Remote Electrical Neuromodulation for Migraine Prevention Is Safe, Effective

The use of remote electrical neuromodulation (REN), applied every other day, is safe and effective for the prevention of migraine, significantly reducing the number of migraine days per month, according to findings from a prospective, randomized clinical trial published in the journal Headache.

Migraine, which is known to impact more than 1 billion individuals worldwide, has been linked to significant disability and a major socioeconomic burden. Although advances in migraine prevention over the past few years have decreased the number of attacks and improved the quality of life among some patients, low adherence to preventive therapy and significant rates of treatment discontinuation are still reported. Preventive treatment is crucial to the management of migraine, however, it is often underutilized.

For the study, researchers evaluated the clinical efficacy of REN — a nonpharmacologic acute treatment for migraine — for the prevention episodic and chronic migraine. They conducted a multicenter, prospective, double-blind, placebo-controlled, randomized clinical trial (ClinicalTrials.gov Identifier: NCT04828707) at 15 centers in the United States. Trial participants comprised men and women between the ages of 18 and 75.

The study included a 4-week baseline (observation) phase and an intervention phase. During the baseline phase, all participants completed a daily report and continued to take their regular medications as needed. The duration of the intervention phase was 8 weeks. During the intervention period, eligible participants were randomly assigned, in a 1:1 ratio, to the active or the placebo group.

According to the researchers, the REN device “produces a proprietary electrical signal comprising a modulated symmetrical biphasic square pulse with a modulated frequency of 100 to 120 Hz, pulse width of 400 μs, and up to 40 mA output current (adjusted by the participant).” In contrast, the “sham” device “produces electrical pulses of the same maximum intensity (34 mA) and overall energy, but with different pulse durations and much lower frequencies compared [with] the active device.”

The primary efficacy endpoint was the difference between the active and placebo groups in the mean change in number of migraine days per month, compared with the 4-week baseline phase, through the last 4 weeks of the treatment (ie, weeks 9 to 12).

A migraine day was defined as “a calendar day with headache that is accompanied by at least 1 of the following: photophobia, phonophobia, nausea and/or vomiting; or a headache that is treated with a migraine-specific acute medication.”

Regarding safety endpoints, the difference between the active and placebo arms in the percentage of device-related AEs was assessed. The incidence of AEs was evaluated according to severity and association with the device — that is, REN or sham — used.

The intention-to-treat (ITT) dataset, which comprised all participants randomly assigned, served as the dataset for all safety evaluations. The modified ITT (mITT) analysis dataset, which included all ITT participants who had completed at least 22 daily reports and had received at least 12 treatments in the last month of treatment (ie, during weeks 9 to 12), was defined as the “main efficacy dataset.”

Among a total of 335 enrolled participants between April 13, 2021, and August 11, 2022, 74.0% (248 of 335) were eligible for enrollment at the conclusion of the baseline phase, were randomly assigned, and received a device —128 in the active group and 120 in the placebo group. Overall, 72.2% (179 of 248) of these individuals were included in the mITT arm — 95 in the active group and 84 in the placebo group.

The researchers found that the mean change in the number of migraine days per month was –4.0±4.0 in the REN arm vs –1.3±4.0 in the placebo arm, with a net therapeutic gain (ie, the difference between active and placebo treatment) of 2.7 (reduction in active group: from 11.8 migraine days at baseline to 7.8 migraine days during weeks 9 to 12; reduction in placebo group: from 12.0 migraine days to 10.7 migraine days; P <.001).

Subanalyses conducted in the episodic subsample (45 participants in the active arm, 42 participants in the placebo arm) and chronic subsample (50 participants in the active arm, 42 participants in the placebo arm) both demonstrated statistical significance.

The mean change in the episodic subsample was –3.2±3.4 in the REN group vs –1.0±3.6 in the placebo group (net therapeutic gain, 2.3; P =.003). Further, the mean change in the chronic subsample was –4.7±4.4 in the REN arm vs –1.6±4.4 in the placebo arm (net therapeutic gain, 3.0; P =.001).

REN was also significantly superior to placebo with respect to the following secondary and exploratory endpoints:

• Reduction in number of moderate/severe headache days: 3.8±3.9 vs 2.2±3.6, respectively; P =.005
• Reduction in number of headache days of all severities: 4.5±4.1 vs 1.8±4.6, respectively; P <.001
• Percentage of patients achieving a 50% reduction in number of moderate/severe headache days: 51.6% vs 3.57%, respectively; P =.033
• Reduction in number of days of acute medication use: 3.5±4.2 vs 1.4±43, respectively; P =.001

There were similar results reported in the ITT analysis. Additionally, no serious device-associated AEs were reported in either treatment arm.

Several limitations of the study warrant mention. The subanalyses that were designed to differentiate between participants who took additional preventive medication and those who did not were based on a partial, smaller sample size of individuals who took preventive medications. In addition, medical history on patients’ failure on prior preventive medications was not obtained during the study.

“Applied every other day, REN is safe and effective for the prevention of migraine,” the researchers emphasized. “Given the previously well-established clinical efficacy and high safety profile in acute treatment of migraine, REN can cover the entire treatment spectrum of migraine, including both acute and preventive treatments,” they concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.