Medical Policy

Policy Num:      07.001.167
Policy Name:    Remote electrical Neuromodulation for Migraines
Policy ID:          [07.001.167]  [Ac / B / M- / P-]  [7.01.171]

Last Review:      December 03, 2024
Next Review:     November 20, 2025
 

Related Policies: None

Remote electrical Neuromodulation for Migraines

Summary

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 small (N=212) RCTs with numerous relevance limitations. Based on the existing evidence, it is unclear how Nerivio would fit into the current acute migraine management pathway. The specific intended use and associated empirically-documented recommended regimen(s) must be specified in order to adequately evaluate the net health benefit. Additionally, functional outcomes and quality of life must be evaluated in well-designed and conducted studies in defined populations using documented Nerivio regimens. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For 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 small (N=248) RCT with numerous relevance limitations. 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 specific intended use and associated empirically-documented recommended regimen(s) must be specified in order to adequately evaluate the net health benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether acute treatment or preventive treatment with remote electrical neuromodulation improves the net health outcome in patients with acute migraine due to episodic or chronic migraine.

Policy Statements

Remote electrical neuromodulation for acute migraine or prevention of migraine is considered investigational.

Policy Guidelines

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity. 

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
 

Background

Migraine

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,

Rationale

This evidence review was created in March 2022 with a search of the PubMed database. The most recent literature update was performed through August 9, 2024.

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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

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.

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.

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

Table 1. Health Outcome Measures Relevant to Acute Migraine Attack^3,14,15,

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, 2017^16, and 2019 ^17,) 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.^16, 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).^17, 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. Notable limitations include an unclearly defined intended use population, a non-empirically determined optimum treatment regimen, and no assessment of functional or quality of life outcomes.

Table 2. Summary of Key RCT Characteristics

Table 3. Summary of Key RCT Results

Table 4. Study Relevance Limitations

Table 5. Study Design and Conduct Limitations

Avoiding medication overuse has been postulated as a potential benefit of REN treatment of acute migraine. Marmura et al (2020)^18, 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.

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.^19, 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.

Nonrandomized Studies

Numerous nonrandomized, uncontrolled studies have been conducted examining the effectiveness of REN with the Nerivio device for acute migraine.^{20,21,22,23,24,25,26,} 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^25,23, in patients with chronic migraine and 1 study^22, in adolescents. In the 2 studies^23,25, of patients with chronic migraine, the mean age was 42 and 44 years, and was 15 years in the study of adolescents.^22, 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)^22, 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 small sample sizes with variable follow-up.

Table 6. Summary of Key Nonrandomized Clinical Trial Characteristics

Table 7. Summary of Key Nonrandomized Clinical Trial Results

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.^21, 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.^20, 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.

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. Outcomes related to functional disability and quality of life were not reported. The remaining evidence from post-hoc and nonrandomized studies suggests that REN with the Nerivio device may provide improvements in acute pain and symptomatology. Based on the existing evidence, it is unclear how Nerivio would fit into the current acute migraine management pathway. The specific intended use and associated empirically-documented recommended regimen(s) based on test results must be specified in order to adequately evaluate net health benefit.

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 small (N=212) RCTs with numerous relevance limitations. Based on the existing evidence, it is unclear how Nerivio would fit into the current acute migraine management pathway. The specific intended use and associated empirically-documented recommended regimen(s) must be specified in order to adequately evaluate the net health benefit. Additionally, functional outcomes and quality of life must be evaluated in well-designed and conducted studies in defined populations using documented Nerivio regimens. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Prevention of Acute Migraine due to Episodic or Chronic 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.

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.

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.^27, 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. Tables 10 and 11 describe notable limitations.

Table 8. Summary of Key RCT Characteristics

Table 9. Summary of Key RCT Results

Table 10. Study Relevance Limitations

Table 11. Study Design and Conduct Limitations

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.^28, 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.

Section Summary: Prevention of Acute Migraine due to Episodic or Chronic 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. The specific intended use and associated empirically-documented recommended regimen(s) based on test results must be specified in order to adequately evaluate net health benefit.

For 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 small (N=248) RCT with numerous relevance limitations. 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 specific intended use and associated empirically-documented recommended regimen(s) must be specified in order to adequately evaluate the net health benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

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

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^29, and prevention of migraine^8, 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. ^30,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

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

References

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2. 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
3. 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, 2024.
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10. U.S. Food and Drug Administration. De Novo Classification Request for Nerivio Migra. Accessed August 7, 2024.
11. U.S. Food and Drug Administration. 501(k) Summary: Theranica Bio-Electronics LTDs Nerivio. Accessed August 9, 2024.
12. U.S. Food and Drug Administration. 510(k) Summary: Nerivio Approval in Adolescents. Accessed August 8, 2024.
13. U.S. Food and Drug Administration. 510(k) Summary (K223169): Nerivio Approval for Preventative Treatment. Accessed August 5, 2024.
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. 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
21. 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
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24. 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
25. 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
26. 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
27. 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
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29. 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
30. 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

Codes

Policy History