Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double‐Blind, Placebo‐Controlled, Multicenter Trial

Abstract

Objective To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. Background There is a significant unmet need for novel effective well‐tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation – an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double‐blind, sham‐controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine. Methods This was a randomized, double‐blind, sham‐controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty‐two adults meeting the International Classification of Headache Disorders criteria for migraine with 2‐8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone‐controlled wireless device was applied for 30‐45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non‐painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post‐treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post‐treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain‐free at 2 hours were key secondary endpoints. Results Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI95%, 15.6‐40.2]; P < .0001), pain‐free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post‐treatment. The pain relief and pain‐free superiority of the active treatment was sustained 48 hours post‐treatment. The incidence of device‐related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499). Conclusions REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non‐pharmacological alternative for acute migraine treatment.

Incorporating Remote Electrical Neuromodulation (REN) Into Usual Care Reduces Acute Migraine Medication Use: An Open-Label Extension Study

“…Active stimulation was more effective than sham stimulation in achieving pain relief (66.7 vs. 38.8%, p < 0.0001), pain freedom (37.4 vs. 18.4%, p = 0.003), and relief of most bothersome symptom (46.3 vs. 22.2%, p = 0.0008) at 2 h post-treatment. The pain relief and pain freedom superiorities of the active treatment were sustained for 48 h post-treatment (15). This study also demonstrated a low incidence of device-related AEs which was similar between the treatment groups (4.8 vs. 2.4%, p = 0.499).…”

“…Detailed descriptions of the study design and the stimulation properties of the REN device (Nerivio TM , Theranica Bio-Electronics Ltd., Israel) have been reported elsewhere (15). Briefly, after enrollment, the participants were trained to use an electronic diary, and then they completed a 2-to 4-weeks runin phase, during which the attacks were treated according to usual care and pain scores (none, mild, moderate, or severe) were recorded at baseline and 2 h post-treatment.…”

“…This study also demonstrated a low incidence of device-related AEs which was similar between the treatment groups (4.8 vs. 2.4%, p = 0.499). All device-related AEs, mainly sensations of warmth and redness of the treated arm/hand, were mild, resolved within 24 h, and did not require medical treatment (15).…”

“…The objective of this study was to evaluate the potential of REN in reducing acute medication use, which may in turn decrease the risk for MOH and shed light on the potential utilization of a nonpharmacological neuromodulation treatment as an alternative or supplement to usual care. Here we report the results of an openlabel extension (OLE) study of people with episodic migraine completing a 6-weeks, double-blind, sham-controlled pivotal study of REN for acute treatment of migraine (15).…”

Migraine Care in the Era of COVID‐19: Clinical Pearls and Plea to Insurers

“…These devices typically require patient payment and need to be obtained from the manufacturer directly 22 Remote electrical neuromodulation (REN) device 23 External trigeminal neurostimulation (eTNS) device 24 …”