Entering a New Realm of Migraine Treatment, Research Priorities

Walter Koroshetz, MD

Migraine headache has long been recognizing as one of the most burdensome and prevalent diseases worldwide, affecting more than 1 billion individuals each year. It is associated with a wide range of comorbidities, which range from stress and sleep disturbances to suicide. Over the years, there have been several significant advances in the treatment of migraine, mainly powered by the introduction of calcitonin gene-related peptide (CGRP) monoclonal antibodies, which are designed to target the root cause of the disease.

CGRP inhibitors, along with advances in neuromodulation devices, behavioral strategies, and lifestyle changes, have all made significant impacts on the quality of life and management of patients with migraine; however, there are still unmet needs. The complex and largely unclear mechanisms of migraine development have resulted in the proposal of various social and biological risk factors, such as hormonal imbalances, genetic and epigenetic influences, as well as cardiovascular, neurological, and autoimmune diseases. In addition, some research has shown that one-third of patients with chronic migraine are satisfied with their current therapy.

At the 2023 American Headache Society (AHS) Annual Meeting, held June 15-18, in Austin, Texas, Walter Koroshetz, MD, presented a talk on the “State of Science of Neurology,” and the forward-looking thoughts in migraine research. Koroshetz, director of the National Institutes of Neurological Disorders and Stroke at the National Institutes of Health, sat down with NeurologyLive^® at the conference to discuss the presentation, including some of the notable advances and unmet needs in migraine care. He spoke specifically about the need for additional research understanding the underlying circuitry of migraines, and why they impact certain people in different ways. Additionally, he touched upon the shift in conversations in the field, and why industry leaders are looking to find medications that help patients with drug-resistant forms of the disease.

NeurologyLive^®: Can you provide an overview of your presentation?

Walter Koroshetz, MD: There have been great advances in neurology, and particularly in the treatment of headache. Also, there have been new tools developed to look at problems that cause neurologic issues for patients. The tools that are coming out now and those looking to the future are focused on understanding how circuits work and how they malfunction. A lot of what's been happening in headache is related to the molecular side of, say, the pain system, but we have a very poor understanding of how the circuits are dysfunctional. There's so many different symptoms that go along with migraine. Besides that, you have the pain itself, and that's a circuit problem. Then you have the aura, which is also a circuit problem. Some people have vestibular trouble, some people have autonomic troubles that come even before the headache. There are a still lot of mysteries in terms of what circuits are malfunctioning in migraine.

Over the last decade or so, what progress have we made in understanding some of the circuitry behind migraine and headache?

The work that I'm most comfortable with is the research on the release of neuropeptides, from the trigeminal fibers that innovate around the surface of the brain, the dura, the pier, the blood vessels, and how things like spreading depression can cause release of these peptides and activate pain systems. But on the other hand, there's also the theory that the headache may actually proceed centrally and then go off peripherally. Some of the neuroimaging studies have been showing abnormalities related to migraine in the brainstem and diencephalon. And yet, the therapies are all based on these molecular findings, watching CGRP levels go up on the side of the headache in some patients and [eventually] leading to blockade of CGRP, showing effectiveness, and preventing headache. So there's been advances on the molecular side. The Lundbeck Brain Prize was given to people working on these neuropeptides that are released. It's been hard to get at the circuit abnormalities, but those tools are now available. Certainly, [there are] very sophisticated tools to look at mouse models, and the hope is that we can move those and get parallel information out to patients.

[One of] the sessions that I attended was on how you make these treatments accessible to people across the country, independent of the socio economic, racial, and ethnic status. In this country, I think we have a big problem there. For most of the headache centers, there are all these different bars you have to go through. There’s thousands of people who are not getting the most appropriate treatment for their headaches. So making access to the best treatment, making it more equitable, I think, is a big issue.

People always have to go through developing methods of care, in terms of what is the best treatment for what type of migraine, and then how to manage those individuals who are resistant to to all the known drugs. That's a problem that we run into, particularly in epilepsy. In the beginning, we were trying to find new epilepsy drugs. Now, there’s not that much interest in another epilepsy drug, the interest is in a drug that works when none of the other ones work. When you make progress, it's great, but it also then identifies the resistant categories that you have to go after, which we clearly don't know in migraine, it's episodic. Why do you get it one day and another day? Certainly, the genetics has been a mess, trying to figure out if it’s heavily familial, but we haven't been able to find the common gene variants that are associated or driving migraine. There’s still a lot of questions on why kids have more abdominal symptoms, as opposed to headache. There's a whole list of things that are still left to be understood about migraine.

Considering there are several approved therapies for migraine, how do we continue to work towards treatment optimization?

That's where the community has to come together and try to look at the landscape and develop guidelines that can then be propagated throughout the community. I'm not sure what the percentage is, but I'm guessing that most of patients with migraine are seen by general neurologists, not necessarily specialists, so you have to move that education into the general neurologist space. The bigger issue is most people present to a primary care physician. And so, that kind of knowledge has to go across all these different levels of care for all people to benefit. That being said, there's also big gaps in knowledge that need comparative effectiveness studies that are focused on the population that you're most interested in, and where you want to find out what treatment works best.

Transcript edited for clarity. Click here for more coverage in AHS 2023.