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Combining Acute and Preventive Therapy


Migraine experts consider how to safely and effectively combine acute and preventive therapy to meet individualistic and complex management needs.


Neil Minkoff, MD: We talked at the beginning about acute therapies. Then we talked about traditional preventive therapies and the newer preventive therapies. But that means we have a world where there are patients who are on the newer preventive agents but also need help with their acute migraines. You’re hoping to get them to a 50% reduction, right? That means we still have to treat half the migraines they were having before in the acute phase.

Dr Nahas, if you don’t mind, I’m calling on you first. How do you try to look at the appropriate combination to treat acute breakthroughs in a patient on a preventive drug? How do you pick those? How do you work that into your clinical practice?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: We’re going for the Reese’s peanut butter cup here, right?

Neil Minkoff, MD: It’s 2 great tastes that taste great together.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: It’s the perfect combination of chocolate and peanut butter; acute and preventive. It just works best together. We don’t have a lot of evidence, or even much inquiry into, the best combinations. What are the flavors that work best together with acute and preventive therapy? It’s more trial-and-error while trying to avoid any untoward effects from polypharmacy.

In my practice, I have patients who are on a number of different preventive medications. I have some patients who are on 2, 3, or even 4 preventive agents. Many patients will want to have multiple options for their acute therapy as well, with differing mechanisms of action and different degrees of intensity for fighting back against the attack.

Primarily, what I’m concerned about is making sure that I’m not doing harm to a patient by overmedicating them with medications that are duplicitous or that may have drug-drug interactions. That’s really what it comes down to. I would love to see the day when we start to discover some of these magical combinations that are actually synergistic, whether that involves combining 2 preventive agents or a preventive with an acute agent.

We may be getting close with this CGRP pathway, at which we now have both acute and preventive drugs that are targeted. Can we use these drugs together? It may seem counterintuitive. Why would you want to do the same thing twice? One works on a long-term basis, and the other on an on-demand basis.

We do this in medicine already. It’s 1 of the basic management principles of asthma, for example. You have your long-acting beta-agonist inhaler that you use on a daily basis to control the disease, and your rescue short-acting beta-agonist inhaler that you use in the midst of an attack. Perhaps for migraine, that would include these longer-acting anti-CGRP therapies, whether they are injected or taken orally repeatedly—although we don’t have any option that’s FDA approved—plus an oral drug that works quickly to further antagonize or break through the CGRP system. This is a first for headache medicine. It’s something we’ll have to try to get comfortable with. Hopefully, it is something that will work and will get some signals of synergy too.

Neil Minkoff, MD: Let me ask a follow-up question. You mentioned mechanism of action. Then you talked about potentially having the long-acting vs short-acting therapies. You use that as 1 of the examples. Could one also be thinking about this from the point of view in which the steroid is used on the long-term basis in combination with the short-term beta-agonist to treat the acute symptoms and flares? That would mean mixing mechanisms of action. I don’t think I know the answer to that question. I’m asking you, as the expert, if you think there’s something to that. Then maybe Dr Dodick can weigh in as well.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Yes, that’s our magical combination of synergy. We’re looking at multimodal therapy and coming at it from different mechanisms of action.

Neil Minkoff, MD: Yes.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: With acute therapy we do that already. We might have 2 or 3 different agents that a patient takes for a really bad attack that work in different mechanisms of action to shut down all the pieces and parts. Every element of the circuit that’s generating that migraine attack is targeted. That may be what’s necessary to put the fire out completely.

Neil Minkoff, MD: Yes. Dr Dodick?

David W. Dodick, MD: Yes. Neil, I’ll make a couple of comments. First, to your point, it’s rare that we will start a patient on any prophylactic therapy and render them completely migraine-free, right?

Neil Minkoff, MD: Right.

David W. Dodick, MD: They’re going to require acute or on-demand treatment. That’s the first thing. I agree with that.

The second thing is regarding all these onabotulinum toxin A trials, and then the monoclonal antibody [MAB] trials. They’ve demonstrated that there’s a significant reduction in the consumption of not only acute medicines but the consumption of triptans, or migraine-specific drugs. That may be because when you’re on 1 of these preventive treatments, and it’s working by reducing the frequency, those breakthrough attacks that occur are less intense. They’re shorter in duration. They may be more responsive to “lower-end medication.” For example, the patient may respond to an over-the-counter medication, but in the past they didn’t because they’re responding to the preventive medication. That’s the second point I’ll make.

The third point I’ll make is that we don’t know whether there’s synergism yet. I can tell you that even though we couldn’t have predicted this, we’re starting to see that patients who are responding to a monoclonal antibody may indeed respond better to a gepant. They’re blocking the same pathway. As Dr Nahas said, that would seem counterintuitive. Why would a breakthrough attack, when you’re already blocking the pathway, respond to something taken orally to block the same pathway?

The answer to that may be that the pathway isn’t saturated if you have a breakthrough attack and you’re responding to blocking that pathway. Let’s say you had a 70% reduction, so clearly you respond. But the receptors, or the peptides, are not saturated. Perhaps by adding a receptor blocker to a patient who’s responding to an MAB, there may be a synergistic action there.

Time will tell. We need a lot more data to show whether that’s a) actually the case and b) safe. As we start to gain more real-world evidence, look systematically, and collect standardized information in these real-world studies, we’re going to be able to parse out which acute therapies are working best with which preventive therapies.

Neil Minkoff, MD: This is a very open-ended question. With the information we have right now, do you 2 treat acute headaches in a patient on prophylactic medication differently from how you would acute headaches in a patient not on prophylactic medication?

David W. Dodick, MD: The short answer is no.

Neil Minkoff, MD: I’m good with short answers. I’m just trying to make sure that there isn’t anything I’ve left behind on the table.

David W. Dodick, MD: No, I will let the patient decide, as long as they’re responding to whatever acute treatment they’re using. Whether they’re on or off preventive medication, that’s all I’m shooting for. It’s worth saying that many patients don’t just use 1 acute treatment, right? They have a whole portfolio of treatments that they may use.

They often use this step-care strategy with an attack. They’ll start with an over-the-counter NSAID [nonsteroidal anti-inflammatory drug], let’s say 800 mg of ibuprofen. Sometimes they’ll respond, and sometimes they won’t. They’ll graduate to, let’s say, a triptan or a gepant.

If they’re on preventive treatment and they’re responding, then maybe all they need is the ibuprofen or acetaminophen—pick your over-the-counter du jour—and they don’t need to graduate as often to that higher-end treatment. That’s why we’re seeing a reduction in the consumption. But the short answer to your question is, “No, I manage their acute attacks the same way.”

Neil Minkoff, MD: Dr Nahas, do you agree?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: I would agree. The only nuance to that, and I touched on it earlier, is that someone on prevention may be having a higher frequency of attacks. You always have to be careful that the acute drugs aren’t being relied upon too heavily.

Neil Minkoff, MD: OK. Dr Stephens, this area of prophylactic migraine therapy has grown. With it, the number of patients who are on combination therapies has grown. As this continues to grow, how do you see the payers evolving with the way that they try to manage it and push toward appropriate care?

Kevin Stephens Sr., MD: That’s a very good question. Technology is constantly pushing. We’re learning new things every day. We have to be cognizant of advances in medical science. But you also have to look at the studies and see the validity of these therapies to make sure that scientifically, it’s not just isolated and incidental. We have to ensure that the weight of scientific evidence supports the therapies.

As this body of literature comes out, and as these new modalities are being proven and accepted by the scientists, that’s what we embrace. Our goal is outcome. We look around at utilization outcome. That’s our primary indicator, as opposed to days of work missed. We don’t see that as much with a volumes view. But we look at other things, like policy calls, ED [emergency department] visits, and those things we talked about earlier.

We also look at patient satisfaction. That’s a very important component in health care. How are you feeling? How are you doing? If you have healthy, happy patients, then that’s ultimately the goal for all of us. Not just reduced costs, but better health outcomes and better health care.

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