Description
Migraine attacks due to episodic or chronic migraine require acute management. Current first-line therapy for treatment 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.

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 percent 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 days or more headache days per month.³ Specific International Classification of Headache Disorders⁴ diagnostic criteria is as follows:

• Episodic migraine:
  1. Untreated or unsuccessfully treated headache lasting 4 to 72 hours
  2. Headache has at least two 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 one 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 – 3, and/or at least 5 headache attacks with aura meet episodic migraine criteria 2-3
  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 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

Remote electrical neuromodulation (REN) may offer an alternative to pharmacologic interventions for patients with acute migraine or it may decrease the use of abortive medications and the risk of medication-overuse to treat acute migraines. The only currently available REN device (Nerivio™) cleared for use by the 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.⁶ Control of the REN device is accomplished through Bluetooth communication between the device and the patient's smartphone or tablet. At onset of migraine or aura and no later than within one hour of onset, the user initiates use of the device through their mobile application. Patient-controlled stimulation intensity ranges from 0 to 100 percent, 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 U.S. Food and Drug Administration (FDA) (class II, special controls, product code: QGT).⁷ The 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 U.S. Food and Drug Administration (FDA) through the 510(k) process (K201824). FDA determined that this device was substantially equivalent to Nerivio Migra for use in adults.⁸ 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.⁹ 

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

Policy Guidelines 
Coding
See the Codes table for details.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., 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. 

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 one 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 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 Attack Due to Episodic or Chronic Migraine
Clinical Context and Therapy Purpose
The purpose of remote electrical neuromodulation in patients who have acute migraine attack 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(s) of interest is individuals with acute migraine due to episodic or chronic migraine.

Interventions
The therapy being considered is remote electrical neuromodulation 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 or 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 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^3,10,11

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 remote electrical neuromodulation (REN) for treatment of migraine has been assessed in 2 RCTs (Yarnitsky et al., 2017¹² and 2019 ¹³) comparing an active REN device (Nerivio Migra) with a sham device in patients with an acute migraine attack due to episodic migraine.

A pilot, crossover trial conducted by Yarnitsky et al. (2017) included data from 71 (of 86 randomized) patients who received active REN or sham REN.¹² 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 5 migraine attacks per month with a mean pain intensity of 8.8, corresponding to severe pain. Race and/or ethnicity was 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).¹³ The mean age of study participants was 43 years, 81 percent were female. Most participants were White race (88%); 7 percent were Black and less than 1 percent 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 percent 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. 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 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 percent of active REN and 2 percent 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

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Yarnitsky et al. (2017)12	Israel	1	2016 – 2016	Adults (18 – 75 years) with ICHD-3 migraine 2-8 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)13	U.S., Israel	12	2017 – 2018	Adults (18-75 years) with ICHD-3 migraine 2 – 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; 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)12
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	p = .005	p = .005	NR	NR	NR	NR
Yarnitsky et al. (2019)13
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	p = .003	p < .001	p = .014	p = .001	p = .55	p = .001

MBS: most bothersome symptom; RCT: randomized controlled trial; REN: remote electrical neuromodulation
¹ Change in headache severity from mild, moderate, or severe at baseline, to none
² Change 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.

Tables 4 and 5 display notable limitations identified in each study.

Table 4. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Yarnitsky et al. (2017)12	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 not reported		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)13	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 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	1, 2 Details and subgroup analysis on the effect of preventive medication use in 29% of active and 37% of sham participants were not reported; Comparison versus an acute treatment with established efficacy would be preferred	1, 5 Functional and quality of life outcome measures not addressed

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population 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.
^b Intervention 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.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes 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.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 5. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Yarnitsky et al. (2017)12	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)13,7				1 19% (49/252) of randomized participants not accounted for in analysis described as intention to treat

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data 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.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical 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)¹⁴ 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.¹⁵ 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.^{16,17,18,19,20,21,22} The most relevant studies are discussed below.

Three single-arm, open-label clinical trials of the Nerivio device were used to inform FDA approval for use in patients other than those with acute migraine due to episodic migraine (Table 6). This includes 2 studies^21,19 in patients with chronic migraine and 1 study¹⁸ in adolescents. In the 2 studies^19,21 of patients with chronic migraine, mean age was 42 and 44 years, and was 15 years in the study of adolescents.¹⁸ In all 3 studies most participants were female (60% – 83%) and White race (86% – 100%). In the study by Hershey et al. (2021)¹⁸ 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 three studies. Adverse events related to the Nerivio device occurred in 1.0 to 2.0 percent 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 designs, lack of control groups, and small sample sizes with variable follow-up.

Table 6. Summary of Key Nonrandomized Clinical Trial Characteristics

Study	Country	Dates	Participants	Treatment	Follow-Up
Nierenburg et al. 202019	US, Israel	2019-2020	N = 42 Adults (18 – 75 years) with ICHD-3 chronic migraine	REN (Nerivio)	24 hours
Grosberg et al. 202121	US	2019-2020	N = 126 Adults (18 – 75 years) with ICHD-3 chronic migraine	REN (Nerivio)	24 hours
Hershey et al. 202118	US	2019-2020	N = 45 Adolescents (12 – 17 years) with ICHD-3 migraine ≥ 3 attacks/month	REN (Nerivio)	24 hours

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. 202019	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. 202121	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. 202118	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

^1  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.¹⁷ 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 2021.¹⁶ 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 the 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 percent for freedom from pain, 38.5 to 51.3 percent for pain relieft, 11.0 to 19.7% for return to normal function, and 39.8 to 49.6 percent 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 symptomology. Based on the existing evidence, it is unclear how Nerivio would fit into the current acute migraine management pathways. 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.

Summary of Evidence
For individuals with acute migraine due to episodic or chronic migraine who receive remote electrical neuromodulation (REN), the evidence includes 2 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 (total 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 pathways. The specific intended-use (e.g., treatment naive, those with contraindications to medication, or those who have failed pharmacologic treatment); and associated empirically-documented recommended REN regimen(s) (e.g., a clinically relevant effective device intensity threshold) must be specified in order to adequately evaluate net health benefit. Additionally, functional outcomes and quality of life must be evaluated in well-designed and well-conducted studies in well-defined populations using well-defined and documented Nerivio regimens. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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 U.S. professional society, an international society with U.S. 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 Headache Society
In 2021, the American Headache Society (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 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 two 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

American Academy of Neurology/American Headache Society
A 2019 joint guideline issued by the American Academy of Neurology and the American Headache Society on the treatment of acute migraine in children and adolescents did not address the use of REN or other nonpharmacologic treatments.²³

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 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT04828707a	A Prospective, Randomized, Double-blind, Sham-controlled Multi-center Clinical Study Assessing the Safety and Efficacy of Nerivio for the Preventive Treatment of Migraine	300	Sep 2022
NCT05102591	A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents Visiting the Emergency Department	40	Feb 2025

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

References 

1. 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
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 April 5, 2022.
4. 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
5. 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
6. Nierenburg H, Stark-Inbar A. Nerivio (R) remote electrical neuromodulation for acute treatment of chronic migraine. Pain Manag. Apr 2022; 12(3): 267-281. PMID 34538078
7. U.S. Food and Drug Administration. De Novo Classification Request for Nerivio Migra. Accessed March 7, 2022.
8. U.S. Food and Drug Administration. 501(k) Summary: Theranica Bio-Electronics LTDs Nerivio. Accessed March 31, 2022.
9. U.S. Food and Drug Administration. 510(k) Summary: Nerivio Approval in Adolescents. Accessed March 8, 2022.
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. 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
21. 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. Nov-Dec 2021; 6(4): e966. PMID 34667919
22. 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
23. 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

Coding Section  

Codes	Number	Description
CPT	no code
HCPCS	K1023	Distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm
ICD10-CM	G43.001-G43.919	Migraine code range
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
TOS	Medicine

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, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2022 Forward     

05/11/2022

New Policy

Appendix 

Literature Review 
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

To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults. The American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine. This update, which is based on the expanded evidence base and emerging expert consensus concerning postapproval usage, provides practical recommendations in the absence of a formal guideline. This update involved four steps: (1) review of data about the efficacy, safety, and clinical use of migraine treatments introduced since the previous Statement was published; (2) incorporation of these data into a proposed update; (3) review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation; (4) consideration of these collective insights and integration into an updated Consensus Statement. Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment. Newly introduced acute treatments include two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT 1F ) agonist (lasmiditan); a nonsteroidal anti-inflammatory drug (celecoxib oral solution); and a neuromodulatory device (remote electrical neuromodulation). New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab). Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation) and biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation). The integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.

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

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

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

Accurate, up-to-date estimates of the burden of migraine and severe headache are important for evidence-based decision-making about workforce needs and the distribution of health resources. We used data from U.S. government health surveys to report the prevalence, trends, and impact of this condition by age, sex, and poverty status. We identified the most recent, publicly available summary statistics from the National Hospital Ambulatory Medical Care Survey, the National Ambulatory Medical Care Survey, and the National Health Interview Survey. We extracted and compiled relevant information from each study, with an emphasis on sex, age, and economic-related statistics. The age-adjusted prevalence of migraine and severe headache in the United States has remained stable over many years. In 2018, the age-adjusted prevalence was 15.9% across all adults. The sex ratio also remains stable, with 21% of women and 10.7% of men affected. Migraine continues to be an important public health problem, accounting for roughly 4 million emergency department (ED) visits in 2016, when headache was the fifth most common reason for an ED visit overall and the third most common reason for ED visits in females 15 – 64. Migraine also accounted for over 4.3 million office visits. Many adults with migraine or severe headaches are disadvantaged. In 2018, for example, roughly 40% of US adults with migraine were unemployed, and a similar proportion were classified as poor or "near poor." Roughly one in five had no health insurance and about a third had a high school education or less. Migraine and severe headaches are a serious public health issue in the United States, with the highest impact in women of childbearing age and those of lower socioeconomic status. Socioeconomic disadvantages also are highly prevalent among those with headaches. The economic consequences of the current coronavirus pandemic are likely to exacerbate all of these inequities. Increased attention to this high impact chronic pain condition, and improved funding for treatment provision and research, are warranted to reduce the future burden of disease.

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

The US National Center for Health Statistics, which is part of the Centers for Disease Control, conducts ongoing public health surveillance activities. The U.S. Armed Forces also maintains a comprehensive database of medical information. We aimed to identify the most current prevalence estimates of migraine and severe headache in the United States adult civilian and active duty service populations from these national government surveys, to assess stability of prevalence estimates over time, and to identify additional information pertinent to the burden and treatment of migraine and other severe headache conditions. We searched for the most current publicly available summary statistics from the National Ambulatory Medical Care Survey, the National Hospital Ambulatory Medical Care Survey, and the National Health Interview Survey (NHIS). Summary data from the Defense Medical Surveillance System were also obtained, and PubMed was also searched for publications reporting summary statistics based on these studies. Data were abstracted, double-checked for accuracy, and summarized over time periods and as a function of demographic variables. 14.2% of U.S. adults 18 or older reported having migraine or severe headache in the previous 3 months in the 2012 NHIS. The overall age-adjusted 3-month prevalence of migraine in females was 19.1% and in males 9.0%, but varied substantially depending on age. The prevalence of migraine was highest in females 18-44, where the 3-month prevalence of migraine or severe headache was 23.5%. The 3-month prevalence of migraine or severe headache has remained relatively stable over the period of2005-2012, with an average prevalence of 20.2% in females, 9.4% in males, and 14.9% overall [corrected]. During this time, the average female to male sex ratio for migraine or severe headache was 2.17. The unadjusted 1-year prevalence of migraine in active duty US military service members varied from 1% to 1.9% between 1998 and 2010, ranging from 0.7% to 1.2% in males and 3.5% to 6% in females. The 1-year prevalence of "other headache" in this military population ranged from a low of 1.9% in 2003 to a high of 3% in 2010. Headache or pain in the head was the fourth leading cause of visits to the emergency department (ED) in 2009-2010, accounting for 3.1% of all ED visits. Across all ambulatory care settings, migraine accounted for 0.5% of all visits and other headache presentations for 0.4% of all ambulatory care visits. 52.8% of all visits for migraine occurred in primary care settings, 23.2% in specialty outpatient settings, and 16.7% in EDs. In 2010, opioids were administered at 35% of ED visits for headache, while triptans were administered in only 1.5% of visits. This report summarizes the most recent government statistics on the prevalence and burden of migraine and severe headache in the US civilian and active duty military populations. The prevalence of migraine headaches is high, affecting roughly 1 out of every 7 Americans annually, and has remained relatively stable over the last 8 years. Migraine and headache are leading causes of outpatient and ED visits and remain an important public health problem, particularly among women during their reproductive years.

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

The quality of clinical trials is an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for controlled trials of drugs in migraine. Scientific and clinical developments in headache medicine led to second and third editions in 2000 and 2012, respectively. The current, fourth edition of the Guidelines retains the structure and much content from previous editions. However, it also incorporates evidence from clinical trials published after the third edition as well as feedback from meetings with regulators, pharmaceutical and device manufacturers, and patient associations. Its final form reflects the collective expertise and judgement of the Committee. These updated recommendations and commentary are intended to meet the Society's continuing objective of providing a contemporary, standardized, and evidence-based approach to the conduct and reporting of randomised controlled trials for the acute treatment of migraine attacks.

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. Nov-Dec 2021; 6(4): e966. PMID 34667919

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

Hershey AD, Irwin S, Rabany L, et al. Comparison of remote electrical neuromodulation (REN) and standard-care medications for acute treatment of migraine in adolescents: a post-hoc analysis. Pain Med. Jun 29 2021. PMID 34185084

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

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

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

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

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

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

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

Nierenburg H, Stark-Inbar A. Nerivio (R) remote electrical neuromodulation for acute treatment of chronic migraine. Pain Manag. Apr 2022; 12(3): 267-281. PMID 34538078

Nerivio ® (by Theranica Bio-Electronics Ltd, Tel Aviv, Israel) is a wireless, wearable, noninvasive, battery-operated, remote electrical neuromodulation device controlled by a smartphone application. It is US FDA authorized for the acute treatment of migraine with or without aura in people 12 years and older in the US, and European Conformity (CE) marked for the same indication in the EU. The American Headache Society Consensus Statement recommends Nerivio as a tier 2 treatment for migraines. This review summarizes a series of five independent clinical trials and two real-world evidence studies that established safety, tolerability and efficacy of Nerivio in treating migraine attacks. It further provides up-to-date practical information on device usability. Based on findings of this review, Nerivio offers a safe and effective nonpharmacological alternative for acute treatment in patients with chronic (and nonchronic) migraine.

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

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

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

To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine. We performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence. There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia. Recommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counselling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse.

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

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

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 April 5, 2022.

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

Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine. An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine. Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created. Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment.

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

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

U.S. Food and Drug Administration. 501(k) Summary: Theranica Bio-Electronics LTDs Nerivio. Accessed March 31, 2022.

U.S. Food and Drug Administration. 510(k) Summary: Nerivio Approval in Adolescents. Accessed March 8, 2022.

U.S. Food and Drug Administration. De Novo Classification Request for Nerivio Migra. Accessed March 7, 2022.

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

Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy. To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults. Multiple databases from database inception to February 24, 2021. Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks. Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small. The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham. There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

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

To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. There is a significant unmet need for novel effective well-tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation - an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double-blind, sham-controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine. This was a randomized, double-blind, sham-controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty-two adults meeting the International Classification of Headache Disorders criteria for migraine with 2-8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone-controlled wireless device was applied for 30-45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post-treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain-free at 2 hours were key secondary endpoints. Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI 95% , 15.6-40.2]; P < .0001), pain-free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post-treatment. The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment. The incidence of device-related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499). REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non-pharmacological alternative for acute migraine treatment.

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

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

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 days or more headache days per month.^3, Specific International Classification of Headache Disorders^4, diagnostic criteria is as follows:

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 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,

Remote electrical neuromodulation (REN) may offer an alternative to pharmacologic interventions for patients with acute migraine or it may decrease the use of abortive medications and the risk of medication-overuse to treat acute migraines. The only currently available REN device (Nerivio™) cleared for use by the 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.^6, Control of the REN device is accomplished through Bluetooth communication between the device and the patient's smartphone or tablet. At onset of migraine or aura and no later than within one hour of onset, the user initiates use of the device through their mobile application. Patient-controlled stimulation intensity ranges from 0 to 100 percent, 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.

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 one 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 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.

XTERNAL Content PreviewThe 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^3,10,11,

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)

ICHD: International Classification of Headache Disorders; RCT: randomized controlled trial; REN: remote electrical neuromodulation.

Table 3. Summary of Key RCT Results

MBS: most bothersome symptom; RCT: randomized controlled trial; REN: remote electrical neuromodulation
¹ Change in headache severity from mild, moderate, or severe at baseline, to none
² Change 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.

Tables 4 and 5 display notable limitations identified in each study.

Table 4. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Yarnitsky et al. (2017)12	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 not reported		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)13	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 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	1, 2 Details and subgroup analysis on the effect of preventive medication use in 29% of active and 37% of sham participants were not reported; Comparison versus an acute treatment with established efficacy would be preferred	1, 5 Functional and quality of life outcome measures not addressed

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population 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.
^b Intervention 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.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes 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.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 5. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Yarnitsky et al. (2017)12	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)13,7				1 19% (49/252) of randomized participants not accounted for in analysis described as intention to treat

Three single-arm, open-label clinical trials of the Nerivio device were used to inform FDA approval for use in patients other than those with acute migraine due to episodic migraine (Table 6). This includes 2 studies^21,19, in patients with chronic migraine and 1 study^18, in adolescents. In the 2 studies^19,21, of patients with chronic migraine, mean age was 42 and 44 years, and was 15 years in the study of adolescents.^18, In all 3 studies most participants were female (60%-83%) and White race (86%-100%). In the study by Hershey et al. (2021)^18, 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 three studies. Adverse events related to the Nerivio device occurred in 1.0 to 2.0 percent 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 designs, lack of control groups, and small sample sizes with variable follow-up.

Table 6. Summary of Key Nonrandomized Clinical Trial Characteristics

Study	Country	Dates	Participants	Treatment	Follow-Up
Nierenburg et al. 202019	US, Israel	2019 – 2020	N = 42 Adults (18 – 75 years) with ICHD-3 chronic migraine	REN (Nerivio)	24 hours
Grosberg et al. 202121	US	2019 – 2020	N = 126 Adults (18 – 75 years) with ICHD-3 chronic migraine	REN (Nerivio)	24 hours
Hershey et al. 202118	US	2019 – 2020	N = 45 Adolescents (12 – 17 years) with ICHD-3 migraine ≥ 3 attacks/month	REN (Nerivio)	24 hours

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. 202019	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. 202121	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. 202118	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

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.^17, 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.^16, 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 the 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 percent for freedom from pain, 38.5 to 51.3 percent for pain relieft, 11.0 to 19.7% for return to normal function, and 39.8 to 49.6 percent 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.

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

The AHS determined that initiation of a neuromodulatory device is appropriate when all of the following criteria are met:

Codes	Number	Description
CPT	no code
HCPCS	K1023	Distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm
ICD10-CM	G43.001-G43.919	Migraine code range
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
TOS	Medicine

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, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

05/11/2022

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