Coverage Policy Manual
Policy #: 2022030
Category: Medicine
Initiated: July 2022
Last Review: July 2022
  Remote Electrical Neuromodulation for Migraines

Description:
Migraine is a neurologic disease characterized by recurrent moderate to severe headaches with associated symptoms that can include aura, photophobia, nausea, and/or vomiting (VanderPluym, 2021). Overall migraine prevalence in the United States is about 15% but varies according to population group (Burch, 2021). Prevalence is higher in women (21%), among American Indian/Alaska Natives (22%), and among 18- to 44-year-olds (19%). Social determinants including low education level (18%), use of Medicaid (27%), high poverty level (23%), and being unemployed (22%) are also associated with higher rates of migraine.
 
Migraine is categorized as episodic or chronic depending on the frequency of attacks. Generally, episodic migraine is characterized by 14 or fewer headache days per month and chronic migraine is characterized by 15 or more headache days per month (Singh, 2020). Specific International Classification of Headache Disorders (Ailani, 2021), diagnostic criteria are 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 using triptans or an NSAID-triptan combination. Antiemetics can be added for migraine accompanied by nausea or vomiting, though certain antiemetic medications used as monotherapy can also provide migraine relief. Other pharmacologic interventions used to treat acute migraine include calcitonin-gene related peptide antagonists, which can be used in patients with an insufficient response or contraindications to triptans, lasmiditan, and dihydroergotamine. Migraine can be managed at home, although acute migraine is a frequently cited reason for primary care and emergency department visits (Burch, 2015). 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 (Ailani, 2021).
 
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 Food and Drug Administration (FDA) is worn on the upper arm and stimulates the peripheral nerves to induce conditioned pain modulation (CPM). The conditioned pain in the arm induced by the Nerivio REN device is believed to reduce the perceived migraine pain intensity (Nierenburg, 2022). 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 1 hour of onset, the user initiates use of the device through their mobile application. Patient-controlled stimulation intensity ranges from 0 to 100%, corresponding to 0 to 40 milliamperes (mA) of electrical current. Patients are instructed to set the device to the strongest stimulation intensity that is just below their perceived pain level. The device provides stimulation for up to 45 minutes before turning off automatically. The Nerivio manufacturer indicates that the device can be used instead of or in addition to medication.
 
Regulatory Status
In May 2019, Nerivio Migra™ (Theranica Bio-Electronics Ltd.) was granted a de novo classification by the FDA (class II, special controls, product code: QGT) (FDA, 2022). This new classification applied to this device and substantially equivalent devices of this generic type. Nerivio Migra was initially cleared for treatment of acute migraine in adults who do not have chronic migraine.
 
In October, 2020, Nerivio was cleared for marketing by the FDA through the 510(k) process (K201824). FDA determined that this device was substantially equivalent to Nerivio Migra for use in adults (FDA, 2022). 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 (FDA, 2022).
 
Coding
There is no specific CPT code for remote electrical neuromodulation for migraines. The following CPT or HCPCS codes could be billed.
 
CPT
64999 Unlisted procedure, nervous system
 
HCPCS
 
K1023 Distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm

Policy/
Coverage:
Effective October 15, 2022
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Remote electrical neuromodulation for acute migraine does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, remote electrical neuromodulation for acute migraine is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
Use of REN for the treatment of migraine has been assessed in 2 RCTs comparing an active REN device (Nerivio Migra) with a sham device in patients with an acute migraine attack due to episodic migraine (Yarnitsky, 2017; Yarnitsky, 2019).
 
A pilot, crossover trial conducted by Yarnitsky included data from 71 (of 86 randomized) patients who received active or sham REN (Yarnitsky, 2017). 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 milliseconds, and 1 sham session of 0.1 hertz (45 millisecond pulse width). Both active and sham treatments were programmed for a duration of 20 minutes each. Most patients were women (80%) in their mid-40s (mean age: 46 years), with a mean of 5 migraine attacks per month with a mean pain intensity of 8.8, corresponding to severe pain. Race and/or ethnicity were not reported. In the trial, treatment with active REN was more frequently associated with reduction in, and freedom from, migraine pain than sham REN at 2-hour follow-up. 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.
 
A second, larger (N=252) RCT was conducted by Yarnitsky (Yarnitsky, 2019). The mean age of study participants was 43 years, 81% were female. Most participants were of White race (88%); 7% were Black and less than 1% were Asian. Time since migraine diagnosis was not reported; participants experienced a mean of 7 migraine days per month. Seventy-one percent of participants managed migraines with the use of acute medication, but important details about type and dosage were not provided. At baseline, 50% of participants reported that light sensitivity was their most bothersome symptom apart from migraine pain, followed by nausea (27%) and sound sensitivity (19%). After a 2 to 4-week run-in during which study participants kept a headache diary, participants were randomized to 4 to 6 weeks of at-home active or sham REN. The frequency was 100 to 120 Hz for the active device and less than 0.1 Hz for the sham device. The pulse width was 400 microseconds for the active device and ranged from 40 to 550 microseconds for the sham device, with the intent of mimicking a similar sensation as that delivered by the active device. At the time of randomization, participants were instructed on how to determine their optimal REN intensity, but this was unclearly defined as a threshold that was "perceptible not painful" (e.g., no specific measure of intensity was described) and no data on the actual intensities used during the study were reported. Participants were instructed to treat their migraine with the REN device as soon as possible following migraine onset, and no later than within 1 hour of onset. Participants who initiated device use more than 1 hour following onset were excluded from the outcome analyses. Patients treated with active REN were more likely to report freedom from pain and pain relief at 2-hour follow-up, and sustained freedom from pain and pain relief at 48-hour follow-up compared with the sham REN group. There was no statistical between-group difference in the proportions of patients reporting freedom from their most bothersome symptom (MBS) at 2-hour follow-up, but a greater proportion of active REN patients reported MBS relief at 2 hours relative to sham REN. Device-related adverse events were reported in 5% of active REN and 2% of sham REN participants (p=.49). At the conclusion of the study, participants were asked whether they believed they had received active or sham treatment as a measure of blinding. Half as many active participants correctly identified their device as did sham participants (23% in the active group vs. 50% in the sham group), although statistical analyses determined the treatment outcome differences between groups were not affected by participants perceived treatment group. 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.
 
Avoiding medication overuse has been postulated as a potential benefit of REN treatment of acute migraine. Marmura et al, reported the results of an observational 8-week open-label extension study following the double-blind phase of the Yarnitsky 2019 trial (Marmura, 2020). 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 (Rapoport, 2019). 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.
 
Numerous nonrandomized, uncontrolled studies have been conducted examining the effectiveness of REN with the Nerivio device for acute migraine. 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. This includes 2 studies in patients with chronic migraine and 1 study, in adolescents (Grosberg, 2021; Nierenburg, 2020; Hershey, 2021). In the 2 studies, of patients with chronic migraine, the mean age was 42 and 44 years, and was 15 years in the study of adolescents (Nierenburg, 2020; Grosberg, 2021, Hershey, 2021). In all 3 studies most participants were female (60% to 83%) and of White race (86% to 100%). In the study by Hershey et al, conducted in adolescents, patients with episodic and chronic migraine were eligible for study inclusion (Hershey, 2021). The Nerivio device was associated with improvements in pain, symptoms, and function in all 3 studies. Adverse events related to the Nerivio device occurred in 1.0 to 2.0% of study participants across the 3 studies; no serious adverse events were reported in any of the studies. Results from these studies are limited due to their open-label study design, lack of control groups, and small sample sizes with variable follow-up.
 
A post-hoc analysis of the Hershey et al 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 (Hershey, 2022). 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 by Ailani et al in 2021, sponsored by the Nerivio manufacturer collected data from 23,151 treatments from 5,805 Nerivio users between October 2019 and May 2021 (Ailani, 2021). This study is unique in including data on use of the Nerivio device as monotherapy and in combination with medications. Nerivio users reported use of medications (over-the counter, triptans, or other medications) in addition to the Nerivio device for about one-third of the treatment sessions. For use of Nerivio as monotherapy at 2-hour follow-up, the proportion of patients with freedom from pain, pain relief, return to normal function, and functional disability improvement was 20.3%, 55.6%, 24.9%, and 51.2%, respectively. When the Nerivio device was used in conjunction with medication, proportions ranged from 10.1 to 15.5% for freedom from pain, 38.5 to 51.3% for pain relief, 11.0 to 19.7% for return to normal function, and 39.8 to 49.6% for functional disability improvement, depending on the drug class used. While these results suggest that REN with the Nerivio device is efficacious in a highly selected group of individuals, additional evidence from well-designed RCTs is needed to thoroughly assess comparative effectiveness.
 
Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
 
American Headache Society
In 2021, the American Headache Society (AHS) issued guidance on the integration of new migraine treatments, including REN, into clinical practice (Ailani, 2021). 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 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 2 or more oral triptans, as determined by EITHER of the following:
            • Validated acute treatment patient-reported outcome questionnaire (Migraine Treatment Optimization Questionnaire, Patient Perception of Migraine Questionnaire-Revised, Functional Impairment Scale, Patient Global Impression of Change)
            • Clinician attestation.
 
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 (Oskoui, 2019).
 
Ongoing and Unpublished Clinical Trials
 
NCT04828707 A Prospective, Randomized, Double-blind, Sham-controlled Multi-center Clinical Study Assessing the Safety and Efficacy of Nerivio for the Preventive Treatment of Migraine
 
Planned Enrollment: 300 Completion Date: September 2022
 
NCT05102591 A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents Visiting the Emergency Department
 
Planned Enrollment: 40 Completion Date: February 2025

CPT/HCPCS:
64999Unlisted procedure, nervous system
K1023Distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm

References: Ailani J, Burch RC, Robbins MS.(2021) The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. Jul 2021; 61(7): 1021-1039. PMID 34160823

Ailani J, Rabany L, Tamir S, et al.(2021) Real-World Analysis of Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine. Front Pain Res (Lausanne). 2021; 2: 753736. PMID 35295483

Burch R, Rizzoli P, Loder E.(2021) 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

Burch RC, Loder S, Loder E, et al.(2015) 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

Diener HC, Tassorelli C, Dodick DW, et al.(2019) 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

Grosberg B, Rabany L, Lin T, et al.(2021) 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

Hershey AD, Irwin S, Rabany L, et al.(2022) Comparison of Remote Electrical Neuromodulation and Standard-Care Medications for Acute Treatment of Migraine in Adolescents: A Post Hoc Analysis. Pain Med. Apr 08 2022; 23(4): 815-820. PMID 34185084

Hershey AD, Lin T, Gruper Y, et al.(2021) Remote electrical neuromodulation for acute treatment of migraine in adolescents. Headache. Feb 2021; 61(2): 310-317. PMID 33349920

Marmura MJ, Lin T, Harris D, et al.(2020) 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

Nierenburg H, Rabany L, Lin T, et al.(2021) 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

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

Nierenburg H, Vieira JR, Lev N, et al.(2020) 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

Oskoui M, Pringsheim T, Holler-Managan Y, et al.(2019) 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

Rapoport AM, Bonner JH, Lin T, et al.(2019) 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

Singh RBH, VanderPluym JH, Morrow AS, et al.(2022) 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.(2021) 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

Tepper SJ, Lin T, Montal T, et al.(2020) Real-world Experience with Remote Electrical Neuromodulation in the Acute Treatment of Migraine. Pain Med. Dec 25 2020; 21(12): 3522-3529. PMID 32935848

U.S. Food and Drug Administration.(2022) 501(k) Summary: Theranica Bio-Electronics LTDs Nerivio. https://www.accessdata.fda.gov/cdrh_docs/pdf20/K203181.pdf. Accessed March 31, 2022.

U.S. Food and Drug Administration.(2022) 510(k) Summary: Nerivio Approval in Adolescents. https://www.accessdata.fda.gov/cdrh_docs/pdf20/K203181.pdf. Accessed March 8, 2022

U.S. Food and Drug Administration.(2022) De Novo Classification Request for Nerivio Migra. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm?ID=DEN180059. Accessed March 7, 2022.

VanderPluym JH, Halker Singh RB, Urtecho M, et al.(2021) Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis. JAMA. Jun 15 2021; 325(23): 2357-2369. PMID 34128998

Yarnitsky D, Dodick DW, Grosberg BM, et al.(2019) Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Headache. Sep 2019; 59(8): 1240-1252. PMID 31074005

Yarnitsky D, Volokh L, Ironi A, et al.(2017) Nonpainful remote electrical stimulation alleviates episodic migraine pain. Neurology. Mar 28 2017; 88(13): 1250-1255. PMID 28251920


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