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The Calcitonin Gene-Related Peptide Receptor: A New Source of Acute Migraine Relief
Abstract & Commentary
By Dara G. Jamieson, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College, New York, NY. Dr. Jamieson reports she is a retained consultant for Boehringer Ingelheim, Merck, and Ortho-McNeil, and is on the speaker's bureau for Boehringer Ingelheim and Merck.
Synopsis: Telcagepant, a new oral calcitonin gene-related peptide receptor antagonist, has similar efficacy and better tolerability for acute migraine headaches as compared to a triptan.
Sources: Ho TW, Ferrari MD, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: A randomised, placebo-controlled, parallel-treatment trial. Lancet 2008;372:2115-2123; Edvinsson L.CGRP-receptor antagonism in migraine treatment. Lancet 2008;372:2089-2090.
Knowledge of the pathophysiology of migraine has resulted in specific therapy for acute migraine headache attacks. Recognition of 5HT1B,1D receptors in the trigeminovascular system led to the development of 5HT1B,1D receptor agonists, triptans, with demonstrated therapeutic efficacy. For almost two decades, patients with migraines have used one of the seven triptan medications to relieve the pain of an acute migraine. As a migraine-specific alternative to over-the-counter medications or narcotics, triptans have improved the quality of life for millions of migraineurs who know that dependable headache relief is minutes to hours away. However, not all migraine patients experience tolerable pain relief with triptans, and the medications are not appropriate for use in patients with vascular disease or uncontrolled hypertension.
Calcitonin gene-related peptide (CGRP), an endogenous vasoactive neuropeptide, also has a key role in migraine pathophysiology. CGRP receptors are found on first- and second-order trigeminal neurons and on smooth muscle cells in meningeal vessels. Concentrations of CGRP are increased in the blood of patients with migraines, and injection of CGRP can induce a migraine-like headache in migraineurs. While CGRP is a vasodilator, antagonism of CGRP receptors does not cause vasoconstriction, and CGRP antagonists may provide migraine relief without the vasoconstrictor effects of triptans.
With funding from Merck Research Laboratories, a randomized, parallel-treatment, placebo-controlled, double-blind trial, conducted at 81 sites in Europe and the United States, evaluated the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of the CGRP receptor. Patients age 18 years or older, without vascular disease or uncontrolled hypertension, with migraine diagnosed by International Headache Society criteria, treated moderate or severe migraine attacks with either oral telcagepant 150 mg or 300 mg, the oral triptan zolmitriptan 5 mg, or placebo. The five co-primary endpoints at two hours after treatment were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea. The 1,380 migraineurs were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (27% vs 10%, p<0.0001), pain relief (55% vs 28%, p<0.0001), and absences of phonophobia (58% of vs 37%, p<0.0001), photophobia (51% vs 29% of p<0.0001), and nausea (65% vs 55%, p=0.0061). Telcagepant 300 mg and zolmitriptan 5 mg had similar efficacy, and both were more effective than telcagepant 150 mg. Adverse events were noted for 31% or 37% of patients taking telcagepant 150 mg or 300 mg, respectively, 51% taking zolmitriptan 5 mg, and 32% taking placebo. The most common adverse events noted with the CGRP antagonist at 300 mg were dry mouth (6%), somnolence (5%), and dizziness (5%). The investigators concluded that telcagepant 300 mg had an efficacy for acute migraine comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. The accompanying editorial by Lars Edvinsson noted that these results provide a new option for migraine treatment, even though the anti-migraine targets (e.g., peripheral sensory nerves or brainstem nuclei) of CGRP-receptor antagonists are still being explored.
With close to 30 million Americans suffering from chronic disabling headaches this new treatment option should bring relief to many headache sufferers. This large, phase III trial demonstrated that the benefit of telcagepant is comparable to that of a specific triptan. By extrapolation, these encouraging efficacy and tolerability results should be similar when telcagepant is compared with other triptans. Treatment of migraine headaches often necessitates multiple medications, and the safety profile of this CGRP antagonist should allow combination with over-the-counter medications and triptans, as well as daily preventative medications.
In this study, patients with vascular disease were excluded because of the possible randomization to a triptan. Further study is needed to determine the safety of telcagepant in patients with cerebrovascular and cardiovascular disease. However, if vascular safety is established, then migraineurs for whom triptans are prescribed should be able to enjoy relief with a migraine-specific acute pain medication. Triptans, and now CGRP antagonists, are the end result of years of laboratory and animal research into migraine pathophysiology, and are an affirmation of the benefits of time and money spent on basic science research and pharmaceutical development.