#406 ‒ Migraine, cluster headache, and tension headache: symptoms, causes, prevention, and treatment | Brian Grosberg, M.D.

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My guest this week is Dr. Brian Grossberg. Brian is an internationally recognized headache specialist. He's the director of the Hartford Healthcare Headache Program and a professor of neurology at the University of Connecticut School of Medicine. He's one of the leading experts in migraine, cluster headache, and other complex headache disorders, and has spent his career treating patients who are often profoundly impacted and debilitated by these conditions. In this episode, we talk about how headaches are classified and what distinguishes a migraine from a tension-type headache and a cluster headache, why migraine is often misunderstood and underdiagnosed despite affecting tens of millions of people, the phases of migraine, including prodrome, aura, headache, and postdrome, the genetic, hormonal, and environmental factors that influence migraine risk, especially in women, the societal and economic burden of headache disorders, including its impact on disability, how clinicians think about diagnosis when there are no obvious consequences, and how they can improve their health and well-being. In this episode, we talk about how headaches are classified and what distinguishes a migraine obvious biomarkers or imaging findings, lifestyle factors, triggers, and risk modifiers that influence headache frequency and severity, preventive versus acute treatment strategies and how treatment decisions are individualized, advances in migraine therapy, including CGRP targeted medications, neuromodulation devices, and even Botox, and when headaches may signal a secondary, more serious underlying condition. So without further delay, please enjoy my conversation with Dr. Brian Grossberg. Brian, thank you so much for coming. And I didn't realize until a few minutes ago that not only had you never been on a podcast, which these days is pretty unusual, especially if you're an expert in something, which you are, but that you've never listened to a podcast. Yes. It makes me a unicorn. Yes. Yes. Okay. This is a topic that I think just affects so many people. I want to maybe understand the landscape a little bit about the field of neurology, what fraction of neurologists, especially neurologists, are involved in the field of neurology. How did you decide that this is what you wanted to do? So first of all, thank you very much for having me. I really appreciate it, Peter. It's important to understand that headache is one of the most common neurologic symptoms. Nearly at some point in every person's life, they're going to experience a headache. Surprisingly, in medical school, maybe medical students and residents get a few hours across entire medical school of lectures. I actually don't recall any of it. It's possible I had it and I just don't recall it, but I actually don't recall any of it. Yeah. And so that's a gap in education. And then in neurology residencies, that is similar, where people are only neurology residents or depending on the program, of course, may only get a few hours of headache lectures or education, and then they're experts. And so for my journey, if you will, into headache medicine was actually by accident, complete serendipity. My first year of a neurology residency, I took care of a litigator who was out of work for six weeks due to a prolonged migraine that had been going on for six weeks straight. And without knowing, the person who was caring for her turned out to be my future mentor. And so I had called this person and- And you were a resident at this time? I was a resident. I was probably a month into my neurology residency, so it was really early on. So the patient took a history, read up on it, and then detailed the history to him. And he said, thank you so much. Are you in your last year of residency? I said, no, I'm a month in. He said, well, that was- That's great. Why don't you come by my office and let's talk? And so I did that. I got very interested in seeing patients with him. He offered to see patients with me. Residency at that time, when you were on call, the hours weren't restricted. And so if you were in the hospital, 30 or 34 hours, whatever the case was, I would change out of scrubs into a shirt and tie, and then I would go see patients with him in the office, even though I'd already been in the hospital for that prolonged period of time. So my training in headache medicine was very expedited, if you will, during my residency. And then from there, after I finished, my pursuit advanced training in headache medicine. And there are just a limited number of programs in the country that offer fellowship training in headache medicine. So basically during your residency, you did a fellowship in headache medicine on your own time with the fellow who would become your mentor. And then obviously you went and did the formalized training. But going back to that first interaction with that first patient where you must've had some intuition about this that allowed you to take a history that elicited enough that this doctor felt like, wow, you're a seasoned pro at this. Any idea thinking about what it was? If I saw a patient with headaches, I don't think I could ask two intelligent questions. How long has it been aching and what part of your head? And I wouldn't ask a single smart question. I'm sure you would. Once again, in reading up about it, I was able to end up obtaining the features and characteristics. What really struck me was the fact that she was so debilitated and that she was coming into the hospital, receiving treatments, leaving the hospital completely headache-free. That for me was an epiphany, if you will. And it led me to end up thinking about something that is, if you will, an invisible disease that I wasn't really getting a lot of education during necessarily during my neurology residency up until I started pursuing it, you know, led me into the field today. So Brian, we communicated over email 10 years ago. I can't believe it's been that long. It's kind of amazing, right? Obviously through how all doctors meet through patients. So I was taking care of a woman in my practice who I remember during my intake with her headaches were a huge part of her life. And I got the impression through my intake with her, which of course is trying to focus on every aspect of her health, that this headache issue was a major issue. And I also gathered through that history that you personally were a major part of her care. Now that is not normal in my practice. And I think that's a really good point. I think it's a really good point. where usually the people that are of major impact in their life is not someone's neurologist because I'm not taking care of people that have debilitating neurologic disease. So that was just an interesting perk to me. And so many of the amazing doctors I've met are exactly this way. Like a patient of mine has a debilitating orthopedic injury that gets me down the rabbit hole of what's going on. And so in many ways, you personally became the sort of through line to understanding this patient's migraine situation. And obviously that's turned out to be beneficial to my patients because now no matter where they are in the country, I say, well, you're going to New York and ultimately Hartford, which is where you are now, because the only person I'm going to send you to is Brian when it comes to headaches. Thank you for that. Let's now help the audience orient to the types of headaches. You mentioned something a moment ago, which I think is obvious, but always worth restating. We don't have a biomarker for headaches. We don't have a finding on a CT scan or an MRI that says, oh, this is what's hurting you. We take that for granted sometimes that in many other aspects of medicine, when something is hurting, we have proof. Proof is maybe the wrong word, but we have guidance as to what's hurting. If you twisted your knee badly enough, I would be able to see which ligaments were damaged. This makes the entire field of neurology challenging, but I would guess that in the frequency with which headaches are a problem, it's not a problem. I think that headache medicine is actually quite challenging. And part of the reason, and you stated it very articulately, is the fact that the MRI doesn't always tell us the diagnosis and often doesn't. And so headache is really a symptom that nearly everyone in the world will experience at one time. And it's the perception of pain, whether it's in the head, the face, the scalp, the neck. And there are a litany of things that can cause headache. The differential diagnosis list of things is probably one of the most extensive in all of different types and causes of headache. The International Classification of Headache Disorders, kind of like the Bible of headache, but with no mention of God in it, breaks down primary and secondary headaches. Primary headaches is a headache in and of itself. It's a syndrome. It's not attributable to some other underlying condition. Most commonly, migraine or tension-type headache, cluster headache are the primary headaches. And you're right that there really aren't biomarkers. There aren't substances that we can detect, if you will, that tell us this is what the diagnosis is. And so, I think that's a good thing. And I think that's a good thing. And so, the diagnostic criteria are outlined, and they always say not attributable to another disorder. The secondary headaches are headaches that are attributable to some other underlying condition, where people will ask me, Dr. Gersberg, do I have a brain tumor? Do I have an aneurysm? Is there something that's life-threatening? And that's where a detailed history becomes important to try to not only understand all the factors, but also the person that's sitting in front of me. No person or presentation is identical. So, primary headache, we'll start with those, but just to make sure I'm clear and everybody is clear, does a second secondary headache always have a pathologic driver underneath? Because the examples you gave of mass, a mass effect, whether it be ultimately benign and therefore not life-threatening if removed or malignant, that's pathology. Aneurysm, of course, pathology. Are there any non-pathologic causes of secondary headache? There are non-life-threatening things that are causes of secondary headache. So one example would be if somebody is frequently using acute pain medication, that may lead to medication overuse. It's not life-threatening, but the resulting increase in the frequency of headache is attributable to some underlying condition. Caffeine withdrawal would be another example of secondary then, even though it's not life-threatening. Right. And they have pathophysiological and mechanistic reasons for the development of those headaches, but nothing that is pathological. Yeah. And so I guess I just answered my second question with the example of caffeine. Not every secondary cause has a radiographic or biologic marker. Okay, great. So now let's go in the, I think you described the big three, migraine, cluster, and tension headaches. Those are three enormous categories of primaries. And then you kind of have another category of the sort of others that make up that, but let's take those in any order you would like. Sure. So tension type headache is the most common headache that people experience. Migraine is the leading reason why people seek care, either in their primary care office with somebody like myself or in an emergency room. And so tension type headache is often thought about as a headache that affects both sides of the head or the face or the neck, where it's mild to moderate. It's not pulsating or throbbing. There may be light sensitivity or sound sensitivity, but never both. There's no nausea. And that headache can last anywhere from 30 minutes to 30 minutes. And so tension type headache is the most common headache that people experience. Migraine is the leading reason why people seek care, and that headache can last anywhere from 30 minutes up to a week. It's everything that migraine isn't. So that's the most common type of headache that people experience. So someone listening to us right now who said, I remember having a brutal headache a couple of years ago, that's most likely what they had if it was a one and done and- Well, a brutal headache, I wouldn't say that would be tension type headache. I see. That's something that often people can end up working through. It doesn't necessarily impact their ability to perform activities. Whereas, with migraine, the diagnostic criteria is where somebody has at least five lifetime attacks, where the attacks last anywhere from four to 72 hours, either untreated or unsuccessfully treated. And then they need to have two of the four following qualities. Pain is often one-sided, but up to 40% of people with migraine can have pain that affects both sides of the head or the face. Most people don't know that. The pain could be pulsating and throbbing. It could be associated with causing avoidance of light and activity. And then people can have light and sound sensitivity and or nausea and vomiting. So people don't necessarily need to have nausea if they have light and sound sensitivity, and people can have light and sound sensitivity, but no nausea. But if you are not nauseous and you do not have light or sound sensitivity, you probably are not experiencing a migraine? So there are people, if they meet criteria for one-sided pulsating and throbbing, moderate to severe, causing avoidance of routine physical activity, meaning those may mean that they have what's called probable migraine versus tension-type headache. And so sometimes the elicitation of the symptoms, people who may be light and sound sensitive, they may fall into different categories. So some people will say, "I'm definitely light and sound sensitive." Other people often need the question reframed, "Are you more sensitive to lighter sound when you have the headache than when you don't experience the headache?" "Oh, yeah." "Do you prefer a darker, quieter room?" "Oh, yeah." Yeah, that makes sense. Does the precipitating or exacerbating feature, as you've described them here, give you as the clinician insight into which therapies are going to be more or less successful? Or is it purely a binary thing at this point where either you're having migraines or you're not, and my playbook is going to be independent of how you got there or how you presented? Through a detailed history, once a diagnosis of migraine is established, the question then, becomes is, what's the attack profile? And then even within the same individual, the attack profiles may be different. Somebody may have an attack of migraine that gradually builds up over hours, where others will have an attack that wakes them from sleep at 3:00 AM in the morning. So the treatment paradigms may be different for those different attack profiles. And so you're looking at, obviously, location and character and quality of the pain. You're looking at rapidity of onset. You're looking at timing of onset. You're looking for accompanying symptoms. You're looking at, I don't know, how long it's going to take for them to get better. You're looking for level of impact and disability, because migraine carries a very heavy burden, not only personally, but also societally, family-wise. And then, is there presence of nausea or vomiting? Most people may not be aware that with migraine, and based on the pathophysiology of migraine, people may have a sensitivity referred to as allodynia, which is an uncomfortable sensation to things that normally aren't uncomfortable. And that's present in about. Say more about what that means? Sure. Yeah. So allodynia is a phenomenon where somebody experiences an uncomfortable sensation to things that normally aren't uncomfortable. An example would be a woman pulling their hair back in a ponytail, brushing their hair, wearing a tight hat, wearing glasses that rest on the rim of the nose or the eyes. And that uncomfortable sensation is present in about two-thirds to 70% of people with migraine. The reason why that's important is when people experience this allodynia, if they use certain migraine-specific treatments like triptans, but they wait too long, those treatments may be less effective. Are those symptoms prodromal? So I think to answer that question, it would be important to explain that migraine is not just a headache. There are phases that people experience. There are distinct phases, but they're not distinct. And so sometimes there can be overlap of symptoms. So the first phase is a premonitory phase, whereby people experience, it's kind of like the calm before the storm, yawning, craving certain foods, tiredness, irritability, light sensitivity, neck stiffness. And that may occur minutes, hours, or even days up to before migraine occurs. What's the median duration that that's showing up? So I would say hours. Yeah, hours beforehand. And that could actually be helpful because then people know how to think about it. And there is actually a treatment that was studied premonitory or what's called the prodromal phase. Then about a quarter to a third of people with migraine will experience an aura. And aura is a reversible neurologic symptom. So most people with migraine actually do not experience aura. The vast majority who experience migraine don't have aura. Explain to folks what aura is. Aura is a reversible neurologic phenomenon. So this is whereby there's a phenomenon called cortical spreading depolarization in English, even though I'm from Brooklyn. There's a wave of excitability that starts in the back of the brain and then spreads across nerve cells, followed by a period of relaxation. And because it's starting in the back of the brain, the back of the brain is the visual cortex. So the most common type of aura is a visual aura where people may experience what's called positive and or negative visual phenomena. And that's where people may have zigzag lines, difficulty seeing on one half of their world, spots, black spots, distortions, perceptions. And generally this evolves gradually over about five to 60 minutes. That's the most common type of aura. Which the first time it happens must be terrifying. Think you're having a stroke. Correct. And so there are things that can mimic aura and they need to be excluded. And that's the reason why a detailed history, particularly if it's a one-time event versus recurrent episodes, becomes very important to elicit when seeing somebody. Is there a pattern to aura that if a person shows up in the ER makes you more or less likely to think this is aura? Is there a pattern to aura versus TIA or stroke or something really dangerous? Yes. So one, it's very helpful to know if somebody has a history of migraine. I think that's one thing that's very important to know. Two is what is the evolution? Is it stereotyped? Is this the first episode or are there multiple episodes? Usually when somebody experiences TIA or stroke, the symptoms are maximal in onset. And contrary to aura of migraine, there's this kind of gradual evolution often over five to 60 minutes. And so once again, that's helpful to know. Are there sequential aura symptoms? So the most common aura symptom is a visual aura symptom, but people also may experience sensory, language, or motor aura symptoms. And so do people have this sequential progression, if you will, in their aura symptoms? That's generally not seeing in stroke. And so those are helpful points of distinction. Do people end up having, if they have a visual aura, do they have positive and negative visual symptoms? Meaning, do they have kind of zigzag lines or whiteout over half of their world and, so to speak, darkness, if you will, in the periphery? Often with TIA or stroke, if people have a visual disturbance, it's negative visual phenomenon only. Negative means subtracted. Subtracted. They lose vision. And so that's another helpful point of distinction as well. And then aura symptoms, at least one aura symptom, if it's going to occur, is usually on one half or one side of the world. Once again, teasing apart that history is very helpful to make the distinction if it's migraine or if it's a cerebrovascular event like a stroke. I guess we'll come to it when we're we talk about treatments, you've alluded to the pathophysiology of the migraine. So clearly this must have to do with ion channels, calcium channels, or all sorts of the usual suspects for excitability. So maybe we'll come back to that, but obviously I want to make sure we do talk about that through the lens of treatment. What else should we know? I mean, again, I think most people listening who themselves have not had a migraine, I'm fortunate to be in that category. By the way, what is the prevalence? 12%. So 1 billion worldwide. Wow. Roughly 45 million people in the United States impacted by migraine. Has anyone done the exercise of quantifying the economic consequence in the United States? Because this has to be even higher than lower back pain in terms of work missed, or at least on par with it. Yeah. So there are the economic impact, at least in the workplace, is in the billions of dollars. Maybe more, right? It could be. Certainly hundreds of billions would be my guess. Yeah. The impact is not only on absenteeism, but on presenteeism. By that, I mean, presenteeism, you know, somebody there. Somebody there, but they're just not working at full capacity. But they're not working at the full capacity versus absenteeism where they don't show up to work due to migraine. And the heaviest burden I would say is on presenteeism. Interesting, which is much harder to quantify. Correct. We're actually doing it right now through a study that we're doing. That's interesting. There's an enormous incentive to fix this problem. Yeah. Even if you personally have not experienced it. Society suffers as a result of it on both absenteeism and presenteeism. So again, for those of us that have not experienced it, we have this sort of maybe stereotypical impression of it. I'm thinking of a person who has to lay in a dark room with a towel on their head and bear it until this thing passes. And it strikes without a warning and it's a lightning strike. And how many people are walking around having- Yeah. Having migraines a couple times a year and not knowing that it's a migraine? Is that a pretty rare phenomenon or? I think it's actually quite common. And I think the spectrum of migraine is very broad. I think you elicited one person who is bedridden, but many people with migraine are significantly impacted and walking around. And you'd never know necessarily that they're impacted unless you're asking them or seeing their behaviors by the way they dim the lights or try to end up pushing through. A lot of people with an invisible disease, I think back to a famous comedian, Rodney Dangerfield, that I don't get respect. I think that's migraine, right? Where most people think of it just as a headache without realizing it's a neurologic disease. And it disproportionately affects women three times more often than men. Oh, wow. So 12% is aggregate. Correct. But if you do the math- 18%. Yeah, 18% of women. Yeah, it's disproportionately women. So almost one in five women. Correct. I'm actually amazed at how many women are affected by it. I think it's almost one in five women. Correct. I'm actually amazed it's that high. Yes. And the hard part is that demand for outstripped supply, right? So demand for headache care, the number of people, number of clinicians across the country that are providing and able to provide headache care, there's just not enough, just because of the numbers. Yeah, there's not enough Bryans. There's not enough Bryans or other people. Yeah, yeah. And then the training also is very different. So I'm very fortunate not only to have had great mentorship, but to be able to mentor the next generation of headache specialists, but there are 50 or so. So minted a year. That's just not enough. There are only 50 fellowship-trained headache neurologists that are coming out of training a year-ish. Ish. Amazing. For a condition that affects 10%, 12% of the population. Correct. Yeah. We could almost come up with some interesting parallels there in terms of how many dermatologists would be trained that could treat a dermatologic issue that affects 12% of the population. Right. And the spectrum of migraine is so broad because we're just talking about migraine as a disease, but there are people who have episodic migraine, and then there are people who have chronic migraine. So episodic migraine is where people have less than 15 days of migraine per month. Chronic migraine is where people experience 15 or more days of headache per month. That's most of the people that I'm fortunate to care for. And that's about 1% to 2% of the population that experience 15 or more days. These people are thoroughly debilitated. Half their time is in a state of headache. Correct. Correct. Okay. So 10% of the population is experiencing up to 50% of their time in headache. 1% to 2% of the population experiences chronic migraine where they have more than 50% of the time experiencing headaches. So the vast majority of people experience episodic migraine, but that episodic migraine is a range, right? It could be a couple of times a year to- Up to 50% of the month. Up to 50% of the month. Yeah. Okay. Before we get into treatments and other things I want to talk about, well, we can talk about them now. Tell me a little bit about genetic susceptibility. Obviously, genetics matter given the fact that women are three times more likely than men. The first thing one might think is, well, is it hormonal? How much does it relate to estrogen, progesterone? We know that there are receptors for these things in the brain. Does the frequency of this type of headache, is it higher during the reproductive years? Is it higher during the menopausal years? That would give us a clue as to the role of hormones. And then during the reproductive years, is it higher during any part of the cycle? Yeah. That's a lot of information packed. I will try to tease that apart. And so ultimately, yes, hormones plays a role. Yes, genetics plays a role, but migraine is multifactorial in the sense that genetic environmental factors play a role in experiencing migraine. So if somebody has a family history of migraine, they're more likely to end up experiencing migraine. And through a woman's reproductive cycle and across hormonal milestones, migraine can certainly have a predilection around times of puberty, around times of menses, pregnancy, lactation, perimenopause, and menopause. And so across these hormonal milestones, migraine certainly will fluctuate, if you will. I would say about two-thirds of women will experience migraines with perimenstrual attacks, with a node and association of migraine around their menstrual period. And that association comes in two possible forms. One is women who experience pure menstrual migraine, where they experience menses and headaches and migraine occurring around their menses, solely around their menses, but not at other times of the month. That's less common. That occurs in probably less than 10% of women who experience what's called pure menstrual migraine, where the migraine are just around the menstrual period, usually a couple of days before and a couple of days into. Which of course is the lowest period of hormones, which suggests hormone deprivation is driving that subset. Correct. And then menstrual-related migraine, which is present in about 50% of women, is where they experience migraine not only in temporal association with their menstrual period, but at other times of the month. And so this is a very common occurrence for women. The estrogen, that dates back to the 1970s studies that were looked at, that natural decline in estrogen in the late luteal phase and the development of migraine. If we fast forward in time, what we know from studies is that it's the faster rate of estrogen decline in that late luteal phase that is unique in women who experience migraine. So it's this more rapid rate of decline in estrogen. I'm very proud because one of the people I was fortunate to mentor actually did those studies. I'm surprised that we don't also see that post-ovulation because you also have a very sharp decline in estradiol post-ovulation. They kind of have two. They're sharp after ovulation and then not as sharp at the end of the luteal phase. Did they see anything mid-cycle? So interestingly, around ovulation, there doesn't necessarily seem to be a much higher risk of developing migraine. And I think that's in part to this more rapid, faster rate of decline of estrogen in that late luteal phase, which is the unique part. Yeah. It could also be the progesterone because we don't see, progesterone hasn't risen in ovulation. You know this, but just for the listener. So we don't see a progesterone crash post-ovulation, whereas post-luteal, we're seeing both estrogen and progesterone come down. So is it possible that it's the combination of them or the progesterone that's causing the problem? Right now, the belief is really the estrogen, that decline of estrogen, not the decline per se, but the degree and rapidity of the decline that is unique mostly in women who experience migraine. The other couple of things to end up thinking about is we know estrogen can have effects on serotonin transmission. And so serotonin is involved in migraine, right? If I go back to the 1940s, when serotonin was first discovered in blood, and then fast forward, serotonin was identified and noticed to be lower in blood during migraine attacks, and then the recovery phase would increase. Those studies ended up leading to. The development of triptans. So estrogen has a number of different roles to play in the pain pathways. Has the experiment been done where you take susceptible women and you selectively give them estrogen during the period of time in anticipation of that? So for example, seven days post-ovulation, which would be peak estrogen as it's about to crash into menses, you give them physiologic estrogen replacement levels, and does that mitigate any of this? Yeah. So estrogen has been given, those studies have been done. The hard part is predicting necessarily who is going to respond. So there are some women that will get improvement in migraine. There are some women, they may not get improvement. And there are some women who will take combined hormonal contraceptives and they may get worsening of their migraine. And so it's very hard to tease apart and know who's the individual that will necessarily respond. In caring for those patients, one of the things that I try to do that's unique is actually in a collaborative care model, work with a gynecologist who is a specialist on hormones. And so working together, we actually try to end up mapping out a plan for individual patients. What else do we know genetically about predispositions? Are people whose parents, sufferers of migraines, more likely to be sufferers themselves? Yes. People ask me why they have migraine. If their parents in the room, I usually point to them and I say, you're the cause. Not to place blame. No, of course. But we think it's very, very highly genetic then. Correct. But there are many genes that have been identified for migraine. So it's not a specific gene. Right. So it's polygenic. Polygenic, but highly hereditary. Correct. And the nervous system, if you will, of people who have migraine is more hyper excitable than people who don't have migraine. So it's not that there's more lighter sound, but the perception, if you will, the sensitivity has just increased. Maybe a silly question you haven't thought of, but is there an evolutionary benefit to it? Not that this would have weighed heavily in selection, but is there an upside to the hyper excitability? Does it manifest itself? In other positive traits during the period of time when the individual is not suffering. My question is through the lens of like, hey, if we're on a continuum of excitability and when the thing goes too far, you end up with a headache and that's bad. But if you pull back just a little bit from the brink, is there some benefit to that state? So a colleague of mine ended up writing about this a number of years ago where she postulated that the evolutionary benefit to women in particular may have been, if they're the caregivers of their migraine, that they're not going to have as much of an impact on their family, that they would know if there was inclement weather coming, rainy storms, if they had to end up, signs of danger. And so that may be one of the evolutionary benefits. The other thing is, you know, if I think about the neural networks in men versus women, women generally have to multitask much more than men in general. And so the question is whether the neural networks, if you will, are better. That is super interesting. So one of those says, look, women might be more wired to be better at multitasking. And the migraine is just a manifestation of an extreme, more extreme version of that, which you're going to get if you shift the population over that way. And then the second issue is, presumably through changes in barometric pressure, is that the most common weather-related triggering event? Triggers are not the cause of the headache. Triggers are factors that will elicit a headache in somebody who's biologically predisposed. So meaning if somebody is not biologically predisposed to having migraine, then they're not going to have as much of an impact on their health. There may be a weather storm that's coming through and they may not experience a migraine. But in somebody who has migraine, they may have one or more triggers. Some people with migraine have no triggers. Others have multiple triggers. Changes in weather, the letdown phenomenon after stress, drinking or eating certain types of foods that may trigger. And it's usually a combination of two or more triggers that will precipitate an attack of migraine. Do you have a sense of what subset of patients are indeed triggered by weather patterns? And changing barometric pressure? It varies from person to person. My patient population is one that generally suffers more because it's more so in the people who are experiencing 15 or more days of headache per month. And so that reporting bias may occur. I may hear that more often than others may. That kind of makes sense. The more severely impacted people would presumably have more diversity in their triggers as well? Correct. They may, but not necessarily. And that's what makes migraine very nuanced, if you will. If you will. That's why the history needs to be detailed. So the questionnaire that people are filling out for me are 15 pages, pretty extensive in trying to end up determining if I'm dealing with a primary or secondary headache. And then if it's migraine, how does it present? Because a headache diary is probably the most important thing that your listeners can do for not only themselves, because it really empowers patients, but for a clinician like me to understand, because the patterns may be different from person to person. Do you have an online version? On your website that patients can download? Yes. Okay. So we'll link to that in the show notes so that anybody listening to this who wants to actually have a diary and know what things to put in the diary, they can do it. I agree. It's funny. We live in this world where we're so obsessed with really high-tech things and sleep trackers and all these things. But honestly, like a sleep doctor, if you go and see a sleep physician, they're going to want you to do a really good pen and paper sleep diary. And we still give those to our patients who were in the biggest, biggest distress around sleep, because the information it captures is so much more rich, so much more temporally related to what's happening. And two weeks of painstakingly doing this will offer more than two years of tracker data. Sounds like very similar for you in getting a good diary. Obviously, it might take more than two weeks, given the frequency of the headache. Yeah. Usually we're looking at a period of several months, particularly if it's a woman who's reporting a relationship between her and her patient. And if it's a woman who's reporting a relationship between their migraine and menstrual period, because ultimately to make a diagnosis of perimenstrual migraine, whether it's pure menstrual or menstrual-related migraine, that association is known in at least two out of three cycles. Obviously, thinking about the patient that first connected us 10 years ago, one of the things that stands out about me, because she was a menopausal patient. This was a woman who at the time was in her probably late 50s, early 60s. She did better on hormones, but it couldn't be too much. She was a menopausal patient. There was a very, very fine line. In other words, we ended up having to use estradiol and progesterone, as you do in perimenopausal women, but less than you would normally have treated someone. In other words, we couldn't take her to full therapeutic dose. Is that common in menopausal women? Those transitions, if you will, from perimenopause to menopause, not only are hormonal fluctuations are occurring in perimenopause, but so is migraine. And so in a patient like that during menopause, there are women that will experience a significant worsening of migraine. Probably about two-thirds of women who, after they've transitioned to menopause, they've finished perimenopause, they will notice improvement in migraine. But 10 to 20 percent may actually either continue or get worse. I find that there's a fallacy where some patients are told that once you hit menopause, you're finished and you're not going to have migraine anymore. And the hard part becomes is it's not only the hormonal fluctuations, but the impact. On others' symptoms. So there may be sleep disruption. There may be other pains, joint pains. And so there are risk factors that put one at greater risk for more frequent migraine. If somebody experiences five or more days of headache per month, they're at greater risk. Sleep disturbance, changes in mood, which can end up happening in perimenopause, going into menopause. So all of these things have either direct or indirect impacts potentially. I mean, this just makes it a very complicated thing because now in addition to all the reasons you would consider HRT, you have to then consider if you're in that group of women who are improving in menopause, presumably adding hormones makes you worse. Not always. I mean, unless you figure out that sweet spot like we did in this patient where we could still give hormones to maybe two-thirds of the level without making it worse and then still capturing two-thirds of the benefit or something. Yeah. There are, just like in this patient, there are some women who will not, necessarily need HRT or hormone-related therapy. And there are others that, despite best efforts with non-medication and medication approaches, will need HRT. The hard part becomes is, like you're pointing out, it becomes very individualized. What may work, what dose may work for one person may not work for another, and too much may potentially exacerbate versus too little may not end up providing the relief that's needed. Yeah. Anything else about presentation and migraine? I want to then talk briefly about, see if we have anything to finish on tension and then get the cluster. Yeah. So I think presentation of migraine is, we spoke about a couple of the phases and not all people with migraine have all the phases of migraine. So the first phase is that premonitory phase, the calm before the storm, and a quarter, two or third of people experience aura. And then it's the migraine phase, but it's not just the pain. It is potentially a constellation of symptoms, that light sensitivity, the sound sensitivity, nausea. It may be autonomic symptoms, so if somebody has tearing or redness of the eyes or congestion running in the nose, often people think that they have, quote, a sinus headache, but there's no such thing as a sinus headache. There's acute rhinosinusitis, there's chronic rhinosinusitis, but based on the pathophysiology of migraine, there is involvement of an aspect of the parasympathetic nervous system that has a connection, if you will, with the nerve called the trigeminal nerve, which is the main nerve that's involved in the experience of migraine and headache. And when people's parasympathetic nervous system becomes activated, people may experience tearing or redness of the eye or congestion running in the nostrils, which is pretty common in people with migraine, and they think they have, quote, a sinus headache. And then ultimately, at the end of the day, after the pain is gone, they can experience a post-trome, which is the pain is gone, but I don't feel back to myself. I feel hungover, and that can last for hours up to even a couple of days. And so when I take a history of migraine, I want to understand, What's the total impact? Meaning, if they experience all the phases. What is the duration of each of them? What's the personal impact? Because we just focus on the pain and not necessarily the impact in totality. The other thing is the interictal burden. One of the things that you pointed out, I really appreciate it, is how are people thinking about their plans, their daily activities in anticipation of experiencing a migraine? Meaning I'm not experiencing a migraine now, but I don't know when it's going to come. How am I going to plan that vacation? That's what's referred to as interictal burden. Interictal, meaning between the pain bouts. Between the pain bouts. And so that's where, when I'm eliciting all these pieces of history, I'm thinking about how am I thinking about their acute treatment plan? How am I thinking about their preventive treatment plan if they need that? How am I thinking about non-medication approaches? And then combining the picture together, obviously with the patient driving the decision-making, once they understand the rationality of the patient's decision-making, once they understand the rationality of the patient's decision-making, once they understand the rationality of the patient's decision-making, of how I'm putting it together. Can you say a little bit more about some of those post-ictal experiences? What fraction of migraine sufferers, once the pain is gone, are largely able to resume activity versus those that have that post-ictal period where they're not back to normal for a day or more? There are population-based studies and there are clinic-based studies that have been done. So population-based studies, looking at the general population, clinic-based studies, somebody would do an academic headache program like my own. Those numbers can range anywhere from like 60% to in the high 80s. But it's still a big number. It's a big number. The same thing with the premonitory symptoms, kind of that calm before the storm. Okay. Now you said, by the way, for everything we're talking about here, 12% of the population, three to one women to men, going back to tension, which we talked about very briefly, you said that's the single most common cause. It's the anti-migraine. So it's all the things that are migraine. What's the prevalence of that? Lifetime incidents maybe or lifetime? That's pretty high. Yeah. A lot of it. A lot of people are going to experience that. Yes. Okay. Female to male difference? Pretty evenly split. What are some of the triggers and how genetic is it? I think the name lends people to think necessarily that it's just tension or stress that causes the headache. And that's not necessarily the case. That's why it's referred to as tension type headache. And so that's the experience where people have that lighter sound sensitivity, mild to moderate pain that can be around the head, the muscles around the head, the muscles in the neck. And the nerves that are involved, the anatomy and physiology, there's overlapping, if you will, because the nerves that supply sensation to the face and the head of the neck are similar to what's involved in migraine. There are genetic factors that are responsible, there are environmental factors, and then there's pericranial or around the head muscle nerve tenderness, if you will, that's a contributing factor as well. If a person has a tension headache and they take a thousand milligrams of Tylenol and they get better, do they have a chance of getting better? Do they have a tension headache? Or in other words, could it respond to something as simple and over-the-counter as that? Yes. Okay. Yeah. As long as we know that that's what it is, that it's a tension type headache, because making any diagnosis not only meets criteria, but also that it's not attributable to something else. Okay. And obviously we're going to come and talk about the potential treatments for these things. So let's round it out with cluster then. So what's a cluster headache? So cluster headache is relatively uncommon, pretty rare relative to migraine and tension type headache. But it's one of the most painful disorders known in the world. I have a woman patient who's likened it to giving birth to a hundred babies at the same time without an epidural. I mean, that's the exquisite nature of the pain. And so it's pretty distinctive in its presentation. It disproportionately affects men more often than women. So that ratio that is now about three to four to one, it has characteristics where people may have a cercanual periodicity or circadian periodicity. By that, I mean the longest and shortest days of the year, January and February and July and August, people can experience cluster periods where they may have daily or near daily attacks, sometimes multiple attacks per day. And this pain often is conceptualized as in and around or behind one eye. It's usually almost exclusively side-locked. So just on one side of the head or the face, the rapidity of onset is very quick. Unlike migraine, which generally will gradually drop, cluster headaches peak within about five to 15 minutes. The attacks generally last anywhere from 15 minutes up to three hours and can be characterized as stabbing, boring, exquisite nature. And then as soon as it came can often be as soon as it goes. And with the pain, people can end up getting very characteristic features. About 97% of patients can experience a droop of the eye or redness of the eye on that side, congestion or running of the nostril. And so not only can you see the experience on the person's face, but you can actually see the visual symptoms often. And about 90% of people with cluster headache can experience a sense of restlessness with the attacks where they can't sit still. They need to move about. That's in contrast to migraine, where the vast majority prefer to be still or lie down in a dark, quiet room. And so the presentations are very, very distinctive. And where cluster headache is also a very, very distinctive feature. And it's also been nicknamed suicide headache, not only because of the intensity of the pain, but the frequency of which these attacks occur. So on average, people can experience three attacks per day. The criteria allow people to have one attack every other day, up to eight attacks per day. And these cluster periods could be, depending on the person, weeks to months, sometimes longer. So depending on if somebody has episodic cluster headache, where they get this cluster period and then a break in time, or chronic cluster headache, where they have no break in time, or chronic cluster headache, where they have no break at all. They're just having multiple attacks per day. Does the term suicide headache stem from the fact that people will take their life if it's extreme enough? Yes. That's terrifying. Does that suggest that the drive to move provides some relief? I don't know if the drive to move provides relief as much as the areas in the brain that are involved during the attack of cluster headache can cause manifestation of symptoms. And one of those symptoms is a sense of restlessness or agitation. What else do we know about these things? How genetic are these? We know that there are genetics that play into cluster headache as well. First-degree relapse may be at higher risk. Like I said, it's not common, but these are very highly motivated patients, just like migraine, but maybe even more so because of the exquisite nature. They also, like migraine, often go underdiagnosed or misdiagnosed because of the presentation of pain. Because it can be a risk, it can be a risk. It can be a predilection for attacks to occur January and February. So people may come into their doctor at that period of time, say that I have pain, I have nasal congestion, and they may be told, oh, you have a sinus infection, then receive an antibiotic. July and August, they may come to their doctor and say, I have pain, tearing or redness of the eye, and they may be told, you have allergies, you need allergy shots. Some people will have pain that's around the teeth or the face, and they have had teeth pulled or major dental surgery. Or sinus surgery without realizing that the presentation is actually cluster headache. Part of the log that people can download from your site that allows them to take an accurate history, is that something they could take into their primary care physician if they're having a headache? And does it highlight enough for the doctor, the flag that says, hey, this might actually be a cluster headache, and this might be one of the times when, even though it's hard to get to headache specialists because of the frequency or the low, low-level, low-level headache, it's not going to be a cluster headache. Number of them, it's worth taking the time to get the right clinician on board before we make a mistake and treat you for something you don't have. Yes. I think that becomes very important. I think about my primary care colleagues and the number of things that they have to address in a relatively short period of time. And headache may be just one of them, and I think that's the hard part. So we want to kind of arm patients with a ton of data so that when they meet their PCP, they can do the lifting for them. The 10 minutes that that primary care doc has, they're not going to be able to do the detailed history you would do. But if they can walk in with it, hopefully the doctor is receptive and says, oh, gosh, yeah, I wouldn't have had the time to elicit this or wouldn't have even had the knowledge base to elicit it. I was about to say, it's not only receptive, it's the time. It's also having the knowledge and education experience to make the diagnosis and then offer the appropriate treatments. All the stars need to align, if you will. Most people with headache, if they're coming in, they're not coming to me for the first time. Sometimes they do, but they're often going to their primary care. So that's the gateway, if you will. The hard part becomes is kind of navigating afterwards the gateway, particularly if they don't have a diagnosis or they're misdiagnosed. And patients come and see you from all over the place. Yeah. That means that obviously a lot of them can't see you when they're in the throes of suffering. Does that matter? So for patients with cluster headache, that's kind of the password, if you will, in the sense that if somebody who's either an established patient or somebody who's trying to get in, we'll say that they have cluster headache. And if in fact they, at least on the basis of their questionnaire, seem to check off information that alludes to that possibility, then yes, they're seen quicker in general, just because it's been nicknamed suicide headache. Is there a benefit to you seeing them while suffering to make a diagnostic or treatment decision? Yes. And the reason why is often patients with cluster headache require multiple treatments. One could be acute treatment, meaning when they experience the attack, they're using a treatment to rapidly abort the pain. The other is a preventive treatment. So they're taking something, one or more things to prevent attacks because often these patients with cholesterol are experiencing frequent attacks a day over a period of potentially weeks to months. And then transitional treatment. The preventive treatments often take weeks to months to build up, even for migraine. And so what is being done in the transitional period? Sorry to interrupt, Brian. When you say preventive treatments, do you mean lifestyle preventive treatments like changing diet or do you mean actual pharmacologic prophylactic drugs that you need to just have on board to reduce the probability of an attack? Yeah. So a multidisciplinary approach. So meaning for patients with cholesterol headaches, some of the examples would be avoiding alcohol, avoiding foods with nitrates, not taking naps during the day, preferably if they have a sleep apnea, addressing that because hypoxia can sometimes be associated with it. And then at the same time, preventive treatment is taking a pharmacological, right, a medication treatment that may take time to build up. And while that is being built up, offering something to try to rapidly suppress the attacks until those preventive treatments kick in. Yeah. Well, let's use that to pivot to the first thing that you talked about there, which is what are the modifiable lifestyle treatments that can be used to reduce the probability of an attack? Interventions that you would keep in your playbook for these patients. And are they the same across all the headaches? Everything you just said, for example, around correcting sleep apnea, minimizing alcohol, avoiding naps during the day. Would you give that advice to any person suffering from headache or are you really narrowing that on the cluster patient? Whereas the migraine patient, you have a different playbook. Migraine itself has certain identified risk factors. Even the subtypes of migraine may have their own identified risk factors. So if we know from studies that were done that if somebody's experiencing at least one migraine a week, more than that may put them at greater risk for more frequent attacks of migraine. So the higher the frequency of attacks at baseline may lead to chronification or transformation of more frequent migraine. Somebody who has stressful life events, we all do, but that's a risk factor as well. Sleep disturbance. That may be insomnia. That may end up being sleep apnea. So once again, modifiable. Person's mood. Depression and anxiety are comorbid with migraine. They coexist at a higher than expected by chance. And there's a bidirectional relationship between mood disorders and migraine. And so addressing those, that's why I try to explain to patients that all the stars kind of need to align. It's not just taking care of your pain, but we need to end up addressing these risk factors. People frequently using acute pain medications. So there are risk factors. There are some classes of pain medications where if they're used two or more days per week on a regular basis over an extended period of time, that can actually create more frequent headaches. It doesn't happen for everybody. That could be NSAIDs and acetaminophen or opioids. It could be non-steroidal anti-inflammatories, simple analgesics. It could even be triptans, migraine-specific medications. It could be barbituric-containing combination analgesics medications like Fioricet or Fiorinol, opioids. And then if somebody has other pain disorders, obesity is a risk factor. And then if somebody has other pain disorders, it's a risk factor for more frequent migraine. And the greater the degree of obesity, the greater the risk. And do you think that's inflammatory? Do you think it's insulin-related? It's probably multifactorial as well. Migraine itself has a pro-inflammatory component to its pathophysiology. And so there may be shared mechanisms that underlie that. And is this modifiable if a person is. So first of all, do you know what the hazard ratio is or the increase in relative risk with obesity versus not with respect to the headaches? So people who are morbidly obese are at five times. Five times higher risk for more frequent migraine. Oh, so it's not subtle. It's not subtle. This is dramatic. Dramatic. And there are studies with weight loss, surgical and non-surgical, showing improvement in migraine, not uniformly across the board for every individual, but certainly showing improvement. Modifying that risk factor is very helpful as well. Some of these numbers are shocking. The women being three to one is not shocking with my lived experience because when I stopped to think about it, almost all of the women that I've seen or the people I've encountered with migraines or most of them are women. I get that. The obesity is 5X. That is surprising. Morbidly obese. Okay. So morbid meaning 35 BMI? Yeah. Yeah. But what about obese? What about 30 to 35? Greater risk. How much? 2X? 2X. Okay. Still a big deal. Yeah. So in other words, if you're looking for a reason to correct obesity, there are plenty of them on a health perspective as it pertains to chronic disease like heart disease and cancer. But when you think about two dramatic things that improve the quality of your life, one would be orthopedic. You just have less wear and tear on your joints. And then another could be for the susceptible individual, these headaches. Correct. And then having other pain disorders, which you just alluded to, whether joint pain, neck pain, back pain. Which leads you to more of the medications that then also become the trigger. And has that been corrected for in the analysis? Yes. Having other pain disorders in and of itself puts one at greater risk. Having the presence of nausea, nausea that's not optimally used. If a migraine attack is sub-optimally treated, also greater risk. So when I'm listening to history, I'm almost doing this computational analysis and then explain to people, here's how I'm thinking about it. This is why your treatment plan is being designed this way. And no two people are going to necessarily have the same treatment plan. That's what you were asking in terms of migraine versus cluster. Cluster headaches, certainly we're trying to do that. But if a migraine attack is suboptimally treated, whether it's the food, the nitrates, the sleep apnea, taking naps during the day with migraine, it's one of those risk factors. And how do we address not only the disease migraine, but also those risk factors to try to prevent progression? Okay. Just to play that back, make sure I heard it. Prophylaxis on the cluster side is around identifying the triggers. What's the acute, what's the thing that's making it happen? On the migraine side, it's because there are fewer acute triggers that we are aware of, it's more just generally reducing probability of it happening. Let me clarify. So for cluster headache, it's not the triggers. Those are things, lifestyle changes that I may suggest to them. It's the pathophysiology and the mechanisms that are underlying cluster headache that will precipitate attacks potentially at different times of the year and different times of the day or the night, because there's involvement of the sleep-wake cycle. And that's why people have this, this circannual periodicity and this circadian periodicity, because there's involvement of the hypothalamus and the pineal gland and the changing of the clock for daylight savings time. So I know when the clock has changed, I'm going to hear from people with cluster headache. In both spring and fall? Yeah. I mean, I have patients, I have a patient from Australia who, when he travels there, he'll get cluster attacks because the season's changing when he comes here, if he comes at the different season. And how much of that do you think is fixable with circadian rigidity? In other words, if you said to a patient, look, Bob, I don't care that we're going to change the light. We're going to get a 50,000 lux light in your home. And we are going to make sure that your pituitary, your hypothalamus, your pineal gland, every part of your brain is seeing light and darkness at the exact same time. Again, I'm using this as a thought experiment, right? But we are going to completely control your light environment independent of the seasons. Would that have an impact? I don't think that's going to happen. I don't think that's going to eliminate a person's cluster headaches. I think what it will do is if you, if somebody is not necessarily going to areas or time zones where there may be seasonal changes, they may not necessarily experience cluster attacks, but that's not a certainty. And how often do you just take an empirical approach to this and say, look, we're going to throw the kitchen sink at this two interventions at a time until we find things that work? I mean, for example, we do this all the time with dietary sensitivities. So you get a patient who's just got debilitating bloating and GI issues, autoimmune conditions that aren't otherwise easy to identify. And one path is I'm going to run a bunch of blood tests on you that are totally bogus and bullshit and made up and have no verifiable causes. And I'm going to come up with a bunch of silly recommendations and give you a bunch of dumb supplements. Obviously, that's not our approach, as you can tell by my language. An alternative approach that seems way less scientific, but frankly works a lot more is we're going to do an elimination diet. We're going to hypothesize that something in your diet is causing this. And we are going to selectively and ruthlessly pull things out of your diet until we find the trigger, which means pull it out, wait for an improvement, reintroduce it one at a time and watch to see if we can precipitate it. And this is how we will figure out the role of dairy, alcohol, caffeine, wheat, all of these things. Again, seems less scientific, way more practical than using bogus metrics that don't mean anything. Do you ever do the same thing in the headache landscape? Yeah. So a big focus of what I do is on lifestyle. How do we modify things that will set that person up for best success that may be triggers or that help reduce risk factors? I try to take a very calculated approach. I also try to understand the person who's sitting in front of me. Right. How willing are they to be empirical? So it's, what's the diagnosis? What are their coexisting medical conditions? What's their preference? What are their expectations? Before I start a visit, I ask people, what are the one or two most important questions I can answer today? And I want to understand that person's perspective. It's not enough to end up giving them the medical information, but I want to make sure it aligns with how they're thinking about it. And then it becomes very tailored. If I'm thinking about lifestyle modification, we're focusing on diet, routine meals a day that are not delayed. And if there are particular food triggers, asking them to track with the headache. Unless I understand the individual, I don't necessarily ask them to eliminate everything at the same time. I also want to know if there's a family history of either gluten sensitivity or celiac disease. And so that may lead me down the path to end up thinking about them getting tested for that. But there are certain, like you said, certain foods that may be triggers for certain people. Alcohol may be triggers, but not everyone. And that's why I say it's very individualized. And then the importance of sleep, hormones, environmental factors, exercise, and reducing trigger burden. So meaning if somebody knows that I may be set up for an attack at this particular time, then I may say, okay, you may be able to mitigate that risk by doing X, Y, and Z. And an example of that is when people keep headache diaries and they may experience attacks on the weekend. I'll say, okay, so what happens during the week? You go very hard, endorphin levels go up, and then they drop down. And then you go to sleep later on Friday night, and you wake up later on Saturday, and your caffeine intake is delayed. That's three triggers. And so then people have like the aha moment. Oh, I didn't realize that. And this is especially valuable when they're doing the log, because you can see during the week, I have my coffee at six in the morning. On Saturday, I'm not even getting up till eight o'clock in the morning. I'm having coffee at nine. And you wouldn't think of that. Right. And those are the nuances that I point out. And usually the diaries that I ask people to keep are a month view. And so that way I'm able to quickly glance, and I actually pull the diary off into patience. And I'll say, okay, here's how I'm thinking about it. This is why we're going to end up using these treatments. And so an example would be if someone experienced menstrual migraine, which is quite common, I may say, oh, okay. So your menses, how long does it last? What's the intercycle length? What's the length in between the cycles? What's the characterization of the flow? When do you experience headaches in relationship to that? I see that it is the same every single time. Because of that, that timing, we may be able to use preemptive treatment. We may be able to. We may actually start treatment in advance and then carry it through the days that you would normally anticipate it. The diary, it's an effort that not only empowers patients, but it really helps guide decision-making. Yeah. I like that you're talking about this because it's a great call-out to patients for why you want to invest in this effort. Let's admit it. It's a bit of a pain to have to fill out one of these diaries. It is. To have to write down what time you go to bed, what time you wake up, when your period starts, how long it lasts, what the characteristics of it are, when you have caffeine, when you have alcohol, when you work. I mean, that's a lot to keep track of. It's a 20-minute added burden every day. And I thank people for it. Yeah. I said, listen, I know you're putting in effort. But it pays huge dividends. We don't need to go through every single lifestyle adjustment because all the ones that are in the obvious category are worth stating. Everyone who has sleep apnea should have it corrected. Everyone should exercise. Everyone should moderate alcohol intake. Everyone should be sleeping a certain period of time. Everyone should be trying. Everyone should be trying to fix bedtime and wake-up time relatively. Everybody should be doing circadian health, et cetera. Is there any non-obvious lifestyle thing that you can think of? A couple of things that I would think about that. So one is, I'm not sure when I see patients whether every risk factor is weighted the same way. There may be some that if somebody is not getting enough sleep and insomnia is quite common in people with migraine, that we may be able to try. We may be able to try the best medications in the world. But if they're not addressing that, it's going to get harder to get that under control. I think the regularity. Migraine has that hypersensitivity. And so if people are adhering to routine meals, drinking enough water, exercise, getting appropriate sleep, which is not so easy because sometimes they have to employ non-medication approaches, which are hard to do, but ultimately pay dividends. I think the important also thing that people may not think about is that stress. Stress reduction, whether it's meditation, biofeedback, cognitive behavioral techniques. Autonomic control. Correct. I think people, not everybody, but I think some people sometimes focus on the medications and don't realize it's a holistic approach. It's looking at the whole individual and trying to kind of present those lifestyles in the way of being able to end up helping their migraine and making them feel better overall. Yeah, and as you said right there, it's a double win because if we get those things right, it's actually a benefit outside of the realm of your headache. All those things are actually just better for your risk of chronic disease, your health span and other capacities as well. So let's now talk a little bit about pharma through both lenses, the prophylactic lens, the things that you would have somebody take all the time to reduce the probability or severity of an attack. After that, we'll talk about the treatments that you would use acutely as a rescue medication. We're going to do it by class of drug. We can talk about it by class. We can also, then talk about it by pros and cons of each drug, success rate or things like that. I think I would start off first by saying, what are the goals of preventive therapy? Because I think that's important for your listeners to know. The idea of using prophylaxis or prevention is not to cure headache, it's not to cure migraine, but to ultimately reduce the frequency, intensity or duration of attacks. It also helps improve potentially responsiveness to acute treatments. It can, by using prevention, you can reduce disease burden and you can end up reducing progression of migraine. So as I said, people who experience more frequent migraine are at greater risk for developing even more frequent migraine attacks. It could end up improving other comorbidities. So some prevention may be helpful with sleep. Some prevention may lead to potential for weight loss. And so you may be able to leverage some of those benefits as well. The other thing is, is it improves functionality and quality of life, which is obvious. But it also ends up helping reduce interictal burden. So that was one of the things I was talking about where people have this almost anticipatory anxiety. So there are multiple goals for using prevention. The indications for using a preventive medication are as if somebody is experiencing frequent attacks or attacks that are very disabling, even despite acute treatment. If somebody has rare types of migraine or headaches that may limit their ability to use certain acute treatments or if acute treatments are either contraindicated, poorly tolerated or ineffective. And so that's where some of the indications for preventive therapy. The preventive therapy come into a number of classes, which you're alluding to. Before we do that, Brian, just to close the loop on that point. Overall, all comers of people who suffer from migraine, what percentage do you think do not meet criteria to justify the drug burden of a preventive drug? So I would say, probably about 40% or so of people with migraine may be eligible for prevention. Eligibility is, I don't just mean through the lens of reimbursement on insurance, but in your mind, medically justified. 40%, yes, 60%. They don't have it enough or it's not severe enough to justify. And we can do enough good with an acute medication. Once again, looking at population-based studies. Yeah, your population is going to be totally discused. The hard part is that the discrepancy or the gap, if you will, where 40% of people may be eligible based on indications for migraine prevention, but only like 16% or 17% are actually receiving preventive therapy. And how much of that is economic where their insurance companies don't cover? These drugs can be pretty expensive. Yeah, so I think it's varied. I think it may end up being that it's not recognized by the treating clinician and it may be economic. So I think there are a number of different factors. And then what about on the cluster side of things? At the population level, what percentage of patients does it make sense? For them to be on prophylactic therapy? Again, in your population, I'm sure it's much higher. I'm going to say even outside of my patient population, the vast majority. So unless the cluster period is a week, which is not the norm, if it's going on weeks, months, yes, the vast majority of those people are going to need, every one of them, I would say, are going to end up requiring a preventive therapy. And then on tension headaches, presumably none? So it depends. So there are people who experience episodic, tension-type headache, less than 15 days per month. And then there are people who experience chronic tension-type headache. Oh, I didn't realize that, okay. That experience 15 or more days of tension-type headache per month. It depends on the frequency responsiveness to acute treatments that are being used or other modalities, and then functionality and impact on quality of life. Okay. Let's talk about some of the drugs that are used to reduce risk here. So let's start with beta blockers. That's literally one of the only things I remember is that triptans and the beta blockers but I think the triptans are for acute. But anyway, let's start with beta blockers. I remember that from USMLE studying. Is that still used? Yeah. Okay. Beta blockers are a class of blood pressure medications. The exact mechanism how they work isn't known. It's postulated that it may have effects on the sympathetic aspect of the nervous system. And so two of the beta blockers that are FDA approved are propranolol and timolol, but there are other beta blockers that are used as well. They can be very effective for people. Once again, there's caution if somebody has asthma So there are different types of beta blockers, so it can potentially exacerbate asthma. Potential side effects include lowering of blood pressure or heart rate or exercise intolerance. That's the other reason why I say it's really important to understand the person so that you're using a preventive treatment that aligns with that person, their lifestyle, their risk factors, their comorbidities. But yes, that can end up being helpful. And that's mostly for migraine. Correct. And then what about antidepressants? Yeah, so antidepressants have been used for years. Which is a dumb term, by the way. I can't stand, I cannot stand that that class of drug is called antidepressant. I'll save that rant for another day. No, I think it's an important rant. And what I explain to patients is there are supplements or medications that are used for prevention of migraine that weren't specifically designed for migraine prevention, but through serendipity or studies were found to be helpful for migraine prevention. And by using one of these medications, it doesn't mean that they have high blood pressure. It does not mean that they have depression. Yes, we know depression or anxiety can exist at a higher than expected by chance in migraine. But please, they should not assume that that's the indication that I'm using it for. My gripe goes even further, Brian, because I actually think some of the things that antidepressants, quote unquote, work best for are not even depression. It's not even dysthymia, anhedonia. I actually think when you look at mood stabilization, anxiety, migraines, those are places where they can really work. And the stigma that goes around the drug prevents people from utilizing it. It's just infuriating. I agree with you. Migraine itself has its own stigma. But yes, I think there's a high degree of stigma. And that's why I explain to patients, even in using this class of medications, this antidepressants, the doses that are often being used are not even doses that would be starting doses to treat depression. And so that's why I like to make that distinction, let them know that if we're using a medication like amitriptyline and nortriptyline. Often the doses we're using are much lower than what would be needed to treat depression. And rarely are these medications used to treat depression anymore. So they can be very effective. One of the potential side effects could be some tiredness. And so usually there are medications that are taken before they go to sleep. And because if somebody has difficulty falling asleep, that potential side effect of tiredness may actually be helpful, not for every patient, but for a number of people with migraine who have insomnia. Do we have a sense of? Of why? Presumably it ties to serotonin and norepinephrine. Is that basically our belief? Yes. Okay. And then what about on the anti-epileptic side? Talk about getting a patient anxious, right? It's like, we're going to give you a drug for epilepsy. Yeah. Yeah. Is that GABA related? What do we think is the pathway there? I think it depends on the anti-seizure medications to then are FDA approved or to pyramid, which is known as Topamax and valproic acid known as Depakote. These medications have different mechanisms of action. So for to pyramid or Topamax, that can work on particular channels, which is what you spoke about early on, but also has effects on glutamate and GABA. And so glutamate is the excitatory neurotransmitter in the brain. GABA is the suppressor, if you will. That can be very effective for people who have migraine. So does it enhance GABA and suppress glutamate, presumably? So yeah. Yeah. That can be very effective for people, but it does have like every other medication potential side effects. And then valproic acid. Valproic acid or Depakote, once again, can have effects on GABA as well. That medication also may be helpful, but also has potential side effects. And it's really important that we go back to the patient population where I have migraine, so I'm not only sympathetic, but empathetic, but the vast majority of people who have migraine are women. And so it really becomes important when we're thinking about women during their reproductive years, if they're sexually active, what form of contraceptive they're on. That's another piece of information that becomes important in setting. I'm trying to avoid then, or at least counsel patients on the possibility that some of these medications may not be safe during pregnancy. So I want to understand that piece. I didn't realize you had migraines, by the way. So did you have them even at the time when you were a neurology resident? Do you think that's part of what allowed you to take such a good history? So I did have them when I was a neurology resident. I'm not sure that ended up giving me a leg up on taking a history. And the reason why is many people that I see with migraine, who experience it, they know what it feels like. Often it's hard for them to put into words. They have to like pause, reflect, think about their answers. Not always, but some people. I really like the fact that it's a group of people that I can really help. And sadly, there are not a lot of people that have the knowledge or information on how to do that in a systematic fashion. Okay. The class of drug that I remember when it came about. Were these monoclonal antibodies. In fact, the patient that we keep referring to, I remember being one of the first patients on it because you got her into a clinical trial and it was a resounding success. Can you say a little bit more about these drugs and their utility today? The class of what are called CGRP or calcitonin gene-related peptides. I think in order to be able to speak about the class, I'd probably have to give a little bit of background on the pathophysiology of migraine. Absolutely. And this is a podcast where we don't shy away from depth. So treat this as though you're giving a lecture. Okay. Always trying to understand my audience. I'll speak a little medicalese and speak English at the same time. We're 25% physician by audience, by the way. I love it. It's crazy. I love it. The brain itself is insensate. It's not pain-sensitive, but the coverings around the brain, like the meninges or specifically the dura and the blood vessels that are both within the dura and in the brain have pain-sensitive nerve terminals, nerve endings. Every nerve that's involved in migraine is the trigeminal nerve. If we go back in time to probably the 1940s, the thought of migraine is that there was a vascular hypothesis where the thought about migraine is it was purely a vascular phenomenon. There was dilation of blood vessels that occurred during the pain phase and then a constriction that occurred during the, so to speak, recovery phase, if you will. With the advent of increasing research, particularly over the past, I would say, 50 years, we know that model is just too simplistic. So now we know that it's a neurovascular phenomenon. And so that there's involvement of not only the nervous system, but the cranial blood vessels as well. And so what ends up happening is that these nociceptive or pain-sensitive information is conveyed from these pain-sensitive structures, so the dura mater, that covering around the brain and the dura and intracranial blood vessels. And then it relayed back centrally along a nerve called the trigeminal nerve that has a problem. And that pain-sensitive information, which is primarily along the first division, the ophthalmic division of the trigeminal nerve, passes through an area called the trigeminal ganglion and then synapses or connects in an area of the brain stem called the trigeminal nucleus caudalis. That pain-sensitive information is carried back there. At the same time, nerves that supply sensation to the back of the head, the neck, and the shoulders from the upper cervical roots in the neck, so C1, C2, C3, carries information back. C1, C2, and C3 into the same area of the brain stem, which is why people with migraine often will have associated neck pain, or people with tension-type headache will have associated neck pain, where they may not realize that it's a referral pain pattern because of this convergence of information. Now, when those nerves become stimulated, people can experience peripheral sensitization. If they're turning their head or bending down, they can get a throbbing type of feeling that can occur early into a migraine. And when pain-sensitive information goes back to the brain stem, if there's sustained firing of nerve cells, people can get central sensitization. And one clinical marker for that, that presentation, is the phenomenon of valadynia, that uncomfortable sensation to things that normally aren't uncomfortable. That's the putting the hair back in the tight ponytail and brushing hair. That generally will kick in about 30 to 60 minutes or so into a migraine headache. And then using triptans during that time may be less effective. So that's the reason why knowing if somebody experiences that with their migraine becomes important when you're advising them when to treat. And we'll come back to the triptans when we talk about acute treatments. Yeah. And then that pain-sensitive information then travels from the brain stem to the thalamus, which is kind of the sensory processing area of the brain. So there's some nuclei like ventral postomedial thalamic nuclei that are involved. And then from there, gnosis of the information then goes to the sensory cortex of the brain. Now, while this is all occurring, there's a cascade of events that occurs. So that trigeminal nerve information has a reflex with that parasympathetic information in the brain stem, which is why people can experience those autonomic symptoms, the tearing, the redness of the eye, the congestion or running of the nostril. At the same time, parasympathetic innervation is relayed to the cranial blood vessels, the blood vessels within that dura mater, with that covering around the brain and the intracranial blood vessels. And people can experience dilation of blood vessels and the release of chemical messengers or neurotransmitters. So things like substance P, neurokinin. I haven't heard substance P in years. Okay, yeah. I'm happy to bring you back. And then there's the calcitonin gene-related peptide, or what's known as CGRP. At the same time, there's a pro-inflammatory response that occurs, what's called neurogenic inflammation, and then a release of histamine, male cells, nitric oxide, once again, a full cascade of events. This becomes important because through studies that have been done over the years, studies that looked at jugular venous blood noted elevations of CGRP during migraine, that calcitonin, gemelio, peptide, those studies led to the possibility that this may be a target for migraine treatments. And then when sumatriptan or imitrex came on the market, there were studies that looked at patients who were treated with it and what happened to their CGRP or calcitonin, gemelio, peptide levels, and they normalized. So meaning they were increased during migraine and then the use of sumatriptan would end up normalizing levels. And so there was like that aha moment. And that's what led to the class of what are known as CGRP antagonists. And the CGRP antagonists are kind of broken down into two buckets. One are what are called large monoclonal antibodies, which is the medication that our patient was placed on. And then small molecules, what are known as GPANs. So that's kind of the history that led into the formulation of that class of medication. These are drugs that are administered intravenously at what frequency? The CGRP antagonists, the large monoclonal antibodies, three of them are self-injection medications, almost like EpiPens. And those medications have a long half-life. So roughly about 28 days, they're administered. In a monthly fashion or every 28 days. And that's the three of them. There's one that's actually given quarterly as an effusion every three months. Any difference in efficacy? Varies from person to person. There are no large head-to-head studies of these medications. That's the challenge with being able to end up using data to end up answering that question. So basically you might start with the home use pen because it's easier. I assume it's cheaper. If you're failing those things, you would have to just go with the quarterly infusion. Right. So that's one reason. The other reason is what the insurance will dictate in terms of what they will allow me, the clinician, to prescribe. These have changed the game though. Obviously I'm biased perhaps by my small, small sample set of the patients I know that have had a significant improvement with these. But across your clinic, which is very high risk, but obviously very diverse, how much have these been an improvement in mitigating onset and severity? Significant improvement. The biggest change you've seen in your clinical practice? Yes. Wow. It doesn't mean that they work for everyone. For what fraction of patients do they not work? So they probably work for up to 60% or so of patients with migraine. That's why I say sometimes there is trial and error. The other thing is there are some people that will be much quicker responders than others. So some people will get benefit within the first month with these medications. Other people may take up to three to four months. And when you say 60% success, does that mean 60% of patients who take this drug regularly will no longer suffer migraines? No. There's a spectrum. Uh-huh. So it's like oncology where success is a partial response, a complete response, and you're including the partial response in here as well. Correct. In oncology, a partial response has a very specific definition, which I won't bore listeners with. How are you defining a partial response? Based on what information the patients are providing me. Doesn't have to be at least a 50% reduction? Correct. Correct. That would be wonderful if I could end up providing people who have 30 days of headache per month for 20 years, a 50% reduction. But sometimes the timeline, and once again, it's usually a multidisciplinary approach that I'm employing in order to be able to continue for building on incremental gains. As difficult as it might be to get this data from a patient, unless they're very good at logging it and their temporal history is very consistent, are there people in the 40% group that we're considering? Non-responders who have no abatement in frequency, but severity does go down and or responsiveness to acute treatments improves. Or does that automatically put them in the 60% bucket? For me, I'd probably put that group into the 60% bucket. But once again, there are people that will get variable ways of getting improvement. That's why the diaries become very important to understand. Yeah. Sorry to just harp on this, but given the importance of it, when a patient does not have success on this drug, do you have a sense that most people will have the ability to progress through all of them so that we know that, hey, if you're going to fail this treatment, you've failed the class? No. I'm very happy that you're raising this point. If somebody doesn't respond to one of the treatments within the class, that does not dictate that they're not going to respond to another treatment in the class. And the challenge becomes is I can't tell by looking at somebody if they're going to respond to. One medication in the class versus another. We don't have biomarkers, and so we can't end up telling. But ultimately, I do tell people that if one may not work, another one may. Again, it's an important lesson, I think, for clinicians, although I would hope most people understand this. Whenever you're using these monoclonal antibodies, by definition, because different drugs have different patents, they have to have different IP, meaning they can't be the same molecule, which means they could be binding to different parts of the epitope. And therefore. When you look at a person's genetics, and not everybody has the same receptor, as an example, and therefore, just because one drug doesn't bind perfectly doesn't mean another one won't. We see this, by the way, with PCSK9 inhibitors in the lipid space, where if you don't respond to one, you might respond to the other and vice versa. Super interesting. You mentioned the oral equivalent of these as well. Yes. So there are oral medications that are known as GPANs that are small molecule CGRP antagonists. These medications have shorter half-lives, and there are fewer of them. There are a couple that are oral, and there's one that is a nasal spray. These medications can be used acutely when somebody ends up having a migraine. One of them has an indication both for acute and preventive treatment. Yeah, that's autogepant or something like that? A togepant. I can't even pronounce the drug. That's okay. That's okay. That is for preventive treatment. That's not one that you can use acutely. No, that would not be used acutely. Remedgepant, or what's known as Nertek, has an indication for preventive and acute treatment. Gubrogepant or Ubrelvi, which is another medication in that class, has an FDA approval for acute treatment to migraine. Got it. Do you have a sense, by the way, what the out-of-pocket cost on these drugs is? They're expensive. All of these medications are expensive. Thousands of dollars a year, I'm assuming, if it's based on other monoclonal antibodies. And then do you have a sense of what patients are getting? Patients that come to see you, do you have insurance coverage on these? It's variable because there are so many plans. And then within the plans, there are high deductible, low deductible, big co-pays, low co-pays. Yeah. That's the biggest frustration, I would say, both for patients and for people like myself who are caring for them. Yeah. And if it's like every other drug in the United States, we're paying probably three to 10x what the rest of the world pays for the same drug. Yes. Some of these drugs get so expensive that it's cheaper to fly out of the country to get the drug and bring it back. I have patients who do that, and I have patients who live outside the country. They have an easier time in some respects of getting these medications and paying for them. I used to take care of a patient with type 1 diabetes who used to fly to Europe to buy his insulin. And it was still cheaper to fly first class to Europe, stay at the Four Seasons, buy his three months of insulin, put it in a cooler, fly back. He saved money doing this. Can you just imagine the absurdity of this? Sadly, yes, because I have patients who fall into that category. I think the hard part also is maybe the short side, if you will, meaning the cost of these medications may be very expensive, but- It's trivial compared to the economic cost. The personal costs, the trips to emergency rooms, the loss costs and insurance of people at work. Loss work time and productivity. I mean, it's just, it's short-sighted, I think. Rounding out this list, calcium channel blockers and Botox, correct? Yeah. Yeah. Let's talk a little bit about those two. So calcium channel blockers doesn't have as much data for prevention of migraine. More classically, it's used for prevention of a headache like cluster headache. But still, people may end up using calcium channel blockers, which is a blood pressure medication for prevention. And they're doing this at a lower dose, I'm assuming as well? A lower dose, but sometimes the doses are increased, particularly in patients with cluster headache. So what do you do if you have a normotensive person with cluster headaches? How do you treat them with verapamil? There are some patients that I have where, usually in collaboration with a cardiologist, there's one patient I'm thinking of that I just recently saw where this person was on at one point over a thousand milligrams of verapamil. And for your audience to know, that is an exceedingly high dose. Once again, EKGs need to be checked. Blood pressure, pulse needs to be checked. Tolerability needs to be checked. But that was the dose that was needed, and that person tolerated it amazingly. And obviously, it reduced significantly the frequency of cluster headaches. Correct. This is the trade-off in pharmacology, right? Right. Nothing comes without a side effect, but the side effect can often be well worth it. And then you mentioned Botox. Botox. See, when I think about Botox, I think about tension headaches, but does it also play a role in migraines and clusters? Surprisingly, Botox doesn't work. doesn't work well for tension type headache. - Okay. - Yeah. It's a good thing I'm not a neurologist. Okay, you have me on set, so I'm more than happy to help. Serendipitous finding that Botox was helpful for migraine. There was a plastic surgeon, Bill Binder, in California, who was giving it to patients cosmetically and then was told by patients that, you know, my headaches are getting better, my migraines are getting better. And that's actually what led to Botox or onobotulidum toxin being studied for prevention of migraines, specifically chronic migraine. So that's whereby people experiencing 15 or more days of headache per month, that's where Botox has mostly been studied and where it has the current FDA approval for that. And so it's not by cosmetic effects that it works, but actually it interferes with the release of certain SNAR and SNAP proteins, certain proteins, and also involvement in CGRP, calcitonin gene-related peptide. Once again, we come back. We come back to this. Because of systemic delivery? So it has effects on pain pathways. Pardon my ignorance. Okay, so obviously this was discovered probably on the face and forehead, because that's where he was administering it. Is that how it's administered today? So the protocol went through a number of iterations until the current protocol, which is called the PREEMPT protocol, which is standard across the world, where injections are given in the forehead, on the sides of the head, the back of the head. The neck and the shoulders. And they're given around areas where there are superficial nerves. The postulated mechanism is that it may have interference in the release of certain vesicles and certain proteins, called SNAR and SNAP proteins, as well as CGRP, which is that chemical messenger, that neuropeptide we were talking about, heavily involved in migraine. How many patients that qualify for this are able to get insurance coverage? Because they're not going to get insurance coverage. They're not going to get insurance coverage. This would be even more expensive than monoclonal antibodies. I mean, Botox must be insanely expensive. So not necessarily relative to the monoclonal antibodies. Because the monoclonal antibodies. I guess you're taking them every week, whereas you do this maybe quarterly. Right. And the Botox is administered quarterly. Yeah. Okay. The insurance companies won't let me say, oh, of course, Dr. Grossberg, you can end up prescribing Botox. You think this person has chronic migraine. Often they will ask me or mandate that I have to try and get it done. I at least two or three conventional non-migraine specific preventive therapies and either try and fail or been poorly intolerant to them before they let me end up looking at Botox for prevention of chronic migraine. Got it. Okay. So let's talk about the rescue drugs. You're now in the throes of a headache. What can you do? So there are many classes that we end up using. There are non-migraine specific classes and then there are migraine specific classes, non-migraine specific. So. Yeah. Analgesics like acetaminophen, non-steroidal anti-inflammatory drugs like NSAIDs. Do opioids play any role here? Notwithstanding the loaded nature of addiction and things like that or dependency. We go back to the risk factors for migraine chronification and one of the risk factors is medication overuse. And the two largest culprits for the possibility of medication overuse are opiates and barbiturate containing combination analgesics like Fioricet or Fiorinol, which is even banned in some countries in the world. And the two largest culprits for the possibility of medication overuse are opioids or this class of medications, the barbiturate containing combination analgesics, even used a handful of times per month, even if it's not for migraine. The nervous system, once again, may not like that and they have a particularly high risk for medication overuse. Is the issue that? In other words, is the issue that if we give patients these drugs, the probability of excessive use becomes high enough, which is itself a trigger? Yes. Or a potentiating mechanism. I see. Okay. So, in other words, you would not prescribe these in your practice. You have enough other tools that you're not going to do that. Once again, opioids for me are a last line after people have explored everything, if you will. Even in the emergency room, we really try to end staying away from opioids just because of this potential. In terms of migraine-specific medications, triptans were the first class that was specifically designed for the acute treatment of migraine. What predated that were the agonamines, which are still used. And so, these are medications that come from a particular type of fungus that have effects on serotonin, which is heavily involved in migraine. And so, they work on not only serotonin receptors, but they work on other receptors as well. Whereas triptans work specifically on certain subtypes of migraine receptors, namely what is called 5-HT1B1D receptors. And the 1B receptors have different effects. Those are on smooth muscle cells, and so they are involved on that aspect. And the 5-HT1D are involved in some of the chemicals that are neurotransmitters that are released. And so, triptans, the advent of them really ended up was a game changer for migraine. And even now. 20, what, 30 years ago? We're probably going back to the 1990s. Yeah, mid-90s maybe. Yeah. So, ultimately, sumatriptan was the first one. It was in tablet and injection form. It's also available in nasal spray. And then since that time, there are six more that came along. So, there are seven triptans in total. Are these drugs like statins or GLP-1 agonists where each new version gets more effective and has fewer side effects? Not necessarily. So, there are plenty of people. Sumatriptan was the first one. Some people may be sensitive to sumatriptan versus some of the later triptans. One of the potential side effects of triptans is a sense of warmth or heat or tightness anywhere in the body. It's usually short-lived, but for some people, it's extremely uncomfortable. Flush, like a niacin flush? Yeah, like a flushing. And then other people use sumatriptan, no issues whatsoever, right? Like, God made this for me. Some of the half-lives of the triptans may be different. So, there may be some that are quicker onset, some that may last longer. And so, that's where the decision-making makes. Some may come in. Some may be tablet versus a melt versus a nasal spray versus an injection. And so, depending. Once again, going back to that attack profile, presence of nausea, we know that both during and in between attacks of migraine, there can be delayed gastric motility or gastric stasis. So, absorption of medications may be slowed. And so, if I need to think about absorption and rapidity of onset of attack and speed of the treatment and trying to bypass the gut, I may be trying to do that. I may be trying to choose one formulation over another. So, all of these factors help me kind of hone in on the decision-making. Intuitively, my gut says, no pun intended, the intranasal would have more efficacy than the oral. Like, it would go intranasal, IM, then oral in terms of the speed with which they respond. Is there any truth to that? I'm going to switch the order a little bit. So, IM, intramuscular, is actually. Quicker, the sumatriptan is available, injectable. So, the quicker onset sometimes needs to be balanced versus the, so to speak, if somebody experiences a side effect, it may be more heightened than what they're taking as a nasal spray or as a tablet. So, they may feel that flesh in the knee. So, the oral would have the lowest amount of that, given that pharmacokinetics. Because of the pharmacokinetics. And that may be potentially, obviously. This may be different if I'm, let's say, treating somebody with migraine versus cluster headache. So, cluster headache. If I'm using sumatriptan, I'd really love to end up using the injection because the median time to pain relief may be, like, nine minutes. So, for somebody who really needs quick onset because they're having a rapidly onset attack, that's like, God made this for me. It's a preloaded pen that they can carry around with them? So, often it's a preloaded pen that they give themselves an injection. Or if somebody's experiencing a migraine attack at night that wakes them up from sleep or builds up quickly, the nasal spray, that bioavailability that you were talking about, doesn't pan out for all the nasal sprays. So, the sumatriptan nasal spray, and there are a couple of them, but we'll talk about the, not a brand form of sumatriptan nasal spray, but the, so to speak, the generic or the form of sumatriptan nasal spray, the bioavailability is not so great. It's higher in imitrex than it is for generic sumatriptan, you're saying? The nasal spray itself, there are other brand formulations of sumatriptan, like nasal powder, if you will. The nasal spray of sumatriptan, the bioavailability across the nasal mucosa is not so good, so the absorption sometimes is actually by swallowing something that doesn't taste so good. The zometriptan, which is known as zomig nasal spray, which is a triptan, and zavagipant or zavzapret, which is a gpant, once again, that's in the class that we were talking about, that's CGRP antagonists, those bioavailabilities are higher. And so, that's where somebody may end up getting. faster relief. Okay. Success rate for these across all comers? So, looking at triptans, or for any acute treatment, I'm looking at speed of onset, improvement in associated symptoms, functionality, which is very, very important. Generally, the mark of time that's used is by two hours. And then, what's the rate of recurrence or the rate of return of headache either that day or within 24 hours? And certain triptans may have a higher recurrence than others. And so. that's where the decision-making is, used based on all the factors that patients tell me about. Okay. Outside of these treatments, what about any sort of electrical stimulation, TENS, have any of these other things shown any benefit? Yeah. So you're referring to the class of- Or TMS, I'm sorry. I said TENS, but what I meant was TMS, yeah. Neuromodulation devices, right? So the idea of neuromodulation is a stimulus is being used and that stimulus may be in various forms. It may be magnetic stimulation, it may be electrical stimulation that targets some system, if you will, in this case, the nervous system. And there are different forms of neuromodulation that have postulated mechanisms that work on different targets based on the pathophysiology or the anatomy of migraine. So one example would be a device that delivers stimulation to the nerves, the superficial branches of the trigeminal nerve over the eyebrow. So there's a device that will do that. And that works by, so to speak, suppressing pain transmission, if you will, superficially to end up having effects centrally within the nervous system. There are devices that will stimulate electrically the vagus nerve. That can also be helpful for prevention and acute treatment of migraine. What I'm talking about are external devices. These are devices that can be applied or held, not necessarily implanted. I think that becomes a very important thing. And I think that's a very important thing. And I think that's a very important point of distinction. A device like remote electrical neuromodulation, which is an armband device called Nerevio that is worn on the arm that's operated by an app on the phone that delivers a level of stimulation to a nerve in the arm that relays messages to the brain that uses the brain's own natural mechanisms to downregulate pain. And that's used as a prevention or a treatment? That particular device has an indication for prevention and acute treatment of headache. How successful is it? Across neuromodulation, there are varying successes. There are no head-to-head studies of these devices where medications have to be FDA approved. Devices get FDA cleared. Our headache center was actually the lead site in the world that led to that FDA clearance for that armband device. And so once again, depending on the study, the benefits are pretty significant depending on the patient and the attack profiles, if you will. Are these devices expensive? They can be depending on the devices. So some of them are bought, like the device that's worn on the head that delivers stimulation. The device that applies vagal nerve stimulation is actually kind of like rented or leased. And so there's a monthly payment for that. The armband device has a certain number of treatments within a month. And so that's purchased or gets some reimbursement through insurance. And then there's another device that delivers stimulation both to the nerves in the front of the head as well as the nerves in the back of the head that can be purchased or quote, rented or leased as well. Are you under the impression that a lot of patients who are suffering from headaches don't even know these devices exist and therefore they're missing out on another therapeutic opportunity? Yes. The devices themselves may be used either as first line or in conjunction or as rescued, depending on the person and their attack profiles. I think the hard part becomes is some people are coming in waiting for a prescription in the form of a medication. Some people, because of the cost prohibition, may not want to end up looking at devices. But there may be other people that have preferences. I prefer not to be on a prescription medication to the extent possible. Can we try nutraceuticals or supplements? Could we end up trying neuromodulation devices? If it's somebody who may be looking to get pregnant, we may for that, aside from patient preference, but if we're looking for a prescription, we may be looking for a prescription. So if we're looking for a for people who are in that period of time, and during that time, even though the devices have not necessarily been studied during pregnancy, one of them has for acute treatment, knowing their mechanisms of action, they're not associated with medication, it's presumed that their safety and tolerability would be okay during that period of time. Do we know anything about THC or cannabis directly? It's interesting that you asked that. I hear mixed things, right? Yeah. So we actually ended up doing one of the largest studies looking at THC and cannabis. And I think it's a good example of that. We're looking at use in our patient population, an academic headache program of people using cannabinoids. And what we found, which was about a third of our patient population are using cannabinoids. And so the hard part becomes, it's not, not everybody's using- And in the study, did you standardize the vehicle or was it an outpatient- Outpatient survey study. It's next to impossible because- We have no idea what they're using. Roots, formulations, combinations, right? It's very hard. The other challenge because even those people who say that they may get benefit, the question becomes is- What else are they doing? Right. What else are they doing? Is it direct benefit for headache? Is it indirect benefit by helping with sleep or anxiety that may be comorbid with migraine? So I think that's the hard part to tease apart. The other challenge is sometimes it's hard to advise patients because we don't know about the potential drug-drug interactions. So no one's done or is doing an RCT where you're using a pharmacologic consistent grade of THC and trying to identify the actual effect of the active agent delivered in a standardized way. There is a study that was done that looked at it for acute treatment of an attack using one formulation because of regulatory concerns. These are really hard studies to implement. There's a company right now that is also looking at doing larger studies in the future on this. So I think those studies will come, but they're going to be very slow. But these have to be done as almost, I think you almost have to have the patient's come in to be administered the drug because it's schedule one. Correct. Yeah, the feasibility is not so easy. Yeah. Brian, is there anything we haven't talked about as far as headaches that people should know from a primary perspective? So I think from a primary perspective, what I would end up saying is people should have hope in the sense that it's very important to be as empowered as possible by keeping a log of information, by providing their clinicians, their treating physicians or providers with the details of their headache and recognizing the importance of those lifestyle factors, which can't be overstated. I often think about an equation of expectations over reality, E over R. What is their reality? How do I try to match it as long as the expectations aren't necessarily exceeding reality? I think it's important for people to take ownership, which is not so easy. Some people will say, you're the doctor, you tell me what to do. I have to say, well, we're partnering together. This is a partnership. Recognizing that preventive medications may take weeks to months. I often say that this is not Amazon Prime. I know we live in Amazon Prime Society. Everybody's used to next day delivery, but often good things come to those who wait. We're building on incremental gains. And so I'm sometimes cheerleading people, if you will. Then in thinking about the overall frequency of attacks, knowing that preventive options, sometimes people need one, one or more preventive medications. It's not one size that fits all. So it really is a very tailored approach. For acute treatment, it's also knowing and for clinicians to know that not everybody is necessarily going to respond to one acute treatment. They may need a backup. They need a rescue treatment. So I think that's important. For patients who are very debilitated, there are also intravenous medications that can sometimes be used to try to suppress a prolonged attack that may be known as status migranosa. Where a migraine is occurring for longer than three days, like that first patient I was telling you about who had a prolonged migraine for six weeks. And then recognizing that ultimately at the end of the day, it's a marathon, not a sprint. I just want to spend a minute on secondary causes because I want to make sure that people understand that if you're having a headache for the first time or a headache that's not well characterized and documented as one of the ones we've spent the last couple hours on, you're not missing something medically. So when a person experiences a headache, not to create fear, because I'm guessing most of the time, 99 times out of 100, it is not going to be a mass effect or a vascular lesion or something. But I'll give you an example of something that has now come across my radar twice, meaning I've known two people in the last year who have had CSF leaks. One was traumatic. So they fell skiing. And then over the ensuing months, they just kept getting these headaches. And it took months to figure out, oh my God, I'm going to have a headache. You have a leak of the CSF and we're going to go down the path of fixing it. In the other case, it was an individual who had a spontaneous CSF leak. And you can imagine how long it took to figure that out, which says nothing of how difficult it was to treat that. So I don't know, do you want to say anything about CSF leaks? My bias is like, oh my God, these are occurring all the time, but they're clearly not, but they're debilitating and they're easy to miss. I think maybe if I could provide some, pieces through the mnemonic that people should be aware of that may raise concern. So if somebody is having new onset headaches or a change in the headache pattern, that may be something that they want to speak to their doctor about. If they're having associated fevers, rashes, a headache that's painful to flex their head and touch their chin to their chest, that may be signs of something that's concerning. If somebody is having unintended weight loss, that may be a reason to those systemic symptoms. If somebody is having new types of headaches or change in a headache pattern during pregnancy, once again, migraine can occur during pregnancy, but as a general rule, migraine without aura improves during pregnancy. And so probably about 47% of people notice and women notice improvement in the first trimester and then 80 to 87% or so in the second, third trimester. I think that's estrogen related, presumably. Yeah. Once again, if it's worsening, there are people who can have new onset migraine where migraine may not improve. But if that's the case, that would be something that I would look at a little bit more closely. If people are on medications that suppress their immune system and they're starting to have headaches or experiencing more frequent headaches, I'd look at that. If somebody is having neurologic symptoms with the headache, so weakness, numbness, problems with speech or language, double vision, loss of vision, problems with balance. If somebody is older than the age of 50 with a new type of headache or a change in the pattern, we have to think about secondary conditions. One of them being temporal arteritis. Most people who experience this are older, but sometimes the misconception, is that the pain is just in the temple because it's called temporal arteritis. But the pain of that headache could be anywhere in the head or face. And then is the headache thunderclap? Does the pain peak at maximal intensity within seconds to a minute? That can be what's referred to as a thunderclap presentation. Sometimes a CSF leak can actually present as that if it's a spontaneous leak, not always. And then we get to the other factors like, is the headache specifically provoked by cough, exertion, sexual activity or sleep, there's a positional component. Often people with a CSF or cerebrospinal fluid leak may have a positional component to their headache, such that if they sit up or stand either right away or a quote, second half of the day syndrome, meaning as the day goes on, they start developing a headache. That can be issues. Sometimes people with a CSF leak can have intrascapular pain, so pain that develops in between the scapula. There are a myriad of manifestations which makes it so difficult to get rid of that headache. And then there's a second half of the day syndrome, meaning as the day goes on, they start developing a headache. That can be issues. There are a myriad of manifestations which makes it so difficult to diagnose and treat. It's people like myself ultimately and others, other colleagues of mine that may be seeing patients like this. That's why Duke has a CSF program, right? That's one of the programs that's dedicated specifically for patients like that. Well, Brian, this was really interesting. Incredibly grateful for the work you're doing with patients, but also just really grateful for you taking the time to come out here and be away from those patients for a couple of days to have this discussion, because I think a number of them are going to want to come and see you. What is the wait list like for people to come and see you? Obviously, when there's only so few doctors doing what you're doing, I know how difficult it is to get in to see you. Yeah. So me personally, when I moved to Connecticut about 10 years ago from New York, I would say probably the vast majority of those patients I was seeing in New York who were driving or flying are now just coming to Connecticut, which is humbling and flattering. The hard part becomes is I want to take care of everybody, but it's hard. So my personal wait list is actually quite long, but there is a lot of people who are coming to see me, and there's a link that people can go on. Often if people live out of the state or out of the country, I'll ask them just to have like a local physician that can help with prescribing medications and be able to help implement the plans. Thankfully, I have other great colleagues as well, and so- In your practice? In my practice, yeah. Yeah, we're probably one of the largest programs in the country. Got it. Okay. People can get in the door into your practice, and if it's anything like my practice, seeing one of my colleagues is no different than seeing me. Right. Is it the same with you? It's the same with my colleagues who have the same philosophy. I was very fortunate to have great mentors, and so- But can they curbside you? Yes, they can curbside me. Yeah, yeah, yeah. That's sort of what I mean. It's an open system. It's a collaborative system. Yeah, yeah. Awesome. And then again, I think encouraging people to go to the site, we'll link to your headache journal so that anybody, whether they're going to see their local doctor or ultimately coming to see you, should really, really, as you said, put in the time, the effort, 10 to 15 minutes, 20 minutes a day that it would take to really accurately log this for a month because you're going to get better treatment. At the end of the day, it's just going to improve the quality of your care and your outcomes. So, Brian, thank you again. This was really exciting. Thank you so much. Both for the physicians listening, but I think of the hundreds of thousands of people that are not physicians that are going to be hearing this on their podcast player, something I encourage you to do with other podcasts is get a good podcast player and find the time when you're exercising or driving to listen. Please share those with me. I will share for sure. I look forward to it. All right. Thank you, Peter. Thank you, Brian. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services. If you have any questions, please feel free to reach out to me at peteratiamd.com forward slash show notes. I look forward to hearing from you. Thank you. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.