expert roundtables

Migraine Pathophysiology: Updates and Implications for Therapy

by David W. Dodick, MD; Deborah I. Friedman, MD, MPH, FAAN, FAHS; and Paul G. Mathew, MD, DNBPAS, FAAN, FAHS

Overview

A growing recognition of the differing pathophysiologic mechanisms involved in migraine is leading to more options for effective treatment than in the past. Our featured experts discuss the newest discoveries in migraine pathophysiology and their implications for therapy.

Q:

How has the understanding of migraine pathophysiology advanced in recent decades? Where do you see things going in the future?

David W. Dodick, MD

Professor, Department of Neurology
Director, Concussion Program
Director, Headache Program
Mayo Clinic
Scottsdale, AZ

“As our understanding of these mechanisms continues to grow, additional therapies will be developed to target areas specifically inside and outside the brain.”

David W. Dodick, MD

Much of the research driving the development of pharmacological therapies for migraine has previously focused on the trigeminal vascular system, particularly on identifying inhibitors of neurogenic inflammation. Such efforts have led to the identification of various neuropeptides that communicate with the central nervous system (CNS), including calcitonin gene-related peptide (CGRP). This ultimately resulted in the discovery that the triptans, initially developed to constrict blood vessels, work by binding to the trigeminal nerve itself and inhibiting the release of CGRP. These advances in knowledge account for the emergence of the monoclonal antibodies and small-molecule CGRP receptor antagonists specifically targeting CGRP, as well as investigational agents such as pituitary adenylate cyclase-activating peptide 38 (PACAP-38), another neuropeptide target for migraine therapy. Other important mediators are also likely responsible; migraine cannot be distilled to just 1 peptide.

The CNS is clearly emerging as the primary driver of migraine attacks, with the hypothalamus and multiple other brain networks serving as key drivers of episodic and chronic migraine attacks. Functional imaging has shown that the hypothalamus and pain matrix are deactivated in patients who respond to treatment with the CGRP antagonist erenumab but remain activated in nonresponders. The question is: Is erenumab dampening a peripheral effect that modulates CNS activity? Or are enough antibodies getting across the CNS in the hypothalamus, the area postrema, and the choroid plexus to modulate CNS activity? As our understanding of these mechanisms continues to grow, additional therapies will be developed to target areas specifically inside and outside the brain.

Deborah I. Friedman, MD, MPH, FAAN, FAHS

Professor of Neurology and Ophthalmology
University of Texas Southwestern Medical Center
Dallas, TX

It has been fascinating to see how this has all evolved over the years. We have learned from our treatments, and we have developed newer treatments based on what we have learned.”

Deborah I. Friedman, MD, MPH, FAAN, FAHS

We sometimes speak of nontargeted therapies, and much has been learned about migraine pathophysiology through these agents (ie, antidepressants, antihypertensives, and epilepsy drugs) that have been found to work in the body and brain to treat migraine. Migraine is no longer thought to be the result of the dilatation of blood vessels. Instead, a growing body of evidence points to migraine as a heterogeneous disorder pathophysiologically, involving multiple areas of the CNS and peripheral nervous system.

This knowledge has led to the development of the monoclonal antibody–based treatments that target the CGRP, which is a potent vasodilator of cerebral and dural vessels. Research indicates that CGRP mediates trigeminovascular pain transmission from intracranial vessels to the CNS, as well as the vasodilatory component of neurogenic inflammation. Although CGRP is important in migraine, anti-CGRP therapies work well for some patients but not for others, which, again, suggests heterogeneity and potentially important influences from other pathways. Newly identified peptide targets such as PACAP-38 and therapies such as vagus nerve stimulation point to a continuing revolution in migraine therapy.

Thus, it has been fascinating to see how this has all evolved over the years. We have learned from our treatments, and we have developed newer treatments based on what we have learned.

Paul G. Mathew, MD, DNBPAS, FAAN, FAHS

Assistant Professor of Neurology
Harvard Medical School
Boston, MA

“These migraine-specific therapies stand in contrast to traditional migraine medications that were developed to treat other conditions but were found, fortuitously, to also address migraine.”

Paul G. Mathew, MD, DNBPAS, FAAN, FAHS

These are very exciting times, as we are understanding more about the underlying pathophysiology of migraine, which is leading to an increasing number of disease-specific treatments. These migraine-specific therapies stand in contrast to traditional migraine medications that were developed to treat other conditions but were found, fortuitously, to also address migraine.

We know that migraine involves a cascade of complex pathophysiological events that can respond well to interventions that prevent, slow, or even halt the neurogenic inflammation and CNS sensitization that are characteristic of migraine. A better understanding of the mechanisms of action of these therapies can help headache specialists and neurologists to better collaborate with our colleagues in primary care. This partnership is essential, as there are not enough headache specialists given the high number of patients with migraine.

Furthermore, knowledge of basic migraine pathophysiology is helpful when speaking with patients and with shared decision making. For example, I find that when patients understand the mechanisms of action of a medication and how they apply to migraine, it can improve compliance and the timely administration of abortive medications, which tend to be more effective when taken earlier in the course of a migraine. As such, I use the analogy that treating migraine is like extinguishing a fire. It is easy to put out a match, but it is much more difficult to put out a fully engulfed building.

References

American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice [published correction appears in Headache. 2019;59(4):650-651]. Headache. 2019;59(1):1-18. doi:10.1111/head.13456

Chan C, Wei DY, Goadsby PJ. Biochemical modulation and pathophysiology of migraine. J Neuroophthalmol. 2019;39(4):470-479. doi:10.1097/WNO.0000000000000875

Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019;394(10210):1765-1774. doi:10.1016/S0140-6736(19)32504-8

Kim S-K, Chong CD, Dumkrieger G, Ross K, Berisha V, Schwedt TJ. Clinical correlates of insomnia in patients with persistent post-traumatic headache compared with migraine. J Headache Pain. 2020;21(1):33. doi:10.1186/s10194-020-01103-8

Marmura MJ. Triggers, protectors, and predictors in episodic migraine. Curr Pain Headache Rep. 2018;22(12):81. doi:10.1007/s11916-018-0734-0

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