Ineffectiveness of Neurokinin-1 Antagonist in Acute Migraine

Abstract

Lanepitant is a high-affinity, selective neurokinin-1 receptor (NK-1) and is effective in the dural inflammation model of acute migraine. Lanepitant 30, 80, and 240 mg given orally was evaluated in a double-blind, placebo-controlled crossover study to determine its effect in reducing migraine pain and severity of associated symptoms. Outpatients treated four migraine headaches of moderate or severe pain intensity with study drug according to a randomization schedule. They recorded their pain intensity and severity of migraine-associated symptoms at 30, 60, 90, and 120 min. Although 53 patients were randomly allocated to a treatment sequence, only 40 patients completed all treatments. There was no statistically significant difference in improvement in migraine pain at any time for any of the treatments. Additionally, there was no change in severity of migraine-associated symptoms associated with lanepitant therapy. No adverse events could be attributed to lanepitant. Lanepitant was ineffective orally in treating acute migraine in this trial. This may be due to poor bioavailability during a migraine attack. Alternatively, the neurogenic inflammation hypothesis may not apply to migraine.

Release of immunoreactive substance P in the brain stem upon stimulation of the cranial dura mater with low pH – inhibition by the serotonin (5‐HT1) receptor agonist CP 93,129

“…Although the site of action of these drugs can be located peripherally (including the trigeminal ganglion), they may cause a general decrease of neuropeptide release, the main bene®t of which may be the reduced release and action of SP within the spinal trigeminal nucleus. This may also explain why NK-1 receptor antagonists with limited penetration through the blood-brain barrier are ine ective in the treatment of migraine attacks (Goldstein et al, 1997).…”

Neurobiology in primary headaches

“…Several studies have suggested that SP is involved in plasma extravasation from postcapillary venules in the dura mater during primary headache attacks [131]. While neurokinin receptor antagonists are potent inhibitors of neurogenic inflammation [155,172,173] clinical studies have shown that these blockers do not have any significant effect in acute migraine attacks [86]. Furthermore, while CGRP is released during the headache phase of a migraine attack, SP is not [76,79,171,200].…”

Current and prospective pharmacological targets in relation to antimigraine action

“…Redrawn from Saxena and Tfelt-Hansen (2006) trigeminal ganglion or systemic administration of capsaicin, has allowed studies on the activation of the trigeminal system and its effects on the cranial vasculature (for review, see Arulmani et al 2006). This review also contains data on the ability of several drugs to inhibit plasma protein extravasation (e.g., Weiss et al 2006), although it should be kept in mind that extravasation inhibitors, such as CP-122,288 (Roon et al 2000), the neurokinin-1 receptor antagonist lanepitant (Goldstein et al 2001a;Goldstein et al 1997), and the mixed ET A /ET B receptor antagonist bosentan (May et al 1996) proved ineffective in the treatment of migraine. Thus, the relevance of plasma protein extravasation in migraine is no longer tenable (Peroutka 2005).…”