Current Series: New Paradigms: Preventive Treatment for Chronic Migraine

Stephen Silberstein, MD: What is your personal approach to preventive treatment? How do you prioritize things and what do you do?

Deborah Friedman, MD, MPH: When thinking about the oral preventive medications, it’s interesting that a lot of people will say, “what’s your favorite oral preventive?” And there is no favorite oral preventive. It’s a real process of interviewing the patient and determining whether they have any comorbid conditions or coexisting conditions that might benefit from 1 particular oral preventive over another, or medical problems that you want to avoid using 1 particular treatment or another.

I think that in a lot of ways there’s a real art to it. As you know, we always start with a low dose and gradually increase the dose. Stephanie already mentioned that you have to be patient, and a lot of people don’t really want to be patient, because we want to try to get the lowest dose that works. But there’s no 1 size that fits all with the oral preventives. You just have to make the best choice you can. I’m very upfront with the patient that I may or may not get it right the first time, we may have to explore some other options, and sometimes we have to combine treatments.

Stephen Silberstein, MD: That’s going to lead to 2 more questions. Stew, how long do you try a medicine before you think it’s not going to be working?

Stewart J. Tepper, MD: As Deb said, it’s generally a period of ramping up the dose. We know the optimal dose or the range for the optimal dose for most of the oral preventive medicines. Once they’re at the optimal dose, I like to have a patient go at least 2 or 3 months before evaluating efficacy. So often this is a 4-month trial. And again, returning to the fact that we’re talking about chronic migraine, of the oral preventives the only preventive that really has good, modern, and randomized control data for efficacy is topiramate, and not 1 of the oral preventive medicines is FDA approved for chronic migraine. This adds to the frustration as Stephanie said—you’re actually trying medicines that either have no evidence for effectiveness in chronic migraine, or modest effectiveness, and a very long prospect of trial potentially laden with adverse events.

Stephen Silberstein, MD: Deb.

Deborah Friedman, MD, MPH: I think people should understand that though topiramate is the only oral preventive approved for chronic migraine, mostly the approved oral preventives are approved for “migraine.” So, it’s not that you can’t use something that’s approved for migraine in a patient who has chronic migraine; I think some people make that mistake.

Stephen Silberstein, MD: Yes.

Deborah Friedman, MD, MPH: We’ll be talking about the newer drugs later and they’re all approved for migraine, it doesn’t just have to be chronic migraine.

Stephen Silberstein, MD: I think that’s an extremely important point. For most of eternity, there was no difference between episodic and chronic migraine. For the development of an injectable treatment,  turns out in the past, it only worked for patients with more frequent headache. Hence, it was given a label for—onabotulinumtoxin type A—for the treatment of headache in patients with chronic migraine. That’s when the division began. I think you need to realize that, theoretically, the older drugs never had to be tested for chronic migraine. I can tell you, some of the old-fashioned people in the headache world believed you couldn’t have a migraine headache every day, and they called it tension headache. For all intents and purposes, in ancient, prehistoric, headache times, there was no chronic migraine, it was really chronic-tension headache and migraine combination.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Or chronic daily headaches.

Stephen Silberstein, MD: Or chronic daily headaches. How about mixing things? Do you mix drugs?

Andrew Blumenfeld, MD: Yes. I think that we should now think about migraine in terms of striving to achieve a migraine-free state, which is a lofty goal. It could be looked at in different ways by different providers. I think if we set this goal of migraine freedom, and it’s at the top of our mindset, it encourages you to use combinations to try and continually improve the patient’s state. We should no longer be satisfied with monotherapy and maybe a 50% improvement. We should be thinking about synergistic combinations that we can layer on top of each other, as long as they’re well tolerated, patients can adhere to them, and build that cocktail up to achieve a greater state of migraine freedom.

Stephen Silberstein, MD: I think there’s been a change. I think that the idea in the past, the monotherapy, is dead, and I think what we’re trying to do is find the right combination of medicines at lower doses with fewer adverse effects.

Andrew Blumenfeld, MD: It’s very much like treating epilepsy. If you’re treating a patient with epilepsy, and they continue to have seizures, you wouldn’t stop with 1 medication.

Stephen Silberstein, MD: Or hypertension. Most of them are on 2 or 3 drugs, right?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Exactly. We have very little evidence to guide us from the scientific literature on how to combine preventive therapies. In fact, the only NIH [National Institutes of Health]-sponsored large trial, double-blind and controlled for this purpose, failed to meet its endpoints and was stopped early for that reason.

Stephen Silberstein, MD: I’m embarrassed for that paper.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: But we do it all the time. And in some later studies of preventive therapies, some patients were allowed to stay on their preventive treatment and take the experimental treatment and they saw a benefit. So I think that we all believe in our hearts that combining therapies is necessary.
 
People ask me, “If a drug isn’t working optimally and you want to change the preventive plan, do you take them off of that drug before you put them on something else?” I would say, “No, unless there’s a contraindication to the combination.” Why would I pull the rug out from under the feet of my patient who is getting at least some benefit, just suboptimal benefit, from their current preventive?

Andrew Blumenfeld, MD: It does raise the question of, “What is an adequate response?”

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: It does.

Andrew Blumenfeld, MD: If someone has a 30% response on a particular medication, should you pull that medicine to switch to the next one?

Stephen Silberstein, MD: Never.

Andrew Blumenfeld, MD: I agree with you, you keep the 30% and then you look to add to it if they’re not having [adverse] effects.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Thirty percent is a miracle for some patients.

Stephen Silberstein, MD: Can you imagine having a headache every day of your life and now you have 10 days a month of headache freedom? That’s a miracle.

Deborah Friedman, MD, MPH: Sure, but in epilepsy that’s nothing, right? The epilepsy standard is seizure-freedom. And I agree with Andy, I think that’s what we should be aiming for.

Stephen Silberstein, MD: Oh, I’m not disagreeing. But the point is, from the point of view of the patient, a reduction of that burden is the beginning of the end, not the end of the beginning.

Deborah Friedman, MD, MPH: Sure.

Stewart J. Tepper, MD: In terms of the analogy to hypertension and other disease states, we do have an opportunity to layer on treatments that probably have different mechanisms of action. Migraine has some heterogenous mechanisms of action, and we can come at this very disabling disorder from different directions—by polypharmacy, by co-pharmacy.

Stephen Silberstein, MD: Co-pharmacy. I don’t like poly.

Stewart J. Tepper, MD: That’s why I corrected myself.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Words matter, don’t they?
Stephen Silberstein, MD: In terms of tolerability, Deb, could you tell us something about the extended-release topiramate. Who should use it, what are the doses?

Deborah Friedman, MD, MPH: Sure. There are some advantages to using extended-release topiramate, and there are 2 different brands on the market. One is Trokendi XR and 1 is Qudexy. Certainly 1 of the advantages is that it has a long half-life. So you only take it once a day, and it’s hard for a lot of people to take topiramate immediate-release more than once a day.

In theory, and to some extent in reality, once-a-day dosing allows for a much smoother pharmacokinetic profile during the day, less peak and trough occurring during the course of a day. It may be that many patients will tolerate the extended-release better than they do the immediate-release. There have been some studies with Trokendi XR looking at word-producing—which we know is a problem with topiramate—that many people have trouble with word finding and memory loss. It seems that the extended-release may also be beneficial for some patients in that regard, being less likely to cause that word-finding difficulty.

Stephen Silberstein, MD: How do you start it? Do you go to full dose? Do you start at lower dose? Do you ramp up?

Deborah Friedman, MD, MPH: Well you start it just like you start regular topiramate. We start with usually 25 mg a day for a week or two. It has a long half-life, so some people say, “Maybe you should go every 2 weeks instead of every week like we do with the immediate-release, and then gradually increase it by 25 mg a day just like you do with regular topiramate.” The dose is equivalent.

Stephen Silberstein, MD: The basic principle of headache prevention for the old classic oral medications is slow and steady wins the race. Start low, go slow. But there may be a change in the paradigm.