Differentiating between episodic, chronic, and acute migraine and discussion of unmet needs in traditional acutely acting therapies for migraine.

® titled, “Advances in the Management of Acute Treatment of Migraine.” I’m Dr Peter Goadsby from the University of California, Los Angeles Goldberg Migraine Program in Los Angeles, California.

Joining me today for the virtual discussion are my colleagues Dawn Buse from the Albert Einstein College of Medicine in the Bronx, New York; Wade Cooper from Michigan Medicine Headache & Neuropathic Pain Clinic in Ann Arbor, Michigan; Dr Paul Mathew, from the Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts; and Dr Jelena Pavlovic from the Montefiore Headache Center and Albert Einstein College of Medicine in the Bronx, New York. Today we’re going to discuss a number of topics pertaining to the diagnosis and treatment of acute migraine. Let’s get started on our first topic.

We’re going to talk about unmet needs. I’m going to ask Dawn Buse to take us through a bit of the current state of thinking around the prevalence and disease burden of migraine in the United States.

Thank you, Dr Goadsby, and hello to our virtual audience. We’re speaking to neurologists. This is no surprise. You know that migraine is quite prevalent. In fact, the World Health Organization reminded us recently that there are over a billion people, about 1.04 billion, who live with migraine around the world. In the United States, we have at least 12% of adults, including up to 18% of women and about 6% of men—a 3:1 female-to-male ratio—at any given time living with migraine.

You know this because this is 1 of the most common reasons for visits to a neurologist. You’re going to see plenty of migraine in your practice. We know that migraine is most common in midlife. It may start in childhood. It often starts in teens or young adulthood and stays most frequent, severe, and disabling through the 30s, 40s, and 50s. It then tends to become less frequent and less disabling but not always. That’s the broad snapshot of migraine in the world, in the United States, and in your practice.

 Thanks, Dawn. People often talk about the underdiagnosis and undertreatment of migraine, particularly in the context of episodic and chronic migraine. I’ll ask you, Paul, to comment about that differentiation between episodic and chronic migraine and comment a bit on undertreatment.

 refer to how many headache days per month someone is having. 

 [EM] is defined as fewer than 15 headache days per month, while 

 [CM] is 15 or more headache days per month. That may seem like an arbitrary number. It’s just divided by the number of days per month, which is 30. But there is some significance to it. As you’re having more frequent migraine, such as with chronic migraine, there is a bit of a difference in terms of the pathophysiology and likelihood of progression of migraine.

A simpler way of saying it is, the more frequently you’re having migraine, the more frequently you’re going to have migraine moving forward, from a statistical standpoint. In addition, the 2 labels are important because certain therapies like botulinum toxin injections are FDA approved for chronic migraine and not for episodic. As time goes by, we see that a lot of the treatments for migraine don’t make that differentiation. A lot of the newer treatments, which we’ll be talking about today, are applicable for both episodic and chronic migraine.

The other term that is sometimes floated around is 

. That’s not a reference to the frequency of migraine or headache days per month. Rather, 

 refers to medications that are used to treat individual attacks. In terms of diagnosis, it is still striking to me that about 44% of people with headache disorders are actually diagnosed, leaving 56% of people undiagnosed.

Obviously, if you never make the diagnosis, then you’re never able to get proper treatment for your headache disorder, which is really problematic and leads to many people suffering unduly. Many of our patients in this country find that they can’t treat their headaches properly because they assume that over-the-counter treatments are all that’s available. In fact, there is a growing armamentarium of both abortive and preventive treatments available.

The other thing I’ll say is that among the people who are not diagnosed, which is that 56% number, 24% of them are seeking headache care and never receive a diagnosis, even though 1 of their complaints is headache. Raising awareness in both clinicians and the public is tremendously important so that more people are diagnosed and more people are able to get the care they need.

Paul made a very good point around the 15 days, which is that it does seem arbitrary. It was arbitrary, actually. It was an arbitrary decision made by the Headache Classification Committee of the International Headache Society. If you look at a population, when does the number start to get bothersome? Fifteen is just a line in the sand. When should you get concerned and get thinking?

Dr Goadsby, you were part of the Headache Classification Committee, which made some of those important decisions.

No. We continue to do epidemiological research and clinic-based research to see where things change. A very high percentage of neurologists live with migraine. Sixty percent of headache expert neurologists have migraine. Another 20% have a family member with migraine. A lot of us are personally familiar with the burden and the experience. You might say the number at which the impact increases is much lower than about every other day.

If we think back to about 4 headache days per month—about 1 day of your life per week lost—we start to see dramatic reductions in socioeconomic status and quality of life, increases in depression and anxiety, and burden on the family. That is not only the person with migraine, but burden increases on their children and their partners or spouses. We’ve seen this in CaMEO, or Chronic Migraine Epidemiology and Outcomes, study data. We also see it in an AMPP [American Migraine Prevalence and Prevention] study in which we looked at a couple different groups in the EM group—0 to 3, 4 to 7, and 8 to 14 days per month.

In 1 of the studies, we also divided the CM group, because having headache every other day might be quite different from having daily or nonstop migraine. We see that with each of these increases, there are dramatic increases in comorbidities, reduction in quality of life, increases in disability, and financial and costly wellness burdens on people living with migraine. We see that stepping as low as 4 days per month, and I say 

 with the caveat that someone losing a whole day every week of their life is nothing to be taken lightly.

 It makes the point that clinicians need to be thinking about burden in proportion to how the patient feels it, rather than some number that would drive it. If it weren’t for the legal things, as Paul said, maybe the 15-day thing would be less important.

We did see some changes in more recent clinical trials. There were also some changes with the approvals for the newer preventive classes. Fewer than 15 days a month are being required. In fact, the newer preventive class didn’t have any day requirement. It was more about clinician judgment on the level of disability impact or possibly a patient benefiting from prevention.

Of course, we’ve been handing out old-style routine preventives—propranolol, topiramate, amitriptyline—at much lower frequencies than 15 days per month for at least as long as I’ve been practicing

We’ve been recommending it at 4 or more headache days per month, right? That has been the recommendation, but it’s also what the patient needs. All of us have had patients who have 10 headache days a month and are reluctant to go on preventatives, particularly women of reproductive age. That is where migraine seems to fall and live primarily, and is particularly burdensome. The wonderful studies Dawn has conducted with Richard Lipton in AMPP show the gender difference. Migraine is particularly burdensome in women.

The second problem when we’re talking about underdiagnosis is that migraine is more frequently underdiagnosed or misdiagnosed in women. We know that when women seek help for headache that’s frequent and bothersome, they’re less likely than men to get the correct diagnosis, further complicating this very significant issue.

Unmet Needs in the Management of Migraine

Approaching the acute treatment of migraine, including the use of triptans in therapy.

Let’s talk about some of the treatments. I wanted Wade to talk us through what we’re currently thinking about, in terms of the acute therapies. What are the questions around how satisfied patients are at the moment? What sort of responses do they get? What are the broad, traditional acute therapies that we have to work with at the moment?

Thanks, Peter. We know that our patients really want effective medicine, medications that have minimal adverse effects, medications that are reliable, and treatments that they know if they take, they can turn off an episode of migraine. That’s been quite a struggle. We know before the 1990s that there was no designed medicine for acute headache. We had stuff that we knew helped turn off headache by helping other things in the body, like NSAID [nonsteroidal anti-inflammatory drug] class medicines and opioids.

It wasn’t until the 1990s when they designed specific medication that targeted what we thought were keys to treating acute migraine. I’m referring to the triptan class medicines. From the mid-1990s through the early 2000s, we had the advent of 7 FDA-approved triptan class medicines for migraine in the United States. Those performed quite well. When we went from nothing to medications that are designed specifically for migraine, that was exciting.

Our patients got to have relief relatively quickly, and sometimes completely. If you look at those medications, they were performing quite well. We think that acute triptan medications—all 7 of them—were somewhere between 50% and 70% effective at reducing pain, or taking pain from moderate to severe to mild, which we call pain relief. But we thought that wasn’t good enough. We started focusing on pain freedom and moving the goalpost a bit. Instead of going from moderate to severe down to mild, we’re talking going from moderate to severe down to nothing.

The triptans really hunkered around 20% for those. Then we started looking at 24-hour pain freedom, meaning how well did it last over 24 hours, as well as complete pain freedom for 24 hours, or “sustained pain freedom” as they would call it. Our medications held that line. Thirty percent or so of triptans maintained that pain freedom for 24 hours. Pain relief was a bit less because it would not always last for a full 24 hours. We’ve built from there with some of the newer, acute therapies.

It always struck me as odd at some level that we would give a person 1 clever treatment and there would still be pain left. As an outsider, I don’t get headache. I know the historical development a bit. As 1 of my older colleagues might say, they advised early triptan manufacturers that if they used pain-free as a goal, people would be disappointed with the outcomes. That’s how the headache response metric got started. I wish it were more intellectual. It wasn’t magic at all. Patients want to be pain-free. Paul, what do you think?

You’re absolutely right. A big component of all this is patient communication, and that starts in the office. One of the first things that I always do is I ask if the lights are bothering them, and if they say no, I turn them down anyway. You can see a twinkle in their eye, and there’s a look of appreciation because the lights were, in fact, bothering them.

When we take histories, a lot of the time we do need to give ample time for patients to communicate and express themselves, ask open-ended questions, and do the things we’ve all been taught in medical school. Also, it’s important to ask questions even though we know the answers to them, such as, “Is your headache throbbing?” We need to ask about disability and all these details because patients realize, “This doctor gets it. They understand what’s going on.” I find that’s very important in terms of developing the therapeutic alliance.

I can’t stress enough the importance of keeping diaries as well. Keeping diaries is important, not just for the patient to realize just how severe their headaches are and how disabling they are, but also for us to be able to adjust our treatments. It does give a level of satisfaction when you spend some time to review these diaries and really take notes. I transcribe that data into my notes, and the patient says, “Wow, this doctor is really taking the effort that I put in seriously.”

In this newer age in which all these new treatments are coming out, I find 1 amazing question. I might be getting a bit ahead of the game here, which will lead us into some discussions we’re going to have later. I ask, “How satisfied are you with your abortive therapy? Are you having any adverse effects at all?” In the past, that would be looking for trouble, because you’d have an effective treatment, and you wouldn’t have anything else to offer them. You’d say, “Great, I’m glad that worked for you. Sorry, there’s not much better we can do.”

I find myself asking those questions more and more. When you probe, it’s amazing how many people have trouble tolerating their current abortive but bear through it and don’t even mention it to you, because that’s all there is. Likewise, with efficacy, they’ll say the medication works great. When you really probe, they say, “I have to take a second dose 80% of the time,” which clearly is unacceptable, and we’re going to get into that a bit more.

Totally. We have to ask questions we don’t want to hear the answer to. Wade, you mentioned the triptans. They are serotonin 5-HT1B/5-HT1D receptor agonists with very specific pharmacology, which is 1 of the more interesting things, and no general pain effects. Some of them have more 5-HT1F action. What about adverse effects? Paul just brought that up. That’s terribly important. Can you outline for us the general effects, contraindications, and adverse-effect problems that are really bothersome with the triptans?

Sure, Peter. I’m glad you asked that because it’s a bit sneaky how the triptan adverse effects are listed. They list these in small subgroups. They have chest tightness separate from jaw pressure and whatever else. If you ignore what’s published out there on their package inserts and talk to patients, you’ll find—

We’re not recommending to our colleagues to ignore package inserts. That’s just for clarification, because we support reading FDA package inserts. Sorry to interrupt.

Thanks, Peter, for your regulatory influence there. Our patients will tell us they like the fact that the triptan medicines work many times for them. However, a lot of the time, they say it makes them feel icky, like they have a pressure in their chest or squeezing of their neck muscles. I hear patients describe scalp tingling and paresthesia. What’s curious about this is that many times, this will delay treatment, or this will make someone not want to use the medicine.

They’ll walk into your office and say, “This works. When I take it, it seems to help my headache.” But what you’ll find, to Paul’s point, is that their calendars don’t go along with this. They’ll have a headache attack, they won’t treat it, and when you ask them why, they’ll say, “I just don’t want to feel gross after my medication. I don’t want to feel medicated. I don’t want to feel prickly, so I have to decide whether I want to use the medicine.” Many times, they wait because of that.

There’s a last part I wanted to cover, because we need to move to the next segment. I wanted Dawn to wrap up by discussing the cardiovascular and cerebrovascular problems with triptans. How common are cardiovascular and cerebrovascular disease in our migraine population?

The epidemiology shows that the migraine population tends to be female, at least 3:1. It tends to be active in midlife, rather than at an older age, so we’re starting with a population that does not have as high a risk for cardiovascular events. We need to think about if someone is taking certain exogenous hormones such as birth control or HRT [hormone replacement therapy] if they’re a smoker, and think about the BMI [body mass index]. There may be individual risks within a patient that we want to assess, as well as assessing personal history and family history. It’s something to think about, but it tends to be a population in which we have primarily younger and middle-aged females. We want to remain vigilant, but it may not be as heightened a concern as if we had more men or an older population.

Acute Treatment of Migraine: Traditional Therapies

Exploring the current recommended approaches for selecting, combining, and sequencing acute therapies for the treatment of migraine.

I’m going to transition to the next segment. In this segment, I’d like to cover the recent evolution of acute therapies. When we were speaking last, we alluded to this. Jelena, set the scene for us. We’re getting later into 2020. Tell us how you think about combining, selecting, and sequencing acute therapies with all the developments that are happening.

 It’s 2020, right? It’s been an interesting year. In terms of acute migraine therapy, it’s an exciting year because new molecules have emerged. I want to put that into context of what our patients want and how we, as headache specialists, and the American Headache Society have traditionally thought of acute migraine treatment. Then I’ll discuss the emergence of new therapies and their incorporation into our practice.

As both Wade Cooper and Paul Mathew mentioned, studies have shown that patients with migraine want rapid, sustained, complete alleviation of their migraine pain. They would like to be pain-free at 2 hours. They would like to have sustained pain relief up to 24 hours. They would like not to have adverse effects, though they’re willing to tolerate a lot. We know this because there aren’t better-available options. When there are adverse effects that they’re tolerating for the sake of pain treatment, they will often delay treatment, which we know is not the optimal way to acutely treat migraine.

In terms of what the guidelines for treatment have traditionally recommended, they have staged 3 ways of treating acute migraine. One, treat with the first-line drug, which traditionally is an NSAID [nonsteroidal anti-inflammatory drug] or a triptan. Second, treat with a backup plan with another drug. For some, that could be a triptan, for other people it could be opioids, for some it could be antiemetics.

If both a repeat of acute treatment, and the backup treatment fails, a patient would generally be recommended to go to urgent care and receive IV [intravenous] or IM [intramuscular] administration of medications in that setting. Thankfully, given the emergence of the 2 new drug classes, ditans and gepants, during the last year, we now have more options.

These options are currently being incorporated into our practice. A lot of their promise concerns the vasoconstrictive properties of triptans, and therefore some contraindications to use in people who have a history of cardiovascular disease.

Both the gepants and the ditans do not have these limitations. Thus, they provide much better options, and they do have various profiles of the kind of patient in whom we would use 1 or the other. They do also have a much better tolerability profile with significantly fewer adverse effects. At this point, they have a safety profile that is very favorable, though they have been on the market for a somewhat limited time.

Evolution of Acute Treatment of Migraine

The panel reviews outcome expectations for the acute treatment of migraine, and Jelena Pavlovic, MD, PhD, provides insight on her personal experience as both a clinician and migraine sufferer.

Wade, we’ve been talking broadly about these new medicines. Take us through how you might compare triptan development with outcome standards for what we’re using now and how we monitor those.

We’re building on what we’ve learned over the past couple of decades. Now we’re using pain freedom, both at 2 hours and sustained 24-hour pain freedom. We’ve also invented a new end point for measurement of acute migraine treatments using the most bothersome symptoms. These aren’t what you think. They aren’t anything under the sun. It’s restricted to only 3 subcategories: light sensitivity, sound sensitivity, and nausea.

Those are helpful end points to see what else your acute therapy can do, besides treating the head pain component. Now they’re also looking at acute medication utilization afterward, or redosing, and even more important, some functional outcomes. How functional are people 24 hours after using acute therapy vs using placebo or those types of things?

Yes, exactly. Dawn, you might like to come in on this to discuss functional outcomes, some of the scales that are used, and how meaningful they are to patients

 Absolutely. Some new functional scales were developed specifically for testing some of the MAD [multiple ascending dose] clinical trials and were accepted by the FDA as end points. Those are the MPFID [Migraine Physical Function Impact Diary] and MFIQ [Migraine Functional Impact Questionnaire], as well as another end point that was more recently accepted by the FDA, which was the subscale of the migraine-specific quality-of-life questionnaire.

There is much more awareness of the need to think about patient-reported outcomes and end points that are important to patients. Peter, I should share with our listeners that you and I are working together on a current FDA grant. We are gathering input from patients—real people living with migraine—about what matters to them and trying to think about how to design clinical trials with the end points that are meaningful and important to those patients.

That’s a goal in the next few years. Together with our colleagues, we hope to move further in that direction. The FDA actually mentioned this more than 10 years ago in a publication, and to their credit, created this whole line of research grants to gather patient end point data, not only for migraine, but for all sorts of clinical disease states. It’s a good direction we’re moving in.

We often criticize the regulators, but you have to give them the credit that they’re not only expressing an interest but actually putting up funds to explore patient-orientated outcomes. It’s the way the world should be. It has to be said. Paul, how do you explain these novel medications to patients? How do you incorporate starting to talk about these with your patients in practice?

 Whenever I’m discussing these medications, I try not to bog it down too much in terms of the mechanisms and the specifics. But I do also tell them that these are migraine specific, as triptans were. I also talk about tolerability and adverse-effect issues. One end point that we didn’t really touch on much, which is very exciting to patients, is return of headache within 24 to 48 hours.

Some of the newer treatments are actually collecting these data, and it is really impressive that many of the subjects in these trials do not have a recurrence of headache in 24, 48, or even 72 hours sometimes. That is really exciting because it could potentially be employed situationally. If there is a patient who will typically get a headache that lasts multiple days after flying, they may consider using 1 of these treatments during those times. That also applies to menstrual headache, when they know they’re going to have a consistent headache for multiple days in a row.

That’s certainly something I pitch to the patients. I also reinforce, as my colleagues mentioned, the importance of timing. This is when referring to the diaries can be tremendously useful. If a patient has an 8-of-10 pain for 6 days in a row, I look at their diaries with them and tell them, “Listen, if you had taken your abortive medication early enough, this could have been a headache that was terminated on day 1, and you may not have had these subsequent headaches on the multiple days thereafter.”

 But people with migraine have had low expectations for a long time. You think of our grandmothers going to a dark room and putting a cold washcloth on their heads and saying, “It’s OK. I’ll sleep it off.” We think of people 20 years ago, before there were migraine-specific treatments, struggling through. Once there were treatments with either lower tolerability, lower efficacy, or both, people said, “Well, it’s OK. It’s better than nothing. I’m getting by.”

What we can see in the data are high numbers of headache days, high amounts of disability, yet mediocre levels of satisfaction. We’ve actually arrived at this renaissance in which people living with migraine can have efficacy and tolerability and start to raise their expectations a bit.

 The other thing that’s so encouraging with these newer treatments is that they’re going to help us end hoarding behavior. We’re able to better educate our patients about the importance of early dosing, and patients don’t have to live in fear of running out of their abortive medication.

I can comment on my own practice. For patients who are partial responders to triptans, it’s great to be able to have a rimegepant, ubrogepant, or lasmiditan as their go-to medication. If they run out of that, they still have a triptan as a backup. Patients have not only better therapies but adequate numbers of tablets to be able to survive, which is very powerful.

When patients have 8 tablets of a newer medication and 12 tablets of a triptan, it gives them the confidence to dose early. A lot of the time, that allows them to not have to use the triptan, because they’re dosing early enough that they’re able to terminate the attack.

 Paul, I imagine that could help not only with medication overuse, but also with anxiety and well-being. When someone feels as if they can count on something, they can start living their life again.

 I know, Dawn. That’s why, since I met you, I can count on living my life again.

Paul, can you clarify for our listening audience? You’re allowed to combine ditans and triptans. You can combine CGRP-targeted therapies like gepants and triptans, right?

 Yes. Thank you for clarifying, Wade. I do instruct the patients not to take these 2 medications on the same day. I tell them not to use 2 different therapies within a 24-hour period. Thank you for bringing that up. You should absolutely not take triptans and ditans on the same day, and just to conserve medications, I tell them not to take a CGRP antagonist and a triptan on the same day as well.

Paul, just to look at that even further, is that because you’re worried about a safety issue of those 2 together, or is it more that you’re trying not to complicate their medication treatment history?

 It’s both, actually. We don’t know if taking more than 1 serotonergic agent at once is safe, and certainly I wouldn’t push the buck in that situation. Thank you for that question. That’s a good clarification.

We’re all expressing excitement about new therapies, and we’re all expressing optimism because the clinical trials have been good. It’s 1 thing to have 25 years of experience as we have with the triptans, and we’ve learned to absorb a bit of buffering, so to speak.

We don’t have 25 years’ experience with these new medicines, so we’re encouraging our colleagues to go forward with enthusiasm but not undue speed, and to always be reflective about what we’re doing. We’re going to move from this into some further detail about the future acute treatments.

Acute Treatment of Migraine: Progress With Novel Medications

A review of the FDA approval of lasmiditan, a selective 5-HT1F receptor agonist, for the acute treatment of migraine.

: As we move into talking about the new acute therapies, what I want to do is talk a bit about the new mechanisms of action. We’ve talked about specific migraine therapies, particularly triptans, which act at the serotonin 5-HT1B and 1D receptors. Some, like Naratriptan or Sumatriptan, act on the 1F receptor. Others, like Rizatriptan, for an example, don’t effectively act at the 1F receptor. 

The 5-HT1F receptor is being pursued because it has a purely neural effect. We’re calling drugs that target the 5-HT1F receptor ditans. In contrast, the other group of new therapies, the gepants, are calcitonin gene-related peptide [CGRP] small-molecule receptor antagonists. 

Two of them, which we are able to discuss, ubrogepant and rimegepant, have very distinct mechanisms of action. Jelena, the FDA approved the first of the ditans, or 5-HT1F agonists. That was late in 2019. Tell us a bit about how important it is to have a new FDA-approved ditan and how to use it. 

: Thank you, Peter. As we were saying, triptans have the challenge of binding to 5-HT1B and blood vessels, and therefore causing vasoconstriction. Lasmiditan is unique in the sense that it is highly selective to the 5-HT1F receptor. It’s the antagonist of 5-HT1F, and it has much higher selectivity for that receptor than the triptans have for the 5-HT1B and 1D. Therefore, it has no vasoconstriction properties, which have been the primary challenge with triptans. 

5-HT1 receptors are present at multiple locations in the trigeminal vascular system, but they’re not on the blood vessels. It likely works at the level of the trigeminal ganglion, trigeminal nucleus caudalis, cerebral vessels, neocortex, and hippocampus. It has multiple modalities in the pain activation of migraine. There were multiple studies, especially the SPARTAN study, that chose 3 doses—50, 100, and 200 mg—where 1 dose of lasmiditan could improve pain and most bothersome pain symptoms in 2 hours. 

A portion of patients actually became pain-free within 2 hours. Overall, across 2 clinical trials with these 3 doses, there were 28% to 39% of patients who achieved complete elimination of migraine pain at 2 hours, compared with 15% and 21% with placebo. The challenge with lasmiditan, though it is not a vasoconstrictive, is that given its CNS [central nervous system] penetration, it does have CNS adverse effects. Those primarily manifest as dizziness, feeling tired, paresthesia, and cognitive impairment. 

The FDA required additional studies for lasmiditan for this reason, including a study showing potential for addiction. They finally awarded a controlled substance Schedule V rating to lasmiditan, so it is a controlled substance at this point. There is an 8-hour driving restriction, given the cognitive impairment seen after dosing. The recommendation is not to drive for 8 hours or operate heavy machinery. Though some may find this very limiting, in terms of their prescribing, what does the migraine patient do when they have a really bad attack? 

They go home, go to bed, and want to sleep. Generally, they’re not setting off on a 3-hour driving trip. Though this is somewhat limiting, and we obviously have to emphasize this to patients, in my practice I typically find that patients don’t find it limiting if it works for them. If this is a medication that provides relief, they will take it in the evening after they go home and are able to relax and recuperate following their migraine attack.

: It’s an extraordinary development to be able to have selectivity over the 1B and 1D of 500-fold. We’ve all had people in our practices over the years who we felt a bit wobbly about putting on a triptan because of the 1B effect. All of a sudden, it is remarkable to find an era when that problem just went away. Nothing is perfect, as you outlined, but it’s hard not to think of that as an advantage. In clinical practice, that’s certainly the case. 

: Let me just add that 1 of the reasons I like lasmiditan in my practice is that it does have some ability to lower CGRP concentration in the periphery. There is a peripheral anti-CGRP effect. The effect is not strong, but it’s 1 of the few FDA-approved medicines for migraine that goes centrally. That’s what defines it and separates it from some of the other agents out there. 

That central function allows you a 4-hour same efficacy of treatment. If someone has to delay 4 hours, they still do really well with this medicine. But you pay a price for the central action, and that’s the adverse-effect profile, which was already mentioned. 

Use of 5-HT1F Agonists in Acute Treatment of Migraine

Assessing the differences in dosing and adverse-effect profiles when using small-molecule CGRP receptor antagonists rimegepant and ubrogepant vs lasmiditan.

: Wade, contrast for us the small-molecule CGRP receptor antagonist with the gepants. In any 1 year, just 1 development would be great. It’s fantastic to have a second. 

: You’re referring to ubrogepant and rimegepant. Both are FDA approved here in the United States for acute treatment of migraine. What’s cool about these medicines is that they work mostly in the periphery, and they block that inflammatory signal coming from the pain-sensitive nerves. They suppress inflammation of the meninges when they’re effective. 

What’s also cool about these is that they tend to work relatively quickly. Most remarkable from my perspective is their almost complete lack of adverse effects. When you compare the gepants class medicines with the triptan adverse effects, it’s quite phenomenal. Nausea seems to be a reported adverse effect in the clinical trials. If you talked to me 2 weeks ago, I would have told you I hadn’t seen much of that from my patient profile. I’ve had 1 or 2 people with some pretty severe nausea from it, but as a whole, it’s really well tolerated. 

As Paul was saying earlier, because they work on a different mechanism of action than triptans, just like the ditans, these pick on receptors that the triptans just don’t focus on. These medications can be really helpful for people who haven’t responded previously to acute triptan therapy.

: We have the new medicines, and they have a range of doses. There are choices in the ditan dosing and ubrogepant dosing. Let’s talk about dosing for a moment. Jelena, tell me about how you see the dosing choices and what your experience has been with lasmiditan dosing. 

: It’s 50, 100, and 200 mg, right? They’re comparable in terms of efficacy. We see that they work at 1 hour post-treatment, but they all work better and have better separation from placebo at 2 hours post-treatment. At this point, because of the associated CNS [central nervous system] effects with ditans and with lasmiditan specifically, I like to start low and go slow. 

I start at 50 mg in patients who feel relief and may have a lower adverse-effect profile. If they can’t achieve pain freedom completely, then because there is an additive effect to a higher dose, I will increase the dose at that point.

: Wade, where are you with dosing with ubrogepant, for example?

: First, let’s go back to lasmiditan. When it came out, I was so geeked about this. I went to pretty high dosing, and it worked really well for some people. The problem was, I had some people tell me it made them feel a bit spacey and weird. Just as you heard earlier, I’m using lower doses to start. As people do well with it and as we show some efficacy, I’m willing to expand into the 100- or 200-mg doses. 

For the gepants class medicines, you have rimegepant, which has 1 set dose at 75 mg. Ubrogepant has some dosing selections to choose from. What’s interesting, from my perspective, is that unlike with the lasmiditan, where I have to go a bit slower because I want to make sure I don’t make someone feel sick and write an angry email to me, the gepants are just so gosh darn well tolerated, so I tend to use the top-end dosing with them. That’s where the most efficacy has been with those.

: I’ll try to avoid using inappropriate language like “gosh darn,” but just to punctuate those points, I actually do the same thing. I’ll also give patients the instruction that if they tolerate lasmiditan 50 mg just fine and find it partially effective, they should try taking 2 of them. If that works, they can call my office and leave a message, and I’ll call in a prescription for the 100 mg. Similarly, I will do the same thing with ubrogepant with the instructions that if they tolerate the 50 mg just fine and find it partially effective, try taking 2 of them, then let my office know, and I’ll call in a refill for the 100 mg of that medication as well.

: While you’re talking about ditans, I wanted to pick that up, and then we’ll swing to others. Tell me about how you see the adverse-effect profile and the safety issues when you contrast ditans or gepants with the older medicines.

: I agree with Jelena and Wade. I found them to be really well tolerated. I find the gepants to be better tolerated than lasmiditan, so that might push my hand a bit. The other thing that will push me in 1 direction or the other is if the person is on a CGRP antibody. In clinical practice, I have yet to see any issues with people who are on a CGRP antibody and also on a gepant. But if they are on an antibody, my preference, at least initially, is to try them on lasmiditan first. 

Why not take advantage of a different mechanism for abortive therapy than what they’re on for prevention when 1 is available? Again, that doesn’t prevent me from using a gepant in those patients if they can’t tolerate lasmiditan or if some other issue arises.

: It’s certainly mechanistically attractive to think that if you have a CGRP blockade, the ditan will come along and block other things that are prejunctionally and presynaptically released. Glutamate is the obvious thing, and perhaps it blocks other peptides that are for another day. The multimechanistic side is useful. Colleagues are also finding that there’s room still to push on the CGRP mechanism, even in people with monoclonal antibodies. We have a lot of things to learn practically. 

: The way I describe it to patients is, the antibody is lowering your overall level of CGRP, and if you happen to have a migraine, you’ll have an episodic burst of CGRP, which will then be suppressed by the gepant. That’s how I explain it to patients. If they have a better understanding, even if it’s simplistic, they’re more likely to be compliant. 

: That’s in line with the theoretical model.

: It’s good basic science evidence. What we’re talking about has a very good laboratory base. For example, take glutamatergic transmission across the trigeminal cervical complex. You can certainly alter that whole transmission with the 1F agonists in the lab. There’s so much to be understood.

 Paul, I like the way you described that, because these are 2 whole new classes. These are complex with many neurotransmitters involved, and when someone knows a bit of what is going on, they’re going to be more comfortable. They’re going to tolerate any adverse effects that might arise early a bit better, and they’re going to tend to be more adherent. They’re also going to have more comfort with their provider when they’re told in advance what to expect. All of us as humans like to know what to expect, so I like the explanation you just gave with your visuals too. That was helpful.

: One of the nice things about using ditans is you can tell the patients, “You’re going to F migraine.” By that I mean, we’ll affect it in multiple areas. Sometimes, I’ll even share with our patients that we believe their light and sound sensitivity relates to thalamic processing, and we have a receptor there that a ditan might be effective on. 

When we talk about allodynia, or the shutoff switch of migraine, we have F receptors in those regions too. Those become delicious targets. To Paul’s point, the idea of inflammation in the lining of the brain resonates really well with our patients. Using gepants or CGRP-targeted therapies to lower that inflammatory cascade and shut off migraine works really well.

: That’s a wonderful way to express it to patients, Wade. I really like that. May I borrow that?

: The other thing I’ll sometimes say is that triptans and ditans are preventing the inflammatory soup. Once the inflammatory soup has started, an NSAID [nonsteroidal anti-inflammatory drug] can help curb that inflammation that’s already started. Again, teaching these very simplistic mechanisms can really educate patients and make them appreciate why combination therapy in certain situations is an advantage.

: Peter, I wanted to add another comment to your question about dosing. We did not mention rimegepant, which comes in 1 dose currently and is an ODT, an orally disintegrating tablet, of 75 mg. There isn’t much of a debate of what to do other than give it. It tastes little like licorice, but most patients seem to really like it. The ease of administration—of being in a meeting, turning around, and treating one’s migraine—is really appealing.

: This might be excessive salesmanship, but I also tell patients that because of the rapid-dissolving technology, if you have a sweaty palm, it might actually dissolve in your palm. That’s true, and it accentuates just how rapidly it can dissolve. That it’s rapidly acting further encourages patients to take it soon.

: With the consideration that they washed their hands already and all good hygiene has been accepted. I tend to tell patients that the CGRP drugs like ubrogepant or rimegepant block the effect of this chemical we know is in migraine, and that the 1F drug turns the pathways off. I’m completely agnostic about inflammation as a cause of migraine. 

As you probably know, I sail in my own little sea around that. I am prepared to say to patients sometimes that it’s a really complex problem, and it’s really a devastating problem. That means part of the honesty of it is that we don’t understand precisely how these things work. We don’t understand precisely how triptans work 25 years later, but that has not stopped 10 million people from taking and benefiting from them. It’s an evolving process.

Safety of CGRP Receptor Antagonists vs 5-HT1F Agonists

INP104, the intranasal formulation of DHE in development for the treatment of acute migraine, is examined along with its use as a treatment option for women of childbearing age.

: We must not let listeners think that gepants and ditans are the only thing that’s happening. There are some reformulations of an old friend. Paul, can you tell us about what’s happening with dihydroergotamine [DHE]? 

: To people’s surprise, dihydroergotamine has been around for a long time. When I say a long time, I mean DHE first came out in the 1940s. It takes me back to my fellowship, when I actually gave a lecture at Mayo Clinic called, “DHE: An Old Dog With New Tricks.” Way back then, the inhaled version of DHE was under development and Dr Wade Cooper was still playing varsity football in high school. It was quite a long time ago.

Unfortunately, that inhaled formulation never came to fruition, but that did not cause people to drop the ball. To give some background, DHE is 1 of those few drugs that unfortunately is not absorbed orally. You can try to try to take a tablet of it, but it’s not going to be absorbed. The only formulations that have been available are IV [intravenous], IM [intramuscular], subcutaneous, and inhaled. DHE gets a bad name because of its tolerability. It does cause significant nausea, so the vast majority of the time, it has to be codosed with an antiemetic. 

My general rule of thumb is, if you can’t tolerate a triptan very well, you’re probably not going to tolerate DHE well. Intravenous DHE gives you a blood plasma level of 10 ng/mL at the time of administration, while the older intranasal forms gave a dose of 0.01 ng/mL. It’s a huge difference in plasma levels. Unfortunately, that IV dose was so high in terms of initial plasma dosing that people had trouble tolerating it, while the older intranasal forms were so low that patients didn’t get a consistent therapeutic benefit from it. 

The 2 newer forms of DHE are both intranasal. One of them is a proprietary pump, which squirts the DHE into a particular part of the nose where it’s able to get absorbed much more consistently. It’s still in liquid formulation. The other is a small vial about this size. You squeeze it, and a powder form of DHE is injected into the nose. 

These 2 proprietary delivery systems for DHE are quite encouraging because they reach plasma levels that are not as high as with the IV, subcutaneous, or IM administrations. They don’t cause a lot of those adverse effects, yet they’re able to deliver a much more consistent dose than the traditional intranasal formulation. That was very inconsistent in terms of dosing and rarely ever met the threshold of being able to effectively treat a headache. 

It is exciting. For patients who don’t respond to triptans and don’t find some of these other agents useful, it’s a good option. The other place where I envision this being used, although this is not being looked at in studies, is in a patient who is status migrainosus. They have exhausted their oral home medications that Jelena had mentioned in a stepwise fashion. Oral steroids are not effective. 

Nerve blocks are something you can consider in the office, urgent care, or emergency department. But if either of these formulations gets approved, there may potentially be a DHE protocol in which you give the patient a prescription and they can take 1 of these 2 intranasal formulations for a few days. That’s going to be potentially useful for when someone has status migrainosus that nothing else is working.

: You certainly need to try to keep people out of emergency departments. If you have migraine, emergency departments are noisy. They’re loud. They don’t smell very good, and people move people about. It’s the reverse of the canonical migraine symptomatology. I tell people, “Could you think of a worse place to be, short of being thrown onto a freeway?

: I was going to say, they have the harshest lights you can find anywhere. 

: Emergency departments are also the most likely place for opioids to be prescribed for migraine, and often with clinical reason. Without having a history, knowing someone’s tolerability and cardiovascular history, and without having a follow-up plan for the future, their treatment options are limited. 

: This is where I’d like to see a parenteral form of a ditan. You would never have a cardiovascular problem, it seems to me, if you thought someone had migraine and gave them a ditan. I can’t see how that could cause a catastrophic problem. Even if they were a bit dizzy afterward, so what, compared with the kinds of problems that we’re talking about? You can see that as the formulations get better, the options are there. 

: Paul, what advice do you have for women of childbearing age? How do you think about that as you’re considering DHE as a treatment option? Is that an area in which extra education and caution is required?

: Yes. It’s just like all the medications we’ve talked about. If someone is thinking about getting pregnant or gets pregnant, I often warn them to be in touch with their doctors regarding what medications are safe and not safe to continue during pregnancy. That certainly applies to the ditans, as well as to the gepants. 

Although this might be getting a little ahead, that’s why gepants are particularly exciting, because everyone knows they are being studied for preventive therapy. With the new antibodies, there is concern that if someone of childbearing age is on an antibody and happens to get pregnant, there is no way to undo that. They just have to wait until it washes out of their system, while with a gepant, they can discontinue oral treatments and go from there. 

Regarding pregnancy, the advice I give many of my patients is that—this is just my view—getting pregnant can take weeks, months or even years. To discontinue someone’s medications because they’re trying to get pregnant can really limit their ability to get pregnant and can lead to a lot of migraines and unnecessary suffering. My advice to these patients is, the minute you become pregnant, call your doctor. We’ll rapidly wean you off everything. 

That’s a pretty practical approach, and unfortunately, I relate it to alcohol. Many people in this world do get pregnant while they’ve had a couple of drinks. Obviously, continued drinking while you’re pregnant is not a good idea. But there is no significant risk to the fetus if you stop drinking after conception. That’s the way I visualize medications as well.

: That’s very good advice, Paul. In the CaMEO study, we found that 10% of women with chronic migraine chose not to have children or delayed having children because of concerns associated with their migraine care, either that they would pass on their migraine disease, that they would have to stop their medications, or that their migraine would get worse.

Anything we can do to treat them as well as possible, keep them comfortable, and allow them to make those lifestyle choices—including reproductive choices, which are core to being human—is important. I’m looking around. We’re all parents on this panel. It is pretty important. I also want to make 1 comment about the flip side. We’re thinking about protecting our pregnant women during pregnancy. We also need to think about how, as women age out of a childbearing age and get older, their risk for cardiac events might increase again. We may need to think about a woman who’s maybe been on a triptan for decades, since she was a teen or a young adult. It may be time to reconsider her options as she ages into the postmenopausal age bracket.

: I want to dovetail on your point, Dawn. As people who take care of headache patients, although it’s true that most women experience an improvement of their migraines during pregnancy, that should not be cavalierly thrown out to the patient by saying, “Oh, the best treatment is just to get pregnant. We’re going to discontinue everything, just get pregnant.” Although factual, that is not really helpful to the patient.

: The challenge with migraine and pregnancy is a catch-22 of attempting conception. The patient needs to come off preventives to conceive, but is then burdened by migraines so heavily that she cannot conceive and ends up in an anxiety and chronic migraine cycle that’s unbreakable. In the meantime, time is passing, and with each year the genetic risk to her embryo increases more and more. 

: Jelena, you’re NIH [National Institutes of Health] funded in this area, so this is your sweet spot to talk about female hormones and migraine. Not everyone gets better during pregnancy. Sometimes we almost think it’s a third, a third, and a third. There is sometimes worsening in the first trimester. Sometimes, the second trimester is the sweet spot. In the third trimester and postpartum, there could be a dramatic drop. 

It’s a bit of a roller coaster for women with migraine trying to guess what their pregnancy will be. We can’t afford child support for all the women we tell to get pregnant to treat their migraine. That’s a pretty big ask, to recommend that someone should have a child for their migraine to get better. It might not.

: We need registries of all the new medications in pregnancy, because we know that women will inadvertently use them in early pregnancy before awareness that they are pregnant. These medications will be used, and having registries that are active and already started will be very helpful.

: It was very helpful in the triptan era. The triptan pregnancy registry is a source of great reassurance, along with the various Scandinavian, particularly Norwegian, pregnancy data. Twenty years is a long time to collect that information, but it’s so important that it needs to be collected.

Intranasal DHE in Acute Treatment of Migraine

The role of novel therapies in transforming the acute treatment of patients with migraine.

: When we think about these novel things that we’ve discussed—the ditans, the gepants, and the new formulations of DHE—are there particular patients who you think might benefit from 1 or the other, Wade? Are there people who walk in and you think, “I’ve got news for you”?

: It changes the conversation. Now I can confidently ask about their triptan experience and respond to what they’re telling me. If someone says, “It doesn’t work all the time, and I just feel like it’s helpful,” most of the time, they won’t want to give up their triptan therapy, but they’re hungry for something that’s effective and not going to give them adverse effects. They want some faith that if they have an acute headache, they’re not going to lose the day. 

What is most problematic to our patients are these gaps in their lives that are robbed by the demon of migraine. Generally, if someone comes in and you ask about their triptan or their other acute therapy, and they say, “I don’t like taking it. It makes me feel sick or funny,” I’m thinking gepants in that type of situation. Someone comes in and says, “I use it, and it seems like it helps, but it just doesn’t have the power I’m looking for. I lose time from my family and from my life.” They’re still remarkably ill. 

Even if the triptan is effective 50% of the time, that’s still half the time that it’s not effective. That’s where I tend to go to the lasmiditan. Fair or not, I have pigeonholed it that way. Lasmiditan, based on clinical trials, showed efficacy that rivaled sumatriptan, and perhaps bested it in a few spots. Compare that with the gepants, whose adverse-effect profile was their heralding call. That’s where I am with those medications.

: There’s a mechanistic basis for people to think about DHE, because you get all the serotonin receptors, plus you pick up some adrenergic receptors that are probably important in process. It’s the price you pay, isn’t it? The more specific something is, the fewer mechanisms it interferes with, the fewer adverse effects you’ll get, and the smaller the group that responds. 

The messier a drug is, the more people who will respond, you’ll find more adverse effects, and the more who might want to use it. I think of amitriptyline like that—noradrenergic, serotonergic, dopamine reuptake. It’s a messy drug, but it has some utility. Topiramate is like brain Drano. It affects practically every pathway you can think of. Patients respond, but they can barely remember what the response was because of the broad adverse effect. 

It’s inevitably what we do. We home in on specific targets. Tolerability is great, but the range of people who respond to this is interesting. It’s an interesting balancing that we do. Jelena, do you have people who stand out for you? Are there those who, when they walk in, you say, “I’ve got some news for you”?

: I have 1 general response to your comments, which I completely agree with. That’s precision medicine, right? Precision medicine often requires a lot of precision, and a cost comes with that. It takes a lot of time and these evolving stories from our patients. We may give them 1 medication. They may have a response. 

What I try to teach our fellows is that the response to medication is also informative. You get a sense of, is this GABAergic tone, glutaminergic tone, or CGRP? 

I fully agree with everything that Wade said. I would add that because of the ODT [orally disintegrating tablet] formulation we spoke about earlier of rimegepant, I consider it for those who have very quick onset of headache. The headache increases in severity quickly, and if they treat 30 to 45 minutes later, it’s hard to pull back and get relief. That is my first choice in those headache cases.

: Peter, I’d like to share 2 things that I found very surprising. When these new classes of medications came out, we all envisioned our patients who complain about adverse effects or people who find them inconsistently effective. What I didn’t think we would see in clinical practice, and I see it all the time, is that when you probe these patients who have told you it works and they don’t have any adverse effects, these are the people who are taking a second dose frequently or having adverse effects that they don’t talk about. 

I’ll be bold and say that in a few years, we’re going to see a shift, in which 60% to 70% of our patients are on ditans or gepants and only 20% to 30% are truly happy with their triptans, in terms of not having adverse effects and finding them effective. The other thing that surprised me, and you certainly can comment if you had similar experiences, is how many people have taken a CGRP antibody and found it ineffective after taking it for 3 or 4 months. Then you put them on abortive therapy and they surprisingly work well. 

I don’t have a good explanation for it, but that’s been a big surprise for me in clinical practice since the advent of the gepants.

: It’s beyond irritating, isn’t it? The book would suggest that if a monoclonal antibody didn’t work, targeting the receptor ought to not work either, but the problem is that we haven’t written the right chapters in the book yet. 

: The only thing I can think of is, if you have an antibody that suppresses the overall level of CGRP, does the system or the body have some kind of compensatory mechanism? If you’re suppressing episodically with a gepant, does that compensatory response not happen? That’s 1 thing I can think of, but that’s only speculation.

: I haven’t given up on the central nervous system as a possibility. The gepant access to the central nervous system is better than monoclonal antibody access. The idea that everyone has the same problem with migraine and that it’s all centered on 1 structure doesn’t make any sense if you look at the complexity of the network disorder. 

The problem we have is not that we have wonderful tools. We have wonderful tools, but it’s always been and continues to be a question of how you pick the patient to put the tool in. We do this alchemy business, but I much prefer to ultimately be able to say to a patient, “This will fit for you because of X.” That’s going to be 1 of our great challenges going forward.

: That really punctuates the point that migraine is actually a massive umbrella term that contains so many subtypes. Some people are successful with the beta-blockers. Some people are more CGRP based. As you said, the Holy Grail, which we all look forward to, is that someone comes in with a diagnosis of migraine, we do a blood test, and we’ll be able to genetically subtype them and then refer them to the appropriate therapy. But that’s many moons away.

: In the meantime, we have headache medicine doctors to struggle with the details. Thank you for that.

Patient Selection of Novel Therapies for Migraine Treatment

Current devices and mechanisms available for neuromodulation for acute treatment of migraine.

: We’re going to transition to the next section. In this section, we’re going to be talking about neuromodulation. Neuromodulation has been the poor cousin of pharmaceutical development because the beauty of a specific receptor is that you can talk about it and you have a target. Neuromodulation is a step back because it effectively takes advantage of nerve neurotransmitter change in a much broader fashion. It’s much harder to design good-quality clinical trials because of the nature of the stimulus and the problem of unblinding. 

That said, we’ve had progress, and things are available. Jelena, can you set out some of the things physicians might be interested in regarding neuromodulation? 

: Sure, Peter. As you said, the question is, can we manipulate central and peripheral pain pathways? Can we use ways to modulate the activity of nerve pathways? There are attractive alternatives, though they have been a stepchild to the medication revolution that we have had in the past few years. They’re quite attractive because it is hard for us to predict which patients will be most responsive to various medical treatments. 

Given the adverse effects, comorbidity profiles, and so on, it is very attractive to have a treatment that presumably doesn’t have adverse effects and can be used with many comorbidities of migraine. It is also useful in patients who are worried about medication overuse in headache, specifically with triptans and even with lasmiditan, with which there’s a warning that there may be that potential. 

With gepants, we don’t think there is, but at this point we don’t have enough evidence to fully assess that. The overall goals of neurostimulation can be summarized in 3 parts. One goal is to wind down the central sensitization that we know drives migraine. Another is to block processes for attack duration. The third is to enhance pain inhibitory networks, so potentiating. Inhibiting networks, downplaying the central sensitization, and preventing propagation of attack are the goals of neurostimulation. 

We have 3 principal devices that have been studied and have FDA approval for migraine. The first is transcutaneous supraorbital neurostimulation. Simply put, that is the stimulation of the supratrochlear supraorbital branches of the trigeminal nerve. It is a device that’s placed right here. It works by modulating trigeminal nerve nociception and gradual neuromodulation of central pain processing areas. 

There have been several trials of it. They’re relatively small, and as you mentioned, there’s an issue with devising a good sham control, because the feeling is electrical. It’s a small stimulus, which a majority of patients tolerate quite well, but there are patients who cannot tolerate it, particularly patients who tend to have chronic allodynia in that area. It does have a good safety profile, but some patients do report such things as fatigue and insomnia. Very rarely, some patients have reported activation of headache and worsening of local pains and paresthesia. 

That’s something to be aware of, and it’s contraindicated in patients who have metal implants or electronic devices in their heads. It is also contraindicated in patients with cardiac defibrillators and pacemakers. I don’t know if I mentioned that in the United States, it was first approved as a preventive treatment for migraine. Currently, it is approved as both treatment for acute and chronic migraine, and the same device can have both modes of treatment. 

The second device of interest is the noninvasive vagal nerve stimulation, which is a device that’s placed over the area of the vagus nerve in the neck. It has received FDA approval for both acute and preventive treatment of migraine and also for episodic cluster headache, in which it has some interesting data. What is good is that while the supratrochlear and supraorbital stimulation takes at least 20 minutes for preventive and acute treatment, the acute treatment via stimulation of the vagus nerve is 2 minutes. That can be repeated after 20 minutes and 2 hours as needed. The preventive treatment is 2 minutes, 3 times a day. 

The mechanism of action is possibly to decrease glutamate and suppress neuronal firing in the trigeminal cervical complex, as with everything else. It also further modulates the trigeminal autonomic reflex through the vagus nerve. There are contraindications in people who have implanted medical devices, especially metallic devices in the neck. Carotid atherosclerosis, which generally happens in older patients, a history of cervical vagotomy, significant hypertension, and bradycardia are also contraindications. 

Finally, the most recently approved neurostimulation mechanism is the remote electrical neuromodulation, which is a placement of an electrical stimulus on the deltoid area of the upper arm. It’s a single 45-minute treatment within 1 hour of migraine onset. 

All the publication materials from the manufacturer make it look like the most relaxing migraine attack ever. The mechanism of action is believed to be through a conditioned pain modulation by stimulating C- and A-delta nociceptive sensory fibers in the upper arm and musculoskeletal nerves. That stimulation then activates descending pain inhibitory pathways that originate in the periaqueductal gray and rostroventromedial medulla. That down-regulates the activation of the trigeminal cervical complex. 

: We have quite a range of options and some detailed understanding.

: Yes, and how long we have had these treatments available to us varies. The supraorbital neurostimulation has been available for the longest time. I would say that most of us have had the most extensive experience with it. The transcutaneous option is somewhat newer. It was FDA approved more recently, so there is somewhat limited experience with it.

Role of Neuromodulation for Acute Treatment of Migraine

Factors considered for patient selection of neuromodulation devices for acute treatment of migraine, including access and cost.

: Wade, how would you place these options when you talk to patients?

: The discussion about these devices is very stimulating, pun intended. But the thing about this is that when you stop and think about how these operate and what they do, it sounds too good to be true. My experience so far with using all 3 of these devices is very hit-or-miss. Unfortunately, the peripheral TENS [transcutaneous electrical nerve stimulation] device that we were talking about for the supraorbital nerves is something that a lot of my patients have purchased. A lot of them don’t continue to use it, for whatever reason. It may be lack of efficacy, feeling that it’s cumbersome, or whatnot. 

I don’t end up recommending that a lot. I know that’s somewhat blasphemous for an almost adverse-effect-free treatment option, but that’s been my experience. The vagus nerve stimulator has been really hard for me to get my hands on and hard for my patients to get access to. The few who have used it have seemed to like it, which is a good sign, but I don’t have a many people in my practice using that. 

The remote electrical neuromodulation, the device you wear on your arm, essentially tricks your nervous system into feeling a pain signal enough to send an antipain signal from the rest of your brain to the rest of your body. That is quite appealing. I’ve just started using that, and it’s been somewhat hit-or-miss with this also. There is a lot of appeal in the concept behind that treatment, but I don’t know if it’s going to be able to deliver what it’s reporting. 

Their studies were done with low-impact migraine patients, and they did only a short-term study with it. I’m more eager to see what the outcomes are going to show with that approach.

: The biggest issue with these treatments is access. The 1 stimulation device that wasn’t mentioned is the transcranial magnetic stimulation [TMS] device, which is a device that you hold to the back of your head and it emits a magnetic pulse. This device came out before any of these newer treatments came out, and it had a golden opportunity to put a foothold in migraine therapy. The problem was that it was a rental device that costed—correct me if I’m wrong—$300 to $500 a month to rent. 

It was completely inaccessible to patients. Even though I saw some value in it, I never prescribed it because of cost. The same thing is true with the other 3 stimulators that were mentioned. Although it’s not prohibitively expensive, I can speak to the simulator on the arm. That’s approximately $100 for 10 treatments. The way I pitch it is just like any other abortive treatment. It’s like playing golf. Depending on which hole you’re on, you’ll select the right club. 

Having these stimulators as your first-line treatment may be prohibitively expensive, but it is worthwhile to keep 1 or several of these options at bay. If your traditional abortive treatments are ineffective, or if you can sense a bad migraine coming on, you can use a stimulator treatment in conjunction with the pharmacological treatment. 

There is some value there when you’re not bankrupting the patient with these stimulators. But by the same token, it is a viable option to use in conjunction with their routine medications.

: Speaking of bankruptcy, the reason we haven’t talked so far about the single-pulse transcranial magnetic stimulator is that the company went into bankruptcy and it now can’t be found. I don’t want anyone listening to this to be frustrated and sending their patients to find something while no one is answering the telephone at the moment. 

: I guess they wouldn’t spring into action.

Advances in the Management of Acute Treatment of Migraine