{"version":1,"type":"rich","provider_name":"Libsyn","provider_url":"https:\/\/www.libsyn.com","height":90,"width":600,"title":"Pharmacologic Treatment for Migraine Prevention in Adults Practice Guideline Recommendations","description":"Dr. Tesha Monteith talks with Dr. Tamara Pringsheim about the updated American Academy of Neurology (AAN) and American Headache Society (AHS) guidelines on pharmacologic treatment for migraine prevention in adults.  Read the related article in Neurology\u00ae. Disclosures can be found at Neurology.org.  Show transcript:  Dr. Jose Merino (00:08): This is Jose Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week. Dr. Tesha Monteith (00:23): Hi, this is Tesha Monteith with the Neurology Podcast. I'm excited to talk to you today about the update in Migraine Guideline: Pharmacologic Treatment for Migraine Prevention in Adults: Practice Guideline Recommendations, a report of the American Academy Neurology Guidelines Subcommittee, and the American Headache Society. Since the last guideline in 2012, there's been a lot of new advances, including the introduction of CGRP inhibitors for acute and preventive treatment. (00:53): With me to discuss is the lead author, Tamara Pringsheim, a neurologist at the Department of Clinical Neurosciences, Psychiatry, Pediatrics, and Community Health Sciences at the University of Calgary. How are you, Tamara? Dr. Tamara Pringsheim (01:06): Great. Thank you for asking me to talk to you about this. Dr. Tesha Monteith (01:09): Why don't you tell me a little bit about yourself and how you got involved in this work? Dr. Tamara Pringsheim (01:14): Sure. I've been working as a methodologist for the American Academy of Neurology Guidelines Subcommittee for a number of years, since 2015. Prior to that, I was a member of the guideline development subcommittee from 2011. I've worked on a number of different guidelines across neurological conditions. Dr. Tesha Monteith (01:36): Great. So how do these new guidelines compare, just broadly speaking, with the older guidelines? Dr. Tamara Pringsheim (01:43): I guess since the last guidelines were published more than 10 years ago, we've had changes to our methodological process. We had a major update to our guideline process manual in 2017, and guideline methodology has continued to evolve over that time period. And as well, a number of targeted treatments for migraine have come out. So there's been an explosion of evidence, particularly in the last five to seven years. And so we have a whole new class of medications available for migraine prevention, which really target our underlying understanding of the condition, whereas most of the other medications were discovered through serendipity. Dr. Tesha Monteith (02:33): So I know that you reviewed over 200 randomized controlled trials. And so how was the quality or confidence of the evidence determined? Dr. Tamara Pringsheim (02:47): With our process, we start by rating risk of bias for every article. This basically gets at a number of different features related to the clinical trial methodology and reporting, and it helps us determine how confident we are in the evidence. In order for us to be highly confident that the results that we are seeing reflect the truth, we typically need to have at least two Class 1 studies for any intervention outcome pair. The effect size estimate also has to meet a certain threshold in terms of the effect size and the precision surrounding that estimate. So if we feel that based on what the panel decides in terms of what is the minimal clinically important difference between an intervention and placebo, that will help us determine our confidence in the evidence. (03:51): So there's this critical coming together of the number of studies, the quality of studies, the effect size, and the precision of the evidence that helps us determine our confidence in the evidence. And all of this is done behind the scenes using a very algorithmic approach so that these rules are faithfully applied across the different interventions we're looking at. This complexity makes it hard for people to understand why certain drugs land in a certain area, but it's one of the things that we do to make this process standardized and rigorous. Dr. Tesha Monteith (04:37): So I do want to talk to you about that, where drugs have landed. One newer thing was that the review was not just episodic migraine, but also chronic migraine. Dr. Tamara Pringsheim (04:47): Yes. Dr. Tesha Monteith (04:48): Were there important differences in the strength of evidence between these populations? Dr. Tamara Pringsheim (04:53): One thing that's really important to remember is that the use of the term chronic migraine is fairly new. So a lot of the trials of the older headache preventive medications were done in the 80s and the 90s. And at this time, there wasn't a definition which distinguished chronic migraine in particular. So a lot of the trials for amitriptyline, for example, were not done in a purely episodic or chronic migraine population. And so this really contrasts with the newer studies where these populations were well-defined. And so we're going to have higher quality evidence or evidence specifically for chronic migraine with the new drugs, whereas for the old drugs, we won't have that. Dr. Tesha Monteith (05:50): Let's get into the preventive treatments that had the strongest level of evidence for episodic migraine. Dr. Tamara Pringsheim (05:57): We had high confidence in the evidence for two of the CGRP medications, erenumab and galcanezumab. Again, these high confidence in the evidence statements are based on the fact that for both these drugs, there were multiple Class 1 studies showing that they were efficacious. And the effect size was in the range that was pre-specified. So the lower level of the 95% confidence interval was clearly higher than what we decided was the minimal clinically important difference. Both these drugs, one had two Class 1 studies, one had three Class 1 studies, so we could be very highly confident that these two medications were efficacious. (06:50): Now for the moderate confidence drugs, we have a longer list for episodic migraines. So it includes atogepant, eptinezumab, fremanezumab, propranolol, rimegepant, topiramate, and valproate, and then a slightly longer list for the low confidence drugs. So amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan. (07:18): And for this outcome, I'm specifically talking about episodic migraine headache days. Now, one of the layers of complexity, again for this guideline, is that we had a few different outcomes that we were looking at. So the two main outcomes we were looking at were the headache frequency, the change in the number of headache days, but also the 50% responder rate. That's the proportion of people in the treatment group who had at least a 50% reduction in their headache frequency. And some drugs would make it for one endpoint, but not the other. And this is an important nuance that, again, adds complexity to our data synthesis. Dr. Tesha Monteith (08:06): And what about for chronic migraine? Dr. Tamara Pringsheim (08:08): So for chronic migraine, for the number of headache days, we had high confidence for fremanezumab, galcanezumab and onabotulinumtoxinA, and moderate confidence for atogepant, eptinezumab, erenumab, topiramate, rimegepant, and valproate. We didn't have any medications that were in the low confidence in the evidence category. Dr. Tesha Monteith (08:33): Oftentimes in the newer clinical trials, we're looking at change in monthly migraine days, but interesting that you looked at headache days. Dr. Tamara Pringsheim (08:42): Yeah. So another difficulty is that there's not always consistency in what's reported. So some trials would report headache days and some trials would report migraine days per month. Wherever possible, we use the change in the number of days with migraine. And where this was not present, we would use headache days. Dr. Tesha Monteith (09:08): Now, a drug that we use very often in clinical practice is rimegepant, which has a dual benefit of acute attack treatment as well as prevention. And that was rated as low confidence, but in a recent International Headache Society, Italian guidelines, that was noted as moderate quality evidence, strongly in favor of. What do you think that discrepancy was about? Is that a matter of outcomes or? Dr. Tamara Pringsheim (09:38): This guideline includes clinical trials that were published up until June of 2024. And so at that time, the only trial of rimegepant versus placebo that was published was in a population of patients that had episodic or chronic migraine. The population was combined. And so we only have one study. And as I was explaining at the beginning, in order for us to have high confidence in the evidence, we have to have at least two Class 1 studies and the minimal clinically important difference has to meet a certain threshold. So for rimegepant in June of 2024, there's only one study published versus placebo. So the highest possible confidence in the evidence we could have for rimegepant based on the fact that just one study would be moderate. (10:38): The reason why it's not listed in recommendation 3A as high or moderate confidence is because while we had moderate confidence in the evidence for rimegepant on the number of headache days, we had low confidence in the evidence for the 50% responder rate. And that's because for the 50% responder rate, it did not meet the pre-specified cutoff with respect to the minimally clinically important difference. (11:11): So again, it's a small nuance in the evidence, but for an evidence-based guideline, we really pay attention to these things. I know it makes it complex and hard for people who are not immersed in the evidence to understand. This is part of the rigor. There's a temptation to oversimplify things so that it's easy to understand, but that's really one of the strengths of the AAN process is that we take the evidence very seriously. We are truly evidence-based. We are going through every data point very carefully, and so that you should feel confident when you see that we've rated these medications as a higher moderate confidence, that we've really looked and evaluated these data points very carefully. Dr. Tesha Monteith (12:01): We can say that different guidelines have different outcomes. And to your point, it's more than just the data. It's your pre-specified process that then led to those recommendations, right? Dr. Tamara Pringsheim (12:14): Yeah. And I feel pretty confident that if we were to update the evidence, including the last two years, that rimegepant would move up, right? Because just looking even quickly now, we can see that since 2024, there have been several additional studies published. So now we wouldn't just be basing our evidence review on one placebo controlled study. There have been several more, the medications FDA approved. Dr. Tesha Monteith (12:44): Right. Dr. Tamara Pringsheim (12:45): I don't think anyone should change their practice based on this and people should be using rimegepant. That's not the message that we're trying to send. Dr. Tesha Monteith (12:54): That's really important. Dr. Tamara Pringsheim (12:55): Yes. We are not on a campaign to say that rimegepant is not a treatment option. As you can see, it is listed and it is in the guidelines. It's just based on the data we had available, we had low confidence in one of the outcomes, the 50% responder rate. So I hope that makes sense. Dr. Tesha Monteith (13:14): Yeah, I think it makes sense. It's the processes, it's a 2017 guideline manual, and that does make sense. So thank you for that clarification because a lot of our clinicians will be asking questions about this. Dr. Tamara Pringsheim (13:26): I mean, the same goes for another drug, candesartan is the other one. Dr. Tesha Monteith (13:30): Yeah. Candesartan recently had a paper published in the Lancet. Dr. Tamara Pringsheim (13:33): Yes. Dr. Tesha Monteith (13:33): And it did well, and people are using candesartan. Dr. Tamara Pringsheim (13:38): Yes. Yes, exactly. I prescribe candesartan for migraine prevention. At the time we did the evidence review, we had a couple of positive studies, a couple of negative studies. And when we put the data together, it came out as very low confidence because there's a discrepancy. And then we have a huge trial published that is a positive study, but it came out in 2026. It was not part of our evidence review. We don't say anywhere in the guideline, don't use candesartan, right? We don't say that. We highlight the drugs for which we have the confidence in the evidence and put them in there. But we need to remember that new drugs are coming out all the time and that they didn't factor into our decision making. (14:26): So again, I hope that people don't read the guideline and say, "Oh my God, I can't use candesartan." That's not true. Dr. Tesha Monteith (14:33): So one thing I want to look at is quality of life outcomes. That was something also not seen in the first or the 2012 guidelines. And so how did you look at quality of life outcomes and how should we consider them? Dr. Tamara Pringsheim (14:47): Yeah, so we wanted to make sure that we incorporated patient reported quality of life outcomes in the guideline, recognizing that this is very important. And the newer trials of the more recent medications have been incorporating patient reported quality of life outcomes in their clinical trials. This adds overall credibility that we are incorporating into our decision-making evidence that not only are patients' number of headache days decreasing, but their quality of life is improving because that's important to patients and hence is important to us. (15:31): So we used outcomes from validated measures of migraine related quality of life. So there's the MIDAS, there's the HIT-6, and there's something called the migraine specific questionnaire, which has three subscales. One is emotional function, one is role function preventive, and one is role function restriction. And then a few studies use something called the migraine physical function impact diary. So those were the main instruments that we looked at. And again, we had a pre-specified minimally clinically important difference on these instruments that we looked at. (16:19): And we had a reasonable amount of data, not as much data as we had for headache days or the responder rate, but certainly again, for the CGRP antagonists, we had high confidence in the evidence for galcanezumab, for example, in episodic migraine. And for chronic migraine, we had moderate confidence in the evidence for a number of medications including topiramate and onabotulinumtoxinA. So these quality of life measurements seem to be increasingly used in our modern clinical trial era. Dr. Tesha Monteith (17:07): Great. Another question is just thinking about some of the limitations of this work. There were very few high quality head-to-head trials. How does that limit your comparative effectiveness data? Dr. Tamara Pringsheim (17:19): This is a major issue that most, but not all of the head-to-head trials were investigator-led. Many were done a very long time ago before the modern clinical trial era, and so the quality of these studies was low. And also they were not non-inferiority studies. So basically the only question they could answer is whether drug A is better than drug B based on their trial protocol and methodology. And for most of the comparisons, we have very low quality evidence, so we really cannot support or refute that drug A is better or worse than drug B. So we can't really say anything. There were a few instances where we could say that drug A is better than drug B, but it's low confidence evidence, very few comparisons. (18:17): Some evidence is emerging so that some of the CGRP drugs are being compared to some of the older drugs now with the hope that we can prescribe these sooner to migraine patients. That evidence will probably emerge in the coming years. Dr. Tesha Monteith (18:31): And another question is how should these guidelines be incorporated in clinical practice also while balancing tolerability, comorbidities, patient preference, reproductive considerations, access, and costs? Dr. Tamara Pringsheim (18:47): So we have the evidence synthesis. So you can say, okay, this is the evidence. These are the effect sizes. This is the number of studies to support this outcome, that outcomes. You have the details in the systematic review, right? And then how do you take those details and apply them in the practice? And that's the art of medicine. And we don't make decisions without our patients. All of our decisions are collaborative. I say to my patients, "It's my job to tell you what your options are. It's your job to discuss these options with me and for us to make a decision together regarding which one is the best for you in your situation." (19:30): And that's what we're trying to do in the recommendations. In the recommendation statements, you'll see that in this specific situation, this might be a better choice. We talk a lot about when you're going to decide to even start a preventive and the importance of shared decision making, that those are our first two sets of recommendations. Recommendations one and two are about those things. (19:56): And then our recommendation three statements just tries to gently offer some advice on when you should think about which medication, where efficacy is the priority, tolerability is the priority, long-term harms, cost. Cost is a really tricky one because cost really depends on the person's specific pharmaceutical formulary plan and healthcare insurance. I know that for some patients, their insurance plans require a certain number of oral medications to be tried before an injectable like a botulinum toxin or a subcutaneous medication or one of the newer medications can be prescribed. Dr. Tesha Monteith (20:41): So you put a lot of work in this, your team, the American Academy of Neurology, the American Headache Society, outstanding work. What should we take away from this? Dr. Tamara Pringsheim (20:52): I think that we should take away that a lot of work is being done by headache neurologists and neuroscientists who are interested in headache to develop new treatments for people with migraine. I think that the CGRP drugs are a major advance and that now we have many new medications that are specifically designed for migraine treatment and these treatments are changing people's lives for the better. I think it's brought new hope to people with migraine and it's an exciting time to be a clinician who treats patients with migraine when you have several new medications where the companies have invested the time to do the research, do well-designed clinical studies, and that we can feel confident that these medications are helping our patients. Dr. Tesha Monteith (21:51): Excellent. I couldn't have said that better. Thank you again for your work and your time and for being on our podcast. Dr. Stacey Clardy (22:00): This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org\/podcast for our full list of past episodes, or you can also search by keyword on the podcast app for any neurology specific topics.   ","author_name":"Neurology\u00ae Podcast","author_url":"https:\/\/www.neurology.org\/podcast","html":"