S2:Ep9 – A Guide to Neuromodulation for Migraine

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TRANSCRIPT

Voice-over: Welcome to Spotlight on Migraine, hosted by the Association of Migraine Disorders. Join us for fresh perspectives by medical experts and advocates as we explore the spectrum of migraine and dig deeper into this complex disease. This episode is brought to you in part by our generous sponsor, Lilly.

Stay tuned as Dr. Stewart Tepper explains key points you need to know about four neuromodulation devices for the treatment of migraine, including Cefaly, the sTMS device, gammaCore and Nerivio. Tepper outlines the differences between each option including cost, how they are used, who they are best for, and more, helping you and your doctor narrow in on the best fit for you.

For more than 25 years, Lilly has been committed to helping people affected by headache, investigating more than a dozen different compounds for the treatment of migraine and cluster headache.

Molly O’Brien: Hello and welcome to Spotlight on Migraine. I’m your host, Molly O’Brien. Today we’re talking about the latest news in neuromodulation for migraine treatment. I’d like to say hello and welcome to our guest, Dr. Stewart Tepper. He’s a professor of neurology.

Dr. Tepper, thank you so much for joining us today.

Dr. Stewart Tepper: Well, thank you for asking me to talk about something I think is very important for patients.

Molly: We’re so excited to have you. And you’re a headache specialist, so you have a lot of experience and a lot of knowledge in neuromodulation as well as other headache treatment options. But today we’re going to focus specifically on the newest and latest information on neuromodulation. It seems like we keep getting new updates on different devices and different ways that these devices can be used for patients. So it seems that it is possible for patients to find relief in noninvasive ways. Can you tell us how this is possible?

Dr. Tepper: These neuromodulation devices are what are referred to as noninvasive. They don’t have to be implanted. They’re portable, and patients use them in various ways with various programs. They don’t have significant side effects. The FDA calls them nonsignificant risk devices, and they change the way the brain processes pain by various mechanisms from various approaches. 

And one of the advantages of them — besides the fact they don’t have side effects — is that when medications have failed, it’s often because, for whatever reason, we picked the wrong target. A particular medicine targets a particular chemical within the brain, and the advantage of going into the brain and slowly changing the nerves in the brain is that you are affecting targets that we know about, but also targets that we don’t know about yet. And so many patients who have had a lack of success with medicines — the medicines have failed one after another — will find that neuromodulation can be helpful.

Molly: So let’s talk about a couple of these devices and the latest information that’s behind them.

Dr. Tepper: There are only four of them, so it’s relatively straightforward. The first one that was approved is called an external trigeminal stimulator, and it is made by a company called Cefaly, so everybody calls it the Cefaly device, and that is C-E-F-A-L-Y. And this is a device that is a stimulator that is put on the forehead. There’s a sticky electrode that goes underneath it, and the device has a mini-USB charger. And once it’s on the forehead with a magnet on the electrode, there are two programs for Cefaly. 

And Cefaly is FDA cleared both to prevent migraine and to treat migraine acutely. And the device that has both programs is called the Cefaly Dual device. The Cefaly Dual device, when one turns on that particular program, it goes on for 20 minutes. It’s worn at night for 20 minutes, and it stimulates the nerves on the forehead, the supraocular and supratrochlear nerves. And the stimulus goes into the brain and gradually turns down migraine over many months, over two or three months. 

And during the 20 minutes that it’s worn, the device gradually ramps up the intensity of the treatment, and then it turns off automatically at the end of the 20 minutes. So a dose is 20 minutes nightly. It also has an acute setting where when a person’s going into a severe attack, they can turn on the acute setting for Cefaly, and it turns on a different program and stays on for an hour and brings the headache down and then turns off automatically.

Cefaly costs, for the Dual device, about $550. It’s not paid for by any insurance except the VA, to my knowledge, a few government insurances, but that’s it. So people have to pay out of pocket. It’s ordered online. It requires a provider prescription. Patients got to Cefaly.us to do that. And if they hate the device, they can’t stand it, they can return it in 60 days for their money back. But it really takes three months at least for the preventive treatment to work. So that is Cefaly.

The second device is called sTMS, or sTMS mini, and that stands for a single-pulse transcranial magnetic stimulator. And the sTMS device is a big magnet — smaller than a shoebox, but nonetheless pretty big — and it has a charger. And patients put it on the back of the head and turn it on, and it pulses a magnet that fast. And the device, the STMS, is cleared by the FDA for prevention of migraine and for acute treatment of migraine, so it makes it like Cefaly in that regard. The preventive program is to pulse the magnet four times in the morning and four times at night, and then the person with migraine can supplement with additional pulses if they feel a migraine accelerating during the day. And the FDA has approved up to 17 pulses in a day. So there’s quite a lot of flexibility with this, and the device delivers the magnet very quickly. It’s very convenient. 

It is only available by rental. You can’t buy it. And so there needs to be form filled out by the provider and a prescription, and then that’s faxed in to the company, and then the patient calls the company to set up a payment regimen. And the way that it currently works is it costs $150 a month to rent for the first three months, and then if the person who’s using it likes it and wants to sign up for further — a prescription for further months, it goes up to $250 a month. If they don’t like it, they can send it back and get their money back for the three months. So they do have an opportunity to try it out for three months, and if it doesn’t work, they didn’t lose anything for that. 

And it can be a little less than $250 per month if they sign up for a really long time — for example, for a year of rental. And it’s very convenient, and as I say, it works both ways — preventively with the four pulses twice a day over about three months to see the migraine frequency drop and the intensity, and it has been studied in both episodic and chronic migraine for prevention. That’s the STMS device. Again, almost no insurance coverage whatsoever, so everything out of pocket for these devices.

The third device is a noninvasive vagal nerve stimulator, NVNS, which has the brand name of GammaCore. And it looks a little bit like an old-fashioned Norelco electric razor, with two little metal discs on the top. And it’s put on the neck above the vagus nerve with a little bit of goop, and it’s turned on for two minutes at a cycle, so it activates the vagus nerve for two minutes at a time. And when it’s on, the lip on that side twitches so that people know that it’s actually working and in the right place. 

And then the FDA has cleared this device for a number of uses. On the migraine side, it’s approved for the acute treatment of migraine, with two or three two-minute cycles in a row to terminate an attack. For cluster headache, the device is approved for the acute treatment of episodic cluster headaches. It didn’t work for chronic cluster; it worked for episodic cluster. And there were two studies, and they both showed the same thing: that it could stop attacks of episodic cluster headache but not of chronic cluster headache. Usually three cycles of two minutes administered when a patient first is going into a cluster headache. 

But it also turns out that it can be used on top of conventional cluster medicine to prevent cluster. And in study that was done in Europe, it showed that if a patient did two or three cycles of this vagus nerve stimulation twice a day on top of conventional cluster preventive medicine, that that reduced the cluster attacks further and reduced additional medicines that people would take for cluster like oxygen or triptans. 

So the FDA cleared it as what’s called an adjunctive treatment for prevention of cluster headache, meaning that it’s added to what is usually used. And it was cleared for both the prevention of episodic cluster, but also of chronic cluster, so it’s actually the only treatment that we have that has any FDA approval for prevention of chronic cluster headache on top of our usual treatments.

The noninvasive vagal nerve stimulator is not paid for by any insurance except the VA, and currently, the way that it’s made available is that it costs close to $600 a month to recharge the noninvasive vagal nerve stimulator, which has made it very difficult to get for anybody, for anybody to afford for acute treatment of migraine, preventive treatment of cluster, or acute treatment of episodic cluster. There may be a change in how it is marketed, but right now, the cost has been extremely prohibitive in terms of people being able to access it.

The last device that is FDA cleared is called a Nerivio device, or a remote electrical neuromodulation device. This device is a patch that is sticky and put on the arm with a little tourniquet that holds it in place. And an app is downloaded on a smartphone, and a person at the beginning of migraine turns on the patch, and the idea is to set the patch so it buzzes the arm in advance so that you know that it’s not going to be painful. If you just [take?] it up, you can turn on the intensity and then bring it down just below where it’s painful so it’s not painful, and turn it on. And it turns on for 45 minutes and works through a reflex in the brain to terminate migraine within two hours, especially if they turn it on within the first hour of the attack. It works better if they turn it on in the first hour of the attack. Again, no side effects.

The cost is $99 for one of these patches, and each patch contains enough juice to treat 12 separate migraine attacks. So it’s $99 to treat 12 attacks, and most patients say, “Well, I’m willing to try that, $99 to treat 12 migraines, and I’ll know whether it works or not if I use it in the first hour of an attack.” Nerivio, therefore, is probably the most accessible of the neuromodulation devices as well as being the newest one. 

And unlike the other three, Nerivio is only approved for the acute treatment of migraine. Remember, the vagus nerve stimulator, GammaCore, is approved for acute treatment of migraine, not prevention of migraine, but also acute and preventive treatment of cluster. And then the first two devices, the Cefaly and the sTMS, they’re cleared for both the prevention of migraine and the acute treatment of migraine.

Molly: So, Dr. Tepper, these devices range in price, they range in access for patients, and they range in what they can be used for. They also range in the amount of time that you can actually use them for. So, Nerivio, you use it for 45 minutes; it looks like the GammaCore, you use in a two-minute cycle; and then the Cefaly, you use for a certain amount of time. I’m wondering, when patients — if they actually obtain these devices, and then they’re using them, depending on which device — what can you be doing? 

So for the Cefaly, you put it on, you have it for, I believe — what did you say? You have it on for 20 minutes. Do patients need to be lying down when they’re using these devices? Can they be sitting up watching TV? Can they be walking around the house? Depending on where they’re at in their migraine attack or if they’re using it for preventive treatment, how do patients use these devices, and what is their demeanor like when they are using them?

Dr. Tepper: Let me tell you how I counsel patients on Cefaly to begin with. When people turn on the prevention modality — the program for Cefaly — initially, it can be very painful because it ramps up over the 20 minutes, and some people don’t tolerate the full dose immediately. So we actually tell people to ramp it up slowly. If they turn it on and let it ramp up for 5 minutes, they can press the button, and it’ll stay on, but it won’t ramp up any further for their additional 20 minutes. They ramp it up for 5 minutes and press the button every night for a week, but keep it on for the full 20 minutes, then to 10 minutes every night for a week, then to 15 minutes. And finally, over a month, they can ramp it up to the full dose of 20 minutes, letting it go the whole time. And when one takes time to get used to it and learn how to gradually tolerate the ramping up, almost everybody can tolerate it if they do it slowly. 

Once they get to the regular dose, most patients report that it makes them feel relaxed, and that’s why we recommend that it be done in the evening. And I say to people, “Look, if you fall asleep with it on, it’s going to turn off automatically. It doesn’t burn people. It doesn’t have risks.” But we do recommend using it in the evening. And once they get used to it, they can watch TV, they can walk around, they can do whatever they want. But initially we tell them, “You may not want to try to walk around while you’re first getting used to it, because it is a very odd sensation that you feel on the forehead.”

With the sTMS device, the pulsing of the magnet is very quick. I mean, it takes about 20 seconds to reboot it. They pulse, reboot, pulse, reboot, pulse, reboot, pulse, reboot, done. So that’s the easiest one and the fastest one to use. I mean, they’re not going to be watching TV while they do it, probably, and it’s a little bit heavy to be carrying around, but people do put it in their pocketbooks. And the charge lasts quite a while, up to a month, so it’s less of an issue in terms of what you’re doing with the sTMS device.

The GammaCore device, although you would think it would be quick, it’s not that quick because you gotta do a two-minute cycle, then it takes a while to reboot, then you do another two-minute cycle, then it takes a while to reboot, then you do another two-minute cycle. So by the time you’re done, it’s 10 to 15 minutes of downtime every time people use it. And you could be doing something during that time. You could be watching TV, and it’s going to twitch your neck while you watch it. But you’ll be holding it with one hand, and so there’s a little bit limited opportunity to do other things with it. And it’s a little less convenient than the sTMS or the Cefaly or the Nerivio, and it also requires goop on the neck each time it’s applied, so you have to leave some time to clean that off as well.

The Nerivio device is very convenient because it can be put on the arm and turned on, and you roll the sleeves down on your arm and go about your business, and people don’t know that it’s on. I mean, other people don’t know that it’s in place or that it’s working for a particular person. There’s no limitations on what you do. Obviously, you don’t take a shower or go swimming with it on; but otherwise, there’s really not any limitation to using the Nerivio device. And it is discreet. Of the four non-invasive neuromodulation devices, it’s the most discreet as well as the least expensive.

Molly: Okay. Thank you for going over those with us in terms of how you can use them and what you can be doing while you’re using them if you decide to use those for treatment options. 

Now, if someone’s interested in a neuromodulation device, obviously, cost might play a role, and what they want to use [for a?] neuromodulation device can also play a role. But if you’re looking at all four devices that are out there, how can one decide between the four devices what might work for them?

Dr. Tepper: Well, one decision is, What’s the frequency of the migraines? So if somebody has an attack a week, even a disabling attack a week, Nerivio would probably be the way to go, because one $99 fee is going to work for three months. And they just treat once a week and maybe not need their triptan or their [fast-needed?] treatment. 

If they have chronic migraine and they can afford it, the best data are for the sTMS device because that was specifically tested in both episodic and chronic migraine. Most of my patients can’t afford the sTMS device, and so that leaves the Cefaly device. So if they have chronic migraine, we usually start with the Cefaly device. And for those patients who want both acute and preventive treatment, most patients start with Cefaly, again because of cost and access. So that pretty much sums up how I approach it. 

And almost nobody, unfortunately, can afford the GammaCore. So the first question I ask is, “Are you a veteran?” And if they have cluster, then we try really hard to see if there’s a way they can try it out for cluster because it’s so disabling. But it’s hard to get patients to be able to afford it.

Molly: Yeah, that is tough. It’s interesting to see the variety in treatment options available with these neuromodulation devices and the cost in what’s out there. And you said that in all four of these devices, insurance doesn’t cover any of them. Is that correct?

Dr. Tepper: I’ve never seen insurance coverage for any of them.

Molly: Which is interesting. And does it seem like in the healthcare world that neuromodulation devices are not the first line of treatment for patients? If that’s the case, why is that, and do you think it can change?

Dr. Tepper: Yeah, it’s one of the great disappointments that payors are resistant to covering these, and they make all kinds of excuses, and all of the excuses are inexcusable, in my judgment. I mean, it’s really something that patients and providers need to lobby about. One technical difference between neuromodulation devices and medications is that neuromodulation devices are cleared by the FDA, while medications are approved by the FDA. However, the neuromodulation devices — many of them –have superb randomized controlled trials with sham, rated extremely high in terms of the quality of the studies done and by reputable journals like our Journal of Neurology. And despite the quality of the evidence and despite the fact that most of these cost less than the monoclonal antibodies, insurers remain absolutely resistant to covering them, without any legitimate reason, in my judgment. They don’t know what they don’t know, they’re not interested in finding out, and it’s really a shame. It’s a real problem.

So I personally think we all should be lobbying our payors continuously about this and bringing it up. I think that neuromodulation should be integrated into headache treatment. And there are some patients who want to use neuromodulation first. There are some patients who want to use neuromodulation as an add-on to medication. There are some who don’t want to deal with it until all other medication options have been theoretically failed, where the previous medicines have failed, multiple medicines have failed. 

We use neuromodulation in pregnancy. The sTMS device is approved in the UK for use in pregnancy. So sTMS and Nerivio and GammaCore and Cefaly, none of which has been officially cleared by the FDA for use in pregnancy — we can’t see any reason why people can’t use them in pregnancy, and especially the sTMS device, which has actually been explored by the UK regulatory people. So, again, there’s a time when we should be using neuromodulation. 

Older patients who have multiple medical illnesses that prevent them from using our medication, they’re good candidates for neuromodulation. When we teach residents in neurology, when we teach our colleagues, we try to include the neuromodulation devices by their level of evidence, integrated into an approach to the appropriate treatment of headache patients, and the cost and the payors are the biggest problem.

Molly: Dr. Tepper, can you tell us about the efficacy of these neuromodulation devices?

Dr. Tepper: Well, it’s a little bit of a problem because of apples and oranges, and we try to convert the data for some of the earlier studies into numbers that can be compared to our medical treatments, our medication treatments. Cefaly, for example, had two endpoints in their preventive trial: one was the reduction of mean monthly migraine days, which is similar to what we look at for the monoclonal antibodies; the other was the 50 percent responder rate, meaning what percentage of patients had at least a 50 percent reduction in their mean monthly migraine days? And it was only significant for the second endpoint, not for the first endpoint. So that doesn’t look as strong for efficacy numbers as our traditional medications. In the acute study for Cefaly in migraine used what’s called a visual analog scale where, from 1 to 100, the patients were asked whether they improved using the Cefaly device, and they did, but that’s not the same as asking people whether they’re pain-free at two hours the way we do with acute medications. And I always tell patients that neuromodulation is not the same as neurotermination. So sometimes these devices modulate pain downward without getting people completely pain free, and people are very happy with that because they don’t have side effects from that. 

The STMS device in the study that led to the FDA clearance for prevention studied people from 4 to 24 headache days per month, so from episodic to chronic migraine. And then magnitude of drop in monthly migraine days was pretty similar to what one sees with monoclonal antibodies across time, but that was not a placebo-controlled trial or sham-controlled trial. They used a statistical sham to make the argument to the FDA.

In the study that used STMS to terminate migraine with aura, they evaluated pain freedom at two hours, and it was effective versus a sham device for that. A little bit less than a triptan, but still in the ballpark. 

For the GammaCore device, there was a large Italian study that evaluated the non-invasive vagal nerve stimulator for acute treatment of migraine, and it did not statistically result in a pain-free response at two hours, but it did result in pain freedom at one hour and at later endpoints and at headache relief at two hours, and the FDA felt that was good enough with a high enough quality sham-controlled study to clear it for the acute treatment of migraine. But you could argue that it didn’t actually hit the primary endpoint of pain freedom at two hours compared to placebo.

The Nerivio device for pain freedom at two hours in a sham-controlled trial really looked a lot like a triptan. So it achieved pain freedom in over a third of patients at two hours compared to the sham device. Now, the difference comparing to a medication, acute medicine, is that the patients didn’t all wait to a moderate to severe level of pain to treat. Many of them treated earlier to achieve that pain freedom. But they did achieve the pain freedom, and they also reduced what’s referred to in the biz as the most bothersome symptom, where people were able to choose from dislike of light, dislike of noise, or nausea what was bothering them the most at the beginning of an attack, and the Nerivio did clear that in a statistically significant way compared to sham at two hours.

Also, interestingly, in an open-label study of Nerivio, people who continued to use it often more often than not chose to use it rather than acute medication, so it does suggest that when it works for people, it works similarly to a triptan, works better if taken early, and many people choose it over oral medications. That’s a quick look at efficacy. It’s not exactly the same apples and apples in comparing the end points, but enough to give us a feel for the relative efficacy of these devices.

Molly: I’m interested, Dr. Tepper, when you’re looking at efficacy and you’re looking at patients, obviously we know that migraine patients are different and their attacks are all different, but can patients use neuromodulation devices in conjunction with other therapies and find success?

Dr. Tepper: Absolutely, and we do that all the time. So if they can afford a particular neuromodulation device, we can add a monoclonal antibody or vice versa. I actually took care of a patient yesterday who in the days before the monoclonal antibodies had been through every conceivable preventive medicine, and these medicines had uniformly failed. And so I put her on Cefaly, and she did very well, and she felt like it had made a very big difference for her. Then I added a monoclonal antibody to the Cefaly because she was eligible because all these medicines had failed, and she said the combination had been life-changing, and it was both. She said it had to be both the Cefaly plus the monoclonal antibody. So, yes, we use them, together in the patients that can afford them.

Molly: And that’s so promising to hear someone say it changed their life. I think those words resonate with all of us who have migraine and probably for providers like yourself, that has to be so rewarding.

Dr. Tepper: I was going to say, it sure resonated with me. I wrote it in the chart and quoted it.

Molly: That does bring some joy. That’s really exciting. So as we continue to look at recent updates with neuromodulators and neuromodulation devices, I’m interested to see — do you think that providers will begin to get more comfortable with these devices as they possibly become more popular, or as we get more information and they get approved or, as you said, as they get cleared for different treatment options?

Dr. Tepper: I think it’s all [accepts?], I’m sorry to say. I mean, we teach at every American Headache Society meeting, every Diamond Headache Clinic meeting. We try all the time to put these devices into the acute and preventive treatment lectures for our colleagues, bring them up, and many providers are unwilling to go through the gymnastics involved in getting the prescriptions to whatever company they need, and many patients cannot afford them, and it’s a real shame. And I think the likelihood of uptake is directly related to payor access, and I’m hopping that some of our patient organization and advocacy groups will be more aggressive in lobbying for this. I mean, it’s really a shame that FDA cleared devices that have proven effective in randomized-controlled sham-controlled trials and are relatively inexpensive compared to designer medications are not being covered.

Molly: And I hope with more stories like one of the patients that you treated that it was life changing — I hope that we can start to see more advocacy for access to these type of devices.

And that wraps up this episode of Spotlight on Migraine. I’d like to thank our guest, Dr. Stewart Tepper. Until next time, I’m Molly O’Brien.

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Voice-over: Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.

This podcast is sponsored in part by Eli Lilly and Co.

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