Advocating for Migraine Research, Overcoming Stigma, and Improving Treatment: A Chat with Robert Shapiro

By Kayt Sukel | June 8, 2022 | Posted in

“There has been an incredible flood of new therapies for migraine, and, remarkably, these advances have occurred in the face of the most egregious underfunding by the National Institutes of Health [NIH]. Yet I’m still a deep believer that if we had more NIH funding, commensurate with migraine’s burden, the ripple effect benefits would be massive. It would draw more investigators into the field to understand the disease and find new therapies. It would inspire doctors to take better care of patients. And it would bring more credibility and seriousness to the condition, lessening the stigma.”

Robert Shapiro, MD, PhD, is a professor in the Department of Neurological Sciences at the Larner College of Medicine, University of Vermont, US. He has spent decades advancing the understanding of migraine and headache disorders, as well as advocating at the federal level to lessen the stigma surrounding these disorders and to increase research funding.  

Here, Shapiro speaks with freelance writer Kayt Sukel about how he got into migraine research, the problems of migraine stigma and research underfunding, the use of CGRP drugs, and, interestingly, why migraine may actually be protective against COVID. This interview has been edited for clarity and length.

What first inspired you to study migraine?

I think it’s fair to say that people come into this field one of two ways. First, it’s because they or their family members have migraine and they feel a mission to take it on. The second way it happens is that they inadvertently find themselves in a situation where they are compelled to study it, and soon realize that was a great thing.

I was in the latter category. In the early 1990s, I was a junior faculty member at Johns Hopkins University, and my PhD work was on central autonomic nervous system anatomy and connectivity. I was trying to set up a narrow niche practice in autonomic diseases, which would be compatible with my research. As I was building that practice, however, my clinic was filled with patients that other doctors didn’t want to see. Those patients often tended to have migraine, because migraine is an extraordinarily stigmatized disease.

The thinking at the time was that migraine was not important. But as I saw these patients and started taking their histories, it became clear that most also presented with autonomic symptoms like nausea, abdominal pain, diarrhea, or sinusitis. It made me realize that migraine might be a headache disorder with some autonomic features, or equally could be considered an autonomic disorder with some headache to go along with it. This seemed like a good thing to investigate.

Robert Shapiro

Robert Shapiro

Within months, my clinic was inundated with migraine patients because I was just about the only physician expressing any remote interest in migraine. It quickly became clear to me that it was an incredibly interesting disease that is dramatically prevalent. And because the research field was running as fast as possible away from it, I realized that I might not need to be as smart as other people to make big discoveries. It seemed like an opportunity to learn more about this big disease, not to mention headache disorders in general.

I should also add that the patients I was taking care of were often getting better, even with limited treatment options. That’s not something that was always true for many diseases in neurology. It was clear that I could make a difference for so many of my patients.

You were involved with the OVERCOME study, published earlier this year, which highlighted some of these issues. Tell me more about it.

The OVERCOME study is the largest population-based study ever undertaken to look at migraine. Over 60,000 people with migraine were studied. It is an incredible study, and I’m very grateful that I was asked to be a part of it.

The study found that while 40% of people with migraine could benefit from taking preventative medications, only 17% are actually doing so, and for those people who have higher-frequency migraine, experiencing eight or more days with headache per month, the numbers are even worse. We are failing to get things that could help patients into their hands. That’s a systemic failure of our healthcare system – a failure to recognize that migraine is an extremely common and treatable disease.

Primary care physicians learn almost nothing about migraine during medical school or their residencies. Given that migraine has a population prevalence of around 15%-16%, and that it’s the second leading cause of global disability, these physicians should know the first steps in diagnosis and treatment, but we’ve failed to engage primary care to do this.

What’s the path forward?

First of all, this problem can’t be solved just by adding more headache doctors. Certainly, we do need far more clinicians with expertise for patients with less tractable symptoms. But we should be doing everything appropriate to train primary care physicians to make migraine part of their purview and take care of these patients.

There are other issues at play here, too. Part of it is the healthcare system. Insurance barriers and drug costs make it harder for patients to access medications. Then there is the barrier of stigma, which leads people not to seek care because having migraine has perils in terms of employability and can lead to family issues. So, if you are taking medications or seeing doctors regularly for a problem, and you are self-identifying with that stigmatized problem, it can impose limitations on other aspects of your life. Perhaps unsurprisingly, data from the OVERCOME study indicate that nearly half of people with migraine hesitate to seek care for it.

We should also look at the medications themselves. Prior to calcitonin gene-related peptide [CGRP] medications, all oral medications for migraine prevention had actually been developed for some other purpose. They were serendipitously found to be helpful for migraine, but these drugs were originally developed for high blood pressure, depression, or to manage seizures. All of those conditions may carry their own stigma, and that can lead to people not wanting to take these drugs.

There is also the issue that these drugs aren’t always effective, and then the side effects are so bad that 80% of people, if they start a new medication, aren’t taking it a year later. The compliance is terrible for most oral medications for migraine prevention, and it’s something that needs to be addressed.

Let’s talk about the CGRP drugs. Will this form of treatment live up to its promise?

Unfortunately, they can never fully live up to the promise, because there’s always hype that’s deeply embedded in all the marketing. No, they don’t cure migraine. But as long as you have reasonable expectations, it’s worth celebrating these drugs. They are the second major example of rational drug design and development for migraine – the first being the triptans – and it’s a huge success story.

Thirty years ago, Lars Edvinsson and Peter Goadsby, working in Sweden, made the great discovery that CGRP is expressed in nerves, and that during migraine attacks CGRP is markedly elevated in the blood in many, but not all, people. We now understand that this is at least part of the story for how the trigeminal nerve is involved in migraine. Following this discovery, a 30-year process was launched to find drugs that could reduce the availability of CGRP to either shorten migraine attacks or try to prevent them altogether.

A truly remarkable thing about this process has been that every drug that reduces or sequesters CGRP, and that has then been tested in migraine, has been found to be effective. It’s hard to find another story in drug development that is more validating than this. It’s led to seven new FDA-approved drugs since 2018 that modulate CGRP, which work in different ways on different targets. Over the same time frame, there have been several other novel migraine medications approved by the FDA, as well as at least five medical devices cleared by the FDA for marketing.

It’s important to emphasize how extraordinary this is. The last time a drug was FDA-approved specifically for any other pain disorder, that is, not as a “me too” or follow-on drug, was in 2004. So virtually all of the recent successes in pain therapeutics have been in migraine treatments.

You tackled the issue of stigma in a 2020 article in the journal Headache titled “What will it take to move the needle for headache disorders? An advocacy perspective.” How can we better address stigma in migraine?

Stigma in migraine is something that helped prompt my initial research interest in migraine, though I really didn’t realize it at that time. But stigma became an interesting issue unto itself. Stigma is an incredibly enduring and stubborn social phenomenon – it’s deeply embedded almost everywhere. There are reasons why people identify people as “other.” We see stigma as a vile thing – an incredibly non-inclusive, discriminatory thing – but there’s another side to it. Stigma may be partly an adaptive process as well.

For example, you can imagine why some infectious diseases – those really threatening diseases – may be more highly stigmatized. Consider Hansen’s disease, which we know as leprosy. It’s so highly stigmatized because people don’t want to catch it. The stigma is a terrible thing, and it’s not a justification, but there’s a rational basis for people who are uneducated about the disease to be scared of it.

As a consequence, when we think about how to move past stigma, we may sometimes end up with these barriers that are hard to overcome because of this negative but rational basis. There have been public programs to try to bring awareness to affective disorders like depression or diseases like obesity in Great Britain and Europe. They’ve spent millions on these outreach programs. Yet they’ve really moved the needle very little.

But there have been modest successes in programs where people who are stigmatized have direct contact with the people who stigmatize them. When there is a personal interaction – it’s called the contact hypothesis – people can learn that the stigmatized person is not really all that different from them. It’s been identified as the most successful way to moderate some of these negative attitudes. That being said, I don’t think anyone has yet identified the best ways of bringing these different people into contact, but we’re working on it.

The problem of stigma is where Headache on the Hill comes in, right?

It’s one of the big reasons why we do Headache on the Hill, an advocacy program that highlights the impact of migraine and headache disorders to [the US] Congress to improve equity in federal policies. When people with these diseases and their healthcare providers can talk to people who may carry stigmatizing attitudes but are also policy makers, we can help reduce stigma among the very people who can make a real policy difference at the federal level. It really does move the needle, maybe not across the big clock, but at least it moves the needle a few seconds, and that can still be a monumental thing in this world.

After spending almost 20 years advocating in Congress, I’m deeply proud to be an American. And I’ll tell you, I’m less cynical now than I was then. That’s because I can see how this can work when you have the right people advocating on behalf of others for a cause that has been utterly neglected. It can be deeply empowering for the people who have participated. And, like me, they come back year after year.

Switching gears, a significant number of COVID long haulers are reporting headaches. Do we understand why?

Just under half of people with long COVID report headache. In fact, headache at the onset of COVID is strongly associated with headache post-COVID, with an odds ratio of 2.6 or 2.7 increased likelihood. But this relationship between headache and COVID is complex. To an academic neurologist, it’s deeply fascinating, though not so much for patients – they just want to feel better. But understanding this association is something that is important and could be helpful. And, as it turns out, it actually relates to stigma, too.

Let me explain. It turns out that about half of people who develop COVID as an outpatient at home will report having headache. But if you look at the population of people who show up at the emergency department or are admitted to the hospital, only 10% report headache. It’s a big disparity, and it suggests that having headache at the onset of disease may lead to better outcomes. Headache at the onset of COVID is also, unsurprisingly, associated with a prior history of migraine – there’s an almost threefold-higher likelihood that you have a history of migraine if you had headache at the onset of COVID.

We decided to investigate this further with a group at Cerner [a healthcare information technology company], and with a collaborator, Patricia Pozo-Rosich, who is in Barcelona. We looked at a large US survey, the National Health and Wellness Survey, which has been fielded every year for the last 25 years. There’s a baseline question asked about whether you’ve been diagnosed with migraine. In the first half of 2020, they added some questions, unsurprisingly, about COVID.

What did you find?

So, in this group of over 41,000 people, we saw that people with migraine were 60% more likely to either report COVID symptoms or have a positive COVID test, and then far more likely to have more symptoms of COVID, than people who did not have migraine. It looked like having migraine might be a huge risk factor for bad outcomes with COVID.

Yet the data also showed us that among people with COVID, those with migraine were 40% less likely to be admitted to the hospital than those without migraine. What could account for that?

In a prior study that Patricia had performed, she found that those with headache and COVID had, on average, a one-week shorter COVID disease course than those without headache.

We weren’t sure what may be behind that. To follow up, we did a big meta-analysis looking at more than 43,000 patients from 48 studies across the globe to see whether patients who were admitted to the hospital with COVID, and had headache, had better or worse mortality outcomes. We found that those who had headache were about twice as likely to survive COVID compared to people who didn’t have headache.

So those with headache had a shorter COVID disease course and higher COVID survivability. That is, the trait of migraine and the symptom of headache appear to be positive prognostic indicators for COVID. This is a really surprising thing. It’s gotten little attention, and we think it deserves closer study.

Any hypotheses as to why headache may be protective?

We know that evolution is opportunistic – you can’t assume that any feature of our bodies only serves one function. There are many traits that coalesce around migraine that could be married to other things. And when you consider that the genome-wide association studies [GWAS] for migraine have identified over a hundred different genes, we know those genes could be involved in dozens of other things.

When it comes to COVID – and I should emphasize these data are all incredibly tentative – there are some early data suggesting that some of the genes related to migraine may play an anti-viral role. Consider what people do when they get a migraine attack. At the most basic level, they withdraw from social interactions. They isolate themselves. At a population level, this kind of social distancing may reduce contagion. Also consider the fact that migraine is a stigmatized disorder, so other people may be less inclined to interact with people when they are experiencing migraine. Both of these factors may lead to a reduction in contagion at a population level. These migraine variant alleles may be beneficial to the individual to reduce virulence, but they may also lead to behaviors that are beneficial to the population to reduce contagion.

One could propose that, if migraine alone reduced contagion, the symptoms of migraine might act as an early warning signal that you’ve been exposed to a viral threat. It may be that you are exposed to a virus, you get the migraine attack, you take the behavioral action to withdraw, and that has benefit. That alone may be enough to keep some of these migraine genes at a higher prevalence in the population. Even if pandemics only come around once every hundred years, there’s a benefit to the population as a whole. Pandemics are major drivers of human evolution.

What do you hope to see in migraine research and treatment in the future?

There has been an incredible flood of new therapies for migraine, and, remarkably, these advances have occurred in the face of the most egregious underfunding by the National Institutes of Health [NIH]. Yet I’m still a deep believer that if we had more NIH funding, commensurate with migraine’s burden, the ripple effect benefits would be massive. It would draw more investigators into the field to understand the disease and find new therapies. It would inspire doctors to take better care of patients. And it would bring more credibility and seriousness to the condition, lessening the stigma.

So, NIH needs to be more accountable, and I think we have to run the table to get them to be. One of our legislative asks this year during Headache on the Hill was directed towards the House [of Representatives] committee with authority over NIH. We are urging them to order a US General Accountability Office [GAO] audit of NIH’s failure to meet its stated commitment to make disease burden one of their key funding priorities. Having that kind of independent GAO review could help improve transparency and might finally get migraine, which affects so many people, the kind of funding it deserves.

Kayt Sukel is a freelance writer based outside Houston, Texas.

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Kayt Sukel is a passionate traveler and science writer who has no problem tackling interesting (and often taboo) subjects spanning love, sex, science, technology, travel and politics. Her work has appeared in the Atlantic Monthly, New Scientist, USA Today, Pacific Standard, the Washington Post, ISLANDS, Parenting, the Bark, American Baby, National Geographic Traveler, and the AARP Bulletin, among others. She has written stories about out-of-body experiences, artificial intelligence in medicine, new advances in pain treatments, and why one should travel to exotic lands with young children.

She is the author of two books: Dirty Minds: How Our Brains Influence Love, Sex, and Relationships (re-titled as This Is Your Brain on Sex: The Science Behind the Search for Love in paperback) and The Art of Risk: The New Science of Courage, Caution, and Chance.

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