Treating Migraine With External Trigeminal Nerve Stimulation

Deena Kuruvilla, MD

At the 2021 American Headache Society (AHS) Annual Scientific Meeting, June 3-6, data were presented that suggest that external trigeminal nerve stimulation (e-TNS), done with the Cefaly device, displayed superiority to a sham device in providing 2-hour pain freedom and freedom from the most bothersome symptom (MBS), as well as sustained pain freedom at 24 hours.

The patients with migraine assessed were included in the TEAM study (NCT03465904). In total, the active stimulation group experienced markedly more efficacy than those in the sham group in achieving 2-hour pain-freedom (active: 27.27%; sham: 17.72%; P = .0167) for a therapeutic gain of 9.55%, and a significantly higher proportion of active stimulation patients achieved freedom from their MBS (58.85% vs. 42.19%; P = .0006).

Deena Kuruvilla, MD, medical director, Westport Headache Institute, presented these data at AHS 2021, and shared her perspectives on the implications of the data in a conversation with NeurologyLive. She also spoke to the potential of e-TNS in the treatment of migraine overall and for which populations these devices might help fill in the gaps that remain in care.

NeurologyLive: Could you offer a little bit of background on the TEAM study and its goals?

Deena Kuruvilla, MD: For several years now, the e-TNS device has been accepted for the prevention of migraine. Initially, the device was studied in patients to see if there would be a reduction in monthly migraine days—and it did. That particular study for prevention kind of showed us that it is helpful in dropping those overall monthly migraine days. We know that this stimulator specifically targets the nerves in the forehead, called the supratrochlear nerve, and the supraorbital nerves, and then we know that it affects the pain pathway by directly stimulating these nerves.

The next natural thing was to study it for the acute treatment of migraine. Denise Chou, MD, and colleagues have done a pilot study, the ACME study, specifically looking at the device for the acute treatment of migraine, just a couple of years ago. We wanted to see with the current TEAM study 2 things: What happens when we apply this study to a larger population—and so that's why the team studies a multicenter, randomized sham-controlled trial—and how would patients do with using the device outside of our clinic setting or hospital setting.

In the previous ACME study for the acute treatment of migraine patients, participants came to the study clinic and used the device there in-person. But with the TEAM study, participants took the device home. And prior to taking the device home and using it on a qualifying migraine attack, they did undergo specific training on how to use the device, making sure that they know which buttons to push, and how to wear the device correctly. Essentially ensuring that they're putting on the electrodes correctly and making sure that they know how to use those devices. So, in this study, we really wanted to see how the device works for the acute treatment of migraine in the real world when the participant or the patient is outside of our office.

What, ultimately, were the findings and how do they translate to the clinical use of the device?

The TEAM study had 2 primary end points, and 5 secondary end points. In this particular study, we met all but 1 of the secondary end points. Basically, the study showed that 25% of patients who used the active device had pain freedom at 2 hours—that was our primary endpoint. We found that 56% of participants had absence of their most bothersome symptom at 2 hours—either absence of photophobia, photophobia, or nausea. Those were our 2 primary end points that were met.

Then we had 5 additional secondary end points. We had pain relief at 2 hours, absence of all of migraine-associated symptoms, sustained pain freedom at 24 hours, and sustained pain relief at 24 hours, as well as the use of rescue medications within that 24-hour period. The only secondary end point that did not meet statistical significance in the trial was that there was no difference of acute medication use in 2 to 24 hours, whether the participant used the active device or the sham device. Apart from that, we met all of the end points for the trial.

Do you find that to be a good number of patients, even though there was no difference, who still didn't need to use rescue medic medication? Does this imply anything about the possible utility of the e-TNS device?

It's really that's a really interesting question. I think that there are different roles for neuromodulation in general, and for this e-TNS device. In the real world, I'll tell you that 1 of the biggest challenges for patients is getting enough of their acute migraine treatments approved by their insurance company. I just saw a patient, for whom the insurance company approved 4 tablets over a 30-day period. Now, this is a patient with chronic migraine, who has disabling attacks and is having 20 headache days per month. That's while on preventive treatments. Often, we run into this huge challenge in the real world, where insurance companies and payers are not covering acute pharmacological migraine treatments, like triptans. Often, the insurance company does not give enough tablets of the gepants, or other new-wave treatments. For ditans, insurance companies are not giving enough. There is a lot of room to add neuromodulation, or the e-TNS device, to those treatments.

One way, for example, that I have patients use the e-TNS in clinic, is to use e-TNS at the onset of their headache with an acute treatment. Then, at the 2-hour mark, they may not need to re-dose that acute treatment. We're able to save tablets that way, and really get the patient returning to their baseline activities and getting them pain-free while also trying to save that medication. That's scenario 1, trying to add it to the acute treatment regimen. The focus of my practice is headache, and the vast majority of folks I see have migraine. Medications often aren't enough; something has to be added on. Every patient is different, we often have Plan A for acute treatment, Plan B, Plan C, and so on. Everyone's lives are independently different. We need different approaches. That's the first kind of area that I see it helpful.

The second area where I see neuromodulation, and e-TNS specifically, being helpful is in those who cannot tolerate acute treatments. We have so many people who have other medical conditions that may preclude them from taking acute migraine treatments. They may have found them not to be helpful in the past, or they may have had adverse effects that really limit their functioning. I find that especially with triptans, a lot of patients say that it makes them groggy, they're having trouble functioning, so they don't want to take them if they're at work, or they're taking care of their children, just with their lifestyle. So, this can come in as a treatment option that they can use in place of acute treatments.

I think the most impressive aspects of this TEAM study specifically are that we found a statistical significance for pain freedom at 2 hours, which is the new benchmark as of 2018 from the FDA as the primary end point for migraine and acute treatment trials. The other impressive thing is the absence of the most bothersome symptom at 2 hours. Many patients tell me that that sensitivity to light, sensitivity to loud noise, and nausea sometimes is more disabling than the actual pain. Those are kind of, you know, the 2 areas where I see e-TNS being very helpful for patients. Every patient is different. Patients will also try it in different ways that work for them and let me know what's worked the best for them.

Do you think that having that flexibility really lends itself to the unique approach you have to take with each patient?

Absolutely. There's this concept that's really important in migraine management of mini-prevention. One example of that is in menstrual migraine. Folks with menstrual migraine or menstrually-related migraine develop migraine attacks 2 or 3 days before that first day of their period. Often, in clinical practice, we give them mini-prevention in those 2 to 3 days before. We may start a course of treatment for 5 days to try to break that cycle in advance because we can predict when the migraine is going to happen. I certainly see a role for rimegepant [Nurtec ODT; Biohaven] in that scenario, and for the e-TNS device, especially if we come to find that enough tablets are not going to be approved for rimegepant, we may have to supplement with that neuromodulation.

What is the ultimate takeaway from these phase 3 data and the use of e-TNS, in general?

Research studies have shown that many patients may prefer nonpharmacological approaches to management. I often make it a point in my discussions with patients to discuss mainstream pharmacological therapy for prevention of migraine, and I discuss neuromodulation because, especially with a study like the TEAM study, we now have multiple randomized, sham-controlled trials and multicenter trials, looking at it for acute treatment and preventive treatment. I also talk about more natural approaches, which may have less evidence, but the patients may want to add to mainstream therapy. I always add neuromodulation, a part of that conversation being about e-TNS. Specifically, we know that it has evidence for the preventive treatment of migraine and the acute treatment of migraine. And so, I often run through some scenarios with the patients on how to add the e-TNS device to those mainstream pharmacological approaches for the acute treatment of migraine and the preventive treatment of migraine. It is over the counter, as well, so many patients can just order it themselves online, which has been a benefit for me. As far as accessibility goes, patients are able to access it themselves and just decide for themselves if it's something that they want to pursue.

Is there anything else you’d like to add?

Perhaps just about the use of e-TNS in clinical practice. I often just guide patients that when they're in clinic, that for prevention of migraine, the device should be worn for 20 minutes daily. I often have them wear it for 20 minutes at bedtime to prevent migraine and have them maybe add a mindfulness exercise or meditation exercise with it right before bedtime. I find that this combination also kind of helps improve sleep. Then, for the acute treatment of migraine, I ask the patients to wear the device for 1 hour as needed when they have an attack at the very onset. And I often have them add it to an acute treatment that they may have on hand if they need a little extra help with breaking that attack.

Transcript edited for clarity. For more coverage of AHS 2021, click here.

REFERENCE
Kuruvilla DE, Starling AJ, Tepper SJ, Mann JI, Johnson M. A phase 3 randomized, double-blind, sham-controlled trial of e-TNS for the acute treatment of migraine (TEAM). Presented at 2021 AHS Annual Scientific Meeting; June 3-6. Abstract IOR-02.