Emerging Treatments in Headache

Emerging Treatments in Headache

Rapoport Alan M , Sun-Edelstein Christina
Published: BTG - FUTURE DIRECTIONS IN NEUROLOGY
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Migraine is a common and disabling disease, with a one-year prevalence of 12% in Western countries such as the US.1 It is associated with significant societal costs in terms of pain, bedridden days, and lost days of work. Although the development and availability of triptans over the past 17 years has revolutionized the acute treatment of migraine, many patients report an incomplete or delayed response, while others experience intolerable adverse events.2,3 Furthermore, triptans are contraindicated in patients with cardiovascular disease because of their vasoconstrictive activity. Therefore, other options are needed for those who do not respond optimally to triptans, as well as for those with possible drug–drug interactions, contraindications, or risk factors. Additional goals for medications in development include rapid onset of action, bypassing the gastrointestinal (GI) tract, sustained treatment response, and solid safety and tolerability profiles. In this overview of emerging treatments in headache, the current understanding of migraine pathophysiology will be outlined and medical and surgical therapies at various stages of development will be discussed. Advances in headache diagnosis and classification will also be discussed in detail.

Migraine Pathophysiology
In recent years, significant advances have been made in the understanding of migraine pathophysiology. Although the exact etiology remains to be defined, the currently prevailing theories are based on a hyperexcitable ‘trigeminovascular complex,’ and possibly cortex, in patients who are genetically predisposed to migraine. In these susceptible individuals, the trigeminovascular neurons release neurotransmitters, such as calcitonin gene-related peptide (CGRP) and substance P, when headache triggers are encountered. This leads to vasodilation, mast cell degranulation, increased vascular permeability, and blood vessel edema, resulting in meningeal neurogenic inflammation. This nociceptive information is transmitted from the periphery along the trigeminal nerve to the brainstem trigeminal nucleus caudalis, and then to the thalamic nuclei and the cortex, where migraine pain is ultimately perceived.4 The locus coeruleus, which contains noradrenergic neurons, the dorsal raphe nuclei, which consist of serotoninergic neurons, and the periaqueductal gray also play modulatory roles in the transmission of pain.5

The aura of migraine can be explained by the phenomenon of ‘cortical spreading depression’ (CSD). In experimental animals and in human neocortical and hippocampal tissue in vitro, CSD occurs when an electric or chemical stimulus is applied to the cerebral cortex, resulting in an excitation followed by a prolonged depolarization of cortical neurons that gradually spreads across the cortex. This wave of depolarization occurs in conjunction with a wave of oligemia.6–10 Activation of the N-methyl-D-aspartate (NMDA) receptor subtype is required to trigger CSD in the rat cerebral cortex11 and in human neocortical tissues.12 A similar phenomenon is hypothesized to occur spontaneously in humans, producing the aura. Recent evidence obtained from functional magnetic resonance imaging,13 epidural electrophysiological recordings,14–16 and intracortical multiparametric electrodes17 have supported this hypothesis. The mechanism by which the headache phase develops from the aura is unknown and somewhat controversial, but it may be related to the cortical release of CGRP, nitric oxide, arachidonic acid, or various ions and their effects via the trigeminal nerve into the brainstem and back to the dural blood vessels.18,19

The rationale of the emerging therapies is based on the understanding of the above pathophysiology, with various treatments targeting different components of the operative pathways discussed above.

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