Remote Electrical Neuromodulation for Migraines - CAM 701171

Description
Migraine attacks due to episodic or chronic migraine require acute management. Some individuals may also require preventive migraine therapy. Current first-line therapy for treatment and prevention of acute migraine involves use of various pharmacologic interventions. Regular use of pharmacologic interventions can result in medication overuse and increased risk of progression from episodic to chronic migraine. Nonpharmacologic remote electrical neuromodulation (REN) may offer an alternative to pharmacologic interventions for patients with migraine.

Summary of Evidence
For individuals with acute migraine due to episodic or chronic migraine who receive remote electrical neuromodulation (REN), the evidence includes 2 randomized controlled trials (RCTs) and nonrandomized, uncontrolled studies. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Use of an active REN device resulted in more patients with improved pain and symptoms at 2-hour follow-up compared with a sham device based on 2 RCTs (N=212) with numerous relevance limitations. Based on the existing evidence, it is unclear how Nerivio would fit into the current acute migraine management pathway. No significant between-group difference in functional disability or quality of life was noted in a post-hoc analysis of the pivotal RCT. Additionally, controlled studies in adolescent and pediatric populations are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For adult individuals who may benefit from preventive migraine therapy, including those with frequent or long-lasting episodic or chronic migraines, migraine attacks that diminish quality of life or cause significant disability despite acute treatment, contraindications to or failure of acute therapies, and risk of medication overuse headache, who receive REN, the evidence includes 1 RCT and 1 prospective, observational study. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Use of an active REN device resulted in more adults with decreased migraine days per month, regardless of episodic or chronic subtype, when used every other day for 8 weeks compared with a sham device based on 1 RCT (N=248). Prospective, observational data in 2 real world evidence studies using the device for acute treatment of migraine demonstrated a significant reduction in migraine headache days from baseline to months 2 and 3 with device use in adolescent patients. Based on the existing evidence, it is unclear how Nerivio would fit into the current migraine prevention pathway, although it could provide benefit for those who do not receive adequate benefit from pharmacologic first- or second-line therapies, or who may have a contraindication to pharmacologic therapies. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For adolescent individuals who may benefit from preventive migraine therapy who receive REN, the evidence includes data from the summary submitted in the FDA approval packet and 1 RWE analysis. The data in the FDA summary were collected from adolescents who used the device for acute migraine treatment, but use was equivalent to the suggested preventive use (10 times per month or higher). There was substantial reduction from baseline during months 2 and 3 of device use. This data is limited by a lack of comparator and no description of medications or alternative interventions patients were additionally using. A prospective, real-world evidence analysis investigated the use of Nerivio in adolescents over a 3 month period. There was a statistically significant monthly reduction in mean monthly migraine treatment days. Well-defined, controlled studies are required to confirm benefit in this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For children who may benefit from preventive migraine therapy who receive REN, the evidence includes the FDA summary for the expanded approval of preventive use of Nerivio in pediatric patients (ages 8-11) based on a retrospective real-world analysis. Preventive use of the device was assumed by analyzing patients whose frequency of use in month one was suggestive of preventive treatments. No specific data on proportion of patients in whom preventive use was assumed or efficacy outcomes in the assumed preventive use population were reported. Well-defined, controlled studies are required to confirm benefit in this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information
2025 Input
Clinical input was sought to help determine whether the use of remote electrical neuromodulation (i.e., Nerivio) for the listed populations would provide a clinically meaningful improvement in net health outcome and represents generally accepted medical practice:

Individuals who are 12 years and older with episodic or chronic migraine, with or without aura, who are treated for acute migraine or migraine prophylaxis
Individuals who are 8-11 years old with episodic or chronic migraine, with or without aura, who are treated for acute migraine or migraine prophylaxis

In response to structured requests, clinical input was received from 4 respondents, including 1 physician-level respondent identified by the American Academy of Neurology (AAN), and 3 physician-level responses identified by various academic medical centers. In addition, an informal response was provided by the American Academy of Pediatrics Section on Neurology (AAP).

Clinical input supports this use provides a clinically meaningful benefit, with the majority of respondents supportive that its use is consistent with generally accepted medical practice, although the societal responses were neutral. Respondents noted that all patients with migraine may benefit from a nonpharmacologic option for either stand-alone or adjunctive use, particularly among those who have failed other options, who have contraindications or an intolerance to alternatives, who are at risk for or have a history of medication overuse headache, or who are at risk of drug-drug interactions. While some clinicians trial acute treatment with REN first, failure in the abortive setting does not preclude success with preventive use. Additionally, clinicians support first-line use of REN for acute or preventive treatment, particularly in adolescent and pediatric populations where there are limited alternatives with evidence of efficacy or tolerable side effect profiles. Respondents emphasize that the discreet nature of the REN device is ideal for use by children and adolescents in the school setting.

Further details from clinical input are included in the Appendix.

Background
Migraine is a neurologic disease characterized by recurrent moderate to severe headaches with associated symptoms that can include aura, photophobia, nausea, and/or vomiting.^1, Overall migraine prevalence in the United States is about 15% but varies according to population group.^2, Prevalence is higher in women (21%), among American Indian/Alaska Natives (22%), and among 18- to 44-year-olds (19%). Social determinants including low education level (18%), use of Medicaid (27%), high poverty level (23%), and being unemployed (22%) are also associated with higher rates of migraine.

Migraine is categorized as episodic or chronic depending on the frequency of attacks. Generally, episodic migraine is characterized by 14 or fewer headache days per month and chronic migraine is characterized by 15 or more headache days per month.^3, Specific International Classification of Headache Disorders^4, diagnostic criteria are as follows:

Episodic migraine:
1. Untreated or unsuccessfully treated headache lasting 4 to 72 hours
2. Headache has at least 2 of the following characteristics:
  1. Unilateral location
  2. Pulsating quality
  3. Moderate or severe pain intensity
  4. Aggravation by or causing avoidance of routine physical activity
3. At least 1 of the following during headache:
  1. Nausea and/or vomiting
  2. Photophobia or phonophobia.
Chronic migraine:
1. Migraine-like or tension-type headache on 15 or more days per month for more than 3 months
2. At least 5 headache attacks without aura meet episodic migraine criteria 1 to 3, and/or at least 5 headache attacks with aura meet episodic migraine criteria 2 to 3
3. On more than 8 days per month for more than 3 months, fulfilling any of the following criteria:
  1. For migraine without aura, episodic migraine criteria 2 and 3
  2. For migraine with aura, episodic migraine criteria 1 and 2
  3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative.

Migraine attacks, whether due to episodic or chronic migraine, require acute management. The goal of acute treatment is to provide pain and symptom relief as quickly as possible while minimizing adverse effects, with the intent of timely return to normal function. Pharmacologic interventions for treatment of acute migraine vary according to migraine severity. First-line therapy for an acute episode of mild or moderate migraine includes oral non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen. Moderate to severe migraine can be treated through the use of triptans or an NSAID-triptan combination. Antiemetics can be added for migraine accompanied by nausea or vomiting, though certain antiemetic medications used as monotherapy can also provide migraine relief. Other pharmacologic interventions used to treat acute migraine include calcitonin-gene related peptide antagonists, which can be used in patients with an insufficient response or contraindications to triptans, lasmiditan, and dihydroergotamine. Migraine can be managed at home, although acute migraine is a frequently cited reason for primary care and emergency department visits.^5, Regular use of pharmacologic interventions can result in medication overuse, which in turn could lead to rebound headache and increased risk of progression from episodic to chronic migraine.^4,

Many individuals who suffer from migraine may also benefit from preventive migraine therapy, including those with frequent or long-lasting migraines, migraine attacks that diminish quality of life or cause significant disability despite acute treatment, contraindications to or failure of acute therapies, and risk of medication overuse headache.^6,7,8, The main goals of preventive therapy are to reduce future attack frequency, severity, and duration, improve responsiveness to acute treatments, improve function and reduce disability, and prevent progression of episodic migraine to chronic migraine. For most adults with episodic migraines who may benefit from preventive therapy, initial therapy with an antiepileptic drug (divalproex sodium, sodium valproate, topiramate) or beta-blockers (metoprolol, propranolol, timolol) is recommended. Frovatriptan may be beneficial as initial therapy for prevention of menstrually associated migraine. Antidepressants (amitriptyline, venlafaxine), alternative beta-blockers (atenolol, nadolol), and additional triptans (naratriptan, zolmitriptan for menstrually associated migraine prevention) may be considered if initial therapy is unsuccessful. For preventive treatment of pediatric migraine, many children and adolescents who received placebo in clinical trials improved and most preventive medications were not superior to placebo. Possibly effective preventive treatment options for children and adolescents may include amitriptyline, topiramate, or propranolol.

Remote Electrical Neuromodulation
Remote electrical neuromodulation (REN) may offer an alternative to pharmacologic interventions for patients with acute migraine or it may decrease the use of abortive or preventive medications and the risk of medication overuse to treat or prevent acute migraines. The only currently available REN device (Nerivio™) cleared for use by the Food and Drug Administration (FDA) is worn on the upper arm and stimulates the peripheral nerves to induce conditioned pain modulation (CPM). The conditioned pain in the arm induced by the Nerivio REN device is believed to reduce the perceived migraine pain intensity.^9, Control of the REN device is accomplished through Bluetooth communication between the device and the patient's smartphone or tablet. For acute treatment, at onset of migraine or aura and no later than within 1 hour of onset, the user initiates use of the device through their mobile application. When used for preventive treatment, the device should be used every other day, controlled by the individual through their smartphone or tablet application. Patient-controlled stimulation intensity ranges from 0% to 100%, corresponding to 0 to 40 milliamperes (mA) of electrical current. Patients are instructed to set the device to the strongest stimulation intensity that is just below their perceived pain level. The device provides stimulation for up to 45 minutes before turning off automatically. The Nerivio manufacturer indicates that the device can be used instead of or in addition to medication.

Regulatory Status
In May 2019, Nerivio Migra™ (Theranica Bio-Electronics Ltd.) was granted a de novo classification by the FDA (class II, special controls, product code: QGT).^10, This new classification applied to this device and substantially equivalent devices of this generic type. Nerivio Migra was initially cleared for treatment of acute migraine in adults who do not have chronic migraine.

In October 2020, Nerivio was cleared for marketing by the FDA through the 510(k) process (K201824). FDA determined that this device was substantially equivalent to Nerivio Migra for use in adults.^11, The device name changed to just “Nerivio” and the exclusion of chronic migraine patients was removed. The Nerivio device can provide more treatments than the predicate Nerivio Migra (12 treatments vs. 8 treatments) and has a longer shelf life (24 months vs. 9 months). In January 2021, the Nerivio device was cleared for use in patients aged 12 to 17 years.^12, In February 2023, Nerivio's indication was expanded to include preventive treatment of migraine with or without aura in individuals 12 years and age or older and was cleared for marketing through the 510(k) process (K223169).^13, In May 2025, the Nerivio and rechargeable Nerivio Infinity devices were cleared for marketing (K241756) with an expanded indication for acute and/or preventive treatment of migraine with or without aura in patients 8 years and older.^14,

Policy
Acute Treatment

Remote electrical neuromodulation for acute migraine is considered investigational therefore NOT MEDICALLY NECESSARY.

Preventive Treatment: Initiation of Use

Remote electrical neuromodulation (REN [e.g. Nerivio]) for the prevention of migraine may be considered MEDICALLY NECESSARY in individuals when the following criteria are met:

Individual is 18 years of age or older; AND
Headaches meet the International Classification of Headache Disorders (ICHD-3) diagnostic criteria for migraine with or without aura (see Policy Guidelines); AND
The REN device will be used in the following clinical scenario:
- For the prevention of migraine in individuals with 6 to 24 headache days (defined as a calendar day with headache regardless of severity or duration) per 28-day period in each of the 3 months preceding use of the REN device); AND
1 of the following additional criteria must also be met:
- Insufficient response, contraindication, or intolerance to 2 or more guideline-recommended preventive headache medications (e.g., anticonvulsants, antihypertensives, antidepressants, CGRP inhibitors); OR
- Pregnancy, breastfeeding, or planning to conceive; OR
- At risk for or have a history of medication overuse headache; OR
- At risk for drug-drug interactions with medications for comorbid conditions.

Preventive Treatment: Continuation of Use

Continued use of the REN device and/or accessories for the prevention of migraine is considered medically necessary in individuals when the following criteria are met:

Compliance with ongoing use; AND
Documentation of clinical benefit (see Policy Guidelines).

Remote electrical neuromodulation for prevention of migraine outside of the above criteria is considered investigational (see Policy Guidelines Considerations).

Policy Guidelines
Remote Electrical Neuromodulation Contraindications
Nerivio is contraindicated in patients with uncontrolled epilepsy and patients with an active implantable medical device, such as a pacemaker, hearing aid implant, or any implanted electronic device. Nerivio has not been evaluated in patients with congestive heart failure, severe cardiac or cerebrovascular disease, pregnancy, or patients under the age of 8 years.

Considerations
There is significant unmet need for migraine treatments, including lack of access. Plans may need to consider local issues in determining coverage, particularly in pediatric populations. Clinical input respondents note that first-line use is especially recommended in children and adolescents due to limited alternatives with demonstrated efficacy or tolerable adverse effects. Reduction in school absenteeism is recommended in this age group to ascertain clinical benefit.

Remote electrical neuromodulation (REN [e.g. Nerivio]) for the prevention of migraine may be considered medically necessary in individuals when the following criteria are met:

Individual is 8-17 years of age; AND
Headaches meet the International Classification of Headache Disorders (ICHD-3) diagnostic criteria for migraine with or without aura (see Policy Guidelines); AND
The REN device will be used in the following clinical scenario:
- For the prevention of migraine in individuals with 6 to 24 headache days (defined as a calendar day with headache regardless of severity or duration) per 28-day period in each of the 3 months preceding use of the REN device).

Criteria for Migraine
The International Classification of Headache Disorders ICDH-3 criteria for migraine with and without aura can be accessed at https://ichd-3.org/1-migraine/.

Clinical Benefit for Continuation of Use
Documentation of clinical benefit for continuation of use may include a clinician attestation regarding any of the following outcomes:

Improvements in pain relief or freedom, particularly for acute use;
Reduction in headache frequency, duration, or severity;
Reduction in functional disability;
Reduction in absenteeism;
Reduction in concomitant headache medications.

Based on observed outcomes of pivotal studies of Nerivio and study duration recommendations from the International Headache Society concerning migraine neuromodulation trial designs, assessment for clinical benefit is reasonable after a minimum of 8-12 weeks for preventive treatment.

Coding
See the Codes table for details.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Acute Migraine due to Episodic or Chronic Migraine
Clinical Context and Therapy Purpose
The purpose of remote electrical neuromodulation (REN) in individuals who have acute migraine attacks due to episodic or chronic migraine is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with acute migraine due to episodic or chronic migraine.

Interventions
The therapy being considered is REN with the Nerivio device.

Comparators
The following therapies are currently being used to treat acute migraine due to episodic or chronic migraine: medical management or no treatment. A number of medications are used to treat migraine. First-line therapy for mild or moderate migraine includes oral non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen. More severe migraine can be treated through the use of triptans or an NSAID-triptan combination through a variety of routes (e.g. oral, nasal spray or powder, subcutaneous). Antiemetics can be added for migraine accompanied by nausea or vomiting. Other pharmacologic interventions used to treat acute migraine include calcitonin-gene related peptide antagonists, which can be used in patients with an insufficient response or contraindications to triptans, lasmiditan, and dihydroergotamine. Pharmacologic therapies have not been extensively studied in adolescent and pediatric populations. Options in this population have typically focused on use of ibuprofen, acetaminophen, and select triptans.

Outcomes
The general outcomes of interest are: symptoms, functional outcomes, quality of life, and treatment-related morbidity. Specific important health outcomes include freedom from migraine pain and bothersome symptoms, restored function (e.g. return to normal activities), and patient-assessed global impression of treatment. Examples of relevant outcome measures appear in Table 1. In adolescent and pediatric populations, functional disability can also be captured as changes in missed days of school.

Follow-up over several hours is needed to monitor for treatment effects.

Table 1. Health Outcome Measures Relevant to Acute Migraine Attack^3,^15,^16,

Outcome	Description
Pain free	No pain at defined assessment time (e.g. 2 hours)
Pain relief	Improvement of pain from moderate to severe at baseline to mild or none or pain scale improved at least 50% from baseline at defined assessment time (e.g. 2 hours)
Sustained pain free	No pain at initial assessment (e.g. 2 hours) and remains at follow-up assessment (e.g. 1 day) with no use of rescue medication or relapse (recurrence) within that time frame
Sustained pain relief	Improvement of pain from moderate to severe at baseline to mild or none or pain scale improved at least 50% from baseline at defined assessment time (e.g. 2 hours) and remains improved at follow-up assessment (e.g. 1 day) with no use of rescue medication or relapse (recurrence) within that time frame
Symptom relief	Improvement of most bothersome symptom(s) from moderate to severe at baseline to mild or none at defined assessment time (e.g. 2 hours)
Function relief	Improvement of function from moderate to severe at baseline to mild or none at defined assessment time (e.g. 2 hours)
Restored function	No restriction to perform work or usual activities at a defined assessment time (e.g. 2 hours)
Global impact of treatment	Patient assessment of functional disability and health-related quality of life using a Likert or other validated scale at a defined assessment time (e.g. 2 hours)
Global evaluation of treatment	Patient assessment of overall treatment effect (pain, symptom relief, adverse events) using a Likert or other validated scale at a defined assessment time (e.g. 2 hours)

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought;
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Use of REN for the treatment of migraine has been assessed in 2 RCTs (Yarnitsky et al, 2017^17, and 2019 ^18,) comparing an active REN device (Nerivio Migra) with a sham device in patients with an acute migraine attack due to episodic migraine (Table 2).

A pilot, crossover trial conducted by Yarnitsky et al (2017) included data from 71 (of 86 randomized) patients who received active or sham REN.^17, All patients were given an identical REN device that was preprogrammed to deliver in random order 4 active treatment sessions ranging from 80 to 120 hertz (Hz), corresponding to pulse widths of 50 to 200 millseconds, and 1 sham session of 0.1 hertz (45 millsecond pulse width). Both active and sham treatments were programmed for a duration of 20 minutes each. Most patients were women (80%) in their mid-40s (mean age: 46 years), with a mean of 5 migraine attacks per month with a mean pain intensity of 8.^8, corresponding to severe pain. Race and/or ethnicity were not reported. 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 (Table 3). When the device was programmed to deliver an active treatment session, it was most effective at reducing pain when used within 20 minutes of migraine onset. Treatment response to active REN diminished over time of initiation following migraine onset, and no active REN participants reported complete pain relief if the device was initiated more than 1 hour from onset. No adverse events 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. Study limitations appear in Tables 4 and 5.

A second, larger (N=252) RCT was conducted by Yarnitsky et al in 2019 (Table 2).^18, The mean age of study participants was 43 years, 81% were female. Most participants were of White race (88%); 7% were Black and less than 1% were Asian. Time since migraine diagnosis was not reported; participants experienced a mean of 7 migraine days per month. Seventy-one percent of participants managed migraines with the use of acute medication, but important details about type and dosage were not provided. At baseline, 50% of participants reported that light sensitivity was their most bothersome symptom apart from migraine pain, followed by nausea (27%) and sound sensitivity (19%). After a 2 to 4-week run-in during which study participants kept a headache diary, participants were randomized to 4 to 6 weeks of at-home active or sham REN. The frequency was 100 to 120 Hz for the active device and less than 0.1 Hz for the sham device. The pulse width was 400 microseconds for the active device, and ranged from 40 to 550 microseconds for the sham device, with the intent of mimicking a similar sensation as that delivered by the active device. At the time of randomization, participants were instructed on how to determine their optimal REN intensity, but this was unclearly defined as a threshold that was "perceptible not painful" (e.g., no specific measure of intensity was described) and no data on the actual intensities used during the study were reported. Participants were instructed to treat their migraine with the REN device as soon as possible following migraine onset, and no later than within 1 hour of onset. Participants who initiated device use more than 1 hour following onset were excluded from the outcome analyses. Study results are summarized in Table 3. Patients treated with active REN were more likely to report freedom from pain and pain relief at 2-hour follow-up, and sustained freedom from pain and pain relief at 48-hour follow-up compared with the sham REN group. There was no statistical between-group difference in the proportions of patients reporting freedom from their most bothersome symptom (MBS) at 2-hour follow-up, but a greater proportion of active REN patients reported MBS relief at 2 hours relative to sham REN. Device-related adverse events were reported in 5% of active REN and 2% of sham REN participants (p=.49). At the conclusion of the study, participants were asked whether they believed they had received active or sham treatment as a measure of blinding. Half as many active participants correctly identified their device as did sham participants (23% in the active group vs. 50% in the sham group), although statistical analyses determined the treatment outcome differences between groups were not affected by participants perceived treatment group.

Relevance and methodological limitations of the study are detailed in Tables 4 and 5. Several critical limitations were identified, primarily related to study design and conduct. The most significant limitations pertain to the 1) selection and measurement of outcomes and 2) imbalances in baseline characteristics that are potentially important confounders and 3) absence of statistical adjustments to account for these confounders. These limitations are detailed next.

Outcome Selection and Assessment
Contemporary best practices in migraine research emphasize the importance of aligning study endpoints with outcomes that matter most to patients- complete resolution of pain and most bothersome migraine-associated symptom (MBS).^19, Instead, Yarnitsky et al. (2019) measured pain relief as the primary endpoint relegating pain-free status and freedom from MBS to secondary outcomes. Pain-free status, which reflects total resolution of pain, is more consistent with patient expectations and real-world therapeutic goals. In contrast, pain relief is a subjective measure that may not fully restore functional capacity. Similarly, while MBS relief targets the symptom most disruptive to quality of life, its clinical relevance is diminished if it does not translate into improved daily functioning.

Migraine trials typically focus on individuals with moderate to severe pain as it reflects the typical clinical presentation. Only 10% of participants reported severe pain, and 51% reported moderate pain at baseline. Remaining 39% of patients reported mild pain at the baseline. Further, the primary outcome was a composite of improvement from severe/moderate pain to mild/ none, or improvement from mild pain to none. It is unclear whether the observed pain relief in 67% (66 of 99) of treated patients was primarily driven by clinically meaningful improvement (i.e. severe/moderate pain to mild/none), or merely resolution of mild pain to none. It is important to recognize that only 7 patients with severe pain at baseline were treated with Nerivio.

To assess precision, we calculated 95% confidence intervals for two key outcomes: pain-free status and MBS relief at two hours. In the treatment group, 37.4% of participants were pain-free (95% CI: 27.8-46.9), compared to 18.4% in the sham group (95% CI: 10.9-25.9). Although the 19% between group difference was statistically significant, the wide confidence interval (7% to 30%) indicates substantial uncertainty. No significant effect was observed for MBS resolution.

Imbalances in Baseline Characteristics
A second major limitation was the lack of stratified randomization for potentially important confounders that could influence treatment response, including duration of migraine, response to triptans, and current use of preventive medication. Despite randomization, the treatment and sham groups differed in triptan use (52% vs. 44%) and preventive medication use (29% vs. 37%). Migraine duration was not reported. Additionally, there were intra-group differences in baseline pain severity: mild (35% vs. 42%), moderate (58% vs. 45%), and severe (7% vs. 14%) in the treatment and sham groups, respectively.

Lack of Adjusted Analysis
Despite these imbalances, the study did not include adjusted analyses to control for key covariates such as triptan response (responder, insufficient responder, or naive), preventive medication use, or baseline headache severity. This omission limits the interpretability of the findings and raises concerns about residual confounding.

Conclusion
In the light of these major limitations, the results of Yarnitsky et al. (2019) cannot be interpreted at face value due to the potential for confounding. An adequately powered randomized, double-blind, placebo-controlled trial is necessary to clearly ascertain the net health outcome for Nerivio in treatment of acute migraine in individuals with moderate to severe headache.

A post-hoc analysis of the Yarnitsky 2019 RCT 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- to 4-week run-in phase of the trial.^20, Pharmacologic treatment used during the run-in phase consisted of NSAIDs, acetaminophen (alone, or in combination with aspirin and caffeine) or triptans. In 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=.099) at 2-hour follow-up. Results were similar for achievement of pain relief (66.7% [66/99] vs. 52.5% [52/99]; p=.034). Randomized controlled trials directly comparing REN with pharmacologic management are needed to confirm these pain findings and to compare the effect of REN versus pharmacologic management on other outcomes.

Table 2. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Yarnitsky et al (2017)^17,	Israel	1	2016-2016	Adults (18 to 75 years) with ICHD-3 migraine 2 to 8 days/month with no preventive medication use 2 months prior to enrollment	n=86 Active REN device; 4/5 preprogrammed treatment sessions	NA; crossover trial Sham REN device; 1/5 preprogrammed treatment sessions
Yarnitsky et al (2019)^18,	US, Israel	12	2017-2018	Adults (18 to 75 years) with ICHD-3 migraine 2 to 8 days/month but <12 days/month, with no or stable preventive medication use 2 months prior to enrollment	n=126 Active REN (Nerivio) device	n=126 Sham REN device

ICHD: International Classification of Headache Disorders; NA: not applicable; RCT: randomized controlled trial; REN: remote electrical neuromodulation.

Table 3. Summary of Key RCT Results

Study	Pain Free¹, 2 hours	Pain Relief², 2 hours	Sustained Pain Free, 48 hours	Sustained Pain Relief, 48 hours	MBS Free, 2 hours	MBS Relief³, 2 hours
Yarnitsky et al (2017)^17,
Active REN	44.1% (19/43)	76.7% (33/43)	NR	NR	NR	NR
Sham REN	5.9% (1/17)	23.5% (4/17)	NR	NR	NR	NR
p value	.005	.005	NR	NR	NR	NR
Yarnitsky et al (2019)^18,
Active REN	37.4% (37/99)	66.7% (66/99)	20.7% (18/87)	39.1% (34/87)	40.7% (33/81)	46.3% (44/95)
Sham REN	18.4% (19/103)	38.8% (40/103)	7.9% (7/89)	16.9% (15/89)	36.4% (32/88)	22.2% (22/99)
p value	.003	<.001	.014	.001	.55	.001

MBS: most bothersome symptom; NR: not reported; RCT: randomized controlled trial; REN: remote electrical neuromodulation.
¹ Change in headache severity from mild, moderate, or severe at baseline, to none.
²Change in headache severity from moderate, or severe at baseline, to none or mild, or a reduction in headache severity from mild to none.
³ Subjective (undefined) relief of most bothersome symptom.

Table 4. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Duration of Follow-up^e
Yarnitsky et al (2017)^17,	1, 2 Time since migraine diagnosis and details about current migraine management regimen not reported	4 Predicate device not commercially marketed	2 Comparison versus an acute treatment with established efficacy would be preferred	1, 5 Functional and quality of life outcome measures not addressed
Yarnitsky et al (2019)^18,	1, 2 Time since migraine diagnosis and details about current migraine management regimen not reported	1, 5 Details about the mean timing of device initiation and mean, recommended or optimal device intensity (in mA) were not reported; a clinically relevant device intensity threshold has not been established; mean duration of treatments not reported	1, 2 Details and subgroup analysis on the effect of preventive medication use in 29% of active and 37% of sham participants were not completely reported; comparison versus an acute treatment with established efficacy would be preferred	1, 5 Functional and quality of life outcome measures not addressed

mA: milliamperes.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aPopulation key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^bIntervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^cComparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^dOutcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^eFollow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 5. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Yarnitsky et al (2017)^17,	3 Method of allocation to active or sham treatment session not reported			1 No data reported for 17% (15/86) of enrolled participants	1 This was a pilot study; no sample size rationale or power calculations were reported
Yarnitsky et al (2019)^18,^10,		4 23% of REN vs. 50% of sham participants correctly identified their treatment allocation; however, ad-hoc statistical analyses determined between-group treatment differences were not affected by perceived treatment group		1 19% (49/252) of randomized participants not accounted for in analysis described as modified-ITT

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aAllocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^bBlinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^cSelective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^dData Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^ePower key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^fStatistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Avoiding medication overuse has been postulated as a potential benefit of REN treatment of acute migraine. Marmura et al (2020)^21, reported the results of an observational 8-week open-label extension study following the double-blind phase of the Yarnitsky 2019 trial. The Marmura study compared within-subject data (N=117) from the trial run-in phase with data from the open-label phase, finding that a higher proportion of patients avoided medication use during the open-label phase (when the REN device was available for use; 89.7%) than in the run-in phase (when the REN device was not available for use; 15.4%). Although these results suggest that use of the REN device could result in less medication use and therefore reduce the risk of medication overuse, confirmatory studies designed to directly assess the role of REN in populations at risk of medication overuse are needed.

Nonrandomized Studies
Numerous nonrandomized, uncontrolled studies have been conducted examining the effectiveness of REN with the Nerivio device for acute migraine.^{22,23,24,25,26,27,28,} The most relevant studies are discussed below.

Three single-arm, open-label clinical trials of the Nerivio device were used to inform US Food and Drug Administration (FDA) approval for use in patients other than those with acute migraine due to episodic migraine (Table 6). This includes 2 studies^27,25, in patients with chronic migraine and 1 study^24, in adolescents. In the 2 studies^25,27, of patients with chronic migraine, the mean age was 42 and 44 years, and was 15 years in the study of adolescents.^24,In all 3 studies most participants were female (60% to 83%) and of White race (86% to 100%). In the study by Hershey et al (2021)^24, 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; study results are summarized in Table 7. The Nerivio device was associated with improvements in pain, symptoms, and function in all 3 studies. Adverse events related to the Nerivio device occurred in 1.0% to 2.0% of study participants across the 3 studies; no serious adverse events 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 variable follow-up.

Table 6. Summary of Key Nonrandomized Clinical Trial Characteristics

Study	Country	Dates	Participants	Treatment	Follow-Up
Nierenburg et al 2020^25,	US, Israel	2019-2020	N=42 adults (18 to 75 years) with ICHD-3 chronic migraine	REN (Nerivio)	24 hours
Grosberg et al 2021^27,	US	2019-2020	N=126 adults (18 to 75 years) with ICHD-3 chronic migraine	REN (Nerivio)	24 hours
Hershey et al 2021^24,	US	2019-2020	N=45 adolescents (12 to 17 years) with ICHD-3 migraine ≥3 attacks/month	REN (Nerivio)	24 hours

ICHD: International Classification of Headache Disorders; REN: remote electrical neuromodulation.

Table 7. Summary of Key Nonrandomized Clinical Trial Results

Study	Pain Free, 2 hours	Pain Relief, 2 hours	Sustained Pain Free, 24 hours	Sustained Pain Relief, 24 hours	Symptom free, 2 hours	Functional improvement, 2 hours	Return to normal function, 2 hours
Nierenburg et al 2020^25,	N=38	N=38	N=20	N=32	N=31	N=35	N=35
Proportion (n/N)	26.3% (10/38)¹	73.7% (28/38)¹	45.0% (9/20)¹	84.4% (27/32)¹	Nausea/vomiting: 58.3% (14/24) Photophobia: 35.5% (11/31) Phonophobia: 40.0% (10/25)	45.7% (16/35)	28.6% (10/35)
Grosberg et al 2021^27,	N=99	N=99	NR	N=54	N=82	N=40	NR
Proportion (n/N)	19.2% (19/99)²	54.5% (54/99)³	NR	53.7% (29/54)	Nausea/vomiting: 40.8% (20/49) Photophobia: 36.6% (30/82) Phonophobia: 39.7% (129/73)	47.5% (19/40)	NR
Hershey et al 2021^24,	N=39	N=39	N=11	N=22	N=31	N=33	NR
Proportion (n/N)	35.9% (14/39)²	71.8% (28/39)³	90.9% (10/11)	90.9% (20/22)	Nausea/vomiting: 54.5% (12/22) Photophobia: 41.9% (13/31) Phonophobia: 40.0% (10/25)	69.7% (23/33)	NR

NR: not reported.
¹ Pain free and pain relief for at least 50% of treated attacks.
² Change in headache severity from mild, moderate, or severe at baseline to none.
³ Change in headache severity from moderate or severe at baseline to none or mild; or a reduction in headache severity from mild to none.

A post-hoc analysis of the Hershey et al (2021) study, conducted in adolescents, compared the effect of Nerivio use (during the study phase) versus medication use (during the run-in phase) based on within-subject data.^23, Thirty-five 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. Nerivio users were more likely to report freedom from pain than medication users (p=.004) but there was no difference between Nerivio and medication in the proportions of patients who achieved pain relief (p=.225). Studies designed to directly compare the Nerivio device with medication are needed to adequately assess comparative effectiveness.

A real-world study (Ailani et al, 2021) sponsored by the Nerivio manufacturer collected data from^23,151 treatments from 5,805 Nerivio users between October 2019 and May 2021.^22,This study is unique in including data on use of the Nerivio device as monotherapy and in combination with medications. Nerivio users reported use of medications (over-the counter, triptans, or other medications) in addition to the Nerivio device for about one-third of the treatment sessions. For use of Nerivio as monotherapy at 2-hour follow-up, the proportion of patients with freedom from pain, pain relief, return to normal function, and functional disability improvement was 20.3%, 55.6%, 24.9%, and 51.2%, respectively. When the Nerivio device was used in conjunction with medication, proportions ranged from 10.1% to 15.5% for freedom from pain, 38.5% to 51.3% for pain relief, 11.0% to 19.7% for return to normal function, and 39.8% to 49.6% for functional disability improvement, depending on the drug class used. While these results suggest that REN with the Nerivio device is efficacious in a highly selected group of individuals, additional evidence from well-designed RCTs is needed to thoroughly assess comparative effectiveness.

Pediatric Experience
The FDA 510(k) summary for the 2024 expanded approval of acute use of Nerivio in pediatric patients (ages 8-11) was based on a retrospective real-world analysis of 293 children, aged 6-11 at their first use of the device.^14, Median patient age was 11 (73.7% female). Safety data were primarily collected via self-reported customer service complaints, which indicated no adverse events. Effectiveness was assessed in patients who completed voluntary pre- and post-treatment surveys. Available efficacy data was only available in 18 participants, of which consistent headache relief was reported by 72.2% (13/18), consistent freedom from headache by 83.3% (15/18), and consistent functional disability freedom by 38.9% (7/18). Additional controlled studies are required to confirm efficacy in this population.Patients in this population used REN as a standalone treatment, with over-the-counter medications, and with prescribed headache medications, in 45.4%, 34.4%, and 20.9% of treatments, respectively.^29,

In 2024, Hershey et al published the results of a survey of 332 students aged 7-17 (80.4% female).^30,After being prescribed REN, the percentage of students reporting having their headaches treated at school increased by 11.5%. The most common reasons given for preferring REN treatment at school are the ability to avoid going to the nurse's office (42.5%) and the ability to treat discreetly (39.2%). Barriers to treatment included concerns about standing out (42.2%), and permission to use a smartphone in class to control the REN device (22.9%).

Coverage with Evidence Development Study
In 2025, Synowiec and coworkers published the outcomes of a real-world postmarketing coverage with evidence development study conducted in partnership with Highmark Inc.^31, Members aged 12-75 years who were diagnosed with migraine were prescribed REN. Eligibility criteria included: (1) at least 1 standard-of-care acute migraine therapy had failed for 1 or more of the following reasons: contraindication, lack of sufficient efficacy, or intolerability of adverse effects; (2) were at risk of drug-drug interaction with other medications; (3) were a pregnant woman, woman trying to conceive, or breastfeeding woman; (4) had chronic migraine and were at risk of or diagnosed with medication overuse headache (MOH); or (5) were younger than 18 years. Efficacy was assessed by changed in Migraine Disability Assessment (MIDAS) score from baseline to 3 months of treatment and by prospective pain and disability reports 2 hours post treatment. Device utilization was assessed through prescription fulfillment rates. A total of 381 patients (mean age, 40.5; 91.1% female) participated in the study. Change in MIDAS score was calculated for all participants who answered the questionnaire twice (n=116), indicating a statistically and clinically meaningful improvement of -12.1 point (p =.014). Pain relief, pain freedom, functional disability relief, and functional disability freedom were reported in 77.8%, 33.3%, 70.6%, and 50.0% of participants, respectively Three minor adverse events were reported and patients used a mean of 4.0 (SD, 3.1) devices annually. Generalizability of outcomes is limited due to lack of a control group and high degree of missing data (70%).

Section Summary: Acute Migraine due to Episodic or Chronic Migraine
Evidence from 2 small RCTs found REN with the Nerivio device was more effective than a sham device for measures of pain and symptom relief at 2-hours post-treatment. Patients treated with the Nerivio device were also more likely than those treated with a sham device to report 48-hour freedom from pain and pain relief based on 1 RCT. No significant between-group difference in functional disability or quality of life was noted in a post-hoc analysis of the pivotal RCT. The remaining evidence from post-hoc and nonrandomized studies suggests that REN with the Nerivio device may provide improvements in acute pain and symptomatology. Controlled studies in adolescent and pediatric populations are lacking.

Prevention of Migraine
Clinical Context and Therapy Purpose
The purpose of REN as preventive therapy in individuals who have acute migraine attacks due to episodic or chronic migraine is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who may benefit from preventive migraine therapy, including those with frequent or long-lasting episodic or chronic migraines, migraine attacks that diminish quality of life or cause significant disability despite acute treatment, contraindications to or failure of acute therapies, and risk of medication overuse headache.

Interventions
The therapy being considered is REN with the Nerivio device.

Comparators
The following therapies are currently being used to prevent acute migraine due to episodic or chronic migraine: medical management or no treatment. A number of medications are used as prevention for migraine. For most adults with episodic migraines who may benefit from preventive therapy, initial therapy with an antiepileptic drug (divalproex sodium, sodium valproate, topiramate) or beta-blockers (metoprolol, propranolol, timolol) is recommended. Frovatriptan may be beneficial as initial therapy for prevention of menstrually associated migraine. Antidepressants (amitriptyline, venlafaxine), alternative beta-blockers (atenolol, nadolol), and additional triptans (naratriptan, zolmitriptan for menstrually associated migraine prevention) may be considered if initial therapy is unsuccessful. For preventive treatment of pediatric migraine, many children and adolescents who received placebo in clinical trials improved and most preventive medications were not superior to placebo. Possibly effective preventive treatment options for children and adolescents may include amitriptyline, topiramate, or propranolol. Non-pharmacologic interventions may include behavioral interventions and lifestyle changes focused on the avoidance of known migraine triggers.

Outcomes
The general outcomes of interest are: symptoms, functional outcomes, quality of life, and treatment-related morbidity. Specific important health outcomes include reduction of future attack frequency, severity, and duration, improved responsiveness to acute treatments, improved function and reduced disability, and prevention of progression of episodic migraine to chronic migraine. In adolescent and pediatric populations, functional disability can also be captured as changes in missed days of school.

Follow-up over several days to months is needed to monitor for preventive treatment effects.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought;
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Use of REN for the prevention of migraine has been assessed in 1 double-blind, multicenter RCT by Tepper et al (2023), comparing an active REN device (Nerivio) used every other day with a sham device in adult patients with at least a 6-month history of headaches that meet the International Classification of Headache Disorders, third edition (ICHD-3) and 6 to 24 headache days per 28-day period in the past 3 months.^32, Included participants either did not use preventive medicine or were on a stable dose of a single migraine preventive medication during the 2 months before enrollment and throughout the study. Prior to initiation of REN, all patients participated in a 4-week baseline phase, where they were instructed to continue their regular medications when needed, and document daily reports, regardless of if they had a headache that day or not, to rate symptoms using a 4-point scale. Symptoms that were collected included pain, functional disability, presence or absence of nausea and/or vomiting, photophobia, and phonophobia, and acute medication usage.

To be eligible for the intervention phase, individuals had to have had 6 to 24 headache days during the 28-day baseline period, with at least 4 headache days fulfilling ICHD-3 criteria for migraine, and had at least 80% compliance on completing their daily record of symptoms. The intervention phase was 8 weeks long and included participants were randomized 1:1 to active REN or sham REN. The active and sham devices were visually identical, so staff and participants were blinded to their randomized group. Participants were directed to complete a full 45-minute treatment with REN every other day and to complete a daily diary. If acute treatment was needed, participants were instructed to use their usual acute treatments. The primary outcome was the mean change in number of migraine days per month in the 4-week baseline phase compared to the last 4 weeks of treatment phase (weeks 9 through 12). Overall, patients treated with the active REN device had statistically significantly fewer migraine days during the intervention period compared to baseline compared to those treated with sham. This was also demonstrated in subanalyses based on episodic or chronic migraines. Of the participants, 40.8% used a preventive medication in combination with REN. Half of the medication users were on first-line preventive medications (e.g., amitriptyline, topiramate), while the other half were on second line agents (e.g., anti-calcitonin gene-related peptide monoclonal antibodies, onabotulinumtoxin A, gepants). There were 2 non-device-related serious adverse events both in the REN arm. There was a single device-related adverse event in the sham group and no device-related adverse events in the active group. 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. These results are limited by the 8-week duration, shorter than the recommended 12-week duration by the International Headache Society guidelines for neuromodulation devices and lack of medical history reporting previous preventive medications used by participants. Tables 8 and 9 describe the key characteristics and results of the RCT. No significant difference between REN and sham groups was noted for mean change in the Headache Impact Test Short Form (HIT-6) or Migraine Specific Quality of Life Questionnaire - Function Domain (MSQ). Tables 10 and 11 describe notable limitations.

Table 8. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Tepper et al (2023)^32,	US	15	2021-2022	Adults (18 to 75 years) with ICHD-3 migraine at least 4 days/month in baseline period with no preventive medication use or stable medication use 2 months prior to enrollment; 85% female, mean age of 41.7 years; and ratio of episodic to chronic patients was 47.6%: 52.4%.	n=128 (ITT); 95 (mITT) Active REN device, use every other day	n=120 (ITT); 84 (mITT) Sham REN device

ICHD: International Classification of Headache Disorders; ITT: intention to treat; mITT: modified intention to treat; RCT: randomized controlled trial; REN: remote electrical neuromodulation.

Table 9. Summary of Key RCT Results

Study	Overall mean change in migraine days/month¹	Mean change in migraine days/month: Episodic subgroup¹	Mean change in migraine days/month: Chronic subgroup¹	Mean change in moderate/severe headache days	Mean change in number of headache days	Percentage of patients achieving at least 50% reduction from baseline in headache days
Tepper et al (2023)^32,
n	n=95 active REN; n=84 sham REN	n=45 active REN; n=42 sham REN	n=50 active REN; n=42 sham REN	n=95 active REN; n=84 sham REN	n=95 active REN; n=84 sham REN	n=95 active REN; n=84 sham REN
Active REN	-4.0±4.0	-3.2±3.4	-4.7±4.4	-3.8±3.9	-4.5±4.1	26.3%
Sham REN	-1.3±4.0	-1.0±3.6	-1.6±4.4	-2.2±3.6	-1.8±4.6	11.9%
Difference versus sham (95% CI); p value	-2.7 (-3.9 to -1.5); <.001	2.3 (NR);.003	3.0 (NR);.001	-1.6 (-2.7 to -0.5);.005	-2.7 (-3.9 to -1.5); <.001	NR; NR;.015

CI: confidence interval; NR: not reported; RCT: randomized controlled trial; REN: remote electrical neuromodulation.
¹ Change in migraine days from baseline (weeks 1 through 4) compared to last 4 weeks (weeks 9 through 12)

Table 10. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Duration of Follow-up^e
Tepper et al (2023)^32,	1, 2. Intended use population is unclear (e.g., treatment naive, those with contraindications to medication, or those who have failed pharmacologic treatment); time since migraine diagnosis and details about current migraine management regimen and previously failed treatments not reported	1. A clinically relevant device intensity threshold has not been established	2. Comparison versus specific pharmacologic preventive treatments with established efficacy would be preferred if attempting to establish first-line use		3. 8-week duration is less than the recommended 12-week duration by IHS guidelines for neuromodulation devices

IHS: International Headache Society.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aPopulation key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^bIntervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^cComparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^dOutcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^eFollow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 11. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Tepper et al (2023)^32,				2 LOCF imputation methodology for full ITT set not prespecified and generally does not meet MCAR assumptions; worst case sensitivity analysis not reported; 28% of data missing in mITT analysis

ITT: intention to treat; LOCF: last observation carried forward; MCAR: missing completely at random; mITT: modified ITT.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aAllocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^bBlinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^cSelective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^dData Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^ePower key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^fStatistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Nonrandomized Studies
Prospective, real-world data collected and analyzed by the manufacturer on the use of Nerivio in adolescents was summarized in the FDA approval packet for the indication of Nerivio in migraine prevention in adolescents and adults.^13, The data were collected from adolescents who used the device for acute migraine treatment, but use was equivalent to the suggested preventive use (10 times per month or higher). Prospective data were collected through the Nerivio app between January 2021 and November 2022. Eligible adolescent patients used Nerivio on at least 10 days in their first 28-day month of using the device, and used the device on at least 3 days in each of the 2 subsequent months. The goal of analysis was to assess the mean reduction in migraine headache days from the first month of use to the second and third month of use. In total, 61 patients (mean age, 15.7±1.3 years, 87% female) were eligible for analysis. Investigators found significant month-to-month reduction in migraine headache days from 15 days (standard error [SE], 0.6) in month 1, to 10.6 days (SE, 0.8) in month 2 (p<.0001), and 8.7 days (SE, 0.7) in month 3 (p<.0001), demonstrating substantial reduction from baseline during months 2 and 3 of device use. This data is limited by a lack of comparator and no description of medications or alternative interventions patients were additionally using.

A prospective, real-world evidence analysis investigated whether the use of Nerivio in adolescents who have frequently utilized the REN wearble device had reduced mean monthly migraine treatment days (MMTD) compared to baseline.^33, Patients (N=83) were 15.9 ± 1.3 years of age (mean±SD) and were evaluated for a 3 month period. There was a statistically significant monthly reduction in MMTD (a reduction of 3.6 [±4.8] MMTD) from the first month to the second month of consecutive use ( p<.001). In the third month of treatment, there was a further reduction of 1.6 (±4.1) MMTD ( p<.001), for a cumulative total reduction of 5.2 (±4.8) MMTD throughout the first 3 months of consecutive treatment.

The FDA 510(k) summary for the expanded approval of preventive use of Nerivio in pediatric patients (ages 8-11) was based on a retrospective real-world analysis of 293 children, aged 6-11.^14, Preventive use of the device was assumed by analyzing patients whose frequency of use in month one was suggestive of preventative treatments. No specific data on proportion of patients in whom preventive use was assumed or efficacy outcomes in the assumed preventive use population were reported in the 510(k) summary. Well-defined, controlled studies are required to confirm benefit in this population.

Section Summary: Prevention of Migraine
Evidence from a small RCT found REN with the Nerivio device was more effective than a sham device for decreasing migraine days per month, regardless of episodic or chronic subgroup, when used every other day for 8 weeks. Patients treated with the Nerivio device were also more likely than those treated with sham to have reduced moderate to severe headache days, reduced headache days in general, and at least a 50% reduction from their baseline in overall headache days. Approximately half of patients included in this study were also taking preventive pharrmacologic therapy. There were no differences in quality of life or functional health patient-reported outcomes between groups at any time point. Prospective, observational data in 2 real world evidence studies using the device for acute treatment of migraine demonstrated a significant reduction in migraine headache days from baseline to months 2 and 3 with device use in adolescent patients. Based on the existing evidence, it is unclear how Nerivio would fit into the current migraine prevention pathway, although it could provide benefit for those who do not receive adequate benefit from pharmacologic first- or second-line therapies, or who may have a contraindication to pharmacologic therapies. Study limitations include a high-degree of missing data and choice of imputation method.Controlled data in pediatric populations is lacking.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2025 Input
Clinical input was sought to help determine whether the use of remote electrical neuromodulation (i.e., Nerivio) for the listed populations would provide a clinically meaningful improvement in net health outcome and represents generally accepted medical practice:

Individuals who are 12 years and older with episodic or chronic migraine, with or without aura, who are treated for acute migraine or migraine prophylaxis
Individuals who are 8-11 years old with episodic or chronic migraine, with or without aura, who are treated for acute migraine or migraine prophylaxis

Clinical input supports this use provides a clinically meaningful benefit, with the majority of respondents supportive that its use is consistent with generally accepted medical practice. Respondents noted that all patients with migraine may benefit from a nonpharmacologic option for either stand-alone or adjunctive use, particularly among those who have failed other options, who have contraindications or an intolerance to alternatives, who are at risk for or have a history of medication overuse headache, or who are at risk of drug-drug interactions. While some clinicians trial acute treatment with REN first, failure in the abortive setting does not preclude success with preventive use. Additionally, clinicians support first-line use of REN for acute or preventive treatment, particularly in adolescent and pediatric populations where there are limited alternatives with evidence of efficacy or suitable side effect profiles. Respondents emphasize that the discreet nature of the REN device is ideal for use by chldren and adolescents in the school setting.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Neurology/American Headache Society
A 2012 joint guideline by the American Academy of Neurology (AAN) and the American Headache Society (AHS) on pharmacologic treatment for episodic migraine prevention in adults was published prior to the approval of Nerivio in the US and did not address the use of remote electrical neuromodulation (REN) or other nonpharmacologic treatments.^7, Similarly, 2019 joint guidelines issued by AAN and AHS on the treatment of acute migraine^34, and prevention of migraine8, in children and adolescents did not address the use of REN or other nonpharmacologic treatments.

American Headache Society
In 2021, AHS issued guidance on the integration of new migraine treatments, including REN, into clinical practice.^4, The AHS addressed the use of neuromodulatory devices as a group that included electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation, and REN; no guidance specific to REN use was issued.

The AHS determined that initiation of a neuromodulatory device is appropriate when all of the following criteria are met:
Prescribed/recommended by a licensed clinician
Patient is at least 18 years of age (the guidance noted that 3 devices, including REN, are approved for use in patients age 12 to 17 years)
Diagnosis of International Classification of Headache Disorders (ICHD)-3 migraine with aura, migraine without aura, or chronic migraine
Either of the following:
- Contraindications to or inability to tolerate triptans
- Inadequate response to 2 or more oral triptans, as determined by EITHER of the following:
  - Validated acute treatment patient-reported outcome questionnaire (Migraine Treatment Optimization Questionnaire, Patient Perception of Migraine Questionnaire-Revised, Functional Impairment Scale, Patient Global Impression of Change)
  - Clinician attestation.

Department of Veterans Affairs/ Department of Defense
The U.S Department of Veterans Affairs/Department of Defense (VA/DoD) 2023 guidelines for the management of headache state that "there is insufficient evidence to recommend for or against any form of neuromodulation for the treatment and/or prevention of migraine"; examples of neuromodulation treatments mentioned include remote electrical neurostimulation. ^35,

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
*Unpublished*
NCT05940870^a	A Prospective, Open-label, Post-marketing Observational Study Assessing the Safety and Efficacy of Nerivio for Migraine Prevention in Real-world Environment	250	Aug 2024 (completed)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References

VanderPluym JH, Halker Singh RB, Urtecho M, et al. Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis. JAMA. Jun 15 2021; 325(23): 2357-2369. PMID 34128998
Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: Updated age, sex, and socioeconomic-specific estimates from government health surveys. Headache. Jan 2021; 61(1): 60-68. PMID 33349955
Singh RBH, VanderPluym JH, Morrow AS, et al. Acute Treatments for Episodic Migraine. Rockville (MD): Agency for Healthcare Research and Quality (US); December 2020. Accessed August 9, 2025.
Ailani J, Burch RC, Robbins MS. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. Jul 2021; 61(7): 1021-1039. PMID 34160823
Burch RC, Loder S, Loder E, et al. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache. Jan 2015; 55(1): 21-34. PMID 25600719
Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review) [RETIRED]: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Sep 26 2000; 55(6): 754-62. PMID 10993991
Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. Apr 24 2012; 78(17): 1337-45. PMID 22529202
Oskoui M, Pringsheim T, Billinghurst L, et al. Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. Sep 10 2019; 93(11): 500-509. PMID 31413170
Nierenburg H, Stark-Inbar A. Nerivio ® remote electrical neuromodulation for acute treatment of chronic migraine. Pain Manag. Apr 2022; 12(3): 267-281. PMID 34538078
U.S. Food and Drug Administration. De Novo Classification Request for Nerivio Migra. Accessed August 7, 2025.
U.S. Food and Drug Administration. 501(k) Summary: Theranica Bio-Electronics LTDs Nerivio. K203181. Accessed August 9, 2025.
U.S. Food and Drug Administration. 510(k) Summary: Nerivio Approval in Adolescents. K203181. Accessed August 8, 2025.
U.S. Food and Drug Administration. 510(k) Summary (K223169): Nerivio Approval for Preventative Treatment. Accessed August 5, 2025.
Food and Drug Administration (FDA). 510(k) Summary. Theranica Bio-Electronics LTD.'s NerivioInfinity and Nerivio (K241756). October 8, 2024. https://www.accessdata.fda.gov/cdrh_docs/pdf24/K241756.pdf. Accessed August 18, 2025.
Tassorelli C, Diener HC, Silberstein SD, et al. Guidelines of the International Headache Society for clinical trials with neuromodulation devices for the treatment of migraine. Cephalalgia. Oct 2021; 41(11-12): 1135-1151. PMID 33990161
Diener HC, Tassorelli C, Dodick DW, et al. Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults: Fourth edition. Cephalalgia. May 2019; 39(6): 687-710. PMID 30806518
Yarnitsky D, Volokh L, Ironi A, et al. Nonpainful remote electrical stimulation alleviates episodic migraine pain. Neurology. Mar 28 2017; 88(13): 1250-1255. PMID 28251920
Yarnitsky D, Dodick DW, Grosberg BM, et al. Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Headache. Sep 2019; 59(8): 1240-1252. PMID 31074005
Migraine: Developing Drugs for Acute Treatment Guidance for Industry. FDA (2018)
Rapoport AM, Bonner JH, Lin T, et al. Remote electrical neuromodulation (REN) in the acute treatment of migraine: a comparison with usual care and acute migraine medications. J Headache Pain. Jul 22 2019; 20(1): 83. PMID 31331265
Marmura MJ, Lin T, Harris D, et al. Incorporating Remote Electrical Neuromodulation (REN) Into Usual Care Reduces Acute Migraine Medication Use: An Open-Label Extension Study. Front Neurol. 2020; 11: 226. PMID 32318014
Ailani J, Rabany L, Tamir S, et al. Real-World Analysis of Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine. Front Pain Res (Lausanne). 2021; 2: 753736. PMID 35295483
Hershey AD, Irwin S, Rabany L, et al. Comparison of Remote Electrical Neuromodulation and Standard-Care Medications for Acute Treatment of Migraine in Adolescents: A Post Hoc Analysis. Pain Med. Apr 08 2022; 23(4): 815-820. PMID 34185084
Hershey AD, Lin T, Gruper Y, et al. Remote electrical neuromodulation for acute treatment of migraine in adolescents. Headache. Feb 2021; 61(2): 310-317. PMID 33349920
Nierenburg H, Vieira JR, Lev N, et al. Remote Electrical Neuromodulation for the Acute Treatment of Migraine in Patients with Chronic Migraine: An Open-Label Pilot Study. Pain Ther. Dec 2020; 9(2): 531-543. PMID 32648205
Tepper SJ, Lin T, Montal T, et al. Real-world Experience with Remote Electrical Neuromodulation in the Acute Treatment of Migraine. Pain Med. Dec 25 2020; 21(12): 3522-3529. PMID 32935848
Grosberg B, Rabany L, Lin T, et al. Safety and efficacy of remote electrical neuromodulation for the acute treatment of chronic migraine: an open-label study. Pain Rep. 2021; 6(4): e966. PMID 34667919
Nierenburg H, Rabany L, Lin T, et al. Remote Electrical Neuromodulation (REN) for the Acute Treatment of Menstrual Migraine: a Retrospective Survey Study of Effectiveness and Tolerability. Pain Ther. Dec 2021; 10(2): 1245-1253. PMID 34138449
Werner K, Gerson T, Stark-Inbar, A, et al. Acute treatment of migraine in children aged 6-11: Real-world analysis of remote electrical neuromodulation (REN). Annals of the Child Neurology Society. May 21, 2024; 2(2): 135-145. https://doi.org/10.1002/cns3.20073.
Hershey AD, Shmuely S, Stark-Inbar A, et al. Patterns, Barriers, and Preferences of Treating Migraine Within the School Setting: A Survey Study of Students. Children (Basel). Oct 25 2024; 11(11). PMID 39594861
Synowiec A, Stark-Inbar A, Santamaria DD, et al. Coverage with evidence development study shows benefits in patients with migraine treated with remote electrical neuromodulation. Am J Manag Care. Apr 08 2025. PMID 40834199
Tepper SJ, Rabany L, Cowan RP, et al. Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial. Headache. Mar 2023; 63(3): 377-389. PMID 36704988
Monteith TS, Stark-Inbar A, Shmuely S, et al. Remote electrical neuromodulation (REN) wearable device for adolescents with migraine: a real-world study of high-frequency abortive treatment suggests preventive effects. Front Pain Res (Lausanne). 2023; 4: 1247313. PMID 38028429
Oskoui M, Pringsheim T, Holler-Managan Y, et al. Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society. Headache. Sep 2019; 59(8): 1158-1173. PMID 31529481
Management of Headache Work Group. VA/DoD Clinical Practice Guideline.Washington, DC. September 2023. Accessed August 13, 2024. https://www.healthquality.va.gov/guidelines/pain/headache/VA-DoD-CPG-Headache-Full-CPG.pdf

Coding Section

Codes	Number	Description
CPT	N/A
HCPCS	A4540	Distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm (eff 01/01/2024)
	K1023	Distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm (deleted eff 12/31/2023)
ICD10-CM	F90.0- F90.9	Attention-deficit hyperactivity disorder code range
	G25.0	Essential tremor
	G25.2	Other specified forms of tremor
	G25.3	Myoclonus
	G43.001-G43.919	Migraine code range
	R21.5	Tremor, unspecified
ICD10-PCS		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure
POS	Outpatient/Professional
TOS	DME

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2022 Forward

01/05/2026	Interim review, policy statement changed from investigational to medical necessary with criteria . Also updating summary of evidence, background, policy guidelines, rationale, and references.
06/20/2025	Annual review, no change to policy intent. Updating summary of evidence, rationale, and references.
06/03/2024	Annual review, no change to policy intent. Updating coding, rationale and references.
06/08/2023	Annual review, no change to policy intent. Updating Coding.
05/11/2022	New Policy

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Remote Electrical Neuromodulation for Migraines - CAM 701171