One-Year Consistent Safety, Utilization, and Efficacy Assessment of Remote Electrical Neuromodulation (REN) for Migraine Treatment.

INTRODUCTION: Migraine is a chronic neurological disorder causing severe pain and disability in more than a billion people worldwide. Ideal treatment should provide long-term efficacy with minimal side effects. Previous studies indicate that remote electrical neuromodulation (REN) is an efficacious and safe treatment option for the acute treatment of migraine in clinical practice. This study examined long-term safety, utilization, and efficacy of REN during 12 consecutive usage months. METHODS: Data from patients with migraine across the USA using REN to treat their migraine attacks were electronically collected from the Nerivio® device. All patients who used REN during 12 consecutive months were included, and data were compared across months. Safety was assessed by the number and type of adverse events. Utilization was measured by the number of monthly treatments. Efficacy was evaluated as consistent change in headache pain intensity, functional disability, and disappearance of associated symptoms from baseline to 2 h post treatment. RESULTS: Data were analyzed from 409 people living with migraine who treated with REN for 12 consecutive months, performing a total of 39,531 treatments. The incidence of device-related adverse events (dAEs) was 1.96% (8/409), including two negligible (0.49%), five mild (1.22%), one moderate (0.24%), and no severe events. All patients continued treatment with REN despite dAEs. One-year average monthly utilization was 8.05 treatments (SD 1.15). Month-to-month utilization did not change during 12 months of consecutive use [F(4.895, 1997.204) = 2.014, p = 0.075, repeated-measures ANOVA]. One-year average efficacy showed 74.1% of users reported consistent 2-h pain relief, and 26.0% reported consistent pain freedom. Month-to-month pain relief and pain freedom did not change during 12 months of consecutive use [F(11, 1069) = 0.55, p = 0.873 and F(11, 1295) = 0.69, p = 0.750 respectively; generalized linear mixed model analysis]. CONCLUSION: REN is a safe and well-tolerated acute migraine treatment, with stable efficacy and utilization over 1 year, making it an advantageous non-drug option for the long-term management of this chronic disease. TRIAL REGISTRATION NUMBER: NCT05760638.

Migraine is a chronic disease leading to decades of significant disability, thus requiring safe, effective, and tolerable treatment for years. Remote electrical neuromodulation (REN) is a smartphone-controlled wearable device (Nerivio^®) indicated for the acute and/or preventive treatment of migraine in patients 12 years of age or older. It is a prescribed, self-administered device for use at the onset of migraine headache or aura for acute treatment, or every-other-day for preventive treatment. Treatments are automatically registered in the REN app and database, and users can prospectively report subjective migraine indicators and response to the treatment in the REN app, at treatment onset and again 2 h later. This study analyzed data from people who used REN for the acute treatment of their migraine attacks at least once per month, for at least 12 consecutive months. Data from 409 patients who met the study criteria and performed a total of 39,531 treatments was analyzed. Safety was measured by the incidence of device-related adverse events, which was 1.96%. Severe device-related adverse events were not reported, and all patients continued treating after the events. Efficacy over the year showed that 74.1% of the patients reported consistent pain relief, and 26.0% reported consistent pain freedom. Average monthly utilization over the year was 8.05 treatments. Month-to-month pain relief, pain freedom, and utilization did not differ between 12 months of consecutive use. These results show that REN is a safe and well-tolerated treatment, with stable efficacy and utilization over at least 1 year, making it an advantageous non-drug option for the long-term management of migraine.

Remote electrical neuromodulation (REN) wearable device for adolescents with migraine: a real-world study of high-frequency abortive treatment suggests preventive effects.

Introduction: Migraine is a chronic neurological disease manifesting as attacks of disabling head pain and associated symptoms. Remote electrical neuromodulation (REN) is a non-pharmacological, prescribed, wearable device (Nerivio®). This device has been certified by the FDA for the acute and/or preventive treatment of migraine with or without aura in patients 12 years of age or older. The device is affixed to the user's arm during 45-min treatment sessions and is operated using a smartphone app. This study (NCT05769322) aims to evaluate whether frequent use of REN for the acute treatment of migraine in adolescents resulted in a reduction in monthly migraine treatment days (MMTD), as previously demonstrated in adults through a dedicated prevention clinical trial (NCT04828707). Methods: The study included real-world prospective data from adolescent patients who used REN on at least 10 days every 28-day month, following the REN migraine prevention guideline of an every-other-day pattern. Additional requirements were at least three REN treatment days in each of the two subsequent months. The number of MMTD was used as a proxy measure for the number of monthly migraine days (MMD). The change in MMTD from the first month, taken as a "baseline," to each of the following months was used to evaluate the presence and size of potential migraine preventive benefits of REN in adolescents. Results: A total of 83 adolescents were eligible for analysis. The users were 15.9 ± 1.3 years of age (mean ± SD), and 89% of them were female. The results demonstrated a substantial month-to-month reduction in the mean (±SD) number of REN treatment days from 12.6 (±3.2) MMTD in the first month to 9.0 (±4.8) MMTD in the second month (p < 0.001), and a further decrease to 7.4 (±4.2) MMTD in the third month (p < 0.001). This indicates an accumulative reduction of 5.2 (±4.8) mean REN MMTD from the first month to the third month of consecutive REN treatment. The users also reported consistent 2-h acute pain responses in at least 50% of their treated attacks, with 61.9% of the users reported experiencing pain relief, 24.5% reported pain freedom, 67.4% indicated relief in functional disability, and 41.3% reported complete freedom from functional disability. Conclusion: The frequent use of REN among adolescents as an acute treatment for migraine attacks resulted in a decrease in the mean number of monthly treatment days in the subsequent months, suggesting that REN may have potential preventive benefits for migraine in this subpopulation.

Temporal analysis of remote electric neuromodulation for the prevention of migraine.

Aim: To evaluate the onset, magnitude and persistence of efficacy of remote electrical neuromodulation (REN) compared with placebo for the preventive treatment of migraine. Materials & methods: Analysis was conducted on data from a prospective, double-blind, placebo-controlled clinical trial, which assessed the efficacy of REN for the prevention of migraine. The number of monthly migraine days (MMD) per group was calculated in 2-week intervals and compared between the groups. Results: Differences between the active (N = 95) and placebo (N = 84) groups reached significance at 2 weeks: therapeutic gain 0.84 MMD; p = 0.036. 4 weeks gain 1.59 MMD; p = 0.025, 6 weeks gain 2.27 MMD; p < 0.001, 8 weeks gain 2.68 MMD; p < 0.001. Conclusion: REN provides rapid and consistent efficacy in preventive treatment of migraine.

Clinical benefits and economic cost-savings of remote electrical neuromodulation (REN) for migraine prevention.

AIMS: Assess the clinical benefits and associated direct and indirect cost-savings from Remote Electrical Neuromodulation (REN) for migraine prevention. METHODS: REN, a prescribed, wearable, FDA-cleared neuromodulation-device for acute and/or preventive treatment of migraine, recently demonstrated efficacy for migraine prevention when used every-other-day, in a prospective, randomized, double-blind, placebo-controlled, multi-center study. Following baseline (4-weeks), subjects underwent treatment with REN or placebo (8-weeks), and electronically reported migraine symptoms and acute treatments daily. Therapeutic-gain was the between-groups difference (REN minus placebo) in change from baseline to the second month of intervention. Health-economics impact was derived as cost-savings associated with REN's clinical benefits. RESULTS: Out of 248 subjects randomized (128 active, 120 placebo), 179 (95:84) qualified for modified intention-to-treat (mITT) analysis. Significant therapeutic gains favoring REN vs. placebo were found (Tepper et al. 2023), including mean (±SD) reduction in number of acute medication days (3.5 ± 0.4 vs. 1.2 ± 0.5; gain = 2.2; p = .001) and presenteeism days (2.7 ± 0.3 vs. 1.1 ± 0.4; gain = 1.6, p = .001). Mean changes of provider visits (reduction of 0.09 ± 0.1 vs. increase of 0.08 ± 0.2; p = .297), and reduction of absenteeism days (0.07 ± 0.1 vs. 0.07 ± 0.2; p = .997) were not significant. Mean annual cost-saving for one patient using REN for migraine prevention estimated $10,000 (±$1,777) from reductions in these four clinical outcomes relative to baseline without REN treatment. Extrapolated to a hypothetical US commercial health-plan of one-million covered lives, assuming the national prevalence of migraine patients on preventive treatment, annual mean (±SE) cost-saving from using REN migraine prevention estimated $560.0 million (±$99.5 million) from reduction in direct (∼$330 millionm) and indirect costs (∼$230 millionm) measured. LIMITATIONS: Clinical and cost-savings benefits presented are conservative, assessed only from endpoints measured in the clinical trial. Moreover, some of the endpoints had only scarce or no occurrences during the study period. CONCLUSIONS: Coverage of the REN-device for migraine prevention may significantly reduce disease-burden and save a one-million-member payer plan at least $560 million per year.

Migraine affects more than 1 billion people worldwide, causing significant disability and substantial clinical economic burden. Remote Electrical Neuromodulation (REN) is a prescribed, wearable, non-pharmacological, non-invasive device (Nerivio), indicated for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older. Efficacy of REN for migraine prevention was recently demonstrated in a randomized, blinded, placebo-controlled clinical-trial. This study further analyzes clinical benefits from endpoints measured in the clinical-trial as well as their associated direct and indirect costs. Out of 248 subjects randomized (128 active, 120 placebo), 179 (95:84) qualified for modified intention-to-treat (mITT) analysis. Significant therapeutic gains favoring REN over placebo were found, including an average reduction of 3.4 acute medication days/month, and an average reduction of 2.7 presenteeism days/month. A reduction in the number of provider visits and absenteeism days was also reported, though not significantly differed from changes in the control group. Mean annual cost-saving from reductions in these four clinical outcomes relative to baseline without REN treatment for a patient using REN for migraine prevention estimated $10,000. Extrapolated to a hypothetical US commercial health-plan of one million covered lives, annual mean cost-saving from using REN for migraine prevention is estimated to be $560.0 million, composed of $327.8 million direct costs and $232.2 million indirect costs. Thus, REN preventive treatment for migraine reduces disease burden and leads to meaningful cost-saving, both direct and indirect, proposing clinical and financial incentives for patients, health insurance systems, and employers to utilize REN for migraine prevention.

Acute Treatment of Migraine in Adolescents: Real-World Analysis of Remote Electrical Neuromodulation (REN).

Nearly 10% of children and adolescents in the United States experience migraine. Pharmacologic treatment of migraine in adolescents is limited due to only few US Food and Drug Administration (FDA)-approved medications, limited efficacy, or lack of tolerability. Remote Electrical Neuromodulation (REN) is a nonpharmacologic abortive treatment for migraine, cleared by the FDA for patients aged 12 years and above. This study evaluated real-world efficacy of REN in adolescents aged 12 to 17 years. Real-world data were collected from patients aged 12 to 17 years treated with the REN device (Nerivio) from January 1, 2021, to May 31, 2022. Study's end points included consistent efficacy two hours after treatment, use of REN as a standalone versus as an adjunct therapy, treatment intensity, and safety. Of 1629 adolescents included in the study, consistent response in at least 50% of treatments at two hours posttreatment was achieved by 60.3% of patients for pain relief, 26.3% for pain freedom, 66.3% for functional disability relief, and 41.2% for functional disability freedom. Of 2365 treatments in which medication usage was reported, REN was used as standalone therapy in 64.4% of the treatments, REN was combined with over-the-counter medications in 18.6%, and it was combined with prescription medications in 17%. Mean treatment intensity from 13,716 treatments was 28.5% (±13.6%) of the max stimulator output. Only three device-related adverse events were reported, all minor. This real-world analysis demonstrates the persistent efficacy of REN for abortive treatment of migraine in adolescents, extending findings of prior clinical trials in adolescents and real-world studies in adults.

Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine. BACKGROUND: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary. RESULTS: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval -3.9 to -1.5], p < 0.001). The significance was maintained when analyzing the episodic (-3.2 ± 3.4 vs. -1.0 ± 3.6, p = 0.003) and chronic (-4.7 ± 4.4 vs. -1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group. CONCLUSION: Applied every other day, REN is effective and safe for the prevention of migraine.

Effectiveness comparison of remote electrical neuromodulation and standard-care medications for acute treatment of chronic migraine: a post-hoc analysis.

Aim: The current study compared the effectiveness of remote electrical neuromodulation (REN) to that of standard-care medications for acute treatments of migraine, using a within-subjects design. Materials & methods: Post-hoc within-subject analysis was performed on data from 78 adult chronic migraine patients who participated in a clinical trial with REN, on four end points: single-treatment pain relief, single-treatment pain freedom, consistency of pain relief and consistency of pain freedom. Results: No statistical differences were found between REN and the tested medications, in any of the effectiveness outcomes: single-treatment pain relief p = 0.056, single-treatment pain freedom p = 0.532, consistency of pain relief p = 0.369, consistency of pain freedom p = 1.00. Conclusion: The results suggest that REN may provide an effective non-pharmacological alternative for standard care abortive medications in individuals impacted by chronic migraine.

Due to the high frequency of headaches, patients impacted by chronic migraine are struggling with poor quality of life, as well as elevated risk of medication overuse headache (which might cause migraine chronification). Thus, there is a need for non-pharmacological migraine treatments that are both effective and well tolerated. Remote electrical neuromodulation (REN) is a non-pharmacological abortive migraine treatment, which is US FDA cleared for adults and adolescents with episodic or chronic migraine. The current study compared the effectiveness of REN to that of standard-care medications (i.e., over-the-counter medications and triptans), using data from 78 individuals with chronic migraine who participated in a clinical trial. During the study, each participant treated their attacks with their preferred medication for the first 4 weeks, and then treated their attacks with REN (only) for the following four weeks. The participants rated their pain level prior to each treatment, and 2 h after the beginning of the treatment. The results indicate no statistical difference between the effectiveness of REN and standard care medications and suggest that REN may provide an effective non-pharmacological alternative for standard care abortive medications, for individuals with chronic migraine.

Combining Guided Intervention of Education and Relaxation (GIER) with Remote Electrical Neuromodulation (REN) in the Acute Treatment of Migraine.

BACKGROUND: Evidence indicates that combining behavioral treatments with pharmacological treatments for migraine prevention improves efficacy, but little is known about the outcomes of combining neuromodulation and behavioral interventions for acute treatment of migraine. Remote electrical neuromodulation (REN) is a U.S. Food and Drug Administration (FDA)-cleared nonpharmacological migraine treatment. The present study evaluated the clinical benefits of augmenting REN treatment with a specially tailored behavioral therapy consisting of Guided Intervention of Education and Relaxation (GIER) for the acute treatment of migraine. METHODS: In this two-arm observational study, real-world data were collected from patients across the United States who were using the REN device. Eighty-five migraine patients ≥18 years of age who treated their attacks with REN in parallel with the GIER intervention were individually matched on age and sex with 85 patients who used REN alone. The groups were compared on the proportion of migraine attacks in which they achieved pain relief, pain freedom, improvement of function, and return to normal function, all at 2 hours after treatment. RESULTS: Data from 170 users were analyzed (85 per group). Compared with the REN-only group, the REN+GIER group displayed a statistically significant higher proportion of patients achieving consistent pain relief (P = 0.008), consistent improvement in function (P = 0.014), and consistent return to normal function (P = 0.005), all at 2 hours after treatment. CONCLUSIONS: The results suggest that combining the GIER behavioral intervention with REN treatment can improve the therapeutic efficacy beyond that of REN alone, in terms of both pain level and improvement of disability.

Comparison of Remote Electrical Neuromodulation and Standard-Care Medications for Acute Treatment of Migraine in Adolescents: A Post Hoc Analysis.

OBJECTIVE: There is an unmet need for new, efficacious, well-tolerated, acute treatments for migraine in adolescents. Remote electrical neuromodulation (REN) is a novel, nonpharmacological treatment that provides significant symptom relief with good tolerability. The current post hoc analysis compared the efficacy of REN to that of standard-care medications for the acute treatment of migraine in adolescents. DESIGN: Within-participant post hoc analysis of data from a clinical trial. SETTING: Data from a clinical trial. SUBJECTS: Data from 35 adolescent participants were analyzed. METHODS: Efficacy was compared between a run-in phase, in which attacks were treated with standard-care medications (triptans or over-the-counter medications), and an intervention phase, in which attacks were treated with REN. Efficacy was compared within participants through the use of McNemar's test at four endpoints (2 hours after treatment): single-treatment pain freedom and pain relief, and consistency of pain freedom and pain relief (defined as response in at least 50% of the available first four treatments). RESULTS: At 2 hours after treatment, pain freedom was achieved by 37.1% of the participants with REN, vs 8.6% of the participants with medications (P = 0.004). Pain relief was achieved by 71.4% with REN, vs 57.1% with medications (P = 0.225). Consistency of pain freedom was achieved by 40% with REN, vs 8.6% with medications (P < 0.001). Consistency of pain relief was achieved by 80.0% with REN, vs 57.2% with medications (P = 0.033). CONCLUSIONS: Our results suggest that REN may have higher efficacy than certain standard-care medications for the acute treatment of migraine in adolescents. A larger-scale, blinded comparative-effectiveness and tolerability study is needed.

Safety and efficacy of remote electrical neuromodulation for the acute treatment of chronic migraine: an open-label study.

INTRODUCTION: Remote electrical neuromodulation (REN) is an acute treatment of migraine. The results from several studies in patients with episodic migraine suggest that REN is an effective and safe acute treatment of migraine. A recent pilot study provided initial support that REN is effective in patients with chronic migraine as well. OBJECTIVES: The current study aimed to validate and provide further evidence for the safety and efficacy of REN in a large sample of patients impacted by chronic migraine. METHODS: In this open-label, single-arm study, patients with chronic migraine treated their headaches with the REN device (Nerivio, Theranica Bio-Electronics Ltd, Israel) for 4 weeks. Participants used an electronic diary to record their symptoms at treatment initiation, 2 hours after treatment, and 24 hours after treatment. The primary end point was the percentage of subjects who achieved pain relief at 2 hours posttreatment. Secondary end points included pain freedom and improvement of associated symptoms and functional disability. RESULTS: One hundred twenty-six subjects were enrolled into the study, of which 91 subjects had an evaluable treatment with REN. Pain relief and pain disappearance at 2 hours were achieved by 59.3% (54/91) and 20.9% (19/91) of modified intent-to-treat subjects, respectively (with worst-case sensitivity analysis indicating 54.5% and 19.2%, respectively). Sustained pain relief at 24 hours was observed in 64.4% (29/45) of those who achieved pain relief at 2 hours (with worst-case sensitivity analysis indicating 45.6%). The findings of the study show that REN has a favorable effect on nausea, photophobia, and phonophobia and improves functional ability. One device-related adverse event was reported. CONCLUSIONS: Remote electrical neuromodulation treatments results in the relief of migraine headaches and associated symptoms, thus offering a drug-free acute treatment option for people with chronic migraine. TRIAL REGISTRATION: ClinicalTrials.gov NCT04194008.

Remote Electrical Neuromodulation (REN) for the Acute Treatment of Menstrual Migraine: a Retrospective Survey Study of Effectiveness and Tolerability.

INTRODUCTION: Migraine is one of the most prevalent neurological disorders worldwide, and estimations are that 60% of women who suffer from migraines experience attacks that are associated with menstruation. Menstrual migraines are typically more debilitating and less responsive to pharmacological treatment. Remote electrical neuromodulation (REN) is a non-pharmacological abortive treatment of migraine headache. The current study evaluated the self-reported effectiveness and tolerability of REN for the acute treatment of menstrual migraine, via a retrospective structured survey that was sent to adult female REN users. METHODS: Women aged 18-55 years who experience menstrually related or pure menstrual migraine and have completed at least four REN treatments, participated in this retrospective, observational survey study. Participants completed a short online survey assessing effectiveness, satisfaction, and safety outcomes. RESULTS: Ninety-one participants qualified for the analysis, out of which 74.7% (68/91) reported that the treatment was at least moderately effective (moderately effective 37.4%, very effective 26.4%, extremely effective 11.0%). Additionally, 45.1% (41/91) reported satisfaction from REN (slightly satisfied 33%, extremely satisfied 12.1%), while 34.1% were neutral and 20.9% (19/91) were not satisfied. Lastly, 100% of the participants reported that the treatment is at least moderately tolerable (moderately tolerable 8.8%, very tolerable 20.9%, extremely tolerable 70.3%), and 13.2% (12/91) of respondents reported mild short-term side effects. CONCLUSIONS: Nearly 75% reported that the treatment was at least moderately effective, 45% reported satisfaction, and 100% of the participants reported that the treatment is at least moderately tolerable. Thirteen percent reported mild short-term side effects. REN was thus reported as effective for menstrual migraine by most participants and was very well tolerated. Therefore, REN may provide a safe, non-pharmacological alternative for the acute treatment of menstrual migraine. CLINICALTRIAL. GOV REGISTRATION NUMBER: NCT04600388.

Remote electrical neuromodulation for acute treatment of migraine in adolescents.

OBJECTIVES: Migraine is a common disabling neurological disorder. Current acute treatments for migraine in adolescents are mostly pharmacological and may have limited effectiveness, can cause side effects, and may lead to medication overuse. There is an unmet need for effective and well-tolerated treatments. Remote electrical neuromodulation (REN) is a novel acute treatment of migraine that stimulates upper arm peripheral nerves to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism. The REN device (Nerivio® , Theranica Bio-Electronics Ltd., Israel) is a FDA-authorized device for acute treatment of migraine in adults. This study assessed the efficacy and safety of REN in adolescents with migraine. DESIGN AND METHODS: This was an open-label, single-arm, multicenter study in adolescents (ages 12-17 years) with migraine. Participants underwent a 4-week run-in phase. Eligible participants continued to an 8-week treatment phase with the device. Pain severity, associated symptoms, and functional disability were recorded at treatment initiation, and 2 and 24 hours post-treatment. The primary endpoints of this study were related to the safety and tolerability of REN. The secondary endpoints were related to device efficacy and included the proportion of participants who achieved pain relief at 2 hours post-treatment and the proportion of participants who achieved pain freedom at 2 hours. The presented results reflect an interim analysis with subsequent stopping of the rest of the study. RESULTS: Sixty participants were enrolled for the study; of these, 14 failed to meet the run-in criteria and 1 was lost to follow-up. Forty-five participants performed at least one treatment, of which 39 participants completed a test treatment with REN. One device-related adverse event (2%) was reported in which a temporary feeling of pain in the arm was felt. Pain relief and pain-free at 2 hours were achieved by 71% (28/39) and 35% (14/39) participants, respectively. At 2 hours, 69% (23/33) participants experienced improvement in functional ability. CONCLUSIONS: REN may offer a safe and effective non-pharmacological alternative for acute treatment in adolescents.

Real-World Analysis of Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine.

Introduction: Migraine is a chronic neurological disease that is the primary cause of years lived with disability in people under the age of 50. Remote electrical neuromodulation (REN) is a novel drug-free acute treatment of migraine, that is FDA cleared for episodic and chronic migraine. As a prescribed digital therapeutic, REN enables large-scale post-marketing research, thus providing real-world information on the use of the intervention in a wide range of populations, environments, and situations. Methods: The REN device (®Nerivio) includes a secured, personal migraine diary, which patients can use to record their symptoms before treatment and 2 h post-treatment. Real-world data on REN treatments were collected via the app from patients across the United States who used Nerivio between October 1st, 2019, and May 24th, 2021. Data analysis focused on four metrics: 1. Per-treatment patterns of REN use as a standalone treatment vs. in combination with medications. 2. Per-user intra-individual efficacy across multiple treatments. 3. Distribution of treatment intensity among users (the electroceutical equivalent to treatment dose). 4. Prevalence and severity of adverse events. Results: 1. Out of 23,151 treatments, in 66.5% of treatments REN was used as a standalone treatment, in 12.9% it was followed by over-the-counter medications, and in 20.6% followed by prescription medications. 2. Out of 2,514 patients, response in at least 50% of treatments was achieved in 66.5% of cases for pain relief, and in 22.6% for pain freedom. 3. Out of 117,583 treatments, in 80% of cases intensity levels were between 18 and 55% of the stimulator's range. The mean intensity was 34.3% of the stimulator's output (±16.6%). 4. Out of 12,368 users (121,947 treatments), there were 59 users (0.48%) who reported device related adverse events, 56 (0.45%) of which were mild, three (0.03%) were moderate, and none were severe. Conclusions: The current analysis of real-world clinical data indicates that REN provides an efficacious, stable, and safe treatment option for acute treatment of migraine in real-world settings, both as a standalone replacement of pharmaceuticals, as well as an adjunct to medications.

Real-world Experience with Remote Electrical Neuromodulation in the Acute Treatment of Migraine.

OBJECTIVE: Remote electrical neuromodulation (REN) is a nonpharmacological acute migraine treatment that stimulates upper-arm peripheral nerves. The aim of this investigation was to evaluate the effectiveness and safety of REN for acute treatment of migraine in a real-world setting. METHODS: Real-world data were collected from patients who were using REN (Nerivio®, Theranica Bio-Electronics Ltd., Israel) between October 1, 2019, and March 31, 2020. Patients recorded their symptoms at baseline, two hours, and 24 hours post-treatment. Patients were stratified based on the type of visit and provider; in-person visits with headache specialists (HS group) or virtual visits with nonheadache specialists (NHS group). Efficacy outcome focused on intra-individual consistency of response across multiple attacks. RESULTS: We found that 58.9% (662/1,123) of the patients in the HS group and 74.2% (23/31) of the patients in the NHS group experienced pain relief at two hours in at least 50% of their treated attacks and 20.0% (268/1,339) of the patients in the HS group and 35.6% (16/45) of the patients in the NHS group experienced pain freedom at two hours in at least 50% of their treated attacks. The effects of REN on associated symptoms and improvement in function were also consistent in both groups. The incidence of device-related adverse events was very low (0.5%). CONCLUSIONS: Real-world data confirm that REN results in meaningful clinical benefits with minimal side effects. REN may provide an effective drug-free treatment option for achieving consistent relief from migraine symptoms and may reduce the use of acute medications.

Remote Electrical Neuromodulation for the Acute Treatment of Migraine in Patients with Chronic Migraine: An Open-Label Pilot Study.

INTRODUCTION: Remote electrical neuromodulation (REN) is a novel acute treatment of migraine. Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. The REN device (Nerivio®, Theranica Bio-Electronics LTD., Israel) is FDA-authorized for acute treatment of migraine in adults who do not have chronic migraine. The current study assessed the consistency of response over multiple migraine attacks in people with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans. METHODS: This was an open-label, single-arm, dual-center study conducted on adults with chronic migraine. Participants underwent a 4-week treatment phase in which they treated their migraine headaches with the device for 45 min within 1 h of attack onset. Pain levels were recorded at baseline, 2 h, and 24 h post-treatment. Efficacy outcomes (pain relief and pain-free responses at 2 h, sustained pain relief and sustained pain-free responses at 24 h) focused on intra-individual consistency of response across multiple attacks, which was defined as response in at least 50% of the treatments. RESULTS: Forty-two participants were enrolled, and 38 participants were evaluable for analyses; 73.7% (28/38) achieved pain relief at 2 h, 26.3% (10/38) were pain-free at 2 h, 84.4% (27/32) had sustained pain relief response at 24 h and 45.0% (9/20) had sustained pain relief response at 24 h in at least 50% of their treated attacks. The effects of REN on associated symptoms and improvement in function were also consistent. The incidence of device-related adverse events was low (1.8%). CONCLUSIONS: REN used for a series of migraine attacks was effective and well tolerated across attacks. REN may offer a safe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04161807. Retrospectively registered on November 13, 2019.

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

Background: A recent randomized controlled study showed that 66.7% (66/99) and 37.4% (37/99) of people undergoing remote electrical neuromodulation (REN), a novel non-pharmacological migraine treatment, achieve pain relief and pain freedom, respectively, at 2 h post-treatment. The participants who completed the 6-weeks double-blind phase of this study were offered to participate in an open-label extension (OLE) with an active REN device. Objective: This study investigated the clinical use of REN, focusing on its potential in reducing the use of acute migraine medications. Methods: The parent study for this open-label extension (OLE) was a randomized, double-blind, sham-controlled study of acute treatment conducted on 296 participants enrolled at 12 sites in the USA and Israel. This study included a run-in phase, in which migraine attacks were treated with usual care, and an 8-weeks double-blind treatment phase. One hundred sixty participants continued in an 8-weeks OLE phase in which they could incorporate a REN device into their usual care. Medication use rate (percentage of participants who treated their attacks only with REN and avoided medications in all their attacks) and pain outcomes at 2 h post-treatment were compared between the OLE and the run-in phase in a within-subject design. Results: The analyses were performed on 117 participants with episodic migraine. During the OLE, 89.7% of the participants treated their attacks only with REN and avoided medications in all their attacks compared with 15.4% in the run-in phase (p < 0.0001). The rates of pain relief and pain-free in at least 50% of the treatments at 2 h post-treatment were comparable (pain relief: 58.1% in the run-in phase and 57.3% in the OLE, p = 0.999; pain-free: 23.1% in the run-in vs. 30.8% in the OLE, p = 0.175). Conclusions: REN may reduce the use of acute migraine medications. Thus, incorporating REN into usual care may reduce the risk for medication overuse headache (MOH). Future studies should evaluate whether REN reduces the use of acute migraine medications in a population at risk for MOH.

Remote electrical neuromodulation (REN) in the acute treatment of migraine: a comparison with usual care and acute migraine medications.

BACKGROUND: There is a significant unmet need for new, effective and well tolerated acute migraine treatments. A recent study has demonstrated that a novel remote electrical neuromodulation (REN) treatment provides superior clinically meaningful pain relief with a low rate of device-related adverse events. The results reported herein compare the efficacy of REN with current standard of care in the acute treatments of migraine. METHODS: We performed a post-hoc analysis on a subgroup of participants with migraine from a randomized, double-blind, parallel-group, sham-controlled, multicenter study on acute care. The original study included a 2-4 weeks run-in phase, in which migraine attacks were treated according to patient preference (i.e., usual care) and reported in an electronic diary; next, participants entered a double-blind treatment phase in which they treated the attacks with an active or sham device. The efficacy of REN was compared to the efficacy of usual care or pharmacological treatments in the run-in phase in a within-subject design that included participants who treated at least one attack with the active REN device and reported pain intensity at 2 h post-treatment. RESULTS: Of the 252 patients randomized, there were 99 participants available for analysis. At 2 h post-treatment, pain relief was achieved in 66.7% of the participants using REN versus 52.5% participants with usual care (p < 0.05). Pain relief at 2 h in at least one of two attacks was achieved by 84.4% of participants versus 68.9% in usual care (p < 0.05). REN and usual care were similarly effective for pain-free status at 2 h. The results also demonstrate the non-inferiority of REN compared with acute pharmacological treatments and its non-dependency on preventive medication use. CONCLUSION: REN is an effective acute treatment for migraine with non-inferior efficacy compared to current acute migraine therapies. Together with a very favorable safety profile, these findings suggest that REN may offer a promising alternative for the acute treatment of migraine and could be considered first line treatment in some patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03361423 . Registered 18 November 2017.

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

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.

Nonpainful remote electrical stimulation alleviates episodic migraine pain.

OBJECTIVE: To evaluate the efficacy of remote nonpainful electrical upper arm skin stimulation in reducing migraine attack pain. METHODS: This is a prospective, double-blinded, randomized, crossover, sham-controlled trial. Migraineurs applied skin electrodes to the upper arm soon after attack onset for 20 minutes, at various pulse widths, and refrained from medications for 2 hours. Patients were asked to use the device for up to 20 attacks. RESULTS: In 71 patients (299 treatments) with evaluable data, 50% pain reduction was obtained for 64% of participants based on best of 200-µs, 150-µs, and 100-µs pulse width stimuli per individual vs 26% for sham stimuli. Greater pain reduction was found for active stimulation vs placebo; for those starting at severe or moderate pain, reduction (1) to mild or no pain occurred in 58% (25/43) of participants (66/134 treatments) for the 200-µs stimulation protocol and 24% (4/17; 8/29 treatments) for placebo (p = 0.02), and (2) to no pain occurred in 30% (13/43) of participants (37/134 treatments) and 6% (1/17; 5/29 treatments), respectively (p = 0.004). Earlier application of the treatment, within 20 minutes of attack onset, yielded better results: 46.7% pain reduction as opposed to 24.9% reduction when started later (p = 0.02). CONCLUSION: Nonpainful remote skin stimulation can significantly reduce migraine pain, especially when applied early in an attack. This is presumably by activating descending inhibition pathways via the conditioned pain modulation effect. This treatment may be proposed as an attractive nonpharmacologic, easy to use, adverse event free, and inexpensive tool to reduce migraine pain. CLINICALTRIALSGOV IDENTIFIER: NCT02453399. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with an acute migraine headache, remote nonpainful electrical stimulation on the upper arm skin reduces migraine pain.