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Emerging Therapies and Preventive Treatments for Migraine

Emerging Therapies and Preventive Treatments for Migraine

Emerging Therapies and Preventive Treatments for Migraine
A migraine is often perceived as “just a bad headache.” However, to those suffering from this disabling neurologic disease, it is an incapacitating and chronic illness.1,2 Viewed as a hereditary disease that disproportionately affects females, migraines often begin in childhood. Puberty is a common trigger for their onset, and the frequency only increases with age.1 Characterized as a throbbing headache, there are often accompanying sensory abnormalities, the most notable of which is an aversion to light.3 According to the Migraine Research Foundation, migraines make up the third most prevalent disease in the world, affecting 1 billion people worldwide; in the United States, they affect 18% of women, 6% of men, and 10% of children.1 In 2013, the World Health Organization updated the ranking of migraine among other conditions in the gloal burden of disease, placing it at the No. 6 spot for years lost to disability worldwide.4 It is estimated that nearly 90% of migraine sufferers experience moderate to severe pain during an attack and 75% of suffers have a reduced ability to function normally during their attack.5

Despite a growing amount of research, the underlying mechanisms that trigger and propagate the migraine cycle are not well understood. It is well known that migraine attacks are associated with triggers , which include stress, hormonal fluctuations, sleep disturbances, skipping meals, and sensory overload; however, the neural and vascular pathophysiology of a migraine is not well understood.6 As such, the pathophysiology behind migraines is a highly debated topic. One theory for the origin of a migraine headache is that it is a vascular disorder and focuses on the dilation of blood vessels as the root cause during an attack.6 However, newer evidence suggests the involvement of underlying mechanisms of the trigeminovascular system.6 In this model, a migraine headache is thought to occur when meningeal pain networks are activated by signals emanating from the trigeminovascular system.7 The cortex, brainstem, trigeminal nerve, meninges, and hypothalamus are also thought to play a role in migraine pathophysiology.3 The hypothalamus is of particular interest for its role in maintaining homeostasis. While it not known whether the disease itself causes alterations in brain structure and function or if there is a genetic component, the brain of a migraine sufferer has abnormalities and differences from that of a person who does not experience migraines. It is believed that these abnormalities result in a greater sensitivity to changes in the neurochemical balance maintained within the brain, along with a decreased ability to adapt to fluctuations, which ultimately lead to repeated attacks.7 Evidence suggests that repeated headaches are involved in the progression of disease and are linked to changes in brain anatomy and function.7

Role of Calcitonin Gene-Related Peptide
Advancements in migraine research over the past few decades have led researchers to identify the possible role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology. CGRP is a neuropeptide and a potent dilator of both peripheral and cerebral blood vessels.3,8 Its effects vary widely; however, where migraines are concerned, it is most notably involved in the regulation of the cardiovascular system, the modulation of nociceptive receptors and blood vessels, pain signaling, vasodilation, and mediation of neurogenic inflammation.8,9 Early evidence implicating CGRP in migraine came from groundbreaking research in 1990, which demonstrated a rise in CGRP levels in jugular outflow during attacks. Elevated serum and saliva levels of CGRP have also been reported in spontaneous and induced migraines. Additionally, it has been noted that when a migraine is treated with 5-hydroxytryptamine receptor 1B/D agonists, commonly referred to as triptans, there was either a reduction of CGRP or pain relief.

Despite a mounting body of evidence, the significance of increased blood levels of CGRP remains controversial due to 1 well-controlled trial that failed to demonstrate elevations during migraine.9 However, compelling evidence points to an increased sensitivity to CGRP in patients who experience migraines. Researchers came to this conclusion based on a study of CGRP injections in both healthy individuals and those who suffer from migraines. Between 57% and 75% of the migraine study group experienced a delayed migraine-like headache, while similar effects were not seen in the healthy group.8 Despite having vasodilatory effects similar to those of nitroglycerin and pituitary adenylate cyclase-activating polypeptide, which are both used to induce delayed migraine-like headaches, CGRP is not considered to be within a class of vasodilators.3 This is evidenced by other strong cerebral vasodilators, such as vasoactive intestinal peptide, which do not result in migraine induction. However, although the mechanism of action of CGRP in migraine induction involves more than just vasodilation, vasodilation still occurs at some level during an episode and therefore its role in migraine propagation remains controversial.3

Given this line of evidence, it is not surprising that there have been multiple attempts to develop pharmacologic agents directed at decreasing CGRP levels or blocking CGRP receptors. There have been 6 CGRP receptor antagonists researched and tested, and other agents are in development.9 Although the actual site of action of this class is unknown, it is thought that CGRP receptor antagonists act on the central nervous system (CNS). Despite the fact that many drugs do not cross over well into the CNS because of the blood-brain barrier, it is likely that small amounts can penetrate the CNS to act centrally. However, the efficacy of CGRP-blocking antibody therapy, which acts in the periphery, in clinical trials suggests that CGRP has a peripheral site of action as well.9
Olcegepant, an intravenous drug formulation, was the first of the CGRP receptor antagonists studied. Results of a study showed a 66% response rate in reducing headache. Olcegepant at a dose of 2.5 mg was also successful at reducing nausea and sensitivity to light and sound.9

In 2007, telcagepant, an orally bioavailable drug, was developed and studied in multiple clinical trials, including in head-to-head trials against triptans. One of those trials was a large phase 3 study that evaluated telcagepant against zolmitriptan and placebo. Telcagepant was found to have a similar efficacy to triptans, with an adverse effect (AE) profile consistent with the placebo. In another long-term study, telcagepant was found to have fewer AEs than rizatriptan. However, development was halted in 2011 after increased liver enzymes were detected in 2 patients in a phase 2 study evaluating the prophylactic use of telcagepant. Additionally, 4 other CGRP antagonists (MK-3207, MK-1602, BI44370 TA, BMS-927711) have been studied in phase 2 clinical trials. An additional 2 drugs have been developed with better pharmacokinetic and pharmacodynamic properties, but they have not been tested clinically. The current CGRP antagonist pipeline appears to be at a standstill.9

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