S6:Ep1 – What is Refractory Migraine?
Voice-over: Welcome to Spotlight on Migraine, hosted by the Association of Migraine Disorders. In this episode of Spotlight on Migraine, Dr. Jennifer Robblee talks about what refractory migraine is, how it differs from other migraine types, and what we know about it. She also talks about some of the off-label treatments and strategies she uses.
Molly O’Brien: Hello and welcome to Spotlight on Migraine. I’m your host, Molly O’Brien. Today, we’re diving into refractory migraine, and I’d like to welcome our guest, Dr. Jennifer Robblee. Dr. Robblee is a neurologist and headache specialist at the Lewis Headache Center, which is part of the Barrow Neurological Institute. She’s also a member of AMD’s executive advisory board. Dr. Robblee, thanks so much for joining us today.
Jennifer Robblee, MD: Thanks for having me, Molly. I’m excited to be here.
O’Brien: We’re always happy to have to you. And this is actually really exciting because refractory migraine is kind of your jam. This is what you love to talk about, so we’re very excited to have all of your insight and expertise.
Robblee: Well, I’m excited to talk about it. It’s by far my biggest topic in the headache world.
O’Brien: Let’s just go over a basic definition of what is refractory migraine.
Robblee: Sure. So you would think that would be a very easy, straightforward answer, but the reality is, is that we don’t have a focused sense of on what the definition should be. So in the headache world, we use the International Classification of Headache Disorders to diagnose how we, you know, define a headache based on, you know, whether it’s migraine or tension-type headache, cluster headache. But each of those also have subtypes. So, for instance, migraine can be with or without aura. You can have vestibular migraine. And each of those have very specific criteria.
Refractory migraine does not yet have a place in this diagnostic manual, but over the years there’s been a lot of proposed criteria. The most recent were in 2020 and they were put out by the European Headache Federation, and those are my favorite criteria that have come out so far. I think they’re the most stringent and they give some allowance for new medications that are coming out to be considered. So based on this diagnosis, you do need to have a diagnosis of migraine. They do allow for it to be episodic or chronic, but they do specify that you need to have debilitating headache at least eight days per month. And this isn’t just, you know, you have that for a few weeks. They need to be something that’s been consistent over at least three months *correction* (6 months).
And then what they specify is that you need to have tried all classes of medications with established evidence to migraine prevention, and that has to be, you know, you’ve done the appropriate dose, you’ve tried it for an appropriate duration, which is usually about 2 to 3 months, or you have a clear contraindication to these medications. And they do allow that you’ve just had a complete intolerance and you could not, you know, handle doing the medication for a full trial. And so, because this is a European criteria, the medications that they specify are the ones that are in Europe, but they do, in their manuscript, comment that you may want to use your own regional criteria.
So, for instance, here in the US we have the American Headache Society’s consensus statement and that would be, you know, in the US, but we would use a switch medication that we would consider as having established evidence, so things like the beta-blockers, topiramate, divalproex, amitriptyline, venlafaxine, candesartan, lisinopril, memantine, Botox, and then the CGRP monoclonal antibodies. And then technically the gepants. So those were actually authorized by the FDA for migraine prevention after those criteria came out, but likely they will eventually be included.
So, I think that would be a good definition to use moving forward, at least until we have some sort of consensus. Because basically this is what I see in my practice, the patients who are truly refractory have tried all of the options that we’ve got guideline evidence for and they are still not responding. So to make a very long story short, basically you have refractory migraine if you continue to have very frequent, debilitating headaches despite having tried all our evidence-based medications, at least all of the classes.
O’Brien: It’s always a little tricky when the first question, which should be the easiest, is actually kind of the most complicated.
Robblee: That we need a lot more attention put here.
O’Brien: It definitely is, which is part of the reason why we’re talking about it today and hoping to help educate patients, providers, and whoever else. Okay. So if someone is refractory, can you have a different type of refractory migraine? Like if someone has visual aura or if someone has vestibular migraine, can they classify into that refractory state or is it just kind of a typical migraine?
Robblee: You can absolutely have refractory migraine and have any of the different what we call phenotypes of migraine. So you could be with aura, without aura, you know, vestibular symptoms. I mean you could even have hemiplegic migraine. So I think any type of migraine as long as it has at least eight days per month to account towards at least the definition I’m recommending you use.
O’Brien: Okay. And within that definition – I’ll just backtrack for a second to help make it a little bit more clear for people, maybe – it’s if you have all of those things and then treatment just doesn’t work. You’re not responding to anything. Is that fair?
Robblee: The disease state is not responding to preventive treatment. So it’s not about, it’s about your ongoing disease state over time.
O’Brien: Okay. All right. So with that in mind – again, we’re going to get a little trickier – what is the difference then between refractory migraine, intractable migraine, and then we have the other spot of status migrainosus. What’s the difference between them?
Robblee: So refractory and intractable can probably be used interchangeable. Some of the previous diagnostic criteria that have been proposed for refractory migraine actually use the term intractable. So I think it’s kind of an either/or. The more recent ones seem to have settled on using the term refractory, but meaning wise, I don’t think there’s a big difference there.
Status migrainosus, though, is completely different. So if we talk about refractory migraine as being about the disease state, status migrainosus is about an individual migraine attack. And so, the formal definition for status migrainosus is that you have a severe migraine attack and it’s been going on for over 72 hours. Now, there’s nothing in the actual diagnostic criteria, which we do actually have in the ICHD-3 manual, that says that it has to be an attack that has not responded to treatment. So in reality, usually, it’s going an attack that, despite your typical acute rescue medications, the attack has been persisting. So in my experience, it is a refractory attack but that is not currently part of the criteria for it.
O’Brien: Okay. That can be confusing.
Robblee: It may be worth also defining the difference between episodic and chronic because those are also completely different than the two things we’re talking about. So those are more about how often your headache is happening as opposed to how it’s responding to treatment. With episodic migraine, you have less than 15 days per month and chronic migraine you have 15 or more days per month. And so, again, another sort of set of criteria that’s worth differentiating as we talk about all these different type of migraines.
O’Brien: Okay. So hopefully it’s becoming a little bit clearer to our followers what the differences are, what the different ways to talk about migraine are. So it seems to be me like there could be some overlap, too, with medication overuse headache as well as refractory migraine. There might be some similarities, but they are different things. So, can you tell us maybe one, how they could be connected and two, how we tell them apart?
Robblee: Yeah, I think that’s a really good insight that there is some overlap there. When you look at the different criteria that has been proposed for refractory migraine, some of them allow for there to be medication overuse and some of them need that to be ruled out. And it’s important to differentiate medication overuse versus medication overuse headache. Medication overuse is when you’re using your rescue medications more than what the sort of threshold that’s recommended. So for most medications, that’s if you’re using it 10 or more days per month. Now, if we’re getting to some of the more over-the-counter medications, other than Excedrin, so things like Tylenol or Advil, then you can get up to 15 days per month. But those are general.
And the whole concept there is if you’re using a rescue medication too much in the context of the primary headache disorder like migraine, you can lead to worsening of headache over time. And so, that’s because you’re actually increasing central sensitization, which means all those pathways in your brain are getting reinforced and it’s just perpetuating the whole cycle of what’s causing migraine in the first place.
A lot of people misunderstand this concept. So they think that medication overuse or medication overuse headache is the concept of rebound and what they think is, you know, I have a headache, I took my medication, and then the headache came back. That’s actually got nothing to do with what we’re talking about. That concept is actually that your headache is actually undertreated and so it has returned. In fact, in that case we’d be more aggressive with your treatment, not less aggressive. So important thing to differentiate.
So when you have medication overuse, you have the medication overuse headache, it is what is causing your headache to become more chronic and more frequent. And then in that setting, you may have poorer response to treatment. So it may be one reason that you start to become refractory, but when we talk about refractory migraine, it means even if you did not have medication overuse headache, you would still be refractory to preventive treatments. It’s just one thing that may be a risk factor for developing refractory headache.
We know certain medications are likely higher risks for that. So things like opioids are particularly high risk for medication overuse headache. And medications like Fioricet that contain butalbital are particularly high risk. We do think the gepants, so things like Nurtec and Ubrelvy, are unlikely to cause medication overuse headaches, which is a really great thing about them. Also a lot of the neuromodulation devices, those probably the more you use them the more they help, so they do not cause medication overuse either.
So it’s definitely linked and definitely something that may be a risk factor, but they are two different brain states that just may have some overlap in what’s happening in the brain.
O’Brien: Okay. And I love the way you phrase that, they’re brain states. That’s like a really helpful way to picture what’s happening. Okay, so let’s talk about this. Is there anyone that could be more susceptible to going into that state of refractory migraine?
Robblee: So the answer is that we don’t know, but definitely some theories that we can make. This is actually something that I’m planning on studying, so hopefully in the future we’ll have some more information, provided I get funding and I’ll move forward. So there are some things that we do know. So we do know of some risk factors for what makes migraine progress, but here we’re talking in terms of the headache frequency. So this is where we’re talking about moving from episodic to chronic as opposed to what’s making you treatment responder versus refractory to treatment.
So some of the risk factors just in general that make migraines progress: your headache gets more and more frequent; it’s allodynia, which is where just even touch is painful; certain mood disorders, like depression. Medication overuse is definitely a risk factor. There can be some sort of socioeconomic factors there that play into it. The more medical diagnoses just in general you have, that seems to have an effect. And then another thing is this concept of what’s called pain catastrophizing. So we know that pain has a physical component, so what you physically feel, and then an emotional component develops this sort of hypervigilance where you’re overly aware of what your body is feeling, and it can start to feel like the pain is actually controlling you. This is the concept of an internal locus of control.
And so, with pain catastrophizing, you get anxiety, basically, and that actually drives some of the pain response and can make pain feel worse. And even if we fix the physical pain, it may not fix that emotional component of response and coping mechanisms. And so, if you have a lot of that aspect, it can be that that headache can actually worsen. So that’s another concept to consider that plays into all that.
Now, when it comes to treatment response, while we don’t have specific risk factors for refractory migraine, there are some studies that have looked at very specific treatments. So like the CGRP monoclonal antibodies, so things like Aimovig, Emgality, Ajovy, Vyepti, and then Botox. The studies have looked at either that group of medications or individual medications. People seem to be less likely to respond to those medications when they’ve had other ineffective treatments, when they have medication overuse headache. Allodynia, there again, seems to be a risk factor, especially if you have it even in between your migraine attacks. Depression, again, is a risk factor. Obesity seems to be a risk factor. The pain catastrophizing, again, is a risk factor. If even in between your attacks you have a daily baseline headache that’s milder, that seems to be a risk factor.
The longer you have migraine seems to be a risk factor. And if you have a lot of like stressors, so things that are causing anxiety and things like that in your life, that can be a risk factor as well. It seems like you’re more likely to respond to those if you have a lower headache frequency. So like if you have episodic migraine as opposed to chronic migraine. And the more classic your actual migraine presentation is. So, for instance, classically we think of migraine as a one-sided headache that’s throbbing – and that’s not necessary, that’s just a classic presentation that we think of. But that classic presentation does seem to respond better to these medications.
If you respond to triptans, that seems to be predictive that you’ll have a better response. Younger, which means probably shorter disease duration, again, better response. And it seems like having vomiting with your response often makes it more likely to respond though it doesn’t mean just because you have any of these things that you will respond, just a higher likelihood.
So some of those things then may be part of what will be risk factors that we eventually find for refractory migraine, but that’s still something we need to study.
O’Brien: That is fascinating to me.
Robblee: It’s such an intricate disease and there’s so many things that are at interplay within the different parts of your brain and how all the things also affecting your body. That’s why we say obesity (15:22).
O’Brien: This is really insightful to learn about, and yeah, migraine is complicated. So complicated. Okay, so now that we have a better understanding of what refractory migraine is, the differences between how we classify these different brain states, now maybe someone, they know that they have refractory migraine, what do you do about it? Can you treat it? Do you just always have it forever? Like what do we do?
Robblee: I mean, that’s a really good question, and again, here I’m not going to have a perfect answer because like we don’t have good evidence-based treatments. I think this is a time where you definitely should be seeing a headache specialist because you’re getting off-label. This is beyond what most doctors are going to be comfortable treating. So I think that, definitely number one is getting an opinion from someone where this is what they do because we’re going to be going off-label. The treatments we use are going to have less evidence, so there may not even be a randomized controlled trial, which is our standard of what a really high-quality study is.
We may be using things for people just that are observed or there’s some case studies or there’s something anecdotal or maybe just theoretically it makes sense to try. We’re going to be doing more combinations of therapies. We definitely want to encourage multidisciplinary care, so you want to be a clinic where you have good access to those types of things. And then we may do some planned admissions to do intravenous medications. So a lot of different things that.
The approach that I typically use, and most headache neurologists will also be using, is what is called an n-of-1 trial. So this is basically where n is usually in a clinical study, N is counting the patients there are. And so, in an n-of-1 trial, you are basically your own study. And so, it’s this awful game of trial and error of different treatments. And it can be really frustrating to patients. They can start to feel kind of like they’re a rat in a maze that we’re studying. But it’s the best that science has right now.
And so, basically you try treatment after treatment. As long as you’re tolerating it, you want to get it up to a good dose and you want to be at that dose for at least three months. And it may be in these refractory patients perhaps you should be doing longer treatments, but typically what we’re doing is three months. And you need to find things that have some sort of evidence. So things that I might try – and this is not saying that you should go ahead and try those – but these are things that I personally do. You know, medications that we have less evidence for. So, for instance, we often try medications like gabapentin, even though the evidence isn’t great. I often will try zonisamide in these patients. So a lot of the antiseizure medications.
Other antidepressants that are not in the guidelines you might try. So, for instance, there’s duloxetine, which is Cymbalta. That’s used often in things like fibromyalgia and other pain disorders. Then we’ll get into some of the older types of antidepressants that have a lot more risks, so things like the MAOIs. So phenelzine would be an example there. There’s a lot of drug interactions so be really careful when you use a medication like that. It puts you at risk for something called serotonin syndrome if you get drug interactions. There’s a little bit of evidence for trying medications that are antipsychotic, but again those come with a lot of risks.
Sometimes we’ll even use something like a triptan daily. If you’re a really good triptan responder, we may take the risk of medication overuse and actually put you on something daily but more in order to make sure that you’re not getting worse and if you are, then we take you off of it. A lot of patients will tell me that they’re trying, you know, cannabinoids like marijuana or just the CBD and various forms of that. Actually, I haven’t seen anything amazing there, but the jury’s still out on what that does. Some of these patients end up on opioids, though I have to say, unfortunately, I’ve rarely seen anything magical there. (19:18) things like ketamine infusions, lidocaine infusions. And definitely if they haven’t tried it, dihydroergotamine, DHE, because that actually does have some other evidence.
Nerve blocks are something that we use all the time in this patient population. And we definitely need some better studies and better guidelines on how to use them, what to use, timing, and all of that, but we use it all the time. And occasionally these patients will go for some sort of surgery, though we don’t have anything that called a “migraine” surgery. But if there’s a component of a neuralgia, so if you have a lot of nerve pain, like your occipital nerve is particularly tender, you have some sort of electrical burning, sensitivity there, then we could have you do something like an occipital nerve stimulator. There you have nerve decompression surgery where they go in very slowly take out the tissue and any scar tissue next to the nerve. Sort of hard to access. Again, that’s not something you’re doing after you’ve tried a few medications. That’s when we’re getting to the end of the line.
And it’s just, you kind of have to individualize for each patient. You definitely want to do a lot of multidisciplinary care. So if there’s any degree of, you know, issues coping with being in the state of chronic pain, anxiety, any of that pain catastrophizing, often there’s worries about the change in your life. If you have associated mood disorders, some of these patients if there’s an underlying PTSD, history of some sort of trauma or abuse in their life, all of those emotional components you definitely want to consider cognitive behavioral therapy. And usually by the time you’re in a refractory state, even if you’re not prone to a mood disorder, it is just so defining in your life how debilitated you are that there’s at least going to be some degree of grief and some degree of how you cope with it every day.
So every single patient with refractory migraine could benefit from cognitive behavioral therapy. Honestly, I think every human could benefit from cognitive behavioral therapy because you just learn such important skills. But those types of things are really useful. Getting in some of the manual work, like a physical therapist who’s really familiar with headache and neck pain. Things like dry needling, acupuncture, we can add those types of things in. So those are all the types of things that we try.
Every once in a while, I have someone where they’re like yeah, I just found something that works, but this can be a really long road of years and just trial after trial. It can be pretty discouraging, honestly.
O’Brien: I’m so glad that you hit on that it takes a multidisciplinary approach because of those emotional factors that go into this. And if, you know, chicken or the egg, but they’re all intertied and intertwined. So, I’m really glad that you hit on that and how valuable it can be to get some help through that.
Robblee: It’s stigmatizing in our society still, but I mean if you’re dealing with this every day, you’re not a zombie, you have emotions, and those brain structures are linked. The hormones and those neurotransmitters in the brain, those are all being affected by that and part of what gets you into that vicious cycle. And we’ve already said you’re less likely to respond if you have things like that. And I mean, just by virtue of being in a refractory state, I would consider that a significant stressor, which we’ve already said is a risk factor for not responding. And so, how do we help manage all these different stressors, which includes the state of being in pain. That’s a physical stressor. That is a massive stressor.
O’Brien: Exactly. So, Dr. Robblee, you talked a little bit about all the different ways to treat refractory migraine and you mentioned this is probably if you’re in this state it’s time to go get some extra strong help, someone who specializes in this. And some of the treatments you mentioned, it seems like you might be able to work one-on-one just going to appointments, but some of the treatments you mentioned seem like you might need to be there for a while and be inpatient care. So, am I picking that up right? Can you have some type of inpatient care where you stay a while? And also can you work with a specialist just doing regular appointments? It kind of just depends on the person?
Robblee: This is mostly an outpatient situation. There are the occasional times that we bring someone in hospital. Usually, it’s just for a handful a days for defined treatment. There are a couple of centers where they are able to do a more multidisciplinary inpatient treatment. It’s really rare to get, it’s very hard to set up, and I=it’s really hard to get insurance to actually fund it. So it’s just not a great reality and basically the current setting of the insurance world and what’s realistic for being able to get reimbursed. But it’s the reality.
O’Brien: Unfortunately, that is the reality. So you talked about a couple different ways and avenues to treat. Is there any time that someone who’s living with refractory migraine should head right to the ER or go right to urgent care? Probably more so the ER. Is there any time when it’s like, you need to go?
Robblee: Unless you’re in a clear crisis, it’s rarely helpful is the reality. Often, what an emergency room is going to note what to do is things you’ve already tried. And so, I don’t find it’s usually helpful. If we’re going to admit you, typically it’s a planned admission, and when possible that actually means straight to the floor and hopefully skipping the emergency room experience. At least in our institution we’re able to do that. Sometimes they use admissions just for the practicality you do go through the emergency room, but it’s nice when you’re able to skip that piece.
Now the other half is clearly different headache than what your typical is, you know, you have what we call a thunderclap headache or like boom, someone hits you on the head with a hammer, maybe lost consciousness, you have neurologic symptoms, something like that. That, you should still treat as a medical emergency and get checked because just because you have migraine doesn’t mean you’re not allowed to have something else serious happen. So that would definitely be a time to go.
I mean, it’s not like my patients with refractory migraine don’t ever go to the emergency room, but I do try to have steps in place to try to prevent an emergency room visit. So I’ll give them, you know, here’s what you’re doing for your day-to-day pain, here’s what you do when you have a clear exacerbation, here’s your backup if that doesn’t work. And for some of them, even here’s your backup for your backup and so on, which may include having infusion clinic visits and things like that. And for the ones who occasionally do end up in the emergency room, it’s worth having something like a migraine action plan where you actually have a recommendation for if you’re going to go to your clinic, you should get.
And that’s something useful, so for some of those patients right now that’s happening. Or let’s say they may be out of the state and I’m not going to be able to help very much because of where they are I might give them for travel here’s a plan for while you’re traveling or what can be done, and some of those things are considerations. But unfortunately, it’s not usually helpful and the ER’s a pretty crappy place to be when you feel like crap. For better or worse, people in there caring for you are human and patients often tell me they get misinterpreted there. I mean they live with this awful pain every day so they look like they’re pretty comfortable, despite being in severe pain but, you know, pain is invisible.
I’ve had patients tell me that they’ve been assumed to be drug seekers. So it’s a crappy place to be and I’ve had negative feedback. And I don’t know how to fix that system issue, but we’re aware of it. We’re trying to make it better.
O’Brien: Would you think that that’s good advice and honestly good for anyone who just has migraine in general that you don’t necessarily want to be in the ER, and you probably already have tried a lot of things they’re going to do. And if you have a plan and you have that plan with endorsement from your doctor if you do need to go somewhere, I think that’s all great advice that anybody with migraine can use. So that’s super helpful.
All right. Well, Dr. Robblee, we are wrapping up here, winding down on time. So before we say goodbye to all of our followers, is there anything else poignant or prominent that you think people should know about refractory migraine?
Robblee: I think just making a plug that I feel like this is a massive proportion of my headache population that I care for, we don’t know the etiology, we don’t know for sure what the risk factors are, we don’t understand the pathophysiology of why it happens, and obviously we don’t have evidence-based treatments. We don’t even have accepted diagnostic criteria. So we need more advocacy. Know that there’s not something wrong with you, you’re not the only one, and there are some of us that really want to work on finding this. So, you know, continue to do all the advocacy and we’ll continue to try to do some work and research to understand why this is happening to you. Hopefully in the future as we get closer to where it’s personalized medicine, more treatments coming out, we’ll start to find some answers and slowly make you not refractory.
O’Brien: I think that’s so valuable that there are people out there just like you, if you live with refractory migraine, and it seems like the cards are stacked against these people, but they’re not. There are advocates, there are doctors like yourself, there are specialists, there are researchers out there who are working to help make everyone’s lives better who live with refractory migraine.
Robblee: So hang in there.
O’Brien: We’ve got you. We’re working on it. All right. Dr. Robblee, thanks so much for joining us here today on Spotlight on Migraine. I really appreciate it. It’s been wonderful to chat with you and get your insight, as always.
Robblee: Thank you so much for having me, Molly. It was just a pleasure to be here, and I hope eventually some of this stuff we talked about will change.
O’Brien: I do as well. Well thanks again. And to all of our followers and listeners out there, thanks so much for following along with the Association of Migraine Disorders. I’m Molly O’Brien.
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