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

00:00:00.000 Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Atiyah. This podcast,

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00:01:04.120 My guest this week is Dr. Brian Grossberg. Brian is an internationally recognized headache

00:01:08.620 specialist. He's the director of the Hartford Healthcare Headache Program and a professor of

00:01:12.860 neurology at the University of Connecticut School of Medicine. He's one of the leading experts in

00:01:16.860 migraine, cluster headache, and other complex headache disorders, and has spent his career

00:01:21.780 treating patients who were often profoundly impacted and debilitated by these conditions.

00:01:26.740 In this episode, we talk about how headaches are classified and what distinguishes a migraine

00:01:31.280 from a tension-type headache and a cluster headache, why migraine is often misunderstood

00:01:35.320 and underdiagnosed despite affecting tens of millions of people, the phases of migraine,

00:01:39.900 including prodrome, aura, headache, and postrome, the genetic, hormonal, and environmental factors

00:01:45.720 that influence migraine risk, especially in women, the societal and economic burden of

00:01:49.900 headache disorders, including its impact on disability, how clinicians think about diagnosis

00:01:55.180 when there are no obvious biomarkers or imaging findings, lifestyle factors, triggers, and risk

00:02:00.080 modifiers that influence headache frequency and severity, preventive versus acute treatment

00:02:04.680 strategies and how treatment decisions are individualized, advances in migraine therapy,

00:02:09.700 including CGRP-targeted medications, neuromodulation devices, and even Botox, and when headaches

00:02:15.820 may signal a secondary, more serious underlying condition.

00:02:19.180 So without further delay,

00:02:20.720 please enjoy my conversation with Dr. Brian Grosberg.

00:02:28.400 Brian, thank you so much for coming.

00:02:30.840 And I didn't realize until a few minutes ago

00:02:33.020 that not only had you never been on a podcast,

00:02:35.680 which these days is pretty unusual,

00:02:37.340 especially if you're an expert in something, which you are,

00:02:40.360 but that you've never listened to a podcast.

00:02:42.780 Yes, it makes me a unicorn.

00:02:43.960 Yes.

00:02:44.300 Yes.

00:02:44.520 Okay, this is a topic that I think just affects so many people. I want to maybe understand the

00:02:50.440 landscape a little bit about the field of neurology, what fraction of neurologists

00:02:55.860 specialize in headache. How did you decide that this is what you wanted to do?

00:02:59.880 So first of all, thank you very much for having me. I really appreciate it, Peter.

00:03:03.200 It's important to understand that headache is one of the most common neurologic symptoms.

00:03:07.280 Nearly at some point in every person's life, they're going to experience a headache.

00:03:11.420 Surprisingly, in medical school, maybe medical students and residents get a few hours across

00:03:18.080 entire medical school of lectures.

00:03:21.040 I actually don't recall any of it.

00:03:23.440 It's possible I had it and I just don't recall it, but I actually don't recall anything.

00:03:26.620 Yeah.

00:03:27.160 And so that's a gap in education.

00:03:29.220 And then in neurology residencies, that is similar where people are only neurology residents

00:03:35.240 who, depending on the program, of course, may only get a few hours of headache lectures or education,

00:03:41.500 and then they're experts. And so for my journey, if you will, into headache medicine was actually

00:03:48.420 by accident, complete serendipity. My first year of a neurology residency, I took care of a litigator

00:03:55.260 who was out of work for six weeks due to a prolonged migraine that had been going on for

00:04:00.040 six weeks straight. And without knowing, the person who was caring for her turned out to be

00:04:05.000 my future mentor. And so I had called this person. And you were a resident at this time?

00:04:09.860 I was a resident. I was probably a month into my neurology residency. So it was really early on.

00:04:14.500 So the patient took a history, read up on it, and then detailed the history to him.

00:04:19.340 And he said, thank you so much. Are you in your last year of residency? I said, no, I'm a month

00:04:23.880 in. He said, well, that was great. Why don't you come by my office and let's talk? And so I did

00:04:30.060 that. I got very interested in seeing patients with him. He offered to see patients with me.

00:04:35.560 Residency at that time, when you were on call, the hours weren't restricted. And so if you were in

00:04:41.000 the hospital 30 or 34 hours, whatever the case was, I would change out of scrubs into a shirt and tie.

00:04:47.560 And then I would go see patients with him in the office, even though I'd already been in the

00:04:50.380 hospital for that prolonged period of time. So my training in headache medicine was very

00:04:55.360 expedited, if you will, during my residency. And then from there, after I finished my pursuit

00:05:00.540 advanced training in headache medicine, and there are just a limited number of programs in the

00:05:03.820 country that offer fellowship training in headache medicine. So basically during your residency,

00:05:08.700 you did a fellowship in headache medicine on your own time with the fellow who would become your

00:05:13.320 mentor. And then obviously you went and did the formalized training. But going back to that first

00:05:17.120 interaction with that first patient where you, you must've had some intuition about this that

00:05:21.760 allowed you to take a history that elicited enough information that this doctor felt like,

00:05:27.120 wow, you're a seasoned pro at this. Any idea thinking about what it was? If I saw a patient

00:05:32.760 with headaches, I don't think I could ask two intelligent questions. How long has it been

00:05:37.000 making and what part of your head? And I wouldn't ask a single smart question.

00:05:40.900 I'm sure you would. Once again, in reading up about it, I was able to end up obtaining the

00:05:46.240 features and characteristics. What really struck me was the fact that she was so debilitated.

00:05:51.760 and that she was coming into the hospital and receiving treatments,

00:05:56.240 leaving the hospital completely headache-free.

00:05:58.400 That, for me, was an epiphany, if you will.

00:06:01.780 And it led me to end up thinking about something that is, if you will, an invisible disease

00:06:06.500 that I wasn't really getting a lot of education during, necessarily during my neurology residency

00:06:12.400 up until I started pursuing it, you know, led me into the field today.

00:06:18.080 So, Brian, we communicated over email 10 years ago.

00:06:21.320 I can't believe it's been that long.

00:06:22.560 It's kind of amazing, right?

00:06:23.640 Yeah.

00:06:24.060 Obviously, through how all doctors meet, through patients.

00:06:26.840 So I was taking care of a woman in my practice who I remember during my intake with her,

00:06:33.580 headaches were a huge part of her life.

00:06:36.640 And I got the impression through my intake with her, which of course is trying to focus

00:06:41.320 on every aspect of her health, that this headache issue was a major issue.

00:06:46.080 And I also gathered through that history that you personally were a major part of her care.

00:06:52.460 Now, that is not normal in my practice, where usually the people that are of major impact

00:06:58.280 in their life is not someone's neurologist, because I'm not taking care of people that

00:07:02.500 have debilitating neurologic disease.

00:07:04.780 So that was just an interesting perk to me.

00:07:07.940 And so many of the amazing doctors I've met are exactly this way.

00:07:11.520 like a patient of mine has a debilitating orthopedic injury that gets me down the rabbit

00:07:17.460 hole of what's going on and so in many ways you personally became the sort of through line to

00:07:24.320 understanding this patient's migraine situation and obviously that's turned out to be beneficial

00:07:30.440 to my patients because now no matter where they are in the country i say well you're going to

00:07:35.160 new york and ultimately hartford which is where you are now because the only person i'm going to

00:07:39.000 send you to as Brian when it comes to headaches. Thank you for that. Let's now help the audience

00:07:43.760 orient to the types of headaches. You mentioned something a moment ago, which I think is obvious,

00:07:49.360 but always worth restating. We don't have a biomarker for headaches. We don't have a finding

00:07:55.920 on a CT scan or an MRI that says, oh, this is what's hurting you. We take that for granted

00:08:00.720 sometimes that in many other aspects of medicine, when something is hurting, we have proof. Proof

00:08:07.360 is maybe the wrong word, but we have guidance as to what's hurting. You know, if you twisted your

00:08:11.680 knee badly enough, I would be able to see which ligaments were damaged. This makes the entire

00:08:16.580 field of neurology challenging, but I would guess that in the frequency with which headaches are a

00:08:21.060 problem, it's unusually challenging. Yes. The field of headache medicine is actually quite

00:08:26.380 challenging. And part of the reason, and you stated it very articulately, is the fact that

00:08:31.520 The MRI doesn't always tell us the diagnosis and often doesn't. And so headache is really a symptom

00:08:37.340 that nearly everyone in the world will experience at one time. And it's the perception of pain,

00:08:41.360 whether it's in the head, the face, the scalp, the neck. And there are a litany of things that

00:08:48.300 can cause headache. The differential diagnosis, the list of things is probably one of the most

00:08:52.400 extensive in all of medicine with over 300 different types and causes of headache.

00:08:56.720 The international classification of headache disorders, kind of like the Bible of headache,

00:09:00.640 but with no mention of God in it, breaks down primary and secondary headaches. Primary headaches

00:09:06.560 is a headache in and of itself. It's a syndrome. It's not attributable to some other underlying

00:09:11.020 condition. Most commonly, migraine or tension-type headache, cluster headache, or other primary

00:09:16.180 headaches. And you're right that there really aren't biomarkers. There aren't substances that

00:09:21.360 we can detect, if you will, that tell us this is what the diagnosis is. And so the diagnostic

00:09:25.920 criteria are outlined and they always say not attributable to another disorder. The secondary

00:09:31.880 headaches are headaches that are attributable to some other underlying condition where people will

00:09:37.140 ask me, Dr. Gersberg, do I have a brain tumor? Do I have an aneurysm? Is there something that's

00:09:40.820 life-threatening? And that's where a detailed history becomes important to try to not only

00:09:46.880 understand all the factors, but also the person that's sitting in front of me. No person or

00:09:51.740 presentation is identical. So primary headaches, we'll start with those, but just to make sure I'm

00:09:57.540 clear and everybody is clear, does a secondary headache always have a pathologic driver underneath?

00:10:04.960 Because the examples you gave of mass, mass effect, whether it be ultimately benign and therefore not

00:10:10.840 life-threatening if removed or malignant, that's pathology. Aneurysm, of course, pathology. Are

00:10:18.060 there any non-pathologic causes of secondary headache? There are non-life-threatening

00:10:24.080 things that are causes of secondary headache. So one example would be if somebody is frequently

00:10:30.780 using acute pain medication, that may lead to medication overuse. It's not life-threatening,

00:10:37.200 but the resulting increase in the frequency of headache is attributable to some underlying

00:10:42.760 condition. So caffeine withdrawal would be another example of secondary then,

00:10:45.580 even though it's not life-threatening. Right. And they have pathophysiological

00:10:48.840 and mechanistic reasons for the development of those headaches, but nothing that is pathological.

00:10:54.260 Yeah. And so I guess I just answered my second question with the example of caffeine.

00:10:58.440 Not every secondary cause has a radiographic or biologic marker.

00:11:03.140 Correct.

00:11:03.420 Okay, great. So now let's go in the, I think you described the big three,

00:11:08.940 migraine, cluster, and tension headaches. Those are three enormous categories of primary

00:11:15.540 and then you kind of have another category of the sort of others that make up that.

00:11:19.160 But let's take those in any order you would like.

00:11:21.840 Sure.

00:11:22.180 So tension-type headache is the most common headache that people experience.

00:11:26.680 Migraine is the leading reason why people seek care either in their primary care office

00:11:31.760 with somebody like myself or in an emergency room.

00:11:35.160 And so tension-type headache is often thought about as a headache that affects both sides

00:11:41.160 of the head or the face or the neck, where it's mild to moderate.

00:11:44.780 it's not pulsating or throbbing. There may be light sensitivity or sound sensitivity,

00:11:50.400 but never both. There's no nausea. And that headache can last anywhere from 30 minutes

00:11:54.220 up to a week. It's everything that migraine isn't. So that's the most common type of headache that

00:11:59.320 people experience. So someone listening to us right now who said, I remember having a brutal

00:12:04.660 headache a couple of years ago. That's most likely what they had if it was a one and done.

00:12:10.100 Well, a brutal headache, I wouldn't say that would be tension type headache.

00:12:13.420 I see. That's something that often people can end up working through. It doesn't necessarily impact their ability to perform activities. Whereas with migraine, the diagnostic criteria is where somebody has at least five lifetime attacks, where the attacks last anywhere from four to 72 hours, either untreated or unsuccessfully treated. And then they need to have two of the four following qualities.

00:12:38.820 Pain is often one-sided, but up to 40% of people with migraine can have pain that affects both

00:12:42.980 sides of the head or the face. Most people don't know that. The pain could be pulsating and

00:12:47.280 throbbing. It could be associated with causing avoidance of light and activity. And then people

00:12:53.840 can have light and sound sensitivity and or nausea and vomiting. So people don't necessarily

00:12:59.580 need to have nausea if they have light and sound sensitivity. And people can have light and sound

00:13:04.720 sensitivity, but no nausea. But if you are not nauseous and you do not have light or sound

00:13:09.660 sensitivity, you probably are not experiencing a migraine? So there are people, if they meet

00:13:14.660 criteria for one-sided pulsating and throbbing, moderate to severe, causing avoidance of routine

00:13:21.460 physical activity, meeting those may mean that they have what's called probable migraine

00:13:25.960 versus tensioned diabetic. And so sometimes the elicitation of the symptoms. People who may be

00:13:32.100 light and sound sensitive, they may fall into different categories. So some people will say,

00:13:36.320 I'm definitely light and sound sensitive. Other people often need the question reframed. Are you

00:13:41.740 more sensitive to lighter sound when you have the headache than when you don't experience the

00:13:45.700 headache? Oh yeah. Do you prefer a darker, quieter room? Oh yeah. Yeah, that makes sense.

00:13:53.400 Does the precipitating or exacerbating feature, as you've described them here, give you as the

00:14:01.540 clinician insight into which therapies are going to be more or less successful? Or is it purely a

00:14:07.660 binary thing at this point where either you're having migraines or you're not, and my playbook

00:14:12.480 is going to be independent of how you got there or how you presented? Through a detailed history,

00:14:17.800 once a diagnosis of migraine is established, the question then becomes is what's the attack profile?

00:14:23.300 And then even within the same individual, the attack profiles may be different. Somebody may

00:14:26.780 have an attack of migraine that gradually builds up over hours, where others will have an attack

00:14:31.840 that wakes them from sleep at 3 a.m. in the morning. So the treatment paradigms may be

00:14:37.660 different for those different attack profiles. And so you're looking at, obviously, location

00:14:42.500 and character and quality of the pain. You're looking at rapidity of onset. You're looking

00:14:46.620 at timing of onset. You're looking for accompanying symptoms. You're looking for level of impact and

00:14:52.740 disability, because migraine carries a very heavy burden, not only personally, but also societally,

00:14:59.160 family-wise. And then is there presence of nausea or vomiting? Most people may not be aware that

00:15:06.220 with migraine, and based on the pathophysiology of migraine, people may have a sensitivity

00:15:10.900 referred to as allodynia, which is an uncomfortable sensation to things that normally aren't

00:15:15.520 uncomfortable. And that's present in about... Say more about what that means.

00:15:19.440 Sure, yeah. So allodynia is a phenomenon where somebody experiences an uncomfortable sensation to things that normally aren't uncomfortable. An example would be a woman pulling their hair back in a ponytail, brushing their hair, wearing a tight hat, wearing glasses that rest on the rim of the nose or the eyes.

00:15:37.740 And that uncomfortable sensation is present in about two-thirds to 70% of people with migraine.

00:15:44.900 The reason why that's important is when people experience this allodynia, if they use certain

00:15:50.720 migraine-specific treatments like triptans, but they wait too long, those treatments may be less

00:15:55.560 effective. Are those symptoms prodromal? So I think to answer that question, it would be

00:16:01.980 important to explain that migraine is not just a headache. There are phases that people experience.

00:16:09.200 There are distinct phases, but they're not distinct. And so sometimes there can be overlap

00:16:13.640 of symptoms. So the first phase is a premonitory phase, whereby people experience, it's kind of

00:16:19.560 like the calm before the storm, yawning, craving certain foods, tiredness, irritability, light

00:16:25.860 sensitivity, neck stiffness. And that may occur minutes, hours, or even days up to before migraine

00:16:33.220 occurs. What's the median duration that that's showing up? So I would say hours. Yeah, hours

00:16:39.360 beforehand. And that could actually be helpful because then people know how to think about it.

00:16:44.820 And there is actually a treatment that was studied during the premonitory or what's called the

00:16:50.340 prodromal phase. Then about a quarter to a third of people with migraine will experience it or

00:16:56.360 And aura is a reversible neurologic symptom.

00:16:58.320 So most people with migraine actually do not experience aura.

00:17:01.360 The vast majority who experience migraine don't have aura.

00:17:04.700 Explain to folks what aura is.

00:17:06.620 Aura is a reversible neurologic phenomenon.

00:17:08.700 So this is whereby there's a phenomenon called cortical spreading depolarization in English,

00:17:15.260 even though I'm from Brooklyn.

00:17:16.680 That's where there's a wave of excitability that starts in the back of the brain and then

00:17:21.160 spreads across nerve cells, followed by a period of relaxation.

00:17:25.040 And because it's starting in the back of the brain, the back of the brain is the visual cortex.

00:17:29.460 So the most common type of aura is a visual aura, where people may experience what's called

00:17:35.080 positive and or negative visual phenomena. And that's where people may have zigzag lines,

00:17:41.020 difficulty seeing on one half of their world, spots, black spots, distortions, perceptions.

00:17:46.540 And generally, this evolves gradually over about five to 60 minutes. That's the most common type

00:17:52.260 of aura. Which the first time it happens must be terrifying. You think you're having a stroke.

00:17:56.260 Correct. And so there are things that can mimic aura and they need to be excluded. And that's

00:18:01.800 the reason why a detailed history, particularly if it's a one-time event versus recurrent episodes,

00:18:08.180 becomes very important to elicit when seeing somebody. Is there a pattern to aura that if a

00:18:14.380 person shows up in the ER makes you more or less likely to think this is aura versus TIA or stroke

00:18:21.540 or something really dangerous?

00:18:25.020 Yes.

00:18:25.420 So one, it's very helpful to know

00:18:27.340 if somebody has a history of migraine.

00:18:29.900 I think that's one thing that's very important to know.

00:18:32.640 Two is, what is the evolution?

00:18:35.400 Is it stereotyped?

00:18:36.520 Is this the first episode or there are multiple episodes?

00:18:39.300 Usually when somebody experiences TIA or a stroke,

00:18:42.500 the symptoms are maximal in onset.

00:18:45.160 And contrary to an aura of migraine,

00:18:47.980 there's this kind of gradual evolution often

00:18:50.580 over five to 60 minutes. And so once again, that's helpful to know. Are there sequential

00:18:57.560 aura symptoms? So the most common aura symptom is a visual aura symptom, but people also may

00:19:03.780 experience sensory language or motor aura symptoms. And so do people have this sequential

00:19:10.120 progression, if you will, in their aura symptoms? That's generally not seeing in stroke. And so

00:19:15.320 those are helpful points of distinction. Do people end up having, if they have a visual or do they

00:19:20.360 have positive and negative visual symptoms, meaning do they have kind of zigzag lines or

00:19:24.880 whiteout over half of their world and, so to speak, darkness, if you will, in the periphery.

00:19:30.840 Often with TIA or a stroke, if people have a visual disturbance, it's negative visual

00:19:35.540 phenomenon only.

00:19:37.200 Negative means subtractive.

00:19:38.140 So subtractive, they lose vision.

00:19:40.560 And so that's another helpful point of distinction as well.

00:19:43.600 And then aura symptoms, at least one aura symptom, if it's going to occur, is usually

00:19:47.680 on one half or one side of the world.

00:19:50.880 Once again, teasing apart that history is very helpful to make the distinction if it's

00:19:55.400 migraine or if it's a cerebrovascular event like a stroke.

00:19:59.000 I guess we'll come to it when we talk about treatments.

00:20:01.200 You've alluded to the pathophysiology of the migraine.

00:20:04.100 So clearly this must have to do with ion channels, you know, calcium channels or all sorts

00:20:08.900 of the usual suspects for excitability.

00:20:11.600 So maybe we'll come back to that.

00:20:13.260 But obviously I want to make sure we do talk about that through the lens of treatment.

00:20:17.480 What else should we know?

00:20:18.800 I mean, again, I think most people listening who themselves have not had a migraine, I'm

00:20:23.200 fortunate to be in that category. By the way, what is the prevalence?

00:20:26.160 12%. So 1 billion worldwide, roughly 45 million people in the United States impacted by migraine.

00:20:33.200 Has anyone done the exercise of quantifying the economic consequence in the United States? Because

00:20:38.740 this has to be even higher than lower back pain in terms of work missed, or at least on par with it.

00:20:46.140 Yeah. So there are, the economic impact, at least in the workplace, is in the billions of dollars.

00:20:53.840 Maybe more, right? I mean, it could be certainly hundreds of billions would be my guess. Yep.

00:20:58.140 The impact is not only on absenteeism, but on presenteeism. By that, I mean,

00:21:02.680 presenteeism, you know, somebody there. Somebody there, but they're just not working

00:21:06.620 at full capacity. But they're not working at full capacity versus absenteeism where

00:21:09.720 they don't show up to work due to migraine. And the heaviest burden, I would say, is on presenteeism.

00:21:15.840 Interesting, which is much harder to quantify.

00:21:17.260 Correct.

00:21:17.840 We're actually doing it right now through a study that we're doing.

00:21:20.920 That's interesting.

00:21:22.020 There's an enormous incentive to fix this problem, even if you personally have not experienced

00:21:27.280 it.

00:21:27.820 Society suffers as a result of it on both absenteeism and presenteeism.

00:21:32.260 So again, for those of us that have not experienced it, we have the sort of maybe stereotypical

00:21:38.820 impression of it.

00:21:40.220 I'm thinking of a person who has to lay in a dark room with a towel on their head.

00:21:45.140 and bear it until this thing passes, and it strikes without a warning, and it's a lightning

00:21:50.440 strike. And how many people are kind of walking around having migraines a couple times a year

00:21:56.500 and not knowing that it's a migraine? Is that a pretty rare phenomenon?

00:22:00.640 I think it's actually quite common. And I think the spectrum of migraine is very broad. I think

00:22:07.480 you elicited one person who is bedridden, but many people with migraine are significantly

00:22:14.240 impacted and walking around. And you'd never know necessarily that they're impacted unless you're

00:22:19.060 asking them or seeing their behaviors by the way they dim the lights or try to end up pushing

00:22:25.440 through. A lot of people with an invisible disease, I think back to a famous comedian,

00:22:31.640 Rodney Dangerfield, that I don't get respect. I think that's migraine, right? Where most people

00:22:35.920 think of it just as a headache without realizing it's a neurologic disease. And it disproportionately

00:22:40.560 affects women three times more often than men. Oh, wow. So 12% is aggregate. Correct. But if you

00:22:46.820 do the math. 18%. Yeah. It's disproportionately women. So almost one in five women. Correct.

00:22:53.080 I'm actually amazed it's that high. Yes. And the hard part is that demand for outstrip supply,

00:22:59.460 right? So demand for headache care, the number of people, number of clinicians across the country

00:23:04.100 that are providing and able to provide headache care, there's just not enough just because of

00:23:08.700 the numbers. There's not enough Bryans or other people. And then the training also is very 1.00

00:23:14.100 different. So I'm very fortunate not only to have had great mentorship, but to be able to mentor

00:23:19.600 the next generation of headache specialists, but there are 50 or so minted a year. It's just not

00:23:24.960 enough. There are only 50 fellowship trained headache neurologists that are coming out of

00:23:30.180 training a year-ish. Amazing. For a condition that affects 10, 12% of the population.

00:23:38.020 Correct. Yeah. We could almost come up with some interesting parallels there in terms of

00:23:42.300 how many dermatologists would be trained that could treat a dermatologic issue that affects

00:23:46.980 12% of the population. And the spectrum of migraine is so broad because we're just talking

00:23:52.440 about migraine as a disease, but there are people who have episodic migraine and then there are

00:23:56.480 people who have chronic migraine. So episodic migraine is where people have less than 15 days

00:24:02.820 of migraine per month. Chronic migraine is where people have experienced 15 or more days of headache

00:24:08.080 per month. That's most of the people that I'm fortunate to care for. And that's about one to

00:24:13.360 2% of the population that experienced 15 or more days. These people are thoroughly debilitated.

00:24:20.160 Half their time is in a state of headache. Correct. Okay. So 10% of the population

00:24:25.960 is experiencing up to 50% of their time in headache. One to 2% of the population experiences

00:24:32.000 chronic migraine where they have more than 50% of the time experiencing headaches. So the vast

00:24:37.600 majority of people experience episodic migraine, but that episodic migraine is a range, right? It

00:24:42.100 could be a couple of times a year to up to 50% of the month, up to 50% of the month. Yeah. Okay.

00:24:47.660 Before we get into treatments and other things I want to talk about, well, we could talk about

00:24:52.460 them now. Tell me a little bit about genetic susceptibility. Obviously genetics matter,

00:24:56.100 given the fact that women are three times more likely than men, that always makes the first

00:24:59.800 thing one might think is, well, is it hormonal? How much does it relate to estrogen, progesterone?

00:25:05.440 We know that there are receptors for these things in the brain. Does the frequency of this type of

00:25:10.500 headache, is it higher during the reproductive years? Is it higher during the menopausal years?

00:25:16.640 That would give us a clue as to the role of hormones. And then if during the reproductive

00:25:20.740 years, is it higher during any part of the cycle? That's a lot of information packed. I will try to

00:25:25.480 tease that apart. And so ultimately, yes, hormones plays a role. Yes, genetics plays a role. Migraine

00:25:32.460 is multifactorial in the sense that genetic environmental factors play a role in experiencing

00:25:39.100 migraine. So if somebody has a family history of migraine, they're more likely to end up

00:25:44.200 experiencing migraine. And through a woman's reproductive cycle and across hormonal milestones,

00:25:51.700 Migraine can certainly have a predilection around times of puberty, around times of menses,

00:25:58.660 pregnancy, lactation, perimenopause, and menopause.

00:26:02.980 And so across these hormonal milestones, migraine certainly will fluctuate, if you will.

00:26:08.340 I would say about two-thirds of women will experience migraines with perimenstrual attacks

00:26:13.960 with a nodal association of migraine around their menstrual period.

00:26:18.580 and that association comes in two possible forms. One is women who experience pure menstrual migraine

00:26:25.280 where they experience menses and headaches and migraine occurring around their menses

00:26:29.620 solely around their menses but not at other times of the month. That's less common. That occurs in

00:26:35.660 probably less than 10% of women who experience what's called pure menstrual migraine where the

00:26:40.700 migraine are just around the menstrual period, usually a couple days before and a couple days

00:26:45.260 into. Which of course is the lowest period of hormones, which suggests hormone deprivation

00:26:50.900 is driving that subset. Correct. And then menstrual-related migraine, which is present in

00:26:57.340 about 50% of women, is where they experience migraine not only in temporal association with

00:27:04.520 their menstrual period, but at other times of the month. And so this is a very common occurrence

00:27:09.280 for women. The estrogen, that dates back to the 1970s studies that were looked at, that natural

00:27:16.760 decline in estrogen in the late luteal phase and the development of migraine. If we fast forward

00:27:23.760 in time, what we know from studies is that it's the faster rate of estrogen decline in that late

00:27:31.640 luteal phase that is unique in women who experience migraine. So it's this more rapid

00:27:38.820 rate of decline in estrogen. I'm very proud because one of the people I was fortunate to

00:27:43.660 mentor actually did those studies. I'm surprised that we don't also see that post-ovulation because

00:27:49.640 you also have a very sharp decline in estradiol post-ovulation. They kind of have two. They're

00:27:54.400 sharp after ovulation and then not as sharp at the end of the luteal phase. Did they see anything

00:28:00.200 mid-cycle? So interestingly, around ovulation, there doesn't necessarily seem to be a much

00:28:07.660 higher risk of developing migraine. And I think that's in part to this more rapid,

00:28:13.240 faster rate of decline of estrogen in that late luteal phase, which is the unique part.

00:28:18.540 Yeah. It could also be the progesterone because we don't see, progesterone hasn't risen in

00:28:23.560 ovulation. You know this, but just for the listener. So we don't see a progesterone crash

00:28:27.540 post-ovulation, whereas post-luteal, we're seeing both estrogen and progesterone come down.

00:28:34.560 So is it possible that it's the combination of them or the progesterone that's causing the

00:28:38.860 problem? Right now, the belief is really the estrogen, that decline of estrogen, not the

00:28:44.160 decline per se, but the degree and rapidity of decline that is unique mostly in women who

00:28:50.240 experience migraine. The other couple of things to end up thinking about is we know estrogen can

00:28:55.620 have effects on serotonin transmission. And so serotonin is involved in migraine, right? If I go

00:29:00.920 back to the 1940s when serotonin was first discovered in blood, and then fast forward,

00:29:07.240 serotonin was identified and noticed to be lower in blood during migraine attacks, and then the

00:29:14.340 recovery phase would increase. Those studies ended up leading to the development of tryptans.

00:29:19.600 So estrogen has a number of different roles to play in the pain pathways.

00:29:23.780 Has the experiment been done where you take susceptible women and you selectively give them

00:29:30.220 estrogen during the period of time in anticipation of that? So for example,

00:29:35.820 seven days post-ovulation, which would be peak estrogen as it's about to crash into menses,

00:29:42.760 you give them physiologic estrogen replacement levels and does that mitigate any of this risk?

00:29:48.680 Yeah, so estrogen has been given, those studies have been done.

00:29:52.880 The hard part is predicting necessarily who is going to respond.

00:29:57.100 So there are some women that will get improvement in migraine.

00:30:00.600 There are some women, they may not get improvement.

00:30:04.480 And there are some women who will take combined hormonal contraceptives and they may get worsening of their migraine.

00:30:11.120 And so it's very hard to tease apart and know who's the individual that will necessarily respond.

00:30:16.040 And in caring for those patients, one of the things that I try to do that's unique is actually

00:30:21.120 in a collaborative care model, work with a gynecologist who is a specialist on hormones.

00:30:26.120 And so working together, we actually try to end up mapping out a plan for individual patients.

00:30:31.680 What else do we know genetically about predispositions?

00:30:35.120 Are people whose parents sufferers of migraines more likely to be sufferers themselves?

00:30:40.540 Yes.

00:30:41.200 People ask me why they have migraine.

00:30:42.660 And if there are parents in the room, I usually point to them and I say, you're the cause.

00:30:46.740 Not to place blame.

00:30:47.840 No, of course.

00:30:48.320 But we think it's very, very highly genetic then.

00:30:51.560 Correct.

00:30:52.260 But there are many genes that have been identified for migraine.

00:30:55.720 So it's not a specific gene.

00:30:57.000 So it's polygenic, but highly hereditary.

00:31:00.820 Correct.

00:31:01.560 And the nervous system, if you will, of people who have migraine is more hyper excitable

00:31:06.500 than people who don't have migraine.

00:31:08.240 So it's not that there's more lighter sound, but the perception, if you will, the sensitivity

00:31:13.800 has just increased.

00:31:16.540 Maybe a silly question you haven't thought of, but is there an evolutionary benefit to

00:31:21.120 it?

00:31:21.340 Not that this would have weighed heavily in selection, but is there an upside to the

00:31:25.600 hyper-excitability?

00:31:26.800 Does it manifest itself in other positive traits during the period of time when the

00:31:31.460 individual is not suffering?

00:31:32.840 My question is through the lens of like, hey, if we're on a continuum of excitability and

00:31:37.880 when the thing goes too far, you end up with a headache and that's bad. But if you pull back

00:31:43.340 just a little bit from the brink, is there some benefit to that state? So a colleague of mine

00:31:47.280 ended up writing about this a number of years ago where she postulated that the evolutionary benefit

00:31:53.100 to women in particular may have been, if they're the caregivers of their family, that they would

00:31:59.600 know if there was inclement weather coming, rainy storms, if they had end up, signs of danger. And

00:32:05.600 so that may be one of the evolutionary benefits. The other thing is, you know, if I think about

00:32:10.340 the neural networks in men versus women, women generally have to multitask much more than men

00:32:15.660 in general. And so the question is whether the neural networks, if you will, are better.

00:32:21.120 That is super interesting. So one of those says, look, women might be more wired to be better at 0.97

00:32:27.700 multitasking. And the migraine is just a manifestation of an extreme, more extreme

00:32:32.980 version of that, which you're going to get if you shift the population over that way? And then the

00:32:37.160 second issue is presumably through changes in barometric pressure. Is that the most common

00:32:42.060 weather-related triggering event? Triggers are not the cause of the headache. Triggers are factors

00:32:48.540 that will elicit a headache in somebody who's biologically predisposed. So meaning if somebody 0.97

00:32:53.540 is not biologically predisposed to having migraine, then there may be a weather storm that's coming

00:32:59.960 through and they may not experience a migraine. But in somebody who has migraine, they may have

00:33:05.460 one or more triggers. Some people with migraine have no triggers. Others have multiple triggers,

00:33:10.280 changes in weather, the letdown phenomenon after stress, drinking or eating certain types of foods

00:33:16.380 that may trigger. And it's usually a combination of two or more triggers that will precipitate

00:33:20.600 an attack of migraine. Do you have a sense of what subset of patients are indeed triggered by

00:33:26.000 weather patterns and changing barometric pressure? It varies from person to person. My patient

00:33:33.140 population is one that generally suffers more because it's more so in the people who are

00:33:39.080 experiencing 15 or more days of headache per month. And so that reporting bias may occur. I

00:33:43.580 may hear that more often than others may. That kind of makes sense. The more severely

00:33:47.780 impacted people would presumably have more diversity in their triggers as well?

00:33:51.900 Correct. They may, but not necessarily. And that's what makes migraine very nuanced, if you will. That's why the history needs to be detailed. So the questionnaire that people are filling out for me are 15 pages, pretty extensive in trying to end up determining if I'm dealing with a primary or secondary headache.

00:34:08.580 And then if it's migraine, how does it present?

00:34:11.660 Because a headache diary is probably the most important thing that your listeners can do

00:34:16.460 for not only themselves, because it really empowers patients, but for a clinician like

00:34:21.380 me to understand, because the patterns may be different from person to person.

00:34:25.800 Do you have an online version on your website that patients can download?

00:34:29.720 Yes.

00:34:30.160 Okay, so we'll link to that in the show notes so that anybody listening to this who wants

00:34:33.900 to actually have a diary and know what things to put in the diary, they can do it.

00:34:38.580 I agree. You know, it's funny. We live in this world where we're so obsessed with really high

00:34:42.780 tech things and sleep trackers and all these things. But honestly, like a sleep doctor,

00:34:46.900 if you go and see a sleep physician, they're going to want you to do a really good pen and

00:34:51.520 paper sleep diary. And we still give those to our patients who were in the biggest distress around

00:34:58.000 sleep because the information it captures is so much more rich, so much more temporally related

00:35:04.820 to what's happening. And two weeks of painstakingly doing this will offer more than two years of

00:35:11.400 tracker data. Sounds like very similar for you in getting a good diary. Obviously,

00:35:16.300 it might take more than two weeks given the frequency of the headache. 1.00

00:35:19.660 Yeah, usually we're looking at a period of several months, particularly if it's a woman

00:35:25.240 who's reporting a relationship between their migraine and menstrual period, because ultimately

00:35:30.520 to make a diagnosis of perimenstrual migraine, whether it's pure menstrual or menstrual-related

00:35:35.940 migraine, that association is known in at least two out of three cycles.

00:35:40.400 Obviously, thinking about the patient that first connected us 10 years ago, one of the things

00:35:45.160 that stands out about me, because she was a menopausal patient. This was a woman who

00:35:49.160 at the time was in her probably late 50s, early 60s. She did better on hormones, 1.00

00:35:55.820 but it couldn't be too much. There was a very, very fine line. In other words,

00:36:01.540 we ended up having to use estradiol and progesterone as you do in perimenopausal women,

00:36:07.500 but less than you would normally have treated someone. In other words, we couldn't take her to

00:36:11.960 full therapeutic dose. Is that common in menopausal women? 1.00

00:36:15.980 Those transitions, if you will, from perimenopause to menopause, not only are hormonal fluctuations

00:36:21.520 are occurring in perimenopause, but so is migraine. And so in a patient like that during

00:36:26.720 perimenopause, there are women that will experience a significant worsening of migraine.

00:36:31.820 Probably about two-thirds of women who, after they've transitioned to menopause,

00:36:36.260 they've finished perimenopause, they will notice improvement in migraine. But 10 to 20% may

00:36:41.340 actually either continue or get worse. I find that there's a fallacy where some patients are

00:36:47.480 told that once you hit menopause, you're finished and you're not going to have migraine anymore.

00:36:51.520 And the hard part becomes is it's not only the hormonal fluctuations, but the impact

00:36:56.540 on others' symptoms. So there may be sleep disruption, there may be other pains, joint

00:37:03.520 pains. And so there are risk factors that put one at greater risk for more frequent migraine.

00:37:08.680 If somebody experiences five or more days of headache per month, they're a greater risk.

00:37:12.520 Sleep disturbance, changes in mood, which can end up happening in perimenopause going into

00:37:17.340 menopause. So all of these things have either direct or indirect impacts potentially.

00:37:24.100 I mean, this just makes it a very complicated thing because now, in addition to all the reasons

00:37:29.060 you would consider HRT, you have to then consider if you're in that group of women who are improving

00:37:36.220 in menopause, presumably adding hormones makes you worse.

00:37:40.860 Not always.

00:37:41.680 I mean, unless you figure out that sweet spot like we did in this patient where

00:37:44.940 we could still give hormones to maybe two-thirds of the level without making it worse and then

00:37:49.880 still capturing two-thirds of the benefit or something. Yeah, there are, just like in this

00:37:53.460 patient, there are some women who will not necessarily need HRT or hormone-related therapy,

00:37:59.360 and there are others that, despite best efforts with non-medication and medication approaches,

00:38:05.840 will need HRT. The hard part becomes is, like you're pointing out, it becomes very individualized.

00:38:11.120 What may work, what dose may work for one person may not work for another and

00:38:15.200 too much may potentially exacerbate versus too little may not end up providing the relief that's

00:38:21.720 needed. Yeah. Anything else about presentation and susceptibility of migraine? I want to then

00:38:28.240 talk briefly about, see if we have anything to finish on tension and then get the cluster.

00:38:32.440 Yeah. So I think presentation of migraine is, I spoke about a couple of the phases and not all

00:38:37.120 people with migraine have all the phases of migraines. The first phase is that premonitory

00:38:41.820 phase, the calm before the storm, and a quarter to a third of people experience the aura. And then

00:38:47.140 it's the migraine phase, but it's not just the pain. It is potentially a constellation of symptoms,

00:38:52.060 that light sensitivity, the sound sensitivity, nausea. It may be autonomic symptoms. So if

00:38:58.000 somebody has tearing or redness of the eyes or congestion, running of the nose, often people

00:39:02.560 think that they have, quote, a sinus headache, but there's no such thing as a sinus headache.

00:39:05.820 There is acute rhinocytositis, there's chronic rhinocytositis, but based on the pathophysiology

00:39:12.200 of migraine, there is involvement of an aspect of the parasympathetic nervous system that

00:39:18.600 has a connection, if you will, with the nerve called the trigeminal nerve, which is the

00:39:22.180 main nerve that's involved in the experience of migraine and headache.

00:39:27.240 And when people's parasympathetic nervous system becomes activated, people may experience

00:39:32.140 tearing or redness of the eye or congestion ring of the nostril, which is pretty common in people

00:39:36.600 with migraine and they think they have, quote, a sinus headache. And then ultimately at the end

00:39:41.340 of the day, after the pain is gone, they can experience a post-trome, which is the pain is

00:39:46.660 gone, but I don't feel back to myself. I feel hungover. And that can last for hours up to even

00:39:52.700 a couple of days. And so when I take a history of migraine, I want to understand what's the total

00:39:57.420 impact, meaning if they experience all the phases, what is the duration of each of them?

00:40:03.300 What's the personal impact? Because we just focus on the pain, but not necessarily

00:40:07.120 the impact in totality. The other thing is the intractal burden. One of the things that you

00:40:13.780 pointed out, I really appreciate it, is how are people thinking about their plans, their daily

00:40:19.940 activities in anticipation of experiencing a migraine, meaning I'm not experiencing a migraine

00:40:25.420 now, but I don't know when it's going to come. How am I going to plan that vacation? That's

00:40:29.240 what's referred to as interectal burden. Interectal meaning between the pain bouts.

00:40:33.400 Between the pain bouts. And so that's where when I'm eliciting all these pieces of history,

00:40:38.940 I'm thinking about how am I thinking about their acute treatment plan? How am I thinking about

00:40:45.340 their preventive treatment plan if they need that? How am I thinking about non-medication

00:40:49.760 approaches? And then combining the picture together, obviously with the patient driving

00:40:54.720 the decision-making, once they understand the rationality of how I'm putting it together.

00:41:00.940 Can you say a little bit more about some of those post-ictal experiences? What fraction of

00:41:05.060 migraine sufferers, once the pain is gone, are largely able to resume activity versus those

00:41:11.640 that have that post-ictal period where they're not back to normal for a day or more?

00:41:17.580 There are population-based studies and there are clinic-based studies that have been done. So

00:41:21.120 population-based studies, looking at the general population, clinic-based studies like

00:41:24.720 Somebody would do an academic headache program like my own. Those numbers can range anywhere

00:41:29.080 from like 60% to in the high 80s. But it's still a big number.

00:41:34.060 It's a big number. The same thing with the premonitory symptoms, kind of that calm before

00:41:37.760 the storm. Okay. Now you said, by the way, for everything we're talking about here, 12% of the

00:41:42.460 population, three to one women to men, going back to tension, which we talked about very briefly,

00:41:47.380 you said that's the single most common cause. It's the anti-migraine. So it's all the things

00:41:52.220 that are in my migraine. What's the prevalence of that? Lifetime incidents maybe or lifetime?

00:41:56.080 That's pretty high. Yeah. A lot of people are going to experience that.

00:41:59.180 Yes. Okay. Female to male difference?

00:42:01.780 Pretty evenly split. What are some of the triggers and how genetic is it?

00:42:07.200 I think the name lends people to think necessarily that it's just tension or stress that causes the

00:42:12.320 headache. And that's not necessarily the case. That's why it's referred to as tension type

00:42:15.940 headache. And so that's the experience where people have that lighter sound sensitivity,

00:42:20.860 of mild to moderate pain that can be around the head, the muscles around the head, the muscles

00:42:26.180 in the neck, and the nerves that are involved, the anatomy and physiology, there's overlapping,

00:42:32.900 if you will, because the nerves that supply sensation to the face and the head and the neck

00:42:38.420 are similar to what's involved in migraine. They're genetic factors that are responsible,

00:42:43.020 they're environmental factors, and then there's pericranial or around the head, muscle nerve

00:42:47.860 tenderness, if you will, that's a contributing factor as well.

00:42:52.120 If a person has a tension headache and they take a thousand milligrams of Tylenol and they get

00:42:56.820 better, do they have a tension headache? Or in other words, could it respond to something as

00:43:01.100 simple and over-the-counter as that?

00:43:03.480 Yes.

00:43:03.980 Okay.

00:43:04.460 Yeah. As long as we know that that's what it is, that it's a tension-type headache, because

00:43:08.440 making any diagnosis not only meets criteria, but also that it's not attributable to something else.

00:43:13.840 Okay. And obviously we're going to come and talk about the potential treatments for these things.

00:43:17.860 So let's round it out with cluster then.

00:43:19.780 So what's a cluster headache?

00:43:21.680 So cluster headache is relatively uncommon,

00:43:24.820 pretty rare relative to migraine and tension to a pedic,

00:43:28.000 but it's one of the most painful disorders

00:43:29.780 known in the world.

00:43:31.340 I have a woman patient who's likened it

00:43:33.780 to giving birth to 100 babies at the same time

00:43:35.920 without an epidural.

00:43:37.220 I mean, that's the exquisite nature of the pain.

00:43:39.360 And so it's pretty distinctive in its presentation.

00:43:42.660 It disproportionately affects men more often than women.

00:43:45.940 so that ratio that is now about three to four to one. It has characteristics where people may have

00:43:52.960 a circannual periodicity or circadian periodicity. By that, I mean the longest and shortest days of

00:43:59.400 the year, January and February and July and August. People can experience cluster periods

00:44:04.480 where they may have daily or near daily attacks, sometimes multiple attacks per day.

00:44:09.300 And this pain often is conceptualized as in and around or behind one eye.

00:44:15.300 It's usually almost exclusively side-locked, so just on one side of the head or the face.

00:44:20.980 The rapidity of onset is very quick.

00:44:24.740 Unlike migraine, which generally will gradually build up,

00:44:28.580 cluster headaches peak within about 5 to 15 minutes.

00:44:32.080 The attacks generally last anywhere from 15 minutes up to 3 hours

00:44:37.240 and can be characterized as stabbing, boring, exquisite in nature.

00:44:43.520 And then as soon as it came can often be as soon as it goes.

00:44:48.520 And with the pain, people can end up getting very characteristic features.

00:44:52.080 About 97% of patients can experience a droop of the eyelid on that side,

00:44:57.320 a tearing or redness of the eye on that side, congestion or running of the nostril.

00:45:02.120 And so not only can you see the experience on the person's face,

00:45:06.440 but you could actually see the visual symptoms often. And about 90% of people with cluster

00:45:11.600 headache can experience a sense of restlessness with the attacks where they can't sit still.

00:45:15.480 They need to move about. That's in contrast to migraine where the vast majority prefer to

00:45:19.340 be still or lie down in a dark, quiet room. And so the presentations are very, very distinctive.

00:45:26.300 And where cluster headache has also been nicknamed suicide headache, not only because of the

00:45:30.680 intensity of the pain, but the frequency of which these attacks occur. So on average,

00:45:36.260 people can experience three attacks per day. The criteria allow people to have one attack every

00:45:41.640 other day, up to eight attacks per day. And these cluster periods could be, depending on the person,

00:45:47.480 weeks to months, sometimes longer. So depending on if somebody has episodic cluster headache,

00:45:52.360 where they get this cluster period and then a break in time, or chronic cluster headache,

00:45:56.580 where they have no break at all. They're just having multiple attacks per day.

00:46:00.080 Does the term suicide headache stem from the fact that people will take their life if it's extreme enough?

00:46:05.940 Yes.

00:46:06.540 That's terrifying. Does that suggest that the drive to move provides some relief?

00:46:13.640 I don't know if the drive to move provides relief as much as the areas in the brain that are involved during the attack of cluster headache can cause manifestation of symptoms.

00:46:27.020 And one of those manifestation of symptoms is a sense of restlessness or agitation.

00:46:31.420 What else do we know about these things?

00:46:32.460 How genetic are these? 0.94

00:46:33.760 We know that there are genetics that play into cluster headache as well.

00:46:38.000 First degree realms may be at higher risk.

00:46:40.260 Like I said, it's not common, but these are very highly motivated patients, just like

00:46:46.280 migraine, but maybe even more so because of the exquisite nature.

00:46:50.460 They also, like migraine, often go underdiagnosed or misdiagnosed because of the presentation

00:46:55.620 of pain, because it can be a predilection for attacks to occur January and February.

00:47:00.700 So people may come into their doctor at that period of time, say that I have pain, I have

00:47:05.560 nasal congestion, and they may be told, oh, you have a sinus infection.

00:47:09.620 then receive an antibiotic. July and August, they may come to their doctor and say,

00:47:14.020 I have pain, tearing, or redness of the eye, and they may be told, you have allergies.

00:47:18.480 You need allergy shots. Some people will have pain that's around the teeth or the face,

00:47:23.820 and they have had teeth pulled or major dental surgery or sinus surgery without realizing

00:47:30.020 that the presentation is actually clusterheading. Part of the log that people can download from

00:47:37.620 your site that allows them to take an accurate history. Is that something they could take into

00:47:41.520 their primary care physician if they're having a headache? And does it highlight enough for the

00:47:46.520 doctor the flag that says, hey, this might actually be a cluster headache, and this might be one of

00:47:51.700 the times when, even though it's hard to get to headache specialists because of the frequency or

00:47:56.640 the low number of them, it's worth taking the time to get the right clinician on board before we make

00:48:02.540 a mistake and treat you for something you don't have. Yes. I think that becomes very important.

00:48:08.000 I think about my primary care colleagues and the number of things that they have to address

00:48:13.060 in a relatively short period of time. And headache may be just one of them. And I think

00:48:17.040 that's the hard part. So we want to kind of arm patients with a ton of data so that when they

00:48:23.620 meet their PCP, they can do the lifting for them. The 10 minutes that that primary care doc has,

00:48:28.620 they're not going to be able to do the detailed history you would do, but if they can walk in

00:48:32.340 with it, hopefully the doctor is receptive and says, oh gosh, yeah, I wouldn't have had the time

00:48:36.980 to elicit this or wouldn't have even had the knowledge base to elicit. I was about to say,

00:48:40.200 it's not only receptive, it's the time. It's also having the knowledge and education experience

00:48:45.920 to make the diagnosis and then offer the appropriate treatments. All the stars need

00:48:51.220 to align, if you will. Most people with headache, if they're coming in, they're not coming to me

00:48:56.360 for the first time. Sometimes they do, but they're often going to their primary care. So that's the

00:49:00.840 gateway, if you will. The hard part becomes is kind of navigating afterwards, the gateway,

00:49:05.900 particularly if they don't have a diagnosis or they're misdiagnosed.

00:49:09.380 And patients come and see you from all over the place.

00:49:11.540 All over the world.

00:49:12.220 Yeah. That means that obviously a lot of them can't see you when they're in the throes of

00:49:16.020 suffering. Does that matter?

00:49:17.920 So for patients with cluster headache, that's kind of the password, if you will, in my office,

00:49:22.100 in the sense that if somebody who's either an established patient or somebody who's trying to

00:49:26.200 get in, they will say that they have cluster headache. And if in fact they, at least on the

00:49:30.880 basis of their questionnaire, seem to check off information that alludes to that possibility,

00:49:37.180 then yes, they're seen quicker in general, just because it's been nicknamed suicide headache.

00:49:42.660 Is there a benefit to you seeing them while suffering to make a diagnostic or treatment

00:49:46.920 decision? Yes. And the reason why is often patients with cluster headache require multiple

00:49:52.640 treatments. One could be acute treatment, meaning when they experience the attack, they're using

00:49:57.780 a treatment to rapidly abort the pain. The other is a preventive treatment. So they're taking

00:50:03.960 something, one or more things to prevent attacks because often these patients with cholesteroid

00:50:09.840 are experiencing frequent attacks a day over a period of potentially weeks to months. And then

00:50:16.080 transitional treatment. The preventive treatments often take weeks to months to build up, even for

00:50:21.800 migraine. And so what is being done in the transitional period? Sorry to interrupt, Brian,

00:50:27.540 when you say preventive treatments, do you mean lifestyle preventive treatments like changing

00:50:32.440 diet or do you mean actual pharmacologic prophylactic drugs that you need to just have

00:50:36.800 on board to reduce the probability of an attack? Yeah, so a multidisciplinary approach. So meaning

00:50:42.140 for patients with cholesterol headaches, some of the examples would be avoiding alcohol,

00:50:46.520 avoiding foods with nitrates, not taking naps during the day, preferably. If they have a sleep

00:50:52.440 apnea, addressing that because hypoxia can sometimes be associated with it as well. And

00:50:57.460 then at the same time, preventive treatment is taking a pharmacological, right, a medication

00:51:04.160 treatment that may take time to build up. And while that is being built up, offering something

00:51:11.640 to try to rapidly suppress the attacks until those preventive treatments kick in.

00:51:16.720 Yeah. Well, let's use that to pivot to the first thing that you talked about there,

00:51:23.360 which is what are the modifiable lifestyle interventions that you would keep in your

00:51:28.720 playbook for these patients? And are they the same across all the headaches? Everything you

00:51:35.940 just said, for example, around correcting sleep apnea, minimizing alcohol, avoiding naps during

00:51:40.920 the day, would you give that advice to any person suffering from headache, or are you really

00:51:45.740 narrowing that on the cluster patient, whereas the migraine patient, you have a different playbook?

00:51:50.620 Migraine itself has certain identified risk factors. Even the subtypes of migraine may have

00:51:56.440 their own identified risk factors. So if we know from studies that were done that if somebody is

00:52:02.700 experiencing at least one migraine a week, more than that may put them at greater risk for more

00:52:09.160 frequent attacks of migraine. So the higher the frequency of attacks at baseline maybe lead to

00:52:15.360 chronification or transformation of more frequent migraine. Somebody who has stressful life events,

00:52:20.380 right? We all do, but that's a risk factor as well. Sleep disturbance. That may be insomnia.

00:52:25.920 That may end up being sleep apnea. So once again, modifiable. Person's mood. Depression and anxiety

00:52:33.860 are comorbid with migraine. They coexist at a higher than expected by chance. And there's a

00:52:39.020 bi-directional relationship between mood disorders and migraine. And so addressing those, that's why

00:52:44.120 I try to explain to patients that all the stars kind of need to align. It's not just taking care

00:52:49.640 of your pain, but we need to end up addressing these risk factors. People frequently using acute

00:52:54.420 pain medications. So there are some classes of pain medications where if they're used two or more

00:52:59.800 days per week on a regular basis over an extended period of time, that can actually create more

00:53:05.020 frequent headaches. It doesn't happen for everybody. That could be NSAIDs and acetaminophen

00:53:08.580 or opioids. It could be nonsteroidal anti-inflammatories, simple analgesics. It could

00:53:11.880 even be triptans, migraine-specific medications. It could be barbitric-containing combination

00:53:17.160 analgesics, medications like fioracetofioranol, opioids. And then if somebody has other pain

00:53:24.360 disorders, obesity is a risk factor for more frequent migraine. And the greater the degree

00:53:29.040 of obesity, the greater the risk. And do you think that's inflammatory? Do you think it's

00:53:33.220 insulin-related? It's probably multifactorial as well. Migraine itself has a pro-inflammatory

00:53:39.520 component to its pathophysiology, and so there may be shared mechanisms that underlie that.

00:53:46.060 And is this modifiable if a person is... So first of all, do you know what the hazard ratio is or

00:53:50.120 the increase in relative risk with obesity versus not with respect to the headaches?

00:53:54.320 So people who are morbidly obese are at five times higher risk for more frequent migraine.

00:53:58.140 Oh, so it's not subtle.

00:53:59.060 It's not subtle.

00:53:59.860 This is dramatic.

00:54:01.000 And there are studies with weight loss, surgical and non-surgical, showing improvement in migraine,

00:54:07.840 not uniformly across the board for every individual, but certainly showing improvement.

00:54:13.700 Modifying that risk factor is very helpful as well.

00:54:17.120 Some of these numbers are shocking. 0.94

00:54:18.620 The women being three to one is not shocking with my lived experience because when I stop

00:54:23.720 to think about it, almost all of the people I've encountered with migraines, or most of

00:54:28.440 them are women. I get that. The obesity is 5X. That is surprising.

00:54:34.260 Morbidly obese. 0.91

00:54:35.200 Okay. So morbidly meaning 35 BMI?

00:54:37.700 Yeah.

00:54:38.040 Yeah.

00:54:38.400 But what about obese? What about 30 to 35?

00:54:40.940 Greater risk.

00:54:41.680 How much? 2X?

00:54:42.700 2X.

00:54:43.300 Okay. Still a big deal.

00:54:44.500 Yeah.

00:54:45.020 So in other words, if you're looking for a reason to correct obesity, there are plenty

00:54:51.340 of them on a health perspective as it pertains to chronic disease like heart disease and

00:54:55.840 cancer. But when you think about two dramatic things that improve the quality of your life,

00:55:00.580 one would be orthopedic. You just have less wear and tear on your joints. And then another could

00:55:05.200 be for the susceptible individual, these headaches. Correct. And then having other pain disorders,

00:55:11.460 which you just alluded to, whether joint pain, neck pain, back pain. Which leads you to more

00:55:15.500 of the medications that then also become the trigger. And has that been corrected for in the

00:55:19.320 analysis? Yes. Having other pain disorders in and of itself puts one at greater risk. Having

00:55:23.940 the presence of nausea, nausea that's not optimally treated. If a migraine attack is

00:55:29.000 suboptimally treated, also greater risk. So when I'm listening to history, I'm almost doing this

00:55:35.640 computational analysis and then explaining to people, here's how I'm thinking about it. This

00:55:41.340 is why your treatment plan is being designed this way. And no two people are going to necessarily

00:55:46.220 have the same treatment plan. That's what you were asking in terms of migraine versus cluster.

00:55:51.200 Cluster headaches, certainly we're going to talk about lifestyle modifications,

00:55:54.580 but it may be things that are particular triggers, whether it's the food, the nitrates,

00:55:59.560 the sleep apnea, taking naps during the day. With migraine, it's what are those risk factors

00:56:04.960 and how do we address not only the disease migraine, but also those risk factors to try

00:56:09.360 to prevent progression. Okay. Just to play that back, make sure I heard it. Prophylaxis on the

00:56:14.400 cluster side is around identifying the triggers. What's the thing that's making it happen?

00:56:20.480 On the migraine side, it's because there are fewer acute triggers that we are aware of,

00:56:26.680 it's more just generally reducing probability of it happening?

00:56:30.840 Let me clarify.

00:56:32.080 So for cluster headache, it's not the triggers.

00:56:34.900 Those are things, lifestyle changes that I may suggest to them.

00:56:39.460 It's the pathophysiology and the mechanisms that are underlying cluster headache that

00:56:45.300 will precipitate attacks potentially at different times of the year and different times of the

00:56:50.060 day or the night because there's involvement of the sleep-wake cycle. And that's why people have

00:56:55.560 this circanual periodicity and this circadian periodicity because there's involvement of the

00:57:01.140 hypothalamus and the pineal gland and the changing of the clock for daylight savings time. So I know

00:57:05.980 when the clock has changed, I'm going to hear from people with cluster headache.

00:57:08.600 In both spring and fall?

00:57:09.960 Yeah. I mean, I have patients, I have a patient from Australia who, when he travels there,

00:57:14.240 he'll get cluster attacks because the season's changing when he comes here, if he

00:57:17.920 comes with the differences and how much of that do you think is fixable with circadian

00:57:22.860 rigidity in other words if you said to a patient look bob i don't care that we're going to change

00:57:28.560 the light we're going to get a 50 000 lux light in your home and we are going to make sure that

00:57:36.080 your pituitary your hypothalamus your pineal gland every part of your brain is seeing light

00:57:43.540 and darkness at the exact same again i'm using this as a thought experiment right but it

00:57:47.920 we are going to completely control your light environment independent of the seasons.

00:57:53.360 Would that have an impact?

00:57:55.120 I don't think that's going to eliminate a person's cluster headaches.

00:57:59.440 I think what it will do is if somebody is not necessarily going to areas or time zones

00:58:06.740 where there may be seasonal changes, they may not necessarily experience cluster attacks,

00:58:12.980 but that's not a certainty.

00:58:14.880 And how often do you just take an empirical approach to this and say, look, we're going

00:58:19.180 to throw the kitchen sink at this two interventions at a time until we find things that work?

00:58:23.760 I mean, for example, we do this all the time with dietary sensitivities.

00:58:27.060 So you get a patient who's just got debilitating bloating and GI issues, autoimmune conditions

00:58:33.180 that aren't otherwise easy to identify.

00:58:35.560 And one path is I'm going to run a bunch of blood tests on you that are totally bogus 0.98

00:58:40.700 and bullshit and made up and have no verifiable causes. And I'm going to come up with a bunch of 0.98

00:58:45.340 silly recommendations and give you a bunch of dumb supplements. Obviously, that's not our approach, 0.98

00:58:49.480 as you can tell by my language. An alternative approach that seems way less scientific,

00:58:54.380 but frankly works a lot more is we're going to do an elimination diet. We're going to hypothesize

00:58:59.460 that something in your diet is causing this, and we are going to selectively and ruthlessly pull

00:59:04.600 things out of your diet until we find the trigger, which means pull it out, wait for an improvement,

00:59:10.140 reintroduce it one at a time and watch to see if we can precipitate it. And this is how we will

00:59:16.500 figure out the role of dairy, alcohol, caffeine, wheat, all of these things. Again, seems less

00:59:22.980 scientific, way more practical than using bogus metrics that don't mean anything. Do you ever do

00:59:28.760 the same thing in the headache landscape? Yeah. So a big focus of what I do is on lifestyle.

00:59:33.560 How do we modify things that will set that person up for best success that may be triggers or

00:59:39.980 that help reduce risk factors. I try to take a very calculated approach. I also try to understand

00:59:45.340 the person who's sitting in front of me. How willing are they to be empirical?

00:59:49.260 So it's, what's the diagnosis? What are their coexisting medical conditions?

00:59:54.520 What's their preference? What are their expectations? Before I start a visit, I ask

00:59:58.940 people, what are the one or two most important questions I can answer today? And I want to

01:00:03.280 understand that person's perspective. It's not enough to end up giving them the medical

01:00:07.300 information, but I want to make sure it aligns with how they're thinking about it. And then it

01:00:11.200 becomes very tailored. If I'm thinking about lifestyle modification, we're focusing on diet,

01:00:17.680 routine meals a day that are not delayed. And if there are particular food triggers, asking them

01:00:22.700 to track with the headache. Unless I understand the individual, I don't necessarily ask them to

01:00:27.500 eliminate everything at the same time. I also want to know if there's a family history of

01:00:31.460 either gluten sensitivity or celiac disease. And so that may lead me down the path to end up

01:00:36.640 thinking about them getting tested for that. But there are certain, like you said, certain foods

01:00:42.560 that may be triggers for certain people. Alcohol may be triggers, but not everyone.

01:00:47.080 And that's why I say it's very individualized. And then the importance of sleep, hormones,

01:00:53.360 environmental factors, exercise, and reducing trigger burden. So meaning if somebody knows

01:01:00.620 that I may be set up for an attack at this particular time, then I may say, okay, you may

01:01:06.160 be able to mitigate that risk by doing X, Y, and Z. And an example of that is when people keep

01:01:11.720 headache diaries and they may experience attacks on the weekend. I'll say, okay, so what happens

01:01:17.400 during the week? You go very hard, endorphin levels go up and then they drop down. And then

01:01:23.000 you go to sleep later on Friday night and you wake up later on Saturday and your caffeine intake is

01:01:27.200 delayed. That's three triggers. And so then people have like the aha moment. Oh, I didn't realize

01:01:33.020 that. And this is especially valuable when they're doing the log because you can see during the week,

01:01:37.880 I have my coffee at six in the morning. On Saturday, I'm not even getting up till eight

01:01:41.560 o'clock in the morning and having coffee at nine. And you wouldn't think of that.

01:01:44.860 Right. And those are the nuances that I point out. And usually the diaries that I ask people

01:01:48.560 to keep are a month view. And so that way I'm able to quickly glance and actually pull the

01:01:54.880 diary off into patients and I'll say, okay, here's how I'm thinking about and interpreting this.

01:01:59.660 This is why we're going to end up using these treatments.

01:02:02.720 And so an example would be if someone experienced menstrual migraine, which is quite common,

01:02:08.000 I may say, oh, okay, so your menses, how long does it last?

01:02:11.920 What's the intercycle length?

01:02:13.160 What's the length in between the cycles?

01:02:14.800 What's the characterization of the flow?

01:02:17.480 When do you experience headaches in relationship to that?

01:02:19.900 I see that it is the same every single time.

01:02:22.860 Because of that, that timing, we may be able to use preemptive treatment.

01:02:27.120 we may be able to actually start treatment in advance and then carry it through the days that

01:02:32.860 you would normally anticipate it. The diary, it's an effort that not only empowers patients,

01:02:38.100 but really helps guide decision-making. Yeah. I like that you're talking about this because

01:02:42.620 it's a great call out to patients for why you want to invest in this effort. Let's admit it,

01:02:48.140 it's a bit of a pain to have to fill out one of these diaries, to have to write down what time

01:02:51.880 you go to bed, what time you wake up, when your period starts, how long it lasts, what the

01:02:55.520 characteristics of it are when you have caffeine, when you have alcohol, when you work. I mean,

01:02:59.220 that's a lot to keep track of. It's a 20-minute added burden every day.

01:03:03.760 And I thank people for it. I said, listen, I know you're putting in effort.

01:03:07.440 But it pays huge dividends. We don't need to go through every single lifestyle adjustment because

01:03:12.980 all the ones that are in the obvious category are worth stating. Everyone who has sleep apnea

01:03:19.240 should have it corrected. Everyone should exercise. Everyone should moderate alcohol

01:03:23.140 intake. Everyone should be sleeping a certain period of time. Everyone should be trying to fix

01:03:28.500 bedtime and wake-up time relatively. Everybody should be doing circadian health, etc. Is there

01:03:34.120 any non-obvious lifestyle thing that you can think of? A couple of things that I would think about

01:03:40.260 that. So one is I'm not sure when I see patients whether every risk factor is weighted the same

01:03:49.580 way. There may be some that if somebody is not getting enough sleep and insomnia is quite common

01:03:55.120 in people with migraine, that we may be able to try the best medications in the world. But if

01:03:59.260 they're not addressing that, it's going to get harder to get that under control. I think the

01:04:04.440 regularity, migraine has that hypersensitivity. And so if people are adhering to routine meals,

01:04:13.940 drinking enough water, exercise, getting appropriate sleep, which is not so easy,

01:04:18.680 because sometimes they have to employ non-medication approaches, which are hard to do,

01:04:22.640 but ultimately pay dividends. I think the important also thing that people may not think

01:04:26.920 about is that stress reduction, whether it's meditation, biofeedback, cognitive behavioral

01:04:31.640 techniques. Autonomic control. Correct. I think people, not everybody, but I think some people

01:04:37.460 sometimes focus on the medications and don't realize it's a holistic approach. It's looking

01:04:43.380 at the whole individual and trying to kind of present those lifestyles in the way of being

01:04:49.500 able to end up helping their migraine and making them feel better overall.

01:04:52.900 Yeah. And as you said right there, it's a double win because if we get those things right,

01:04:57.240 you're getting a benefit outside of the realm of your headache. All those things are actually

01:05:01.020 just better for your risk of chronic disease, your health span and other capacities as well.

01:05:05.720 So let's now talk a little bit about pharma through both lenses, the prophylactic lens,

01:05:11.340 the things that you would have somebody take all the time to reduce the probability or severity of

01:05:16.920 an attack. After that, we'll talk about the treatments that you would use acutely as a rescue

01:05:22.160 medication. We're going to do it by class of drug. We can talk about it by class. We can also then

01:05:27.640 talk about it by pros and cons of each drug, success rate, or things like that. I think I'd

01:05:32.780 start off first by saying, what are the goals of preventive therapy? Because I think that's

01:05:37.020 important for your listeners to know. The idea of using prophylaxis or prevention is not to cure

01:05:42.960 headache, is not to cure migraine, but to ultimately reduce the frequency, intensity,

01:05:47.940 or duration of attacks. It also helps improve potentially responsiveness to acute treatments.

01:05:54.120 It can, by using prevention, you can reduce disease burden. You can end up producing

01:05:59.060 progression of migraine. So as I said, people who experience more frequent migraine are at

01:06:04.380 greater risk for developing even more frequent migraine attacks. It could end up improving

01:06:10.400 other comorbidities. So some prevention may be helpful with sleep. Some prevention may lead to

01:06:16.860 potential for weight loss. And so you may be able to leverage some of those benefits as well.

01:06:22.720 The other thing is, is it improves functionality and quality of life, which is obvious, but it

01:06:28.020 also ends up helping reduce interictal burden. So that was one of the things I was talking about,

01:06:32.900 where people have this almost anticipatory anxiety.

01:06:35.900 So there are multiple goals for using prevention.

01:06:38.560 The indications for using a preventive medication

01:06:41.020 are as if somebody is experiencing frequent attacks

01:06:44.400 or attacks that are very disabling,

01:06:48.820 even despite acute treatment.

01:06:50.080 If somebody has rare types of migraine or headaches

01:06:54.700 that may limit their ability to use certain acute treatments,

01:06:58.660 or if acute treatments are either contraindicated,

01:07:01.120 poorly tolerated, or ineffective,

01:07:02.900 And so that's where some of the indications for preventive therapy, the preventive therapy

01:07:08.000 come into a number of classes, which you're alluding to.

01:07:11.120 Before we do that, Brian, just to close the loop on that point, overall, all comers of

01:07:16.180 people who suffer from migraine, what percentage do you think do not meet criteria to justify

01:07:23.600 the drug burden of a preventive drug?

01:07:25.880 So I would say probably about 40% or so of people with migraine may be eligible for

01:07:32.700 prevention. Eligibility is, I don't just mean through the lens of reimbursement on insurance,

01:07:38.120 but in your mind, medically justified. 40%, yes, 60%. They don't have it enough or it's not severe

01:07:44.320 enough to justify. And we can do enough good with an acute medication. Once again, looking at

01:07:49.060 population-based studies. Yeah, your population is going to be totally discute. My population,

01:07:52.240 in the vast majority. The hard part is that the discrepancy or the gap, if you will, where 40%

01:07:58.260 of people may be eligible based on indications for migraine prevention, but only like 16 or 17%

01:08:05.080 are actually receiving preventive therapy. And how much of that is economic where their

01:08:08.380 insurance companies don't cover? These drugs can be pretty expensive. Yeah. So I think it's varied.

01:08:12.680 I think it may end up being that it's not recognized by the treating clinician and it

01:08:18.120 may be economic. So I think there are a number of different factors. And then what about on the

01:08:22.180 cluster side of things, at the population level, what percentage of patients, does it make sense

01:08:27.140 for them to be on prophylactic therapy? Again, in your population, I'm sure it's much higher.

01:08:31.480 I'm going to say even outside of my patient population, the vast majority. So unless the

01:08:36.720 cluster period is a week, which is not the norm, if it's going on weeks, months, yes, the vast

01:08:44.740 majority of those people are going to need, every one of them, I would say, are going to end up

01:08:48.920 requiring a preventive therapy. And then on tension headaches, presumably none? So it depends.

01:08:55.240 So there are people who experience episodic tension type headache less than 15 days per month.

01:09:00.060 And then there are people who experience chronic tension type headache that experience 15 or more

01:09:04.940 days of tension type headache per month. It depends on the frequency responsiveness to

01:09:11.100 acute treatments that are being used or other modalities and then functionality and impact

01:09:16.220 on quality of life. Okay. Let's talk about some of the drugs that are used to reduce risk here.

01:09:22.560 So let's start with beta blockers. That's literally one of the only things I remember

01:09:25.860 is the triptans and the beta blockers, but I think the triptans are for acute. But anyway,

01:09:30.120 let's start with beta blockers. I remember that from USMLE studying. Is that still used?

01:09:34.220 Yeah. Okay. Beta blockers are a class of blood pressure medications. The exact mechanism how

01:09:40.060 they work isn't known. It's postulated that it may have effects on the sympathetic aspect of

01:09:45.240 the nervous system. And so two of the beta blockers that are FDA approved are propanolol

01:09:52.020 and timolol, but there are other beta blockers that are used as well. They can be very effective

01:09:56.080 for people. Once again, there's caution if somebody has asthma. So there are different

01:10:00.760 types of beta blockers. So it can potentially exacerbate asthma. Potential side effects

01:10:05.500 include lowering of blood pressure, heart rate, or exercise intolerance. That's the other reason

01:10:09.880 why I say it's really important to understand the person so that you're using a preventive

01:10:14.320 treatment that aligns with that person, their lifestyle, their risk factors, their comorbidities.

01:10:19.260 But yes, that could end up being helpful. And that's mostly for migraine.

01:10:22.960 Correct. And then what about antidepressants?

01:10:26.800 Yeah. So antidepressants have been used for years.

01:10:29.040 Which is a dumb term, by the way. I cannot stand that that class of drug is called 0.86

01:10:34.680 antidepressant. I'll save that rant for another day.

01:10:37.500 No, I think it's an important rant. And what I explain to patients is there are supplements or

01:10:42.860 medications that are used for prevention of migraine that weren't specifically designed

01:10:46.580 for migraine prevention, but through serendipity or studies were found to be helpful for migraine

01:10:52.320 prevention. And by using one of these medications, it doesn't mean that they have high blood

01:10:57.280 pressure. It does not mean that they have depression. Yes, we know depression or anxiety

01:11:01.700 can exist at a higher than expected by chance in migraine, but please, they should not assume

01:11:07.760 that that's the indication that I'm using it for. My gripe goes even further, Brian,

01:11:11.920 because I actually think some of the things that antidepressants, quote unquote, work best for

01:11:16.860 are not even depression. It's not even dysthymia, anhedonia. I actually think when you look at mood

01:11:23.400 stabilization, anxiety, migraines, those are places where they can really work. And the stigma

01:11:30.400 that goes around the drug prevents people from utilizing it. It's just infuriating.

01:11:34.980 I agree with you. Migraine itself has its own stigma. But yes, I think there's a high degree

01:11:40.220 of stigma. And that's why I explain to patients, even in using this class of medications, this

01:11:44.520 antidepressants, the doses that are often being used are not even doses that would be starting

01:11:50.080 doses to treat depression. And so that's why I like to make that distinction, let them know that

01:11:55.200 if we're using a medication like amitriptyline and nortriptyline, often the doses we're using

01:11:59.960 are much lower than what would be needed to treat depression. And rarely are these medications used

01:12:05.900 to treat depression anymore. So they can be very effective. One of the potential side effects,

01:12:10.060 could be some tiredness. And so usually there are medications that are taken before they go to sleep

01:12:15.460 and because if somebody has difficulty falling asleep, that potential side effect of tiredness

01:12:20.400 may actually be helpful, not for every patient, but for a number of people with migraine who have

01:12:25.700 insomnia. Do we have a sense of why? Presumably it ties to serotonin and norepinephrine. Is that

01:12:32.060 basically our belief? Yes. Okay. And then what about on the anti-epileptic side? Talk about

01:12:37.280 getting a patient anxious, right? It's like, we're going to give you a drug for epilepsy.

01:12:41.000 Yeah.

01:12:41.380 Yeah. Is that GABA related? What do we think is the pathway there?

01:12:44.420 I think it depends on the anti-seizure medications, two that are FDA approved or

01:12:49.880 topiramate, which is known as Topamax and valproic acid known as Depakote. These medications have

01:12:56.280 different mechanisms of action. So for topiramate or Topamax, that can work on particular

01:13:01.680 channels, which is what you spoke about early on, but also has effects on glutamate and GABA.

01:13:08.900 And so glutamate is the excitatory neurotransmitter in the brain. GABA is the

01:13:12.540 suppressor, if you will. That can be very effective for people who have a migraine.

01:13:17.600 So does it enhance GABA and suppress glutamate, presumably?

01:13:20.300 Yeah. That can be very effective for people, but it does have like every other medication

01:13:25.260 potential side effects. And then valproic acid or Depakote, once again, can have effects on

01:13:31.040 GABA as well. That medication also may be helpful, but also has potential side effects. And it's

01:13:36.780 really important that we go back to the patient population where I have migraines. I'm not only

01:13:41.320 sympathetic, but empathetic. But the vast majority of people who have migraine are women. And so it

01:13:46.460 really becomes important when we're thinking about women during their reproductive years,

01:13:51.740 if they're sexually active, what form of contraceptive they're on. That's another

01:13:55.620 piece of information that becomes important in setting a preventive plan. I'm trying to avoid

01:14:00.920 then or at least counsel patients on the possibility that some of these medications

01:14:07.160 may not be safe during pregnancy. So I want to understand that piece.

01:14:11.060 I didn't realize you had migraines, by the way. So did you have them even at the time

01:14:14.660 when you were a neurology resident? Do you think that's part of what allowed you to take such a

01:14:17.940 good history? So I did have them when I was a neurology resident. I'm not sure that ended up

01:14:22.800 giving me a leg up on taking a history. And the reason why is many people that I see with migraine

01:14:28.280 who experience it, they know what it feels like. Often it's hard for them to put into words. They

01:14:34.000 have to like pause, reflect, think about their answers. Not always, but some people. I really

01:14:40.180 like the fact that it's a group of people that I can really help. And sadly, there are not a lot

01:14:48.240 of people that have the knowledge or information on how to do that in a systematic fashion.

01:14:52.900 Okay. The class of drug that I remember when it came about were these monoclonal antibodies. In

01:15:00.700 fact, the patient that we keep referring to, I remember being one of the first patients on it

01:15:05.240 because you got her into a clinical trial and it was a resounding success. Can you say a little bit

01:15:10.340 more about these drugs and their utility today? The class of what are called CGRP or calcitonin

01:15:17.500 gene-related peptides, I think in order to be able to speak about the class, I'd probably have

01:15:21.920 to give a little bit of background on the pathophysiology of migraine.

01:15:25.300 Absolutely. And this is a podcast where we don't shy away from depth. So treat this as though

01:15:30.980 you're giving a lecture.

01:15:32.660 Okay. Always trying to understand my audience. I'll speak a little medicalese and speak English

01:15:37.120 at the same time.

01:15:38.020 We're 25% physician by audience, by the way, it's crazy.

01:15:41.140 I love it. The brain itself is insensate. It's not pain sensitive, but the coverings around the

01:15:45.740 brain, like the meninges, or specifically the dura, and the blood vessels that are both within

01:15:52.560 the dura and in the brain have pain-sensitive nerve terminals, nerve endings. And the main nerve

01:15:58.220 that's involved in migraine is the trigeminal nerve. If we go back in time to probably the 1940s,

01:16:04.100 the thought of migraine is that there was a vascular hypothesis, where the thought about

01:16:09.840 migraine is it was purely a vascular phenomenon. There was dilation of blood vessels that occurred

01:16:15.340 during the pain phase and then a constriction that occurred during the, so to speak, recovery

01:16:19.640 phase, if you will. With the advent of increasing research, particularly over the past, I would say,

01:16:25.680 50 years, we know that that model is just too simplistic. So now we know that it's a

01:16:30.440 neurovascular phenomenon. And so that there's involvement of not only the nervous system,

01:16:35.700 but the cranial blood vessels as well. And so what ends up happening is that these nociceptive

01:16:42.540 or pain-sensitive information is conveyed from these pain-sensitive structures. So the

01:16:47.560 dura mater, that covering around the brain, and the dural and intracranial blood vessels.

01:16:51.940 And then it's laid back centrally along a nerve called the trigeminal nerve that has three

01:16:57.320 branches, primarily along the first division, the ophthalmic division of the trigeminal nerve,

01:17:02.180 passes through an area called the trigeminal ganglion, and then synapses or connects in an

01:17:07.440 area of the brainstem called the trigeminal nucleus cordalis. That pain sense of information

01:17:12.840 is carried back there. At the same time, nerves that supply sensation to the back of the head,

01:17:18.560 the neck, and the shoulders from the upper cervical roots in the neck, so C1, C2, C3,

01:17:24.700 carries information back primarily C2 and C3 into the same area of the brainstem, which is why people

01:17:31.420 with migraine often will have associated neck pain, or people with tension-type headache will

01:17:36.420 have associated neck pain, where they may not realize that it's a referral pain pattern because

01:17:41.820 of this convergence of information. Now, when those nerves become stimulated, people can experience

01:17:47.800 peripheral sensitization. If they're turning their head or bending down, they can get a throbbing

01:17:54.100 type of feeling that can occur early into a migraine. And when pain-sensitive information

01:17:59.460 goes back to the brainstem, if there's sustained firing of nerve cells, people can get central

01:18:04.900 sensitization. And one clinical marker for that, that presentation, is the phenomenon of allodynia,

01:18:11.700 that uncomfortable sensation to things that normally aren't uncomfortable. That's the putting

01:18:16.280 the hair back in the tight ponytail and brushing hair that generally will kick in about 30 to 60

01:18:21.760 minutes or so into a migraine headache. And then using triptans during that time may be less

01:18:27.080 effective. So that's the reason why knowing if somebody experiences that with their migraine

01:18:31.940 becomes important when you're advising them when to treat.

01:18:35.260 And we'll come back to the tryptans when we talk about acute treatments.

01:18:38.520 And then that pain sense of information then travels from the brainstem to the thalamus,

01:18:44.100 which is kind of the sensory processing area of the brain.

01:18:46.540 So there's some nuclei like ventropostomal medial thalamic nuclei that are involved.

01:18:51.460 And then from there, gnosis of the information then goes to the sensory cortex of the brain

01:18:56.520 and then other pain matrix areas of the brain.

01:18:59.020 Now, while this is all occurring, there's a cascade of events that occurs. So that trigeminal nerve

01:19:05.060 information has a reflex with that parasympathetic information in the brainstem, which is why people

01:19:12.660 can experience those autonomic symptoms, the tearing, the redness of the eye, the congestion

01:19:16.980 or running of the nostril. At the same time, parasympathetic innervation is related to the

01:19:22.620 cranial blood vessels, the blood vessels within that dura mater, with that covering around the

01:19:27.680 brain and the intracranial blood vessels, and people can experience dilation of blood vessels

01:19:32.160 and the release of chemical messengers or neurotransmitters. So things like substance P

01:19:38.880 neurokinin. I haven't heard substance P in years. Okay. I'm happy to bring you back. I'm happy. I

01:19:44.620 love it. And then calcitonin gene-related peptide, or what's known as CGRP. At the same time,

01:19:50.360 there's a pro-inflammatory response that occurs, what's called neurogenic inflammation, and then

01:19:55.860 release of histamine, male cells, nitric oxide. Once again, a full cascade of events.

01:20:01.700 This becomes important because through studies that have been done over the years,

01:20:06.460 studies that looked at jugular venous blood noted elevations of CGRP during migraine,

01:20:12.180 that calcitonin gemulopeptide. Those studies led to the possibility that this may be a target

01:20:16.700 for migraine treatments. And then when sumatriptan or imatrex came on the market,

01:20:23.440 there were studies that looked at patients who were treated with it and what happened to their

01:20:29.740 CGRP or calcintone gene-related peptide levels, and they normalized. So meaning they were increased

01:20:35.400 during migraine, and then the use of sumatriptan would end up normalizing levels. And so there was

01:20:39.800 like that aha moment. And that's what led to the class of what are known as CGRP antagonists. And 0.78

01:20:45.720 the CGRP antagonists are kind of broken down into two buckets. One are what are called large

01:20:53.320 monoclonal antibodies, which is the medication that our patient was placed on, and then small

01:21:00.420 molecules, what are known as G-pants. So that's kind of the history that led into the formulation

01:21:06.020 of that class of medication. These are drugs that are administered intravenously at what frequency?

01:21:12.140 The CGRP antagonists, the large monoclonal antibodies, three of them are self-injection

01:21:20.540 medications, almost like EpiPens. And those medications have a long half-life, so roughly

01:21:26.740 about 28 days. They're administered in a monthly fashion, or every 28 days, and that's the three

01:21:34.980 of them. There's one that's actually given quarterly as an effusion every three months.

01:21:40.020 Any difference in efficacy?

01:21:42.300 Varies from person to person. There are no large head-to-head studies of these medications.

01:21:47.100 That's the challenge with being able to end up using data to end up answering that question.

01:21:52.500 So basically, you might start with the home-use pen because it's easier. I assume it's cheaper.

01:21:58.620 If they're failing those things, you would have to just go with the quarterly infusion.

01:22:03.180 Right. So that's one reason. The other reason is what the insurance will

01:22:06.580 dictate in terms of what they will allow me, the clinician, to prescribe.

01:22:10.940 These have changed the game though. Obviously, I'm biased perhaps by my small, small sample set

01:22:16.240 of the patients I know that have had a significant improvement with these, but

01:22:19.280 across your clinic, which is very high risk, but obviously very diverse,

01:22:24.660 how much have these been an improvement in mitigating onset and severity?

01:22:29.640 Significant improvement.

01:22:30.680 The biggest change you've seen in your clinical practice?

01:22:33.300 Yes.

01:22:34.220 Wow.

01:22:34.460 It doesn't mean that they work for everyone.

01:22:37.600 For what fraction of patients do they not work?

01:22:39.380 So they probably work for up to 60% or so of patients with migraine.

01:22:44.200 That's why I say sometimes there is trial and error.

01:22:48.040 The other thing is there are some people that will be much quicker responders than others.

01:22:52.780 So some people will get benefit within the first month with these medications.

01:22:57.140 Other people may take up to three to four months.

01:22:59.520 And when you say 60% success, does that mean 60% of patients who take this drug regularly

01:23:04.440 will no longer suffer migraines? No, there's a spectrum. So it's like oncology where success is

01:23:11.020 a partial response, a complete response, and you're including the partial response in here as

01:23:14.960 well. Correct. In oncology, a partial response has a very specific definition, which I won't bore

01:23:20.000 listeners with. How are you defining a partial response? Based on what information the patients

01:23:25.380 are providing me. Doesn't have to be at least a 50% reduction. Correct. That would be wonderful

01:23:31.000 if I could end up providing people who have 30 days of headache per month for 20 years,

01:23:36.120 a 50% reduction. But sometimes the timeline, and once again, it's usually a multidisciplinary

01:23:42.560 approach that I'm employing in order to be able to continue for building on incremental gains.

01:23:48.500 As difficult as it might be to get this data from a patient unless they're very good at logging it

01:23:52.760 and their temporal history is very consistent, are there people in the 40% group that we're

01:23:58.420 considering non-responders who have no abatement in frequency, but severity does go down and or

01:24:04.720 responsiveness to acute treatments improves? Or does that automatically put them in the 60%

01:24:11.040 bucket? For me, I'd probably put that group into the 60% bucket. But once again, there are people 0.99

01:24:17.560 that will get variable ways of getting improvement. That's where the diaries become

01:24:23.220 very important to understand. Yeah. Sorry to just harp on this, but given the importance of it,

01:24:27.620 When a patient does not have success on this drug, do you have a sense that most people will have the ability to progress through all of them so that we know that, hey, if you're going to fail this treatment, you've failed the class?

01:24:42.540 No. I'm very happy that you're raising this point. If somebody doesn't respond to one of the

01:24:47.700 treatments within the class, that does not dictate that they're not going to respond to another

01:24:52.120 treatment in the class. And the challenge becomes is I can't tell by looking at somebody if they're

01:24:57.060 going to respond to one medication in the class versus another. We don't have biomarkers, and so

01:25:02.320 we can't end up telling. But ultimately, I do tell people that if one may not work, another one may.

01:25:09.020 Again, it's an important lesson, I think, for clinicians, although I would hope most people understand this. Whenever you're using these monoclonal antibodies, by definition, because different drugs have different patents, they have to have different IP, meaning they can't be the same molecule, which means they could be binding to different parts of the epitope.

01:25:27.060 and therefore when you look at a person's genetics and not everybody has the same receptor

01:25:33.440 as an example and therefore just because one drug doesn't bind perfectly doesn't mean another one

01:25:38.600 won't we see this by the way with pcsk9 inhibitors in the lipid space where if you don't respond to

01:25:43.120 one you might respond to the other and vice versa super interesting you mentioned the oral equivalent

01:25:49.120 of these as well yes so there are oral medications that are known as g pants that are small molecule

01:25:56.620 CGRP antagonists. These medications have shorter half-lives, and there are fewer of them. There

01:26:04.400 are a couple that are oral, and there's one that is a nasal spray. These medications can be used

01:26:11.240 acutely when somebody ends up having a migraine. One of them has an indication both for acute and

01:26:18.660 preventive treatment. Yeah, that's autogepent or something like that? Atojepent. I can't even

01:26:25.320 pronounce the drug. That's okay. That's okay. That is for preventive treatment. That's not one that

01:26:29.680 you can use acutely. No, that would not be used acutely. Remedjapant, or what's known as NERTEC,

01:26:34.440 has an indication for preventive and acute treatment. Gubrogapant or Ubrelvi, which is

01:26:40.700 another medication in that class, has an FDA approval for acute treatment, a migraine.

01:26:46.040 Got it. Do you have a sense, by the way, what the out-of-pocket cost on these drugs is?

01:26:49.620 They're expensive. All of these medications are expensive.

01:26:52.680 thousands of dollars a year, I'm assuming, if it's based on other monoclonal antibodies.

01:26:56.660 And then do you have a sense of what patients that come to see you do have insurance coverage

01:27:00.440 on these? It's variable because there are so many plans. And then within the plans, there are

01:27:05.440 high deductible, low deductible, big copays, low copays. Yeah. That's the biggest frustration I

01:27:11.860 would say, both for patients and for people like myself who are caring for them. Yeah. And if it's

01:27:16.640 like every other drug in the United States, we're paying probably three to 10x what the rest of the

01:27:23.580 world pays for the same drug. Yes. Some of these drugs get so expensive that it's cheaper to fly

01:27:29.020 out of the country to get the drug and bring it back. I have patients who do that and I have

01:27:34.720 patients who live outside the country. They have an easier time in some respects of getting these

01:27:40.400 medications and paying for them. I used to take care of a patient with type 1 diabetes who used

01:27:46.020 to fly to europe to buy his insulin and it was still cheaper to fly first class to europe stay

01:27:53.160 at the four seasons buy his three months of insulin put it in a cooler fly back he saved

01:27:59.900 money doing this can you just imagine the absurdity of this uh sadly yes because i have

01:28:06.480 patients who fall into that category i think the hard part also is maybe the short side if you will

01:28:12.620 meaning the cost of these medications may be very expensive.

01:28:17.260 It's trivial compared to the economic cost.

01:28:19.940 The personal costs, the trips to emergency rooms,

01:28:24.080 the lost costs in insurance of people at work,

01:28:27.700 lost work time and productivity.

01:28:29.700 I mean, it's just, it's short-sighted, I think.

01:28:32.640 Rounding out this list, calcium channel blockers and Botox, correct?

01:28:37.940 Yeah.

01:28:38.340 Yeah, let's talk a little bit about those two.

01:28:39.780 So calcium channel blockers doesn't have as much data for prevention of migraine. More classically,

01:28:47.160 it's used for prevention of a headache like cluster headache. But still, people may end up

01:28:53.500 using calcium channel blockers, which is a blood pressure medication for prevention of migraine.

01:28:58.740 And they're doing this at a lower dose, I'm assuming, as well?

01:29:01.400 A lower dose, but sometimes the doses are increased, particularly in patients with

01:29:04.960 cluster headache.

01:29:05.800 So what do you do if you have a normotensive person with cluster headaches? How do you

01:29:09.360 treat them with verapamil? There are some patients that I have where usually in collaboration with

01:29:15.040 a cardiologist, there's one patient I'm thinking of that I just recently saw where this person was

01:29:21.020 on at one point over a thousand milligrams of verapamil. And for your audience to know that

01:29:26.040 is an exceedingly high dose. Once again, EKGs need to be checked, blood pressure, pulse needs

01:29:30.780 to be checked, tolerability needs to be checked. But that was the dose that was needed and that

01:29:34.500 person tolerated it amazingly. And obviously it reduced significantly the frequency of cluster

01:29:40.620 headaches. Correct. It's the trade-off in pharmacology, right? Right. Nothing comes

01:29:44.700 without a side effect, but the side effect can often be well worth it. And then you mentioned

01:29:48.880 Botox. Botox. When I think about Botox, I think about tension headaches, but does it also play

01:29:52.680 a role in migraines and clusters? Surprisingly, Botox doesn't work well for tension type headache.

01:29:59.080 Okay. Yeah. It's a good thing I'm not a neurologist. Okay. You have me on set, so I'm

01:30:04.260 more than happy to help. Serendipitous finding that Botox was helpful for migraine. There was

01:30:09.040 a plastic surgeon, Bill Binder, in California, who was giving it to patients cosmetically and

01:30:15.160 then was told by patients that, you know, my headaches are getting better, my migraines are

01:30:18.920 getting better. And that's actually what led to Botox or anobotulinum toxin being studied for

01:30:27.700 prevention of migraine, specifically chronic migraine. So that's whereby people experiencing

01:30:33.740 15 or more days of headache per month, that's where Botox has mostly been studied and where

01:30:39.880 it has the current FDA approval for that. And so it's not by cosmetic effects that it works,

01:30:47.720 but actually it interferes with the release of certain SNR and SNAP proteins, certain proteins,

01:30:53.840 and also involvement in CGRP, calcitonin gene-related peptide. Once again, we come back to this.

01:30:59.520 Because of systemic delivery?

01:31:01.580 So it has effects on pain pathways.

01:31:04.720 Pardon my ignorance.

01:31:06.080 Okay, so obviously this was discovered probably on the face and forehead because that's where

01:31:10.000 he was administering it.

01:31:11.400 Is that how it's administered today?

01:31:13.520 So the protocol went through a number of iterations until the current protocol, which is called

01:31:19.180 the PREEMPT protocol, which is standard across the world, where injections are given in the

01:31:24.900 forehead, on the sides of the head, the back of the head, the neck, and the shoulders.

01:31:29.220 and they're given around areas where there are superficial nerves. The postulated mechanism

01:31:36.480 is that it may have interference in the release of certain vesicles and certain proteins called

01:31:42.980 sneer and snap proteins, as well as CGRP, which is that chemical messenger, that neuropeptide we

01:31:49.780 were talking about heavily involved in migraine. How many patients that qualify for this are able

01:31:56.760 to get insurance coverage? Because this would be even more expensive than monoclonal antibodies.

01:32:02.000 I mean, Botox must be insanely expensive. So not necessarily relative to the monoclonal

01:32:06.820 antibodies because the monoclonal antibodies... I guess you're taking them every week,

01:32:10.580 whereas you do this maybe quarterly. Right. And the Botox is administered quarterly.

01:32:16.200 Yeah. Okay. The insurance companies won't let me say, oh, of course, Dr. Grossberg,

01:32:20.420 you can end up prescribing Botox. You think this person has chronic migraine.

01:32:24.000 often they will ask me or mandate that I have to try at least two or three conventional

01:32:30.200 non-migraine specific preventive therapies and either try and fail or been poorly intolerant

01:32:36.440 to them before they let me end up looking at Botox for prevention of chronic migraine.

01:32:41.640 Got it. Okay. So let's talk about the rescue drugs. You're now in the throes of a headache.

01:32:47.100 What can you do? So there are many classes that we end up using.

01:32:51.140 There are non-migraine-specific classes, and then there are migraine-specific classes.

01:32:56.340 Non-migraine-specific, so analgesics like acetaminophen, non-steroidal anti-inflammatory

01:33:02.240 drugs like NSAIDs.

01:33:03.720 Do opioids play any role here, notwithstanding the loaded nature of addiction and things

01:33:08.460 like that, or dependency?

01:33:09.740 We go back to the risk factors for migraine chronification, and one of the risk factors

01:33:14.600 is medication overuse.

01:33:15.900 And the two largest culprits for the possibility of medication overuse are opiates and

01:33:21.040 barbitric-containing combination analgesics like fioracet or fioranol, which is even banned in some

01:33:26.400 countries in the world. Opioids or this class of medications, the barbitric-containing combination

01:33:32.080 analgesics, even used a handful of times per month, even if it's not for migraine. The nervous

01:33:37.200 system, once again, may not like that, and they have a particularly high risk for medication

01:33:43.620 overuse. Is the issue that? In other words, is the issue that if we give patients these drugs

01:33:50.500 the probability of excessive use becomes high enough, which is itself a trigger?

01:33:56.120 Yes. Or a potentiating mechanism.

01:33:58.500 I see. Okay. So in other words, you would not prescribe these in your practice.

01:34:03.380 You have enough other tools that you're not going to do that.

01:34:05.400 Once again, opioids for me are a last line. After people have explored everything, if you will,

01:34:14.180 Even in the emergency room, we really try to end staying away from opioids just because

01:34:20.440 of this potential.

01:34:21.980 In terms of migraine-specific medications, triptans were the first class that was specifically

01:34:27.880 designed for the acute treatment of migraine.

01:34:31.100 What predated that were the agotomines, which are still used.

01:34:35.300 And so these are medications that come from a particular type of fungus that have effects

01:34:40.120 on serotonin, which is heavily involved in migraine.

01:34:42.360 And so they work on not only serotonin receptors, but they work on other receptors as well.

01:34:49.160 Whereas tryptans work specifically on certain subtypes of migraine receptors, namely what

01:34:54.920 it's called 5-HT1B, 1D receptors.

01:34:58.480 And the 1B receptors have different effects.

01:35:01.460 Those are on smooth muscle cells.

01:35:03.840 And so they are involved on that aspect.

01:35:06.560 and the 5-HT1D are involved in some of the chemicals that are neurotransmitters that are

01:35:12.260 released. And so tryptans, the advent of them really ended up was a game changer for migraine.

01:35:18.400 And even now- 20, what, 30 years ago? We're probably going back to the 1990s.

01:35:24.160 Yeah, mid-90s maybe. Yeah. Ultimately, sumatriptan was the first one. It was in

01:35:28.680 tablet and injection form. It's also available in nasal spray. And then since that time,

01:35:33.360 there are six more that came along. So there are seven triptans in total. 1.00

01:35:37.340 Are these drugs like statins or GLP-1 agonists where each new version gets more effective and

01:35:44.700 has fewer side effects? Not necessarily. So there are plenty of people, sumatriptan was the first

01:35:50.960 one. Some people may be sensitive to sumatriptan versus some of the later triptans. One of the

01:35:58.780 potential side effects of triptans is a sense of warmth or heat or tightness

01:36:02.180 anywhere in the body. It's usually short-lived, but for some people, it's extremely uncomfortable.

01:36:08.060 Flush, like a niacin flush?

01:36:09.460 Yeah, like a flushing. And then other people use simitriptan, no issues whatsoever, right?

01:36:14.460 Like, God made this for me. Some of the half-lives of the triptans may be different. 1.00

01:36:18.960 So there may be some that are quicker onset, some that may last longer. And so that's where

01:36:26.480 the decision-making may come in. Some may be tablet versus a melt versus a nasal spray versus

01:36:33.080 an injection. And so depending, once again, going back to that attack profile, presence of nausea,

01:36:39.560 we know that both during and in between attacks of migraine, there can be delayed gastric motility

01:36:44.480 or gastric stasis. So absorption of medications may be slowed. And so if I need to think about

01:36:50.320 absorption and rapidity of onset of attack and speed of the treatment and trying to bypass the

01:36:56.420 gut. I may be trying to choose one formulation over another. So all of these factors help me

01:37:03.220 hone in on the decision-making. Intuitively, my gut says, no pun intended, the intranasal would

01:37:11.780 have more efficacy than the oral. It would go intranasal, I am, then oral in terms of the

01:37:19.680 speed with which they respond. Is there any truth to that? I'm going to switch the order a little

01:37:23.680 bit. So IM intramuscular is actually quicker. The sumatriptan is available, injectable. So the

01:37:32.160 quicker onset sometimes needs to be balanced versus the, so to speak, if somebody experiences

01:37:38.260 a side effect, it may be more heightened than what they're taking as a nasal spray or as a

01:37:42.840 tablet. So they may feel that flesh into me. So the oral would have the lowest amount of that,

01:37:47.660 given that pharmacokinetics. Because of the pharmacokinetics. And that may be potentially,

01:37:51.620 obviously. This may be different if I'm, let's say, treating somebody with migraine versus

01:37:56.100 cluster headache. So cluster headache, if I'm using sumatriptan, I'd really love to end up using

01:38:01.560 the injection because the median time to pain relief may be like nine minutes. So for somebody

01:38:06.780 who really needs quick onset because they're having a rapidly onset attack, that's like,

01:38:13.260 God made this for me. It's a preloaded pen that they can carry around with them?

01:38:16.540 So often it's a preloaded pen that they give themselves an injection. Or if somebody's

01:38:20.620 experiencing a migraine attack at night that wakes them up from sleep or builds up quickly.

01:38:24.780 The nasal spray, that bioavailability that you were talking about, doesn't pan out for all the

01:38:30.180 nasal sprays. So the sumatriptan nasal spray, and there are a couple of them, but we'll talk about

01:38:35.800 the, not a brand form of sumatriptan nasal spray, but the, so to speak, the generic or the form of

01:38:41.860 sumatriptan nasal spray, the bioavailability is not so great. It's higher in Imatrex than it is

01:38:48.300 for generic sumatriptan, you're saying?

01:38:50.960 The nasal spray itself,

01:38:52.500 there are other brand formulations of sumatriptan,

01:38:55.960 like nasal powder, if you will.

01:38:58.060 The nasal spray of sumatriptan,

01:39:00.840 the bioavailability across the nasal mucosa is not so good.

01:39:04.140 So the absorption sometimes is actually

01:39:06.060 by swallowing something that doesn't taste so good.

01:39:08.800 The zomatriptan, which is known as zomig nasal spray,

01:39:12.300 which is a triptan,

01:39:13.280 and zavagipan or zavzapret,

01:39:15.860 which is a G-PANT, once again, that's in the class that we were talking about, that CGRP

01:39:21.380 antagonists, those bioavailabilities are higher. And so that's where somebody may end up getting

01:39:28.060 faster relief. Okay. Success rate for these across all comers?

01:39:32.980 So looking at triptans or for any acute treatment, I'm looking at speed of onset,

01:39:38.660 improvement in associated symptoms, functionality, which is very, very important. Generally,

01:39:43.900 the mark of time that's used is by two hours, then what's the rate of recurrence or the rate

01:39:49.740 of return of headache either that day or within 24 hours. And certain tryptans may have a higher

01:39:55.880 recurrence than others. And so that's where the decision-making is used based on all the factors

01:40:02.460 that patients tell me about. Okay. Outside of these treatments, what about any sort of electrical

01:40:07.600 stimulation tens have any of these other things shown any benefit yeah so you're referring to

01:40:14.240 the class or tms i'm sorry i said tens but what i meant was tms yeah neuromodulation devices right

01:40:19.180 so the idea of neuromodulation is a stimulus is being used and that stimulus may be in various

01:40:25.060 forms it may be magnetic stimulation may be electrical stimulation that targets some system

01:40:32.300 if you will, in this case, the nervous system. And there are different forms of neuromodulation

01:40:38.520 that have postulated mechanisms that work on different targets based on the pathophysiology

01:40:45.680 or the anatomy of migraine. So one example would be a device that delivers stimulation to the nerves,

01:40:52.720 the superficial branches of the trigeminal nerve over the eyebrow. So there's a device that will

01:40:58.020 do that. And that works by, so to speak, suppressing pain transmission, if you will,

01:41:03.900 superficially to end up having effects centrally within the nervous system.

01:41:08.180 There are devices that will stimulate electrically the vagus nerve. That can also be helpful for

01:41:15.440 prevention and acute treatment of migraine. What I'm talking about are external devices.

01:41:20.020 These are devices that can be applied or held, not necessarily implanted. I think that becomes

01:41:26.160 an important point of distinction. A device like remote electrical neuromodulation, which is an

01:41:31.480 armband device called Nervio that is worn on the arm that's operated by an app on the phone that

01:41:37.280 delivers a level of stimulation to a nerve in the arm that relays messages to the brain that uses

01:41:42.200 the brain's own natural mechanisms to down-regulate pain. And that's used as a prevention or a

01:41:48.280 treatment? That particular device has an indication for prevention and acute treatment of headache.

01:41:55.380 How successful is it in each domain?

01:41:57.540 Across neuromodulation, there are varying successes.

01:42:00.800 There are no head-to-head studies of these devices where medications have to be FDA approved.

01:42:06.380 Devices get FDA cleared.

01:42:08.240 Our headache center was actually the lead site in the world that led to that FDA clearance

01:42:11.940 for that armband device.

01:42:13.320 And so once again, depending on the study, the benefits are pretty significant depending

01:42:18.780 on the patient and the attack profiles, if you will.

01:42:21.840 Are these devices expensive?

01:42:22.800 They can be depending on the devices. So some of them are bought, like the device that's worn on

01:42:28.940 the head that delivers stimulation. The device that applies vagal nerve stimulation is actually

01:42:34.080 kind of like rented or leased. And so there's a monthly payment for that. The armband device has

01:42:39.380 a certain number of treatments within a month. And so that's purchased or gets some reimbursement

01:42:45.820 through insurance. And then there's another device that delivers stimulation both to the nerves in

01:42:50.760 the front of the head as well as the nerves in the back of the head. That can be purchased or

01:42:54.480 quote rented or leased as well. Are you under the impression that a lot of patients who are

01:43:00.060 suffering from headaches don't even know these devices exist and therefore they're missing out

01:43:04.240 on another therapeutic opportunity? Yes. The devices themselves may be used either as first

01:43:11.260 line or in conjunction or as rescued depending on the person and their attack profiles. I think

01:43:17.100 the hard part becomes is some people are coming in waiting for a prescription in the form of a

01:43:22.600 medication. Some people, because of the cost prohibition, may not want to end up looking at

01:43:28.160 devices. But there may be other people that have preferences. I prefer not to be on a prescription

01:43:33.520 medication to the extent possible. Can we try nutraceuticals or supplements? Could we end up

01:43:39.440 trying neuromodulation devices? If it's somebody who may be looking to get pregnant, we may for 1.00

01:43:46.460 that aside from patient preference, but if we're looking for people who are in that period of time

01:43:51.820 and during that time, even though the devices have not necessarily been studied during pregnancy,

01:43:58.660 one of them has for acute treatment, knowing their mechanisms of action, they're not associated

01:44:03.660 with medication, it's presumed that their safety and tolerability would be okay during that period

01:44:09.200 of time. Do we know anything about THC or cannabis directly? It's interesting that you ask that.

01:44:14.380 Mixed things, right?

01:44:15.400 Yeah.

01:44:15.700 Yeah.

01:44:15.980 So we actually ended up doing one of the largest studies looking at use in our patient population,

01:44:22.600 an academic headache program of people using cannabinoids.

01:44:26.100 And what we found, which was about a third of our patient population are using cannabinoids.

01:44:31.500 And so the hard part becomes it's not everybody's using.

01:44:36.520 And in the study, did you standardize the vehicle or was it an outpatient?

01:44:40.680 Outpatient survey study.

01:44:42.360 It's next to impossible because.

01:44:43.740 we have no roots, formulations, combinations, right? It's very hard. The other challenge

01:44:49.160 becomes is even those people who say that they may get benefit, the question becomes is what

01:44:53.800 else are they doing? Right. What else are they doing? Is it direct benefit for headache? Is it

01:44:57.580 indirect benefit by helping with sleep or anxiety that may be comorbid with migraine? So I think

01:45:02.880 that's the hard part to tease apart. The other challenges is sometimes it's hard to advise

01:45:07.600 patients because we don't know about the potential drug-drug interactions. So no one's done or is

01:45:12.540 doing an RCT where you're using a pharmacologic consistent grade of THC and trying to identify

01:45:20.800 the actual effect of the active agent delivered in a standardized way?

01:45:25.800 There is a study that was done that looked at it for acute treatment of an attack using one

01:45:32.240 formulation. Because of regulatory concerns, these are really hard studies to implement. There's a

01:45:37.660 company right now that is also looking at doing larger studies in the future on this. So I think

01:45:43.260 those studies will come, but they're going to be very slow. But these have to be done as almost,

01:45:47.920 I think you almost have to have the patients come in to be administered the drug because it's

01:45:51.280 schedule one. Correct. Yeah. The feasibility is not so easy. Yeah. Brian, is there anything we

01:45:56.880 haven't talked about as far as headaches that people should know from a primary perspective?

01:46:03.940 So I think from a primary perspective, what I would end up saying is people should have hope in the sense that it's very important to be as empowered as possible by keeping a log of information, by providing their clinicians or the treating physicians or providers with the details of their headache and recognizing the importance of those lifestyle factors, which can't be overstated.

01:46:28.860 I often think about an equation of expectations over reality, E over R.

01:46:33.280 What is their reality? 0.96

01:46:34.740 What are their expectations?

01:46:36.340 How do I try to match it as long as the expectations aren't necessarily exceeding reality?

01:46:40.900 I think it's important for people to take ownership, which is not so easy.

01:46:46.340 Some people will say, you're the doctor, you tell me what to do.

01:46:49.720 I have to say, well, we're partnering together.

01:46:51.820 This is a partnership.

01:46:53.560 Recognizing that preventive medications may take weeks to months.

01:46:56.460 I often say that this is not Amazon Prime.

01:46:58.860 I know we live in Amazon Prime Society. You know, everybody's used to next day delivery, but

01:47:02.660 often good things come to those who wait. We're building on incremental gains.

01:47:07.240 And so I'm sometimes cheerleading people, if you will. Then in thinking about the overall

01:47:13.180 frequency of attacks, knowing that preventive options, sometimes people need one or more

01:47:20.060 preventive medications. It's not one size that fits all. So it really is a very tailored approach

01:47:25.600 for acute treatment. It's also knowing and for clinicians to know that not everybody is

01:47:31.700 necessarily going to respond to one acute treatment. They may need a backup. They need

01:47:35.260 a rescue treatment. So I think that's important. For patients who are very debilitated, there are

01:47:41.180 also intravenous medications that can sometimes be used to try to suppress a prolonged attack

01:47:47.500 that may be known as status migranosis, where a migraine is occurring for longer than three days,

01:47:52.160 like that first patient I was telling you about who had a prolonged migraine for six weeks,

01:47:57.700 and then recognizing that ultimately at the end of the day, it's a marathon, not a sprint.

01:48:02.980 I just want to spend a minute on secondary causes because I want to make sure that people

01:48:06.960 understand that if you're having a headache for the first time or a headache that's not

01:48:10.320 well characterized and documented as one of the ones we've spent the last couple hours on,

01:48:14.840 you're not missing something medically. So when a person experiences a headache,

01:48:18.480 not to create fear because I'm guessing most of the time 99 times out of 100 it is not going to

01:48:24.680 be a mass effect or a vascular lesion or something but I'll give you an example of something that has

01:48:30.000 now come across my radar twice meaning I've known two people in the last year who have had CSF

01:48:35.460 leaks one was traumatic so they fell skiing and then over the ensuing months they just kept getting

01:48:44.160 these headaches and it took months to figure out, oh my God, you have a leak of the CSF

01:48:50.980 and we're going to go down the path of fixing it. In the other case, it was an individual

01:48:55.540 who had a spontaneous CSF leak. And you can imagine how long it took to figure that out,

01:49:02.560 which says nothing of how difficult it was to treat that. So I don't know. Do you want to say

01:49:07.700 anything about CSF leaks? My bias is like, oh my God, these are occurring all the time,

01:49:11.900 but they're clearly not, but they're debilitating and they're easy to miss.

01:49:15.540 I think maybe if I could provide some pieces through the mnemonic that people should be aware

01:49:22.980 of that may raise concern. So if somebody is having new onset headaches or a change in the

01:49:29.860 headache pattern, that may be something that they want to speak to their doctor about.

01:49:33.740 If they're having associated fevers, rashes, a headache that's painful to flex their head and

01:49:40.820 touch their chin to their chest, that may be signs of something that's concerning. If somebody is

01:49:45.720 having unintended weight loss, that may be a reason too. So those systemic symptoms. If somebody is

01:49:51.600 having new types of headaches or change in a headache pattern during pregnancy, once again,

01:49:57.020 migraine can occur during pregnancy, but as a general rule, migraine without aura improves

01:50:02.720 during pregnancy. And so probably about 47% people notice and women notice improvement in the first

01:50:08.680 trimester and then 80 to 87% or so in the second and third trimester. I think that's estrogen

01:50:14.880 related, presumably. Yeah. Once again, if it's worsening, there are people who can have new

01:50:19.620 onset migraine where migraine may not improve. But if that's the case, that would be something

01:50:24.740 that I would look at a little bit more closely. If people are on medications that suppress their

01:50:29.100 immune system and they're starting to have headaches or experiencing more frequent headaches,

01:50:32.720 I'd look at that. If somebody is having neurologic symptoms with the headache, so

01:50:36.420 weakness, numbness, problems with speech or language, double vision, loss of vision,

01:50:41.760 problems with balance. If somebody is older than the age of 50 with a new type of headache or a

01:50:47.380 change in the pattern, we have to think about secondary conditions, one of them being temporal

01:50:52.060 otoritis. Most people who experience this are older, but sometimes the misconception is that

01:50:58.280 the pain is just in the temple because it's called temporal otoritis, but the pain of that

01:51:02.340 headache could be anywhere in the head or face. And then is the headache thunderclap? Does the

01:51:07.540 pain peak at maximal intensity within seconds to a minute? That can be what's referred to as a

01:51:12.780 thunderclap presentation. Sometimes a CSF leak can actually present as that if it's a spontaneous

01:51:18.940 leak, not always. And then we get to the other factors like is the headache specifically provoked

01:51:24.520 by cough, exertion, sexual activity or sleep, or if there's a positional component. Often people

01:51:30.000 with a CSF or cerebrospinal fluid leak may have a positional component to their headache such that

01:51:36.420 if they sit up or stand either right away or a, quote, second half of the day syndrome, meaning

01:51:42.120 as the day goes on, they start developing a headache, that can be issues. Sometimes people

01:51:48.300 with a CSF leak can have intrascapular pain, so pain that develops in between the scapula.

01:51:53.380 There are a myriad of manifestations which makes it so difficult to diagnose and treat.

01:52:01.240 It's people like myself, ultimately, and others, other colleagues of mine that may be seeing

01:52:06.500 patients like this.

01:52:08.160 That's why Duke has a CSF program, right?

01:52:10.440 That's one of the programs that's dedicated specifically for patients like them.

01:52:14.380 Well, Brian, this was really interesting.

01:52:16.840 Incredibly grateful for the work you're doing with patients, but also just really grateful

01:52:20.260 for you taking the time to come out here and be away from those patients for a couple of days to

01:52:24.760 have this discussion because I think a lot of people are going to benefit from this. I'm sure

01:52:29.080 a number of them are going to want to come and see you. What is the wait list like for people to come

01:52:32.560 and see you? Obviously, when there's only so few doctors doing what you're doing, I know how

01:52:36.940 difficult it is to get in to see you. Yeah. So me personally, when I moved to Connecticut about 10

01:52:41.640 years ago from New York, I would say probably the vast majority of those patients I was seeing in

01:52:45.860 New York who are driving or flying are now just coming to Connecticut, which is humbling and

01:52:50.640 flattering. The hard part becomes is I want to take care of everybody, but it's hard. So my

01:52:55.180 personal wait list is actually quite long, but there is a link that people can go on. Often if

01:53:00.360 people live out of the state or out of the country, I'll ask them just to have like a local

01:53:04.560 physician that can help with prescribing medications and be able to help implement

01:53:09.960 the plans. Thankfully, I have other great colleagues as well. And so-

01:53:13.640 your practice? In my practice. Yeah. Yeah. We're probably one of the largest programs in the

01:53:17.480 country. Got it. Okay. People can get in the door into your practice. And if it's anything like my

01:53:22.080 practice, seeing one of my colleagues is no different than seeing me. Right. Is it the same

01:53:26.360 with you? I have great colleagues who have the same philosophy. I was very fortunate to have

01:53:30.540 great mentors. And so can they curbside you? Yes, they can curbside me. Yeah. That's sort of what I

01:53:35.120 mean. Like it's, it's a, it's an open system. It's a collaborative system. It's a collaborative

01:53:38.360 system. Yeah. Awesome. And then again, I think encouraging people to go to the site, we'll link

01:53:43.240 to your headache journal so that anybody, whether they're going to see their local doctor or

01:53:48.320 ultimately coming to see you should really, really, as you said, put in the time, the effort,

01:53:53.760 10 to 15 minutes, 20 minutes a day that it would take to really accurately log this for a month

01:53:58.520 because you're going to get better treatment. At the end of the day, it's just going to improve

01:54:01.880 the quality of your care and your outcomes. So Brian, thank you again. This was really exciting.

01:54:06.180 both for the physicians listening, but I think of the hundreds of thousands of people that are

01:54:12.080 not physicians that are going to be hearing this on their podcast player, something I encourage you

01:54:16.540 to do with other podcasts is get a good podcast player and find the time when you're exercising

01:54:22.440 or driving to listen. Please share those with me. I will. I will share for sure. All right. Thank

01:54:26.340 you, Peter. Thank you, Brian. Thank you for listening to this week's episode of The Drive.

01:54:30.880 head over to peteratiamd.com forward slash show notes. If you want to dig deeper into this

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01:55:15.300 should not disregard or delay in obtaining medical advice from any medical condition they have,

01:55:20.240 and they should seek the assistance of their healthcare professionals for any such conditions.

01:55:24.880 Finally, I take all conflicts of interest very seriously. For all of my disclosures and the

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01:55:37.720 an up-to-date and active list of all disclosures.

The Peter Attia Drive - August 31, 2026

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

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