Optimizing the Treatment of Migraine: A Conversation with Richard Lipton

“We used to think the pharmacology of a drug determined whether it works acutely or preventively. Beta blockers, anti-epilepsy drugs, antidepressants, calcium channel blockers, triptans, NSAIDs, and gepants are all acute medications. But the observation that gepants have a preventive benefit, and the demonstration that some preventive treatments work well acutely if you can get them in quickly enough, changes how to think about treatment. We now think, for many drugs, that it’s more a matter of how quickly you can get the drug in, and how you instruct the patient to use it, rather than the specific molecular target of the drug that drives efficacy.” – Richard Lipton 

Richard Lipton, MD, is a professor and director of the Montefiore Headache Center at Albert Einstein College of Medicine, Bronx, New York, US. He has spent much of his career studying the epidemiology and treatment of headache disorders. A neurologist with additional training in clinical neurophysiology and neuroepidemiology, he has published hundreds of original studies on migraine, including some of the field’s most important clinical trials. It’s all the more impressive considering that headache is not the sole focus of his research: Fifty percent of his time is dedicated to cognitive aging and dementia.

In this Migraine Science Collaborative interview, Lipton speaks with freelance writer Kayt Sukel about the questions he’s most interested in as a headache researcher, key results from past migraine clinical trials, what the future may look like for additional trials, and more. The interview has been edited for clarity and length.

What inspired you to specialize in headache medicine?

I did a fellowship in clinical electrophysiology after residency. My first grant was to study electroencephalography [EEG] and evoked potentials in cognitive aging and dementia. But my wife and I had bought an apartment on the Upper East Side of Manhattan and were having trouble covering the mortgage payments. The only legal job I could get was moonlighting at our headache center. I started doing that and found that I really loved it.

Those days, when you worked in cognitive aging and dementia, there weren’t a lot of therapies available, especially for conditions like Alzheimer’s disease. The hope would be to diagnose [vitamin] D-12 deficiency, hypothyroidism, or depression – something we could actually treat. But in headache medicine, I could help so many patients. I remember when I told my wife I was going to take the job in the headache clinic, and she said, “Oh, don’t do it! You’re going to get distracted from what you’re really interested in doing!” I told her that I wouldn’t get distracted. But I definitely did.

Richard Lipton

As you look back over your career, what were the big questions that drove your headache-related research?

There have been a number of them. I’ve had a longstanding interest in the descriptive epidemiology of migraine. Who gets it? At what age does it begin? What are the factors that influence migraine epidemiology? We’ve done a number of US-based studies showing that migraine affects 18% of women and 6% of men in the United States alone. We’ve shown that the incidence of migraine peaks in the early 20s. We’ve shown that migraine is more common in people from low-income households, a little more common in Caucasians than in African Americans, and a little more common in African Americans than in Asians.

Then there was the question of whether migraine is a progressive disorder. We’ve done studies showing that about 2.5% of people with episodic migraine, which is defined as having fewer than 15 monthly headache days, will develop chronic migraine each year. And we’ve identified a number of risk factors for this kind of migraine progression. Of course, people with a higher number of monthly headache days are more likely to progress. People with allodynia, which is experiencing normally not-painful stimuli as painful, are more likely to progress. People with a number of comorbidities, like depression, anxiety, asthma, and other pain disorders are more likely to progress.

I should also add, although we are still in the early days of this work, we are actively trying to find a better definition for progression. Because if you go from 14 monthly headache days to 15 monthly headache days, that’s now considered progression. But going from 1 monthly headache day to 14 monthly headache days is not. We’re working to develop alternative definitions of progression that we hope are more sensitive and can help identify people whose disease is getting worse. We’ve even done a randomized trial looking at whether preventive treatment can prevent progression. That’s an area of active focus for me right now.

Are there other issues regarding treatment you are actively focusing on?

Yes. Another big-picture issue is how to optimize acute treatment for migraine. Since I’ve been in the field, we’ve moved from using non-specific analgesics like anti-inflammatory drugs, caffeine combination products, and opioids to more specific treatments. The triptans emerged in the early ’90s, and there are currently 7 marketed triptans in the US, with multiple routes of administration. But the biggest change in the last few years has been the emergence of calcitonin gene-related peptide (CGRP)-targeted therapies both as acute and preventive treatments. There are four monoclonal antibodies that work as preventives; they are all injectables. There are four gepants, three of which work as acute treatments, and two of which work as preventive treatments. And one of them, rimegepant, works both as an acute and a preventive treatment.

There’s been a major trend in changing the way we use acute treatment. In the triptan era, the FDA mandated that when you study acute treatments, people needed to wait until their pain was moderate or severe. In the Spectrum Study, we learned that triptans work better if you treat when the pain is mild, in a paper led by Roger Cady. This is demonstrably true for aspirin and for non-steroidal anti-inflammatory drugs, too. And it’s even been shown now for gepants. Anecdotally, many people say that, with all the gepants, the earlier you treat, the better the treatment works, and for ubrogepant, we’ve shown that’s true in a clinical trial.

Your work has also shown that treating during the prodromal phase is helpful.

That was the next step. We worked on a study called the PRODROME study, which was led by David Dodick. Thus far, there have been three papers published from it [the latest paper from the PRODROME study appeared on May 12, 2025; see MSC related news]. This work shows that if you treat patients who are symptomatic with warning symptoms that a headache is coming, you can not only shorten that prodromal phase but also reduce the risk of getting a headache. That’s been uniquely shown for ubrogepant. My best guess is that it may be true for other gepants as well, but they haven’t been studied yet.

But when you take these studies together, you see the trend for acute treatment changing from only treating moderate or severe pain, to treating mild pain, to now treating before pain begins in the prodromal phase. That last step has brought about the emergence of what we call situational prevention. When people can identify the circumstances that might bring about a headache, and we treat while they’re still asymptomatic, you can avoid the headache. Some examples of situational prevention include treating women with menstrual-associated migraine when they anticipate their period is coming, treating people who get headaches when they travel before they step on the airplane, or treating people who wake up on weekends with a headache because they slept through their cup of coffee or drank too much the night before.

There’s an abundance of anecdotal evidence to support the idea that situational prevention works. And now there’s some good evidence from double-blind trials for situational prevention of menstrual migraine. That’s a big deal.

How so?

We used to think the pharmacology of a drug determined whether it works acutely or preventively. Beta blockers, anti-epilepsy drugs, antidepressants, calcium channel blockers, triptans, NSAIDs, and gepants are all acute medications. But the observation that gepants have a preventive benefit, and the demonstration that some preventive treatments work well acutely if you can get them in quickly enough, changes how to think about treatment. We now think, for many drugs, that it’s more a matter of how quickly you can get the drug in, and how you instruct the patient to use it, rather than the specific molecular target of the drug that drives efficacy.

What are some of the biggest challenges in migraine clinical trials?

I think there are both a number of obstacles as well as a number of gaps. Let me start with the gaps because there’s a huge gap between treatments we have evidence for and treatments that we deliver to people. That’s true in many fields of medicine, and those gaps arise for a number of reasons. To get someone on the right treatment requires a multi-step cascade of events. First, the person with a headache disorder has to go to the doctor. The doctor then has to make a diagnosis. Working together, the doctor and patient have to figure out the appropriate treatment. And people with frequent migraine may need acute treatment, preventive treatment, lifestyle modifications, maybe some sort of device, or behavioral treatment. Once you try something, you need to figure out if you’ve optimized that treatment. Are patients getting the benefits they are looking for? You may need to modify treatment to get to that point.

But, even today, so many people with migraine don’t go to the doctor, even if they have significant disability. If they do go, we are doing much better in terms of accurate diagnoses. Seventy percent of people with migraine who have seen the doctor for headache over the past year will get a migraine diagnosis. But in terms of delivering minimally appropriate treatment, we’re still not doing well. The patient may not get the outcome they are looking for. So there’s a huge gap between treatments we know about and the treatments we deliver to the huge population of people living with migraine, and that’s before we talk about the economic gaps. Some of our best treatments are quite expensive, and not everyone in the US has insurance coverage. Outside the US, in some places, many of the best treatments are not available.

Now, given that, I’d say one of the biggest barriers in clinical trials is the FDA mandate that, when studying new acute treatments for migraine, you can only treat moderate or severe pain. We know treating earlier, before severe pain sets in, results in better outcomes. So there’s a gap in the way we study medications for regulatory approval and the way we want to deliver those medications to patients so we can get optimal results.

We know that if your acute treatment is not well optimized, that puts you at greater risk for migraine progression. And there’s evidence that preventive treatment is a way to prevent progression to chronic migraine. But, in addition, if you optimize acute treatment, you also make it less likely you’ll progress. So it would be a good thing to have more clinical trials that look at migraine progression. There’s been one, the INTREPID trial, with topiramate. But that’s only one study that has preventing progression as its primary endpoint. That study showed only a non-significant trend, because the sponsor discontinued it before it was fully enrolled. It broke my heart because I really wanted to finish that study.

What other kinds of clinical trials do you hope to see moving forward?

In terms of improving migraine outcomes, there’s a whole set of issues concerning implementation science: Delivering what we know to the people who need it. I do a fair amount of work in the implementation science space with the goal of making the best use of the treatments we have available. Another big gap in clinical trials is that we often give people multiple therapies. Someone might be prescribed one preventive, maybe more than one acute treatment, or a combination of acute and preventive treatment. But combination therapy is virtually an evidence-free zone at this point.

For example, in the most refractory patients in my practice, I might treat them with Botox and a monoclonal antibody, or Botox and another approved preventive CGRP therapy. But there isn’t really good evidence that the combination works better than one therapy alone. The only randomized, blinded study that has evaluated combination therapy is the study by Steve Silberstein and David Dodick where they combined topiramate and propranolol. It was a National Institutes of Health-sponsored study, and it did not demonstrate an incremental benefit of combination therapy. I’d like to see more studies that combine therapies. Those studies are pretty hard to do. But they are important.

I’d like to see more combination studies on the acute treatment side, too. In the past 30 years, there have only been two approved combination acute treatments. One is Treximet, which is a combination of sumatriptan and naproxen. And, just recently, a new therapy, Symbravo, which combines rizatriptan and meloxicam, was approved. To market a fixed-dose combination product, we need factorial studies showing that the combination is better than either of the single ingredients on their own. But it’s clear we need to learn a lot more about combination therapy – not just different medications, but medications paired with behavioral and lifestyle interventions or devices. And we need to learn not just what works in general, but how to select the optimal treatment for particular patients based on symptom profiles, prior treatment response, comorbidities, and genetics or biomarkers. Ultimately, precision medicine approaches to monotherapy and combination therapy will help us optimize treatment for patients.

Kayt Sukel is a freelance writer based outside of Houston, Texas.

Image credit: JuSun/iStock by Getty Images.