Update on Noninvasive Neuromodulation Devices for Headache Treatment

Neuromodulation is widely used in chronic pain management, including applications in primary headache disorders. According to the International Headache Society, a neuromodulation device “modulates the activity of the brain, the spinal cord, or peripheral nerves by means of electricity, magnetic fields, or other device-mediated modalities to either inhibit or facilitate neural impulses to achieve a clinical benefit for patients.”¹ Earlier implantable devices were limited largely because of unacceptable adverse events (AEs) as well as conflicting evidence often attributed to trial design. However, the Food and Drug Administration (FDA) has cleared 6 noninvasive neuromodulation devices for headache treatment, most of them designated as posing nonsignificant risk with minimal to no AEs (Table). Four are cleared for both acute and preventive treatment and were the first therapies to break down the separation dividing acute and preventive treatment. Three are cleared for adolescent use. One is cleared for trigeminal autonomic cephalalgia (TAC) treatment.

Understanding these devices and their mechanisms of action, practical uses, and limitations is instrumental in using them appropriately for the treatment of many headache types.

FDA-Cleared Noninvasive Neuromodulation Devices

External Trigeminal Neurostimulation

The external trigeminal neurostimulator (eTNS) device (Cefaly; Cefaly Technology, Darien, CT) is cleared by the FDA for migraine acute and preventive use in adults (Figure part A). The device is magnetically connected to an adhesive electrode which is placed on the forehead. The acute program for this device is 1 to 2 hours’ duration; the daily preventive program lasts 20 minutes. The device can be recharged, but each electrode lasts no longer than a month. AEs include stimulation-induced paresthesias or dysesthesias.

Transcutaneous Electrical Nerve Stimulation

The transcutaneous electrical nerve stimulator (TENS) device (HeadaTerm 2; WAT Medical, Vancouver, BC, Canada) also affixes to the forehead, but the device and electrode comprise a single unit (Figure part B). FDA clearance is for 20-minute preventive treatments. In 2024 the FDA cleared a rechargeable device for use as well.

Single-Pulse Transcranial Magnetic Stimulation

The single-pulse transcranial magnetic stimulator (sTMS) device (SAVI Dual; eNeura, Baltimore, MD) is held at the back of the head, where it delivers a magnetic pulse in <1 second once activated (Figure part C). sTMS is cleared as an FDA-designated nonsignificant risk device (NSRD) for both acute and preventive migraine treatment for individuals aged 12 years or older. sTMS has been approved by the UK National Health Service for use during pregnancy. Preventive treatment entails 4 pulses twice daily; acute treatment consists of 4 sequential pulses at migraine onset. Individuals can treat again as needed, with no upper limit on number of pulses per day. The sTMS device is rented and reactivated online each month.

AEs include mild and transient lightheadedness and scalp discomfort or tingling. The sTMS device should not be used by people with metal implants; metals or other conductive materials in the head, neck, or upper body; or intracardiac lines or pacemakers.

Noninvasive Vagus Nerve Stimulation

The handheld noninvasive vagus nerve stimulator (nVNS) device (gammaCore; electroCore, Basking Ridge, NJ) is placed over the vagus nerve on the anterolateral neck, and 2-minute stimulation is activated (Figure part D). nVNS is cleared by the FDA as an NSRD for both acute and preventive treatment of migraine in individuals aged 12 years or older. Acute treatment for migraine consists of 2 stimulations of 2 minutes each which can be repeated; migraine prevention consists of 2 stimulations of 2 minutes each twice daily.

The nVNS device is the only FDA-cleared device for treatment of TACs, specifically for acute treatment of episodic, but not chronic, cluster headache. Treatment for this indication consists of 2 stimulations of 2 minutes each, which may be repeated. nVNS is also cleared by the FDA for adjunctive prevention of both episodic and chronic cluster headache with cluster-preventive medication. The preventive protocol is 2 stimulations of 2 minutes each, twice daily.

The nVNS device is the only device cleared by the FDA for treatment of 2 other TACs: paroxysmal hemicrania and hemicrania continua. Both are diagnosed by responsiveness to indomethacin, but many individuals cannot tolerate indomethacin, so nVNS is a useful alternative. Prevention dosing is 2-minute stimulations twice daily.

The main AE associated with nVNS is application site discomfort. Contraindications for nVNS use include implanted medical devices, such as pacemakers or cochlear implants, or any implanted or other noninvasive electronic devices.

Remote Electrical Neuromodulation

The remote electrical neuromodulation (REN) device (Nerivio; Theranica, Netanya, Israel) is placed on the arm with a band and activated by smartphone app, buzzing the arm for 45 minutes per stimulation (Figure part E). REN is cleared as an NSRD by the FDA for both acute and preventive treatment of migraine in people aged 12 years or older. Acute treatment is 45 minutes at migraine onset and can be repeated. Preventive treatment is 45 minutes every other day.

AEs are almost nonexistent. In the preventive trial, the only AE occurred in the sham arm.

Combined Supraorbital, Supratrochlear, and Greater Occipital Nerve Stimulation

Combined supraorbital, supratrochlear, and greater occipital nerve stimulator (COT-NS) (Relivion MG; Neurolief, Coral Springs, FL) consists of a lightweight band placed around the head with electrodes over the supraorbital and supratrochlear nerves and greater occipital nerves (Figure part F). COT-NS is cleared by the FDA for acute treatment of migraine in adults, with each treatment lasting 60 minutes. AEs, generally local on the head, were all mild to moderate and did not occur at a greater rate in the active vs sham arm in the pivotal trial.

Trials Summary

The eTNS device was studied in 1 randomized controlled trial (RCT) for migraine prevention² and 2 RCTs for acute treatment of migraine.^3,4 In the prevention trial, more participants had ≥50% reduction in monthly migraine days (MMDs) with active than sham treatment, but the absolute MMDs were not reduced compared with sham treatment. For acute treatment, 2 hours of acute treatment were superior to sham for 2-hour pain freedom and 2-hour freedom from the most bothersome symptoms, selected by participants from photophobia, phonophobia, or nausea at attack onset.

The TENS device was evaluated for acute treatment of migraine in 1 positive study, demonstrating improvement in the visual analog scale score for reduction in migraine pain.⁵

The sTMS device was evaluated in a positive RCT for acute treatment of migraine with aura.⁶ Prevention was studied in an open-label trial of 4 pulses twice daily with acute treatments as needed. The results compared favorably with mathematically generated sham results.⁷

One 3-month, open-label, real-world UK evidence trial of sTMS demonstrated a reduction in MMDs for episodic migraine and chronic migraine with no serious AEs reported.⁸ Another independent, UK federally funded, large prospective study examined sTMS efficacy among people with difficult-to-treat, high-frequency episodic migraine or chronic migraine with or without aura and with or without medication overuse headache. The researchers reported decreases in MMDs and acute medication use days, increases in headache-free days, and a reduction in incidence of medication overuse headache from 52% of participants at baseline to 8% at 12 months.⁹

nVNS failed to reach the primary end point for either acute or preventive treatment of migraine in RCTs.^10,11 Other end points were positive. Based on safety, tolerability, and preponderance of positive efficacy endpoints, the FDA cleared nVNS for both indications.

Two RCTs of nVNS for acute treatment of cluster headache had positive results, but only for terminating episodic, not chronic cluster headache attacks. Therefore this treatment is cleared by the FDA for acute treatment of episodic headache, but not chronic cluster headache attacks.^12,13 The preventive study for cluster headache was adjunctive and open label; nVNS was either added to conventional medical management or not, resulting in fewer cluster attacks and reduced use of acute therapies, and the FDA cleared it for adjunctive episodic and chronic cluster prevention.¹⁴

Clearance for paroxysmal hemicrania and hemicrania continua was based on case series data only.¹⁵

Both acute and preventive pivotal trials for REN were sham-controlled and positive for the primary end points.^16,17 The device achieved 2-hour pain freedom for acute treatment and prevented both episodic and chronic migraine within 2 months.

A retrospective chart review of 140 individuals who used REN during pregnancy reported normal gestational weight, age, and miscarriage rate compared with controls.¹⁸ A real-world study on long-term use of 1339 REN devices prescribed by headache medicine providers reported that 58.9% of participants experienced 2-hour pain relief, and 20% of participants experienced 2-hour pain freedom without use of medication in ≥50% attacks.¹⁹

The COT-NS device achieved both 2-hour pain freedom and 2-hour freedom from most bothersome symptoms in an RCT for acute treatment of migraine.²⁰

Thus, each noninvasive treatment has positive RCTs demonstrating efficacy, safety, and tolerability. A few studies were negative for the primary endpoint, and 1 used a mathematical sham, but the predominance of the evidence has been attained through small, well-controlled trials.

Mechanisms of Action

Both eTNS and TENS work by sending inhibitory signals through supraorbital and supratrochlear branches of V1, the ophthalmic nerve. Inhibitory afferents then descend to the trigeminal cervical complex, an area of migraine processing.

In addition, cortical changes are associated with preventive use; blood oxygen level–dependent imaging response decreased in the rostral anterior cingulate cortex in people with migraine without aura.²¹

The sTMS device has at least 2 central mechanisms. The magnetic pulses interrupt cortical spreading depolarization, the mechanism for migraine aura. In addition, the pulses reach the thalamus and inhibit both ascending and descending pathways that run between thalamus and cortex, modulating pain.²²

The nVNS device sends inhibitory afferents up the vagus nerve, and has the same demonstrated mechanisms of action as sTMS, interruption of cortical spreading depolarization, and inhibition of thalamocortical pain pathways. nVNS also inhibits trigeminal activation, enhancing descending pain modulation and preventing ascending nociceptive transmission.²³

The REN device works by initiating conditioned pain modulation, predicated on the observation that pain in location A can inhibit pain in location B, either by a brainstem reflex or a multisynapse pathway that begins with ascending spinothalamic pain afferents and activation of descending inhibitory pain pathways through the rostral ventral medulla. The REN device is set by the individual at the maximal stimulation that does not cause pain in the arm but high enough to activate nociceptive afferents and trigger conditioned pain modulation, which then inhibits migraine pain.¹⁶

The COT-NS device combines the previously described effects of supraorbital and supratrochlear neuromodulation through V1 with posterior inhibition by the cervically derived greater occipital nerves. Both cervical and trigeminal inputs terminate in the trigeminal cervical complex, and the pivotal trial suggests that COT-NS may result in additional benefit in terminating migraine acutely.²⁰

Access and Individual Selection

The US VA Health Care System provides coverage for almost all of these FDA-approved devices, however, coverage by other insurers is limited. Providers need to discuss costs and access with individuals who are not veterans. Some health care systems may provide some coverage, so submission for reimbursement may be useful, but not always.

eTNS and TENS (HeadaTerm) devices are available without prescription online. All the other devices require a prescription.

Complicating access, the Centers for Medicare & Medicaid Services (CMS) designated any external (peripheral) electrical nerve stimulation device as a TENS device by definition (code E0720), with a capped purchase price average of $429. CMS set a requirement of 3 years or more of use per device. CMS assigned a K code (K1020) to nVNS but still designated it a TENS with a 1-time purchase price of $429. CMS designated REN as a TENS K1023, writing that REN is a “distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm…the minimum lifetime requirement of three years is not met…[therefore] no benefit category…no Medicare payment. Pricing = 00.”²⁴

sTMS has a National Drug Code providing access as a therapeutic device but not as durable medical equipment or medical benefit; it is only available through a specialty pharmacy.

Reasons stated by commercial payers for not covering these FDA-cleared devices include poor data quality, experimental status, lack of outcome data, lack of demand, and absence of confirmatory guidelines. As documented in this review, however, high-quality data are available. FDA clearance for the devices implies efficacy, safety, and tolerability, belying the claim that the devices are experimental. Multiple real-world studies have provided excellent outcome data. High use by veterans, who have accessibility to these devices by means of the VA Health Care System coverage, suggests that with access, there is demand. In addition, the American Headache Society Consensus Statement notes that noninvasive neuromodulation should be considered for “patients with an inadequate response to a migraine-specific medication, those with frequent attacks who may be at risk of developing medication-overuse headache or chronic migraine due to overuse of acute medication, [and] patients who prefer to avoid medication,” including young individuals with episodic migraine who do not want to use medication, “those with a history of poor tolerability with or contraindications to [medication], and as an adjunct to the existing treatment plan.”²⁵

Other likely candidates for noninvasive neuromodulation include tech-savvy individuals who are eager to embrace new technology, women planning pregnancy, people who take multiple medications with high potential for drug–drug interactions, and individuals with chronic migraine for whom other options are close to exhausted. Noninvasive neuromodulation can be used early in migraine treatment during episodic migraine and late in chronic migraine, with adjunctive use in between. Obtaining and using noninvasive neuromodulation allows the locus of control to shift from the provider to the individual. Similar to medications, monitoring for device adherence and appropriate use is necessary. The range of individuals with migraine for whom noninvasive neuromodulation is appropriate is expansive.

Conclusions

Noninvasive neuromodulation NSRDs should be integrated into daily headache practice. Noninvasive neuromodulation can be used in monotherapy or in conjunction with medication, as there is no risk for interactions with medication, and additive benefit may be achieved. Tolerability, safety, and efficacy are well-established in RCTs, and 6 have been cleared by the FDA. Efforts to compare devices are challenging because of differences in clinical trial populations, design, and efficacy outcomes. Further studies are needed to determine predictors of response and setting optimization. Providers and individuals need to advocate for payer coverage, given continuing cost and access challenges.