AAN 2011: Late Administration of Inhaled Dihydroergotamine Still Reduces Migraine Pain

Patients inhaling a novel formulation of dihydroergotamine (DHE) achieve significant pain relief even when treatment commences more than eight hours after the onset of migraine, according to a study presented at the 63rd Annual Meeting of the American Academy of Neurology.

Patients taking Levadex, an orally inhaled DHE treatment made by MAP Pharmaceuticals, had greater pain relief and were more likely to be pain free whether treatment was started within one hour, up to 4 hours, up to 8 hours, or more than 8 hours after migraine onset, compared to patients taking placebo.

“Early intervention is generally more effective; however, some patients are unwilling or unable to treat migraines early,” said lead study author Shashidhar Kori, MD, a neurologist employed by MAP Pharmaceuticals in Mountainview, CA. He said this reticence to initiate early treatment for migraine may be due to patients wanting to make sure they have a migraine before taking a medication, or to minimize their out-of-pocket costs, which Kori said can “lead to treatment failure and dissatisfaction with acute treatments.” Large studies of triptans, a standard therapeutic option for migraine, have shown that “efficacy is reduced substantially when treatment is delayed well beyond the start of the migraine,” said Kori.

Because DHE reverses central sensitization, “it may work anytime,” he said. Intravenous DHE is available, but causes nausea in a large fraction of patients, and usually requires co-administration of an anti-nausea drug. Orally inhaled DHE requires a lower plasma concentration for effectiveness, and thus is associated with less nausea, but it achieves maximum plasma concentration as quickly.

To assess the ability of Levadex to treat patients who began treatment late, Kori performed a post-hoc analysis on a placebo-controlled phase III study of Levadex, comparing pain relief (PR) and pain-free (PF) rates at 2 hours after treatment in patients who began treatment at various time intervals after onset of migraine. Results from a total of 771 patients were analyzed, all of whom had moderate-to-severe migraine pain.

For patients beginning treatment within one hour, PR was 66% for Levadex, versus 41% for placebo, while PF was 38% and 13%, respectively. For those beginning treatment from 1 to 4 hours after onset, PR was 60% for Levadex versus 35% for placebo, and PF was 28% and 10%. Treatment begun from 4 to 8 hours after onset produced PR of 53% and 30%, and PF of 22% and 8%. For treatment begun after 8 hours, Levadex produced PR of 49% versus 24% for placebo, and PF of 19% versus 9% for placebo. All differences were statistically significant.

The magnitude of the difference between active treatment and placebo also remained approximately the same over time, Kori pointed out, indicating the ability of the treatment to offer substantial relief hours after migraine onset.

Nausea was seen in 4.5% of patients receiving active treatment, versus 2% of patients receiving placebo. Unpleasant taste and cough were also adverse events.

“Levadex showed efficacy in treating a moderate-to-severe migraine attack even when it was administered as late as 8 hours after the start of the attack,” Kori said. “Thus it may help many migraineurs who are unable to treat a migraine early, owing to practical real-life limitations.”

While heart valve fibrosis has been a concern in the use of other ergot-derived drugs, including for Parkinson's disease, Kori noted that Levadex has not shown any safety signal in this regard throughout its long preclinical and clinical trial history. In addition, he said, unlike many other such drugs, Levadex does not bind to the 5-H2T receptor, which is believed to be responsible for the fibrotic effects.