RELIEF: So why don't we start from the top: What exactly is a migraine, and how does it differ from a typical headache?

Transcription

1 Transcript of RELIEF podcast with Robert Shapiro: RELIEF: Hello everyone, and thanks for tuning in to RELIEF s podcast series. I m Neil Andrews, editor of RELIEF. I m really thrilled today to have the opportunity to speak with Dr. Robert Shapiro. Dr. Shapiro is a Professor of Neurological Sciences at the University of Vermont College of Medicine, where he is Director of the Division of Headache Medicine. Dr. Shapiro is very well known for his work in the migraine field, and he's here today to talk to us about the problem of migraine, what causes migraine, how to treat it, and he'll also speak about some of the advocacy work that he's done that's trying to awareness of migraine. Dr. Shapiro, welcome to the podcast, thanks for being here today. Robert Shapiro: Thanks so much for having me. RELIEF: So why don't we start from the top: What exactly is a migraine, and how does it differ from a typical headache? Robert Shapiro: There's actually quite a bit of general misunderstanding about what a migraine is and what it isn't. And the confusion arises is that the symptom of headache is equated with the neurological and medical condition that we call migraine. Migraine is not headache. Headache is a symptom of this brain and neurological state, which has broad manifestations and impact on other body systems. There are many other symptoms of migraine. Headache is not an obligatory symptom of migraine, and often people may have disabling symptoms of migraine which are not headache at all, such as sensitivity to light or sound; GI symptoms, such as nausea or abdominal pain; vertigo; and cognitive changes, and these can be absolutely as disabling as the headache can be for many people. And the headache doesn't even have to be there. About a third of people with migraine will have a temporary disturbance that we call migraine aura, which often takes the form of a flashing or other visual display, which may move across the visual field or it may be some tingling sensations or it may be some changes in language function. So it's really a broad group of symptoms that people may get, which are symptoms of this condition we call migraine. RELIEF: Who suffers from migraine? How common, how widespread is this in the population? Robert Shapiro: Migraine is really one of the most prevalent of medical conditions that people come to see doctors for, and really it's the most prevalent of all the neurological conditions. Very narrowly defined, about 12% of Americans will experience migraine this year. And if you expand the definition a little bit further to include those people who have migraine at least 15 or more days per month, that is with the greatest impact which we call chronic migraine, and you also include some of the more variant conditions of migraine, it's probably upwards of 17 or 18% of Americans [who] will experience migraine this year.

2 It's not evenly distributed. It's about three times more common in women than men, and it generally impacts people during the most productive years of their lives; that is, between 20 and 50. And children and people in their later years of life are less likely to experience migraine. RELIEF: What is the current thinking about the causes of migraine? Robert Shapiro: We know quite a bit about it, but we don't know anywhere near enough about it. We know that about half of the likelihood that someone will develop migraine is related to heritable factors that they receive from their parents. And then there are many internal triggers or cues which can impact whether migraine attacks occur. These can be hormonal. They can be also environmental, so changes in ambient daylight, stressor impacts, chemical exposures we have, that is, different things in foods and medications. There are a wide variety of things which can provoke migraine. We know that it's predominantly a condition which arises as a dysfunction of the brain, but it clearly has impacts across a lot of different body systems. The gastrointestinal tract is clearly impacted. There are vascular changes which occur. And there isn't a complete consensus as to which is the most common way that migraine gets itself generated. RELIEF: You've mentioned migraine as a neurological disease. Is this a new understanding that it's a disease that has a basis in the brain? Robert Shapiro: It really is. The dominant thinking about what migraine should be defined as was really due to experimental observations from the 1930s and 40s, by an investigator named Harold Wolff. He concluded that migraine arose as a dysfunction of blood vessels in the brain and around the brain, and it's clear there are changes in blood vessels which occur. But it isn't quite as clear that these are the things that actually generate the pain or that are necessary for treatments for migraine to be successful. That being said, there are some more recent studies and data which tend to be pointing to important areas of dysfunction which occur outside the brain. Many of the medications which we have as mainstays for migraine treatment, and some of the ones that are being developed, are not allowed to enter the brain. They're excluded by the brain, and therefore, their sites must be outside the brain. More recent studies from genetics more strongly point to genes that may be important to increase migraine susceptibility. Many of them are expressed in blood vessels and vascular tissue, which has kind of swung the pendulum a little bit further towards including these other systems as important in how migraine unfolds. I think the best way to think about this is that migraine is a state of the nervous system with impacts broadly, including vascular systems and what's called the autonomic nervous system; that is the part of the nervous system which controls the internal organs. RELIEF: You mentioned treatments. What are the current treatments for migraine, and are they effective?

3 Robert Shapiro: We have actually a broad range of treatments to try to treat or remedy migraine, but only a handful of them are actually FDA-approved for this indication. Our mainstays for acute treatment of migraine are a group of medications called the triptans, and these are often highly effective within an hour or two for at least three-quarters of people who have migraine, to reduce the symptoms of headache and other symptoms of migraine when they occur. They have some limitations. Not everybody responds, as I said, and in some people there are some small risks for vascular changes, which limit the use by people who have uncontrolled high blood pressure or heart disease. And if they're overused, that is, used too many days per month, they may have the paradoxical effect to actually increase the risk for migraine to occur. So there are limitations on how many days per month people should be taking these medications. And as I say, not everybody responds. We're certainly looking for other treatments which may be more effective and may reach more people who have migraine. That being said, when they [the triptans] first came on the market, the first one in 1992, it was revolutionary for people with migraine to have a treatment as effective as sumatriptan was, which was the first one that came to the market. We also treat migraine with medications that are intended to reduce the frequency and severity of migraine; they're preventive medications. We have four medications that are FDA-approved for this purpose for people who have episodic migraine, that is, less than 15 days per month. And there's one medication which is used and approved for people who have chronic migraine. There are quite a number of other medications that are helpful for migraine. Some have very strong studies, some not quite so strong. And these off-label medications are often applied when people are either intolerant of medications which are FDA-approved or don't respond to them. We also use behavioral measures. It's really important to understand that techniques such as cognitive behavioral therapy and stress reduction are crucial parts of what we do to try to help people with migraine. [Also important is] attending to lifestyle changes which can have a big impact on whether migraine is likely to occur, so keeping regular bedtimes, a regular waking hour, having good quality sleep, not overeating, not undereating, and integrating exercise on a regular basis. These are all healthy things which make a big difference to reducing people's risk to have migraine be provoked or triggered. RELIEF: You see a lot of patients. What type of experience do patients with migraine have as they go through the healthcare system? My understanding is that there is still some stigma attached to patients who have this condition. Is that accurate, and why? Robert Shapiro: It's certainly the case that migraine is a highly prevalent, highly disabling condition, which has virtually no physical manifestations that will permit people to prove that they have something which is disabling. They don't come in with a cast on their leg. There's nothing that says, okay, you have this condition. So that's the first thing.

4 The second thing is, the conflation of migraine as a disease or disorder with headache as a symptom means that people who have migraine are equated with the far more common condition, which is virtually universal, that people have headache. And for people who have never had migraine, the assumption is that this is really just a severe headache that anybody could get, and that there may be a dysfunction in one's ability to cope with that. So people tend to dismiss the real disability that people have as a result of migraine. As a result, people with migraine tend not to want to have that be shown. They tend to hide, if possible, the fact that they're experiencing migraine, because it's not a valid reason to not work to capacity, and it tends not to fall on sympathetic ears on the part of employers and often family members. So work-related issues, the reliability and disability of migraine that migraine produces, the difficulty in maintaining work readiness and the like, end up having a huge ongoing impact on how people are perceived who have migraine. RELIEF: I wanted to talk a little bit now about some of the advocacy work that you've done with regard to migraine. Can you describe some of that work? How did you become involved in it? And what type of advocacy work have you done? Robert Shapiro: We've been working for 10 years now to try to create a larger voice on behalf of people who have disabling migraine and other headache disorders. For me, it arose from my really deep frustration in not having better ways of helping my patients who came to see me. At root I was curious to find out why it was that there were not better medications that were available and better therapies that were available. I mentioned sumatriptan. The triptans were the last class of medications to be FDAapproved that were developed specifically for treating migraine. And before that, the last medication that was developed specifically for treating migraine that was FDA-approved was a medicine that's no longer on the market called methysergide, which was approved in So it's only about once in a generation that we have a new category of medications that were specifically developed for treating migraine. As I dove in to try to understand this, it became immediately clear to me that the NIH was funding very little research related to migraine. The analyses that I did were quite alarming, that relative to the impact that migraine has, that is, its burden on society and on individuals, migraine should be funded approximately 10 times higher, if it's compared to other disorders that NIH funds research for. And that opinion has actually been borne out by independent analyses. There was a study that came out in 2015 that plotted the NIH funding for different disorders as reported by NIH relative to the different impacts of disease as reported by the World Health Organization. And migraine is this outlier way below the rest of the group. And there's a predicted funding line, which provides the indication of where the average funding would be if they were all funded proportionately, and migraine should approximately be funded about 12 times higher. It currently gets about 20 million dollars a year in NIH funding, and by this independent analysis, it should be closer to 240

5 million dollars a year. And NIH has itself last year come out with its own analysis, which really shows the same thing. So this isn't really a mysterious or disputable issue about this underfunding. We've gone to Congress every year in an advocacy event we call Headache on the Hill, and we advocate on behalf of the people who have migraine to try to get federal relief for the inattention to headache disorders, including migraine. We started an organization called the Alliance for Headache Disorders Advocacy, which Headache on the Hill was an activity of, and it is comprised of 13 nonprofit organizations, national and regional nonprofit organizations, who have an interest in these issues. We visit about 140 to 150 Congressional offices each year to try to make the case. This year we've had some significant progress, I think, in trying to move the issue forward as a consequence of the opioid and heroin crisis that's sweeping every community in the country. We've made the argument that if we're to reduce overprescribing of opioids, we need to have something which is safe, effective, affordable and non-addictive to help treat people who have chronic pain, including chronic migraine. We have been working with Senator Brian Schatz and Senator Orrin Hatch, and they introduced a bill which we helped draft called the Safe Treatments and Opportunities to Prevent Pain Act, which they were very successful at having incorporated into this very large bill called the Comprehensive Addiction and Recovery Act, or CARA, which was signed by President Obama at the end of July. The bill that Senator Schatz and Hatch introduced urges NIH to focus on research to understand pain and to discover new therapies for chronic pain, to develop alternatives to opioids for the treatment of pain, and actually have it be commensurate with the impact of pain, that is, the burden that pain, including migraine, have on US society. We're very hopeful that this will make a difference. We don't know for sure. Time's going to tell whether or not this falls on deaf ears or falls on fertile ground, to mix metaphors, in terms of how NIH responds, but clearly, there's a huge need to increase attention towards pain research and migraine research. If you look at the National Academy of Medicine's analyses for what the actual economic costs of pain are, it's really quite stunning. The annual costs of pain exceed a half a trillion dollars a year and are greater than the annual cost of heart disease and cancer combined. And yet relative to the amount of NIH funding that goes to understand pain, it's about five times higher for heart disease and 27 times higher for cancer. So we really need to make some changes in order to help address the overall problem of pain as our most costly medical problem. And so hopefully there'll be some changes soon. RELIEF: Do you think part of the lack of funding has been a lack of understanding of the neurological basis of the disease? How much is that contributing to it? Robert Shapiro: It's certainly a part of it, but I think there has been overall a lack of credibility with respect to migraine being a legitimate area to investigate. It tends to be trivialized. It's a headache; this is not something that's going to kill you, so this is the

6 refrain. And so we have higher priorities, and when that attitude is perpetuated, and it s certainly perpetuated in neurology residencies and within medical school education, very few people are interested in going into this area and investigating it further. This means that there really isn't a constituency at NIH to speak up for it and there aren't study sections which have people with expertise to review grants for it. And so overall it's very hard for there to be traction to get it going. So I think lack of legitimacy is really at the root of this. There is some question about whether or not the stigma may reflect some degree of bias that this tends to be a women s health issue maybe about three-quarters of people who have the disorder are women. But I'm not sure that's the dominant issue in terms of what may drive the stigma. RELIEF: As we move to the latter part of the podcast, I thought we could look to the future a little bit, both in terms of research and treatment. On the research side of things, in your view, what are the most important outstanding questions for the field about the causes of migraine, and what other research questions do you think are important? Robert Shapiro: In terms of causes of migraine, one thing that's important to emphasize is that migraine can be framed as something other than an actual disease, that is, something which occurs as pathology. What I mean by that is that this is a medical problem, a condition, which tends to occur in people who are young, that is with onset in their teens to twenties. It's highly prevalent. It's heavily driven by genetics, and it changes people's behaviors very profoundly; they tend to withdraw from social behavior. Something that is prevalent that affects behavior that profoundly and is driven by genetics, if it was not valuable in some way to us as a species, it probably would have been selected against in evolution. Assuming that migraine is not something which just arose in the last few thousand years, but has been around for quite a long time, we have to think in terms of what the context is about what may have driven migraine to arise. That's kind of an open question about what may be the evolutionary function of migraine, even though we're trying to get rid of it. I think that we're very much in need of identifying the genetic factors which are most important for increasing the susceptibility to the more common forms of migraine. We've identified, overall, maybe four dozen genes which are, to varying degrees, important in driving migraine. Some of these mutations are quite rare; they alone may be enough to increase the likelihood of someone having migraine quite a bit, to the point where it tends to run clearly in families. In other cases, the genetic mutations really don't contribute as much and their expression in concert with other factors are enough to put people at risk. But we need really to find all of those that are most important. The good news is that with the reduction in the cost of sequencing genes and genomes, and with a large international consortium looking for migraine susceptibility genes, we're very hopeful that we'll learn much more about the most important ones soon. The other factors that I think will be understood much better soon are what are called biomarkers, that is, which substances can be measured in blood, spinal fluid or elsewhere that are measures that correlate with whether migraine's going to occur or whether it's

7 occurring, and which reflect changes that occur during this state we call migraine. There are a number of these that have already been identified, and a couple are really promising in terms of trying to develop new medications to interfere with or act on systems. One of them is called CGRP, and that stands for calcitonin gene-related peptide; you'll see CGRP pretty widely if you search the net on migraine now. Another one is called PACAP, and for that one there aren't therapies yet that are available in clinical trials, but probably will be available soon. For CGRP, this is an important, very small protein to peptide which has actions that have been strongly implicated in the development of migraine attacks. There are a couple of different types of medications which have been developed to try and interfere with the actions of CGRP. A group of small drugs was developed 10 to 15 years ago, and looked extremely promising to become the next new class of medicines for migraine, but ran into some side effects which limited their further development. The new category of medications to act on CGRP are mostly medicines which are called antibodies. They're products of cells in the immune system, and they are exquisitely specific for where they bind and what they can interfere with. And antibodies that are able to block the actions of CGRP or the place that CGRP acts, that is, the receptor for CGRP, are now moving through clinical trials for prevention of migraine, as well as a related disorder called cluster headache. There are now four different medications which are working on these systems, and which are in the final stages of clinical trials, called phase III trials. There's a tremendous amount of excitement about the possibility that we may now have a new category of therapies of pharmaceuticals that are effective for prevention of migraine and hopefully cluster headache as well. The earliest that people are projecting that any of these might reach the market, assuming that the trials go well and the FDA accelerates its evaluation, would probably be 2018, but perhaps 2019 is a little more realistic. RELIEF: That's very encouraging to hear the advances in treatment, especially with CGRP. A final question for you is, when you think about migraine research and treatment, and you look towards the future, where do you think things will stand, say, a decade from now? Robert Shapiro: A decade from now, it's very likely, many people are projecting, that we will all have our entire genomes on a credit card we carry with us or in an electronic medical record. And the identification of what our susceptibilities may be which relate to migraine may become clearer. It's possible that this push at NIH for what's called precision medicine may reach people who have migraine. Precision medicine is where the specific knowledge of what leads to disease in you leads to a therapy which may be more tailored to what may be helpful to you, because how you express disease and what led you to develop disease is particular to your circumstances. 10 years from now I'm hopeful that we'll have therapies that are far more effective than the ones that we have for prevention. These may end up being the anti-cgrp antibody

8 medications or possibly anti-pacap medications. Those are the most promising things, I believe. On the other hand, there's been a growth and a lot of enthusiasm for devices, most of them electrical or magnetic, which act on nervous systems to try to reduce migraine symptoms, and there are a couple of these that have been approved already. There's a transcutaneous stimulator device, which has modest effectiveness, which is already being marketed. And there's a transcranial magnetic stimulating device, which has reached the market, although it's not been widely accepted yet, and hopefully will become more widely available as insurance embraces its availability. And there are several other different devices, which are not yet approved, but show significant promise that they will be within the next few years. It's a very promising time from the standpoint of new therapies for migraine. But we still need to know so much more about it, and the only way that's going to happen is with an adequate investment in research, and that research is not going to come or shouldn't be expected to come from pharmaceutical companies. Pharmaceutical companies are very adept at developing drugs, but the real drive to discover drugs is from open-ended research that's publically funded. One of the reasons we may have so few medications for migraine can be traced back to the fact that there really has not been this open-ended research, an adequate amount of it, from NIH to help understand what's going on in order to lead to [more candidates for] drug development. I think that the same can be true for pain therapy overall. If NIH perhaps had invested a sufficient amount in pain research, maybe we would not be quite as stuck as we are now with the over-emphasis on use of opioids for chronic pain, despite the fact that there really is not great evidence that opioids are safe and effective for treating chronic pain. I'm optimistic that with the right investments, we'll be able to have much better ways of helping people who have migraine and headache disorders in general, and certainly chronic pain in general. RELIEF: I think that's a great note to end on. Dr. Shapiro, thank you so much for being here today and for sharing your knowledge and expertise. It's really been wonderful to speak with you, and we look forward to seeing new developments both on the research side and on the treatment side in migraine. Thank you so much. Robert Shapiro: Thank you very much. It's been a pleasure to be here, and I appreciate it.