Emerging Drugs for Migraine Prophylaxis and Treatment

Marcelo E. Bigal, MD, MSc, PhD; Abouch V. Krymchantowski, MD, MSc, PhD

Disclosures
In This Article

Abstract and Background

Migraine is a chronic neurologic disorder with heterogeneous characteristics resulting in a range of symptom profiles, burden, and disability. Migraine affects nearly 12% of the adult population in occidental countries, imposing considerable economic and social losses. The pharmacologic treatment of migraine includes preventive and acute strategies. A better understanding of the migraine pathophysiology along with the discovery of novel molecular targets has lead to a growing number of upcoming therapeutic proposals. This review focuses on new and emerging agents for the treatment of migraine.

Migraine is a highly prevalent, disabling, undiagnosed, and undertreated disease.[1] The phenomenon is a primary neurologic disorder with a clear genetic basis.[2,3] For some uncommon forms of migraine, such as familial hemiplegic migraine, specific pathogenic genes have been identified. The most common mutation affects a gene on chromosome 19 that encodes for a neuronal calcium channel.[4] This observation suggests that other forms of migraine may also be ion channelopathies. During the migraine attack, neural events result in the dilatation of meningeal blood vessels that, in turn, causes pain, further nerve activation, and inflammation.[5] Because neural events are linked to vascular events, migraine is considered a neurovascular headache disorder.

Migraine probably results from dysfunction of brainstem areas involved in the modulation of craniovascular afferent fibers.[2,3,4,5] Brainstem activation may also lead to activation of ascending and descending pathways, with initiation of a perimeningeal vasodilatation and neurogenic inflammation. The pain is understood as a combination of altered perception (related to peripheral or central sensitization) of stimuli that are usually not painful, and the activation of a feed-forward neurovascular dilator mechanism in the first (ophthalmic) division of the trigeminal nerve. Cortical spreading depression is the presumed substrate of migraine aura; spreading depression also occurs in migraine without aura.

The past 15 years has witnessed the development of an arsenal of drugs that act on excitatory glutamate-mediated activity or inhibitory gamma-aminobutyric acid (GABA)-mediated activity, actions that theoretically provide cortical stabilization, therefore counteracting the imbalance supposedly existent in the migraineur's brain.[4,5] In addition, the progressive knowledge about the sequence of phenomena occurring during a migraine attack has stimulated interest in agents that may block the cortical spreading depression, a presumed substrate of migraine. Other targets include the blockage of proinflammatory substances released at the level of the trigeminal end, including neuropeptides involved in initiating the pain of migraine, and substances that may block the sensitization of peripheral and central trigeminal nociceptive pathways.[1,2,5,6,7,8,9]

In this review, we discuss new and emerging agents for the treatment of migraine. For both preventive and acute therapies, we first discuss medications that have been recently proposed for migraine, and then medications in development. None of the drugs discussed, with the exception of topiramate (TPM), have received an indication for the treatment of migraine, according to regulatory agencies.


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