An expert in the management of acute migraine provides an overview of acute treatment and considers the various unmet needs in the space.

: The first question is about acute versus chronic migraine, and we like to separate those out. If someone has frequent migraine attacks, they are usually 4 to 72 hours. Moderate severe intensity, light and sound sensitivity, and nausea—those are the prerequisites, plus a couple of other features that help define migraines. 

We know that if someone has migraine attacks that occur at a frequency that goes over 15 days per month of any kind of headache and more than 8 days per month of migraine, we call that chronic migraine. It has to happen for more than 3 months, but a lot of people make the mistake that chronic migraine is just someone who has had migraine for 10 to 20 years. To be more specific about it, it represents chronicity of migraine over the course of a month. It has to be more than 3 months with more than 15 days of headache, and more than 8 of those 15 days have to have migraine features attached to them.

It turns out migraine patients, many times, don’t get a correct diagnosis, and the American Headache Society has been working on this issue for decades. I remember when the triptan medications came out. There was a lot of energy focused on making accurate diagnoses, and unfortunately, as medical health professionals, we’ve barely moved the needle. We know about half the people out there who have migraine really don’t have the right diagnosis.

Many times, they’re told that they have a sinus headache or a tension headache. A clue is if someone says they had to stay home and were disabled from headache, they had to stop social plans, work plans, whatever they had going on, it’s most likely migraines, statistically speaking. Therefore, anyone who has recurrent headache and is missing time out of their lives, you should certainly suspect migraine.

Still, about 50% of the people in the United States just don’t have the right diagnosis out there. That leads to them not getting the right kind of care. We want people to have the right diagnosis, so they’ve got tools in front of them that we know can be effective.

When we talk about unmet needs, there are many in the migraine space. We first know that there’s a stigma with migraine. A lot of patients aren’t comfortable talking to their providers about migraine. A lot of migraine patients grew up in a migraine household, which means they’ve seen other family members cope with migraine without specifically identifying as such. Even if they know it’s migraine, they feel as if there’s no real hope out there. They’ve come to accept that they’re going to lose chunks of their day, taken away from them randomly, as a function of their migraine experience.

On top of that, we know that acute therapies out there aren’t always effective. For decades, people have used the NSAID [nonsteroidal anti-inflammatory drug]–class medications. Sometimes Ketorolac can be effective, but the over-the-counter acute medications are generally ineffective for moderate to severe migraine. Some people do quite well with over-the-counter medications, but if they use them frequently, we worry about medication-overuse headache syndrome.

When we look at the more commonly used prescription class medications, we know that the triptan-class medications, which had been remarkably effective for a chunk of people with migraine headache, don’t work for everybody. In a study published in 2019, a population-based study of more than 10,000 participants, we learned that triptans were not effective for at least 40% of people with migraine headache. That doesn’t include people who are willing to take triptans but have moderate effects or minimal effects. It also doesn’t include people who take triptans and feel sick from the medication, making them feel unwilling, or want them to delay their therapy, which can all be big issues for people with migraine.

With all these things put together, we know about 40% to 50% of migrainers aren’t getting the acute therapy they need and require. We also know that patient satisfaction with their current therapy—regardless of what it is—before the advent of these newer therapies was really high. About 90% of people who asked about their acute therapies would be willing to try something different, meaning only 10% of people said, “No, I’m good. I’ve got something that I like, that I trust in, that is effective.” Ninety percent of people with migraine are looking for better options, which is a huge statement.

Acute Migraine Management: Overview and Unmet Needs

A discussion on the goals of treatment and the recommended approach for selecting, combining and sequencing acute therapies.

When you look at the clinical trials, the primary end points are 2-hour pain freedom, and that’s what’s defined by the FDA for our acute clinical trials. However, when I’m in the clinic sitting in front of a patient, the goal of acute treatment—and that’s what’s most important when I’m in the clinic with the patient—is what I can do for the patient to help them return to normal life as soon as possible without having adverse effects. That includes relieving not only their pain but also their other symptoms that go along with that migraine attack. I tell patients that I want them to be able to take a medication and, within about 2 hours, be back to their normal selves, so that they’re able to get back to what they need to do, whether it’s being a parent taking care of their kids, going back to school and being in class, or getting back to work. That’s a goal that I define for my patients.

There are different kinds of clinical profiles in the patients I see in clinic. In my clinic population, I’m practicing in a tertiary headache clinic. Many of my patients have not only chronic migraine but chronic daily pain—they have headache on a daily basis. For them and their acute migraine therapy, the goal may not be resolution of head pain, but they always have a certain amount of baseline pain, and then they’ll have headache exacerbations. For them the goal is to get them back to their baseline, get them out of that exacerbation of head pain. However, I do have some patients who have more of an episodic migraine pattern—in general, they have no pain on the majority of their days. For them, the goal is different. The goal is for them to be back to their baseline, and their baseline is no symptoms of migraine, no pain, no other migraine-associated symptoms like sensitivity to light, sound, etc.

As far as prescribing acute therapies, by the time they get to even a neurologist—honestly, for patients with headache disorders, even before they’re diagnosed with migraines perhaps—they’ve already tried some of the more simple analgesics or even combination analgesics. Things like over-the-counter medications like Tylenol or nonsteroidal anti-inflammatory drugs [NSAIDs], such as ibuprofen or naproxen, or the combination analgesics such as medications that have an NSAID or aspirin plus caffeine, like the name brand Excedrin. They may have already tried those even before they’ve received a diagnosis of migraine or if they fit a diagnosis of migraine.

By the time they get to the primary care doctor, they may have been prescribed a triptan medication, but sometimes that triptan may have not been given to them at an optimized dose. You want to make sure that when you, as a neurologist, receive that patient and they mention to you, “Oh, yes, I was given sumatriptan, or Imitrex, or Maxalt,” that you dig a little further and ask them about the dose that they were given. Because sumatriptan at 25 mg may not have done anything, and that may not give you information about what an appropriate dose of sumatriptan may have done.

By the time they get to a general neurologist or even a headache specialist, we want to make sure we understand their medical comorbidities. If they don’t have a contraindication for a triptan medication, meaning they don’t have severe vascular disease, they don’t have a history of stroke or heart attack or significant peripheral vascular disease, or they haven’t had an allergic reaction to a prior triptan medication, a triptan medication is typically going to be our first-line medication. You want to make sure that you use a medication at the appropriate dose.

In the past, if they have used a triptan medication but they’ve experienced a lot of nausea or vomiting, and it was an oral triptan, you may want to use a different formulation, such as a nasal spray formulation or an injection formulation. If someone has tried 1 or 2 triptan medications and they have not had a good response to it, maybe it’s been completely ineffective or they’ve had a significant adverse effect. These things do occur in about 30% to 40% of our migraine patient population, based on studies. In those patients we now have other options. We have medications like lasmiditan. We have gepant medications like ubrogepant, as well as rimegepant. We also have multiple devices that can be used for the acute treatment of migraine. Those are other things that we can explore.

There are patients who have contraindications to triptan medications. However, before they have the contraindication, maybe a triptan worked perfectly. For example, I can recall a patient of mine for whom eletriptan was great. It was a wonderful medication for them, but they came to me and they were scared to report that they had recently been diagnosed with a myocardial infarction. They knew that because of that I would no longer be able to prescribe their eletriptan, but they were scared because they didn’t know what they were going to do for their next migraine attack.

Fortunately, they do have other options now. Lasmiditan still works on the serotonin receptor, very similar to triptan medications. Fortunately, it works only on the 5-HT1F receptor, not on the 5-HT1B receptor, which is the 1 that is located on the blood vessels in the heart and the brain. It would still be OK in individuals who have a history of stroke and heart attack. This was a patient for whom I was able to prescribe lasmiditan.

Goals of and Recommended Approach for Acute Treatment

A key opinion leader considers the importance of the pain freedom end point, and discusses the American Headache Society (AHS) and American Academy of Neurology (AAN) guidelines for the treatment of acute setting.

: It’s important to consider the practical importance of pain freedom versus pain relief. I may have a bit of a biased opinion regarding this because my practice is in a tertiary headache center. The majority of my patients have chronic migraine. Pain freedom is a wonderful goal, and I hope that the majority of my patients with acute migraine treatment options can achieve pain freedom. That is always the ultimate goal. Pain relief from a medication is also a good goal. I understand why, from a clinical trial perspective, it is important for the FDA to have very clear guidelines for pain freedom. It’s a very black-or-white way to compare trials without having head-to-head trials to be able to compare medications and approve medications.

If I also have data from trials that provide medications with pain relief, that’s very important because I can combine medications. If I know that a medication like a triptan provides some pain relief, I can combine that with an NSAID [nonsteroidal anti-inflammatory drug] as well as a neuroleptic medication, like a promethazine, naproxen, and a triptan for a very complicated chronic migraine patient having an acute exacerbation. Together with that combination of medications, if I can get them back to their baseline and out of that migraine attack, it may be helpful. Although pain freedom is a very important clinical end point in trials and does have practical importance in the clinic, pain relief also provides good clinical information for my patient and me when we’re sitting together brainstorming about options for migraine attack treatment.

From a migraine treatment perspective, based on the American Headache Society and American Academy of Neurology guidelines, the most important thing is to remember that we do have migraine-specific therapies that can be used for the treatment of migraine. Although simple analgesics do have some evidence, the majority of patients who have come to a neurologist for the treatment of migraine have already tried those treatment options. We need to use more migraine-specific treatment options such as triptans, or medications like lasmiditan, gepants like ubrogepant and rimegepant, or even device options that have been specifically designed based on what is happening in the brain in migraine. Then we can also use a combination of these treatment options, in combination with neuroleptic medications, to appropriately treat that patient with migraine.

Based on those guidelines, we should personalize the treatment for that patient’s migraine attack. If a patient is having a lot of nausea and vomiting, we want to be able to optimize their formulation. If a person is having a lot of vomiting, we want to be able to use nasal spray formulations, orally disintegrating tablets, injections if we need to, or even devices. We want to personalize the treatment options and use migraine-specific treatment options. 

In the guidelines, it also mentions that when you need to use acute migraine therapies too frequently, you need to start talking about medication-overuse headache, and you need to start thinking about initiating preventive treatment options. These are guidelines that you should talk to patients about whenever you are prescribing your acute medications. Whenever you are prescribing acute medications, have the discussion with patients right away that these are medications that patients should be using 1 to 2 times per week. If patients need acute migraine therapies more than 1 to 2 times per week, then we need to initiate a conversation about prevention to prevent medication overuse headache, which is a complication of frequent migraine attacks in chronic migraine.

Acute Migraine Treatment: Pain Freedom and Guidelines

A discussion on how to measure pain relief in acute migraine treatment and how to monitor the onset of action of therapy.

Wade M. Cooper, DO: When it comes to how to measure relief in migraine, the best question we can ask is, “How well controlled do you feel your migraine is?” A lot of times, patients may say their headache is reduced. They may say they’re feeling a bit better, but they may not be satisfied with that answer.

One of the things I like to ask about if I’m assessing someone for their headache effectiveness is, “How many times in the last month have you been disabled or incapacitated from an acute migraine?” Meaning how many times they have to stop their plans from their work, their family, or their social events that they have going on. Incapacity, taking people out of their daily lives, is a huge issue for people with migraine.

When we ask about onset of action, that’s always a really sticky question, because we first have to expect and hope that our patients are going to use therapies right when their symptoms start. There is some excellent evidence out there that medications like triptans really need to be taken in the beginning phase of someone’s acute headache. A lot of this is scientific. We know that triptans and some of the gepant class medicines work on the lining of the brain, where the meningeal pain through the trigeminal fibers is sent deep into the brain itself. If you wait too long, and that signal from the lining of the brain becomes amplified and it gets reactivated back into the brain stem itself, you’ve lost your opportunity for medications that work in the periphery to have their experience.

We need our patients to take their medications early in many situations. We also asked them, “When you take your medicine, how long does it take before you feel like it’s effective?” This number will vary dramatically. Some patients will say, “I can feel the benefits of my acute therapy within 10 to 15 minutes.” Some people say it can take 4 to 6 hours. Some of my patients even say, “It doesn’t affect me until the next day.” What they mean by that is, what would have been a 3-day migraine attack has been shortened to 1 day, but that’s still 1 full day where they’re being pummeled by migraine—not just the headache component, but the nausea, the light and sound sensitivity, and important to my patients, the impact in their quality of life.

If you’re asking, “Do patients wait? Do they not use their medicines appropriately?” The answer is absolutely. A lot of my patients have to ration their acute therapy. They know that if they’re going to have 15 days of headache per month, and they’re told they can use it only 2 or 3 days a week, they’ve got to save it for when they think a bad headache is coming. Some of my patients save it for when they can’t afford to be incapacitated. If they’ve got a best friend’s wedding coming up on the weekend, they may not use their acute therapy on weekdays. They’ve got to save it for that wedding, even if that means that they go without treating a headache, even when they possibly could.

The other thing that people do is they tend to wait. Part of migraine is a sterile inflammatory response in the lining of the brain, and part of that gives people this confusional element in which they’re not quite themselves. We call this the prodrome, where people don’t have the same awareness. Many times, even if you do psychological testing, people tend to do poorly in the prodrome phase of their migraine, even when they score normally outside their migraine attack. But because of this prodrome, people take awhile to connect the dots that they’re going into a migraine.

Sometimes it means their spouse has to say, “You’re going into a migraine, so take your medicine.” Or someone at work will notice they’re acting funny and say, “I think something is not right with you.” Then the light bulb goes on: “Aha, I might be having a migraine symptom.” But as they wait to take their medications, or they skip taking their medications because they’re afraid of adverse effects, or if they don’t have any faith that it’s going to be effective, that may set them up for bad consequences. More severity of migraine, longer duration of migraine, incomplete response to their therapy.

Therapy Assessment: Pain Relief & Onset Monitorization 

A key opinion leader discusses the importance of patient communication when optimizing the efficacy of acute migraine treatment.

: Our patients with migraine have come to us with a history of stigma: a history of family members, the lay public, their workplace, and even their medical and health care providers not listening to them and not communicating with them, which is why it’s so important that once they come to us as their neurologists and their headache treatment providers, that we emphasize how dedicated we are to communicating with them. Communication is key from the first appointment that we have with them and then through the follow-up and the subsequent communication that we have with them through that entire patient-doctor relationship.

A part of that treatment plan is making sure you describe to the patient what that plan is—for preventive treatment, acute migraine attack, and headache rescue treatment. What happens when my acute migraine attack plan is not going to work, what do I do? What does your patient do? Do they call you? Do they have medications they can take? Do they go to the emergency department? If they go to the emergency department, what do they do, what do they ask for, who do the emergency department doctors call? 

You want to make sure that they have a plan as to what to do because it’s a really scary place to be in for that patient, and often they’re not in a position where they can appropriately advocate for themselves. Then what is the follow-up plan? When should they call you back with their results of how they’re doing with the medications that they’ve been prescribed, or when should they come back to see you in follow-up? When they come back to see you, what is the information you want to know? When you’re talking about acute migraine therapies, what is the appropriate information to know? You want to know not only if it is effective but what do they mean by it’s effective. Does it mean that it’s stopping the attack completely? Are they able to get back to what they need to get back to immediately? Are they able to get back to work, school, taking care of their kids, their pets, etc? Are they having any adverse effects from the medication? Do they have to take a second dose? Do they have to sleep it off because they’re having those adverse effects? Are they having to take something for nausea because the medication is making them nauseous or because the medication is not addressing the nausea that’s related to the migraine attack? You want to dig into all those different factors to see if you can optimize their treatment plan. You want to also find out how often they’re having to take that medication. 

A great way to be able to streamline that communication is to ask the patient to keep a headache diary. I know a lot of patients find this is very frustrating, but 1 of the reasons that a patient finds that this is frustrating is because a doctor doesn’t ask to take a look at it. They feel like it’s frustrating to keep a headache diary if no one is going to take a look at it. If you ask for it and if you look at it, they’re more motivated in keeping it. They can keep it on their phone. They can use any type of app. A lot of my patients like using the app Migraine Buddy, or they can use an old school calendar where you can just flip through it. I usually have patients tick the days where they’re taking a medication or tick the days where they’re debilitated by a migraine attack and they took medication.

Then you can take a look at the calendar and see how many days that is. How that’s helpful from an acute migraine treatment perspective is you can see clusters, or you can see it spread out throughout the month. If you see that and if someone is communicating with you, whether it be through the diary or verbally, that they’re having to use an acute migraine treatment 5 days in a row versus a patient who is taking acute migraine treatment options scattered 5 days randomly throughout a month, it tells me different information. Five days in a row tells me there may be 1 migraine attack that has not been broken, while the 5 random days means there are 5 separate migraine attacks. There’s an increased migraine frequency versus a bad migraine attack that they haven’t been able to break.

I have a different treatment approach for those 2 patients. One patient, I’m going to focus on acute treatment. I’m going to try to optimize my acute treatment options for that patient. I’m going to say, “OK, maybe I need to use something more potent, or maybe that patient is not using their acute treatment options early enough.” This is an issue that I have with a lot of my patients.

Many of our patients, they start getting head pain and they start feeling a little light sensitivity and they think, “Oh, maybe this is just a headache, maybe this isn’t a migraine. I’m just going to wait and see what happens.” And then they start getting nauseous, and they’re like, “Oh, I think it’s a migraine,” and their head is really hurting. Now they’re in their actual moderate to severe pain phase of the migraine attack, and we know that a lot of our acute therapies aren’t as effective when we’re using them in the later stages or the moderate to severe pain stages of a migraine attack. We want to encourage patients to use their as-needed acute therapies for migraine in the early stages of an attack. 

I’ll mention to the patient, “I want you to use your acute migraine medication earlier in the attack. I want you to combine it with an NSAID [nonsteroidal anti-inflammatory drug]. I’m going to prescribe a more potent medication.” Maybe I’ll recommend an injection therapy for them. We’re going to combine it with the NSAID, we’re going to combine it with the neuroleptic medication, we’re going to be more aggressive with it. Then if we can stop that migraine attack, maybe it won’t be 5 consecutive days, maybe it will only be 1 to 2 days. Then with the other patient who has 5 random attacks, I’m probably going to focus on more preventive measures. That’s why it’s so important to increase the communication as well as keep a headache diary, which is a part of communication.

The Importance of Patient Communication

Expert physicians consider the recent treatment approvals for the management of acute migraine, and how the shift in expectations outcomes has impacted treatment selection.

: One of the most exciting things about migraine is the new tools we have at our fingertips. In the last 3 years, we‘ve seen tremendous breakthroughs in our science and understanding of migraine, and this has yielded incredible treatment options for our patients. You may have heard about the CGRP [calcitonin gene-related peptide] monoclonal antibodies. These are medications that got approved in the spring of 2018, and have dramatically changed the landscape of migraine, as well as cluster headache, in the United States.

As an example, we know that in this country, about 1 in 1000 people have multiple sclerosis [MS]. We also know that about 1 in 1000 people in the United States are on a CGRP monoclonal antibody for prevention of headache. The same number of people with MS in the entire country are on the preventive CGRP monoclonal antibodies; it’s rapid adoption.

What also spilled out from that is an understanding of acute therapies, so that the CGRP concept is applied to acute therapies. Instead of focusing on the 5-HT1B and D receptors of serotonin, which is where triptan-class medicines work, now we’ve got agents that focus either on the CGRP inflammatory cascade that can turn off this spike of headache on the inflammation piece and not worry so much about serotonergic transmissions. Or we‘ve got this new medication called lasmiditan, which works specifically on the 5-HT1F receptor, a receptor that’s specifically spared by most triptans out there, and has some benefits to it, not only because it doesn’t affect blood vessel constriction, but also because it has got some targets centrally in the nervous system.

: There have been some shifts in the clinical trials and even the primary end points that the FDA is requiring for the acute treatment trials. One of those is looking at this concept of the most bothersome symptom. I really appreciate that this is an end point in clinical trials because migraine is not just a headache. Migraine is not synonymous with the term head pain. There are so many other disabling symptoms in migraine. Based on the clinical trials, we see that many people have indicated that one of their most bothersome symptoms is photophobia, and nausea. 

I appreciate that this is now an end point, and that this has been able to translate and allow that conversation to take place in the clinic, too, as an expectation we have of these medications that I can discuss with my patients. That not only do I, and also should the patient, expect that these acute medications address their pain, but we are also looking for these medications to address the migraine attack and all that comes with it. I think this is a good shift in the field of headache medicine, in the research world, as well as in the clinical world, and the patient advocacy world, that we should all be expecting more from our medications. And patients should be expecting more from not only their medications but from their headache treatment providers.

Recent Approvals for Acute Migraine

A discussion on the significance of the approval of a 5-HT1F agonist, with special consideration of the safety and efficacy from the respective clinical trial.

: For many years from an acute migraine treatment perspective, especially from an oral migraine treatment perspective, we had only 1 migraine-specific option, and those were our triptan medications. In general, they did work well for many of our patients. But unfortunately, based on trials, for 30% to 40% of patients, it did not work for them. It was either ineffective or it resulted in a lot of adverse effects. A lot of people call these the triptan sensations, where people will have a lot of neck tightness, chest tightness or heaviness, or people would feel like their hair is on fire. Some patients would even describe it to me as, “The migraine attack is awful, but the adverse effects that I’m experiencing from the triptan medication are even worse than the migraine attack itself, so I can’t take it.” Some people would even have jaw pain to the point where they can’t move their jaw because it almost locks into place.

Then there were other patients for whom I was unable to use triptan medications because of a history of severe cardiovascular disease, heart attacks, strokes, angina, TIAs [transient ischemic attacks], or even peripheral vascular disease. We really didn’t have a lot of options for those individuals. However, with the FDA approval of lasmiditan, it was something we were looking forward to because we have known for a long time that the 5-HT1B, 1D, 1F receptor located on the trigeminovascular system is important for migraine. If we could activate that receptor without activating the 5-HT1B/1D receptor on blood vessels, then we could benefit acute migraine attacks without the adverse effect of constricting blood vessels in the brain and on the heart. Then we might be able to use these medications for patients who have had a history of heart disease and cerebrovascular disease, and maybe these medications would be better tolerated in patients who have these severe adverse effects from triptan medications. That’s what we were looking forward to with the FDA approval of this medication.

I also appreciate that the pivotal trials that led up to the FDA approval did include these at-risk populations to make sure that they were investigated, and that there wasn’t an increased risk of having cardiovascular and cerebrovascular events. Because those are the populations for which there are gaps that we need to fill. We have options for them now. Even beyond those populations, we said there are 30% to 40% of patients for whom triptans were simply not effective, and it’s important that we have a different option that isn’t a triptan that we can use for those patients. I’m appreciative that we have lasmiditan for those patients.

From a safety perspective, from the clinical trials, as far as having increased risk of cardiovascular or cerebrovascular events, the safety data looked good. There was an increased adverse event profile of dizziness with lasmiditan, as well as some sedation. If we look back at other acute migraine medications, we have some adverse events in some of those trials, perhaps not as high as lasmiditan. But for example, in the rizatriptan trials, there is some dizziness present. In addition, if you look at our patients with migraine, even in the absence of medications, some will have some fatigue, somnolence, or dizziness associated with their migraine attack. 

I’m not saying that lasmiditan does not have those potential adverse effects with our patient population, but I also don’t want those to make us shy away from prescribing these medications for our patients. We need to inform our patients that these were adverse events in the clinical trials, but we also need to allow our patients to experience these medications, see if they tolerate it. I have many patients who have tolerated the medications very well with minimal adverse effects, with good efficacy. And I have some patients who have not tolerated the medication and have preferred to go on other treatment options.

That’s the key in migraine, whether we’re talking about acute therapies or even preventive therapies, that migraine is a very heterogenetic disease. In the last review article I read, there were over 100 genetic mutations that have been identified that give migraine vulnerability to people with this disease. Everyone’s migraine disease is a little bit different, so we should not expect that the treatment is going to be a one-size-fits-all. What we need as headache treatment providers and as neurologists is a lot of options in our toolbox. It is wonderful to have lasmiditan as a 5-HT1F agonist as an option in our toolbox that we can use in our patients for whom triptan medications were either ineffective, contraindicated, or simply not tolerated.

The Significance of 5-HT1F Agonist Approval

A key opinion leader discusses the adverse event profile of the 5-HT1F agonist lasmiditan and considers its role in the acute migraine treatment paradigm.

: When we talk about lasmiditan, there are a lot of things to think about from an adverse effect concept. The first thing to understand with the adverse effects in lasmiditan, is to appreciate how it’s working. We first know that lasmiditan can reduce CGRP [calcitonin gene-related peptide] effects in the periphery, but we don’t really think that’s its main mechanism of action.

We think the main mechanism of action is reducing the serotonergic 5-HT1F receptor in the periphery, but maybe even more important, lasmiditan can penetrate into the central nervous system, where there are 5-HT1F receptors located. This includes very important areas related to migraine, including the hypothalamus and the thalamus, the locus coeruleus, periaqueductal gray, and many other spaces that are involved in the migraine circuitry.

What’s phenomenal about lasmiditan is it crosses into the central nervous system and has central effects. I also mention that to my patients, because it helps us understand its adverse effect profile. It’s different than peripherally acting gepants, which have minimal adverse effects outside of, perhaps, nausea, and different than the triptans, which typically affect the peripheral nervous system, and give people the serotonergic flushing we see peripherally: increased heart rate, squeezing of the soft muscles in their throat and chest, and paresthesias of the scalp.

We also know that lasmiditan avoids most of that and works on its central effects. Because of that, lasmiditan has a chance to cause dizziness, which is a big issue, rare chance of vertigo, and a lot of people feel weakness, as if they just don’t have energy, not that they can’t move their arms or legs, but they generally feel low energy.

In a recent study, it was found that about 1 in 10 patients who received lasmiditan had 1 of these symptoms, and unfortunately, this can affect people in different degrees. Sometimes severe, about 1 in 100 people have a severe episode of dizziness when they use lasmiditan, and unfortunately, patients can’t always tell when they feel this way. Because the medication is centrally acting, the FDA decided to put a no-driving restriction on this medication, so people who are prescribed lasmiditan, when they use the medicine, can’t drive for 8 hours. 

This is not negotiable, so you can’t tell your patients, try it once, if you feel great, then you can go back to driving or operating heavy machinery. This is a hard stop. Eight hours, no driving, and we really hold tight to that in our practice. Remember, patients may not notice if they feel dizzy or some of the mild vertigo, and you don’t want them behind the wheel of a car. However, I also like to point out, because of these adverse effects, you’ve also got incredible efficacy, and that’s one of the most exciting parts about lasmiditan.

In my opinion, it has more efficacy than a lot of other acute therapies out there. Their published studies show efficacy that is similar or better to almost every triptan study that I’ve seen, including benefits for treating headache 4 hours in. Remember, triptans, many times are less effective the longer you wait. We think that’s because they work mostly peripherally, but lasmiditan, because it works centrally, gives you an even bigger window to take your medication, and offers pretty impressive results with efficacy.

When I think about the role for lasmiditan, in a headache practice, or in a general neurology office, it’s actually quite large, because a lot of times patients won’t tell you they’re not getting the effect they deserve from their acute therapy. So ask the questions, “How effective is your therapy for you? How reliable is your therapy for you? How many times do you get pain freedom of 2 hours?” They’re important questions, because lasmiditan offers the ability to get people pain free at 2 hours, and sustain pain freedom at 48 hours, better than almost anything I am familiar with.

In our practice, we use it for people who have refractory migraine, people who don’t respond well to the typical agents, such as NSAID [nonsteroidal anti-inflammatory drug]-class medicines or over-the-counter medicines, people who haven’t responded to a triptan before, those are the people who I think are excellent candidates for lasmiditan. In my opinion, people who have a large central nervous system component to their migraine, that includes migraine with the prodrome, with autonomic features like…nasal stuffiness, that includes people with migraine who feel fatigued after the migraine in their postdrome, or feel a confusion element, or have episodes where their aura is profound. Those are the people who tend to respond fantastically with lasmiditan in our practice.

We’ve adopted this since it was FDA-approved, and some of my patients have some very creative things to say about it. One of my patients, I’ll have to paraphrase this, says, “It’s better than any of the rest of the blank that you’ve put me on before.” And they also say, “This medication is expletive phenomenal.” What that patient really means is that they’ve been struggling with migraine for a long time, and they’ve looked for ways to stop acute headache when it occurs so that it’s not like a wrecking ball through their quality of life.

Lasmiditan is one of the medicines for this person, the only 1 so far, that has been able to stop their migraine in its tracks and return to them a day that would have been otherwise stolen by the thief of migraine.

5-HT1F Agonist Toxicity Profile and Role in Paradigm

A discussion on the safety and efficacy of various emerging small molecule CGRP receptor agonists.

: We talk about the newer small molecule CGRP [calcitonin gene-related peptide] receptor medications; these are medications that are antagonists to CGRP, meaning they block CGRP. That’s very different than a triptan.

A triptan activates the 5-HT1B/D receptors. The CGRPs turn off CGRP receptors when they’re used, meaning the adverse effect profile is going to be very different. We know that the CGRP small molecule medicines have very few adverse effects. Nausea is the only one that was reported in any consequence above placebo, and encountering that in my practice has been incredibly rare.

We also know that the CGRP small molecule medications can be quite effective for some people, including people who haven’t responded to triptans. Because they’ve got phenomenal adverse effect profiling to them, we also would have expected a lower efficacy, and that has been my experience, too. We know that these small molecule CGRP medicines, ubrogepant, rimegepant, can be quite effective, but they don’t quite have the punching power that we see with triptans sometimes, and don’t quite have the punching power we see with medications like lasmiditan. However, because it’s a different receptor group, people who haven’t responded to triptans might respond well to the small molecule CGRP medications.

Atogepant is a bit different. When we think about atogepant, this is more in the preventive concept, like how people would take topiramate for headache prevention. Topiramate has been around for several decades now. It’s a once or twice a day medication, you take it every day to achieve a steady state to lower your body’s susceptibility to turn on a migraine attack.

Atogepant is showing some promising data with its ability to prevent migraine. In a recently published trial, this included over 800 people who had migraine, they compared it to placebo, and they compared a dose of 10 mg once a day, all the way up to 60 mg twice a day. And what’s unique about atogepant is you had the same efficacy, almost, between the 10-mg once a day and the 60-mg twice a day dosing.

Adverse effects were minimal but did include nausea, just like the small molecule medicines for acute therapy. Interestingly, only 2% more people than the placebo group dropped out because of any kind of adverse event. Similar to the CGRP monoclonal antibodies, there was a drop in days of migraine, and a drop in days of headache. Essentially, in this study, people had an average of about 8 days of headache coming in, and about a 50% drop in headache, down to 4 days, was seen among almost every dose trialed in this, where the placebo dropped down about 3 days of migraine per month. So this was a very well-tolerated medication. Efficacy seems to match our other tablet prevention therapies, and there’s a pretty unique niche for this class of medicine.

Because of its minimal adverse effects, you could take this every day as a prevention, and you don’t have the fluctuating experience like you’d see with the once a month monoclonal antibodies. Remember, the once a month monoclonal antibodies have a very long half-life: 28 days, sometimes as long as 41 days half-life for the monoclonal antibodies. So once you’ve given it, that medication is going to have its effects for a long time, sometimes beyond 3 months. The small molecules are out of the body quickly.

One of the challenges we see with the monoclonal antibodies, those once a month injections for migraine prevention, is they tend to wear off at the end of the month, or you can’t amplify their experience around menses or other situational migraine attacks. They’re locked into a once a month dose, or sometimes a once every 3 months dosing, whereas atogepant might give us some flexibility, and it might also prevent against a wearing off effect at the end of the monthly cycle.

: It is such an exciting time to not only be a provider taking care of patients who have migraine, but also for patients with migraine because we do have many options. For the acute treatment of migraine, like I said before, we have had triptans alone for so long, but now we have other options. We have lasmiditan. We have gepants; we have 2 of them at this time that are FDA approved. We have rimegepant as well as ubrogepant. Rimegepant is a 75-mg dose once daily as needed for an acute migraine attack. In the clinical trial, it did achieve its primary end point of 2-hour pain freedom, as well as achieving the end point for the most bothersome symptom. 

From an adverse effect profile, it seems to be very well tolerated, similar to the CGRP medications that have been used not only for acute but also preventive treatment options. I think the other very attractive thing with the small molecule CGRP medications is since we are targeting this pathway, not only for acute treatment of migraine but also for the prevention of migraine, not only with monoclonal antibodies but also with the small molecules in ongoing studies. There is this concept we are thinking about of, are there now going to be acute migraine medications that may not have the risk of medication overuse because they may have a preventive benefit? We don’t know the answer to that yet, but I think it’s an important thing to consider. Right now, it is only FDA approved for the as-needed treatment of migraine, but I think these are things we can consider when we are prescribing these medications in the clinical setting.

CGRP Receptor Agonists: Safety and Efficacy

Experts in the management of acute migraine consider how the various emerging agents are being used in clinical practice and discuss upcoming studies that are defining the future of treatment.

: When I take a step back and look at what these new tools have offered us, we know that patients with migraine have an unmet need. We know some of them don’t have the right diagnosis; we know those people with migraine who do have the right diagnosis don’t always have reliable treatments available to them. In the last year, we’ve seen 3 different medicines FDA approved for acute therapy.

That includes 2 as-needed medications that work on CGRP [calcitonin gene-related peptide] blockade, it includes 1 brand new class of medicine called lasmiditan, as well as the promise for certain prevention therapies for once a day dosing for the CGRP medications. What’s fantastic about this is our patients who didn’t have a lot of good options for their acute migraine, even just 8 or 9 months ago, now have multiple options that could be really effective for them. And at our practice we’ve used all 3 of these agents extensively; we’ve seen nothing but good results. We know that the CGRP small molecules are well-tolerated, quite effective for some, including those who don’t respond to triptans. We know lasmiditan has some adverse effect issues attached to it, remember, it has an 8-hour no driving restriction after you’ve used the medication, but it has some really impressive efficacy that has saved the day for a lot of our patients with migraine. Hopefully, after watching our presentation, you are going to be able to apply these to your clinical practice and change the lives of people with migraine.

When we talk about what the future holds, there are lots of things to be excited about. We’re starting to understand this inflammatory cascade better, and there are a few exciting inflammatory peptides that could be further targets for us. We also know there’s a hormonal component in regulating the autonomics of migraine, meaning blood vessel dilation and constriction, eyeball watering, or nasal stuffiness, so targeting the hormone control of this central activating pathway might yield really good results. I’m excited to see what we can come up with, with acute therapies and prevention therapies that target these avenues.

On top of that, one of the things we’re missing right now is long-term safety studies on these CGRP medications. Our experience so far with monoclonal antibodies, the once a month or once every 3 month dosing to prevent migraine, has been phenomenal from an efficacy standpoint. It has also shown some adverse effects that weren’t available and weren’t known about in the initial clinical trials.

We know that erenumab had to add on constipation and add on increased blood pressure shortly after starting the medication. And we don’t know what else it’s going to show in 5, 10, 15 years down the road, so those are the things I’m looking to see. So far, I don’t expect anything major coming out of those, but those are the things that will give me confidence when I prescribe those medications to young people who might need them for many years to come.

: It’s such an exciting time for migraine management. We really have an explosion of therapeutics, and it seems like every 6 months there are new treatment options clinically available for our patients. Our toolbox continues to expand, and that is great. That is great for patients, and that is great for health care providers so that we can continue to explore every single treatment option until we find the right one for our patients. For the acute treatment of migraine, at this point, without having a way of individualized, personalized treatment, I dream about being able to take the blood or saliva sample from my patient and it will tell me which migraine treatment option is going to work, which one is not, and which one is going to give them adverse effects. 

Without that, right now, I have a bunch of clinical trials, and I have guidelines from the American Headache Society and the American Academy of Neurology. Based on what I have available now, the patient who comes to me with migraine, based on their medical comorbidities and if they don’t have contraindications, I will start with triptan medications. If they have nausea and vomiting, I will likely explore different formulations like nasal formulations or injection therapies.

If they have contraindications, or if triptans are ineffective or cause adverse effects, I will likely try other options like lasmiditan because it is a 5-HT1F agonist and it does not have any effect on blood vessels, which is a very attractive option for anyone who has cerebrovascular disease, cardiovascular disease, or has a good response to triptans from a pain relief perspective but has adverse effects from triptans that they don’t tolerate. Those are individuals for whom lasmiditan might be a great option, or we have gepants, like rimegepant or ubrogepant, which might be great options. Then we also have devices such as a supraorbital neurostimulation device. We have an arm stimulation device. A lot of these devices could also be acute treatment options for our patients.

There are also many trials ongoing that are exciting in the space of migraine. Some of these are in the device realm. Some of these are still in the CGRP small molecule agonist realm. One of them is looking at the medication rimegepant to see if it might be effective for prevention. The reason I think that is a very interesting trial, and how it can impact the acute treatment of migraine, is this might end up being a medication that we can prescribe for patients as needed. But if they need to use it too frequently, it ends up working as a preventive agent. Then when they’re not having to use it as frequently, it works as an as-needed medication. I feel like that is something patients probably have been seeking for many years, and it may be something that we’ll be able to provide patients in the future. I’m looking forward to seeing those data and that FDA approval in the future for prevention, if possible, and definitely looking forward to other gepant small molecule, CGRP antagonists to become approved for acute therapies.

: When we talk to general neurology colleagues, we know that many times, there’s not an interest to help people with migraine. People with migraine previously had a lot of needs, and a lot of unmet needs. Before now, we just didn’t have the tools to help people, but now we’ve got good prevention therapy, studies for migraine prevention that look really effective with minimal adverse effects, and easy to use prevention therapies that can change people’s lives. On top of that, we’ve got really good, brand new acute therapies, some with minimal adverse effects, some with phenomenal efficacy, and we’ve got to use these tools to help patients in need. So for those who are watching this, make sure you appreciate the new tools out there and start changing the world for people with migraine.

Expert Perspectives: Advances in the Management of Acute Migraine