Large Clinical Trial Shows Efficacy and Safety of External Trigeminal Nerve Stimulation for Migraine Treatment

A study of more than 500 patients across 10 sites in the US reaches its primary outcomes of pain freedom and resolution of most bothersome symptoms. Does this pave the way for more widespread clinical use of neuromodulation?

By Fred Schwaller

Non-pharmacological treatments are commonly sought by people with migraine, with some recent studies suggesting that the majority of those with the condition prefer such approaches. A new study now furthers the case for neuromodulation as a promising therapy to add to the non-drug therapeutic arsenal for migraine.

Building upon previous smaller studies, a Phase 3 clinical trial of more than 500 migraine patients from 10 sites across the US now shows that external trigeminal nerve stimulation (e-TNS) improved pain freedom and the most bothersome migraine-associated symptoms, thus meeting the two primary outcomes of the study.?

The trial, known as TEAM (Trial of e-TNS for the Acute treatment of Migraine) and the largest trial so far showing the efficacy of e-TNS, was led by CEFALY Technology, a company based in Belgium, which collaborated with researchers and clinicians based at medical centers and clinics for the new work. The treatment had no serious adverse effects.

“This paper adds support to the already existing findings that the CEFALY device could be effective in the treatment of migraine, most likely as adjuvants to other treatments,” said Simon Akerman, a migraine researcher at the University of Maryland, Baltimore, US, who was not part of the research.

?The study was published March 24, 2022, in Scientific Reports.

TEAMwork

Patient preference is driving the demand for non-drug therapies, according to Michael Johnson, MD, Medical Affairs Advisor at CEFALY Technology.

“We’re seeing more and more patients prefer non-medication treatment options. There are some medications that may impair people’s day-to-day activities, and they want to avoid that. We’re also seeing a big demand among patients for autonomy and control over what therapies they’re prescribed,” Johnson said.?

Back in 2009, CEFALY performed a pilot study of the effectiveness of e-TNS for the acute treatment of migraine. Ten patients received 20 minutes of e-TNS in a single session and rated how the neuromodulation affected their migraines. But most patients showed no improvement in their symptoms.

“We later suspected and found that the duration of the e-TNS stimulation for an acute treatment of migraine was a critical factor in migraine treatment outcome. Ten years later we performed the ACME study where we increased the duration to one hour and measured outcomes in a larger cohort of patients. The results supported the suspicion that duration of e-TNS treatment for acute migraine treatment is an important parameter in the reduction of migraine severity,” Johnson said, referring to the ACute treatment of Migraine with External trigeminal nerve stimulation (ACME) clinical trial, which was published in 2018.

While the ACME study showed that some study participants were getting migraine pain relief after one hour of e-TNS, some anecdotally reported better pain relief if they used e-TNS for longer. Ad hoc analysis of the ACME trial also suggested higher rates of pain freedom when patients were fully compliant with the duration of e-TNS stimulation.?

Further, a pilot study by Deena Kuruvilla (also first author of the current study) and colleagues provided preliminary evidence supporting the idea that longer-duration e-TNS therapy for migraine was more effective in achieving migraine freedom and freedom from the most bothersome migraine-associated symptoms. That was the starting point of the current TEAM study, where the investigators wanted to see if longer e-TNS treatment was more effective at treating migraine symptoms.

But CEFALY also set its sights on running a trial that would be larger than previous studies.

“There are a lot of people suffering from migraine and other diseases who could benefit from e-TNS, but lack of insurance coverage is a major barrier to using it. Insurance companies said that there weren’t enough large-scale clinical studies showing its efficacy and safety in large numbers of patients to provide it as a care option. We wanted to address this issue with a large-scale, multicenter, randomized sham control trial,” Johnson said.

Designing a trial

The TEAM study tested the e-TNS device on a total of 538 adult migraine patients, aged 18-65 years, across 10 study sites in the US. Patient inclusion criteria were a diagnosis of episodic migraine with or without aura for at least a year, a diagnosis of migraine before the age of 50, and two to eight migraines per month of moderate to severe intensity.?

Participants were randomized to two hours of continuous e-TNS treatment or to a sham stimulation. The sham and treatment devices were identical except that the sham device administered current at a lower frequency, below the clinical threshold of sensory detection, such that the subject can't differentiate the stimulation of the sham device from that of the treatment device.

The stimulation was delivered transcutaneously via electrodes placed on the forehead, with the goal of exciting neurons of the supratrochlear and supraorbital nerves. These trigeminal nerve branches are well implicated in migraine pain.?

According to Johnson, it was important for the investigators to take into account the hurdles patients may experience when using neuromodulation.

“One of the challenges of developing neuromodulation therapies is making it as intuitive as possible. Taking a pill is a mostly passive process but learning how to apply and operate e-TNS has a learning curve. The key is education – patients had a training session in person, which was critical for the device’s performance,” Johnson said.

One of the unique aspects of the trial is that patients indeed self-administered the e-TNS treatment, mimicking how the device would work in a “real-life” setting. That made the education component of the trial particularly important. Patients received instructions about how to apply the treatment and recorded their ratings of migraine-associated symptoms and treatment side effects using a headache diary.

“Testing the device in the home setting is an important step. Here, the paper adds crucial information to the manufacturer and physicians about how likely it is that patients will comply with treatment protocols,” said Akerman.

e-TNS safely relieves migraine pain

Encouragingly, the trial met both of its primary outcomes. A total of 25.5% of patients in the treatment group reported pain freedom two hours after beginning e-TNS, compared to 18.3% in the sham group. Meanwhile, 56.4% of patients in the treatment group had resolution of the most bothersome migraine-associated symptoms at the two-hour mark, compared to 42.3% in the sham group.

Regarding secondary outcomes, 69.5% of patients in the treatment group reported pain relief two hours after starting e-TNS, compared to 55.2% in the sham group. Further, 42.5% of the treatment group showed an absence of any migraine-associated symptoms, compared to 34.1% in the sham group.

e-TNS also had beneficial effects on pain 24 hours after the treatment. Here, 45.9% of patients in the treatment group reported pain relief a day later versus 34.4% in the sham group. And, 22.8% reported sustained pain freedom in the treatment group, compared to 15.8% in the sham group.

Johnson was keen to point out that the beneficial effects of e-TNS in the sham group might be diluting the effect sizes observed in the treatment group.

“Part of the reason why we see such an effect in sham is because they’re possibly getting some therapeutic dose from the stimulation,” Johnson said. “In a randomized, sham-controlled neuromodulation trial, the patients in the sham group must receive a stimulation just enough to perceive an intervention but not to the point of receiving a therapeutic intervention. The inflection point is often a challenge in designing sham-controlled migraine neuromodulation studies," according to Johnson, who will be looking at such issues in future studies.

Overall, the study found that 8.5% of patients in the treatment group reported an adverse event, compared to 2.9% in the sham group. The reported adverse events were minor, with the most common being forehead paresthesias, discomfort, or burning sensations caused by the electrical stimulation. But even then, only 3.5% of patients in the treatment group reported those sensations, compared to 0.4% in the sham group.

“This study defines adverse events and safety of e-TNS in a way that hasn’t been done before. Because of how large and robust the study was, we were able to collect great data on safety, which is incredibly useful for patients and clinicians,” Johnson said.

More extensive clinical use of e-TNS for migraine?

The authors are eager to gain widespread clinical approval of e-TNS as a migraine treatment.

“I think it’s going to be more important for clinicians and researchers in the migraine field to become familiar with neuromodulation – trigeminal nerve stimulation, specifically. As our understanding of the technology increases, and patients start demanding a role for these therapies, we’ll need a broader involvement of neuromodulation for the holistic care of the patient,” Johnson said.

Study co-author Amaal Starling, a clinician at Mayo Clinic in Scottsdale, Arizona, US, agreed.

“In the last 10 years, the availability of options to better individualize migraine treatment is causing a paradigm shift. I strongly encourage patients to have a conversation with their healthcare professional about all of these options to determine the best course of action to target their migraine attacks. I would like e-TNS to be considered as a first-line treatment option,” Starling said.

In the meantime, it remains unclear how e-TNS eases pain.?

“More research is needed on the definite mechanism of action. e-TNS may locally block trigeminal nerve signals and may also alter or normalize the metabolic behavior of pain perceptive networks in the brain,” according to Johnson, who added that some of those central networks are involved in functions like mood regulation and sleep, which can also be altered in migraine.

“This speaks to a potential multimodal effect of the treatment and should be promising considerations for future study,” Johnson said.

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred.?

Reference: Kuruvilla et al.?Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM).?Sci Rep. 2022 Mar 24;12(1):5110.

This article originally appeared on the Migraine Science Collaborative.