 Migraine, as many people know, is probably the third most common medical disorder on the planet; and among people under 50 years of age, it is the most disabling, in terms of years lived with disability, of any disease or disorder in the world. It affects over 40 million people in the United States, roughly 12% of the world's population, and it's an inherited neurological disorder that is accompanied by myriad symptoms, only one of which is headache, of course. That's what it's become synonymous with.

But in addition to headache, patients experience a number of other cognitive, vestibular, mood, gastrointestinal, autonomic symptoms that accompany each individual attack. Patients are sometimes impaired for days at a time. It's not just necessarily the time between when the headache starts and stops, but it's also the prelude or run-up to the headache, which is called the prodrome, for which patients may experience hours to days of symptoms before the actual head pain starts. And then we know of the postdrome, for which patients feel hung over and have a multitude of symptoms that can last for hours or days. So even though an episode of head pain or headache might last 6 to 12 to 24 hours, the total duration of impairment may be 72 hours or even longer.

In terms of impact, every aspect of patients’ lives are impacted—their personal life, their social life, their professional life, their family life. Because of the demographics of the patient population that is affected—principally, it peaks between the ages of 18 and 45—what are people doing between the ages of 18 and 45? They're going to college. They're trying to build a family. They are trying to build a career. Migraine interferes with that.

There's a shocking, stunning number of people who don't take promotions, for example, or can't finish college, or can't build a career that they were otherwise destined to achieve. So it affects every aspect of their life.

For people who are parents, it affects their ability to parent properly. They feel quite guilty about that. They're not the parent. They're not the mother. They're not the father. They're not the spouse. They're not the sibling. They're not the child that they could be. It really steals a lot of life away from people.

Burden of Migraine

 The goal of treatment for acute migraine is to stop all of the symptoms, not just the headache, but all of the symptoms that the patient experiences. If they're nauseated, if they're vomiting, if they're dizzy, if they're cognitively impaired, the goals is to stop all of that and do so with minimal or preferably no adverse effects and to have that relief be sustained. 

One of the frustrating things for patients is that their symptoms may be relieved but come back within 4 hours, 2 hours, 6 hours, 12 hours, or within the next day. Then they have to go through the whole thing all over again. So sustained relief of pain and all other associated symptoms with minimal or no adverse effects is the goal. 

Ultimately, the goal is to get people back to functioning. We're both working today. If you or I had a migraine attack today, we're either A) not going to be able to work, or B) not going to be optimal at your job or whatever it is you’re doing today, whether that's going home and playing some soccer later, or going to a concert, or just doing a job.

The goal is to get people back to normal functioning. Now, can people function normally with some residual symptoms of migraine? Yes. While I say that it’s the complete relief of pain and all associated symptoms with no adverse effects, that's not necessarily achievable for patients for every single attack. But if we can at least get them back to normal function, these patients don't demand a lot. They don't ask for a lot because they're used to getting very little, to be quite honest. Unlike prevailing wisdom or conventional wisdom, these patients don't demand a lot. If you can just get them back to functioning normally at their job, or at home, or at school, or wherever else, that is ultimately the goal of acute therapy.

What’s the difference between pain freedom versus pain reduction, in terms of the way migraine has been measured in this field? The way this has been measured in the headache field is that pain freedom is the complete relief of pain. So, having 0 pain. Normally, the scale that is used is 0 is 0 pain, 1 is mild pain, 2 is moderate pain, and 3 is severe pain. Whether you have mild, moderate, or severe pain—whether you're at a 1, 2, or 3—freedom is going to 0.

Pain relief is going from moderate or severe pain—so a score of 2 or 3—down to a 1 or 0. Pain relief includes both freedom from pain but also mild pain. If I took you from severe pain down to mild pain, that would be pain relief. If I took you from moderate pain to mild pain, that would be pain relief. Pain relief is kind of a less ambitious goal, because I'm not actually getting rid of your pain completely, necessarily. Rather, I'm getting you to at least mild pain. That's the difference. Pain freedom is freedom from pain. Pain relief means that you've relieved pain. You've not necessarily obliterated it. It has not necessarily completely disappeared.

Acute Migraine Treatment Goals

: In terms of recent advances when it comes to acute medications for migraine, there are basically 2 classes that have recently become available, FDA approved, and commercially available for prescription. The first class is comprised of the so-called gepants. They're called gepants because the suffix in the name ends in gepant—ubrogepant and rimegepant. The other class is called the ditan class, and it's called that because the suffix in the name is a ditan—lasmiditan. I guess we should call them gepants and ditans because that's the way they are pronounced when you spell the name, when you say the word. Anyway, ditans and gepants. 

There are 2 approved gepants—rimegepant and ubrogepant—and 1 approved ditan—lasmiditan. The gepants are antagonists to CGRP [calcitonin gene-related peptide], so they are CGRP receptor antagonists.

CGRP is a molecule that, since the 1980s, we knew was involved in the pathophysiology or pathogenesis of migraine. It plays an important role. It's a signaling neuropeptide, so it seems to propagate pain signals along sensory nerves, particularly the trigeminal nerve, which is responsible for migraine. It seemed clear that if you could block that protein, either bind it up so that it doesn't get to its receptor or lock it from attaching to its receptor, you could inhibit the propagation of pain signals. That's what these gepants do. They bind to the receptor for CGRP on trigeminal nerves and block its ability to signal along that pain nerve. 

These 2 gepants were shown to be effective and well-tolerated during their pivotal trials. There were 2 pivotal trials for ubrogepant, and same for rimegepant. Both were shown to be effective, with pain freedom rates around 20%—19% to 21%, but suffice it to say that around 20% of patients achieved freedom from pain at 2 hours.

They were also effective in relieving patients' most bothersome symptom. We talked earlier about the fact that migraine is not just head pain. There are a variety of other symptoms that come with migraine. And so, patients were able to select the symptom. They may have 10 symptoms, but 1 may be most bothersome to them. Maybe it's nausea. Maybe it's sensitivity to light, what have you. And so, in these trials, it was assessed the extent to which they relieved both the pain as well as the most bothersome symptom.

Both of those gepants showed statistical superiority over placebo in the extent to which they both rendered the patient free from pain in 2 hours as well as free from the most bothersome symptom. 

There were a variety of other secondary end points that these 2 drugs also achieved, or were separated from placebo. We've talked a bit about the difference between pain-free and headache relief. From a headache relief standpoint, 58% to 62% of patients achieved relief from pain. In other words, they were either pain free or they still had mild pain. And so, the 2 looked very similar in terms of efficacy, and they looked fairly similar in terms of tolerability as well. There didn't appear to be any serious safety concerns with either of the medications in the clinical trials. 

One of the benefits of this class of medication, beyond the triptans that have been available now for 3 decades, is that they don't constrict blood vessels. They block a protein, CGRP, that dilates blood vessels, but they don't directly constrict the blood vessel like triptans do. From that perspective, they may be used in patients for whom triptans were otherwise contraindicated. So if you had a bypass surgery, for example, for coronary artery disease, or you had hardening of your carotid artery that might have led to a stroke in the past, you couldn't take a triptan. However, you could take these medications because they don't constrict blood vessels. That's one of the major advantages of these medications.  

The other major advantage of these medications is that they don't cause, or don't appear to cause medication overuse headaches. There's this phenomenon known as rebound or medication overuse headache in that the more you use an acute medicine, the more likely it is that you're going to increase the frequency. It's kind of short-term gain for long-term pain, if you will. The more you take, the more attacks you get. That's true with triptans, it's true with over-the-counter analgesics, and it's true with pretty much every acute medicine we use for migraine, except the gepants. Now there are gepants in development that, if you take them every day or every other day, actually show a reduction in the frequency. And since medication overuse headache or this rebound phenomenon appears to be mediated by CGRP, blocking CGRP could actually prevent and treat medication overuse headache.

That's one of the other differences with the gepants: There may be no limit to the use of them, other than cost and access to the number of tablets when it comes to the fear of and the propensity with which you can induce medication overuse headache. That's the other advantage, I think.

Lasmiditan is not a gepant, obviously. It's a selective 5-HT1F receptor agonist. What does that mean? Well, triptans bind to 3 different serotonin receptors. Serotonin is abbreviated by 5-HT. So, when I say 5-HT, I really mean serotonin. Triptans bind to 5-HT1B—B for blood vessel, because those receptors are on blood vessels; 5-HT1D—D for dendrite, because they're on nerves; and a couple of them find the 1F receptor, which is also on nerve endings and not on blood vessels. So ideally, if you developed a molecule like a triptan that bound to either the 1D or the 1F receptor but not to the 1B receptor, because then you wouldn't constrict blood vessels, you would only bind to receptors that are located on nerves and not on blood vessels. And so, that's what this group does. They developed a selective 5-HT1F receptor agonist. So this molecule binds to the 1F receptor on nerves, trigeminal nerves, and, again, prevents the propagation of pain signals. And so, it too, like the gepants, does not constrict blood vessels. That’s a good thing. You can use it in people who would otherwise not be able to use triptans.

The pain-free rates with lasmiditan were somewhere, depending on the dose, between 28% and 38%. So, higher than we saw with gepants. The headache relief rates were similar. About 60% or so had relief of headache. And like gepants, lasmiditan led to the complete relief of patients' most bothersome symptom. It was superior to placebo at 2 hours. So lasmiditan was approved by the FDA for the acute treatment of migraine as well.

The adverse effect profile of lasmiditan appears to be different then it is for gepants. Because it's a centrally penetrant drug—it crosses the blood-brain barrier and gets into the brain more easily—it can cause adverse events like dizziness, sedation, fatigue, or lethargy, and those sorts of things. Because of the propensity with which you could develop some sedation, it's a Schedule V substance. This means you can't operate heavy machinery or operate a motor vehicle within 8 hours of taking the drug because of the probability or propensity of it causing some sedation or a drop in reaction time and things like that.

So the adverse effect profile of lasmiditan looks different than the gepants, at least in clinical trials.

 Advances in the Treatment of Acute Migraine

: The benefit of an oral disintegrating formulation, for patients who don't like to take tablets or have difficulty swallowing tablets, that's obviously an advantage. For patients who may be at work or may be in a situation for which they want to be more discreet and slip something under their tongue and let it dissolve rather than make it look like they're taking a medication, that's obviously an advantage. 

So, there are advantages to having an oral disintegrating formulation that doesn't require water. It can be used more discreetly, and can be used in patients who prefer not to take tablets or swallow tablets. And then, of course, there are patients who prefer taking tablets rather than having something just dissolve. It really does come down to patient preference, but it does give you that option.

In terms of dosing, there's only 1 dose available for rimegepant, and that's 75 mg. For ubrogepant, there is a 50 mg and 100 mg dose, so there are some alternative dosages there. But for this trial and for this medication, as its commercially available, it's a 75 mg oral disintegrating tablet. 

When we look at patient selection for this drug, these were people with episodic migraine. So, they did not really have chronic migraine. They weren't overusing acute medications. They could have failed to respond to triptans in the past. They could have been on preventive medicine as well, so they look like a lot of the patients who are seen in primary care and in general neurology practices. But like all clinical trials, patients had to wait until pain became moderate or severe before they could be treated.

That's not what we do in clinical practice, however. In fact, the regulatory requirements and the way clinical trials are conducted for the acute treatment of migraine are exactly opposite to what we recommend in clinical practice. We tell patients to take the medication as soon as they realize they're having a migraine attack. In other words, while pain is still mild, you should take the drug. We know that you essentially double the pain-free response rates when you take a drug while pain is mild compared to when you take it when pain is moderate or severe. It's important to recognize that the results you see in acute migraine trials are not likely to be the results you see with your own patients, because you tell patients to take the medication quite differently than you would in a clinical trial. You're likely to get a more favorable response in more patients when they take the drug early compared to when you make patients wait until pain is moderate or severe. That's an important thing for clinicians to understand. When they look at results of an acute migraine trial, they have to be aware that what patients were told to do in the clinical trial is not what we tell patients to do in clinical practice. And indeed, when we looked at the response to one of the gepants when they treat mild pain, the pain-free response rates double. 

The other thing we do in clinical practice, of course, is get patients to practice other techniques. We get them to do relaxation therapy, or practice their biofeedback, or maybe even combine rimegepant or ubrogepant with another antinausea medication, for example, or maybe a nonsteroidal anti-inflammatory drug. 

We do things in clinical practice that you can't do in the clinical trial. We beef up and buttress and reinforce the effect of an acute medicine like rimegepant. So while, yes, 20% of patients were pain free in the clinical trials, we can do better than that in clinical practice.

Rimegepant Treatment for Acute Migraine

: For rimegepant, the half-life is about 10, 12 hours. In the paper published in Lancet, there were about 23 secondary end points. The medication separated from placebo in 21 of 23 end points, including sustained relief and sustained pain-free rates.

We talked a little about recurrence before and how that frustrates patients. If you can take something and it sustains the benefit, whether it’s relief or it’s freedom from pain, that’s an advantage.

From an adverse-effect profile, rimegepant looked similar to placebo in terms of the adverse events that it caused. This gepant class of medication seems to be very favorably tolerated. But that’s in clinical trials. When that gets used in clinical practice, it is a different beast, right? Because we have patients who are sicker. We have patients with more medical comorbidities. We have patients on more medicines. And so regarding the results you get in clinical practice once you expose the drug to thousands to tens of thousands to hundreds of thousands of patients, you may start to see adverse events that weren’t seeing in the couple of thousand patients who were exposed to the drug in clinical trials. But certainly, from an adverse-effect and tolerability standpoint, these medications appear to be very favorably tolerated and were similar to placebo. There were no serious treatment-related adverse events, so there were no serious safety concerns that arose from the rimegepant trial.

We have seen 2 pivotal trials of ubrogepant. Very similar to rimegepant, both trials showed efficacy for the coprimary end points of freedom from pain in 2 hours and freedom from most bothersome symptoms, with pretty similar pain-free rates to rimegepant—around 20%, 21%. Those were very similar results, actually, but well tolerated with no serious safety concerns. 

I will say that the restoration to normal function with ubrogepant, which was looked at as a secondary end point, was approximately double or a little more than double the pain-free response rates. That indicates that you don’t need to become pain-free to be restored to normal function or near-normal function. You could have relief of pain. You could still have mild pain but get relief of other associated symptoms and be able to get back to normal or near-normal functioning. 

Although pain-free is an end point that’s used by regulatory agencies to get drugs approved, and it’s a mandatory requirement for companies and for investigators to use as a trial end point, it doesn’t necessarily reflect what we and our patients are actually after, which is getting them back to normal functioning, as we reviewed earlier. It’s worth keeping that in mind. If we can restore 40% to 45% of patients to near-normal or normal function when treating moderate or severe pain, perhaps we can do a lot better than that if we treat them while pain is mild.

Gepants for Acute Migraine: Safety & Efficacy Data

: When you’re conducting a clinical trial, you determine what is going to be a clinically meaningful difference compared with placebo and then power the trial to try to show whether there’s a difference. Once you’ve shown that there is a statistical separation from active drug compared with placebo, then you’ve surpassed what you’ve set as your clinically meaningful threshold. 

After that, I stop looking at placebo. The placebo response rate in the clinical trial is meaningless when I’m sitting in front of the patient trying to make a decision. And so I don’t talk about placebo response rates when I’m sitting with the patient. I simply tell them that in the clinical trial, when patients were treated for moderate or severe pain, about 20% or 21% were pain-free. That’s what I tell them, and I tell them this percentage of patients had relief of headache. To be quite honest, I don’t really talk about the most bothersome symptom, and I don’t get into those numbers. But I tell patients that in addition to relieving pain, these medications have the potential to relieve other symptoms that they’re experiencing. Then I tell them that the way we’re going to use it is we’re going to have them treated at the earliest onset of the attack while pain is still mild. If we treat while pain is mild, we may see better results than what was seen in clinical trials. 

Once a drug has been proven to be superior to placebo based on a clinically meaningful threshold, or delta, or difference that was established at the beginning of the trial, there is no need to start looking at therapeutic gain or placebo response rates in clinical practice. For example, let’s say the active treatment had 20% pain-free response at 2 hours and placebo had a 10% response. The therapeutic difference is 10%. I don’t tell a patient, for example, that the pain-free response rate at 2 hours is about 10%, because it’s not. It’s 20%. The difference between placebo is meaningless when sitting with the patient, to be honest. You look at the magnitude of the effect in the active treatment group and what proportion of patients actually had relief of pain or became pain-free at 2 hours. That’s what you discuss with the patient.

These medications, rimegepant included, can show a difference at earlier time points on any of a number of outcome measures. That’s good. One of the frustrating things is that moderate and severe pain are lumped together. They shouldn’t be, because when treating moderate pain, you get incremental benefit. It’s unfortunate that we lump those 2 together. They should be separated. They’re 2 totally different pain states when you start treating patients. Be that as it may, the fact that you can get separation from placebo at earlier time points on any of a number of outcome measures tells you that this has the potential to work earlier than 2 hours. When we look at 2 hours, it’s important to know what happens at 2 hours. But patients don’t want to wait 2 hours. They would like relief as quickly as possible. Imagine taking something sitting down, looking at the clock, and thinking, “Oh my, I have to wait 2 hours now? I have to wait from 10 am to 12 pm to get some relief?” The onset of relief is actually as important to patients as how complete the relief is.

How quickly will they notice a meaningful difference? If they notice a reduction from severe to moderate pain in 20 to 30 minutes, even though that wouldn’t be captured in a clinical trial, that’s very meaningful to a patient. The onset of meaningful relief is something that’s really important and gets lost in the noise of these clinical trials. The fact that these drugs can work quicker, even when you treat pain that’s moderate or severe, means that if I treat it while pain is mild, I’m likely to get even more benefit earlier on—earlier than 2 hours. 

That’s what those end points mean to me. I don’t really focus on 1 particular end point, because A) I’m going to be using the drug in a way that it wasn’t used in clinical trials, and B) it tells me that the drug can work more quickly than 2 hours, especially in the way we’re going to use it in practice. But even when you let patients go on and let their attack progress, it can still work in them in less than 2 hours.

Gepants for Acute Migraine: Patient Management

: I’ve used rimegepant, ubrogepant, and lasmiditan, actually. My experience with the gepants is that the tolerability profile seen in clinical trials appears to be true in clinical practice. They appear to be well tolerated so far.

In terms of efficacy, I haven’t systematically looked at all the data. So it would be unfair to give you any numbers in terms of the proportion of patients who are responding, because that would require us to go into a database and start systematically looking to see how many patients are responding, how many patients are continuing with the medicine, and what it means to respond. The definitions that we use in clinical practice and that patients use are a little looser than what’s used in clinical trials. All I’ll say is that my experience with gepants, including rimegepant, is that yes, of course patients respond. The tolerability appears to be favorable, much as it was in clinical trials. However, I need more experience in more patients and with more systematic collection of data to see exactly how patients are responding. Is it true that patients who use it when pain is mild get a better response? I think that’s the case, but without going in and looking at the data, I’m talking off the top of my head with a limited sample. These drugs haven’t been around that long. They’ve been around for only a few months. Given that we’re living in a pandemic, our ability to rigorously and systematically follow patients has been hampered somewhat. So there are a lot of circumstances that preclude me from giving you a definitive answer to that question.

Some decisions are taken out of our hands as doctors. If an insurance company won’t reimburse or cover the medication and provide access to the medication for the patient—if they haven’t failed at least 2 different oral triptans—then they’ve taken that decision out of my hands. If I see you, as a patient, and you’ve never been on a triptan before, or your insurance requires the failure of 2 triptans and you’ve only been tried on 1, I can’t even use these medicines. It’s important to recognize that the decision is not up to me and not up to the patient. It’s up to the insurance carrier.

Let’s put that aside for a second, and let’s say a patient meets requirements for access. They’ve taken 2 triptans and failed to respond or failed to tolerate the triptans. That would be a patient for whom I would select a gepant.

In patients who have acute medication overuse or who have chronic migraine and are using at least 10 days of an acute treatment, that’s a patient population for which I would suggest using a gepant as treatment. As we talked about earlier, gepants don’t appear to cause overuse headache, at least in preclinical animal models and clinical practice and clinical trials using gepants for prevention. So that’s another patient population for whom I look to a gepant.

In patients who have a contraindication to the use of triptans—they have vascular disease or uncontrolled hypertension—I would look to a gepant. Those are just some patient populations who would be eligible for a gepant early on. 

Real-World Experience With Gepants for Acute Migraine

: From an acute treatment standpoint, there’s nothing in phase 3 right now that looks groundbreaking. I’m just happy we have 2 new classes of medication that have been approved in the span of about a couple of months of each other after 30 years of having only triptans. I’m happy with the 2 classes that have been approved. 

It’s going to take some time to really understand how these are performing in clinical practice and how to optimally use them in practice. The gepants facilitate treating patients differently. For example, I talked a little about the prodrome, where symptoms precede the headache. Obviously, if you had a medication that could be taken without adverse effects and without fear of medication overuse, because three-quarters of patients have prodromal symptoms before their head pain begins, we start to look at ways of using these acute treatments in ways they’ve never been used before. It would be great if we could actually prevent the headache from even happening in patients who have these symptoms that precede the pain or significantly attenuate or diminish the severity, such that they either spontaneously resolve after starting as mild pain or they respond within minutes of another acute treatment just while the pain is mild. 

The gepants, in particular, usher in a new way to treat migraine acutely, with a new class of medication and a new target and because they can be used in patient populations for whom the use of triptans is contraindicated. But they may also usher in a new way to treat migraine entirely, by going even further at the beginning of the attack. I’m excited about that, and I hope to see future clinical trials evaluate that. 

From an acute treatment standpoint, there’s nothing on the imminent horizon. There have been a couple of neuromodulation devices, using either vagus nerve stimulation or electrical stimulation outside that head. There’s another device that stimulates the trigeminal nerve here, and there is a device that uses magnetic stimulation. There are other techniques using different electrical or nerve stimulation modalities that can be used for acute treatment as well.

There’s nothing to say they can’t be used in conjunction with medicine. If the patient doesn’t respond optimally to either a device or to a medicine, maybe they would respond optimally to using them both together. Clearly, the mechanism of action will be different. Maybe we’ll see some combination trials there, looking at both the implementation of a device as well as a medication.

Acute Migraine Treatment: What’s Next?

: My recommendation is to maximize the potential benefit of these medications by using them early in the course of attacks. That would be my 1 plea. If you do nothing else, assess the attack profile of the patient. What I mean by that are 2 things, basically. For some patients, the majority of their attacks begin during waking hours. However, there are some patients, for example, who always wake up with their attacks. When they wake up they’re already in a moderate or severe state.

Get a sense of the portion of the timing of attacks for the patient. For the patient who has most of their attacks during waking hours and has a mild-pain phase before it escalates, really emphasize the importance of treating early. You have much better success when you treat early.

Most patients will try a medication only twice. If it doesn’t work for them on 2 separate occasions, they’re done. They’re going to move on, and I don’t blame them. I would too. You wouldn’t want to see them using a medication after the pain has already progressed. It doesn’t work in the way they think that it should. And then they would forget about it. That forever becomes a medication on the list that doesn’t work. Whereas if they had taken it early, it could have worked beautifully. 

You’d hate to leave something on the table, and you’d hate to not be able to maximize the full benefit of the medication by not using it appropriately. As important as it is to prescribe something, it’s also important to maximize its full potential by making sure it’s used properly. My plea would be to use it early while pain is still mild.

Treating Acute Migraine in the Community Setting

Dr Robert Cowan provides an overview of the burden, goals of therapy, and the pain freedom end point for acute migraine.

: The burden of migraine is enormous. In the United States alone, there are about 60 million people with headache and about 40 million with migraine. Depending on whom you talk to, it costs the economy between $15 and 30 billion a year. The World Health Organization sees it as the second most disabling condition in the world, based on DALYs [disability-adjusted life years].

The goals for treatment of acute migraine are generally broken into 3 parts. The first is how we manage the acute event. The acute event is the onset of the various symptoms of migraine, including pain, nausea, light and sound sensitivity, imbalance, or other symptoms associated with migraine.

The second part of acute treatment is rescue, which is what you do if the acute treatment doesn’t work. The second component is prevention. Prevention consists of medications, devices, or certain behaviors that will reduce the likelihood of headaches occurring. It will reduce the frequency, severity, or duration of the headaches when they occur.

The third component is lifestyle changes. These are behaviors that you can incorporate on a consistent basis that will also make you more resistant to having headaches. These include regular sleep schedule, regular exercise, regular mealtimes, stress management, and other things like that.

There are a number of ways of assessing how effective a given treatment is for migraine. Generally, in the past we have used pain freedom, either at 2 hours or 24 hours. Another measure has been to look at reduction in pain at 2, 4, or 8 hours. Different studies have used different criteria for identifying how effective a medication is. Because not every study uses the same criteria, it’s very hard to compare them head-to-head. 

More recently, with some of the newer medications, another element has been added. That is the most bothersome symptom. Increasingly, we find that to be a very valuable measure for assessing how well a medication works, because not everyone considers pain to be their most bothersome symptom. For a lot of people, it’s the nausea, light sensitivity, or dizziness.

Treatment Goals for Acute Migraine

The American Headache Society (AHS) Guidelines and the evolution of treatments for acute migraine are outlined.

: The American Headache Society has established criteria for how to best manage headaches, and they have looked specifically at what criteria should be used in assessing how well a given medication works for acute treatment. That is a medication that would be taken at the onset of symptoms of headache. Within that, there are a number of classifications that have been used, such as triptans, anti-inflammatories, combination analgesics, butalbital-containing medications, opioids, and now the new class of CGRP antagonists. 

There have been a number of advances in treating acute migraine recently. In fact, we’ve gone from famine to feast in the past several years. A little historical background is that in the early 1990s—that’s 30 years ago—we got our first exposure to triptans. Over those 10 years, about 7 or 8 triptans or triptan combinations, came to market. Those revolutionized how we approach migraine, because for the first time we were able to actually provide a treatment for migraine per se, rather than a painkiller or an antinausea medication. That was quite revolutionary. We also used anti-inflammatories, either in combination with triptans or alone, and then we used medications to treat other symptoms associated with migraine.

Calcitonin gene-related peptide, which we’ll call CGRP because it takes too long to say every time, will be the next big change in acute treatments. That is, with the exception of the medication called lasmiditan, which came out a couple of years ago and is actually a serotonin 1F receptor agonist, so it is related to the triptans. The CGRP antagonists are the first novel treatments to come out for the acute management of headache, and that’s been a dramatic change, along with the advent of a number of devices for acute treatment which have come to market in recent years as well.

Patient factors to consider when deciding on therapies to treat acute migraine.

: The challenge is in figuring out which therapy to use for which patient. If you look at the International Classification of Headache Disorders diagnostic criteria, 2 people who have headache twice a week with some severe nausea and light and sound sensitivity will get the same diagnosis of episodic migraine. But 1 patient may respond very well to 1 medication, and another patient who has the same diagnosis may not respond to that medication at all, either because of adverse effects, comorbidities, or a variety of other factors. There is no 1-size-fits-all treatment. There is no universal first-line medication. It’s very customizable when it comes to the best treatment for each patient. 

We look at a number of factors. Someone whose headaches come on very quickly—for example, ramping up to a headache of 10 of 10 severity over 10 or 15 minutes—would want a medication that has a very fast maximum concentration and comes up very quickly in the blood supply. But typically, medicines that come on quickly wear off quickly. If someone has headaches that last 24 or 48 hours, a medication that comes on quickly may not be the ideal choice. Rather, a medication that may come on more slowly but lasts longer in the body may be a better choice.

Someone with cardiovascular risk factors may not want to use anything from the class of triptans because there may be a contraindication in that setting. When we think about preventives for patients with episodic migraine, we may not want to use a medication that has as an adverse effect of weight loss if someone is already having trouble keeping food down and maintaining their weight. For someone who’s having trouble staying awake all day, you may not want to give them a medication that has the adverse effect of sleepiness. It really depends very much on the patient and the presentation to determine which medication is best for which patient.

Patient Selection for Acute Migraine Therapy

Robert Cowan, MD, FAAN, reviews the recently approved CGRP receptor antagonist, rimegepant, for the treatment of acute migraine.

: Rimegepant is a very interesting molecule. The reason I say that is because while it is a unique agent in that it’s a CGRP antagonist unrelated to the triptans, it also has some very interesting features in that its adverse-effect profile is minimal. There are very few adverse effects associated with it. What makes it interesting to me is, based on long-term data, there is no medication overuse phenomenon. 

The medication overuse phenomenon is something we see when people take acute medication too often. What happens is the brain quickly starts to think that the medication is part of its normal chemistry, and when you don’t take it, your brain tells you there’s something wrong. The way it says that, of course, is with pain. We always have to limit how often a patient takes a triptan, for example, to no more than 10 days out of the month, which is roughly 2 days a week. That’s fine if you only have 1 or 2 headaches a week. But if you have 3 or 4 headaches a week, you’re in a very difficult position. The nice thing about rimegepant is that in its long-term data, there was no evidence that using the medication more often results in more migraine. In fact, they looked at every-other-day usage with the option of additional rescue and found that there was no escalation in headache frequency, severity, or duration with increased use of the medication. That’s very appealing.

The dosing of rimegepant is 75 mg, and it’s a pill you put under your tongue. It’s used once per day for the acute treatment of migraine. As with other acute treatments, there is no titration necessary. The 75-mg dose is the only dose available. 

Rimegepant is very well tolerated, and while its half-life is on the order of 8 to 12 hours, it seems to show a beneficial effect over 24 to 48 hours. That makes the recurrence of 1 headache less of an issue than it might be with a medication that has a shorter half-life.

As I mentioned earlier, we’re looking increasingly at most bothersome symptom as an important measure of the tolerability and efficacy of these medications. Rimegepant was able to differentiate at 2 hours, which was a secondary end point in the study, with respect to most bothersome symptoms.

One of the nice features of the CGRP antagonists in general is that they are very well tolerated and have very few drug interactions. They appear to be safe in combination with oral contraceptives and are very well tolerated.

Rimegepant: Treatment for Acute Migraine

Recent approval of ubrogepant for treatment of acute migraine is discussed, as well as the overall use of CGRP receptor antagonists in clinical practice for acute migraine.

: Ubrogepant is also a CGRP antagonist, and it has a very similar profile to rimegepant in terms of tolerability and efficacy. At this point, the molecule has not been tested for prevention, so we don’t have data to suggest that it is safe to take on a daily or near-daily basis. But used as an acute rescue treatment, it can be very effective.

If you decide as a physician or a provider that you’re going to use 1 of the CGRP antagonists, patient selection can sometimes be limited by payer decisions. New drugs are generally more expensive, and sometimes there are coupons and special deals made available in order to gain access to these medications. But very often, there will be a step edit requiring that 1 or more triptans be trialed and failed before you can get access to them. That’s a bit of a moving target. We’ll have to see how that plays out over time.

At this point, I don’t have enough experience with ubrogepant. I’ve been using mostly rimegepant, but I have not seen any data to suggest 1 would be favored over the other with the exception of having the advantage of data for long-term use with rimegepant. 

The CGRP antagonists are not currently being used as first-line treatments, mostly because of access issues, rather than anything pharmacological. In patients who have not done well, could not tolerate, or have contraindications to triptans, they are being used increasingly in that function.

The CGRP antagonists are of particular usefulness in patients who have headaches frequent enough to result in medication-overuse headache. That’s a setting in which we would like to transition to or add CGRP antagonists in order to avoid medication overuse.

Ubrogepant: Treatment for Acute Migraine

Upcoming studies for treatment of acute migraine, including some promising devices, are highlighted.

: There are a number of interesting studies coming out, and not only for CGRP monoclonal antibodies and antagonists. There are a number of devices that are coming to market or that have recently come to market for acute treatment, and eventually for prevention, that also have very nice efficacy and adverse-effect profiles. Over time, we will see the devices become more prominent in first-line treatment, assuming they can figure out how to make them affordable and accessible.

There are a number of molecules very early in the pipeline at this point, still a number of years out, that are promising. The PACAP molecule is very promising. This whole field is starting to blossom at this point, and we’re getting better medications with better adverse-effect profiles, fewer downsides, fewer drug interactions, and greater specificity for treating the entity itself rather than the symptoms.

My advice to community neurologists treating migraines is to be open to these new medications. In many cases, it’s worth it to go the extra mile to get these medications approved for patients who have not responded to medications that are more easily accessible. Don’t be overwhelmed by all the marketing. Try to look at the data. Listen to what specialists in the field are suggesting. Pay attention to your patients, and see what they’re looking for.

The Changing Treatment Landscape for Acute Migraine

Burden of Migraine

Acute Migraine Treatment Goals

Advances in the Treatment of Acute Migraine

Rimegepant Treatment for Acute Migraine

Gepants for Acute Migraine: Safety & Efficacy Data

Gepants for Acute Migraine: Patient Management

Real-World Experience With Gepants for Acute Migraine

Acute Migraine Treatment: What’s Next?

Treating Acute Migraine in the Community Setting

Treatment Goals for Acute Migraine

Acute Migraine Treatment Goals

Patient Selection for Acute Migraine Therapy

Rimegepant: Treatment for Acute Migraine

Ubrogepant: Treatment for Acute Migraine

Therapies in Development for Acute Migraine