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.

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.

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.

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.

Neuromodulation techniques for acute and preventive migraine treatment: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Several neuromodulation methods exists for migraine treatment. The aim of the present study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) focusing on migraine treatment using neurostimulation methods. METHODS: We searched Medline and Embase up to July 1, 2020 for RCTs reporting acute or preventive treatment of migraine with either non-invasive or invasive neurostimulation methods. Two researchers independently assessed the eligibility of the retrieved studies and extracted data. Outcomes for the quantitative synthesis were 2 h pain free for acute treatment and headache days per month for preventive treatment. We performed subgroup analyses by treatment (stimulation method and site of application). Estimates were pooled using random-effects meta-analysis. RESULTS: Thirty-eight articles were included in the qualitative analysis (7 acute, 31 preventive) and 34 in the quantitative evaluation (6 acute, 28 preventive). Remote electrical neuromodulation (REN) was effective for acute treatment. Data were insufficient to draw conclusions for any other techniques (single studies). Invasive occipital nerve stimulation (ONS) was effective for migraine prevention, with a large effect size but considerable heterogeneity, whereas supra-orbital transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), and high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) were effective, with small to medium effect sizes. Vagus-nerve stimulation, left prefrontal cortex rTMS, and cathodal transcranial direct current stimulation (tDCS) over the M1 had no significant effect and heterogeneity was high. CONCLUSION: Several neuromodulation methods are of potential interest for migraine management, but the quality of the evidence is very poor. Future large and well-conducted studies are needed and could improve on the present results.

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) for the Acute Treatment of Migraine.

There is a significant unmet need for novel, effective, and well-tolerated acute migraine treatments. Remote electrical neuromodulation (REN) is a non-pharmacological, non-invasive, acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation - an endogenous analgesic mechanism in which a conditioning stimulation inhibits pain in remote body regions. This review presents the method of action and the clinical data of REN and discusses its potential patient benefits. The clinically meaningful efficacy, together with a very favorable safety profile, suggests that REN may offer a promising alternative for the acute treatment of migraine and could be considered first-line treatment in some patients.

Device profile of the Nerivio™ for acute migraine treatment: overview of its efficacy and safety.

Introduction: Noninvasive neuromodulation devices represent an emerging field in the acute treatment of migraine. High efficacy, favorable safety profile, good tolerability and low cost are important factors for the desired shift to non-pharmacological treatments. This will have the potential to improve the quality of life of people with migraine and reduce the risk for adverse events and medication overuse headache (MOH).Areas covered: Nerivio™ (Theranica Bio-Electronics, Israel) is a novel FDA-cleared remote electrical neuromodulation (REN) device for acute treatment of migraine. This review highlights the mechanism of action of REN and summarizes the clinical data. Nerivio™ has been studied in two randomized trials which provide support for the efficacy and safety of the device. Post-hoc analyses suggest that the efficacy of REN is non-inferior to usual care in general and to acute pharmacological treatments specifically.Expert commentary: Nerivo™ integrates clinically meaningful efficacy with a high safety profile, satisfying a great unmet need in migraine acute care. The unique mechanism of action, in which the electrical stimulation is applied to peripheral nerves in the upper arm, permits the introduction of an innovative device with high efficacy and superior and improved usability aspects compared with acute pharmacological treatments and other approved devices.

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.