Autonomic Functions in Migraine Patients as a Function of Migraine Status and CGRP Inhibition

Background:

Headache disorders are among the leading illnesses contributing to the Global Burden of Disease. They are so common, that they rank second in prevalence and years lived with disability. Additionally, headache disorders are the second-ranked cause of years lived with disability in females, worldwide. Migraines are so prevalent in human history that there exist records from the ancient Egyptians documenting symptoms of attacks.

Migraines are classified by the International Headache Society in their International Classification of Headache Disorders 3 (ICHD-3) guidelines as: migraine without aura, migraine with aura, chronic migraine, and probable migraine. They are considered episodic if headache is present on fewer than 15 days per month; or chronic if headache occurs "on 15 or more days/month for more than 3 months, which, on at least 8 days/month, has the features of migraine headache". Until now, researchers have made numerous connections between migraines and the autonomic symptoms that manifest both ictally and interictally. Research, using standardized autonomic tests, has improved our ability to evaluate these symptoms. Furthermore, strides have been made to map migraine attacks and visualize them. Finally, research directed towards the molecular mechanism of these attacks has also yielded results.

Current recommendations for pharmacological migraine treatment comprise abortive drugs (i.e. non-opioid analgesics and triptans) and prophylactic medication (e.g. beta-blockers, calcium-channel blockers, antidepressants, anti-seizure medications and onabotulinumtoxin A). None of these prophylactic drugs were specifically developed against migraine. Their dosages must be slowly increased, since these medications can lead to fatigue, depression, nausea, insomnia, decreased libido, along with many other side effects specific to the individual modalities. Therefore, a more favorable treatment is required.

Molecular evidence is accumulating that calcitonin gene-related peptide (CGRP) contributes greatly to this pathophysiology. In tandem, evidence of CGRP's role in other physiological mechanisms has also been elucidated. These include roles in: vasodilation, cardioprotection, blood pressure regulation, sepsis, wound healing, bone re-growth, among others. The majority of CGRP is sequestered at the trigeminal level; however, it is released from both peripheral and central nerve terminals. As such, investigation of parasympathetic - and reciprocally, the sympathetic - autonomic nervous system (ANS) pathways are of particular interest. It is, however, CGRP's connection to migraines which has, consequently, led to the development of several CGRP receptor antagonists, an anti-CGRP-receptor monoclonal anti-body (mAb) and several anti-CGRP-ligand mAbs.