Current Series: Chronic Migraine: Current Treatment Options and Recent Advances

Richard B. Lipton, MD: It’s important to recognize that migraine is more than one disorder. So we know that from person-to-person with migraine there are differences in symptom profiles. One person has nausea, another has photophobia and phonophobia. We know there are differences in attack frequency. We know there are differences in comorbidity profiles. We know there are differences in prognosis, and we know there are differences in genetics. So for rare forms of migraine, [like] familial hemiplegic migraine, we know that there are three genes that account for the majority. But for ordinary forms of migraine, more than 40 genetic variants have been identified, and those 40 genetic variants account for a small proportion of all migraines.

We also know that there are huge individual differences in treatment response. For one person, topiramate [Topamax] may be a godsend; for another person, it may be unhelpful and produce a lot of [adverse] effects. One acute treatment works for one person and not for another. So, all this means that migraines are [a] highly heterogenous disorder, and one of the hallmarks of clinical trials is that we, for the most part, ignore that heterogeneity. We lump everybody together in a big pot and then we say, well why is it with the best available therapy, only 50% of people respond?

So I think one of the major steps forward we need to take is figuring out ways of identifying more homogenous groups of people with migraine based on symptom profile, based on treatment response, based on prognosis, and develop a clinical strategy for identifying those individuals so we can do a better job of getting treatment right the first time and avoid the process of trial and error therapy, which can be frustrating both for doctors and patients.

So, one area we need in clinical trials is learning enough about patient groups to identify in homogenous groups that do and don’t respond to particular treatments, who do and don’t carry particular genes, and who may differ in their longitudinal trajectory over the course of their lifespan.

Stephen Silberstein, MD: We have a lot of different drugs for the treatment of migraine, but we really don’t know which would be the first and the best to use. So we’re looking for markers, and what we don’t have are many comparative trials of the older drugs versus the new drugs. And lastly, combination therapy. Which drugs work better together and which drugs don’t? So, for example, we did a study a while ago adding topiramate to a beta blocker and the two of them didn’t work any better than topiramate alone. But, in the fremanezumab studies, we allowed the concomitant use of topiramate, and those patients continue to improve. And they [improve] just as well [as] people off of it. What we don’t know is what the additional benefit was, but we know they did just as well.

The other thing we need [is] biomarkers, we need new targets, and we need combination treatment.  People are now looking at marijuana and its derivatives for the treatment of migraine. That’s an ongoing field. And the major problem we have, first, it’s still considered illegal by the federal government, so it’s very difficult to do clinical trials on a drug that’s considered that; even though more and more states are legalizing it. There are new targets like PACAP [pituitary adenylate cyclase-activating peptide] and the delta opioid receptor; a lot of those are coming in the development.

Peter Goadsby, MBBS: At the moment, the most promising agents for change in the preventive space are going to be the CGRP [calcitonin gene-related peptide] monoclonal antibodies. We have one available now. There are another three coming along, three peptide ones, eptinezumab, fremanezumab, and galcanezumab to add into erenumab. So we’re going to have those choices. I think that the development of the small molecule CGRP receptor antagonists—ubrogepant, rimegepant—[are] hugely useful. Lasmiditan, a serotonin 1F receptor agonist, [is] hugely useful in acute therapy, getting away from the vascular side of things.

Coming along after that, there’s work that’s exploring pituitary adenylate cyclase-activating peptide, PACAP at the so-called PAC1 receptor, that’s in clinical trial. And there’s an evidential, there’s some clinical work and laboratory work to make one think about metabotropic glutamate receptors, to make one think about orexinergic mechanisms, acid-sensing ion channels, nitrergic mechanisms, the TRPM8 channel. What’s really exciting about migraine at the moment is all these medicines, neuromodulation approaches, noninvasive vagal nerve stimulation, transcranial magnetic stimulation. There’s an incredible collection now of mechanism-based ways of thinking about what’s going to happen both in acute and preventive treatment.

I don’t know everything we’re going to have in our hands, at our fingertips in say 5 to 7 years, but I do know there will be more, I do know they’ll be effective, I know they’ll be well tolerated. And I know a lot of patients are going to be much, much better and physicians are going to be much more satisfied with their practice, particularly in headache medicine.

Richard B. Lipton, MD: I work in two areas. I work in migraine and I work in Alzheimer disease. And so, it’s been fascinating to go to migraine meetings and to be in the session where we’re presenting the fifth positive randomized trial in a single session and people are sort of bored. And then I go to Alzheimer meetings where nothing has worked for a decade, and even a hint of a subgroup analysis with a positive result is a source of tremendous excitement. So I appreciate that these are really amazing times in migraine, that there are multiple devices, multiple drugs as acute treatments and as preventive treatments that are emerging. You know I recognize there are a billion people globally who have migraines, that migraine is the world’s second leading cause of health-related disability after low back pain. And I’m very excited to be part of the process of bringing new treatments into the clinical sphere, which I believe will materially improve the lives of an uncountable number of people all over the globe.