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MedEvidence! Truth Behind the Data
Welcome to the MedEvidence! podcast, hosted by Dr. Michael Koren. MedEvidence, where we help you navigate the real truth behind medical research with both a clinical and research perspective. In this podcast, we will discuss with physicians with extensive experience in patient care and research. How do you know that something works? In medicine, we conduct clinical trials to see if things work! Now, let's get to the Truth Behind the Data. Contact us at www.MedEvidence.com
MedEvidence! Truth Behind the Data
🎙Migraines: Navigating The War Zone Ep. 297
Doctor Carolyn Tran joins Neurologist Steven Toenjes to discuss migraines. Migraine is a complex brain disease affecting one in five women and one in ten men, with treatments ranging from traditional medications to cutting-edge therapies targeting specific pathways in the brain. The doctors talk about the causes - or lack thereof, the lack of treatment, and common misconceptions about what headaches should be classified as migraines. Dr. Toenjes explains the phases of migraine, including prodrome, aura, pain, and postdrome. Then the two doctors explore many treatment options, discussing the uses, benefits, and drawbacks of each class of treatment.
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Music: Storyblocks - Corporate Inspired
Thank you for listening!
Welcome to the MedEvidence! podcast. This episode is a rebroadcast from a live MedEvidence! presentation.
Dr. Carolyn Tran:Yes, thanks for coming. So, while you're nourishing your bodies, we're going to exercise your brain a little bit by starting out with some questions to get you thinking about migraines. Okay, so which of the following statements is true about migraines? A migraine is just a really bad headache. A migraine aura is your brain's way of previewing the next episode of reality. People with migraines have a secret antenna that picks up bad weather forecasts a day early. Now some of you with arthritis will say that is definitely true, or currently there are no cures available for migraines. Anyone want to venture a guess?
Dr. Steven Toenjes:Yeah, it's the last one that currently we don't have a way to make someone who is a migraine patient not be a migraine patient. Migraine, it turns out, is a polygenetic disorder Some 30 to 35 genes that are involved, and if we happen to inherit the right set of genes and in the right environment, our brain becomes capable of making what happens in a migraine occur. And while there are not cures for that, there are a tremendous number of extremely effective therapeutic options that help us significantly mitigate the impact of migraines on patients' lives. The secret antenna one, I think, is funny. You know, it is actually one of the most common things that migraine patients will tell us that they can't actually predict when they're going to have a migraine event, when barometric pressure changes are occurring, particularly the dropping phase of it, and so there's not really an antenna that's there, but there probably is potentially something for us to discover. We know almost nothing about that, though.
Dr. Carolyn Tran:All right, and to bring you back to your school days of multiple choice questions. Which of the following are possible symptoms of a migraine attack? A nausea and vomiting. B sensitivity to light, also known as photophobia C. Sensitivity to sound, also known as phonophobia D. A persistent fever. E. A, b and C, but there's also F. All of the above?
Dr. Steven Toenjes:Okay, you were saying it correctly
Dr. Carolyn Tran:I heard E.
Dr. Steven Toenjes:Hit it one more. I think it says
Dr. Carolyn Tran:There's A, b and C.
Dr. Steven Toenjes:So those are the symptom complex nausea, vomiting light, sound sensitivity particularly that make people think something is migrainous. But not everybody has these symptoms. 80% of people will be light sensitive and so just because someone does not have light sensitivity does not mean that the headache is not a migraine. But those are extremely common accompaniments so I think we can move on from that.
Dr. Carolyn Tran:Okay, so let's get into what are migraines.
Dr. Steven Toenjes:So this is the World Health Organization's definition, you know, a primary headache disorder that is in most cases episodic, usually lasting between four and 72 hours, with the things we just mentioned nausea, vomiting, photophobia, phonophobia sometimes preceded by the aura phase of a migraine. That we'll talk a little bit more about in detail in just a little in subsequent slides. A couple of words about the first sentence there a primary headache disorder. We categorize headaches and split them into two broadest categories primary and secondary headache syndromes. Secondary headaches have a cause that can or needs to be identified. The example that I give to patients is a silly example. If somebody hits you in the head with a brick, that would hurt. If they did it every day, it would hurt every day. We could give you all the headache medicines on the planet, it would not fix that problem. You would have to figure out that somebody's hitting you in the head with a brick and ask them to please stop Now.
Dr. Steven Toenjes:Primary headache disorders don't have a cause that can or needs to be identified. That doesn't mean there's not a cause. I alluded to the genetic cause earlier. It's just that you can't identify the cause for primary headache disorders and you don't need to, because there's nothing you can do about that, and that's very frustrating for patients and family members who suffer from a recurrent, oftentimes extremely severe headache complaint, and nobody really explains to patients what the cause is. And so, with migraine being by far the most common severe primary headache disorder, the most common primary headache disorder is tension headache, but the most common severe one is migraine.
Dr. Steven Toenjes:It's helpful for people to understand the difference between primary and secondary headaches, and so we don't necessarily need to be searching for the cause for why somebody gets migraines. People just get them
Dr. Carolyn Tran:All right.
Dr. Steven Toenjes:Yeah, sure, okay, you want me to keep going?
Dr. Carolyn Tran:Yes, please
Dr. Steven Toenjes:Okay. So when we look at the frequency, some epidemiologic information about migraines, it's important for us to understand that less than 50% of people with migraines ever go to the doctor and actually ask for help, and so most people with migraines are never diagnosed with migraines. 90% of people affected have some pretty severe impact on their life. In the United States, one of the more recent estimates on the frequency in the US is more than 39 million people have migraines. One way that I think is useful to sort of think through the epidemiologic information with migraines is to understand how frequently the disorder is present in men and women because it's a little more frequent in females than in men. It's two to three times as frequent in females. One in five females is a migraine patient.
Dr. Carolyn Tran:That takes us time for our next slide as well.
Dr. Steven Toenjes:Yep, and one in ten males is a migraine patient.
Dr. Steven Toenjes:And so if we are experiencing headaches and you are either a male or a female, if they are bad headaches, as long as they're not a secondary headache syndrome, you're very likely dealing with migraines. The American Migraine Prevalence Study, which is a little bit of a dated study, but it is actually our more recent epidemiologic studies, are not too different than the data that came from AMPP. You know, 50% of severe migraineurs, you know, never had a formal diagnosis of migraines and that's a mixture of things not going to the doctor, doctors not asking about the problem and then oftentimes being misdiagnosed. Actually, we the next statement that says 12% were in the American Migraine Prevalence Study were on adequate preventive therapies. In the eyes of a headache specialist, that is 12% of patients who we would suggest need to be on preventive medications. 12% of them were on preventive medications, and so that's just a data point pointing out how we are really not adequately taking care of migraine in the United States, based on that report card.
Dr. Carolyn Tran:And since you mentioned migraines are underdiagnosed and sometimes even misdiagnosed. Do you want to say a little bit about the thing we've talked about with patients saying I have a sinus headache.
Dr. Carolyn Tran:I don't have migraines
Dr. Steven Toenjes:So that would be something that you would have come across frequently in a family practice and I mean the data on it are 85% of what a physician has diagnosed as sinus headache. Eighty-five percent of that is all migraine. Of course, sinus infections exist they do. But I gave you the statistics on. A diagnosis of sinus headache is almost all migraine. And that's a good example of and one of the reasons why we very frequently have referrals to the headache clinic from ENT physicians who say there's nothing wrong with your sinuses. This is go see the headache doctor, but that's only true of some headache or some ENT physicians. Some ENT physicians just say there's nothing wrong with your sinuses and then don't follow through with it. Go see the neurologist. So that's a good point.
Dr. Carolyn Tran:All right.
Dr. Steven Toenjes:This is kind of a funny one. When I get a migraine, I always follow the aspirin label take two and keep away from children.
Dr. Steven Toenjes:I think that you know this slide is here to kind of make a point that there are a variety of reasons. There's a list of reasons why patients don't go to the doctor and complain about headaches and why doctors don't necessarily ask about headache disorders. And one big piece of the puzzle turns out to be the stigma that surrounds a migraine diagnosis. Historically, with the little funny business over to the side, that's actually a commercial, a marketing piece. When boredom and emotional fatigue bring on housewife headache, it's actually an advertisement for aspirin, anacin and those sorts of biased approaches, viewing a migraine patient as perhaps having something emotionally wrong with them. You know, I think has been ingrained in our society for generations actually. But we need to and it is appropriate to think of migraine as a brain disease. It is a brain disorder.
Dr. Steven Toenjes:We understand it very well and it is every bit of brain disease as Alzheimer's or Parkinson's or multiple sclerosi.?
Dr. Carolyn Tran:Yes, and aren't we glad that research has taken us away from the housewife headache. My husband and I had a good laugh about that last night.
Dr. Steven Toenjes:Yeah, All right, so it sort of jumps into a little bit of a different topic. Obviously, migraine is more common in females, and one of the more common scenarios that a person is actually likely to seek help is when migraines are tied with menstrual periods. You probably experienced quite a bit of that with your family practice.
Dr. Carolyn Tran:Yes, and fortunately, just like we talked about with sometimes being misdiagnosed, young women will think it's oh, it's PMS, it's just PMS. It's just part of what I have to go through every month.
Dr. Steven Toenjes:I would ask you a question. When, seeing a young female who is having trouble with premenstrual symptoms and a lion's share of that is the headache complaint of it, Be honest, internally do you sort of think, oh brother, this is going to be tough.
Dr. Carolyn Tran:It's going to be tough. It is tough because you know you're asking patients then to like track their periods, track their headaches, track all their symptoms, which is the last thing they want to do at that time.
Dr. Steven Toenjes:Well, the menstrual migraine clinical scenario is a difficult one.
Dr. Steven Toenjes:The problem is is the fluctuations in hormones that are occurring, primarily at the beginning of menstrual flow menstrual flow but also on day 14, where ovulation occurs.
Dr. Steven Toenjes:The swings in hormones that are occurring just turn out to be a really good way to trigger what is capable of being triggered in the brain of a migraine patient. And while it's a prominent trigger, that trigger is sustained. The hormone swings that occur are sustained for days in a row, usually several days in a row, and so to get that migraine process to shut off has historically been quite challenging because it's a prolonged exposure to the trigger. We do have a handful of unique approaches to specifically deal with menstrual migraine, and it is actually very specifically one of the topics of a currently ongoing clinical trial at Jacksonville Center for Clinical Research, and we're certainly a part of and we're excited about participating in that, because the menstrual migraine patient is a challenging patient and, while we have several things that we know of that can really be helpful, we need to expand that medicine cabinet up a little bit to help patients with menstrual migraines.
Dr. Carolyn Tran:So, now that we've talked about one of the subtypes, let's talk about how are migraines diagnosed?
Dr. Steven Toenjes:So when you went through training, did anybody ever talk about diagnostic criteria for migraine?
Dr. Carolyn Tran:Very little. Yeah, very little.
Dr. Steven Toenjes:I would be surprised, if at all. So in 1988 was the first time that the International Classification of Headache Disorders was devised by a handful of really expert lifelong headache specialists, and headache diagnostic criteria exist in this body of literature. Its name is the International Classification of Headache Disorders. You'll see it says ICHD-3. It's been revised three times now since 1988. You'll see, it says ICHD-3. It's been revised three times now since 1988.
Dr. Steven Toenjes:And it is a set of diagnostic criteria for all of the headache disorders that humans experience. And so this is just the listing of migraine's diagnostic criteria. So the first is that a person has had at least five attacks and the reason that that five attacks it really says it's five attacks over a period, had at least five attacks, and the reason that that five attacks it really says it's five attacks over a period of at least six months. That's really addressing the possibility that the patient in front of you is a secondary headache syndrome patient. If somebody's been having a recurrent problem for six months, they probably don't have a hemorrhage in their brain or something like that. It's been going on for six months and so the duration of it, I think, is how long the syndrome has been present, is actually part of the criteria. It turns out that how long a headache lasts turns out to be a really diagnostically useful piece of information. Migraine, untreated or unsuccessfully treated, is almost always going to last between four hours and 72 hours. So up to three days would be pretty typical of a migraine syndrome.
Dr. Steven Toenjes:The characteristics that you see listed under C this is where I think a lot of confusion arises. So the characteristics of being on one side of the head, unilateral, pulsating in quality, moderate or severe in pain and aggravated by routine physical activity it makes people need to avoid routine physical activity. You need to have two of those, and so if something is moderate or severe in intensity and is pulsating and throbbing, it can be anywhere on your head. If it's unilateral and pulsating, it doesn't actually need to be moderate or severe. It could be mild, and so you really just need two of those to be positive or present for us to satisfy diagnostic criteria. Then, lastly, under D, nausea or vomiting, or light and sound sensitivity, we have a lot of confusion with light and sound sensitivity as well.
Dr. Steven Toenjes:The light sensitivity, as an example, exists in a spectrum. There are some people in the midst of a migraine who are so light sensitive they have blackout curtains. They've shoved towels in the cracks of the door so there's no light coming through underneath the door. They're laying in their bed with the pillow over their head and it's still too bright. There are some people with migraines who, if they look at a fluorescent light, will notice it's just a little bit more comfortable. I agree it is a little bit more comfortable. That's light sensitivity. Actions speak louder than words often in this situation, a lot of times people will say no, I don't have migraines, I don't have any light sensitivity. And we'll say well, where do you go when you have a migraine? I go in my room, the lights on or off? They're off. That's light sensitivity. Then E is, of course, not better accounted by some other diagnosis. In other words, it's not going to satisfy migraine's diagnostic criteria if it's not migraine.
Dr. Carolyn Tran:Yes, right satisfy migraine's diagnostic criteria if it's not migraine right, and you had mentioned kind of the timeline there of migraine attacks.
Dr. Steven Toenjes:Yeah, I think that something that we have learned a lot more about is that migraine exists in different phases. It's helpful to think of migraine as having different phases of the disorder. The painfully obvious pain phase is the headache phase, listed on the third column. There, a quarter of migraine patients are capable of also having an aura phase. Raise your hand if you've ever heard of what a migraine aura would be like.
Dr. Steven Toenjes:So that's a lot of hands.
Dr. Steven Toenjes:And so typically a migraine aura would be a visual one, an evolution of changing, evolving over minutes, visual complaints to one side or the other, or perhaps in the center of vision, where a person will see scintillations or lights or colors. Some people will actually see a kaleidoscope. There are interesting visual phenomena that happen, that spread and evolve and the person will generally not be able to see within the light or the visual phenomenon that's occurring. Only a quarter of migraine patients are going to be capable of having aura. You only need to have two auras in your entire lifetime and you're a migraine with aura patient. You can have 10,000 migraines with no aura and two with an aura. You're a migraine with aura patient. It is interesting that aura can produce any symptom your brain can produce, which means aura can produce essentially any symptom you can think of, but it tends to just produce the visual symptom. The second most common migraine aura symptom is an evolution of hemibody numbness. And the third most common migraine aura symptom is an expressive aphasia, where a person in the midst of the migraine has words that they can't get out, something that I think we are starting to learn a little bit more about is actually the prodromal phase Now, while a quarter of patients with migraine are capable of having the aura phase, actually most people with migraine have a prodromal phase.
Dr. Steven Toenjes:These are symptoms like irritability, building neck stiffness, smoldering, building light sensitivity. There are behavioral changes that occur. People can be depressed. A really common one that confuses people is insomnia. A lot of people think, well, I had trouble sleeping last night and that's why I have my migraine today. But realistically, oftentimes it's the reverse of that. You had trouble sleeping because you were in your migraine prodrome and the migraine process was already unfolding. The prodrome can last hours to as much as a day or two before the pain phase will occur, and then the postdrome that we'll call, or often refer to, as a migraine hangover, and so oftentimes patients will be just washed out, could be sleepy, very fatigued, after a migraine event has the pain phase has finished, and so we know the most about the pain phase. We have learned a lot. There's still things a lot that we don't understand about aura. We know very little about prodrome and post-drome, but we are learning a lot more about those different phases.
Dr. Carolyn Tran:And the scary thing about aura, because we'll see that a lot through the emergency room, because some of the symptoms you mentioned aphasia, not being able to get those words out numbness and tingling. As we all learn more about warning signs of stroke, we're seeing a lot of those patients go to the ER and sometimes they're not getting that follow-up. They're like oh, you don't have a stroke, go home. It's like what about the migraine?
Dr. Steven Toenjes:Yeah, and the way to really differentiate the two stroke and TIA are precipitous, maximal and onset disorders that don't really evolve much. When we block a blood vessel in our head, boom. All of the symptoms are there instantaneously. Migraine is an evolving disorder. The visual phenomenon evolves over minutes, generally last 10, 15, 20 minutes, perhaps as much as an hour. If the numbness is something that the person experiences, it will very commonly evolve in the same way. It will spread. A person will literally feel it walking down a portion of their body and that will be after they had the visual symptoms, and then the expressive aphasia component of it will happen then 10 or 15 minutes after the numbness symptoms have happened, and generally it occurs in that way. Then also, if somebody would have numbness or expressive aphasia as an aura symptom, they will also have had visual aura in their past, and so that's an important clinical point as well. So pathophysiology is something that just really refers to. What is it that we understand about physiologically? What's happening in our brain when you would have gone through and I would have gone through is responsible for the throbbing component of migraine. One interesting thing is, if you really try to carefully investigate whether the throbbing symptom coincides with the pulse. It does not.
Dr. Steven Toenjes:Ah, yes, and so we actually have learned a lot about what we call our trigeminal vascular system. We have a cranial nerve called our trigeminal nerve. It supplies essentially everything from our neck up, including our intracranial vasculature and the lining of our brain, the meningeal lining of our brain. And what we don't understand is really what's the first step that gets this system activated. It is something that starts with trigeminal activation. Exactly how that begins is what we don't know, but once it has begun, then we understand that trigeminal nerves release a substance called calcitonin, gene-related peptide, I think it's on the next slide.
Dr. Carolyn Tran:Lots of real changes going on in the brain there.
Dr. Steven Toenjes:And so over. On your left is a little cartoon of a trigeminal nerve, and the little purple dots are this thing labeled CGRP or calcitonin gene-related peptide. It is something that our trigeminal nerves release out in our meninges, the lining of our brain, and that self-stimulates those trigeminal nerves to then send pain signals back to our brain in a positive feedback loop that really just starts like a snowball rolling down a hill, and so it's been very exciting for us to learn about the pathophysiology and then start to devise specific migraine therapeutics that have been developed to very specifically block the function of this neurotransmitter, calcitonin gene-related peptide.
Dr. Carolyn Tran:And then can you talk a little bit about what you know? We're talking about treatments here, and what does the level A evidence mean?
Dr. Steven Toenjes:So level A evidence is just what we're going to refer to, as we've got a substantial amount of well-done studies at least a couple of well-done studies and that they demonstrate pretty clearly that the treatment is effective. The best evidence is a placebo-controlled, blinded, randomized, controlled trial, and so if you've got a couple of those and a treatment seems to be positive, that's fairly strong pieces of information that the medicine we're talking about is actually effective, and we'll call that level A evidence. And then level B is just a step below that and level C is like hey, we think it's probably beneficial. It's got a weak study or two that back it up.
Dr. Steven Toenjes:And so this slide refers to abortive treatment. It's important with migraine therapeutics to think through the treatments and keep them in their respective buckets, and abortive treatments are treatments that are designed to abort the current headache that you have. If I'm developing a headache right now, I would like a drug X, Y or Z or one of these on this list. Please go away. Headache right now. That's what we mean by abortive treatment, and the other class that's important to pay attention to or think about is preventive treatments.
Dr. Steven Toenjes:Preventive treatments we'll get to in just a minute. So here on our level A evidence. Not all of the medicines with level A evidence that are abortive are listed here, but the purpose of this slide and we don't need to go through all of these medications. Medications. Over on your right, the triptan medications. You'll notice the generic medication there. The root all ends in triptan.
Dr. Steven Toenjes:Those were really kind of one of the first true migraine-specific therapies. Sumatriptan was FDA approved in 1991, and there are seven triptans. All seven of them are generic as well, by the way, and so they have been increasingly easy to obtain. Dhe or dihydroergotamine is the parent chemical that the triptans were really derived from to try to make them more safe and have fewer side effects. One of the general points through these slides is for people to not necessarily write down or look at the specific names, but to just take the general point like well, there's a lot of things on this slide. We have a lot of treatments and a number of them are level A, the CGRP-based drugs which have level A evidence we'll kind of show later.
Dr. Carolyn Tran:Yes, and you'll notice as we go through the treatments that they're getting a little bit more specific for migraines, because we all know acetaminophen, tylenol, aspirin, general pain medicines, right, but, like Dr. Toenjes just mentioned, the triptans, these tans on the other side, those are migraine-specific, so we're going to go to the next slide and show you some more. So these are the level B evidence treatments.
Dr. Steven Toenjes:You know. I do think it's worth mentioning that over on the right side. A lot of these are nausea medicines and the anti-emetics. Some of the nausea medicines a lot of people have heard of Zofran or Ondansetron. Notice it's not on the list. Ondansetron is a very good nausea medicine and if somebody has a migraine, ondansetron really may abort the nausea, but it will never abort the headache.
Dr. Steven Toenjes:Some nausea medicines compazine and promethazine, or Phenergan Reglan, which is metoclopramide. Those medications are actually some of the most effective ways to abort a migraine, not just the nausea, they will abort the pain and it's very specifically one of the reasons why, if someone shows up in the emergency room with an intractable headache which is approximately one in ten people in an emergency room one of the most important things that they're supposed to give you is one of these anti-emetics, because they're not a narcotic and they are very, very effective at aborting the pain of a migraine. That always seems to me forgotten. Then the level C evidence medications for abortive. I'd just point out that there are some narcotics on here and then an oldie but goodie that's been around for a long time. The last one Butalbital mixed with acetaminophen and caffeine. That is a medicine that was called Fioricet In the headache clinic that medicine we refer to as the F word.
Dr. Steven Toenjes:One of the things that's true about abortive medications, acute relief medications, is if a migraine patient takes them too frequently, the medication will backfire on them and in a slow, smoldering fashion, slowly, progressively increase the frequency and severity of the headache syndrome and severity of the headache syndrome and we call that rebound phenomenon or medication overuse headache. And Fioricet said the F word. Medication is one of the most potent medicines at doing that. I'm not saying there's no use for Butalbital containing substances in the headache clinic, but we always have to understand and respect the frequency with which we can use that medicine and stay away from progressively worsening someone's headache syndrome. And it turns out somewhere between four and six doses of Butalbital containing substances in a month crosses that line and starts to be able to build the headache syndrome. And so when we see patients that are on six to eight Fioricet a day, those people have a very serious medication rebound problem.
Dr. Carolyn Tran:Yes, and I do see that a lot in primary care patients who come in who want refills of those medications because they've been on them for years and they want at least 30 a month.
Dr. Steven Toenjes:Yeah.
Dr. Carolyn Tran:And it's very hard to convince them that there are better alternative treatments these days.
Dr. Steven Toenjes:Okay.
Dr. Carolyn Tran:Yeah, so let's talk about preventive treatments.
Dr. Steven Toenjes:The goal of preventive medications now is going to be to take the overall frequency of the headache disorder and reduce that, hopefully significantly, and hopefully with either no side effects or tolerable side effects. I share with patients that we'll define what we mean by success with a preventive medication, and we define success as at least a 50% reduction in headache frequency. At least a 50% reduction in headache frequency and either no side effects or tolerable side effects. And I think it's an important thing for patients who oftentimes have lost hope because they've tried a number of things and have not had success. We have a lot of medications where the likelihood of success, as I defined it, is high. Indeed, there are a number of medications that we'll kind of point out here where most people that initiate them achieve success in the way that I defined it, meaning at least a 50% reduction.
Dr. Carolyn Tran:Yes, and just like we talked about in that first slide, there is no cure but there are preventive treatments to kind of decrease that frequency. But keeping it realistic, maybe a 50% decrease for not curing it.
Dr. Steven Toenjes:So the American Headache Society has some guidance on when is it we should be thinking about preventive medications.
Dr. Steven Toenjes:I think it's a busy slide, but the easy way to think through this is certainly if somebody's having four migraine events in a month, if they're beyond that, we really need to be thinking about prevention, or if the patient has significant disability related to their headache syndrome.
Dr. Steven Toenjes:One of the things that has been a little bit eye-opening through global burden of disease studies, it turns out that migraine is number two on the list of disorders that give us years lived disabled. It's only second to low back pain, and if I asked who in here has low back pain, everybody's hand is going to go up. Well, migraine is number two in terms of for humans across the planet Earth, it's the number two disabling condition. It has to do with its sheer frequency. If you look at females in childbearing years, migraine is by far number one, and so one of the focuses that's important is to pay attention to the headache syndrome's impact on a person's ability to function in their life, and if the headache syndrome has a substantial impact on the person's ability to function, it's appropriate to think about preventive medications.
Dr. Carolyn Tran:Yeah, and I think that's important. The word syndrome is, if you think about that slide that we showed you earlier, we're talking about the prodrome, everything leading up, and that's three, four days of your life where you're not functioning at 100%.
Dr. Steven Toenjes:And every once in a while it's not the pain of migraine that is the disabling part. It certainly can be the vomiting, it can definitely be the every once in a while I'll see it be the post-drome or the hangover, where someone just can't, doesn't have enough energy to even get out of bed for an entire day after the pain phase, and so sometimes the pain is only moderate and they can function through that, but they can't function through the post-drone, and so understanding how the different phases of the migraine syndrome impact a person's ability to function, you know, I think is really really important.
Dr. Carolyn Tran:Yes, and that does relate to, you think, four or more headaches. It's four headaches a month and I'd want to take a medicine every day to prevent it. Well, when that prodrome and that post-drome are affecting your week, then that makes a big difference.
Dr. Steven Toenjes:The same sort of designation, preventive therapies of level A. We don't necessarily need to go through all of these. The CGRP-based drugs are purposefully not on this list, so there's even more that have level A evidence in terms of prevention. You'll see down at the bottom, onabotulinum toxin A that is Botox. That is a common that we see commercials for, the up at the top, Diproex, that's a seizure medicine, Topiramate's a seizure medicine, Metoprolol, Propranolol and Timolol those are blood pressure medications. So these are all medications that through the years, you know, patients and doctors have figured out oh, when I use this medication it really helps my migraine syndrome. They're not very specific to migraines pathophysiology though, and they've all been sort of accidentally discovered.
Dr. Steven Toenjes:It is a true story that when people I would guess you know just historically mostly females getting Botox for cosmetic purposes Also females remember they're one in five is a migraine patient that when botulinum toxin was being used for cosmetic purposes, the migraine patients were coming back saying you guys need to study this because my headaches are gone and it is FDA approved as one of our most effective preventive agents, but sort of accidentally discovered and Botox or botulinum toxin injections for migraine is why I have to leave at a hard stop at 1 o'clock because there will be 20 people waiting in the clinic for their Botox injections because they need them.
Dr. Steven Toenjes:It really helps them and it is one that you can make the statement most people get success with this preventive measure as I defined it. Sometimes I think it is useful to understand the other things listed on this Realistically. When we look at if I place a patient on tapiramate for example, Topamax or Topiramate what's the likelihood that that person will achieve success? The answer is actually 20 to 30%, and so most people are not going to either tolerate or respond to our more conventional oral preventive agents in the past, and that has produced a lot of treatment failures and migraine patients. A lot of them have given up hope. But I just alluded to botulinum toxin injections in our newer CGRP-based therapies. You know really do have a much higher rate of efficacy and better tolerance rates too.
Dr. Carolyn Tran:Yes, yes, and some of those medicines. The hard part is convincing patients. This is not a quick fix. You're not going to take it that first month and it's going to change your life.
Dr. Steven Toenjes:Yes, Topiramate.
Dr. Steven Toenjes:Our Topimax studies were actually very well done, randomized controlled trials, and in their studies they're a good example of what you're alluding to. When you look at the Topiramate trials, the first time point that treatment and placebo groups start to split is four weeks. So a month is when they start to split and then if you follow the split it keeps splitting for 18 months and so it's a very slow, smoldering response that we do await for as long as the person's not having side effects.
Dr. Carolyn Tran:Let's take a look at some more preventive therapies that are out there.
Dr. Steven Toenjes:So the things that we list as level B, there are some really good oldies but goodies, and the purpose of this is not to review them all, I do think, but to just note that there's a lot. But I do think that it's worthwhile pointing out that there's a couple over to the right that are not really medicines. Riboflavin is vitamin B2. It does have some reasonable evidence level B evidence in efficacy and migraine prevention and that is not a medication and magnesium. So those are supplements.
Dr. Steven Toenjes:The feverfew is an herbal thing and so, just because we run through medications and our discussions are heavily weighted towards them, you know there are ways to try to achieve success, certainly without things that we would consider a traditional medicine. Level C I think everything on this list does have at least some weak evidence. Candesartan is a blood pressure medicine that folks in other countries would have, actually on the level A category, but again, just the general point that there are a lot of medications in our medicine box. I think we can go by that one.
Dr. Carolyn Tran:Yes, let's talk about the newer treatments out there.
Dr. Steven Toenjes:Yeah, so the CGRP, or calcitonin gene-related peptide antagonists. We have Gepants, and so you see the generic name for all of these medications is going to end in Gepant, just like the triptans do. Rimegepant is Nurtec. You see Lady Gaga's commercials with that medication. That is the medicine that's actually being studied as part of the menstrual migraine trial that we have ongoing. Atogepant is Qulipta. You do see commercials with Qulipta and Ubrelvy or ubrogepant. We aren't seeing Zavzpret or zavegepent, which is a nasal spray that doesn't have any real commercials out yet. If you pay attention to the Qulipta commercials, the atogepant commercials, you'll notice that they'll give a marketing piece. They'll say a chance at headache freedom, and so, while there aren't cures, there are reasonable percentages of patients that, as we initiate some of these medicines like Qulipta, they're literally capable of going an entire month with no headache and they may have started with 20 migraine days in a month, and so the FDA lets them make that statement. You know, the chance for headache freedom.
Dr. Carolyn Tran:You know the chance for headache freedom and you want to talk a little bit about like why this was so different from some of those triptans that we had talked about. You know those Imatrex, Zomig ,those older ones.
Dr. Steven Toenjes:You know, there are some vascular risks that are associated with the triptans. They do bind to receptors that are on some of our blood vessels and make them spasm a little bit, including coronary arteries and intracranial arteries. The spasm is very minimal, but there's at least theoretical vascular risks with the triptans, and those risks don't really exist with the Gepants. They do not cause any vasospasm at all. They prevent the dilatation of blood vessels that occurs during a migraine, but that's very different than producing a spasm, and so we have thought of them as extremely well-tolerated and very safe medications.
Dr. Carolyn Tran:Yes, because a lot of times with the triptans we weren't able to even use them in patients who had any risk factors for heart disease. You know the pharmacist would give us a call back. Are you sure? This patient has high blood pressure. They have coronary heart disease already and this gave us a whole new set of medicines to put in our toolbox as well. And this was exciting for us because Jacksonville Center for Clinical Research actually was involved in some of the studies that involved the calcitonin gene-related peptide antagonists before they were on the market. So that's always exciting for me to see those now be available to patients.
Dr. Steven Toenjes:Yeah, we were part of atogepant study.
Dr. Carolyn Tran:Yes, yeah
Dr. Steven Toenjes:And a number of the self-administered injectable antibodies, and so there are other CGRP antagonist therapies that are preventive therapies. They are self-administered injectables that someone injects every 28 days, so it's not a pill that they have to take and they are extremely well-tolerated. They're listed over to the right. Amavig, which was a renumab, was the first FDA-approved CGRP-based drug, and that was in 2018. And the other four are extremely effective. I use them every day, all four of them, and all four of them. I can say the same statement in terms of, you know, most patients get success, as I defined, success with prevention, and so it's nice for patients to have, you know, a pretty substantial list the CGRP-based antibodies Qulipta and Nurtec, or atogepant, rimegepant, as well as Botox. Those are all our medicines that you, medicines that most people actually tolerate quite well and respond to very, very well.
Dr. Carolyn Tran:Yes, and don't let the name monoclonal antibodies scare you. Many of you may have already experienced some of these with cholesterol medications that are already on the market. It's kind of using the same technology there you know technology there. The
Dr. Steven Toenjes:. That is a very unique uh medication. Its name is trade name is rayval. It's the way to think of Reyvow, which is not really. It's a Eli Lilly drug, but they're not really marketing it much at all. It's actually a really good medication. It functions very much like triptans, but it only binds to a very specific serotonergic receptor and it produces no vasospasm whatsoever, so it's like a triptan that does not have the cardiovascular risk. It does make people sleepy and the FDA required a recommendation that someone not drive for eight hours after taking the dose and I think that Eli Lilly said well, we're not going to make that much money on it, so they don't market it and you don't see commercials for Reyvow very much, but it is an extremely beneficial drug that sometimes is the solution to somebody's migraine abortive treatment.
Dr. Steven Toenjes:Yeah, so one of the more common treatments for chronic migraine patients certainly is Botox, which the generic of Botox is onabotulinum toxin A. There are multiple botulinum toxins. Just Botox happens to be onabotulinum toxin A. It is something. That's a procedure, though, and you see pictured the little dummy head down at the bottom. The little dots that you see on that head are the location of the injections for a migraine protocol injection. If you count them up, it's 31 injection sites and has been FDA approved for chronic migraine since 2010. And millions of people have been given this medication. It's been around a long time decades before it was, you know, a long time before it was even FDA approved for migraine and, as mentioned, is one of our most effective preventive treatments.
Dr. Carolyn Tran:So each time one of your patients comes in, are they getting an injection at every single little red dot there?
Dr. Steven Toenjes:Yes, 31 shots
Dr. Carolyn Tran:31 each time.
Dr. Steven Toenjes:Yes, and every three months.
Dr. Carolyn Tran:Every three months.
Dr. Steven Toenjes:Yes, and if my scheduling is such that they're going to be late by a week, believe me, they are complaining about it. They're beating the door down to come and get their treatment because after two, two and a half months it starts fading out and they feel their migraine syndrome coming back, and so nobody misses their Botox appointments. Nobody likes getting 31 shots in their head, and so the fact that anybody comes back at all is a testament to the efficacy of the medicine.
Dr. Carolyn Tran:That is true
Dr. Steven Toenjes:As a matter of fact, in private practice we never even needed to confirm Botox appointments. Nobody would miss their Botox appointment.
Dr. Carolyn Tran:Do they have amazing foreheads?
Dr. Steven Toenjes:We're not doing that.
Dr. Steven Toenjes:We don't do it for cosmetic purposes. There are a variety of other therapies where this is not an exhaustive review of migraine treatments. Down at the bottom there are device therapies, neuromodulation devices that can be effective. A lot of people have heard about the Cefaly device. They're difficult to use in the United States, mainly because we can't get insurance to cover any of this stuff, despite there being efficacy and safe. These are safe treatments.
Dr. Steven Toenjes:But just because, even if somebody has literally been through all medicines and is really still struggling, there are still other treatment options that we really kind of haven't talked too much about. And the neuromodulation devices are, I think you know, really really beneficial. And behavioral management you know one of the most important things. I give a sheet on behavioral modifications that can be beneficial in migraine patients. Every new patient that comes in is going to get a handout on the kind of behaviors that they need to be paying attention to and those kinds of changes things like staying hydrated, not abusing caffeine, sleeping enough hours in the day an important one, keeping your circadian rhythm the same, meaning going to bed and getting up at the same time every day, trying to get some exercise these minor things can really dramatically impact headache frequency in a migraine patient.
Dr. Carolyn Tran:Yeah, and you just touched on those. I just want to have a question for you, Dr. Toenjes. In terms of Memantine, some of you may recognize this medication. We often use it for Alzheimer's.
Dr. Steven Toenjes:Yes, it's FDA approved to improve cognition in moderate to severe Alzheimer's disease. That's its FDA approval. But there's some pretty good studies on its efficacy in migraine prevention and its mechanism of action. You would guess it may be effective and actually, historically and I know this may sound weird before we got rid of the pregnancy class system Me mantine medications, was pregnancy class B, so it was a migraine preventive agent that, at least theoretically, we would think would be safe to use during pregnancy.
Dr. Steven Toenjes:I've never done that, but that's actually the, it is actually true. So I would say the biofeedback and relaxation training you know these are along the lines of sort of the behavioral modifications that we mentioned. Relaxation training actually has some pretty strong data in functioning as both abortive and migraine prevention. Yoga as an exercise specifically seems to be pretty special in terms of its benefit for migraine patients. I've always thought that it's not just the exercise of yoga, that it's beneficial. Yoga includes some relaxation, and so I've always wondered if that's the reason why, you know, adopting a yoga habit as long as you're careful with your neck and migraine patients, you know is a very, very good idea.
Dr. Carolyn Tran:Is that the relaxation of the muscles that's giving you the benefit?
Dr. Steven Toenjes:Absolutely, and that's what biofeedback is.
Dr. Steven Toenjes:We'll just talk briefly about. Sometimes it's worthwhile for patients to actually kind of formally track exactly how often they're having headaches. I like the Migraine Buddy one, but there are a variety of tracking apps. You know a calendar is a tracking app that works as well, but sometimes it's eye-opening to see really how often somebody's having headaches and how often they're taking medications, and those kind of tracking apps really do exist, and so I guess in conclusions yeah, so what I hope that people can take from this is an understanding of really how common migraine is one in five females, one in 10 males.
Dr. Steven Toenjes:It is an extremely disabling disorder that we usually don't go to our doctor and seek attention or ask for help, and actually usually our doctor does not ask us if we have headache problems. And so increasing awareness of the people sitting in the room and your family members that are around you If you're aware of someone who has a significant impact in their life from a headache disorder, your job now is to educate them about the fact that there really are a lot of treatments and even treatments that we're still studying and that are on the horizon. Keep the thoughts about the different therapeutic, supportive and preventive strategies separate and walk away from this understanding that there are actually a lot of therapies that we have in our toolbox to help mitigate the disabling brain disease that we call migraine.
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