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