Summary of Evidence

Remote electrical neuromodulation (REN) may offer an alternative to pharmacologic interventions for patients with migraine. Nerivio is a prescription digital therapeutic REN device that is worn on the upper arm and stimulates the peripheral nerves to induce conditioned pain modulation, which is believed to reduce the perceived migraine pain intensity. While several studies have evaluated the use of REN for the treatment of migraine, these studies have significant limitations and evidence comparing REN with standard migraine therapy, as well as long-term data, is lacking. In addition, based on existing evidence, it is unclear how REN would fit into current acute migraine management or migraine prevention pathways. In the future, randomized controlled trials with long-term follow up providing direct comparative evidence are needed to establish optimal treatment protocols and long-term safety and effects on health outcomes.

Rationale

Migraine is a recurrent headache disorder with acute painful headache episodes typically lasting 4-72 hours. Additional symptoms may include throbbing unilateral head pain, visual disturbances, nausea, vomiting, dizziness, extreme sensitivity to sound, light, touch, and smell, and possibly aura. Interventions for migraine headache include preventive and acute therapeutic options, generally including avoidance of common migraine triggers, prophylactic pharmacological therapies, and acute abortive or analgesic therapy. More recently, neuromodulation has been proposed as an option for patients who fail to achieve satisfactory results using pharmacological migraine interventions. Electrical currents or magnets are used to modulate signaling activity in the brain to stop a migraine attack or in some cases prevent a migraine from occurring.

Nerivio (Theranica Bio-Electronics Ltd.), previously marketed as Nerivio Migra™, is a prescription digital therapeutic and was originally granted a de novo classification by the FDA in 2019 as a wearable electrical neuromodulator. While originally authorized for use in adults with acute migraine (≤ 12 headache days per month) who do not have chronic migraine, Nerivio was subsequently cleared for marketing by the FDA through the 510(k) process for adults with chronic migraine in 2020, and expanded for use in adolescents aged 12 to 17 years in 2021. Most recently in 2023, Nerivio's indication was expanded further to include preventive treatment of migraine with or without aura in individuals 12 years of age or older. Nerivio provides remote electrical neuromodulation therapy through a disposable, noninvasive, wearable device that delivers low-energy electrical impulses for up to 45 minutes per treatment. It is operated and controlled by the patient via a smartphone application. The Nerivio system consists of a pair of electrodes mounted on an armband with a power source. The wireless device is self-applied to the upper arm and delivers transcutaneous electrical nerve stimulation that is believed to interrupt pain signals traveling to the brain. Nerivio can be used instead of or in addition to medication.

Use of remote electrical neuromodulation (REN) for the prevention of migraine has been evaluated in one clinical trial. In 2023, Tepper et al published results for a randomized, double-blind, sham-controlled, multicenter trial in adults with at least a 6-month history of migraine headaches that meet the International Classification of Headache Disorders criteria (ICHD-3) and 6-24 headache days per 28-day period in the past 3 months (NCT04828707). 248 patients were randomized to either an active REN device (Nerivio; n=128) or a sham device (n=120). The study consisted of a 4-week baseline observation phase followed by an 8-week double-blind intervention phase in which patients used either REN or a sham stimulation for one full treatment every other day. If on a stable dose of migraine preventive medication for 2 months prior to enrollment, patients were allowed to continue with this medication throughout the study. If acute treatment was needed, patients were instructed to use their usual acute treatments during the study. The primary efficacy endpoint was the mean change in number of migraine days per month compared to the 4-week baseline phase (weeks 1-4) to the last 4 weeks of the treatment phase (weeks 9-12). Overall, patients treated with the active REN device had statistically significantly fewer migraine days during the intervention period compared to baseline vs those treated with sham (p<0.001). This was also demonstrated in sub-analyses based on episodic or chronic migraines (p=0.003 and p=0.001, respectively). 40.8% of the patients used a preventive medication in combination with REN. There were no differences in quality-of-life questionnaires or Headache Impact Tests (a tool used to capture the impact of headache on functional health and well-being) between groups at any time period. There was a single device-related adverse event (AE) in the sham group and no device-related AEs in the active group. The researchers concluded that REN is effective and safe for the prevention of migraine if applied every other day, however the researchers discussed several limitations of this study. A significant limitation was the very short 8-week duration, which is shorter than the recommended 12-week duration by the International Headache Society guidelines for neuromodulation devices. Another limitation was that 15% of the randomized patients did not perform the recommended number of treatments, which brings into question compliance outside of the clinical trial setting. In addition, medical history regarding failure on previous preventive medications was not collected during the study, therefore a future designated study will be required for a more profound assessment of the different responses among users of different preventive drugs, as well as history of preventive failures. Lastly, this study did not provide assessment of comparative effectiveness of REN vs first-line therapy (pharmacologic interventions). Further RCTs with long-term follow up and directly comparing the Nerivio REN device to pharmacologic therapy are needed to evaluate efficacy and net health outcomes.

Use of remote electrical neuromodulation (REN) for the treatment of migraine has currently been evaluated in two RCTs and several nonrandomized, uncontrolled studies. In 2017, Yarnitsky et al published results for a small randomized, double-blind, sham-controlled, pilot crossover trial in adults with a history of migraine attacks (NCT02453399). 71 patients received active or sham REN. All patients were given an identical REN device that was preprogrammed to deliver in random order 4 active treatment sessions and 1 sham session, all for a duration of 20 minutes each. In the trial, treatment with active REN was more frequently associated with reduction in, and freedom from, migraine pain than sham REN at 2-hour follow-up. Treatment response to active REN diminished over time of initiation following migraine onset, and active REN was most effective at reducing pain when used within 20 minutes of migraine onset (46.7% pain reduction as opposed to 24.9% reduction when started later [p=0.02]). No AEs were reported, though patients were more likely to rate their treatment perception of the active REN sessions as painful (11%) or unpleasant (28%) compared with sham REN sessions (1% painful; 13% unpleasant). Other outcomes were not reported in this study. The researchers concluded that the REN treatment may be proposed as an attractive nonpharmacologic tool to reduce migraine pain. However, this study was limited by the small sample size, which included all patients being recruited at a single center, and a very short duration of follow up. In addition, there was no true comparator group in this study due to the crossover nature of the design.

In 2019, Yarnitsky et al also published results for a second, larger randomized, double-blind, sham-controlled, multicenter trial in adults to further evaluate the efficacy and safety of REN for the acute treatment of migraine (NCT03361423). 252 adults meeting the ICHD criteria for migraine with 2-8 migraine headaches per month were randomized to 4-6 weeks of either active REN or sham stimulation after a 2-4-week run-in phase. The device was applied for 30-45 minutes on the upper arm within 1 hour of attack onset; migraine pain levels and most bothersome symptoms (MBS) were recorded at baseline, 2, and 48 hours post-treatment. The primary efficacy endpoint was the proportion of patients achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Key secondary endpoints were relief of MBS and pain-free at 2 hours. Active stimulation was significantly more effective than sham in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI 95%, 15.6-40.2]; p<0.0001), pain-free (37.4% vs 18.4%, p=0.003), and MBS relief (46.3% vs 22.2%, p=0.0008) at 2 hours post-treatment. The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment. However, there was no statistical between-group difference in the proportions of patients reporting freedom from their MBS at 2-hour follow-up (p=0.55). The incidence of device-related AEs was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], p=0.499). The researchers concluded that REN offers a safe and effective non-pharmacological alternative for acute migraine treatment, however they also noted several limitations and drawbacks of this study. There was a low rate of severe baseline pain intensity and high rate of mild pain intensity, presumably due to the early treatment. Yet, the rates of pain relief were as high for attacks treated at a moderate pain level, as for those treated at a mild pain level. In addition, this study did not evaluate the efficacy of the REN device at intervention periods over 1 hour of symptoms onset, nor did it compare efficacy of REN vs pharmacologic therapy. Lastly, there was no assessment of functional or quality-of-life outcomes. Overall, future randomized controlled trials are needed that evaluate REN use over longer periods of time.

Rapoport et al published a post-hoc analysis of the Yarnitsky 2019 RCT that retrospectively compared the effectiveness of acute migraine treatment with the Nerivio device with usual care (i.e., pharmacologic acute migraine management) used during the 2-4-week run-in phase of the trial. Pharmacologic treatment used during the run-in phase consisted of NSAIDs, acetaminophen (alone, or in combination with aspirin and caffeine), or triptans. In an analysis of a subset of 99 trial participants, the rate of freedom from pain was similar for Nerivio (37.4% [37/99]) and usual care (26.3% [26/99]; p=0.099) at 2-hour follow up. Results were similar for achievement of pain relief (66.7% [66/99] vs. 52.5% [52/99]; p<0.05). Future randomized controlled trials directly comparing REN with pharmacologic management are needed to confirm these results and to compare the effect of REN vs pharmacologic management on other outcomes.

Three nonrandomized, single-arm, open-label clinical trials of the Nerivio device were used to inform FDA approval for use in patients other than those with acute migraine due to episodic migraine. This includes 2 studies in patients with chronic migraine and 1 study in adolescents. In the study by Hershey et al (2021) conducted in adolescents, patients with episodic and chronic migraine were eligible for study inclusion. The studies reported on the effectiveness of the Nerivio device for acute migraine at 2 and 24 hours. Overall, the Nerivio device was associated with improvements in pain, symptoms, and function in all 3 studies. AEs related to the Nerivio device occurred in 1.0-2.0% of study patients across the 3 studies; no serious AEs were reported in any of the studies. Results from these studies are limited due to their open-label study design, lack of control groups, and small sample sizes with variable short-term follow up. Future large randomized controlled trials with long-term follow up are needed.

In 2022, a post-hoc analysis of the Hershey et al (2021) study, conducted in adolescents, compared the effect of Nerivio use (during the study phase) vs medication use (during the run-in phase) based on within-subject data. 35 adolescents who used medication during the 4-week run-in phase and who had Nerivio use data from the study phase were included in the post-hoc analysis. Results stated that Nerivio users were more likely to report freedom from pain than medication users (p=0.004), however there was no difference between Nerivio and medication in the proportions of patients who achieved pain relief (p=0.225). The researchers concluded that results suggest that REN may have higher efficacy than certain standard-care medications for the acute treatment of migraine in adolescents, however large, blinded studies designed to directly compare the Nerivio device with medication are needed to adequately assess comparative effectiveness.

Hayes evaluates a wide range of medical technologies and provides evidence-based assessments to determine impacts on patient safety and health outcomes. In 2021, Hayes published an Evolving Evidence Review on the Nerivio device for the treatment of acute migraine episodes. At that time, the exploration of clinical studies and systematic reviews uncovered minimal support for using Nerivio for managing acute migraine episodes. After reviewing clinical practice guidelines and position statements, the review concluded there needed to be more guidance for using Nerivio to manage acute migraine episodes and stated that evidence comparing Nerivio with standard migraine care is needed to inform its real-world value as a treatment possibility. The review was updated in 2023, with the same conclusions for systematic reviews (minimal support) and weak support from clinical practice guidelines and position statements. Evaluation of the current literature indicated that new evidence for the safety and efficacy had become available since the 2021 publication, however there was no new evidence with longer-term follow-up, or evidence comparing Nerivio with standard migraine care since the 2021 publication. The updated review maintained the conclusion of minimal support for the technology.

No published clinical practice guidelines have been identified that address the use of Nerivio for the treatment or prevention of migraine. In 2021, the American Headache Society (AHS) published a consensus statement on new migraine treatments that addresses use of neuromodulatory devices as a group, including electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation, and remote electrical neuromodulation (REN). The authors state that all patients with a confirmed diagnosis of migraine may be offered acute treatment with a neuromodulatory device, which modulates pain mechanisms involved in headache by stimulating the nervous system centrally or peripherally with an electric current or a magnetic field. Acute treatment with a neuromodulatory device may be offered alone or together with pharmacotherapy. The consensus statement does not offer guidance specific to REN, nor does it address the Nerivio device.

Reference List

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