406 ‒ Migraine, cluster headache, and tension headache: symptoms, causes, prevention, and treatment

Key Takeaway

Start a one-month headache diary today. Record headache days, onset and duration, severity, light/sound sensitivity or nausea, sleep and wake times, caffeine, alcohol, meals, exercise, stress, menstrual timing, and medications used. Review it for repeatable patterns—such as delayed weekend caffeine, irregular sleep, or menstrual timing—and bring it to your clinician. This low-tech record can distinguish headache types, identify modifiable trigger combinations, and enable a tailored acute or preventive treatment plan.

Episode Overview

Peter Attia speaks with headache specialist Dr. Brian Grosberg about distinguishing migraine, tension-type headache, cluster headache, and secondary headache causes. They cover migraine phases, hormonal and lifestyle influences, the value of headache diaries, red flags requiring evaluation, and treatment options ranging from acute medications and prevention to CGRP-targeted therapies, Botox, and neuromodulation devices.

Full Transcript

Transcript of 406 ‒ Migraine, cluster headache, and tension headache: symptoms, causes, prevention, and treatment from The Peter Attia Drive Podcast. Auto-generated from episode audio; may contain minor errors.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Aia. Brian, thank you so much for 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, um, but that you've never listened to a podcast. Makes me a unicorn. Yes. Yes. So, okay. Um this is a topic that I think just affects so many people. Um I want to maybe understand the landscape a little bit about the field of neurology.

What fraction of neurologists specialize in headache and and 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. Um so I think it's important to understand that headache is one of the most common neurologic symptoms. um nearly at some point in in every person's life, they're going to experience a headache. Um surprisingly in medical school, uh maybe medical students and residents get a few hours across entire medical school of 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 anything. Yeah. And it's um and so that's a a a gap in education. And then in neurology residencies that is similar where people are only neurology residents are uh depending on the program of course may only get a few hours of headache lectures or education and then they're experts. And so uh for my um journey if you will into headache medicine was actually by accident complete serendipity.

[clears throat] Uh my first year of a neurology residency, I took care of a litigator who was out of work for six weeks uh due to a prolonged migraine that had been going on for 6 weeks straight. And without knowing u the person who was caring for her turned out to be my future mentor and so I had called this person and um you know you were a resident at this time. I was I was a resident. I was probably a month into my neurology residency.

So, it was really early on and um saw the patient, took a history, read up on it, and then detailed the history to him and he said, "Are you um you know, 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 great. Um why don't you come by my office and let's talk." Um and so I did that and um I got very interested in seeing patients with him. He offered to see patients with me.

residency at that time. Uh the uh 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, um I would change out of uh 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 um expedited, if you will, during my residency. And then from there after I finished um I pursued 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 with the fellow who had 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 you must have had some intuition about this that that allowed you to take a history that elicited enough information that this doctor felt like wow you're a seasoned pro at this any idea thinking about what it was that allowed you to have because if if if I saw a patient with headaches I don't think I could ask two intelligent questions like uh you know how long has it been aching and what part of your head and is it thro like I I wouldn't ask a single smart Smart question.

I'm sure you would. Uh I once again in reading up about it um uh I was able to end up obtaining the features and characteristics. What really struck me um was the fact that she was so debilitated and that she was coming into the hospital and receiving treatments leaving the hospital completely headache-free. Uh that for me was uh an epiphany if you will and um it led me to end up thinking about something that is if you will an invisible disease um that I wasn't really getting a lot of education during necessarily during my neurology residency up until I started pursuing it.

Um you know led me into the field today. So Brian, we met 10 not met but communicated over email 10 years ago. Uh I can't believe it's been that way. It's kind of amazing, right? Um obviously through how all doctors meet through patients, right? 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. Um 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.

Um 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 where you know 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 a interesting perk to me. And so many of the amazing doctors I've met are exactly this way, right? 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 throughine to understanding this patient's uh migraine situation and 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, cuz the only person I'm going to send you to is Brian." when it comes to headaches. So, thank you for that. Thank you. Um, let's 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 biioarker for headaches, right? We don't have a finding on a CT scan or an MRI that says, "Oh, this is what's hurting you." And it's, you know, 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. You know, if you twisted your knee badly enough, I would be able to see which ligaments were damaged.

Um, this makes the entire field of neurology challenging, but I would guess that in the uh frequency with which headaches are a problem, it's unusually challenging. Yes. uh the field of headache medicine is actually quite challenging and and part of the reason and you stated it very articulately is the fact that um the MRI doesn't always tell us the diagnosis and often doesn't and so um headache is really the is a 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 um and there are a litany of things that can cause headache.

Um the differential diagnosis, the list of things is probably one of the most extensive in all of medicine with over 300 different types and causes of headache. And so the um the international classation of headache disorders uh kind of like the Bible of headache but with no mention of God in it um breaks down primary and secondary headaches. U primary headaches is a a headache in of itself. It's a syndrome, right? It's not attributable to some other underlying condition. most commonly migraine or tension type headache, cluster headache or their primary headaches.

And you're right that there are um there really aren't biomarkers, right? There aren't substances that we can detect, if you will, that tell us this is what the diagnosis is. And so the diagnostic criteria are um are outlined and uh they always say not attributable to another disorder. The secondary headaches are headaches that are attributable to some other underlying condition, right? um where people will ask me, Dr. Gersburg, do I have a a brain tumor? Do I have an aneurysm? Right? Is there something that's life-threatening um and that's where a detailed history becomes important um to try to um not only understand all the factors but also the person that's sitting in front of me, right?

Because um no person or presentation is identical. So, primary headaches, we'll start with those, but just to uh make sure I'm clear and everybody is clear, does a secondary headache always have a pathologic driver underneath? Because the examples you gave of uh mass a mass effect, whether it be ultimately benign and therefore not life-threatening if removed or malignant. Um that's pathology. Aneurysm of course pathology. Are there any non-pathologic uh causes of secondary headache? Yeah, so there are there are non-lifethreatening [snorts] things that are causes of secondary headache.

Um 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 the resulting increase in the frequency of headache is is attributable to some underlying condition. Caffeine withdrawal would be another example of secondary then even though it's not lifethreatening right and they have pathophysiological and mechanistic reasons for the development of those headaches but nothing that is pathological. Yep. And so I guess I just answered my second question with the example of caffeine. Not every secondary cause has a radiographic or biologic u marker.

Correct. So okay great. So now let's go in the sort of I think you described the big three right migraine cluster and tension headaches those are three enormous categories of primaries and then you kind of have a another category of the um the the 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. Uh migraine is the leading reason why people seek care um either in their primary care office um with somebody like myself or in an emergency room.

Um and so tension type headache is often thought about as a headache that is affects both sides of the head or the face or the neck um where it's mild to moderate. It's not pulsating or throbbing. Um there may be light sensitivity or sound sensitivity but never both. there's no nausea 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 oneand done." And I well a brutal headache I wouldn't uh say that would be tension type. I see. That's something that often people can end up working through. doesn't necessarily impact I see their ability to um to perform activities. Whereas with migraine the diagnostic criteria is where somebody has at least five lifetime attacks um where the attacks last anywhere from 4 to 72 hours either untreated or unsuccessfully treated and then they need to have two of the four following qualities.

Uh 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. Um the pain could be pulsating and throbbing. It could uh be associated with causing avoidance of light uh and activity. Um and then people can have light and sound sensitivity and or nausea and vomiting. So people uh don't necessarily need to have nausea if they have light and sound sensitivity. And people don't uh uh 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 uh one-sided pulsating and throbbing, moderate to severe causing avoidance of routine physical activity. Those meeting those may mean that they have what's called probable migraine versus tension diabetic. And so sometimes the elicitation of the symptoms people who may be light and sound sensitive um they may fall into different categories. So some people will say I'm definitely light and sound sensitive.

Other people you have often need the question reframed right. 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 a darker quieter room? Oh yeah. Yeah. That that makes sense. Does the um 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, um 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 a.m. 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. Um you're looking for level of impact and disability. Um because migraine carries a a very heavy burden not only in personally but also society, family-wise. Um and then uh is there presence of nausea or vomiting? Um most people may not be aware that with migraine and based on the pathophysiology of migraine uh people may have a sensitivity uh referred to as aladenia which is an uncomfortable sensation to things that normally aren't uncomfortable and that's present in about can you say more about what that means?

Sure. Yeah. So allenia is a phenomenon where somebody uh experiences an uncomfortable sensation to things that normally aren't uncomfortable. An example would be um a woman pulling their hair back in a ponytail, brushing their hair, wearing um a tight hat, wearing glasses on the that rest on the rim of the nose or the or the eyes. And that uncomfortable sensation is present in about 2/3 to 70% of people with migraine. The reason why that's important is when people experience this alladenia if they use certain migraine specific treatments like tripans but they wait too long those treatments may be less effective and so that's where sorry to interrupt are those symptoms prodal or so so I I I think to answer that question it would be important to explain that migraine uh is not just a headache there are phases that people experience Um there are distinct phases but they're not distinct.

Um and so sometimes there can be overlap of symptoms. So the first phase is a premonatory phase whereby people experience it's kind of like the calm before the storm. Y yawning, craving certain foods, tiredness, irritability, um light sensitivity, neck stiffness, and that may occur minutes, hours, or even days up to before a migraine occurs. What's the median duration that that's showing up? like yeah so I would say hours yeah hours beforehand and um and that could actually be helpful because then people know how to think about it and there is actually a treatment that was studied during the promontory or what's called the prodal phase um 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 and explain to folks what aura is.

Yeah, aura is a reversible neurologic phenomenon. So, this is whereby there's um a phenomenon called cortical spreading depolarization in English, even though I'm from Brooklyn. Um that's a where uh 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, uh the back of the brain is the visual cortex. So the most common type of aura is a visual aura where people may experience um 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 um spots, black spots, distortions, perceptions. Um and generally this evolves gradually over about 5 to 60 minutes. That's the most common type of aura which the first time it happens must be terrifying. like you must you think you're having a stroke. Correct. And so there are things that need to that can mimic aura and they need to be excluded. And that's the reason why a a detailed history um 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 versus TIA or stroke or something really uh dangerous? Yes. So um so one it's very helpful to know if somebody has a history of migraine. Um so that I think that's one thing that's very important to know. Two is what is um the evolution? Is it stereotyped? this is the first episode or there multiple episodes usually when somebody experiences a TIA or a stroke the symptoms are maximal in onset um where and contrary to or of migraine there's this kind of gradual evolution often over 5 to 60 minutes um and so once again that's helpful to know are there sequential uh 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, um, do people have this sequential, uh, progression, if you will, in their aura symptoms? That's generally not seen in stroke. Um, and so those are helpful points of distinction. Do people end up having, if they have a visual or do they have positive and negative visual symptoms? meaning do they have kind of zigzag lines or um white out uh over half of their world um and uh so to speak darkness if you will in the periphery uh often with a TIA or a stroke if people have a visual disturbance it's negative visual phenomenon only subtracted subtracted they lose they lose vision um 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.

Um, and so once again that like kind of teasing apart that history is help very helpful to make the distinction if it's migraine or or if it's a cerevascular event like a stroke. I guess we'll come to it when we talk about treatments. You've alluded to the pathophysiology of the migraine. So clearly this must have to do with uh I assume it has to do with ion channels, you know, calcium channels or all sorts of the usual suspects for for excitability. Um so maybe we'll come back to that, but obviously I want to make sure we do talk about that uh through the lens of treatment.

Um what else should we know? I mean I 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 one one billion worldwide. Wow. Um roughly 45 million people in the United States impacted by migraine. And 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.

Right. Yeah. So there are the the economic impact is um at least in the workplace is in the billions of dollars and maybe more right could be certainly hundreds of billions would be my guess. Yeah. The impact is not only on present not only on absenteeism but on presentism and by that I mean um the presenteism you know is somebody there right? are they are they but they're just not working at their full capacity versus absenteeism where they they don't show up to work due to migraine.

Uh and the the the heaviest burden I would say is unpresentantism. Interesting. Which is much harder to quantify. Correct. Yeah. We're actually doing it right now uh through a study that we're doing. That's interesting. So there's an enormous incentive to fix this problem even if you personally have not experienced it. it just society suffers as a result of it on both absenteeism and and presentism. So um but again for those of us that have not experienced it, we have the 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 just, you know, bear it until this thing passes and it strikes without a warning and it's it's a lightning strike and and you know, um how many people are kind of walking around 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. Um, and I think the spectrum of migraine is very broad, right?

And I think you um, elicited one person, right, who's 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 um, dim the lights or try to end up uh, pushing through. I think 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.

Um, and it disproportionately affects women three times more often than men. Oh wow. So 12% is aggregate. Correct. Um, but if you do the math, 18% disproportionately women. So almost one in five women. Correct. That's a that's a I I'm actually amazed it's that high. Yes. And the and the hard part is that um demand for outstrip supply, right? So demand for headache uh um the number of people number of clinicians across the country that are providing and able to provide headare um there there's just not enough, right?

Just because of the number of There's not enough Brian. There's not enough Brian or or other people. Yeah. Yeah. And that's and then the training also is very different right so um so I'm very fortunate not only to have had great mentorship but to be able to mentor kind of the next generation of edic specialists but you know there there are you know 50 or so mened a year it's just not enough to end up I mean just I I think about there are only 50 fellowship trained headache neurologists that are coming out of training a year ish ish amazing for a condition that affects you know 10 12% of the population.

Correct. Yeah. We could almost come up with some interesting parallels there in terms of disproportionate like how many dermatologists would be trained that could treat a dermatologic issue that affects 12% of the population and and the spectrum migraine is is so broad because um 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 episotic migraine is where people have less than 15 days of migraine per month. Chronic migraine is where people have 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 you know 1 to 2% of the the population uh that experience 15 or more days. These people are thoroughly debilitated. They're half their time is in a state of headache. Correct. Okay. So 10% of people with migraines are experiencing it up to 50% of the time sorry 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.

Um so the vast majority of people experience episodic migraine but that episotic migraine is a range right it could be a couple of times a year to uh up to 50% of the month. Up to 50% of the month. Yeah. Um, okay. Before we get into treatments, um, and other things I want to talk about, well, we could talk about them now. Talk tell me a little bit about genetic susceptibility. Obviously, genetics matter given the fact that women are three times more likely than men. That always makes the first thing one might think is, well, is it a hormonal, right?

Is it uh how much does it relate to estrogen, progesterone? We know that there are receptors for these things in the brain. Um does does the frequency of this type of headache uh is 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 if during the during the reproductive years, is it higher during any part of the cycle? So that's a a lot of information packed. I will I will try to tease that apart.

Um and so ultimately, yes, hormones plays a role. Yes, genetics plays a role, but migraine is multiffactorial in the sense that both genetic environmental factors play a role in experiencing migraine. So, if somebody uh has a family history of migraine, they're more likely to end up experiencing migraine. Um and uh through a woman's um reproductive cycle and across hormonal milestones, migraine can certainly have a predilction around times of puberty uh around times of menes, pregnancy, lactation, um permenopause and menopause. And so across these hormonal milestones, migraines certainly will fluctuate if you will.

Um I would say about twothirds of women will experience um migraines uh with permenstrual attacks or they'll note an association of migraine around their menstrual period. Um and that association comes in two possible forms. Uh one is women who experience pure menstrual migraine where they experience menes and headaches and migraine occurring around their menes solely around their menes 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 days before and a couple days into which of course is the lowest period of hormones which suggests hormone deprivation is driving that subset. Correct. And then me menstrual related migraine which is present in about 50% of women is where they experience u migraine not only in temporal association with their menstrual period but at other times of the month and so this is um a very common occurrence for women. um the the um estrogen uh that dates back to the 1970s studies that were looked at that kind of that natural decline in estrogen the late ludial phase and the development of migraine um if we fast forward in time what we know from studies is that um it's the the faster rate of estrogen decline in that late ludial phase that is unique in women who experience migraine.

So, it's this more that more rapid rate of decline in estrogen. Um, I'm very proud cuz one of the people I was fortunate to mentor actually did the did those studies. I'm surprised that we don't also see that post ovulation because you also have a very sharp decline in estradile post ovulation. They kind of have two, right? Right. They're sharp after ovulation and then not as sharp at the end of the ludal phase. Did they see anything? uh midcycle. No. So, interestingly, around ovulation, there doesn't necessarily seem to be a much higher risk of developing migraine and I think it that's in part to this more rapid faster rate of decline of estrogen in that late ludial phase which is the unique part.

Yeah. Interesting. It could also be the progesterone because we don't see progesterone coming. Progesterone hasn't risen in ovulation. So, it's not you know this but just for the listener. So, so we don't see a progesterone crash at post ovulation, whereas post ludial 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 the belief is really the the the the estrogen that decline of estrogen, not the not the decline per se, but the degree and rapidity of decline that is unique mostly in women who experience migraine.

The other the other couple 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 um 1940s when serotonin was first discovered um in blood um and then fast forward, serotonin was identified and and and noticed to be um lower in blood uh during migraine attacks and then recover and then the recovery phase would increase. And so that was those studies ended up leading to the development of tripans.

Um so estrogen has a um 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, 7 days post ovulation, right? which would be peak estrogen as it's about to crash into menses. You give them physiologic estrogen replacement levels and does that uh uh mitigate any of this risk? Yeah. So estrogen has been given those studies have uh been done.

Um the hard part is predicting necessarily who is going to respond. So there are some women that will get improvement in migraine. Um there are some women who will uh wear um they may not get improvement um and uh there are some women who will take combined hormonal contraceptives and they may get worsening of their migraine. Um and so it's very hard to sort of speak tease apart and know who's the individual that will necessarily respond. And um in in caring for those patients um 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 the for individual patients. What else do we know genetically about predispositions? Are people whose parents uh sufferers of migraines more likely to be sufferers themselves? Yes. Yeah. Often uh people ask me why they have migraine and if they're parents in their room I I usually point to them and I say you're the cause. Um not not place blame. No of course but we think it's very very highly genetic then. Correct. But it's but there are many genes that have been identified for migraine.

So it's not a specific gene. Right. So it's polygenic but um but but but highly hereditary. Correct. Um, and the the nervous system of you, if you will, of people who have migraine is is more hyperexitable, right, than people who don't have migraine. So, it's not that there there's more lighter sound, but the perception, if you will, the sensitivity um is is is just um increased. Maybe a silly question you haven't thought of, but um is there an evolutionary benefit to it? Not that this would have weighed heavily in selection, but is there an upside to the hyperexitability?

Does it manifest itself in other positive traits during the period of time when the individual is not suffering? I almost my question is through the lens of like, hey, if if if we're on a continuum of excitability and when the thing goes too far, it you end up with, you know, the headache and that's bad. But if you pull back just a little bit from the brink, is there some benefit to to that state? Yeah. So I um so a colleague of mine ended up speaking about uh writing about this a number of years ago where she postulated that the evolutionary benefit uh to women in particular may have been if they're the uh caregivers of their family that they would know if there was inclement weather coming, right?

Rainy storms if they had and u uh signs of danger. Um and so that may be one of the evolutionary benefits. The other thing is uh the you know if I I think about the neural networks in men versus women um women generally have to multitask much more than men in general. And so the question is whether the neural networks if you will uh are uh are better. That is super interesting. So, but you know, 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? So 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 there may be a weather storm that's coming through and they may not experience a migraine. But in somebody who has migraine, they uh may have one or more triggers. Some people with migraine have no triggers, others have multiple triggers.

I see changes in weather. um the let down phenomenon after stress um in you know 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 uh barometric pressure? I think it's it varies from person to person. um my patient population is is one that generally suffers more uh because it's more so in the people who are experiencing 15 or more days of headache per month.

And so I see they may um that reporting bias may occur. I may hear that more often than than others may. Um but that kind of makes sense, right? The more the more severely impacted people would presumably have more frequent triggers uh more more diversity in their triggers as well. Correct. They may uh but not necessarily. And that's what makes migraine um very nuanced if you will. And so uh that's why the the history needs to be detailed, right? So the questionnaire that people are filling out for me are, you know, 15 pages.

Um it's it's pretty extensive in trying to end up determining if I'm dealing with a primary, secondary headache, and then if it's migraine, um 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 for a clinician like me to understand because the patterns may be different from person to person. Do you have an online version at your 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 to put in the diary, they can do it.

I agree. You know, it's funny. There are, you know, 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, you know, 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, you know, we still give those to our patients who are in the 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, you know, tracker data. So, sounds like very similar for you in in in getting a good diary. Obviously, it might take more than two weeks given the the frequency of the headache, but yeah, usually we're we're looking at a period of several months, particularly if it's a woman who's reporting a relationship between um their migraine and menstrual period because ultimately to make a diagnosis of um permenstrual migraine whether it's pure menstrual or menstrual related migraine um that's usually that association is noted in at least two out of three cycles.

So that's the reason why. And 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 was in her probably late 50s, early 60s. Um, she did better on hormones, but it couldn't be too much, right? Like there was a very very fine line. She, in other words, we ended up having to use estradiol and progesterone as you do in in permenopausal women, but less than you would normally have treated someone.

In other words, we didn't we couldn't take her to kind of full therapeutic dose. Is that common in in post in in in menopausal women? So in so in um so th those transitions if you will from pmenopause to menopause um not only are hormonal fluctuations are occurring in permenopause but so is migraine and so in a patient like that during pmenopause um I you know there are women that will experience a significant worsening of migraine um probably about twothirds of women who after they've transitioned to menopause right they finished pmenopause is that uh they will notice improvement in migraine but 10 to 20% may actually like either continue or get worse.

Um so so I I find that there's a fallacy for where some patients are told that like you know once you hit menopause you're finished and you're not going to have migraine anymore. Um and the hard part becomes is it's not only the hormonal fluctuations but the impact on others symptoms right 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 or greater risk uh sleep disturbance changes in mood which can end up happening in parmenopause going into menopause so all of these things have either direct or indirect impacts potentially.

And I mean this just makes it a very complicated thing because now in addition to all the reasons you would consider HRT um 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 2/3 of the level without making it worse and then still capturing twothirds of the benefit or something.

Yeah, there are just like in this patient, there are um some women who will not necessarily need hormone HRT or hormone related therapy and there are others that despite best efforts with non-medation medication approaches will need HRT. The hard part becomes is like like you're pointing out it becomes very individualized right there. U 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 that's needed.

Anything else about presentation and susceptibility of migraine? I want to then talk briefly about the see if we have anything to finish on tension and then get to cluster. Yeah. So I I think presentation of migraine is the the I I spoke about a couple of the phases and not all people with migraine have all the phases of migraines. So the first phase is that premonatory phase the kind of the calm before the storm and a quarter to a third of people experience aura and then it's the migraine phase but it's not just the pain right it is that the um potentially a constellation of symptoms right that light sensitivity the sound sensitivity nausea um it may be autonomic symptoms um So if somebody has tearing or redness of the eyes or congestion running of the nose um often people think that they have quote a sinusetic but there's no such thing as a sinusetic there's acute rhinocyusitis there's chronic rhinocytoitis but uh the based on the pathophysiology of migraine uh there is involvement of an aspect of the parasympathetic nervous system that can that uh has a 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.

Um, and when people's parasympathetic nervous system becomes activated, people may experience tearing or redness of the eye or congestion or ring of the nostril, which is uh pretty common in people with migraine. Uh, and they think they have quot sinus headache. Um uh and then ultimately at the end of the day after the pain is gone they can experience a postrome which is um the pain is gone but I don't feel back to myself I feel hung over 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 uh what is the duration of each of them what is the what is what's the personal impact right because we just focus on the pain but not necessarily the impact uh in totality.

The other thing is the interictal burden. And so one of the things that you pointed out Peter which was um I really appreciate it is um how are people thinking about uh 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 interctal burden. And so when we think about all entry till meaning between the pain belts between the pain belts.

And so that's that's where when I'm uh eliciting all these pieces of history, I'm thinking about [sighs] how am I um 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-medation approaches? and then combining the picture together um obviously with the patient driving the decision-m once they understand the rationality of how I'm putting it together. Can you say a little bit more about some of those postal uh experiences? What fraction of migraine sufferers uh once the pain is gone are largely able to resume activity versus those that have that post victal period where they're not back to normal for a day or more.

Yeah. And so there are um population-based studies and there clinic based studies that have been done. So population based studies looking at the general population clinic based studies like where somebody would do in an academic headache program like like my own. Um those numbers can range anywhere from like 60% to in the high 80s. So this can be but it's still a big number. It's a big number. The same thing with the promontory symptoms kind of that calm before the storm. Now you said by the way for everything we're talking about here 12% of the population 3 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 incidence maybe or lifetime uh that's that's pretty high a lot of people are going to experience that yes female to male difference be pretty pretty evenly split what are some of the triggers and how genetic is it yeah So, I I think that the the name is maybe a little bit um 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 of where people have that um no light or sound sensitivity, mild to moderate pain that can be around the head, uh the muscles around the head, the muscles in the neck um and the nerves that are involved uh in the anatomy and physiology. there's overlapping, if you will, uh because the the the nerves that supply sensation to the face and the head and the neck are similar to what's involved in migraine.

Um their genetic factors that are responsible, their environmental factors, and then there's per parranial 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 1,000 milligrams of Tylenol and they get better, do they have a tension headache or in other words, could it respond to something as as simple and you know over the counter as that? Yes. Okay. Yeah. I mean, once again, as as long as we know that that's what it is, that it's attention diabetic 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 these the the the um the potential treatments for these things. Um so let's round it out with cluster then. So what what's a cluster headache? So cluster headache is is relatively uncommon, right? Pretty rare relative to migraine and tension type headache, but it's one of the most painful disorders um known known in the world. Um I I have a a woman patient who's likened it to giving birth to 100 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. Um it disproportionately affects men more often than women. So that ratio that is now about 3 to 4:1. It's um it has a very um uh it's got characteristics where people may have a circanial periodicity or circadian periodicity. By that I mean that at the longest and shortest days of the year uh 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.

Um, and this pain often is conceptualized as in and around or behind one eye. It's it's usually almost exclusively sidelocked. So just on one side of the head or the face. The rapidity of onset is very quick. Unlike migraine which generally will gradually build up, cluster headaches peak uh within about 5 to 15 minutes. The attacks generally last anywhere from 15 minutes up to 3 hours and uh it can be characterized as stabbing, boring, exquisite nature. Um and uh and then as soon as it came 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 eyelid on that side, a tearing or redness of the eye on that side, congestion or running of the nostril. And so, not only can you see the experience of on the person's face, but you could actually see the visual symptoms often. And about 90% of people with cluster head can experience a sense of restlessness with the attacks where they can't sit still. They they're 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 the presentations are very very distinctive. Um and where cluster headache is 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 up three attacks per day. The criteria allow people to have either 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 at all, they're just having multiple attacks per day.

And does the term suicide headache stem from the fact that people will take their life if it's extreme enough? Yes. Um, yeah, that's uh terrifying. Um, does that suggest that 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 are can cause manifestation of symptoms. And one of those manifestation of symptoms is a sense of restlessness or agitation. What what else do we know about these things?

How genetic are these? So we know that there are genetics that play into cluster headache as well. Um and so uh first degree relves may be at higher risk. Um like I said, it's not not common, but these are um very highly motivated patients just like migraine, but maybe even more so because of the exquisite nature. um because um they also like migraine often go underdiagnosed or misdiagnosed because of the presentation of pain. Um because there there can be a prediliction 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 there. And they may be told, "Oh, you have a a sinus infection." Then receive an antibiotic. And 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 uh around the teeth or the face. and they uh have had teeth pulled or major dental surgery or sinus surgery without realizing um that the presentation is actually cluster headache part of um the log that people can download from your site that allows them to take an accurate history.

[clears throat] Is that something they could take into their primary care physician if they're having a headache? and and does it does it highlight enough for the doctor the the flag that says, "Hey, this might actually be a cluster headache and this this might be one of the times when even though it's hard to get to headache specialists because of the frequency or the the low uh number of them. Uh it's worth 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 I think that becomes very important. I I think about my primary care colleagues and the number of things that they have to address in a relatively short period of time. Um and if one of them I think that's the that's the hard part, right? So, we want to kind of uh um arm patients with a ton of data so that when they meet their PCP, um they can do the lifting for them that they, you know, in in 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 didn't I I wouldn't have had the time to elicit this or wouldn't have even had the knowledge base to elicit." I was about to say it's it's not only receptive it's and the time it's also having the knowledge and education experience to make the diagnosis and then offer the appropriate treatments. So I all the stars need to align if you will. Most people with um with headache will 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 the hard part becomes is kind of navigating afterwards the gateway. Um particularly if they don't have a diagnosis or they're misdiagnosed and patients come and see you from all over the place obviously they're Yeah. Yeah. Um uh so I mean that's a that means that obviously a lot of them can't see you when they're in the throws of suffering. Does that matter? So for patients with cluster headache um that's kind of the the password if you will in my office um in the sense that if somebody who's in either an established patient or somebody who's trying to get in um they will say that they have cluster headache and if if in fact they at least uh on the basis of their questionnaire seem to check off um information that alludes to that possibility then yes they're seeing um 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 uh the patients with cluster headache require multiple treatments. And so uh 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 cluster 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 and sorry just to be short and 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 multi-disiplinary approach right? So meaning uh for patients with cluster headaches some of the examples would be avoiding alcohol, avoiding foods with nitrates um you know not taking naps during the day preferably um if they have a sleep apnea addressing that cuz hypoxia can sometimes be associated with it as well.

And then at the same time, preventive treatment is taking u a pharmacological right a medication treatment that uh may take time to build up and while that is being built up offering something to try to rapidly suppress the attacks until that 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 interventions that you would keep in your playbook for these patients? And um are they the same across all the headaches?

is is if if you know does everything you just said for example around correcting sleep apnea, minimizing alcohol, avoiding naps during the day would you give that advice to any uh 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 um certain identified risk factors um and even the subtypes of migraine may have their own um identified risk factors. Um so if we know from studies that were done uh that if somebody's experiencing at least one migraine a week uh more than that may put them at greater risk for more frequent attacks of migraine.

So the higher the frequency of attacks at baseline uh maybe uh lead to chronification or transformation of more frequent migraine somebody who has stressful life events right we all do but that's a risk factor as well sleep disturbance that may be insomnia that may end up being um sleep apnea so once again modifiable uh person's mood depression anxiety are comorbid with migraine right they coexist at a higher than expected by chance and there's birectional relationship between mood disorders and migraine. And so addressing those, that's why I try to explain to patients that um all the stars kind of need to align, right?

It's not just taking care of your pain, but we need to end up addressing these risk factors. Um [snorts] people frequently using acute pain medications. So 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 nonsteroidal anti-inflammatories, simple analesics. It could even be tptans, migraine specific medications. It could be barbbitrate containing combination analesics medications like fioretinol.

So um opioids. So um and then um if uh somebody has other pain disorders, obesity is 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? So it's it's probably multiffactorial as well. Um and um you know uh so I I think there migraine itself has a pro-inflammatory component to its pathophysiology and so there may be shared mechanisms that underlly 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?

Yeah. So people who are morbidly obese are at five five times higher risk for more frequent migraine. Oh, so it's not subtle. This is dramatic. Dramatic. And there are studies um with weight loss um surgical and non-surgical showing improvement in migraine. Not uniformly across the board for every individual, but certainly showing improvement. And so modifying that uh risk factor is very helpful as well. Again, some of these numbers are shocking. the the women being 3 to one is not shocking with my lived experience because when I stop to think about it almost all of the people I've encountered with migraines or most of them are are women.

So that I get that um the obesity is 5x that is surprising that morbidly obese. Okay meaning 35 BMI. Yeah. Okay. So but once again 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 to correct obesity, there are plenty of them on a health perspective um uh as it pertains to chronic disease like heart disease and cancer. But we're, you know, when you think about two dramatic things that improve the quality of your life, one would be orthopedic, right?

You just have less uh wear and tear in 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 right whether joint pain, neck pain, back pain which leads you to more of the medications then also become the trigger and has that been corrected for in the analysis? Yes, having other pain disorders in of itself puts one at greater risk. Having the presence of nausea, nausea that's not optimally treated if a migraine attack is suboptimally treated also greater risk.

So when I'm listening the history, I'm I'm almost doing this computational analysis and then explaining 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 going to talk about lifestyle modifications, but it may be things that are um that are particular triggers. Um whether it's the the food, the nitrates, the sleep apnea, the taking naps during the day.

With migraine, it's um what are those risk factors and how do we address not only the 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 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.

Sorry. Um so for cluster headache, it's not the triggers. Those are things lifestyle changes that I may um suggest to them. It's um pathofysiology 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 um involvement of the of the sleepwake cycle. And that's why people have this circanial periodicity and this circadian periodicity because there's involvement of the hypothalamus and the pineal gland. And so um if people and and the changing of the clock for daylight standard daylight savings time so I know when the clock has changed I'm going to hear from people with cluster heading both spring and fall.

Yeah. I mean I have patients I have a patient from Australia who when he when he travels there he'll he'll get cluster attacks cuz the season's changing when he comes here if he comes at the uh and how much of that do you think is fixable with circadian uh rigidity? In other words, if you said to a patient, look Bob, um 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 hypothalammus, your pineal gland, every part of your brain is seeing light and darkness at the exact same.

Again, I'm using this as a thought experiment, right? But it's um 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 eliminate a person's cluster headaches. I think what it will do is if you uh 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 sort of 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 you get a patient who's just got debilitating bloating and GI issues, um, autoimmune conditions that aren't otherwise easy to identify. And you know, one path is I'm going to run a bunch of blood tests on you that are totally bogus and [ __ ] 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.

Um, 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 sort of 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 and how do we um how do we modify things that uh will set that person up for best success that may be triggers or that help reduce risk factors. Um and it's uh I I I try to take a very calculated approach. Uh I also try to understand the person who's sitting in front of me because they will empirical. So it's what's the diagnosis?

What are their coexisting medical conditions? What's their preference? Um what are their expectations? Before I end up before I start a visit, I ask people what are the one or two most important questions I can answer today. Right? 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. And so if I'm thinking about lifestyle modification, we're focusing on diet routine meals a day um that are not delayed.

Um uh and if there are particular food triggers, asking them to track with the headache. I don't necessarily 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 it is very individualized. And then the importance of sleep, hormones, [snorts] environmental factors, exercise, um, and reducing trigger burden. So meaning if somebody knows that I may be set up for an attack at this particular time um 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 aha moment, right? Like, oh, I didn't realize that when I said, and this is especially valuable when they're doing the log because you can see during the week, I have my coffee at 6:00 in the morning, but during on Saturday, I'm not even getting up till 8:00 in the morning and having coffee at 9:00, right? You wouldn't think of that, right? And and those are the nuances that I point out. And usually the diaries that I ask people to keep are a month view.

Yep. And so that way I'm able to quickly glance and I actually pull the diary off into patients and I'll say, "Okay, here's how I'm thinking about and interpreting this. This is why we're going to end up using these treatments." And so an example would be if someone experienced menstrual migraine, which I I is quite common. I may say, "Oh, okay. So your menes, 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 actually start treatment in advance and then carry it through the days that you would normally anticipate it. So that's what the diary, it's it's it's an effort that not only empowers patients, but really helps guide decision- making. Yeah. So again, I I 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.

Like it's, you know, let's admit it, it's a bit of a pain to have to fill out one of these diaries, 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 it's a 20 minute added burden every day. And I thank people for it. Yeah. I said, "Listen, I I know you're putting in effort.

Ultimately, this is huge dividends. Is there any Cuz I don't we don't need to go through every single lifestyle adjustment because all the ones that are in the obvious category are worth stating, right? Like 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 to fix bedtime and wake up time relatively. Everybody should be doing circadian health, etc. Is there any nonobvious lifestyle thing that you can think of?

I think 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 um that 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. Um I I I think the regularity um because migraine has that hyper sensitivity 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 which are hard to do but ultimately pay dividends.

Um I I think the important also thing that people may not think about is that stress reduction right whether it's meditation bio feedback cognitive behavioral techniques autonomic control correct people um not everybody but I think some people sometimes focus on the medications and don't realize it's it's a it's a a holistic approach right it's looking at the whole individual um and 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, you're getting you're getting a benefit outside of the realm of your headache, right? Which is we're going to all those things are actually just better for your risk of chronic disease, your health span and other capacities as well. Um so let's now talk a little bit about pharma through both lenses. the prophylactic lens uh the things that you would have somebody take all the time to reduce the probability or severity of an attack and then we'll after that we'll talk about the treatments that you would use acutely as a rescue medication.

Sure. So uh from the do it by class of drug and then we can we can talk about it by class. We can also then talk about it by pros and cons of each drug success rate or you know things like that. Yeah. I I think I think I would start off first by saying what are the goals of preventive therapy. Um because I think that's important for your listeners to know. Um 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.

Um it also helps improve potentially responsiveness to acute treatments. It can by using prevention you can reduce disease burden right you can end up reducing progression of migraine right so as I said people who experience more frequent migraine are at greater risk for developing even more frequent migraine attacks um it could end up improving um other coorbidities so some prevention may be helpful with sleep some prevention may lead to uh potential for weight loss and so you may be able to leverage some of those benefits s as well.

The the other thing is is it improves functionality and quality of life um which is obvious um but it also ends up helping reduce interactal burden and so that was one of the things I was talking about where people have this almost anticipatory anxiety. So [snorts] there are multiple goals for using prevention. The indications for using a preventive medication are is if somebody's experiencing frequent attacks or attacks that are very disabling even despite acute treatment. Um if somebody has uh rare types of migraine or headaches that um 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 um 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 um 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 but like as much as eligibility is not I don't just mean through the lens of reimbur reimbursement on insurance but um in your mind medically justified 40% yes 60% we 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 it looking at populationbased studies right the my population, the vast majority, right?

So, um, but the the hard part is the the the kind of the 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 they're insurance companies don't cover these are these drugs can be pretty expensive, some of them. So, I think it's varied. I think it may end up being that it's not recognized by the treating clinician.

Um, 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 are are does it make sense for them to be on prophylactic therapy? Again, in your population, I'm sure it's much higher, but I'm going to say even uh outside of my patient population, the the vast majority, right? So unless the cluster period is a week um which is not the norm um if it's going on weeks months yes the vast majority of those people are going to need a 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, right? 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 that experience 15 or more days of tension type headache per month. Wow. And so once again it u it depends on the frequency responsiveness to acute treatments that are being used or other modalities um and then functionality and impact on quality of life. Let's talk about some of the drugs that are used to to reduce risk here.

Um, so let's start with beta blockers. That's the one that's that's like literally one of the only things I remember is the tryptoins and the beta blockers, but I think the trips are for acute. Um, uh, but anyway, let's start with beta blockers. I remember that from USMLE studying. Is that still used? Yeah. Okay. Yes. So, um, so beta blockers are are a class of blood pressure medications. the the the exact mechanism how they work isn't known. It's it's postulated that it may have effects on on the sympathetic aspect of the nervous system.

And so two of the beta blockers that are um FDA approved are propanol and timol but there are other beta blockers that are used as well. Um they can be very effective for people. Um once again there there's caution if somebody uh has asthma. So there are different types of beta blockers. So can potentially exacerbate asthma. Um potential side effects include lowering of blood pressure, heart rate or exercise intolerance. And so that 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 co-orbidities.

Um but yes, that could end up being helpful. And that's mostly for migraine. Correct. Okay. Um, and then what about anti-depressants? Yeah, so anti-depressants 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 anti-depressant. But anyway, we'll 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. Right? 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 my gripe goes even further, Brian, because I actually think some of the things that anti-depressants quote unquote work best for are not even depression.

It's not even dyeia, anodonia. I I I actually think when you look at mood stabilization, anxiety, migraines, like those are 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 I agree with you. It's it's it's well migraine itself has its own stigma, right? Yeah. Um but yes I I think there's a high degree of stigma and that's why I explain to patients even in using these class this class of medications this anti-depressants the doses that are often being used are not even doses that would be starting doses for 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 amatrippleene and norripane 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.

Um, so they can be very effective. One of the potential side effects could be some tiredness and so usually they're 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 why? Presumably, it ties to serotonin and norepinephrine. Is that basically our belief? Yes. Okay. And then what about on the anti-epilept anti-epileptic side we similarly see it I mean that 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? Yeah. So I I think it depends on the anti-seizure medications to that are FDA approved or to pyramate which is known as topamax and valproic acid known as depicote. Um these medications have um different mechanisms of action. So for top pyramid or topamax that can work on particular channels which is what you spoke about early on but also has effects on glutamate um and GABA um and so glutamate is the excitatory neurotransmitter in the brain.

GABA is the kind of the suppressor if you will and then um and that can be very effective for people who have enhance GABA and suppress glutamate presumably. Yeah. Um and that can be very effective for people. Um but it does have like every other medication potential side effects. Um and then valproic acid or depicote um once again can have effects on uh GABA as well. And uh that medication also may be helpful but also has potential side effects. And it's it's really important that the we go back to the patient population where um you know I have migraines.

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. Uh are they uh if they're sexually active, what form of contraceptive they're on? Because that will that's another piece of information that becomes important in setting a preventive plan. I I'm trying to avoid then or at least um counsel patients on uh you know the possibility that some of these medications may not be safe during pregnancy.

So I want to understand that piece with it. I didn't realize you had migraines by the way. So uh 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 ends up ended up giving me a leg up on taking a history and and the reason why is um many people that I see with migraine who experience it um they know what it feels like.

It's it often it's hard for them to put into words. They have to like pause, reflect, think about uh their answers. Not always, but but some people. So, um I I I really like the fact that um it's a group of people that I can really help and sadly um there not a lot of people that have the knowledge or information on how to do that in a systematic fashion. The class of drug that I remember when it came about were these monoconal antibodies. in fact the patient that we keep referring to um I remember being one of the first patients on it because you got her into a clinical trial um and it was a resounding success.

Can you say a little bit more about these drugs and their utility today? Sure. So the class of what are called CGP or calcetonin gene related peptides. Um so uh I 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 and this is a podcast where we don't shy away from depth. So treat this as though uh you're giving a lecture. Okay. Um always trying to understand my audience.

I um I'll speak a little medical ease and and speak English at the same time. We're 25% physician by audience by the way. It's crazy. So I love it. Um so the brain s the brain itself is insensate. It's not pain sensitive but the coverings around the brain um like the meninges or specifically the dura and the blood vessels that are both within the dura and in the brain have uh pain sensitive nerve terminals nerve endings and the main 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 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. um with the advent of uh increasing research particularly over the past I would say 50 years um we know that that model is just too simplistic so now we know that it's a neurovvascular phenomenon and so that there's involvement of not only the nervous system but the uh cranial blood vessels as well and so what ends up happening is that these uh no susceptive or pain sensitive information is conveyed from these pains sensitive structures so the duramatada that covering around the brain and the dural and intraanial blood vessels and then it re laid back centrally along a nerve called the trigeminal nerve that has three branches primarily along the the first division the athomic division of the trigeminal nerve passes through an area called the trigeminal ganglen and then synapses or connects in an area of the brain stem called the trigeminal nucleus cordialis and [snorts] so uh 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 primarily 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 diabetic 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 the those nerves become stimulated, people can experience peripheral sensitization where if they're turning their head or bending down, they can get a throbbing type of feeling that occurs that can occur early into a migraine. And when pain sensitive information goes back to the brain stem that 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 validia. 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 in about 30 to 60 minutes or so into a migraine headache. And then um using trip hands 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. when we'll come back to the trips when we talk about acute treatments. Yeah. And then that no that pain sensitive information then travels from the brain stem to the phalamus which is the kind of the sensory processing area of the brain.

Um so there's some nuclei like ventroposalamic nuclei that are involved and then from there no information then goes to the sensory cortex of the brain and then other pain matrix areas of the brain. Now while this is all occurring there's a cascade of events that occurs. So that trigeminal nerve um uh 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 intervation is relayed to the cranial blood vessels, the blood vessels within that duramada, that covering around the brain and the intraanial blood vessels.

And people can experience dilation of blood vessels and the release of chemical messengers or neurotransmitters. So things like substance P, neurokinine. God, I haven't heard substance P in years. I'm happy to bring you back. I'm happy to um and then calcetonin gene related peptide or what's known as CGP and so and then at the same time there's a pro-inflammatory response that occurs. So a neur what's called neurogenic inflammation um and then a release of uh histamine male cells nitric oxide once again a full cascade of events.

This becomes important because um through studies that have been done over the years, there have studies that looked at jugular venus blood um noted elevations of CGP during migraine. And so that really that calcetone gimmlopeptide that uh those studies led to the possibility that this may be a target for migraine treatments and and then when sumatript or imitatrix came on the market there were studies that looked at patients who were treated with it um and what happened to their CGRP or calculated peptide levels and um and they normalized.

So meaning they were increased during migraine and then uh the use of simatriptan 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 CGP antagonist and the CGP antagonists are um are kind of broken down into uh two two buckets one are the what are called uh large monoconal antibodies which is the the medication that our patient is uh was placed on and then uh small molecules what are known as G-pants.

So that's the kind of the history that led into the formulation of that class of medication and these are drugs that are administered introvenously at what frequency? Yeah. So um so the CGP antagonists um the large monoconal antibodies three of them are self- injection medications. They're like epi almost like epipens. And those medications have a long halflife. So roughly about 28 days. And so [clears throat] they're administered in a monthly fashion um or every 28 days. Um and uh that's the three of them. There's one that's actually given quarterly as an eusion every 3 months.

So that any difference in efficacy? Once again, it varies from person to person. there no there are no large head-to-head studies of these medications and so that's the challenge with being able to end up using data to end up answering that question. Yeah. So basically you might start with the home use pen because it's easier I assume it's cheaper and if it's if they're failing those things you would have to just go with the quarterly infusion. Right? So that's one reason. The other reason is is what the insurance will dictate in terms of what they will allow me to prescribe.

Right. Yeah. Got it. Um Oh, go ahead. These have changed the game though, right? Is this am I obviously I'm biased perhaps by my small small sample set of the patients I know that have have had a significant improvement with these. But across your clinic, which is very high risk, but obviously very diverse, right? How much have these been uh an improvement in in uh mitigating onset and severity? Significant improvement. I mean the biggest change you've seen in your clinical practice. Yes. Wow. It doesn't mean that they work for everyone.

And for what fraction of patients do they not work? So they probably work for up to 60% or so of patients with migraine, right? And so that's why I say sometimes there is trial and error. Um the other thing is there are some people that will be um much quicker responders than others. So some people uh will get benefit within the first month with these medications. Other people may take up to 3 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. Uhhuh. And so there are 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. Okay. In oncology, a partial response has a very specific definition which result, you know, which I won't bore listeners with. Uh, how how are you defining a partial response? Based on what information the patients are providing me? It doesn't doesn't have to be at least a 50% reduction. Correct. Yeah, I think that's u 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.

Um, but sometimes the timeline and once again it's it's usually a multid-disciplinary approach that that I'm employing in order to be able to continue for building on incremental gains. And 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? Would you still or would or does that automatically put them in the 60% bucket for you?

So for me, I'd probably put that group into the 60% bucket. But there are um once again there are people that will get um very variable ways of getting improvement and so that's why I say it um it that's why the diaries become very important to understand. Yeah. and and sorry to just harp on this but given the importance of it um when a patient does not have success on this drug do you have a sense that most people al 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 yeah so that that becomes I'm 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 end up telling. Um but ultimately I I do tell people that if one may not work, another one may. Yeah. Which is again it's an important lesson I think for clinicians although I would hope most people understand this. Whenever you're using these monoconal antibodies, they're 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, you're 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 in in the lipid space where if you don't respond to one, you might respond to the other and vice versa. Um, okay. [clears throat] Super interesting. Um, you mentioned the oral equivalent of these as well. Yes. So, um, so there are oral medications that are known as G-pants that are small molecule CGP antagonists and these medications have uh shorter half- livives.

So, um, and there are few of them. There are a couple that are oral, um, and there's, uh, one that is, uh, a nasal spray. And so, uh, these medications can be used acutely when somebody ends up having, uh, migraine. Uh, one of them has an indication both for acute and preventive treatment. Yeah, that's auto gapant or something like that. Um so uh a to japant uh which is known as I can't even pronounce the drug. That's okay. That's okay. Um uh that is for preventive treatment.

Oh that's not one that you can use acutely. That would not be used acutely. Remediapant or what's known as nerk has an indication for preventive and acute treatment. Umant or ubelvi which is another medication in that class um has an FDA approval for acute treatment of 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. Like thousands of dollars a year I'm assuming if it's based on other monoconal antibodies.

Yeah. And then do you have a sense of what patients that come to see you get do 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 the biggest challen frustration I would say both for patients and for people like myself who are caring for them. And if it's like every other drug in the United States, we're paying probably 3 to 10x what the rest of the world pays for the same drug.

Yes. Um 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 and so they they you know they have an easier time in some respects of 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 buy 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. Um, because I have patients who fall into that category. I think the hard part also is the maybe the shortsight if you will meaning the cost of these medications may be very expensive but it's trivial compared to compared to the economic the personal costs the trips to emergency rooms the loss costs in insurance of of people at work um lost work time and productivity I mean it's just um [clears throat] it's shortsighted 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 uh doesn't have as much data for prevention of migraine. More classically it's used for prevention of uh a headache like cluster headache. Um but still people may end up using calcium channel blockers which is a blood pressure medication for prevention of migraine. 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? Right. And so there are some patients that I have where the usually in collaboration with a cardiologist. Um there's one patient I thinking of that I just recently saw where um this person was on at one point over a,000 milligrams of rapid mill. and for your audience to know that is an exceedingly high dose. Um so once again EKGs need to be checked, blood pressure, pulse needs to be checked, tolerability needs to be checked. Um but that that that was the dose that was needed and that person tolerated it amazingly and obviously it reduced significantly the frequency of cluster headaches.

Correct. So this is the trade-off in pharmarmacology, right? It's nothing comes without a side effect, but the side effect can often be well worth it. Right. Um, 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 well for tension type headache. Okay. Yeah. Shows up. It's good thing I'm not a neurologist. It's okay. You have me on set, so I'm more than happy to help.

Um, so, u serendipitous finding that Botox, uh, was helpful for migraine. There was um um a plastic surgeon uh Bill Binder in um in uh in California who was giving it to patients cosmetically and then was told by patients that uh you know my my headaches are getting better, my migraines are getting better and that's actually what led to Botox or anabotulum toxin uh being studied for prevention of migraine specifically chronic migraine. So that's where whereby people are 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. Um and so it's not by cosmetic effects that it works but actually it interferes with the release um of a certain uh sneer and snap protein certain proteins and also involvement in CGP calcetonin gene related peptide. Once again we come back to this because of systemic delivery. So it has effects on pain pathways again pardon my ignorance. So this is patients that 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 has gone through went through a number of iterations until the uh 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 u they're given uh around areas where there are superficial nerves. And so the postulated the mechanism is that it may have um interference in the release of certain vesicles and certain proteins called sneer and snap proteins as well as CGP which is that um chemical messenger that neur that neuropeptide we were talking about in heavily involved in migraine.

And how many patients that qualify for this are able to get insurance coverage because this would be even more expensive than the other, you know, than monoconal antibodies. I mean, these Botox must be insanely expensive. So, not necessarily relative to the monoconal antibodies cuz the monoconal antibodies I guess you're taking them every week whereas you monthly maybe quarterly, right? Um and the Botox is is administered quarterly. Okay. And um it's not it's not the insurance companies won't let me say, "Oh, of course, Dr. Gersburg, 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 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. Okay. So, let's talk about the rescue drugs. So, you've you've you're now in the throws of a headache. Yes. What can you do? So, there are many classes that we end up using. Um there are non-migraine specific classes and then there are migraine specific classes.

So, m non-migraine specific um so analesics like acetaminophen, non-steroidal anti-inflammatory drugs like NSAIDs. Um and then do opioids play any role here? So opioids notwithstanding the loaded nature of addiction and things like that or dependency. So uh we go back to the risk factors for migraine uh chronification and one of the risk factors is medication overuse and the two largest culprits for the possibility of medication overuse are opiates and barbbitrate containing combination analesics like Fioret or Fiorinol which is even banned in in some countries in the world.

And so opioids or these this class of medications the barbitric containing combination allergies even used a handful of times per month even if it's not for migraine right the nervous system once again uh may not like that and they have a particularly high risk for medication overuse and so that's the challenge with and is the issue that in other words is the issue that if we give patients these drugs the probability ility of excessive use becomes high enough which is itself a trigger. Yes. Okay. Um or potentiating mechanism.

I see. Okay. So in other words, you would not prescribe these in your practice. We have you have enough other tools that you're not going to do that. Yeah. I once again opioids uh for me are a last line, right? Like um after people have explored everything, [snorts] if you will. Um and so you know even in the emergency room we we really try to end up um staying away from opioids just because of the this potential. Um in terms of migraine specific medications uh tripans were the first class that was uh specifically designed for the acute treatment of migraine.

What predated that were the agotamines which are still used and so these are medications that come from a particular type of fungus um that have effects on serotonin which is heavily involved in migraine and so um they're uh they don't they work on not only serotonin receptors but they work on other receptors as well whereas tryans work specifically on certain subtypes of migraine receptors namely what's called 5HT1B 1D receptor receptors and the 1B receptors have different effects. those are um on smooth muscle cells and so they're involved um uh on that on on that aspect and the 5HT1D are involved in in some of the chemicals neurotransmitters that are released and so try uh the advent of them really ended up was a gamecher for migraine and and even now 20 what 30 years ago so we're probably going back to the the 1990s mid '90s Yeah.

And [clears throat] so um and and so ultimately sumatrian was the first one that 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 tripans in total. And are these drugs like statins or GLP1 agonist where each new version gets more effective and has fewer side effects? Not necessarily. Um so there are plenty of people sumatin was the first one. Um some people may be uh sensitive to sumatrian versus some of the later tripans.

Um one of the potential side effects of tripans 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 or uh it can cause flush. Yeah. Like a flushing. Um and then other people use simatript and they no issues whatsoever, right? Like God made this for me. And um so the some of the half- livives of the tripans may be different. So there may be some that are quicker onset, some that may last longer.

Um and so that's where the decision-m 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 um there's 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 choose one formulation over another.

So all of these factors help me kind of hone in on the decision-m and again intuitively my gut says no pun intended that the intraasal would have more efficacy than the oral u like it would go intraasal I am then oral in terms of the speed with which they respond by is that is there any truth to that? So uh the order is I'm going to switch the order a little bit. So IM is so intramuscular is actually quicker. Okay. Um and so the sumatript is available injectable.

So the quicker onset um 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 a tablet. So they may feel that flushing. They may um oral would have the lowest amount of that given that the pharmacocinetics because of the phocinetics and that may be potentially obviously um we're and this may be different if I'm let's say treating somebody with migraine versus cluster headache. So cluster headache if I'm using sumatript tan I'm I really love to end up using the injection because the median time to pain relief may be like 9 minutes.

So, for somebody who really needs quick onset because they're having a rapidly onset uh attack, um that's like God made this for me, right? And it's a it's a pre-loaded pen that they can carry around with them. So, often it's a pre-loaded pen, right, that they give themselves an injection. Um or if somebody's experiencing a migraine attack at night that wakes them up from sleep or or builds up quickly. um the nasal spray that bioavailability that you were talking about um doesn't pan out for all the nasal sprays.

So the so the sumatript nasal spray um and there are a couple of them but we'll we'll talk about the not a brand form of sumatript nasal spray but the so to speak the generic or the form of sumatript nasal spray the bioavailability is not so great. the um another but it's it's high enough it's higher in imitatrix than it is for generic sumatin you're saying um so the the the nasal spray itself there are other brand formulations of sumatriptan like nasal powder if you will um 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 zomatan which is known as zomig nasal spray um which is a tripan and the zagipan or zabsiprret which is a gpant once again that's in the class that we were talking about that cgp antagonist those bioavailabilities are higher and so that's where somebody may end up getting u faster relief okay um success rate for these across all comers so looking at tripans the or for any acute treatment looking at um speed of onset uh improvement in associated symptoms uh functionality which is very very important generally the mark of time that's used is by 2 hours uh and then uh what's the rate of recurrence or the rate of return of headache either that day or within 24 hours and certain tripans uh may have a higher recurrence than others and so that's where the decision-m is is used based on um all the factors that patients tell me about.

Okay. Outside of these treatments, what about any sort of electrical stimulation? You know, TENS, have any of these other things shown any benefit? Yeah. So, you're you're referring to the class or TMS. I'm sorry, I said TENS, but what I meant was TMS. Yeah. Of neurom modulation devices, right? So, the the idea of neurom modulation is to that a stimulus is being used. Um and that stimulus may be in various forms. It may be magnetic stimulation. It may be electrical stimulation um that uh targets uh some uh system if you will in this case the nervous system.

And there are different forms of neurom modulation that have postulated mechanisms that work on different targets based on the pathophysiology or the anatomy of migraine. [snorts] So uh one example would be a device that delivers stimulation to the nerves um the superficial branches of the trigeminal nerve over the eyebrow. So there's a device that will do that and um they all well I shouldn't say they all but um that works by so to speak uh kind of uh suppressing pain transmission if you will superficially to end up having effects centrally right uh within the nervous system.

There are devices that will uh stimulate electrically the vagus nerve. Um and so uh that uh can also be helpful for prevention and acute treatment of migraine. Right? And these are all what I'm talking about are external devices. These are devices that can be applied or held not necessarily implanted. I think that becomes an important important point of distinction. And then a device like remote electrical neurom modulation which is an armband device um called nerivio that is worn on the arm and that delivers um 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 is it prevention or a treatment.

So uh that particular device uh has an indication for prevention and acute treatment of headache. How successful is it in each domain? Across neurom modulation there are uh varying successes. There are no head-to-head studies of these devices. Um where medications have to be FDA approved. Devices get FDA cleared. Um and so our heading center was actually the lead site in the world that led to that FDA clearance for that armband device. Um and so once again depending on the study um the the the benefits are are pretty significant depending on the patient and the the attack profiles if you want.

Are these devices expensive? They can be depending on the devices. So some of them are bought uh like the device that's worn on the head that delivers stimulation. Um the device that applies veagal nerve stimulation is actually uh kind of like rented or leased and so there's a monthly payment for that. the armband device has a certain number of treatments uh within a month and so that's uh purchased or um gets some reimbursement through insurance and then there's another device that delivers stimulation to both to the nerves in the front of the head as well as the nerves in the back of the head and so that can be purchased or or quote rented or leased as well.

And are you under the impression that a lot of patients who are suffering from headaches don't even know these devices these devices exist and therefore they're missing out on another therapeutic opportunity. So yes uh the devices themselves may be used um either as first line or in conjunction or as rescue depending on the person and their attack profiles. I think the hard part becomes is some people are coming in uh waiting for a prescription in the form of a medication. Um some people uh because of the cost prohibition may not want to end up looking at devices.

Um but there may be other people that have preferences, right? I prefer not to be on a prescription medication to the extent possible. Can we try neutrauticals or supplements? um could we end up trying neurom modulation devices? Uh if it's somebody who may be looking to get pregnant, y um then we may for that aside from patient preference, but if we're looking 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 uh for acute treatment, but um knowing their mechanisms of action, they're not associated with medication, it's presumed that their safety tolerability would be okay during that period of time.

Do we know anything about uh THC or cannabis directly? Uh it's interesting. I hear I hear mixed things, right? Yeah. Yeah. So, uh we actually ended up doing one of the largest studies looking at youth uh in our patient population, an academic headache program of people using canabonoids. And what we found which was uh was about a third of our patient population are using canabonoids. Um and so uh the hard part becomes is uh it's not um it's not standardized and and in the study did you standardize the vehicle right or was it an outpatient outpatient survey study it's it's next to impossible because um formulations combinations right it's it it's very hard the other challenge becomes is even those people who say that they may get benefit the question becomes is what else are they doing 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 with with migraine? So, I think that's the hard part to to tease apart. The other challenge is 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 um that was done that looked at it for acute treatment of an attack using one formulation. And so, these are um 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 I think those studies will come but they're going to be very but these have to be done as almost um you I think you almost have to have the patients come in to be administered the drug because it's schedule one correct which is again kind of it's yeah the feasibility is not so easy.

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 um in the sense that it's very important to be as empowered as possible by keeping a log of information by um uh providing their clinicians or the treating physicians or providers with uh the details of their headache. um recognizing the importance of those lifestyle factors which can't be overstated. Um uh I often think about an equation of expectations over reality E over R.

What are their what is their reality? Right? What are their expectations? And so how do I try to match it as long as the expectations aren't necessarily exceeding reality? Um I think it's important for people to um take ownership which is not so easy. Some people will say, you know, you're the doctor. You tell me what to do. And I have to say, well, you know, you're you're you're we're partnering together, right? This is a partnership. Um recognizing that preventive medications may take weeks to months, right?

I I often say that this is not Amazon Prime, right? I know we live in Amazon Prime society. You know, 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. Um then uh and thinking about the um the overall frequency of attacks, letting knowing that preventive options sometimes people need one or more preventive medications, right? Uh it's not one size that fits all. So it really is a very tailored approach.

Um for acute treatment, it's also knowing and and and for clinicians to know that not everybody is necessarily going to respond to one acute treatment. They may need a backup. they needed a rescue treatment. Um, so I think that's important uh for patients who are uh very debilitated. There are also intravenous medications that can sometimes be used to try to um suppress a prolonged attack that may be known as status migronosis where a migraine is occurring for longer than 3 days like that first patient I was telling you about who is in had a prolonged migraine for six weeks.

um uh you know it's it's um and then and then recognizing that ultimately at the end of the day it's a 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 um you're not missing something medically. So when a person experiences a headache, um what are the not to create fear cuz 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 but you know I'll give you an example of something that 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, 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.

um which says nothing of how difficult it was to treat that. So, uh I don't know. Would you want to say anything about CSF leaks? Again, my 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, right? So, I I think maybe if I could um provide some pieces through the pneumonic that uh people should be aware of. um that may raise concern. So if if somebody is having uh new onset headaches um or a change in the headache pattern, that may be something that they want to speak to their doctor about.

Um if they're having associated fevers, rashes, um a headache that's uh they can't necessarily it's painful to flex their head and touch their chin to their chest, that may be signs of something that's concerning. um if somebody is having unintended weight loss um that may be a reason too. So those systemic symptoms if if somebody is having new types of headaches or change in a headache pattern um during pregnancy once again migraine can occur during pregnancy but as a general rule um migraine without aura improves during pregnancy and so probably about 47% people notice in women notice improvement in the first trimester and then 80 to 87% or so in the second and third trimester.

So you think that's estrogen related presumably? Yeah. Yeah. And so once again, if it's worsening, there are people who can have new onset migraine um and where migraine may not improve. But if 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 uh experiencing more frequent headaches, I'd look at that. Uh if somebody's having neurologic symptoms with the headache, right? So um you know [snorts] uh weakness, numbness, uh problems with speech or language, double vision, loss of vision, problems with balance.

Uh if somebody is u you know older than the age of 50 with a new type of headache or a change in the pattern, we we have to think about secondary conditions. One of them being temporal utteritis. Um most people uh who experience this are are um older. Um uh but sometimes the the the [clears throat] misconception is that the pain is just in the temple cuz it's called temporal arteritis. But the pain of that headache could be anywhere in the head or face. Um 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 [snorts] get to the other factors like is the headache specifically provoked by cough, exertion, sexual activity or sleep or if there's a positional component. Often people with a CSF or cerebral spinal 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.

Um that can be issues. Uh sometimes people with a CSF leak can have interscapular pain. So pain that develops in between the scapula. Um there are a myriad uh of manifestations which makes it so difficult to diagnose and treat. Right? So it's it's people like myself ultimately and others other colleagues of mine that may be seeing uh patients like this. Um that's why Duke um has a a CSF program, right? one of the programs that's dedicated specifically for patients like that. Well, Brian, this was this was really interesting.

Um, incredibly grateful for the work you're doing with patients, but also just really grateful for you taking the time to to come out here and be away from those patients for a couple of days to to have this discussion because I think a lot of people are going to benefit from this. Um, I'm sure a number of them are going to want to come and see you. Uh, do you is your what is the weight list like for people to come and see you? Obviously, when there's only when there's so few doctors doing what you're doing, I know how difficult it is to get in to see you.

So, me personally, when I I I moved to Connecticut about 10 years ago from New York, um I would say probably the vast majority of those patients I was seeing in New York who were driving or flying um are now just coming to Connecticut. Um which is humbling and flattering. Uh the hard part becomes is, you know, I want to care take care of everybody, but it's it's hard. So, my personal weight list is actually quite long, but there is a link that people can go on.

Um, often if people live out of the state or out of the country, I'll I'll ask them just to have like a local physician that can help with prescribing medications and and be able to kind of help implement the P plans. Uh, but I have thankfully I have other great colleagues as well. And so, in in your practice, you have Yeah, we're probably one of the largest headache programs in the country. Got it. Okay. So, so 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.

And is it the same with you? So, yeah, I have great colleagues who have the same philosophy. I would say I I I was very fortunate to have great mentors and so can they curbside you? Yes, they can curbside you. That's sort of what I mean. Like it's it's it's an open system. It's a collaborative system. Awesome. [snorts] Um and then again, I think encouraging people to go to the site. will link to your um 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 the 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 is at the end of the day it's just going to improve the quality of your care and your your outcomes.

So um Brian thank you again. This is really exciting both for the physicians listening, but I think of the hundreds of thousands of people that are not physicians that are 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 us. I will I will share it. All right. Thank you. Thank you, Brent.

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