Nausea-free at 1 hours (%) 71 58 <.05
Photophobia-free at 2 hours (%) 51 36 .0028
Phonophobia-free at 2 hours (%) 55 39 .0002
Sustained pain relief 2 to 24 hours (%) 34 21 .002
No use of rescue medication (%) 60 40 <.0001

Treatment-emergent adverse events were reported in 51% of patients receiving the active device vs 45% in the placebo group. The only adverse events occurring in at least 5% of patients were related to the site of application of the active or placebo device (pain, 23% vs 15%; paresthesia, 12% vs. 19%; pruritus, 8% vs 7%; application site reaction, 7% vs 6%, respectively).

Dr. Goldstein told Medscape Neurology that the iontophoretic transdermal system for sumatriptan is "a step beyond injectable." He said, "We're giving the same dose as an injectable sumatriptan with a smoother delivery pattern, more consistency, and fewer side effects."

In the study, the incidence of triptan-related adverse events was low. "The likelihood of having the sumatriptan side effect profile like tightness of the forehead, heat over the forehead, palpitations, or anything like that is very remote with this," Dr. Goldstein said. He reported in his poster that the iontophoretic delivery system avoids plasma sumatriptan levels above 50 ng/mL.

Patient reaction to this form of sumatriptan delivery was very positive, particularly in those who had previously used the injectable form, he added. He predicted that the device will find a place in clinical practice for the treatment of rapid-onset migraine headache that had usually been treated with injectable sumatriptan. "This really should replace it," Dr. Goldstein said.

Novel Approaches Welcome

Lawrence Newman, MD, director of the headache institute at Roosevelt Hospital, associate professor of clinical neurology at Albert Einstein College of Medicine, both in New York City, and a member of the International Headache Congress organizing committee, told Medscape Neurology, "Whenever we treat people with migraine, we're looking for novel approaches." Because of the high incidence of nausea and vomiting during migraine, "Using a non-oral route of administration just makes perfect sense," he said. "The injection is a great tool, but most people don't want to take an injection." Patients therefore often delay treatment, lessening the chance of aborting a headache.

Dr. Newman said that according to the trial data, the device worked very quickly and very well. "It had all the benefits of an oral medication without the need to take it orally," he said. It eliminated nausea and vomiting, he added, "So it's doing what we would expect it to do and what we need it to do."

Dr. Goldstein said that at this early stage, there have not yet been head-to-head comparisons of this delivery system with other formulations and routes of administration of sumatriptan or other triptans.

The trial was supported by NuPathe, Inc. Dr. Goldstein has disclosed that was an investigator on the clinical trial and is an investigator and an advisor for NuPathe Inc. He is on speakers' bureaus for Novartis, Merck, Pfizer, Eisai, and other companies. Dr. Newman has disclosed that he was not involved in the study but is on the NuPathe Advisory Board and has received grants from Endo and honoraria from Endo, GlaxoSmithKline, Merck, and NuPathe. He also has disclosed that he has served on the advisory boards of or consulted for Endo, GlaxoSmithKline, Merck, MAP, and NuPathe.

14th International Headache Congress: Abstract PO23. Presented September 11 and 12, 2009.

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