Description
There is only one noninvasive vagal nerve stimulation device cleared by the FDA for the acute and preventive treatment of cluster headaches and migraine, and it is supported by several randomized control trials and real-world evidence.
Cluster headaches. Two randomized, double-blind, sham-controlled trials (ACT1, ACT2) have reported tcVNS as safe and efficient in treating acute episodic cluster headaches (30; 16). In ACT1 (NCT01792817), Silberstein and colleagues evaluated 133 subjects (episodic cluster headache n=38, chronic cluster headache n=22, sham n=73) who received tcVNS (three consecutive 120-second stimulations with 60-second intervals) at the onset of premonitory symptoms or pain. Subjects self-treated up to five cluster headache attacks in the double-blind phase; the primary endpoint was the response rate, defined as the proportion of all subjects who achieved a pain intensity score of 0 or 1 on a 5-point scale (0, no pain; 4, very severe pain) at 15 minutes after treatment initiation for the first cluster headache attack. Treatment response was achieved in 26.7% of tcVNS-treated subjects and 15.1% of sham-treated subjects (P=0.1). Response rates were significantly higher with tcVNS than with sham for the episodic cluster headache cohort (34.2% vs. 10.6%; P=0.008) but not for the chronic cluster headache cohort (13.6% vs. 23.1%; P=0.48) (30). In the ACT2 study (NCT01958125), participants were randomly assigned to the tcVNS group (episodic cluster headache=14, chronic cluster headache=34) and the sham group (episodic cluster headache=13, chronic cluster headache=31) for a 2-week double-blinded period. The primary endpoint was the proportion of all treated cluster headache attacks that achieved pain-free status within 15 minutes of treatment initiation. The study demonstrated no significant difference in primary endpoint achievement between tcVNS (14%) and sham (12%) treatments. Similarly, no significant differences were reported between noninvasive vagal nerve stimulation (5%) and sham (13%) in the chronic cluster headache subgroup. However, tcVNS (48%) was superior to sham (6%; p< 0.01) in the episodic cluster headache subgroup (16).
The efficacy of tcVNS for chronic cluster headache prevention was explored in an open-label prospective randomized clinical trial (PREVA) by Gaul and colleagues comparing standard of care (n=49) and adjunctive tcVNS (n=48) treatments (14). After a 4-week randomized phase, the groups were analyzed for achieving the primary endpoint (a reduction in the mean number of cluster headache attacks per week) along with response rate, abortive medication use, and safety. In the randomized phase, the standard of care plus tcVNS group had a significantly greater reduction in cluster headache attacks per week (-5.9 vs. -2.1) and a mean of 3.9 fewer attacks per week (p=0.02). The adjunctive treatment group also demonstrated a higher 50% responder rate (40.0% vs. 8.3%; p< 0.001) (14). After the 4-week randomization phase, 92 of the study participants entered a 4-week extension phase receiving both standard of care and tcVNS interventions. In a post hoc analysis, the response rate was also significantly reduced at the end of the randomized period in the modified intent-to-treat (mITT) population. Comparing adjunctive tcVNS to standard of care alone, 50% response rates were 49% vs. 9% (P < 0.001), and 75% response rates were 22% vs. 2% (P = 0.009) (15). In a retrospective analysis conducted in the United Kingdom on 30 patients with cluster headache, after an evaluation period of 3 to 6 months, there was a significant decrease in mean attack frequency from 26.6 attacks per week to 9.5 attacks per week (p< 0.01). Mean attack duration also decreased from 51.9 minutes to 29.4 minutes (p< 0.01), and mean attack severity decreased from 7.8 to 6.0 (p< 0.01) on a 10-point scale (21). An open-label study of tcVNS in patients with medically refractory CCH shows greater than 50% reduction in headache frequency in 42.5% patients (32). These results are in alignment with the metaanalysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month. The study suggests the potential benefit of tcVNS in CCH, but randomized sham-controlled trials are needed to confirm the beneficial response of vagal nerve stimulation reported in some, but not all open-label studies (32).
Table 1. Summary of Noninvasive Vagal Nerve Stimulation Randomized Controlled Trials on Cluster Headache
Clinical Trial | Headache (number of patients analyzed) | Treatment, study type | Major findings |
NCT01667250 (14) | Chronic cluster headache (n=93) | Preventive, open-label | Adjunctive tcVNS vs. standard of care: reduction in cluster headache attacks/week -5.9 vs -2.1 (p=0.02). 50% responder rate: 40.0% vs. 8.3% (p< 0.001) |
NCT01792817 (30) | Episodic cluster headache and chronic cluster headache (n=133) | Acute, double-blind | tcVNS vs. sham: pain relief in 15 min. Total cohort 26.7 vs. 15.1% (p= 0.1), episodic cluster headache 34.2 vs. 10.6% (p =0.008), chronic cluster headache 13.6 vs. 23.1% (p=0.48) |
NCT01958125 (16) | Episodic cluster headache and chronic cluster headache (n=92) | Acute, double-blind | tcVNS vs. sham: proportion of pain-free in 15 minutes. Total cohort 14% vs. 12% (p=0.71), episodic cluster headache 48% vs. 6% (p< 0.01), chronic cluster headache 5% vs. 13% (p=0.13) |
SOC: standard of care; tcVNS: transcutaneous cervical vagus nerve stimulation
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Migraine. In 2014, Goadsby and colleagues conducted an open-label pilot study to assess the efficacy of transcutaneous cervical vagal nerve stimulator for the acute treatment of migraine. The study assessed the response of transcutaneous cervical vagal nerve stimulator monotherapy on 19 patients with moderate or severe headaches. They reported 21% (n=4) pain-free response and 47% (n=9) pain relief after two hours of noninvasive vagal nerve stimulation therapy (17). This pilot study was followed up in 2018 by PRESTO, a large randomized, double-blinded, sham-controlled clinical trial (NCT02686034). In a total of 248 episodic migraine patients, 12.7% of the transcutaneous cervical vagal nerve stimulator (n=120) group had pain freedom in comparison to the 4.2% response of the sham (n=123) group at 30 minutes (p=0.012); similar response was seen at 60 minutes (21.0% vs 10.0%; p=0.023) but not at 120 minutes (30.4% vs. 19.7%; p=0.067). Transcutaneous cervical vagal nerve stimulator also exhibited significant pain relief at 120 minutes (40.8% vs. 27.6%, p=0.03) while being safe and well-tolerated. Through this study, Tassorelli and colleagues provided evidence of the efficacy and safety of transcutaneous cervical vagal nerve stimulator devices for acute episodic migraines (34).
For migraine prevention, three randomized controlled trials used transcervical vagus nerve stimulation, and two used transauricular vagus nerve stimulation. In the EVENT trial, the efficacy and benefits of transcutaneous cervical vagal nerve stimulator on chronic migraine were tested in an early prospective, double-blinded, sham-controlled pilot study (NCT01667250). Fifty-nine patients with a mean headache frequency of 21.5 days per month were randomized into transcutaneous cervical vagal nerve stimulator (n=30) and sham (n=29) treatment groups. After two months, the mean number of headache days changed by -1.4 for transcutaneous cervical vagal nerve stimulator and -0.2 for the sham group (p=0.56). Of the 30 participants enrolled in the transcutaneous cervical vagal nerve stimulator group, 15 completed a 6-month open-label treatment period. In those who completed a 6-month open-label extension (n=15), the mean number of headache days decreased significantly (-7.9) from baseline (95% CI -11.9 to -3.8; p< 0.01) (29). In the PREMIUM trial, the efficacy of transcutaneous cervical vagal nerve stimulator on episodic migraine was evaluated by a randomized, double-blinded, sham-controlled study (11). After a 12- week randomized treatment of the transcutaneous cervical vagal nerve stimulator group (n=165) and the sham group (n=167), no significant mean reductions in migraine days per month (primary endpoint) were reported. A reduction of 2.26 migraine days per month was observed in the tcVNS group (baseline, 7.9 days) and 1.80 days for the sham group (baseline, 8.1 days) (p=0.15). However, in the mITT population (patients who were 67% or greater adherent to stimulation), patients showed a significantly greater reduction in the monthly migraine days (-2.27 vs. -1.53, p=0.043), monthly headache days (-2.85 vs. -1.99, p=0.045), and acute medication use days (-1.94 vs. -1.14, p=0.039). Interestingly, based on this robust response seen in the sham group in the PREMIUM study, it was theorized that the sham device might have stimulated the vagus nerve. Schroeder and colleagues demonstrated that both transcutaneous cervical vagal nerve stimulator and sham (0.1 hz) produced stimulation, but no stimulation significantly reduced ipsilateral trigeminal autonomic reflex induced by kinetic oscillation stimulation (28).
Several limitations seen in the original PREMIUM study were addressed in a second large, 12-week, randomized double-blinded sham-controlled trial (PREMIUM II, NCT03716505). PREMIUM II applied ipsilateral stimulations to the side of predominant pain compared to the original study that used bilateral stimulations. The study also expanded to both episodic and chronic migraine subjects (8 to 20 monthly headache days) and utilized a modified inactive sham device to avoid sham stimulation. Of 231 randomized patients, 113 (active=56, sham=57; chronic migraine=23, episodic migraine=33) completed 70 or more days of the 12-week double-blind period and adhered 66% or more to treatment each week. The study demonstrated a mean reduction in monthly migraine days of 3.12 days in the active group and 2.29 in the sham group (p=0.2329). They also reported a greater 50% response rate in the active group than in the sham group (44.87% vs. 26.81%, p=0.0481). The trial was terminated early due to the COVID-19 pandemic, leading to a smaller statistical target population. The study reinforced the efficacy and safety of transcutaneous cervical vagal nerve stimulator devices for migraine headaches (25).
In addition to transcervical vagus nerve stimulation, there are two randomized controlled trials that evaluated transauricular vagus nerve stimulation for migraine prevention. Straube and colleagues investigated the therapeutic effects of NEMOS® on patients with chronic migraine by applying the device at the left tragus and stimulating the auricular branch of the vagus nerve. The device was applied to 46 patients over three months, for 4 hours per day, delivering 25 Hz to 1 Hz stimulation. The study showed a significant reduction in the number of headache days in the active control group that received 1 Hz stimulation as compared to the 25 Hz group (-7.0 ± 4.6 vs. -3.3± 5.4 days, p=0.035). They also assessed headache-related disability by the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires, both showing significant improvement (33). Another randomized study was conducted by Zhang and colleagues where 70 patients with episodic migraine received four weeks of treatment with taVNS (30 minutes, total 12 sessions) or sham. The taVNS group significantly reduced the number of migraine days (-2.5 vs. -0.7, p=0.024), pain intensity (-17.4 vs. -4.1, p=0.008), and attack times (-1.5 vs. 0.4, p=0.015) as compared to the sham taVNS. Their study further analyzed the modulatory effect of taVNS devices on the thalamocortical circuits, revealing taVNS induced increased connectivity between the anterior cingulate cortex and the motor-related thalamus subregion (40).
Table 2. Summary of Noninvasive Vagal Nerve Stimulation Randomized Controlled Trials on Migraine
Clinical Trial | Headache (number of patients analyzed) | Treatment, study type | Major findings |
DRKS00003681 (33) | Chronic migraine (n=40) | Preventive, open-label | taVNS 1Hz vs. 25hz: MMD change. ITT -5.6±5.0 vs. -3.0±5.3 (p=0.094), PP −7.0±4.6 vs. −3.3± 5.4 (p=0.035) |
NCT01667250 (29) | Chronic migraine (n=48) | Preventive, double-blind | tcVNS vs. sham: MHD change. ITT -1.4 vs. 0.2 (p=0.56), PP -2.0 vs. -0.1 (p=0.35). |
NCT02686034 (34) | Episodic migraine (n=243) | Acute, double-blind | tcVNS vs. sham: Pain freedom at 120 min. ITT 30.4% vs. 19.7% (p=0.067). Pain relief at 120 min. ITT 40.8% vs. 27.6% (p=0.03) |
NCT02378844 (11) | Episodic migraine (n=332) | Preventive, double-blind | tcVNS vs. sham: ITT -2.26 vs. -1.80 (p=0.15), mITT -2.27 vs. -1.53 (p=0.043) |
ChiCTR-INR-17010559 (40) | Episodic migraine (n=59) | Preventive, single-blind | taVNS vs. sham: MMD change. ITT -2.5 vs. -0.7 (p=0.024) |
NCT03716505 (25) | Episodic migraine and chronic migraine (n=113) | Preventive, double blind | tcVNS vs. sham: MMD change. mITT -3.12 vs. -2.29 days (p=0.23). 50% responder rate. mITT 44.87% vs. 26.81% (p=0.048) |
MMD: mean monthly migraine days. MHD: mean monthly headache days. ITT: intention to treat, mITT: modified intention to treat, PP: per protocol. taVNS: transauricular vagus nerve stimulation. tcVNS: transcervical vagus nerve stimulation
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Other headache disorders. gammaCore received United States Food and Drug Administration clearance for patients with hemicrania continua based on a few case reports. Eren and colleagues reported a man suffering from left-sided hemicrania continua who developed contraindication to indomethacin (12). The patient received transcutaneous cervical vagal nerve stimulator using the PREVA protocol and reported an immediate decline of pain intensity from 8/10 to 5/10 during exacerbation periods. He also reported improved quality of life and subjective reduction in the background pain intensity. Similarly, Tso and colleagues described 10 patients with hemicrania continua and paroxysmal hemicrania who could not tolerate indomethacin and used noninvasive vagal nerve stimulation as adjunctive therapy (35). In patients with hemicrania continua, 78% reported reduced severity of continuous pain. In addition, 67% of patients reported benefits such as being attack-free, reduced attack frequency, reduced severity, and shorter duration of attacks. Patients with primary cough headaches demonstrated improvement with transcutaneous cervical vagal nerve stimulator. Moreno-Ajona and colleagues reported a man with primary cough headaches being treated with transcutaneous cervical vagal nerve stimulator after developing contraindications to indomethacin (23). There was a dramatic improvement over six weeks; he reported complete relief afterward. The treatment efficacy of noninvasive vagal nerve stimulation devices for vestibular migraine was also demonstrated in a case series reported by Beh (03). The patients received bilateral 120-second stimulations on both sides of the neck and were asked to grade their vertigo and headache using a 10-point visual analog scale. The patients reported a difference in their average vertigo severity from 5 to 1.5 and mean headache severity from 4 to 0.7 after noninvasive vagal nerve stimulator use. With these findings, gammaCore was cleared by the FDA for hemicrania continua and paroxysmal hemicrania but not yet for vestibular migraine and primary cough headaches. In a case of cyclical vomiting syndrome, transcutaneous vagus nerve stimulation was applied as a nonpharmacological treatment option. After 3 months of daily administration of 4 hours daily, the patient showed improvement in heart rate variability (06) The efficacy of vagus nerve stimulation in cyclical vomiting syndrome can be explained by the modulatory effects on nucleus tractus solitarius.
Indications
gammaCore Sapphire™ (electroCore, Inc., Rockaway, NJ) is a handheld trans-cervical noninvasive vagal nerve stimulation neuromodulation device that the FDA has cleared for cluster headaches for both acute and preventive treatment. Indications are as follows:
| • Preventive treatment of migraine headache in adolescent (age 12 and older) and adult patients. |
| • Acute treatment of pain associated with migraine headache in adolescent (age 12 and older) and adult patients. |
| • Adjunctive use for the preventive treatment of cluster headache in adult patients. |
| • The acute treatment of pain associated with episodic cluster headache in adult patients. |
| • Treatment of hemicrania continua in adults. |
| • Treatment of paroxysmal hemicrania in adults. |
| • The effectiveness of gammaCore has not been established in the acute treatment of chronic cluster headache. |
tVNS® (tVNS Technologies GmbH, Bayern, Germany), previously knowns as NEMOS, has also received European CE marking for multiple conditions. On the website https://t-vns.com/, the following indications are listed without any link for references: anxiety, asthma, atrial fibrillation, autism, cognitive impairment, Crohn disease, depression, epilepsy, fibromyalgia, inflammation, migraines, Parkinson disease, Prader-Willi syndrome, sleep disorders, stroke, and tinnitus.
Contraindications
Generally, noninvasive vagal nerve stimulation devices are very safe for use. However, noninvasive vagal nerve stimulation is not applicable in patients with altered anatomy (eg, cervical vagotomy, deformed ear, local skin infection). Similar to invasive vagus nerve stimulation, patients with pre-existing swallowing, cardiac, or respiratory difficulties may experience worsening symptoms. nVNS should be removed from the skin or turned off immediately if any of these symptoms occur.
On gammaCore safety information, contraindication includes:
| • Have an active implantable medical device, such as a pacemaker, hearing aid implant, or any implanted electronic device. |
| • Have a metallic device, such as a stent, bone plate, or bone screw, implanted at or near the neck. |
| • Simultaneous use of another stimulation device (eg, TENS unit, muscle stimulator) or any portable electronic device (eg, mobile phone). |
Adverse effects
Noninvasive vagal nerve stimulation is a safe and well-tolerated treatment option, with some mild side effects that have been reported over the years (27). Redgrave and colleagues conducted a systematic review of all the studies that deployed noninvasive vagal nerve stimulation in humans. They reported local skin irritation as the most common side effect, seen in 18.2% of participants. Local skin reactions included tingling or pain around stimulation sites, with only a few participants reporting other skin irritations, such as itchiness or redness. Skin irritation was followed by headaches, seen in 3.6% of the participants. Other rare side effects were also reported, such as heart palpitations, nasopharyngitis, and facial drooping. Gastrointestinal issues such as nausea or vomiting were reported.
Special considerations
The safety and efficacy of gammaCore have not been evaluated in the following patients:
| • Adolescent patients with congenital cardiac issues. |
| • Patients diagnosed with narrowing of the arteries (carotid atherosclerosis). |
| • Patients who have had surgery to cut the vagus nerve in the neck (cervical vagotomy). |
| • Pediatric patients (younger than 12 years). |
| • Pregnant women. |
| • Patients with clinically significant hypertension, hypotension, bradycardia, or tachycardia. |
A single-center randomized, double-blinded clinical trial of taVNS in children and adolescents with primary headache disorders has recently been registered at the following site:clinicaltrials.gov (NCT06277063). The trial will consist of a treatment and a sham group, and an objective evaluation of the treatment response will be made by tracking changes on electrocardiogram and electromyography. The primary outcomes of the study will be changes in the visual analog scale (VAS)-acute period and VAS prevention period. Because this will be the first trial in children with an objective assessment of response, the results will provide valuable evidence for the use of noninvasive vagal nerve stimulation in the younger population.
