State of the Art in the Management of Migraine
A recent study published in Headache: The Journal of Head and Face Pain offers a specialist perspective on the American College of Physicians (ACP) 2025 guideline for migraine prevention. The study, “State of the art in the management of migraine — A response to the American College of Physicians migraine preventive treatment guideline,” was authored by Andrew C. Charles, MD, and colleagues. It addresses the need for a more nuanced interpretation of evidence, clinical experience, and patient-centered decision-making in migraine care.
Dr. Charles, professor of neurology at UCLA, director of the Goldberg Migraine Program, and past president of the American Headache Society, discussed the motivation behind the response in a recent interview with Rashmi Halker Singh, MD, FAHS, FAAN. Dr. Charles explained that the response was prompted by concerns over how the ACP guideline interpreted available data. “The central one is the premise that the evidence for different therapies is more or less equivalent, and therefore one should prescribe preventive treatments primarily based on the cost of medication,” he said. “That’s really the primary issue that we have, and it’s an issue on multiple levels in terms of how we manage patients.”
Watch the whole interview with Dr. Charles:
Evidence Gaps and Limitations in the ACP Guideline
The ACP guideline concluded that older migraine preventives and newer CGRP-targeting therapies offer comparable efficacy, suggesting that treatment decisions should prioritize cost. Dr. Charles emphasized that this conclusion was based on weak and inconsistent evidence. Many of the foundational studies of traditional preventive interventions were conducted decades ago, using outdated diagnostic criteria and outcome measures, with small sample sizes and high variability. In contrast, CGRP studies have involved tens of thousands of participants and have produced far more reliable and reproducible data.
He pointed out that this imbalance violates a key scientific principle, transitivity, which requires comparable trial designs when pooling data through meta-analysis. Because most older trials differ significantly in methodology and scope, comparing them with newer studies can lead to misleading conclusions.
Dr. Charles also noted that clinical experience is essential when interpreting this kind of data. The ACP guideline was developed by authors who lacked direct experience in headache medicine. As a result, important nuances were missed in how evidence translates to real-world care, such as how patients respond differently to treatments, how side effects impact adherence, and how newer therapies improve quality of life beyond headache frequency. He stressed that those treating migraine patients daily can clearly see that CGRP-targeting therapies represent a significant advancement in both effectiveness and tolerability compared to older drugs.
The ACP’s claim that newer therapies offer no “clinically important advantages” over traditional treatments minimizes a transformative shift in migraine care. For many patients, these medications have changed what is possible in prevention, offering better outcomes with fewer side effects.
Prioritizing Patient Outcomes in Migraine Management
Beyond headache frequency, Dr. Charles emphasized that modern trials assess more detailed and meaningful endpoints. Studies now include patients with chronic migraine, those who have failed previous preventives, and individuals with complex symptoms such as aura, neck pain, or medication overuse. By focusing narrowly on headache days, the ACP guideline overlooks these critical aspects of patient experience.
He also expressed concern about how the ACP described adverse events as “generally mild,” particularly for medications like valproic acid. Drawing from his own clinical practice, Dr. Charles countered that this characterization is inaccurate and potentially dangerous, especially for women of childbearing age. The risks of valproic acid are well-documented and make it unsuitable as a first-line treatment in most cases.
Dr. Charles further warned that the ACP’s approach could unintentionally reinforce step therapy, where patients must fail older treatments before accessing newer ones. This, he said, not only delays relief but can also discourage patients from continuing care altogether if early therapies are ineffective or poorly tolerated.
He underscored that migraine management cannot follow a one-size-fits-all model. Every patient’s presentation and response to therapy vary widely, making individualized treatment essential. A rigid cost-based sequence, he explained, risks ignoring this diversity and reducing care quality.
Real-World Impact in Migraine Care
Finally, Dr. Charles reflected on the broader implications of prioritizing drug price over patient outcomes. He cautioned that framing access in terms of cost creates a sense of stigma for patients, suggesting they must “earn” more effective treatments. “If you basically tell a patient you have to try these less expensive ones until you deserve a more expensive one, that really is kind of part of the stigma of the disorder,” he said. He added that the cost of medication is only part of the overall burden, noting that, “If you figure in the cost of lost work and lost family time and side effects and patient visits and ER visits, that’s a cost that also isn’t considered in these guidelines.”
The statement calls on clinicians to prioritize individualized, evidence-based treatment decisions and to recognize the full spectrum of patient outcomes, beyond medication costs alone. It underscores the importance of integrating both robust clinical data and real-world experience to guide migraine prevention strategies. By highlighting these considerations, the response also reinforces the need for guideline developers to involve clinicians with hands-on experience in headache medicine, ensuring recommendations reflect the realities of patient care and support optimal treatment outcomes for diverse patient populations.
Read the Interview Transcript:
Dr. Halker Singh:
I am Rashmi Halker Singh. I'm the Deputy Editor of Headache. I'm joined today by Dr. Andrew Charles, professor of Neurology at UCLA, director of the Goldberg Migraine Program, past president of AHS and one of the most respected clinician scientists in our field. Dr. Charles recently first authored a statement and headache responding to the New American College of Physicians guidelines in migraine management. These guidelines have prompted intense discussion about evidence, interpretation, cost, and how we take care of patients who live with migraine. We'll talk about his perspective and what clinicians should take away. Welcome, Dr. Charles. I'm so excited to talk to you about this topic.
Dr. Charles:
Thanks, Rashmi. Thanks for having me.
Dr. Halker Singh:
So Dr. Charles, for those in the audience who have not yet read the ACP guidelines or our response from the American Headache Society, what's the central issue with ACP guidelines that led you and your colleagues to speak out?
Dr. Charles:
Well, there are a number of them, many actually. But I guess the central one is the premise that there is the evidence for different therapies is more or less equivalent, and therefore one should prescribe preventive treatments primarily based on cost of medication. And so that's really the primary issue that we have, and it's an issue on multiple levels in terms of how we manage patients.
Dr. Halker Singh:
So basically, it's a change in the standard of care because within AHS, we really think about the needs of the patient and really what they need, not so much the cost of medication, and choosing the appropriate medication.
Dr. Charles:
Yes, that's right. And I mean, if I can actually read something from their guidelines, which sort of captures their position, it's basically their statement is ultimately because of the lack of relative net benefit among Amitriptyline, beta blockers, CGRP antagonists, valproic acid, and venlafaxine, they primarily use economic evidence and evidence on patients' values and preferences to prioritize migraine treatment. And so what we're saying is that that's wrong on many levels. And so we've really felt that we had to respond because in many ways it is a step backward from the progress that we've made.
Dr. Halker Singh:
Can you speak a little bit more about that and what sort of evidence we should be taking into consideration when we discuss these options for patients and choosing amongst them?
Dr. Charles:
Yeah. Well, the fundamental problem with the traditional migraine preventive therapies is that the evidence is extremely weak. It is just simply not there in terms of the clinical trial evidence. And what they did was they did a meta-analysis of the clinical trial data and then came to the conclusion that basically there wasn't much difference between any of them in terms of either efficacy or tolerability.
And so part of the problem with this is that if you're going to do a meta analysis, there's something called the transitivity assumption, which basically is that if you're going to compare treatment A and treatment B and there's no head-to-head trials comparing the two, then the evidence that you evaluate has to be similar. In other words, the clinical trials have to be designed more or less in the same way, more or less the same amount of patients, similar sorts of methodology.
And most of the studies that were done for the traditional migraine preventive therapies were done decades ago. And we had different diagnoses of migraine diagnostic criteria, different outcome measures, and then different placebo rates because the placebo rates have changed over time. And so there are many reasons why the transitivity assumption doesn't hold up here because the data is simply not equivalent. There's that, but then there's also the fact that the actual numbers of patients involved in the clinical trials, the traditional migraine preventive therapies is tiny. So take venlafaxine for example, there's basically one trial that they evaluated compared to now tens of trials of the CGRP targeting therapies. And in that one trial, basically they ended up analyzing essentially about 50 patients. And so their whole recommendation is based on 50 patients compared to tens of thousands of patients that have been studied with the CGRP targeting therapy.
So the data is simply not equivalent, and therefore in that circumstance, when you're dealing with inadequate data, then you have to bring clinical experience to bear. And frankly, that's the other problem with this study is that they basically didn't really make any attempt to survey experts in the field. And I'm sorry to say, but none of the authors of this paper are actually in any way experienced with headache medicine. And so then that basically you have people evaluating evidence, but not in a position to bring clinical experience to bear and understand whether or not that evidence really reflects the clinical situation.
Dr. Halker Singh:
I think those are some really important points that you raised. I wanted to highlight a couple of things. The ACP guidelines concluded that there were really no clinically important advantages with these newer preventive medications, specifically the CGRP monoclonal antibodies. What outcomes do you think or should people know were overlooked with that statement?
Dr. Charles:
Yeah, well, quite a few. First of all, just on its face, that statement is silly because those of us who are seeing patients and treating people with these therapies understand that they represent a kind of quantum change in our ability to deal with patients. And that's not to say that they work for everybody, but in comparison to our previous treatments, these therapies are simply more effective and better tolerated. So the outcomes that they looked at were essentially headache days or migraine days, but what they didn't look at are much more granular kinds of endpoints like for example, treatment in patients who have failed previous preventive therapies or people with both chronic migraine and episodic migraine essentially only looked at episodic migraine and ignored all of the CGRP targeting therapy studies on chronic migraine, which as we all know are tougher patients. And those patients actually responded as well.
And there's no similar data for the traditional preventive therapies. Then there's patients with medication overuse, there's significant benefit for those patients. And then there's basically patients with a variety of other non headache symptoms. So just the whole package of the migraine clinical picture, which has been now looked at in a variety of studies, things like depression, other symptoms, aura, neck pain for example. All of these things are symptoms that are being investigated for CGRP therapies that haven't been looked at before. And so it really is a simplistic approach to just say with a tiny number of patients in a trial, if they did have a statistically significant benefit in terms of reduction in headache days, then that basically means that the therapy is effective. The one other one that I didn't mention is responder rates. So this has really become a metric, an outcome measure that we're understanding is very important. And especially for example, the 75% responder rates, if you get patients with a really solid 75% responder rate, that's a reflection that this therapy is working differently and there's no such data for the previous therapies where there's now extensive data on these responder rates for the CGRP treatments.
Dr. Halker Singh:
Yeah, absolutely. I mean, as you all know, because you first authored the statement in 2024, the consensus statement, which came from the American Headache Society as well, which outlined that CGRP targeted treatment should be a first line option for people who live with migraine, that this has really revolutionized the way we take care of people who live with migraine. And along those lines have helped pave the way for that to be an option where we don't have to go through step therapy for people. And I think in my practice, one thing that's allowed us to do is really bypass that lost time because with step therapy, that's what my patients talk about is a time that they lose that they can't get back because when they have to try something that does not help them and then they have to try something else, there's just so much time loss until they can finally get to the medication that finally makes the biggest difference. Is there a concern that having to follow these ACP guidelines might put patients a step back having to go through step therapy again?
Dr. Charles:
Yeah, absolutely. It's a major concern. And it's not just lost time. It's also the fact that some patients will simply give up. If they're put on a treatment that doesn't work and is poorly tolerated, then they'll basically say, well, I'm not going to do this because they're giving me stuff that not only doesn't work, basically is making me feel bad. And that's really another huge issue with the ACP guidelines. And I'll just read something from another statement from the paper. It says, adverse event profiles differed across drug classes, but most medications were associated with generally mild adverse effects such as paraesthesia pain, reduced physical activity, rash or dizziness.
So I mean, valproic acid has mild adverse effects, come on. That's just a statement from people who've never prescribed. I have not used valproic first line for decades, honestly, because of its adverse effects. And it's not just so there's tolerability issues like weight gain, hair loss, tremor, but then there's the safety issues where the world organization basically says we shouldn't be giving valproic at all to any women of childbearing age because of potential adverse effects on the fetus. And so here we have, they're suggesting that these are equivalent therapies equivalent in terms of efficacy and tolerability and safety. And so just pick the cheapest. We should use valproic if it's the cheapest, what happened to first do no harm? I mean, it really is something where this is violating a lot of our principles of treating patients appropriately based on not just efficacy, but safety and tolerability as well.
Dr. Halker Singh:
Absolutely. valproic acid was listed as a first line medication choice in their guidelines, and so many of our patients are women of childbearing potential. So I just want to highlight that one more time. It's a little shocking and problematic in so many ways.
Dr. Charles:
In their defense, our guidelines have it as a first line treatment too. However, we have qualifications all over the place and warnings about the safety issues of it. And so I think we have to, as a society address whether it should be listed as first line. Personally, I don't think it should be. But again, if you're going to put it in there as first line, at least put in there all of the qualifications about the safety and tolerability issues.
Dr. Halker Singh:
Are there other myths or any myths I guess, that you think that the ACP guidelines might be inadvertently reinforcing about migraine?
Dr. Charles:
Yeah. Well, venlafaxine is another one. I mean, venlafaxine may be of benefit. The evidence for it is really not that great. This really comes back to another issue that really isn't addressed at all in the guidelines, which is that some of these traditional migraine preventive medications we use primarily in people who have other comorbidities. And so if you have somebody with comorbid depression, sure, of course, maybe try an SNRI like venlafaxine to be efficient and help with depression and help with migraine. But that again comes back to this whole notion that we as headache specialists are basically evaluating individual situations and comorbidities. And so we'll start with candesartan, for example. If somebody has hypertension or a beta blocker or if somebody's having trouble with sleep, insomnia will use a tricyclic. So evaluating the individual patient based on their situation and then not just picking the cheapest one, but the one that fits best in terms of their situation is how we approach things.
And just having said that, that's another thing that they mentioned. This isn't just all about the CGRP therapies. They don't actually have candesartan as a first line therapy in their recommendations. And the evidence for candesartan is substantially greater than that for a number of the ones that they are recommending. And as you know, worldwide candesartan is now being used very extensively in large part because of its tolerability. And so this, again, is an argument against the point that the tolerability of these is all the same. I mean, we typically will go to candesartan in many patients because we're not as worried about its adverse effects.
Dr. Halker Singh:
If there is a message that clinicians, primary care clinicians should really take away from all of this, what would that be? And then the same thing for researchers as well.
Dr. Charles:
Well, I think the first message is you always have to pay attention when somebody says they've done a meta-analysis, even if they've done the meta-analysis correctly, you still have to look at the quality of the data that they're evaluating. So that's number one. And I would say that goes across for any kind of treatment. I mean, you see all these meta-analysis these days and you have to really closely look at whether the data that they're working with satisfies assumptions about being able to make comparisons. That would be number one. Number two is really the point that because we actually have new migraine specific therapies, we have a variety of different options to individualize therapy for patients. And I will also say that this is kind of a problem with guidelines in general is that they basically kind of assume that a disorder like migraine is this homogeneous kind of one-size-fits-all problem.
And it clearly isn’t, there’s so much variability from patient to patient that it really behooves us to choose therapies wisely based on the individual picture. So that would be number two. And the number three I want would, I guess, be that we've made some extraordinary advances in the field of migraine in terms of understanding pathophysiology, some of the chemical basis for it, the physiological basis for it. And these new therapies are migraine specific based on that understanding. And so that's another really important point is that we have to actually acknowledge how well we've done in some ways in terms of advancing the field and then also pass those advances along to the patients. So I think a final point would be that my own view is that if you basically tell a patient you have to try these more expensive or less expensive ones until you deserve a more expensive one, that really is kind of part of the stigma of the disorder.
It's almost being dismissive of the fact that patients are disabled and just say, well, it's not important enough that you should get things that work better and are better tolerated.
So for me, I think that's also an important message is that, and obviously we have to consider cost, sort of as a society and in our field too, how are we most efficiently treating patients? But this is another point that we make commonly is that the cost of medication is only part of the cost of the disease and what you're treating. And so if you figure in the cost of lost work and lost family time and side effects and patient visits and ER visits, that's a cost that also isn't considered in these guidelines. And so considering costs other than the costs of the medication, I think is another important point.
Dr. Halker Singh:
Dr. Charles, those are all really important points. Thank you so much for speaking with me today.
Dr. Charles:
My pleasure.
Dr. Halker Singh:
I really appreciate your insights and most of all your leadership. This is really important, not only for us within the American Headache Society, but really for all of us who take care of people who live with migraine. And for those of you who are watching, the full statement is available at Headache. I encourage you to read it. It's a really thoughtful call to keep our focus on what's really important in improving the lives of those who live with migraine.
Dr. Charles:
Yeah, thanks. And also, just before we finish, acknowledge the co-authors, Jessica and Stew, who basically made significant contributions to the paper and that we're making the statement on behalf of the American Headache Society Board and really our membership. So I'm talking to you on behalf of all of those people and trying to appropriately represent the views of our entire group.
Dr. Halker Singh:
Absolutely. This is a joint and collective statement, and thank you so much for speaking out.
Dr. Charles:
My pleasure.