LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine.

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.

Emerging trends in the pharmacotherapy of chronic pain.

The pharmacotherapy for pain is dominated by conventional analgesics such as the opioids and the non-steroidal anti-inflammatory drugs. Recent advances in the understanding of the mechanisms of pain in general and chronic pain in particular, opened the field of analgesic therapy to newer pharmacological targets, which are aimed at improved efficacy and enhanced tolerability over conventional antipain treatments. Many novel targets are still in preclinical development, but some have made it into human trials and have shown promise. Newer anticonvulsants, new generation cyclooxygenase inhibitors, better tolerated glutamate modulators and balanced serotonin/noradrenaline re-uptake inhibitors are some targets that have shown promise in the clinic. These and other compounds that are in advanced phases of development for chronic pain are reviewed in this paper. It is hoped that the decade of pain control and research will lead us to an arsenal of effective and safe analgesics that will conquer the problem of chronic pain.