Dr. Jack Schim discusses different types of headaches, including migraines, how to develop individual treatment plans and clinical trial data for therapeutic agents designed to prevent migraine.
Back to Symposium Page » I hate to say that this is the most important talk of the day because obviously everything is important. But there really are very few things that affect as many people in the world as headache and a migraine. You're just kind of back story. Studies have shown that about 90% of people will have a least one headache consistent with a tension type headache in a year. That's not what comes to see any of us. What we mainly C is migrants. So I'm going to focus on migraine here. Andi, let's see here, There we go. So my disclosures are there for you. So here's theater. Jennifer J. I'm going to talk with you about migraine and other headache disorders. But really, the focus is primarily migraine. When I was in training, migraine was a vascular headache, and now we know that was incorrect. That was a very small fraction of what really happened. So we'll talk about Pepe physiology, then talk about treatment, planning. And then I'm gonna bring in some of the newest data of some of the newer clinical trials, things that are available to throw the things that air speculative and kind of out there yet and little leg there. So how common is migraine? Let's start off with. Migraine is more common than asthma and type one diabetes combined. It's more common than asthma or diabetes. Individually, there are about a billion people in the world with migraines. So think of that. That's kind of equivalent or very close to the population of India. And essentially one in seven people in the world have migraine, and they all have the same physiology. We believe they certainly all have bad experience. In fact, it is the second leading cause of days lost to life, Let's say, in terms of functionality after low back pain, leading cause of disability and people less than age 50. So to think of that, well, you know, first of all, primary care cities, most of it there are only about 15,000 neurologists in the United States and on Lee, about 1000 of US air headache boarded, and if you take that population prevalence of almost 40 million by definition, most people with migraine are going to see one of you, which I think is wonderful. On the other hand, my headache education was rather minuscule. That U C San Diego. Thankfully, there's lots of information out, so I'm gonna walk you through a case and then dovetail that with some of the data and some of our experiences. So Sophie, she complains of Sinus Headache, which has now gotten near daily. She describes it is frontal maxillary not throbbing? She's taking acetaminophen almost every day and some meds for decongestants. So if I was seeing Sophie, I would have a lot of questions. Like, When did this start? When you have a headache, how long does it last? If you don't treat, what else have you tried with it? And then many of the other symptoms? I'd be very interested because at that point, with Sinus headache as her description, I don't really know what she's experiencing. Except it probably isn't Sinus headache. So just let you all think about this one, and I don't think we necessarily need to pull you. But first step in diagnosing someone with migraine or headache. Let's start with that. Isn't Imaging isn't testing? It isn't just starting something like, Hey, you know, this might be migraine wanted. We try you on a trip hand is taking a good history and in fact, in neurology. It turns out that probably 90% of correct diagnosis is made by history, and the other part is based on a physical exam. So what are some of the important things in the history? Well, first of all, as I said, we wanted about timing. Like, when did you start getting them? How long do they last untreated? How long does it take from the first part of pain to the worst? So first, the worst is helpful because, for example, if someone has migraines and their headaches built very quickly, you might want to offer them something really fast, like injections from a trip. Dan location is not really that important and headache diagnosis. But it's important to capture the whole phenomenology, you know, these days doing telemedicine, and I'm sure all of you are doing a fair bit Aziz. Well, it turns out that we could do a good diagnostic assessment remotely with people. So there are things in the exam, obviously, that I can't do. I can't do a fun dystopic exam, which I think is really crucial if there's any red flags. But I can see the patient in their own one home environment and say, Oh, I had no idea you were a harder that helps me understand some of the things you told me about. You can have the move close to the camera and, you know, move your eyes right and left and have the patient palpate their arteries. Trigger areas, have them move their head and neck back and forth thio to see what they observe. So it is very, definitely possible to do a headache, history and the fair exam remotely. But of course, we'd rather do it face to face. One possible. The whole point of that isn't necessarily to diagnose migraine, because, in fact, the default diagnosis of someone who has episodic, disruptive headache is going to be migrating. It's to identify things that would be clues to can't misdiagnoses, so secondary headaches are crucial to not miss. But in fact, almost all of the headache patients that you'll see and that I see actually have primary headaches. So the key things that we want to look for, of course, would be changing headache pattern red flags like, you know, you should be cautious about diagnosing migraine if someone has their first onset after each 50 you might want to more carefully, consider. Could they have giants tell arthritis? Do they have an underlying medical condition that might be relevant? Might, depending on what their travel history might consider, other conditions infectious and otherwise. So this kind of looks at some of the primary headaches. First of all, I'm gonna say you probably won't see that much cluster headache because it's uncommon. It's about 100,000 people. It's mostly men. It's differentiated from migraine in that it's a short duration headache. 15 minutes to two hours would be pretty typical. It has autonomic features, so typically someone with cluster has tearing nasal congestion, maybe even corners. The pain is excruciating. It's known as not only alarm clock headache, but suicide headache and people are restless with it. It's very different tension, headache. Virtually everyone gets the occasional tension headache. But based on the definition of it, which basically excludes anything of severe pain, hardly anyone ever comes to see one of us to say, Hey, I had a headache and it was dull and it was mild, and I had no impairment or disability. Most of the time, we're going to see people with migraine. On the other hand, Onley about half of people with migraine are correctly diagnosed, and some of the common misdiagnoses will be tension type headache. If you ever have the notion of diagnosing severe tension, type headache. Reevaluate because it's sort of a conflict of terms. Sinus symptoms, meaning autonomic symptoms with congestion uh, clear drainage often represent migraine. And of course, I'm not saying that Sinus infection doesn't happen. It's just that a large fraction people with migraine probably about 30% have autonomic symptoms that might lead you in the wrong diagnosis. And about 75% of people with migrating get neck and shoulder pain. That, likewise could lead you to a tension headache diagnosis. When in fact, if you ask about functionality, doesn't hinder you and so forth, you're probably going to come up with a correct diagnosis. In fact, that was the focus of a study done years ago published in 2004 called The Landmark Study. The basis of it was going to a number of primary care offices and looking at what the diagnosis was, but then having the history re evaluated by a headache specialist, and you can see that almost all of the people that were diagnosed with headache actually had migraine or probable migraine, in fact, to the point that if you or I see a person in clinic and without some other reason diagnose non migraine, we're usually wrong if we diagnose migraine were right about 85 to 90% of the time, even without taking in a history. So first of all diagnosis, because obviously we can't treat things if we don't have the right diagnosis. The diagnostic criteria are quite nicely formalized and shown here, and it's kind of a Chinese menu. Right, So you need to have two of the four on the left side of the screen one sided, throbbing, moderate to severe, worsened with activity and one of light and noise sensitivity or nausea. But depending on how you ask those questions, your accuracy could go way up. So, for example, if you say to someone you know during your bad headaches, what do you feel like doing? I don't feel like doing anything. Are you saying you'd like laid down and avoid activities? Oh, yeah. My head would start throbbing. It would kill me, and I'd probably turn the lights down and ask the kids to be quiet. You're well on the way to a diagnosis of migraine. Some people do have or a, but it's only about 20% and a diagnosis of chronic migraine turns out to be pretty common. If you think about the total prevalence of migraine in the population is about 12 or 13%. Chronic migraine, which is defined as headache more days than not with at least eight days of migraine, is about 3% of the population. If you kind of relate that to San Diego County, we have roughly three million people in the county. That means there's about 90,000 people with chronic migraine. There's a very simple validated screening, which I would encourage you to incorporate in your practice when you need to. Because you can see this has greater accuracy for diagnosing migraine than pretty much any of the covert screens, right? So if someone says yes to to of these when you're having a headache over the last few months, does your stomach feel bad? Does light bother you? Do you have trouble functioning? 93% of those people are going to fit the full criteria for migraine. Very simple. That doesn't even take 30 seconds. So I think Sophie probably has migraine now. Her headaches last hours to a day. That's pretty typical for migraine. She, in fact, even relates to us that she had quote normal migraine before. Now she's describing pain where she has to lay down. She describes sensitivity, and she describes it, the impact. Another. She's afraid to do things that's really common. People with migraine developed, anticipatory anxiety and one of the things that can help that is, of course, identifying them, diagnosing them and then offering them the right kinds of treatment. So we're gonna look at another person. Martha is clearly having migraine. She was diagnosed back when she was 14. She probably didn't get diagnosed with migraine then, but maybe she did. She's been onto a pyramid. It's a migraine. Preventive actually is developed for diabetes. Most people think it was developed for epilepsy, but it is clear that it can have weight loss effects and is part of a weight loss product, which can be an issue when we're dealing with patients. Sometimes what I'm seeing here is of course, her headaches have escalated in fact, just to think back to our first patient for just a moment. She says. She's having headache most days. She's taking an algae six most days. So I would be really concerned that she may have developed medicine. Overuse. Headache on top of her migrates Martha, on the other hand, is pretty clear that she's had an escalation, her headache frequency. And that's despite top your make. And she's using a trip down appropriately. So let's look at this one for just a minute. What do you think? Get the chat out of my way so I can see everyone. Um, should we try increasing her toe pyramid to 200 mg a day? Would gabapentin and be a good choice? What about the motor gain? Or maybe one of the CTRP medications Calcitonin gene related peptide. So I'll let you all put some messages into the chat. So, Aiken, see what you think here? Yeah. Since I'm not seeing any responses, I'm going to tell you that my choice would be probably to consider a CTRP agent. The approved dose of tapir mate for migraine is 100. You may go higher. The upper and dozing is 1200 a day. But for most people, 100 mg a day is enough. But I certainly, if she's doing well, tolerating it, I might offer. That is one option gap. A Penton really has very little evidence for migraine. It falls into evidence categories C and all of the guidelines and likewise limo tree gain, although we tend to try it when people have a lot of or a because there's some evidence that it could work there. It doesn't usually help the migraine headaches that much, so I would start off with educating her. I think that my observation is most of the time. That's kind of the key thing that we need to do. We need to help set expectations, say, you know, you know, an awful lot of headaches. And despite the toe pyramid, let's look into your triggers. Make sure that you're doing everything that you can. We want to make sure that someone is using her borders. So if I say hey, I see you're on 200 mg, I mean 100 mg a day. She might very well say Oh, no, I stopped that a while ago. It made me is dumb as a rock, and I forgot to mention it to you. I thought I put in my chat, uh, chart message in, but maybe not. We've often found the combination therapy either different pharmacologic agents or combination therapy with behavioral and neuromodulation therapies can be much more effective than medications alone. Sleep is crucial. In fact, when I talked with patients about migraine and their triggers, the ideal ideal lifestyle for someone with migraine is actually a boring one. Meaning keep everything is uniforms as you possibly can. That means consistent sleep habits, consistent exercise habits, doing something for stress management, of course, minimize substances that could be problematic. And keeping a headache diary that enables you and me as the clinicians to look back and say, Hey, you know, I see that you told me that this is really doesn't seem to be working, but your diary of three months ago showed they were having 15 or 20 days of headache a month in your last month or two shows that you're having four. Oh, I was mainly talking about the migraine I had yesterday, so it is helpful to keep that in mind. Everyone with migraine deserves acute therapy. They need to have something that is effective, and the goal overall is one and done something that they could take that gets their headache gone. That has, hopefully no side effects or at least so trivial that they're comfortable using it. And they don't hold back because if people hold back on using their acute, Madison's headache tends to get worse. So this list some of the things that we typically use the non specific agents, um, are just that. So, for example, etcetera, etcetera in migraine. That's the really good stuff. It's eggs, actually identical to the standard Excedrin in terms of doses and content we do to use corticosteroids occasionally when someone has status micro. No, sis. If they have a migraine that goes more than three days, then the likelihood of just treating it with the trip tan or any of the newer agents shutting it down is not so great. And we might offer them that the trip hands have been around since 1993 when sumatriptan and became available. They're now seven, Dhe, 45 other, or gods even proceeded the trip hands, but they still have a role. Dhe 45 is used for status. My Kronos ISS. We might use it in the emergency department and occasionally have patients that will self inject at home. If that's the only thing that really works for them and then listed, there are some of the newer agents that I'm gonna walk you through. What has really happened. Interestingly, over the years has also been the development of, let's Say, old wine in new bottles, So different ways of delivery systems, different sumatriptan and delivery systems. A pending Xoma trip hand micro needle patch is applied to the arm has a little device that presses it on the skin. The needles are sub millimeter co kinetics comparable to intravenous, so that looks very promising. Trials are largely completed. Well, we have a lot of choices, but we also need to make sure that we talked with the patients about what their patients are and line their expectations with what's realistic. So, for example, here focusing for a moment on preventive therapies, they want their headaches gone. I want that, too. We need to clue them in. Hey, if we can cut your headaches down by half, half make them milder, make them briefer. That's usually a pretty good help and at the same time usually better response to the acute medicines most patients want to use, as Little Med says they can. So that kind of fits with our goals of trying to make sure that they get the best results, such that they're not chasing a headache three or four days in a row. Their guidelines that have been published and have been available since 2012. What I'm showing you there and referenced at the bottom is a updated guidelines statement from almost two years ago talking about incorporating the newest agents into clinical practice. So, first of all, the broad guideline of using preventive XYZ more than three migraine days in a month or its consideration of a preventive, it doesn't mean you always have to do that. You know, if someone has three days of migraine, they could take in acute treatment. They're headed, goes away completely in an hour, and they feel fine and get back to function. They may not be that interested. On the other hand, once we get up to four or five, then you start thinking about how many days in a month. People have trouble function. You know people don't die from migraine, but it steals their life away day by day, one at a time, and therefore reducing headache frequency becomes very important for all sorts of reasons. As you can see, sometimes people just want to be on a preventive because they say, You know, the last migraine I had was four or five months ago, but it was so horrendous. I nearly lost my job. I'm willing to be on a preventive so a lot of people could weren't preventive. The estimate is about 40% in the United States. Could weren't prevent is only 15% typically are on them at any one time. And several managed care formulary studies have shown that of people starting an aural migraine preventive, about 70% quit within six months in 80% of 12 months. There off of it. And of course, that's not good. But it's also a message about side effects and effectiveness. In other words, the main reasons that people go off of the migraine preventive are either didn't work well enough or it didn't make them feel better Meeting side effects. What's shown here are guidelines from American Headache Society and the Academy of Neurology of the evidence base level. So class same EDS Are generally those that we would like toa stay with or stick with, but you can see lots of Class B meds that we commonly use. So, for example, tricyclics like am a trip to lean. They don't have that much evidence, but they do have plenty of we have plenty of clinical experience. And, of course, that's kind of the balance in evidence based medicine you gotto tune in with. Clinical experience is, well, you can see that there are meds in there that air potentially used that are not that useful. So, for example, of Rapid Mill and other calcium channel blockers are not really very useful for migraine. And yet I see them ordered all the time. The only calcium channel blocker has really solid evidence is not available in the United States, but occasionally I will order it for people in blue. Narrow seen fact is one of the most widely used migraine preventive agents in the world. On the bottom left of the screen, you can see the migraine antibody meds that have come out over the last two years, and I'll talk a little bit more about those in other wire. Well, um, Mike mentioned earlier. I've been doing Botox for decades. Migraine, chronic migraine can Be Treated with Botox It's actually the only migraine indication for Botox botulinum toxin. It has a very specific regimen. It's not that difficult to learn. If it's something that any of you are interested in learning, you can contact me and we can make arrangements in one way or another to make it happen. But in fact, most of the people that you're going to see in practice probably don't have chronic migraine meaning more days than not. I mentioned earlier that back in the day meeting, in my training, we talked about migraine as a vascular headache. It turns out that it's not particularly related to the blood vessels per se. Very indirectly. It's a neurological headache. It involves pain signaling in the trigeminal pathways, which are across here that descends into the upper spinal cord trigeminal nucleus card. Alice goes down to see to thio even C four, and is the physiologic basis. Uh huh. For the next soreness that many people see, many people experience with migraine on, I mentioned the Sinus headache experience that actually relates to activity in the superior celebratory nucleus here in the brain stem. And when that gets activated and ramped up, people get drainage and congestion, and they may get a Z pack and steroids, which were probably irrelevant for them. This symptom ontology of migraine is often looked at in terms of timeline. So here we've done is wrapped it into a circle because, in fact, people with migraine or either having a migraine they had a migraine or they're gonna have a migraine. In other words, it's a chronic condition that is episodically expressed, and this also gives the opportunity to think about what parts of the nervous system get engaged. So the pain activation is to try general pathway. But many of the premonitory symptoms yawning, food craving. We think those were hypothalamic nausea. That's brain stem, for sure. That's the medulla and aura that has seen maybe 20% of people you know someone shows you the wiggling hand sign. They're probably trying to tell you they get aura that's thought to be cortical, spreading depression. It's an electrical activation of the surface of the brain, not a blood flow issue at all. So we've had the trip hands around. As I said for decades, there's a lot of new things really cool things. The basis for those who is actually discovery of calcitonin gene related peptide er CTRP. It actually has a San Diego anchor. It was discovered in 1983 It Scripts Research Institute. So it's then around, of course, is conserved across evolution. It's in pretty much all animals. CTRP or calcitonin, gene related peptide causes mass LD Granule ation. It's the most potent of Veysel of Dilate Er's, and it enhances no see except of signaling. In other words, it's the volume control on pain. We want to keep the volume low. The initial discovery of it, as I said, was just as a neuro peptide. Essentially, what that means is hormone made by the nervous system but acting at a distance. So it's very different than the usual sorts of neurotransmitters that we think of dopamine and so forth. It worked right across the synapse. CTRP is released, but it diffuses and spreads, and when it does so, it triggers migraine. In fact, if people have migraines and they're given a seat European fusion. It will trigger a headache in seven out of nine. So that tells you something. Also, not 100% of people with migraine are CTRP driven. We think that there are other neuro peptides are being investigated as perhaps therapeutic targets that are going to be relevant for some of the people. Where the CTRP agents don't really do much is part of a family. The calcitonin family there, Alfa and Beta Aisa forms. The beta is through most of the body. The Alfa is in the head and neck and ultimately is the target that we're looking at. Interrupting its activity has been proven to be beneficial, both as a preventive method and as an abortive method. They're different strategies weaken either bind the receptor blocking that that's the target for a rent a mob and the newest medicines for aural migraine acute treatment, the G pants. Or it could be treated, uh, inhibited. Let's say, by binding it the light and itself CTRP And there are three CTRP monoclonal antibodies for migraine that work by that mechanism and then just a couple of other things of note here. The trip cans, which were shown here in kind of purple. They work by blocking. CTRP released. So we've been doing CTRP therapy for decades. We just didn't even talk about it. And for that matter, only botulinum toxin that we use sometimes for chronic migraine likewise works by blocking CTRP release. The first approach addressing CTRP were the G pants. There were a few that were developed years ago that died by the vine due to either tolerable ity and safety issues or not being able to formulate into an aural product. But they're now two that are approved and available as a borders for me, Japan and abroad. Japan, The V Japan is in clinical trials that Phase three have been successful and it's gonna be a nasal product. And then there to to G pants that are showing positive Phase three studies that are functioning as prevented so very interesting room in Japan. In its clinical trial, one of the long term extension studies. They gave people 30 tablets per month and say, take it as you need it for migraine, but please take it at least every other day. When they did, headache frequency dropped by half assed quickly is three months, so it's not indicated as preventive at the moment. But the manufacturer is going to be going for that is just the top line. Look at some of the data. The end Points for Migraine Trials Acute migraine trials used to be focused on headache relief, taking pain for moderate or severe down to mild or none. Now based on patient feedback, they want to be pain free, and they want to get that way quickly. They want to get rid of all of the other symptoms, like light and noise, sensitivity or nausea Theme. The primary end points are now the co primaries of Pain Freedom by two hours and freedom of from Most Bothersome Symptoms. So Rami, Japan's and Blue achieved that and you can see the frequency of pain. Freedom at two hours was about 20%. That's similar to the trip tans and likewise, bro. Japan, also approved as an abortive medicine, had about a 20% pain freedom. But about 60% of people got better to the point of mild pain where they could function normally within two hours, and the likelihood of success went up dramatically over the following 6 to 8 hours. Cesaire long acting medicines with Mom Here's side effects, in fact, with both of those. The most common of side effects was nausea at 2% of people, so they may not be a huge advantage in terms of effectiveness compared to the trip hands. But the tolerable it is enormously better, and many patients in the past have held back on using their acute medicines to the side effects such as then they're headache progressed. They were more likely Thio evolve into chronic migraine. They were more likely toe end up in an e R given an opiate, given a barbiturate, all of the things that we would like to avoid. I mentioned earlier that the first G pants were unsuccessful in the newer ones have been very successful and safe. But at that time scientists said, Well, you know what if we develop medicines that were comparatively metabolized that lasted a long time as migraine preventive, and that was the large molecule approach, Therefore, approved agents that are listed here. The first one that came out was a rent a mob that's the only one that blocks the receptor. The others bind the like in so simple way of conveying that to your patients. And what I tell people is if you think about the c g r p receptor like a lock, and C J R P like the key arena mob is tuned gum in the lock and the others air chewing them on the key. And either way, if you can't get the key into the lock, hopefully fewer headaches. They have different dozing, but they're all approved for monthly dose ing, with the exception of emptiness Mob, which is intravenous but quarterly. It hasn't really had as much uptake because they just launched in April, and they should have seen the pandemic coming and launched earlier. No, I'm just kidding. It was unfortunate timing, but get people to be willing to go into an infusion center is harder these days, but it actually has some advantages because it is intravenous. The team axes 30 minutes. The others have six day T max. We did a trial that has been positive, called relief, where people would come in during a migraine. People who had headache enough that they weren't wanted to being on preventive and they were infused. And the people that got the medication, they're headache went away. So same general mechanism as the G pants, which are acute medicines. This that that particular medicine can be conceptually, at least in acute. Although it's really intended preventively. Galca News mob has a loading dose a little different that gets people up to the desired. Um, steady state like levels very quickly and from a news mob, has the option for the patient and for us as clinicians. That the patient can treat either monthly or quarterly. Monthly is 2 25 mg, which is one auto injector. If someone chooses to go quarterly dosed, That's three auto injectors, and it's the only medicine that has been developed for the treatment of cluster headaches. So that's quite remarkable. I mentioned that you may or may not ever see any. I have some patients with Cluster and to be able to offer them something. Say this was actually designed for you, as opposed to the things that they tried and haven't worked so well has really been quite remarkable. This shows a little bit of the endpoint data. We could, of course, have whole conference about just the CTRP approach. So one thing to note. Please don't take this as an a chance to say one is better than the other, even though some of the responder rates are higher than the others. Because the trials were done with different people, there are no head to head studies. They had different definitions, sometimes of a migraine day or a headache day, and they started with different baselines. Savi disease severity. So, for example, if you start off with nine days of months and you're looking cutting that in half, that's easier than if you start with 14 days a month because you numerically obviously have to drop even more. I think the most useful way to look at this class is that these are medicines that are very well tolerated. Their most common side effects is injection site readiness or this or pain, depending on which medicine which study you look at. That occurred in somewhere between six and 20% of people, but only about 2% of people find that bothersome enough to quit the treatment. So really, the question becomes, are they better? And this is kind of a nice summary just using a random Abbas. One example. The Rent A mob has two different doses available and in blue or some of them, or, uh, typical agents that have been around for a while. So two pyramids and propranolol and on a botulinum toxin on the right side of your screen is those studies that were done with episodic migraine left on chronic migraine. You can see the numbers needed to treat or not all that different, but the numbers needed to harm. When you look at the standard, agents are much, much lower, even two orders of magnitude. If you look at propranolol side effects bad enough to stop it, numbers needed to harm of 11 and rent a mob 1000 so thes have gotten a lot of utility. The American Headaches Society put out a position paper that I mentioned earlier that highlights a couple of things that I think are very important. First of all, the word prescribed by a license prescribed by any licensed and others. That means that if P A or MP and their appropriate meaning, you're comfortable with them managing your migraine patients or you are a P r M p. You should be able to prescribe this. There are some states where the insurers have pushed back against anyone prescribing that it isn't a neurologist or isn't a headache specialist. And there may be two neurologists in the whole state that's not fair to patients. There are slightly different guidelines as to, uh, when we might be prescribing it based on headache frequency. But that's really a matter of we generally start the standard medicines first. As much as I would like to use the design for migraine medicines, these air the first ever medicines designed for migraine as much as I would like to start with those based on insurance coverage issues that they're really typically third line. So that means suppose someone's already been on two different agents, even if they weren't prescribed for migraines. So an example would be can dishearten, can dishearten, has enough evidence that it's potentially going to be reclassified as category class A evidence, but it's not indicated for migraine. But suppose you have someone who's been on that for hypertension, and maybe they've been on an antidepressant and you say, you know your migraines are not so good, and you start talking with them about other Orel agents. Well, at that point, you actually could probably get the medicine approved through their insurance. Another acute medicine and a different strategy is the details. There's one. The trip hands were developed and our serotonin agents they activate the five HT one B and one D receptors. And as I mentioned earlier, the consequence of that downstream is blockade of the release of C G R P. But they have a lot of, uh, let's say, limitations in the sense that first of all, only about 70% of people respond to them. They have cardiovascular contraindications, previous stroke, previous heart attack, uncontrolled hypertension, Bezos, spastic disease. They were developed to be blood vessel constrictors. Well, the one f receptor doesn't have any Veysel constructive activity and has been the target now of the development of a couple of detains. One we did studies on years ago kind of died by divine due to tolerable ity issues. But last minute Dan has been successful and is approved. It is on the market. It has a higher pain freedom rate, um, in its trials than the numbers that I mentioned to you earlier for the G pants close to 40% in some studies on the other hand, the side effect profile is not quite a Zajec tal that g pants. 2% of people had nausea with Lasmo today, and the most common of adverse events was dizziness. Who has seen it up to 18% of people taking the higher dose. On the other hand, it's severely in about 1% of people because it has CNS side effects. Now, since 2017, the FDA requires any medication with CNN's side effects. Thio be studied for driving safety, and at 90 minutes volunteers failed. At eight hours they passed and therefore it is, uh, instructed. We should be instructing. I should say that our patients should not drive for eight hours after taking it, even if they think they're OK. Because, of course, we know that people are not always rated judging their driving capability. It is a Schedule five drug and brief backstory on how things get scheduled. They gather a group of poly substance abusers, drug addicts and, um, offer them forced choice. Do you like Pillay? Or it will be better and the MSC and that would be alprazolam in this case, less midan or placebo, and it had greater likability than placebo, but not as much as alprazolam. So it is a scheduled drugs. Yeah, well, so Helen is a nice example of maybe she may no longer be such a great trip. Tan candidate, right? She's now got coronary artery disease. She's having quite a few migraines five times a month. Certainly would warrant being on a preventive, but she's feeling over it. She doesn't want to be on meds. If she can avoid it, she wants to know. What else could we dio? This is actually a conversation I had with two physicians yesterday about one of my 14 year old patients who we all agreed needed to engage in some non pharmacologic treatment. And maybe Cem Migraine device might be helpful. Maybe cognitive behavioral therapy mindfulness would be helpful for him. Mhm. There are now four F d. A. Cleared, uh, neuro neural stimulators or no modulators is more correct term from left to right, external trigeminal stimulation that's known as separately. It's a device that people can purchase and put on their forehead and use either in a prevention mode, meaning scheduled certain number of times per day or acute leak. They push a button. It puts electric current into the super orbital and super truck feels weird. It feels like ants crawling on the forehead, and that's the most common reason for people stopping it. I've tried it. My PA's tried it. None of us were big fans. Transcranial magnetic stimulation Really cool device. I've got one person e think she's 15 now, she says. I'm not a person that wants to take any pills, but I really have too many headaches. And she came to see me having 38 8 days a month and was being home schooled. And she was able to get one of these devices using it in a daily prevention mode. Plus as needed. It's a device you hold on the back of your head. You push the button, it goes, click. It puts a half Tesla pulse into the brain. So basically a strong as Anne Marie. But just single pulse. It's not the same as the repetitive TMS that is cleared for depression and OCD and so forth. Right? Handheld vagal stimulation is cleared for migraine, both both acutely and preventively, as well as cluster headache. Downside of all of these is they're not covered by insurance so people have to be motivated enough to try it. That one actually got a emergency use authorization from the FDA to be tested in Koven patients because it is Broncho dilating and has been used off label in ers for people with acute asthma. It's a pretty fascinating. It stimulates the vagus nerve the most recent has shown on the right there. Remote electrical neuromodulation works by electric current that is put into the arm that activates brain stem pathways through descending inhibitory pain pathways. Patients link it to their phone via Bluetooth, and they control the intensity by their phone and app on the phone. The idea is, they put it on. They can wear it discreetly all day if they're not sure, And they say, You know, I don't feel like quite yet to treat, but I might be getting there, and it would be nice if I had something that didn't take a pill because all of the pills I tried I don't like him. I'm not going to go deeply into this. I'm just going to say all of this is important. They're supplements that could be beneficial. There's good scientific evidence for riboflavin, magnesium Co. Q 10 While published double blind, placebo controlled trials. There's not much evidence for spinal manipulation or chiropractic or homeopathic hypnotherapy. Melatonin? I don't know. You know, I would look at all of these as they're low risk, whether they're going to help someone or not Hard to know that's very hard to come up with. Like what placebo would you use for Tai Chee, Right? How would you do that? What placebo might you do for massage? So placebo controlled trials are hard to do? Sometimes they're easier to do for drugs. For pharmacologic agents. They're hard to do with devices because you have to have a sham device that gives something that seems like the real thing but has no therapeutic effect. You don't really know if it has a therapeutic effect until you try it. So that's actually been the snafu with a number of device trials, 30,000 ft perspective. If you are, I see someone with recurrent headache is probably migraine. Don't forget to screen them for red flags. Someone presents with a fever, stiff neck, nausea, vomiting in a severe headache. That's meningitis until proved otherwise sudden, catastrophic headache that drops someone to their knees and they pass out and then they wake up. I'd be worrying about subarachnoid hemorrhage, but if you have a person that comes in and said, you know, I've been having these headaches that's the launch point for taking an appropriate headache history, even using the I. D migraine screener, which I showed you earlier, very simple on what I would encourage you to do is maybe se Teoh patient. You know, it really kind of sounds like you have migraine, but I'd like to have more information. Why don't you keep a headache calendar? We'll book the future appointments. Let's say you know, a month or six weeks from now, and at that point we're going to just do a deep dive into the headache issues, and I'd like you to keep track of anything that seems like a trigger to you. Anything that's going on in your life and whatever you do and patient can keep the calendar on a piece of paper. There are a number of free APS. One of the popular ones is migraine buddy. But if you were to go to the Google Play Store or APP store, think you'd probably find several 1000. We do want our patients to have acute therapies that work for them, and if they delay care with those, the result is sensitization. And the basis of chronic migraine is increased sensitive. A patient. We want to dampen that down. So it's important to identify something that works well with people. Make sure that we explain how the medicine works and at least enough to the point that they're comfortable with it. Address the side effect concerns. Address the access, make sure that we follow up with them and, you know, talk to Sally and say So I see that I wrote you. Yeah, rise a trip hand Does that completely meets your needs? Meaning? Does it work effectively? Is it fast? Are you comfortable using it? We do want to make sure that our patients understand that overuse of acute medicines can make their headaches worse. And any person where they have high headache frequency or even not that high of migraine frequency greater than three migraine days a month is enough to consider preventive and think about the other things. They are accessible whether the patient is on commercial or government insurance. By and large, they do have access to these therapies, and we've seen some remarkable outcomes. I've had patients go from 20 days of migraine a month to none in a year and a half, and that's just unheard of. So with that, I think we have some questions here, and I think time wise, we're doing fairly well. We've got another 15 minutes or so. So, Mike, shall I just go ahead and take these one at a time and then let people respond? Or shall I go through and answer them? Go ahead and pick the one. Do you think are appropriate and go through the questions? Okay, well, so let's look at this one. I d Migraine screener. That was the quickie that I walked you through a couple of times. So it evaluates for all of the following except a B, C or D, Nausea, vomiting, light sensitivity, Sinus pain, limitations. You pull the chat box up so I could see your answers here. Yeah, Alrighty. I can't tell who's voted on who hasn't. So I'm going to assume that you are weighing in, and I'm just gonna address that the Sinus symptoms were not part of I d migraine. And that's just a swell, because that's a wrong path, so to speak, What's not an alarm sign? Neurologic symptoms. New abrupt onset, new onset after age 50. Longstanding headache, history or history of cancer. Which of those wouldn't get you concerned? When you're thinking about migrants, think about that one for a minute. Well, so neurologic symptoms aren't necessarily a concern after all. You know people with aura they may get sparkling. But the second most common neurologic symptoms with aura is Paris. Thes is typically creeping, so it's very different than Tia or stroke. Where symptoms are all at once new, abrupt onset would be concerning. I'd be thinking about other things, vascular things. So although I said migraine is not vascular, that's certainly not to say that vasculature is unimportant because an aneurysm rupturing is certainly vascular could present with new, abrupt onset age after 50. That is not a typical migraine story is not that it never happens. But the vast majority of people with migraine have on set in their teens to thirties and cancer. Of course, that would be a concern. In other words, if someone comes to me and says I never had headache, but I've gotten them in the last three or four months. And oh, by the way, I was just recently diagnosed with the foam. I'm going to say Okay, well, your headaches, maybe FINA typically migraine. And maybe you had migraine, but we still have some work up to Dio. I'm going to address this one since I think this one's really pretty straightforward. Someone should be on a preventive for any of those. If someone's using acute medicines more than two times a week, that means they're having, like, eight days of migraine. I should have said days per week rather than times, and that's certainly well within the bounds of at least 44 or more. And if the symptoms interfere with life, they should certainly considered, although they may not need it. Maybe that's a person we're going to refocus on their report of their cute treatments. Preventive could take some time. In fact, one of the really cool things about the newest preventive is in the past. If we were really focusing on things like propranolol or to appear mate, I'd say, Well, you know, the best advice I can say in terms of tolerable. ITI is start low, go slow, build it up to a successful dose, and others don't put someone on. I am a tripling 10 mg and keep them there for a year and expect things to change, because unless it's already gotten better by a month or so, it's not likely to mhm. The right answer here would be depending on the agent. Certainly a month is kind of minimum and and two or three months is reasonable. And the guidance for the starting and stopping of the newest agents would be if it's a monthly dose medicine, the patient should have be allowed to trial of at least three months. And if it's a quarterly dosed agent at least six months, and that fits really well with the data. By and large, if you look back at the data, for example, I'll pick on a rent a mob for a moment. At three months in the chronic migraine trial, 40% of people got better by at least half, and there was some improvement, seen as quickly as a month. But it's six months. The fraction was much higher, and by 4.5 years it was 75% of people. So since these New Tuesday, very few side effects quitting due to side effects is really uncommon. Go back to Sophie. I would steer away from Gabba Penton and the motor Gain Clonazepam. Eo. It really is not a migraine medicine. Many people with migraine have plenty of anxiety. It's the most common of co morbidity is. But I wouldnt commonly used clonazepam as their angsty elliptic. I would probably talk with him about breathing what they do in terms of their life management and so forth. Let's see, I see a question popped up here. Question. If someone wanted to try magnesium or write off leaving with dose what they use. So the evidence is generally in the 3 to 400 mg per day range. Um, right of Flavin. The only caution you need to give your patients not really Much of a caution is that it commonly will cause the urine to be yellow or arms, so they should know that so they don't panic. It's not a side effect is a color. Um, magnesium. Different versions may have different tolerable ity. So, for example, magnesium citrate is great. If you're having a clean out before colonoscopy, but it may not be the best tolerated if you're taking it every day. And so other versions magnesium oxide, for example might be a little bit easier to tolerate. I thank you all for your attention and wonderful conference. Thank you so much, everybody.