Evidence suggests that pharmacologic agents often used to treat migraine may at times be ineffective, poorly tolerated, contraindicated, and—if used too frequently—can cause possible medication overuse headache, migraine chronification, and notable medical complications. A significant unmet need exists for effective and well-tolerated non-pharmacologic acute migraine therapy, according to Alan M. Rapoport, MD.

Studies have found external trigeminal nerve stimulation, non-invasive vagus nerve stimulation, and single-pulse transcranial magnetic stimulation to be safe and well-tolerated, non-invasive neuromodulation approaches. However, “they only work for up to 60% to 70% of patients,” says Dr. Rapoport, with efficacies that are at times inferior to those reported for migraine-specific pharmacologic treatments.


A Novel Approach

A novel alternative to pharmacologic and the above-mentioned non-invasive neuromodulation approaches to acute migraine treatment may be found in the use of remote electrical neuromodulation (REN). With REN, the upper arm peripheral nerves are stimulated to induce conditioned pain modulation, which Dr. Rapoport and colleagues explain as “a descending endogenous analgesic mechanism caused by subthreshold conditioning stimulation that inhibits pain in remote body regions. REN presumably activates descending inhibition pathways that travel through the periaqueductal gray (PAG) and in the rostral ventromedial medulla (RVM) and involve the release of the neurotransmitters serotonin and noradrenalin; they inhibit incoming messages of pain in the trigeminal cervical complex (TCC) that occur during a migraine headache attack.”

A newly FDA-approved and available REN device (Nerivio; Theranica) is a wireless, wearable, battery-operated stimulation unit controlled by the patient through a smartphone app. Applied to the lateral upper arm for 45 minutes, the device mainly stimulates small skin nerves through a proprietary electrical signal comprising a modulated symmetrical biphasic square pulse with a modulated frequency of 100-120 Hz, pulse width of 400 μs, and up to 40 mA output current (adjusted by the patient). In contrast with other neuromodulation treatments for migraine, the REN device uses upper arm stimulation to produce global pain inhibition, allowing patients to continue with daily activities while it decreases migraine pain.

Data Thus Far

A pilot study, a pivotal study, and exploratory within-subject post hoc analyses thus far “show that the REN device works as well as existing treatments with almost no side effects,” says Dr. Rapoport. The pilot study found that treatment with the REN device helped achieve significantly reduced headache pain when compared with a sham device and had the greatest effects when applied within the first 20 minutes from migraine attack onset and used for 45 minutes.

The pivotal study found a statistically significant, clinically important benefit of REN when compared with sham treatment in adults randomized to either treatment for 4-6 weeks. “Pain freedom at 2 hours was 37%,” explains Dr. Rapoport (Figure). “Separate research shows this to be comparable with triptans. Pain relief at 2 hours was 67%, which is better than with many triptans.” Pain freedom and pain relief rates at 2 hours with the sham device were 18% and 39%, respectively. Most bothersome symptom relief rates at 2 hours were 46% for REN and 22% for sham.

Exploratory within-subject post hoc analyses were performed on a subgroup of pivotal study participants who treated at least 1 attack with the active REN device and reported pain intensity at 2­ hours posttreatment. “Each patient used usual care for 1 month before entering the double-blind study,” notes Dr. Rapoport. “Upon comparing their response to REN with that of any usual care, REN was found to be more effective. When compared with migraine-specific medications only, REN treatment was found to be just as effective.”

Looking Ahead

Trials are underway to study REN in more severe chronic migraine, with encouraging early results, according to Dr. Rapoport. “Future studies may also assess REN as a treatment for cluster headache, medication overuse headache, migraine with vertigo, and menstrual-related migraine,” he adds, “as well as for preventive treatment of migraine. For now, REN is a promising new treatment for patients with migraine.”


Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine