Therapeutic Agents for the Treatment of Migraine

Abstract

Migraine is a debilitating condition, often with nearly unbearable throbbing pain, nausea, and greatly reduced thresholds to sensory stimulation. Despite the availability of specific acute medications (such as triptans), for over 15 years, migraine remains an undertreated condition. Although representing a revolution in headache therapy at the time, triptans have a number of shortcomings including cardiovascular side effects resulting from their inherent vasoconstrictive properties, and a significant proportion of refractory patients. CGRP antagonists appear to represent the next revolution in migraine therapy, with clinical safety issues shown to be comparable to placebo and 2 h response rates identical to the triptans. Preventative migraine therapy has been dominated by older drugs developed for other indications such as hypertension, epilepsy, and depression. These agents often have significant side effects. Drugs that act on other relevant mechanisms such as ion channels and nitric oxide generation have been developed and tested in the clinic. These have yet to emerge as rivals to the triptans. However, the pathophysiology of migraine is complex and combination therapies that target multiple mechanisms, including one or more of these, may turn out to be more efficacious than monotherapy. An important aspect of migraine therapy that has been addressed with only partial success is speed of onset. Intranasal and pulmonary delivery offer the potential for more rapid systemic exposure and perhaps faster onset of efficacy. Migraine patients are in particular need of improved nonoral drug delivery systems that can provide rapid relief of headache pain along with associated symptoms.