The Evolution and Potential 'Cure' for Migraines

Indomethacin-responsive headache disorders are rare conditions whose hallmark is an absolute response to the medicine and include paroxysmal hemicrania and hemicrania continua.

In this episode, Gordon Smith, MD, FAAN, speaks with Peter Goadsby, MD, PhD, FRS, author of the article “Indomethacin-Responsive Headache Disorders,” in the Continuum® April 2024 Headache issue.

Dr. Smith is a Continuum® Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Goadsby is a professor of neurology at King’s College London in London, United Kingdom and professor emeritus of neurology at the University of California, Los Angeles in Los Angeles, California.

Additional Resources

Read the article: Indomethacin-Responsive Headache Disorders

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Host: @gordonsmithMD

Transcript

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the Show Notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. AAN members: Stay tuned after the episode to hear how you can get CME for listening.

Dr Smith: This is Dr Gordon Smith. Today, I've got the great pleasure of interviewing Dr Peter Goadsby on indomethacin-responsive headache disorders, which is part of the April 2024 Continuum issue on headache. Dr. Goadsby is a Professor of Neurology at King's College London, in London, United Kingdom and a Professor Emeritus of Neurology at the University of California, Los Angeles, which is located in Los Angeles, California. Dr Goadsby, welcome to the podcast. Well Peter, I'm super excited to have the opportunity to talk to you. And I think, before we begin, we probably ought to expand on your introduction. I think there may be three or four neurologists who don't know who you are, and I think they should know who you are because you've got a really amazing story. These are exciting times in headache, right? And a lot of that's because of your work and you've been widely acknowledged for that; you received the appropriately named “Brain Prize,” which (if I'm correct) is the largest neuroscience award in the world; got to meet Danish royalty; you’re - more recently, the ABF Scientific Breakthrough Award, which is super excited. So, particularly interested in hearing about your Continuum article. But before we get there, I think it would be really great to hear your story. How did you get into this in the beginning, and what's inspired you along the way to the many achievements you've had?

Dr Goadsby: Why, it's a very kind introduction. People have been nice to me. It has to be said, Danish royalty were very nice, I have to say, and the very jolly chap, the Prince of Denmark. I got into neurology - I guess it's all about mentoring for me. I got into neurology because I got into medical school pretty much by accident. I really wasn't that interested and heard a lecture by James Lance, who was Professor of Neurology, University of New South Wales, at the time. He was talking about a nondominant parietal lobe. I'd seen the case as a medical student; it sort of just seemed weird to me and I wasn't that interested. But he set out this way of thinking about things to try and understand why a clinical presentation is what it is - what he described as a physiological approach to clinical neurology. He described a number of things, but he described that in this lecture and then gave a reference to some work that Mountcastle did on nondominant parietal recordings from awake behaving monkeys in the Journal of Neurophysiology. And I thought to myself, “Wow, this is really interesting - you could really get to the bottom of something,” and had that sort of “puzzle-y” thing going on. And I thought Lance was just wonderful, so I became interested in that. And then eventually I asked him about research - actually, I asked him about research after a lecture he gave on migraine, and the explanation of the time was some circulating substance - probably just as silly now. I went up to him afterwards and said to him, I thought the explanation he was giving was wrong. Like, here was a global person - he described Lance-Adams syndrome; this was someone who trained at Mass General, trained at Queen Square; was the first professor of neurology in Australia. I was just – like, it was a stupid thing to do. But I couldn't resist myself - I told him I thought it was wrong. And he's very polite, and he said, “Well, perhaps you could come and help us by doing some research.” And I thought, “Okay, that's a very nice response.” Interestingly, his daughter described him as unfailingly polite at his funeral. Of the many things you'd say about him, he was a kind person. Whether it's science or just the way you practice - that word (kind) - you can know as much about a subject as you like, but if you're not kind to patients, you're probably in the wrong game. He taught me to be curious about a problem and got me interested in headache, and to be kind in clinical practice - just kind – and I think they were very important lessons. So, I got into it because of excellent mentoring, and I’d like to think I've helped some others along the way.

Dr Smith: Well, you certainly have helped a lot of people, Peter, and what a great story. I'm reflecting - I think the first vignette in The Man Who Mistook His Wife for a Hat was a right parietal syndrome - wasn't it? You've read that book?

Dr Goadsby: Yes, I have. And I've met Sacks. When Sacks came to Australia, he wanted to see Lance, and Lance said, “Fine, but you have to meet me between the morning round and the afternoon clinical meeting.” And he got him to come and have lunch with him in the hospital cafeteria at the Prince Henry Hospital and invited me to this lunch. And I sat there and watched them chat. But it was a measure of Lance and how people were interested in him that Oliver Sacks had to get in a taxi and come out to a hospital cafeteria to have lunch if you wanted to have a chat. Because it was - it was a privilege to train with the person. You know, I've done okay, but I only do okay if you've got – you know, you can work with patients, you've got great collaborators, and you've got someone you can get advice from (a great mentor).

Dr Smith: Yeah, that's actually really great words of wisdom for the residents and fellows and junior faculty listening to this. Maybe we should actually talk about your article, which was really great. Your article was on indomethacin-responsive headaches - and we can maybe talk about some specific questions - but what's the main take-home point? If our listeners needed to take or were to take home one point from your article, what would it be, other than it's indomethacin-responsive (that's in the title)?

Dr Goadsby: Yeah, it's what it says on the jar. Well, I think the one thing to take home is that there are forms of headache that seem relatively pedestrian, like one-sided headache that feels like it ought to be migraine that's strictly one-sided, and a small percentage of them respond almost like switching a light off to indomethacin. So, I think you have to have a high index of suspicion. And I’m sure I give indomethacin to ten, twenty times as many people - or thirty - who end up (or even more, probably) who end up having a response. But we do it for a short period of time. For those who get the response - I can tell you, when they come back, they're crying, their partners crying, or the other day I saw one, their child's crying, because all of a sudden, you've basically fixed the problem up. So, the message would be, if you've heard about something and it feels a bit “maybe, could be” - you've heard this indomethacin thing - just do it for a couple of weeks. The worst thing that can happen is nothing (nothing happens). For a couple of weeks, they're not going to have a problem with the tummy (and I'm not advocating taking people with a active gastric ulcer, trying to bump them off). But you cover them properly, you give them a short trial, and occasionally in your practice, you will be so rewarded by that - you will dance home.

Dr Smith: Well, this is going to be my next question. There are very specific criteria, right, for defining cluster, SUNCT, SUNA (and there was a really great Continuum Audio conversation I had with Mark Burish I'll refer our listeners to about cluster, SUNCT, and SUNA), but the indomethacin-responsive headaches - and even migraine - that sounds to me, as someone who's not a headache person, like, that could be challenging to sort out. If you see someone who has consistent, unilateral headache, do you just do an indomethacin trial, or do you select based on other criteria from the classification system?

Dr Goadsby: I'd like to think I was aware of the criteria, and I am. But the longer I practice, the more I'm inclined simply to give the indomethacin and get the question off the table because I don't think there's a sine qua non; there's nothing that will - apart from the indomethacin effect - there's nothing that will convince me 100% to be able to not do it. I've seen enough people who haven't clearly read the classification in detail (patients, I mean) and took indomethacin, and got a response where you wouldn't have predicted it, and they're very happy and the story ends well. So, I would advise people not to worry too much about whether it ought to or not respond, but find out if it does.

Dr Smith: So, the obvious next question is, how does this work? It's pretty unusual in medicine, certainly in neurology, to have something that's so dramatically effective. What's the mechanism?

Dr Goadsby: Well, that's the easiest question - we don't understand it. It is particular to indomethacin - it's weird. Some patients will say, “We'll give you a little bit of a hint by telling you (maybe) that ibuprofen was useful,” but most don't give you that much of a hint (some will even say aspirin is useful). But we haven't really gotten to the bottom of it. What are the current thoughts? It must be something that's not simply cyclo-oxygenase because other cyclo-oxygenase inhibitors don't do that – so, that's helpful. The other broad things people think about are whether there's a nitrergic aspect to it. We've got some basic science work that can show that nitrergically induced changes in experimental animal model of these trigeminal autonomic cephalalgias can be modified by indomethacin in one part of the model, where naproxen (for example) can't. So, we think there may be a nitrergic component to it. The other thing is the structure of the molecule makes you think about melatonin, if you put the two up – it's a work in progress. Of the things I would like to do in my life, I'd really like to get to the bottom of it, I have to tell you, because if we could work out what it is that's great about indomethacin and then get rid of the GI thing . . . Then, if you talk about cure - because when people get a response to this (you know, the oldest reported case with a response took it for thirty-seven years; they died of something else) - and continue to respond. It's one of the sort of upsides and downsides when you diagnose it - you can tell a person that they're going to continue to respond (take a breath) until they die basically, because unfortunately, the problem doesn't tend to settle down - at least the treatment stays consistent. If we could get rid of the tummy problem, that would be real progress.

Dr Smith: So, what do you do with the patient who has the tummy problem? Is there another approach?

Dr Goadsby: Well, there's a range of things you try and do; you use PPIs (proton pump inhibitors) and H2 blockers pretty liberally; you try to get the lowest dose, and that's usually best done by the patient. I give them the ordinary-release indomethacin; it's an impression that I have, over the years, that the slow-release indomethacin is not as efficient (just as a recommendation). I let patients - they take it three times a day, or twice - I let them work out what the littlest amount is that they need, having given them a regime to iron it out, because they can work it out for themselves. It's a partnership. It'll be very individual. If someone wants to take two in the morning and one at night and feels happy, have at it. If they want to take one three times a day, if they want to take one at lunchtime - whatever they - let them work out the minimal amount. And the other thing that we found useful - small percentage (maybe one in five) will find the coxibs useful (like celecoxib), but that's not universal at all; it generally takes the edge off. A palpable percentage will find adding melatonin in can be indomethacin sparing. Then the other (probably most important) thing is that the noninvasive vagal nerve stimulator can be very useful in reducing indomethacin dosing or even getting patients entirely off indomethacin dosing. How that works, of course, is as mysterious in the sense of these problems as is indomethacin. But that's something really worth thinking about - can be very, very useful in getting the doses down.

Dr Smith: You've been doing this for a while, right? And you've seen a lot of –

Dr Goadsby: Let's not emphasize that “for a while” side, right, okay?

Dr Smith: For a while – just a little while, Peter.

Dr Goadsby: A little while.

Dr Smith: I’m just thinking - and I'm a neuromuscular guy, so give me a little latitude - but when I was a resident, our concept of headache was pretty simple; it was migraine, classic or common, and we knew a little bit about cluster. And no one talked about SUNCT or SUNA or all these other things, and wow, what an amazing several decades it's been. What's the future look like? And - maybe think big – so, is a cure for migraine in the foreseeable future? What's coming next?

Dr Goadsby: If you think really big (and I'll think really big), if “cure” means that we could control it sufficiently that you wouldn't notice it, I think that's very much - it's almost here, for some. Now, I think of it like cholesterol - someone's got high cholesterol; they take a statin, and if they don't get any problems, the cholesterol normalizes. I'm simplifying things (I'm not a cardiologist), but you take your cholesterol tablet - you take it once a day; everything's fine and dandy. You never get “cured,” as such, but the effect is an effective cure from manifestations of the problem - and I am simplifying things a little bit. If I look at it like that, then I think we're getting to a place where some patients, we can treat them so well, and the problem is so suppressed, and they have so few problems with side effects (and some have none), that we're really getting there. We saw a study of the promontory phase of migraine using a gepant (ubrogepant), and we saw the ability (if you recognize the attack early enough) to treat and never have pain. Never have pain. Well, that's pretty close. It might sound crazy to think about it as a cure because someone will say, “Well, they've still got their genes,” and so on. Fine. But migraine is about disability, and if you can stop the disability and give a person full function in their life, well, you're pretty much there. And we're getting there, as we understand the disease.

Dr Smith: Really amazing. I have another question that I've actually been really dying to ask you. I'm a peripheral nerve guy, and you may not be aware of this, but those of us who are interested in therapeutic development in peripheral neuropathy, or advocacy, or recognition of neuropathy as a substantive, meaningful entity, are inspired by the work of you and your colleagues in headache. Examples might be advocacy for federal funding or having CDMRP funding - things like this. But an area where - I'm just curious - we spent a lot of effort (and it seems like it's been really transformational for you guys) is having taxonomy, which isn't a particularly sexy topic. But maybe you can talk about the power of having a taxonomic classification and getting towards a cure. Because looking through this Continuum issue - it's really remarkable – it’s just all sorts of things that I never would have thought of twenty years ago, and each of them is treated a bit differently.

Dr Goadsby: Yes. As with all things in medicine, if you don't get the diagnosis, you can't get to the base - you've got to be able to get a diagnosis. And our taxonomy, the International Classification of Headache Disorders, has gone through three editions. We're working on the fourth. I have the privilege of being the chairman for the fourth edition (the first three were chaired by Jes Olesen). I do think it's one of the absolute achievements of our field (and Olesen needs to be really feted for doing this) that we have a definition system - it's operational; it's reasonably straightforward; it's been translated into, like, forty languages; that every government on the planet that I know of - and I'm talking about (I think I'd better mention no governments) but every big government you can think of, without exception, has adopted (‘cause I'll just get in trouble with the ones I’ve mentioned) have all adopted this classification; all the health technology assessments (the FDA, for example; the European Medicine, for another example), the Chinese government (People's Republic), Taiwan. Just, all over the world, people use one thing. So, if we do a randomized control trial - there's one recently came out; it doesn't really matter which gepant it is - but you look at the results in North America, and then you look at the results that were done by the Chinese and the South Koreans in a study, and the placebo rates and the active rates are more or less identical. Because what we've been able to do is homogenize who gets into clinical trials and understand what's happening. So, if I get up and talk about whatever we're going to talk about now, like, in rural India, people will know what we're talking about; all the neurologists will be on the same page and so we can make progress. And when we make progress, it's global progress because we sing from the same hymn sheets. I think the taxonomy has been really important for this. And, of course, if you get the diagnosis right, then you can start to begin to get the treatments right and you can bring all the knowledge from randomized controlled trials. There's no point having a whole lot of data if you can't apply it, and what's great about our taxonomy is we can apply it everywhere in the world.

Dr Smith: Wow, what a cool answer. So, I have a follow up question for you, Peter, which has to do with reproducibility. This is a huge issue, right? In reproducibility and clinical trial evidence and in many fields, this has been a big issue - in psychiatry and other areas of neurology, where trials are nonreproducible. To what extent do you think this problem in other fields is a taxonomic problem, or a internal validity problem, in terms of the populations being recruited? I'm really impressed to hear that you don't have that problem in headache.

Dr Goadsby: I do think one of the advantages that the International Classification of Headache Disorders has given us (International Headache Society being the proponent of that) is that there's clinical homogeneity, relatively speaking, in our clinical trial populations. This comes back to the clinic; good clinical trials are as much about the clinicians who are involved and the care they take in recruiting patients, and so on. Which is not to say that psychiatrists are not careful - not at all. But I do think that if you want to just test a question, everyone in the laboratory will tell you that you need to have - say you're doing work with rodents, for example; you want about the same weight, you want the same strain, they're eating about the same, they're up and down at night - everything is about the same. If you want to do good clinical trial work, you have to tidy up as much as you can so the only thing that's really impacting upon the question is the medicine, or the placebo, or whatever that you're testing. So, I think you're right. I think sometimes the pain people struggle with this because, as you say, a painful neuropathy can come from a lot of places. Well, if you just take all of those etiologies, you throw them into one study, and you test it against something, it doesn't surprise me that that's not so useful, compared to taking an individual thing that's really well defined - where you've understood the clinical side, you've understood the pathophysiology as much as you could - and just test that, one at a time. I think that's been a good lesson for us. And that's why there's nothing that's ever failed in a migraine clinical trial (a properly designed one) that ever was useful, and nothing that was ever successful that didn't continue to be successful. Now, some things were successful, and they produced, like, liver enzyme problems - so, that's “no win-no foul” situation. But the homogeneity's been quite important, I think. And it comes back to good clinical practice.

Dr Smith: Well, thank you for the roadmap - that's really, really interesting. I'd like to finish up with another shift in gears, and to talk about workforce. Obviously, we have a national shortage of neurologists in the United States. We're never going to be able to train enough headache neurologists to take care of all headache patients, and we need to think about systems of care, which I guess we could talk about. But my question for you is, what would you say - a lot of residents listen to Continuum Audio, and hopefully, more medical students in the future and now - what do you say to them about a career in headache? Listening to this, I kind of feel like I want to go do a headache fellowship - it's pretty exciting. What's your pitch to them?

Dr Goadsby: I’ll tell you one small thing first before I say that; I did do twelve months in clinical neurophysiology, doing nerve conduction, muscle biopsies, evoked potentials. I actually did over ninety muscle biopsies (needle muscle biopsies) when I was training, so I understand your feeling. But I just got the feeling many years earlier than you've had it. What do I say to residents? Well, headache is an area where you can make a diagnosis, you can manage the patient, and you can make them better. I'd say to the resident, “Ask - just look in the mirror and ask yourself, why did you get into medicine?” You got into medicine to help people, and headache is an area where you can really help them. Plus, there's tens of millions of people with the problem, so you will always be in demand. And one of the great things about headache (I think it's probably true of neuromuscular) is it's also a very good lifestyle choice because our problems are generally with primary headache disorders - are not emergent (people don't tend to ring you up at night), and it's not really an on-call issue. You can have a proper balanced existence (work-life balance), and you can do it in a way that's really enjoyable. And then there's an extra bonus: there's all the wonderful neuroscience and neuropharmacology that's going on in headache. I just think if a resident looks in the mirror and says, “Why am I doing this?” most of them are going to look back at themselves and say, “Because I want to do good.” And they also want to do good in a way that they can have a proper life themselves. And if they're the two answers you got back when you look in the mirror (“I want to do good” and “I want to have some life myself”) - headache - that's the place to go, because there's plenty of room and you can do both.

Dr Smith: Well Peter, that's great - sign me up. And I think people know where to find you to call for a recommendation. What a great conversation and a really great article. And again, I'll refer our listeners to Mark Burish’s article on cluster, which is a really great companion to your article ‘cause it gives you the full spectrum of trigeminal autonomic cephalgias (which is pretty cool), and the rest of the issue is equally amazing. Peter, you don't disappoint. The next time you see the Danish Crown Prince, say “Hi” from me (I love Denmark - it's a lovely place to be). And thanks again for doing this.

Dr Goadsby: Well, thank you, and thanks for the Academy for organizing. And the other thing about residents - if you want to stay in touch with neurology, stay in touch with the Academy; they're a pretty good bunch.

Dr Smith: Couldn't agree more, couldn't agree more. Again, today we've been interviewing Dr. Peter Goadsby. His article on indomethacin-responsive headache disorders appears in the most recent issue of Continuum, on headache. Be sure to check out our Continuum Audio podcasts from this and other issues. And listeners, thank you very much for joining us today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice. Right now, during our Spring Special, all subscriptions are 15% off. Go to Continpub.com/Spring2024, or use the link in the episode notes to learn more and take advantage of this great discount. This offer ends June 30, 2024. AAN members: go to the link in the episode notes and complete the evaluation to get CME. Thank you for listening to Continuum Audio.