Remote Electrical Neuromodulation Effective for Acute Migraine Treatment


Compared to sham stimulation, the REN device was more effective in achieving pain relief and relief from the most bothersome symptom at 2 hours posttreatment and was maintained at 48 hours post-stimulation.

Dr David Yarnitsky

David Yarnitsky, MD, director, Department of Neurology, Rambam Health Care Campus, and head, Laboratory of Clinical Neurophysiology, Technion-Israel Institute of Technology

David Yarnitsky, MD

The use of Nerivio Migra (Theranica Bio-Electronics), a remote electrical neuromodulation (REN) device, has been shown to be effective in the acute management of migraine, in a double-blind, randomized, sham-controlled trial.1

Compared to sham stimulation, the REN device was more effective in achieving pain relief (P <.0001) and relief from the most bothersome symptom (MBS; P = .0008) at 2 hours posttreatment. Additionally, superiority over the sham treatment was sustained at 48 hours after stimulation.

As for safety, the incidence of adverse events (AEs) related to the device was low and comparable between the groups, occurring at a rate of 4.8% (6 of 126 patients) and 2.4% (3 of 126 patients) in the active and sham groups, respectively (P = .499).

First author David Yarnitsky, MD, director, Department of Neurology, Rambam Health Care Campus, and head, Laboratory of Clinical Neurophysiology, Technion-Israel Institute of Technology, and colleagues wrote that these findings display evidence that “REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non&#8208;pharmacological alternative for acute migraine treatment.”

Yarnitsky told NeurologyLive® that the study was prompted by his work on pain inhibition with conditioned pain modulation [CPM]. "[The] biggest surprise, already in the pilot and repeated here, is that the device achieves a similar extent of pain relief as the triptans, suggesting some common mechanism, but I am not sure if such mechanism exists," he said.

"[My previous work] led me to think that remote stimulation could be effective in reducing migraine headache," he explained. "[Non-pharmacologic options are] very important, mainly because migraine affects young adults, who are usually reluctant to take regular medication, and further, because most of the patients are females in the reproductive stage, and drugs could be a problem with unexpected pregnancy."

The trial randomized 252 adult patients who met the International Classification of Headache Disorders (ICHD) criteria for migraine in a 1:1 fashion to either the REN stimulation device (n = 126) or sham (n = 126). At baseline, 51.6% (n = 65) and 44.4% (n = 56) of the patients in the active and sham arms, respectively, were utilizing triptans. Migraine with aura occurred often for 30.2% (n = 38) and 26.2% (n = 33) of patients, respectively, and never for nearly 50% of both groups. The respective remaining 20.6% (n = 26) and 23.8% (n = 30) of patients in the active and placebo groups had aura rarely.

Yarnitsky and colleagues noted that a therapeutic gain of 27.9% (95% CI, 15.6 to 40.2; P <.0001) was observed. In the REN device group, 66.7% (66 of 99 patients; 95% CI, 56.48 to 75.82) achieved pain relief at 2 hours compared to 38.8% (40 of 103 patients; 95% CI, 29.39 to 48.94).

“Similar results were found when missing data were imputed using a worst&#8208;case scenario,” Yarnitsky and coinvestigators detailed. “Importantly, pain relief at 2 hours post&#8208;treatment did not depend on the site.”

In a worst-case scenario, pain-freedom was achieved by 64.1% (66 of 103 patients) in the active cohort compared to 39.4% (41 of 104 patients) in the sham group (P <.0005). According to the Breslow&#8208;Day test (P = .9706), pain-relief at 2 hours was insignificant depending on the site. The device is intended to be applied for 45 minutes on the lateral upper arm between the bellies of the lateral deltoid triceps, in order to stimulate mainly small skin nerves.

As for relief from the most bothersome symptom (active arm: nausea, 29.4% [n = 37]; photophobia, 43.7% [n = 55]; phonophobia, 20.6% [n = 26]; sham: nausea, 24.6% [n = 31]; photophobia, 57.1% [n = 72]; phonophobia, 17.5% [n = 22]), the active arm achieved this at 2 hours at a rate of 46.3% (44 of 95 patients; 95% CI, 36.02 to 56.85) compared to 22.2% (95% CI, 14.48 to 31.69) in the sham arm (adjusted P = .0008).

Combined pain relief and MBS relief was achieved by 40.0% (95% CI, 30.08 to 50.56) and 15.2% (95% CI, 8.74 to 23.76) in the active and sham groups, respectively (adjusted P = .0004).

“REN likely utilizes a descending endogenous analgesia mechanism to control migraine pains. While the descending pain modulatory system is well characterized, this natural mechanism has not been utilized for non&#8208;pharmacological pain treatments, except for invasive spinal cord stimulation that is believed to activate this system,” investigators wrote. Yarnitsky and colleagues noted that this is, to their knowledge, the first time that exploitation of CPM for non-pharmacologic, non-invasive treatment of pain has been attempted.

Additionally, of note based on previously reported studies, the REN device’s efficacy has been superior to other devices aimed at neuromodulation. In comparison to its aforementioned 27.9% therapeutic gain, single transcranial magnetic stimulation and non-invasive vagus nerve stimulation have only shown gains of 5% and 13.2%, respectively. And while appropriate sham for successful blinding in trials of these type—a limitation of the study&mdash;the authors noted that the placebo effect in this trial was higher than most drug trials (as is often the case in these trials), leading them to believe that “the sham device produced a solid perceivable stimulus.”

The study did have other limitations. First, a low rate of severe baseline pain intensity and high rate of mild pain intensity, believed to be because of early treatment, was observed. Second, the efficacy of the device at 1-hour post symptom onset was not assessed.

“REN has the potential to increase patient adherence, improve migraine management, and improve the health and quality of life of people with migraine,” Yarnitsky and colleagues concluded.


Yarnitsky D, Dodick DW, Grosberg BM, et al. Remote electrical neuromodulation (REN) relieves acute migraine: A randomized, double&#8208;blind, placebo&#8208;controlled, multicenter trial. Headache. Published online May 9, 2019. doi: 10.1111/head.13551.

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