Director, Concussion and Headache Programs, Mayo Clinic; Chair, American Brain Foundation, IHS-Global Patient Advocacy Coalition

David W. Dodick, MD

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.

Videos

Therapies in Development 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

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

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

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.

Acute Migraine Treatment Goals

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

: 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

: 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?

: 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

: 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.