Increased Efficacy Through Combination of Remote Electrical Neuromodulation and Gepants


The combination of both REN and gepants for acute migraine treatment may have an increased efficacy compared with REN alone, an expected result based on the different actions of the treatments.

Nicolas P. Saikali, MD, a neurologist at Dent Neurologic Institute

Nicolas P. Saikali, MD

In a recent prospective, real-world data study, findings showed that the combination of Nerivio’s remote electrical neuromodulation (REN) and gepants significantly increased the percent of pain relief responders in patients with acute migraine. These results suggest that combining these two therapies may be an additive benefit and increase the overall efficacy compared with using REN as a standalone treatment.1

Among 3,725 patients with migraine, 63.4% achieved persistent pain relief using REN for a standalone treatment. At the same time, patients who had a combination of REN with gepants raised the overall pain relief response to 67.2% of the patients with migraine. 

These findings were presented at the 2023 American Headache Society (AHS) Annual Meeting, June 15-18, in Austin, Texas, by lead author Nicolas P. Saikali, MD, a neurologist at Dent Neurologic Institute. Saikali and colleagues assessed the efficacy of the two therapies combined, hypothesizing that they would lead to a beneficial efficacy despite the two different mechanisms of action that REN and gepant have between each other.

Between October 2019 and November 2019, data was collected on patients who use the REN device, with information on patient use of gepants collected in February 2023,. In the analysis, there were 3,725 patients that qualified and among those, there were 3,488 patients who used REN as a standalone treatment, and 237 who also used a gepant in addition to REN therapy in 2 hours (rimegepant, n = 120; ubrogepant, n = 117).

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Patients using REN were directed through the Nerivio smartphone application to use their device immediately as the migraine attack hit them. Users were then instructed at the onset of treatment and 2 hours later to respond to questions about any pain or symptoms they experienced. Patients were also inquired on whether they had combined REN with any further treatment or only used it as a standalone therapy. 

The data included information regarding all REN treatments at baseline and post 2-hour status from using at least 2 treatments, which were provided by the patients. The end point was persistent pain relief post 2 hours of treatment, ranging from moderate or serve headache to mild headache or no pain, from at least half of the users’ treatments. 

REN is designed to activate the conditioned pain modulation mechanism, sending a subpainful stimulation in the arm that propagates to the brainstem and also an endogenous pain inhibition mechanism that causes the increased release of serotonin. Although REN may be an effective therapy for some patients with migraine, other patients may “require more than one treatment modality to manage their migraine attacks.”1 Thus, some patients might include using gepants, which block calcitonin gene-related peptide from attaching to receptors in the central neural system and inhibit a pain signaling effect.

Nerivio’s REN device received FDA approval in February 2023 as a dual-use acute and preventive treatment for migraine with or without aura in patients 12 years of age or older. This approval was supported by the findings from the double-blind randomized clinical trial.2 The device is the first FDA-cleared smartphone-controlled prescription wearable device for acute migraine treatment of episodic or chronic migraine in people 12 years and older. The nonpharmalogical treatment is worn on the upper arm at the onset of a migraine attack and utilizes REN to trigger an endogenous analgesic mechanism, which is known as conditioned pain modulation. Additionally, the device received another prior approval in October 2020 although at the time, it was only approved for patients aged 18 years and older.3 Prior to the approval, its initial de novo clearance was granted for the acute treatment of migraine with or without aura in adults in May 2019.4

The device also received clearance in January 2021 as an acute treatment for migraine, in the same patient population, according to findings from a single-arm, multicenter study. The study enrolled 45 participants with episodic and chronic migraine who completed a test treatment with the REN. In the results, investigators observed only 1 device-related adverse event (AE; 2%) from the arm, which was a temporary feeling of pain in the arm.5 The rest of the findings demonstrated that pain relief and pain freedom at 2 hours were achieved by 71% (28 of 39 participants) and 35% (14 of 39) of participants, respectively.

Click here for more coverage of AHS 2023.

1. Saikali N, Stark-Inbar A, Garas S, Ironi A, Diamond M. Real World Evidence on the Combining Remote Electrical Neuromodulation and Gepants for the Acute Treatment of Migraine. Presented at: AHS Annual Meeting, 2023; June 15-18; Austin, TX. P-159.
2. FDA approves Theranica’sNerivio for acute treatment of migraine in adolescents. News release. January 25, 2021. Accessed June 19, 2023.
3. Nerivio receives clearance of expanded indication to cover chronic migraine patients. News release. Theranica Biotherapeutics. October 26, 2020. Accessed June 19, 2023.
4. FDA Grants Theranica De Novo to Market First Smartphone-controlled Acute Migraine-relief Wearable Device. News release. Theranica. May 28, 2019. Accessed June 2019, 2023.
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