Vagus nerve stimulation for trigeminal autonomic cephalalgias: Evidence,challenges and future directions

Real-world evidence (RWE) offers valuable insights and serves as an important complement to randomized controlled trials (RCTs). However, RWE comes with specific methodological challenges, and dedicated guidelines have been developed for its use in the context of migraine and cluster headache (CH) (1). One critical aspect not fully addressed in these guidelines is the influence of the placebo effect. While open-label studies can offer valuable preliminary insights or provide long-term follow-up data, often lacking in RCTs, their findings must be interpreted with caution, especially in trigeminal autonomic cephalalgias (TACs), where placebo responses can be unexpectedly high. Recent, well-conducted RCTs have highlighted this challenge, reporting placebo response rates of up to 53% in episodic CH (2) and 45% in chronic CH (3). The real-world data presented in the study by Fernandes et al. (4) provide valuable complementary insights to those from previous RCTs.

In the field of pain management, and particularly in headache disorders, there is growing interest in non-pharmacological therapies, with neuromodulation emerging as a key area of focus. Among these approaches, non-invasive vagus nerve stimulation (nVNS) has gained increasing attention. In the specific context of CH, nVNS, and in particular the gammaCore™ (Electrocore) device, has demonstrated efficacy in RCTs. The ACT1 (5) and ACT2 (6) studies evaluated nVNS for acute treatment. While both trials failed to meet their primary endpoints in the overall CH population, they demonstrated positive outcomes specifically in the subgroup of patients with episodic CH. Although fewer than half of the patients are classified as responders in the studies, the effect size is substantial, with a number needed to treat below 5 (7). In the PREVA study (8), gammaCore™ (Electrocore) demonstrated efficacy as a preventive treatment. These trials led to FDA approval of gammaCore™ (Electrocore) for the acute treatment of episodic CH and for preventive use, along with CE marking in Europe. Based on this body of evidence, nVNS is now recommended for use in CH in the European Academy of Neurology (EAN) guidelines (9). However, despite these regulatory milestones and guidelines, clinical uptake has remained limited. Many patients are never offered this therapy, likely due to a combination of factors including lack of awareness, high costs, limited reimbursement and regional disparities in access. The current 11-year retrospective study, although not naming the specific device, almost certainly refers to gammaCore™ (Electrocore), which remains the only nVNS device formally approved for TACs (4). It offers valuable real-world data on long-term outcomes, reinforcing the potential role of this neuromodulatory strategy.

A particularly striking finding of this study is the high rate of treatment discontinuation: more than half of the patients (59 out of 108) ceased using nVNS. These observations align with previous clinical trials, which demonstrated efficacy in only a subset of patients. Notably, 11 of these individuals, representing 16% of those who initially experienced some clinical benefit, discontinued treatment due to factors such as cost or tolerability (4). Although nVNS has a favorable safety profile and can be effective for a significant proportion of individuals, practical barriers, especially high cost and limited access in most countries, continue to hinder its broader adoption. Addressing these challenges is essential to ensure equitable access and long-term adherence.

Beyond gammaCore™ (Electrocore), a variety of devices claim to deliver nVNS, either via the cervical route or the auricular branch of the vagus nerve at the ear. These devices vary widely in their mechanisms of action, regulatory approval status, intended applications, and supporting clinical evidence. Given the rapid pace of innovation in this area, a selection of representative devices is summarized below.

Cervical devices aim to stimulate the vagus nerve transcutaneously in the cervical region. While conceptually similar to gammaCore™ (Electrocore), most of these devices are marketed for general wellness rather than medical treatment. Examples include Pulsetto^® (Pulsetto) (a neck-worn stimulator for relaxation), TruVaga™ (Electrocore) (a handheld cervical device marketed for mood and stress) and various generic transcutaneous electrical nerve stimulation (TENS) units adapted for vagus nerve stimulation. These devices typically lack regulatory approval for medical indications and are unsupported by peer-reviewed data in headache populations.

Ear-based devices target the auricular branch of the vagus nerve through surface electrodes applied to areas such as the tragus or cymba conchae, an approach known as transcutaneous auricular VNS (taVNS). One example is Nurosym^® (Parasym), a CE-marked ear-clip device that has received US Food and Drug Administration (FDA) NSR (i.e. non-significant risk) designation for investigational studies. NSR does not mean the FDA has “approved” the device. While preliminary studies suggest potential benefits in anxiety and fatigue, no RCTs have evaluated its efficacy in CH or other TACs. Another notable device is tVNS^® (tVNS Technologies GmbH) (previously NEMOS), approved in Europe for indications such as depression, epilepsy and pain. However, it has not been tested in TACs. Other auricular stimulators such as Auri-Stim^® (Multisana) or various over-the-counter TENS products are available, though typically unregulated and lacking scientific validation.

Finally, a few wellness-focused devices, such as Sensate^® (Bioself Technology Ltd) and Apollo Neuro^® (Apollo Neuro Fact Sheet), claim to influence vagal tone through acoustic or vibratory mechanisms. These are not designed for medical use and no headache-related evidence supports their efficacy.

nVNS is part of a broader spectrum of neuromodulatory interventions. Implanted vagus nerve stimulation has been used in the treatment of epilepsy for over 30 years. Its potential role in CH remains to be explored, and it would be of particular interest to determine whether a positive response to nVNS reliably predicts responsiveness to implanted VNS. Other invasive approaches, such as greater occipital nerve stimulation (GONS), have shown promise in small studies, particularly in refractory CH. However, they remain underutilized due to limited accessibility and concerns regarding safety. According to the 2023 EAN guidelines, GONS should only be considered when all pharmacological treatments have failed (9). Sphenopalatine ganglion stimulation is another preventive treatment option recommended by the EAN guidelines. However, its clinical application is currently not feasible due to the unavailability of the device.

Another emerging modality for non-invasive neuromodulation is remote electrical neuromodulation, exemplified by the Nerivio™ (Theranica) device, which has gained increasing use in migraine management. Although it has not yet been studied in TACs, its favorable safety profile makes it a compelling candidate for future research. However, similar to nVNS, cost and limited availability may pose barriers to widespread clinical adoption.

In conclusion, this retrospective analysis of long-term nVNS use in TACs contributes valuable RWE to an increasingly promising area. Currently, gammaCore™ (Electrocore) remains the only nVNS stimulation device with demonstrated efficacy in CH, supported by RCTs and regulatory approval. However, cost and limited access hinder widespread adoption. These challenges underscore the need for independent, well-designed comparative trials to determine whether other, more accessible devices can provide similar benefits. Simultaneously, improving reimbursement frameworks and device availability is essential. Such efforts could significantly improve care for patients affected by these debilitating headache disorders, particularly those who do not achieve adequate relief with pharmacological treatments or who experience intolerable side effects.