Clinical UM Guideline

This document addresses low-level electrical stimulation applied to peripheral nerves using a wearable device for the prevention and treatment of headache, especially migraine.

Note: Over-the-counter (OTC) devices are generally excluded from benefit plan coverage.

Note: For further information, please see the following related documents:

• CG-SURG-120 Vagus Nerve Stimulation
• DME.00011 Electrical Stimulation as a Treatment for Pain and Other Conditions: Surface and Percutaneous Devices
• SURG.00096 Surgical and Ablative Treatments for Chronic Headaches
• SURG.00144 Occipital and Sphenopalatine Ganglion Nerve Block Therapy for the Treatment of Headache and Neuralgia

Medically Necessary:

Initial use of the Nerivio^® remote electrical neuromodulation (REN) device for the treatment of migraine is considered medically necessary in individuals who meet ALL of the following criteria:

1. Eight years of age or older; and
2. Six-month history of headaches that meet International Classification of Headache Disorders (ICHD 3-beta) diagnostic criteria for migraine with or without aura; and
3. Meets one of the following two criteria:
   1. Nerivio is used to treat acute migraine; or
   2. Nerivio is used to prevent migraine for individuals with 6 to 24 headache days (defined as a calendar day with headache regardless of severity or duration) per 28-day period in each of the 3 months preceding use of Nerivio.

Continued use of the Nerivio remote electrical neuromodulation (REN) device for the prevention or treatment of migraine is considered medically necessary in individuals when BOTH of the following are demonstrated:

1. Ongoing use (that is, compliance with use); and
2. Clinical benefit (for example, fewer migraines or shorter duration of migraines).

Not Medically Necessary:

The Nerivio^® remote electrical neuromodulation (REN) device for the treatment of migraine headaches is considered not medically necessary in individuals who do not meet the above criteria, and for all other indications.

Surface electrical stimulation devices listed below are considered not medically necessary for the prevention or treatment of headache and migraine:

1. Cefaly^® migraine treatment device^a
2. Non-implantable transcutaneous vagus nerve stimulation devices (such as gammaCore-S^®)

^aOver the counter device.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure code listed above when criteria are not met or for all other diagnoses not listed.

When services are also Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure designated in the Clinical Indications section as not medically necessary.

Nerivio^® REN Device

Nerivio^® (Theranica Bio-Electronics Ltd., Netanya, Israel) was approved by the U.S. Food and Drug Administration (FDA) via the De Novo pathway in May, 2019. The Nerivio system delivers low energy electrical pulses to the individual’s upper arm via an armband. The device is battery-powered and controlled by software installed on a user’s personal mobile device. The FDA stated that the device is indicated for acute treatment of migraine with or without aura in adults who do not have chronic migraine. There were several expansions of the FDA-approved indications. Most recently, in 2024, the FDA expanded the indications for use to include cute and/or preventive treatment of migraine with or without aura in individuals aged 8 years and older.

Two double-blind sham-controlled randomized controlled trials (RCTs) have evaluated the Nerivio REN device, one focused on treatment of acute migraine (Yarnitsky, 2019; Marmura, 2020) and the other focused on migraine prevention (Tepper, 2023). The acute treatment study by Yarnitsky (2019) included 252 adults who met International Classification of Headache Disorders (ICHD-3-beta) criteria for migraine, had 2-8 migraines per month and less than 12 headache days per year. Participants needed either to be on no preventive migraine medication or to be stable on medication. Individuals were randomized to receive either active or sham stimulation devices. A total of 202 participants (99 in the active group and 103 in the sham group) who completed a test treatment session within 1 hour of symptom onset and reported pain at 2 hours formed the modified intention-to-treat population. The treatment session lasted 45 minutes and outcomes were reported at 2 hours. Significantly more individuals in the active treatment group (66 of 99, 66.7%) than the sham group (40/103, 38.8%) (p<0.001) reported pain relief at 2 hours. Rescue medication use at 2 hours was reported by 1% of the active treatment group and 3.8% of the sham group; the difference was not statistically significant (p=0.190). Additional RCTs are needed that seek to replicate positive findings in other groups of individuals and that evaluate REN use over longer periods of time.

An open-label extension of the Yarnitsky RCT included 160 of the 252 (63%) randomized participants (Marmura, 2020). A total of 139 individuals used the REN device at least once during the extension study and the analysis focused on the 117 of these individuals who had treated at least 1 migraine attack with REN and reported pain intensity 2 hours post-treatment. Of the 117 individuals, 57 had been in the active group during the double-blind treatment phase and 60 had been in the sham group. The mean number of reported migraine attacks per person was 3.21 (SD, 2.27) in the extension study compared with 3.44 (SD, 1.25) during the run-in phase of the RCT. A total of 105 of the 117 (89.7%) individuals included in the extension study analysis treated their migraine attacks solely with REN and avoided medication. Medication was avoided by 18 of 117 (15.4%) individuals during the run-in phase of the RCT. In the extension study, 67 of 117 (57.3%) individuals reported pain relief at 2 hours post-treatment for at least 50% of their attacks, compared with 68 of 117 (58.1%) in the run-in phase (p=0.999).

The RCT evaluating Nerivio for prevention of migraine (Tepper, 2023) included 248 individuals aged 18-75 who had a 6-month history of headaches meeting ICHD-3 criteria for chronic or episodic migraine, had 6 to 24 headache days per 28-day period in each of the 3 months preceding study participation and either did not use preventive medication or were on a stable dose. In an initial 4-week baseline phase, individuals completed daily headache diaries and continued using medication, if applicable. If eligible for participation in the 8-week experimental phase based on number of headache days, individuals were randomized to receive either active (n=128) or sham (n=120) stimulation devices and were instructed to conduct a 45-minute session every other day. At baseline, a total of 36% of individuals in the active group and 47% in the sham group were on preventive medication; the proportion did not differ significantly between groups (p=0.094). A total of 179 of the 248 randomized individuals (72%) were included in the analysis (95 in the active group and 84 in the placebo group). Individuals were excluded from the analysis who did not complete at least 22 daily reports, did not complete at least 12 treatments or who dropped out of the study. In weeks 9-12 of the study (the second 4 weeks of the experimental phase), 23 (9.3%) participants did not complete a sufficient number of daily reports, 19 (7.7%) did not perform at least 12 treatments, and 19 (7.7%) did not do both.

The primary study endpoint was the difference between groups in the number of migraine days per month in the baseline phase (weeks 1-4) versus during study weeks 9-12. Mean change in number of migraine days was -4.0 (SD, 4.0) in the REN group and -1.3 (SD, 4.0) in the sham group, a mean difference of 2.76 days (p<0.001). Among the secondary outcomes, 51.6% in the REN group and 35.7% in the sham group had at least a 50% reduction in moderate/severe headache days per month (p=0.033). At the end of the intervention period, 41 of 95 (43.2%) of the participants in the REN group and 29 of 84 (34.5%) of participants in the sham group correctly guessed their group assignment; the difference between groups was not statistically significant. A safety analysis was performed that included all randomized individuals. There were 2 SAEs in the REN group, a suicide attempt and appendicitis surgery. The study investigators deemed these SAEs unrelated to the device or study procedures. There were no SAEs in the sham group. A limitation of this study is that nearly 30% of the randomized individuals were excluded from the primary efficacy analysis and thus the benefits of randomization may not have been maintained, making it more difficult to conclude that the groups were similar other than the intervention. Moreover, 15% of the randomized individuals did not perform the recommended number of treatments which brings into question compliance outside of the experimental setting.

A number of uncontrolled studies evaluating Nerivio have also been published (Ailani, 2022; Grosberg, 2021; Hershey 2021a and 2021b; Nierenburg, 2020 and 2021; Tepper, 2020). A prospective uncontrolled study reporting on REN to treat adolescents with migraine, was published by Hershey (2021a). Eligibility criteria included age 12 to 17 years old, meeting ICHD-3 criteria for migraine with or without aura, history of at least 3 migraine episodes per month for each of the previous 3 months, with typical headache duration of at least 3 hours. A total of 60 individuals were enrolled in the study, 45 continued in the treatment phase that followed a 4-week run-in phase, and 39 were included in the final analysis set. An evaluation of the efficacy of REN was conducted at the time of each individual’s first-treated qualifying migraine headache. During this test treatment, 28 of 39 individuals (71%) reported pain relief at 2 hours post-treatment and 14 of 39 (35%) reported being pain-free at 2 hours. At 24 hours after treatment, 20 of 22 (90%) individuals who had initially reported pain relief and had data available reported continued pain relief. The authors did not report pr-e and post-treatment pain scores. At baseline during test treatment, 56%, 79% and 64% of individuals reported nausea and/or vomiting, photophobia and phonophobia, respectively, and after 2 hours, 54% of these reported disappearance of nausea and/or vomiting, 41% reported disappearance of photophobia and 40% reported disappearance of phonophobia. This study lacked a control or comparison group.

In a post-hoc analysis of data on 35 of the participants in the Hershey (2021a) study, Hershey and colleagues (2021b) compared outcomes during the run-in phase of the study, during which time individuals were treated with medication, to outcomes during the intervention phase when REN was used. Pain relief 2 hours after initiating treatment of a migraine episode occurred in 25 of 35 (71.4%) of participants in the REN phrase and 20 of 35 (57.1%) participants in the medication phase; the difference between groups was not statistically significant(p=0.225). Freedom from pain 2 hours after treatment initiation occurred in 13 of 35 (37.1%) participants in the REN phase compared with 3 of 35 (8.6%) in the medication phase, a statistically significant difference between groups (p=0.004). Limitations of this analysis are that it was not blinded, and severity of migraine episodes are variable.

A number of studies reporting on individuals’ experiences using the Nerivio app have been published (Ailani, 2022; Esparham, 2023; Monteith, 2023; Tepper, 2020; Synowiec, 2024; Werner, 2024). In 2020, Tepper and colleagues reported on the experiences of 4725 individuals in the United States who installed the Nerivio app and used the device between October 1, 2019 and March 31, 2020. An efficacy analysis included 1384 individuals who used REN during at least one episode in which no medication was taken, and recorded pain data using the Nerivio app. In the sub-group treated by headache specialists, 662 of 1123 (58.9%) individuals reported pain relief at 2 hours for at least 50% of their treated attacks, compared with 23 of 31 (74.2%) individuals treated virtually by non-headache specialists. Moreover, 268 of 1139 (20%) individuals treated by headache specialists reported pain freedom (i.e. no pain) at 2 hours in at least 50% of treated attacks, compared with 16 of 45 (35.6%) of those treated virtually by non-headache specialists. Safety analysis included all 4725 individuals enrolled in the study. A total of 23 individuals (0.5%) experienced at least one device-related adverse event (AE). None of the adverse events were considered to be serious and all resolved within 24 hours of treatment.

Ailani and colleagues (2022) reported on data collected from the Nervio app from 5805 users who reported symptoms and medication intake. There were data on 23,151 treatments and medication reports on 22,329 of these (n=822 had no medication report). Efficacy outcomes were calculated for each treatment session based on user reports at baseline and 2 hours after the session. Pain relief was defined as a decrease from moderate or severe headache at baseline to mild or no pain at the 2-hour follow-up. Pain freedom was defined as a decrease from mild, moderate or severe headache at baseline to no pain 2 hours after treatment. Data from 2514 users (12,734 treatments) who used REN as a standalone treatment were available for the efficacy analysis. A total of 66.5% of users reported pain relief after at least 50% of their treatments, 22.6% reported pain freedom in at least 50% of the episodes, 61.3% reported reduction in functional disability in at least 50% of the episodes and 29.8% reported returning to normal function in at least 50% of the episodes. Out of a total of 121,947 treatments by 12,368 users in the analyzed time periods, adverse events were reported by 59 (0.48%) users, none of which were severe adverse events. The analysis lacked data from a comparable control group.

Synowiec and colleagues reported on users who had used REN for 12 consecutive months. The analysis included 409 individuals with a mean age of 45.8 (SD, 15.9) years who received a total of 39,531 treatments. The monthly average number of treatments per user was 8.05 (SD, 115). Efficacy endpoints were calculated using data from all treatments in which users provided information both at the beginning of treatment and at 2 hours after initiating treatment about headache intensity, functional disability, and headache symptoms. An average efficacy of at least 50% of all treatments was reported by 74.1% (180 of 243) for pain relief, 26.0% (67 of 258) for pain freedom, 70.2% (177 of 252) for functional disability relief and by 33.7% (85 of 252) for functional disability freedom. A total of 409 users reported 9 adverse events; 8 were device-related and none of these were severe.

A study evaluating use of the Nerivio app by children aged 6 to 11 years was published by Werner and colleagues in 2024. During the study time period, this was an off-label use of the Nerivio device, which was indicated for individuals 12 and older. The primary study endpoint was device safety, defined as reporting of an adverse event. Calls to customer service regarding adverse events were also assessed. A total of 293 children who used the REN device at least once to treat a migraine attack were included in the analysis. No adverse events were reported to the tracking system and there was a mean of 0.072 customer service inquiries per child, similar to the rate of inquiries in the general population of REN users. REN efficacy was a secondary outcome, and this analysis included app users who voluntarily reported treatment outcomes at 2 hours post-treatment. In analysis that included 18 participants, consistent efficacy in at least 50% of treatments was reported by 13 (72%) for pain relief, by 15 (83.3%) for functional disability relief and by 7 (38.9%) for functional disability freedom. Only a small percentage of participants were included in the efficacy analysis.

In summary, a sham-controlled RCT on use of Nerivio for treatment acute migraine found significantly more pain relief at 2 hours in the active treatment group (although there was no statistical difference in use of rescue medication at 2 hours). In addition, a sham-controlled RCT on use of Nerivio for prevention of migraine found significantly greater reduction in migraine days in the active treatment group. RCT findings are supported by a number of subsequent observational studies.

Cefaly Device

The Cefaly device (STX-Med., Herstal, Belgium) was cleared by the FDA in March 2014 as a De Novo device for prophylactic (preventive) treatment of episodic migraine headaches (that is, migraine headaches occurring less than 15 times a month) in adults 18 years of age or older. On September 15, 2017, the FDA cleared the Cefaly Acute device as substantially equivalent to the predicate device (Cefaly) for use during an acute migraine attack with or without aura.

The externally worn nerve stimulator is applied to the forehead using a self-adhesive electrode positioned bilaterally over the upper branches of the trigeminal nerve. The battery-powered headband device is intended to stimulate the upper branches of the trigeminal nerve in order to reduce the frequency of migraine attacks. The device consists of two distinct components: an electrical pulse generator (EPG) and a self-adhesive electrode. The Cefaly EPG is made of ABS plastic and consists of electrical circuits controlled by firmware and powered by two 1.5V batteries. The front of the Cefaly EPG has a single button that is used to turn the device on/off and adjust the intensity of the electrical stimulus during a treatment session. Visual and auditory indicators inform the user when the device is on or off and assists in troubleshooting if the device it is not working properly (for example, the device indicates if batteries need replacement and if electrical connection between device and skin is unacceptable). The back side of the Cefaly EPG has two metal blades that serve to electrically connect it to the Cefaly electrode.

A treatment session begins by attaching the Cefaly electrode to the middle of the forehead and fastening the Cefaly EPG to the electrode. When the on/off button is depressed, a pulsatile electrical stimulus is applied for 20 minutes. During the first 14 minutes, the intensity of the stimulus gradually increases until it reaches a maximum. At any time while the stimulus intensity is increasing, the user can press the button on the front of the device to select an intensity that is lower than the maximum, and it will remain constant at this lower value for the remainder of the treatment session. The device turns the stimulus off automatically after 20 minutes, or alternatively, the user can stop a treatment session by pressing the button twice or simply removing the device from their forehead.

According to the manufacturer, the following are limitations of use of the device:

• The Cefaly device cannot be used by an individual who has a cardiac pacemaker or an implanted or wearable defibrillator.
• The Cefaly device cannot be used by an individual who has an implanted metallic or electronic device in their head.
• The Cefaly device should not be used by an individual with chronic migraine, refractory migraine, medication overuse headache, or chronic tension-type headaches. The safety and effectiveness of the device has not been demonstrated for individuals with these conditions.
• The Cefaly device should not be applied on the neck or chest, and it should not be used in the presence of electronic monitoring equipment (for example, cardiac monitors), in the bath or shower, while sleeping, while driving, or while operating machinery.
• The long-term effects of using the Cefaly device are unknown.

Schoenen and colleagues (2013) evaluated the safety and effectiveness of trigeminal neurostimulation in migraine headache prevention using the supraorbital transcutaneous stimulator, the Cefaly^® device. The multicenter double-blind, sham-controlled RCT (PREMICE study) included 67 adults (18-65 years) who experienced two or more migraine headache attacks (with or without aura) per month and had not taken any preventive antimigraine medications in the previous 3 months. After a 1-month run-in, participants were randomized 1:1 to active or sham stimulation applied 20 minutes daily for 3 months. Primary outcomes measures included a change in migraine days and at least 50% reduction in migraine days. A total of 59 of the 67 randomized participants were included in the intent-to-treat analysis. The primary outcome measure was reported as a non-significant greater decrease in migraine days per month (active: 6.94 vs. 4.88 [-2.06]; sham: 6.54 vs. 6.22 [-0.32]; p=0.054); however, the 50% responder rate was significantly greater in the active treatment group than in the sham group (38% vs. 12.1%; p=0.023). Monthly migraine attacks (p=0.044), monthly headache days (p=0.041), and monthly acute antimigraine drug intake (p=0.007) were also significantly reduced in the treatment group but not in the sham group. The investigators reported no adverse events in either group. A greater proportion of participants in the active treatment group were moderately or very satisfied with the Cefaly device (71% vs. 39%). Limitations of this study include the small number of participants and the likelihood of bias as potential unblinding to treatment may have occurred during the trial. The investigators noted that the stimulation electrodes of the active device could be painful to finger touch while the sham device electrodes would not be painful. In addition, there were apparent differences between the two groups at baseline, as participants randomized to the treatment group were of younger (average) age and had a shorter duration of migraine attacks.

The FDA 510(k) clearance of the Cefaly Acute device was based on results from a multicenter, randomized, double-blind, placebo-controlled Acute Treatment of Migraine With e-TNS trial (ACME; NCT02590939), completed in March 2017. According the clinicaltrial.gov website, eligible participants were 18 to 65 years (mean age, approximately 40 years), had a history of episodic or chronic migraine with or without aura meeting the diagnostic criteria of the International Classification of Headache Disorders (ICHD-3-beta) with the exception of “complicated migraine”, experienced a migraine attack lasting for at least 3 hours with migraine pain intensity stabilized for at least 1 hour, and not have taken an acute migraine medication within the past 3 hours. Study participants were randomly assigned 1:1 to a single treatment with active or sham stimulation. The primary endpoint was the mean change in VAS pain score at 1 hour compared to baseline. Secondary endpoints included change in VAS pain scores at 2 and 24 hours from baseline, and the proportion of participants who did not use pain medications at these time points. To date, the ACME trial results have not been published in the peer-reviewed medical literature.

Data collected from a satisfaction survey described the observational experience of 2313 individuals with migraine headaches from France, Belgium, and Switzerland who used the Cefaly device for 40 days (Magis, 2013). The rate of reported AEs was 4.3%, and 2% (n=46) of users stopped treatment with the device due to AEs. The most common AE reported was intolerance to the paresthesias felt during electrical stimulation (1.3% of users). Other common AEs included sleepiness (0.5%), headache following treatment (0.5%), and forehead skin irritation (0.2%). A total of 53% of users elected to purchase the device after the trial period; the remainder returned the device. For those individuals who returned the device, 59% used it for the recommended length of time during the rental period, similar to the utilization duration observed in the randomized trial.

In summary, there is insufficient evidence in the peer-reviewed published medical literature demonstrating a significant net health benefit on the use of the Cefaly device for the prevention of migraine headaches or the treatment of acute migraine headaches, with or without aura. Outcomes from RCTs with blinding of participants are needed to determine if supraorbital transcutaneous neurostimulation with any Cefaly device improves health outcomes when compared to existing therapies for prevention of episodic migraine headaches or the treatment of acute migraine headaches, and to assess longer-term safety and adverse effects.

GammaCore transcutaneous VNS device

In 2015, FDA granted De Novo approval of the GammaCore-S^® non-implantable transcutaneous VNS (t-VNS) device (ElectroCore^® Medical, LLC, Basking Ridge, NJ) for the treatment of acute pain associated with cluster headache in adults. On November 27, 2018, the FDA expanded clearance to include adjunctive use for the preventive treatment of cluster headaches in adults. In addition to the FDA indications for cluster headaches, the gammaCore device is FDA cleared for the prevention and acute treatment of migraine headaches in both adolescents (age 12 and older) and adults.

Silberstein and colleagues (2016a) conducted a randomized, double-blind, sham-controlled prospective study (ACT1) evaluating t-VNS as acute treatment of cluster headache. Study participants were aged 18 to 75 years and were diagnosed with episodic cluster headache or chronic cluster headache according to the International Classification of Headache Disorders (ICHD)/International Headache Society (IHS) (2^nd edition) criteria for ≥ 1 year before enrollment. A total of 150 participants were randomized to receive t-VNS or sham treatment for ≤ 1 month during a double-blind phase; study completers could enter a 3-month t-VNS open-label phase. The primary endpoint was response rate, defined as the proportion of participants who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first cluster headache attack without rescue medication use through 60 minutes. Secondary endpoints included the sustained response rate (15-60 minutes). A total of 133 participants were included in the intention-to-treat population, 60 t-VNS-treated and 73 sham-treated. A response was achieved in 26.7% of t-VNS-treated participants and 15.1% of sham-treated participants; the difference between groups was not statistically significant (p=0.10). A total of 35 of 150 participants reported adverse device effects (t-VNS, 11; sham, 24) in the double-blind phase and 18 of 128 participants in the open-label phase. Adverse device effects included application site reactions (such as burning, tingling, soreness, stinging or skin irritation, redness, or erythema), lip or facial drooping, pulling, or twitching, and dysgeusia or metallic taste. No serious adverse device effects were reported.

Goadsby and colleagues (2018) conducted a randomized, double-blind, sham-controlled prospective study (ACT2) comparing non-implantable t-VNS with a sham device for acute treatment of individuals with episodic cluster headache or chronic cluster headache. The trial consisted of a 1-week run-in period; a 2-week, randomized, double blind period during which participants were treated with either t-VNS or a sham device; and a 2-week, open label period where all participants received t-VNS therapy. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. A total of 48 t-VNS-treated (n=14 episodic cluster headache; n=34 chronic cluster headache) and 44 sham-treated (n=13 episodic cluster headache; n=31 chronic cluster headache) participants were included in the full data analysis set. For the primary endpoint, t-VNS (14%) and sham (12%) treatments were not significantly different in the total cohort. In subgroup analysis, a significantly higher proportion of participants in the episodic cluster headache subgroup achieved pain-free status following treatment of attacks with t-VNS (48%) compared with sham treatment (6%). There was no significant treatment difference for this endpoint in the chronic cluster headache subgroup (t-VNS, 5%; sham, 13%). A total of 20 t-VNS-treated participants (40%) and 14 sham-treated participants (27%) had ≥ one adverse effect during the double-blind period, and 23 participants (23%) had ≥ one adverse effect during the open-label period. Limitations of this study include the short duration which did not allow for evaluation of continued/change in response with long-term t-VNS therapy and unequal number of participants in the cluster headache subtype groups, with less than 30% of participants comprising the episodic cluster headache group. In addition, during the open-label period, participants could alter their cluster headache treatment regimens by adding prophylactic therapies, or changing doses of existing treatments, or both, thus confounding the results and making it impossible to distinguish whether changes in efficacy outcomes were attributable to t-VNS therapy or to other changes in treatment during this period.

Gaul and colleagues (2016) reported the results of a randomized, open-label study (PREVA) of the gammaCore t-VNS device in the prophylactic treatment of chronic cluster headache. Participants aged 18 to 70 years were diagnosed with chronic cluster headache according to the ICHD/IHS (3^rd edition) criteria for ≥ 1 year before enrollment The study included a 2-week baseline phase during which all participants received only their individualized standard of care (SoC) plan; a 4-week randomized phase during which participants were randomly assigned to receive either SoC plus t-VNS (prophylactic t-VNS; n=48) or SoC alone (control; n=49); and an optional 4-week extension phase during which all participants received SoC plus t-VNS. The t-VNS prophylaxis treatment consisted of three doses of 2-minute stimulations, 5 minutes apart, administered twice daily for a total of six doses per day to the right side of the neck (right vagal nerve). The primary endpoint was the reduction in the mean number of cluster headache attacks per week. Response rate, abortive medication use and safety/tolerability were also assessed. At 4 weeks, the t-VNS group had a significantly greater reduction in the number of headaches than the control group, resulting in a mean therapeutic gain of 3.9 fewer headaches per week. The response rate, defined as a 50% or more reduction in cluster headaches, was 40% in the t-VNS group versus 8.3% in the control group (p<0.001). A total of 7 participants withdrew from the study due to adverse events; two adverse events (depressed mood and cluster headache) occurred in more than 1 participant. Among participants assigned to SoC plus t-VNS, 38% (18 of 48) experienced adverse events during the randomized phase and 25% (12 of 48) experienced adverse events in the extension phase. Among participants assigned to control, 27% (13 of 49) experienced adverse events during the randomized phase and 24% (12 of 49) experienced adverse events in the extension phase. Overall, the most common adverse events in any treatment group were cluster headache attacks, headache, nasopharyngitis, dizziness, oropharyngeal pain, and neck pain. Limitations of this study include the open-label design and lack of a sham placebo/control group which may have resulted in response to treatment in the placebo t-VNS group, the short duration of treatment, and use of participant-reported outcomes that have the potential to bias the results.

Silberstein and colleagues (2016b) evaluated t-VNS in a double-blind, sham-controlled pilot study of t-VNS for the prevention of chronic migraine attacks in adults (EVENT study). A total of 59 participants (mean age, 39.2 years) with chronic migraine (15 headache days/month; mean headache frequency, 21.5 days/month) entered the baseline phase (1 month) and were subsequently randomized to t-VNS or sham treatment (2 months) before receiving open-label t-VNS treatment (6 months). The primary endpoints were safety and tolerability. Efficacy endpoints in the intent-to-treat population included change in the number of headache days per 28 days and acute medication use. During the randomized phase, tolerability was similar for t-VNS (n=30) and sham treatment (n=29). Most adverse events were mild or moderate and transient (upper respiratory tract infections and gastrointestinal symptoms). Mean changes in the number of headache days were -1.4 (t-VNS) and -0.2 (sham) (p=0.56). A total of 27 participants completed the open-label phase. For the 15 completers initially assigned to t-VNS, the mean change from baseline in headache days after 8 months of treatment was -7.9 (95% confidence interval [CI], -11.9 to -3.8; p<0.01). Limitations of this study include the small sample size and high discontinuation rate. The investigators noted that blinding to active or sham treatment was “challenging, especially in comparison with drug studies.” In addition, the missing data and high discontinuation rates occurring disproportionately across treatment groups could affect study outcomes.

The FDA approval of the gammaCore t-VNS device for migraines was based on the “Prospective Study of nVNS for the Acute Treatment of Migraine (PRESTO)” randomized sham-controlled trial (Tassorelli, 2018). A total of 248 participants with episodic migraines (with or without aura) were randomized to receive t-VNS (n=120) or sham treatment (n=123) within 20 minutes of pain onset, with a repeat treatment available if the pain had not improved in 15 minutes. Inclusion criteria included participants 18-75 years old, a diagnosis of migraine based on ICHD-3 beta criteria, < 50 years old at migraine onset, and attack frequency of 3-8 attacks a month with < 15 headache days per month over the last 6 months. Participants on migraine medication were required to have a stable dose and frequency schedule 2 months before the study, and participants could not start new medications during the study. Device training was provided to the participants by an unblinded trainer; participants and investigators were blinded prior to and during the study for the primary endpoint. The primary endpoint was the proportion of participants who were pain-free up to 120 minutes after a first attack without using medication. Pain was defined according to the IHS guidelines. After the first treated migraine attack, the proportion of participants in the t-VNS group who were pain-free was significantly higher at 30 and 60 minutes but not at 120 minutes. However, a post-hoc repeated measures test found t-VNS to be superior to sham for the pain-free outcome through 30, 60, and 120 minutes (odds ratio [OR] 2.3; 95% CI, 1.2 to 4.4; p=0.012). The most common adverse events were application site discomfort and nasopharyngitis; no serious adverse events were reported.

Diener and associates (2019) evaluated the use of non-invasive vagus nerve stimulation (nVNS) in the prevention of episodic migraine. The PREMIUM trial is a phase 3, prospective, multicenter, double-blind, sham-controlled, randomized trial intended to evaluate efficacy, tolerability and safety using an intent-to-treat (ITT) population. Adults aged 18 to 75 with a history of migraines who experienced 5-12 migraine days per month in the past 4 months, with at least 2 migraines lasting more than 4 hours, were eligible to participate. Participants were randomized to receive the GammaCore VNS device (n=169) or a sham device (n=172). The sham device produced a low-frequency biphasic direct current signal, which was intended to be perceived by the user but did not stimulate the vagus nerve or contract the muscle. Preventive treatment involved administering 2 consecutive bilateral stimulations 3 times a day. The study began with a 4-week run-in period of no study treatment, a 12-week period of use of either the VNS or sham device, followed by a 24-week open label period of VNS. The primary endpoint was mean reduction in number of migraine days per month. The use of the VNS device was not shown to be superior to the use of the sham device. Following the blinded portion of the study, the ITT population reported migraine reductions of -2.26 days in the VNS device group and -1.80 days in the sham device group (p=0.15). The authors noted that treatment responses to the VNS device (migraine and headache days) were maintained during the open-label period. The study had several limitations, including suboptimal adherence to the treatment protocol in both groups, and a significant drop-out rate among participants. The authors noted that the sham device was not inert, providing some vagus nerve stimulation which might have decreased the therapeutic gain in the VNS device group. Finally, the daily treatment protocol required bilateral stimulations, which authors noted could have mitigated the overall efficacy of the device.

In summary, sham controlled RCTs evaluating the GammaCore device for prevention or acute treatment of headache did not clearly find a statistically significant benefits of active treatment. Moreover, RCTs had a variety of limitations including short duration and unequal number of participants in treatment groups. This evidence is insufficient for demonstrating a significant net health benefit of the GammaCore device on health outcomes.

Other Considerations

The American Headache Society published a consensus statement in 2021 (Ailani, 2021) that addressed neuromodulation for migraine. The document stated:

All patients with a confirmed diagnosis of migraine may be offered treatment with a neuromodulatory device, which modulates pain mechanisms involved in headache by stimulating the nervous system centrally or peripherally with an electric current or a magnetic field.122 All four devices that have received FDA clearance (eTNS [electrical trigeminal nerve stimulation, cephaly), nVNS [noninvasive vagus nerve stimulation, GammaCore], REN [remote electrical stimulation, Nerivio],and sTMS [single-pulse transcranial magnetic stimulation [sTMS] (random device we don’t address- SAVI Dual Migraine Therapy] can be used alone or together with pharmacotherapy for acute treatment. Three devices are cleared for use as monotherapy or adjunctive therapy for preventive migraine treatment: eTNS, nVNS, and sTMS. Three devices (nVNS, REN, and sTMS) are also cleared for the acute and preventive treatment of migraine in adolescents between 12 and 17 years of age.

Although the efficacy and safety of neuromodulation is supported by positive results from multiple clinical trials, the use of neuromodulatory devices in clinical practice has been limited. Patients with an inadequate response to a migraine-specific medication, as well as those with frequent attacks who may be at risk of developing medication-overuse headache and/or chronic migraine due to overuse of acute medication, should be considered for a trial of a neuromodulatory device as an adjunct to the existing treatment plan. Patients who prefer to avoid medication, as well as those with a history of poor tolerability with or contraindications to triptans, may be offered a trial of neuromodulatory monotherapy. For preventive treatment, all patients should be considered for a trial of a neuromodulatory device as an adjunct to the existing treatment plan. Determinations about the precise role of neuromodulation in an overall treatment plan must be individualized.

Neuromodulation: A technology that alters (or modulates) nerve activity using electrical stimulation or pharmaceutical agents.

Peer Reviewed Publications:

1. Ailani J, Rabany L, Tamir S. Real world analysis of remote electrical neuromodulation (REN) for the acute treatment of migraine. Front. Pail Res. 2022; 2:753736.
2. Diener HC, Goadsby PJ, Ashina M, et al. Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia. 2019; 39(12):1475-1487.
3. Esparham A, Stark-Inbar A, Jekel L, et al. Acute treatment of migraine in adolescents: Real-world analysis of remote electrical neuromodulation (REN). Pediatr Neurol. 2023; 142:51-55.
4. Gaul C, Diener HC, Silver N, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia. 2016; 36(6):534-546.
5. Goadsby PJ, de Coo IF, Silver N, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia. 2018; 38(5):959‐969.
6. Grosberg B, Rabany L, Lin T, et al. Safety and efficacy of remote electrical neuromodulation for the acute treatment of chronic migraine: an open-label study. Pain Rep. 2021; 6(4):e966.
7. Hershey AD, Lin T, Gruper Y, et al. Remote electrical neuromodulation for acute treatment of migraine in adolescents. Headache. 2021a; 61(2):310-317.
8. 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. 2021b; 23(4):815-820.
9. Magis D, Sava S, d'Elia TS, et al. Safety and patients' satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly^® device in headache treatment: a survey of 2,313 headache sufferers in the general population. J Headache Pain. 2013; 14(1):95.
10. 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 Apr 7; 11:226.
11. Monteith TS, Stark-Inbar A, Shmuely S, et al. Remote electrical neuromodulation (REN) wearable device for adolescents with migraine: a real-world study of high-frequency abortive treatment suggests preventive effects. Front Pain Res (Lausanne). 2023; 4:1247313.
12. 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. 2021; 10(2):1245-1253.
13. Nierenburg H, Vieira JR, Lev N. Remote electrical neuromodulation for the acute treatment of migraine in patients with chronic migraine: An open-label pilot study. Pain Ther. 2020 Dec; 9(2):531-543.
14. Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology. 2013; 80(8):697-704.
15. Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: the EVENT study. Neurology. 2016b; 87(5):529-538.
16. Silberstein SD, Mechtler LL, Kudrow DB, et al. Non-invasive vagus nerve stimulation for the ACute Treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache. 2016a; 56(8):1317-1332.
17. Starling AJ, Tepper SJ, Marmura MJ, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia. 2018;38(6):1038-1048.
18. Synowiec A, Stark-Inbar A, Weinstein M, et al. One-year consistent safety, utilization, and efficacy assessment of remote electrical neuromodulation (REN) for migraine treatment. Adv Ther. 2024; 41(1):170-181.
19. Tassorelli C, Grazzi L, de Tommaso M, et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology. 2018; 91(4):e364-e373.
20. Tepper SJ, Lin T, Montal T, et al. Real-world experience with remote electrical neuromodulation in the acute treatment of migraine. Pain Med. 2020. 25; 21(12):3522-3529.
21. Tepper SJ, Rabany L, Cowan RP, et al. Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial. Headache. 2023; 63(3):377-389.
22. Werner, K., Gerson, T., Stark-Inbar, A, et al. Acute treatment of migraine in children aged 6−11: Real-world analysis of remote electrical neuromodulation (REN). Ann Child Neurol Soc. 2024; 2:135-145.
23. Yarnitsky D, Dodick DW, Grosberg BM et al. Remote electrical neuromodulation (REN) relieves acute migraine: a randomized, double-blind, placebo-controlled, multicenter trial. Headache. 2019; 59(8):1240-1252.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021; 61(7):1021-1039.
2. Food and Drug Administration (FDA). De Novo Summary/ DEN150048. October 15, 2015. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN150048.pdf. Accessed on January178, 2025.
3. Food and Drug Administration (FDA). De Novo Summary. DEN180059. April 17, 2023. Nerivio. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180059.pdf. Accessed on January 17, 2025.
4. Food and Drug Administration (FDA). Evaluation of Automatic Class III Designation – De Novo Request. K122566. March 11, 2014. Cefaly. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf12/K122566.pdf  Accessed on January 17, 2025.
5. U.S. Food and Drug Administration (FDA). 510k Summary K203546. February 12, 2021. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf20/K203546.pdf. Accessed on January 17, 2025.
6. Food and Drug Administration (FDA). 510k Summary. K241756. October 8, 2024. Nerivio. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf24/K241756.pdf.. Accessed on January 17, 2025.

1. National Institute of Neurological Disorders and Stroke. Headache information page. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Headache-Information-Page. Accessed on January 17, 2025.

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