Targeted 5-HT(1F) Therapies for Migraine

Migraine is a common neurological disease characterised by the presence of attacks of unilateral, severe head pain accompanied by other symptoms. Although it has been classified as the sixth most disabling disorder, the available therapeutic options to treat this condition have not progressed accordingly. The advance in the development of 5-HT(1) receptor agonists for migraine, including 5-HT(1B/D) and 5-HT(1F) receptor agonists, has meant a major step forward towards the progression of a better treatment for migraine. Triptans have a limited efficacy, and their effect on vasoconstriction makes them unsafe for patients with cardiovascular and/or cerebrovascular diseases. Therefore, novel effective antimigraine treatments without cardiovascular effects are required, such as selective 5-HT(1F) receptor agonists (ditans). Lasmiditan has much higher affinity for the 5-HT(1F) receptor than for the vasoconstrictor 5-HT(1B) receptor. This has been confirmed in preclinical studies performed to date, where lasmiditan showed no effect on vasoconstriction, and in clinical trials, where healthy individuals and patients did not report cardiac events due to treatment with lasmiditan, although it should be confirmed in larger cohorts. Lasmiditan crosses the blood-brain barrier and may act both centrally and peripherally on 5-HT(1F) receptors expressed on trigeminal neurons. It is a well-tolerated compound that does not induce major adverse events. Although ongoing phase III clinical trials are needed to confirm its efficacy and safety, lasmiditan might offer an alternative to treat acute migraine with no associated cardiovascular risk. This review will focus on the characterisation of 5-HT(1) receptor agonists and their effects as migraine therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-018-0615-6) contains supplementary material, which is available to authorized users.