Current Series: Chronic Migraine: New Paradigms in Management

Stephen Silberstein, MD: Thank you all. I think what we would like to talk about now is concept of prevention: where we are and where we’re going. So, when we have a number of things we’ve been using for prevention for a long time—for example, the guidelines talk about topiramate, divalproex, beta-blockers, and tricyclic antidepressants—I’d like to talk about them as a group. What do you think their strengths are and what their weaknesses are, and what do you think we could do to design new drugs that would improve on that?

Stewart Tepper, MD: The advantages of our current oral preventions are cost, they’re generic, and access is easy, and occasionally, there is an overlap between comorbidity and migraine. So, one can use topiramate in a patient who is overweight. One can use divalproex in a patient with bipolar disorder; one can use a tricyclic in somebody with a sleep disorder and neck pain. One can use a beta-blocker in somebody with hypertension. However, the disadvantages of these medications are very readily apparent. They were developed for other therapeutic areas. They were discovered fortuitously to have modest effects in migraine prevention. They require titration—generally, up to a month—to get to the correct dose. They require 2 to 3 months, generally, to see modest efficacy where responder rates are less than 50% of patients having at least a 50% reduction in their migraine days. And patients don’t like them because of the baggage of adverse effects and generally rather modest clinical efficacy. And, in a study that I think David was on that was published in 2015 by [Zsolt] Hepp[, PharmD], more than 80% of patients who are given these medications are off them by the end of the year. It is very frequently an exercise in futility prescribing these medications for prevention.

Stephen Silberstein, MD: So what you’re really saying is when they work, they work—if you don’t get side effects—but many people discontinue them because they don’t work or they have side effects.

Stewart Tepper, MD: Those are the 2 clear reasons why people stop—lack of efficacy and adverse events.

Stephen Silberstein, MD: What about Botox? David, you know a little bit about Botox—or a lot, I should say.

David Dodick, MD: Botox, or onabotulinum toxin A, was, of course, approved in 2010 for the prevention of chronic migraine. It’s not approved by episodic migraine because the studies were not positive in that. So that’s 1 thing I will say. A second thing is, it’s an attractive treatment option to patients because patients by and large don’t like taking oral medications. They don’t like to feel sick, and they don’t like to take drugs. And so here’s an opportunity to have something administered every 3 months that by and large is very well tolerated; really, very little systemic absorption, so not a lot of systemic adverse effects that we currently experience with the available drugs that we have, like weight gain and hair loss and cognitive impairment etc.

So, from that standpoint based on…and it has a long safety track record used for other disorders. I mean, when you think about it, Botox has been used since the late 1960s. It was first used in kids with strabismus, and since then, there have been a number of different applications and FDA approvals, from dystonia to blepharospasm and so forth, so it has a lot of different applications. So what that means is that the safety profile of the drug, or the biologic, has been around for a very long time. So patients are more comfortable with that, and physicians are more comfortable using it, knowing that safety track record as opposed to something that was just approved and we don’t have that clinical experience yet. And it works.

Obviously, it works in those patients with chronic migraine. It doesn’t in everybody, of course. But in the clinical trials, about half of the patients had a greater than 50% reduction in the number of migraines they had with headache. And I would say that my clinical practice mirrors what we’re seeing in clinical trials, that there’s a substantial proportion of patients who get benefit from this. And look, if you told me…”I’ve got a therapy that’s going to be well tolerated that’s going to help just a third of your more treatment resistant patients, your chronic migraineurs who are really disabled,” I would say, “Hallelujah—bring it on.” And so if it just works in that proportion of people, then I’m happy. And so I have a number of patients who I’ve treated over the years who are very happy with that therapy.

Stephen Silberstein, MD: Can I raise an issue? Onabotulinum toxin is given every 3 months and lasts for approximately 3 months, whereas all of the oral medications have to be taken on a regular basis. Since many patients are noncompliant, could it be that 1 of the reasons that patients drop off because lack of efficacy is they’re not taking their medication on a regular basis? So that’s 1 question I think we need to think about, and we don’t know the answer to. And I agree with you 100% that adverse effects are an issue. But I’m just wondering if how much of the lack of efficacy is due to lack of compliance that’s made up by having an injectable…?

David Dodick, MD: Well, I think that’s a good question, Steve. I don’t think we know the answer. One of my mentors showed that in Canada, 50% of patients who walked out with a prescription never filled it or never took it. So noncompliance may be an issue, but the patients that you and I see are pretty severely disabled.

Stephen Silberstein, MD: My best story…because I was pushing amitriptyline a long time ago in 1 of my patients, and I thought it wasn’t getting anywhere, it wasn’t having side effects, but she swore on a bible she was taking it. I get the blood level back—it’s 0. And I say to her, “What’s going on?” “I didn’t want to disappoint you.” So basically, the patients will not do what we tell them to do…but they’ll tell us that not because they’re lying but because they don’t want to think we’re not listening to them.

David Dodick, MD: I think that may be true in a small number, but I think for the majority of the patients we see, they’re desperate, and they’re desperate for help. And they take these medicines, I know, because they call me back very freely to tell me what all the adverse effects they’re having are. So I really think adverse effects are an issue, and it’s the reason why most patients…you know, if I could get 1 of these drugs to its…you know, if I could get to everyone on topiramate 200 mg—right?—and they tolerated it well, it’s going to work in a lot of people.

Stephen Silberstein, MD:I disagree.

David Dodick, MD: But we simply can’t get them there.

Stephen Silberstein, MD:I think that there are a lot of times that; I like the 50% you just told me—half the patients don’t even fill the prescription. And it may be where we are in the food chain that accounts for the data.

Stewart Tepper, MD: I want to bring up 1 more thing about the onabotulinum toxin issue: It works very well in chronic migraine. We use it in chronic migraine. But even with onabotulinum toxin A—even in the patients in whom it’s working—there are significant problems that have interfered with its effectiveness, the most important of which is that our payers are only allowing the injections every 12 weeks. And very frequently, probably in the majority of the patients, the onabotulinum toxin is wearing off at 10 or 12 at 8 or 10 weeks. And there’s a period of disability when the [onabotulinum] wears off, and then a period that requires that the onabotulinum kick in, and the patients can have anywhere from 2 to 4 weeks out of the 3 months in which they are not getting adequate prophylaxis from the onabotulinum toxin A, even though in the first few months it’s working. And this is actually turning out to be a very significant problem that, when we bring it up with patients, we learn about.

Peter Goadsby, MBBS: I think 1 of the problems with preventives that we’re saying—and maybe partly I think goes to compliance, and putting adverse effects down for a second—it must feel really weird on the other side of the table when everything we offer is not for migraine; everything’s not for migraine. I’ve done it. I know it sounds crazy.  

Jessica Ailani, MD: No, you’re right.

Stephen Silberstein, MD: It’s the last drug we’ve had for migraines.

Peter Goadsby, MBBS: That was actually developed initially as a drug for allergy, as I recall it. But it must be quite crazy to sit on the other side of the table and hear me say, “You’ve got migraine,” and then go through this patter that we all have about, “I’m going to give you this drug. It was designed for blood pressure, but it works.” And we’re the only branch of neurology that has that incredible disconnection between what we diagnose and then what we go and treat. And if I was listening on the other side of the table I’d think, “Really?” 

Stephen Silberstein, MD: It’s just the same as triple neuropathy.

Jessica Ailani, MD: Yes. But to the point of that, on the other side of the table, when you tell a patient, “I believe that you have a brain disorder, but I’m going to give you an antidepressant,” they don’t go home and take the idea that you listened and understood.…Even if you tried to explain to them that this antidepressant has been studied and I’m going to give it to you for migraine, there’s a lot of back and forth, and that causes a problem.

Peter Goadsby, MBBS: I think if you have a migraine, if we had a migraine treatment, even if you had to take it every day and it was well tolerated and it was for migraine, I actually think things would be a lot better. We’ve gotten used to a really low standard of what we could offer. And we started out big—I’m not criticizing anyone around the table at all. And maybe if I was them, I would look at this pretty weird, as well. It’s going to be, that’s why we’re in such a transformational period: because the whole conversation is turning.