Reviewing Noninvasive Vagus Nerve Stimulation for Migraine, Cluster Headache

vagus nerve stimulation
vagus nerve stimulation

A substantial percentage of patients with primary headache disorders are unresponsive to standard pharmacologic therapies, with pain-free response rates of 45% at 15 minutes and 30% at 2 hours, following the use of rescue medications.1 Such findings, along with the range of side effects associated with these agents, highlight the need for novel treatment options for these patients.

Limited evidence supports the efficacy of surgically implanted cervical vagus nerve stimulation (iVNS) for the treatment of migraine and cluster headache, with a 50% reduction in headache frequency and severity according to the results of 2 pilot studies.1 Promising results have also been found for the efficacy of iVNS in the management of seizure-related migraine and chronic daily headache. However, the use of iVNS has been associated with adverse effects related to implantation and/or stimulation.

Emerging findings suggest that cervical noninvasive VNS (nVNS) using the gammaCore device — which was approved by the US Food and Drug Administration2 for the acute treatment of pain associated with cluster headache and migraine — may represent an option with efficacy comparable to iVNS, with a lower risk for side effects.

“The afferent properties of the vagus nerve are well connected via the nucleus tractus solitarii to the locus coeruleus, the dorsal raphe nucleus, the parabrachial plexus, the paraventricular nucleus of the hypothalamus and directly to the [trigeminal nucleus caudalis] and the cervical spinal cord,” note the authors of a narrative review published in the Journal of Pain Research.1 “Given these anatomic reciprocal projections of the vagus nerve, electrical noninvasive modulation of the cervical vagal afferents may impact trigeminovascular nociceptive transmission.”

The authors examined studies in which cervical nVNS (with stimulation protocols that varied across studies) was used for the treatment of episodic and chronic migraine (EM/CM) and cluster headache (ECH/CCH). Their findings are summarized below.

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Episodic and Chronic Migraine

In a 2014 open-label pilot study, investigators examined the abortive effects of nVNS in 27 patients with EM.3 Two hours after the first attack was treated with nVNS, pain-free and pain relief rates of 21% and 47%, respectively, were reported by patients with moderate to severe pain, with similar rates observed for subsequent attacks. For patients with mild pain at baseline, pain-free rates at 2 hours were 63% and 38% for the first and subsequent attacks, respectively. These response rates are comparable with those obtained with pharmacologic therapies.

In a 2015 open-label trial, 38.2% and 51.1% of patients with EM and CM who were treated with nVNS indicated pain relief at 1 and 2 hours after treatment, respectively.4 Pain-free rates were 17.6% at 1 hour and 22.9% at 2 hours.

In a prospective observational cohort study published in 2015 in which the preventive and acute effects of nVNS were examined in patients with treatment-refractory EM and CM, significant reductions in headache severity and frequency were observed after 3 months of treatment (P <.001).5 Results from both studies suggest that nVNS may be more effective for patients with EM vs CM.

In the double-blind sham-controlled EVENT trial in which the use of nVNS for migraine prophylaxis was examined in 48 patients with CM, monthly headache days were found to be reduced with nVNS vs sham during the randomized phase and the open-label phase (P <.05).6

In addition, nVNS has shown promise in treating migraine in adolescents and for menstrual-related migraine.

Episodic and Chronic Cluster Headache

In the first pilot study of nVNS for prophylactic and acute treatment of ECH and CCH in 19 patients, a decrease in headache frequency was noted after 12 months (P <.0005).7 A total of 15 of 19 patients reported an improvement (mean, 48%), and 47% of attacks were aborted within an average of 11±1 min. Oxygen demand decreased by 55%±8% in 71% of patients, and triptan use decreased by 48%±6% in 75% of patients.

The ACT-1 double-blind sham-controlled randomized controlled trial showed higher response rates (ie, scores of 0 or 1 within 15 minutes of treatment) with nVNS vs sham in the entire cohort (P =.04) as well as in the ECH subgroup (P =.008), during the open-label phase.8

In the ACT-2 study, higher pain-free rates were observed with nVNS vs sham for the entire cohort (P =.05), but not the ECH or the CCH subgroups.9 A pooled analysis of ACT-1 and ACT-2 studies indicated improvements in responsiveness to nVNS vs sham for patients with ECH.1 “ACT-1 and ACT-2 confirmed the abortive impact of nVNS with a more pronounced responsiveness for ECH patients,” noted the review authors.1

In the open-label PREVA trial in which the use of nVNS was examined for the treatment of CCH, a greater reduction in weekly attacks was observed in the group receiving nVNS plus standard of care compared with standard of care alone (P =.02).10 A response rate of ≥50% was achieved in the extended phase of the trial (P <.001).

In a post-hoc analysis, nVNS plus standard of care was found to be superior to standard of care only at all time points (P <.02 for all). Further analyses indicated the cost-effectiveness of nVNS for ECH and CCH, in addition to reductions in abortive medication requirements and improved quality of life when nVNS was used in addition to standard of care.1

No serious adverse events associated with the use of nVNS were reported in any of the above-mentioned studies, and the safety/tolerability profile of nVNS was similar to sham stimulation.

“Due to its noninvasive character along with the reported tolerability, cervical nVNS may be justified in the pre-refractory state of migraine and cluster headache, and probably in a migraine subpopulation with limited available options,” including patients with menstrual-related migraine and adolescent migraineurs, the review authors concluded.1


1. Lendvai IS, Maier A, Scheele D, Hurlemann R, Kinfe TM. Spotlight on cervical vagus nerve stimulation for the treatment of primary headache disorders: a review. J Pain Res. 2018;11:1613-1625.

2. PR Newswire. gammaCore® receives FDA clearance for the acute treatment of pain associated with migraine headache in adult patients. January 29, 2018. Accessed June 24, 2019.

3. Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014;34(12):986-993.

4. Barbanti P, Grazzi L, Egeo G, Padovan AM, Liebler E, Bussone G. Noninvasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: an open-label study. J Headache Pain. 2015;16:61.

5. Kinfe TM, Pintea B, Muhammad S, et al. Cervical non-invasive vagus nerve stimulation (nVNS) for preventive and acute treatment of episodic and chronic migraine and migraine-associated sleep disturbance: a prospective observational cohort study. J Headache Pain. 2015;16:101-107.

6. Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic migraine headache prevention with non-invasive vagus nerve stimulation: the EVENT study. Neurology. 2016;87(5):529-538.

7. Nesbitt AD, Marin JC, Tompkins E, Ruttledge MH, Goadsby PJ. Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment. Neurology. 2015;84(12):1249-1253.

8. Silberstein SD, Mechtler LL, Kudrow DB, et al; ACT1 Study Group. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache. 2016;56(8):1317-1332.

9. Goadsby PJ, de Coo IF, Silver N, et al; ACT2 Study Group. 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.

10. Gaul C, Diener HC, Silver N, et al; PREVA Study Group. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomized controlled study. Cephalalgia. 2016;36(6):534-546.