Non-Invasive Vagus Nerve Stimulation for Treatment of Trigeminal Autonomic Cephalalgias: Encouraging Results

A retrospective study spanning 11 years suggests that this neuromodulation approach is useful as a preventive therapy for hard-to-treat headache conditions.

Over the last decade, researchers have looked to neuromodulation of the vagus nerve, a key component of the parasympathetic nervous system, to develop treatments for conditions like epilepsy and depression – and migraine, too. Non-invasive vagus nerve stimulation (nVNS) received approval by the US Food and Drug Administration (FDA) for acute treatment of migraine in 2018. Other studies, like the ACT1 and ACT2 randomized clinical trials, suggested that nVNS may also be effective for cluster headache (CH).

Now, researchers have published a long-term retrospective study of more than 100 patients with trigeminal autonomic cephalalgias (TACs) – most often CH, but also paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform with cranial autonomic symptoms (SUNA), and undifferentiated TACs.

The analysis, from researchers at King’s College London (KCL), UK, found that most patients considered nVNS useful over a median period of 47 months of device use. Interestingly, nVNS appeared most useful for preventive purposes, for all headache types, leaving the door open for more widespread use of nVNS. Those living with CH and SUNCT/SUNA also reported its usefulness as an acute treatment.

“Here we see acute benefit of nVNS for both episodic and chronic cluster headache, and nearly two-thirds of patients with chronic cluster headache show a preventive benefit using nVNS as a monotherapy,” said Stewart Tepper, New England Institute for Neurology and Headache, Stamford, US. “This is the first time we’ve seen nVNS for the prevention of cluster headache, and it offers further evidence that nVNS can be useful for these challenging headache conditions,” according to Tepper, who was not involved in the study.

In an accompanying editorial, Xavier Moisset, Université Clermont Auvergne, France, highlighted the importance of real-world evidence (RWE) as a complement to insights gained from randomized, controlled trials.

“[T]his retrospective analysis of long-term nVNS use in TACs contributes valuable RWE to an increasingly promising area,” according to Moisset.

The study and editorial appeared online in Cephalalgia on September 1, 2025.

A useful approach
Study co-author Usman Ashraf, KCL, said he and his colleagues Peter Goadsby, KCL, and Catarina Fernandes, KCL and University Hospital of Coimbra, Portugal, were inspired to conduct their study for several reasons, including evidence to support the effectiveness of nVNS for migraine, the results from the ACT1 and ACT2 studies of CH, and anecdotal evidence from patients with TACs who already use nVNS. He added that they were also curious whether this kind of neuromodulation would offer preventive benefit.

“The vagus nerve is important for a lot of what we call autonomic function, which is basically how the body responds and balances itself to change in the environment,” he explained. “If you think about it, a lot of headache disorders, especially these debilitating ones, are quite susceptible to changes in our environment. It also makes sense that patients with TACs would respond to nVNS because the vagus nerve is highly connected to areas like the midbrain, hypothalamus, the brainstem, and thalamus, which are relevant to headache disorders as well.”

Ashraf and colleagues looked at data from 108 patients (62 males and 46 females), who previously used or were currently using nVNS between January 2014 and February 2025, while being treated at a tertiary headache center. Seventy-four were diagnosed with CH (27 with episodic CH, and 47 with chronic CH), 10 with paroxysmal hemicrania, 15 with hemicrania continua, 4 with SUNCT, 3 with SUNA, and 2 patients with an undifferentiated TAC.

The researchers analyzed data from documented clinical encounters, as well as demographic information, data on attack frequency, duration, and intensity, and comorbid diagnoses. They further noted how long each participant used nVNS, and for those who stopped using it, why they did so. The team also asked patients if they had previously tried any other preventive treatments.

More than half of study participants (57%) had been diagnosed with some other type of headache condition, especially migraine. Participants also had a median number of 5 previous preventive treatment failures.

Seventy patients overall reported that nVNS was useful during a median time using the nVNS device of 47 months. Most participants (84%) reported that nVNS was useful as a preventive therapy, and 47% found it useful for acute treatment, particularly for those who had CH or SUNCT/SUNA. For those who said nVNS was useful, 70% had a more than 50% decrease in attack frequency, and 23% had a greater than 50% reduction in how long their attacks lasted. In addition, patients who did not consider nVNS to be useful were more likely to have experienced previous preventive treatment failures.

Further, in terms of nVNS tolerability, 22% reported at least one adverse event, most often neck discomfort and face pain on the side of stimulation; no serious adverse events occurred. But there was a high dropout rate for nVNS, with 59 (55%) patients withdrawing from using the neuromodulation, including 11 patients who had reported it was useful at first. For those who withdrew the nVNS, the most common reason was that it did not work for them.

Much to consider
Ashraf said the data gave him quite a bit to think about. He said he and his colleagues expected that nVNS would work as preventive therapy because previous studies suggest the neuromodulation acts on important headache-related pathways in the nervous system. But he was surprised that it took a fair amount of time for some patients to see a benefit.

“When it comes to this preventive effect, it’s not something that kicks in right away for people. It takes time,” he said. “We’ve always recommended that patients try at least 12 weeks at a consistent dosage, because of what we’ve seen works in practice. And the data here support that it does take some time for the neuromodulation to provide an effect.”

He also said that the withdrawal results are something worth paying attention to.

“If you look at the numbers, you see that most patients tolerated the treatment quite well,” he said. “That suggests it’s not a tolerance issue. It may be that the efficacy eventually wears off, but we don’t know why that might be for some people and not for others.”

Tepper said he found the results “very encouraging,” especially since benefits were seen across the different TACs.

“Many of the go-to medications for these conditions are very difficult to tolerate,” he said. “These results suggest that nVNS is useful. But, unfortunately, many of these neuromodulation devices are expensive. Many people can’t afford it. And if they can, the devices aren’t always accessible to them.”

That is why he hopes that the current study results, in combination with the findings from the ACT1 and ACT2 trials, will lead the FDA and other regulatory agencies to loosen clearance indications so more patients have access to nVNS, and that insurance companies will cover it.

Ashraf said he hopes the results raise awareness so more clinicians and patients realize nVNS is a potential treatment option for TACs.

“There’s a fundamental problem in that clinicians not only struggle to treat TACs but to diagnose them in the first place,” he said. “To date, there’s little consensus on what first steps to take when a TAC is diagnosed. But if more headache specialists were aware of non-invasive neuromodulation being an option, it could provide a new, well-tolerated preventive treatment option for patients who live with these incredibly debilitating headache disorders.”

Kayt Sukel is a freelance writer based in Kansas.

Image credit: 123RF Stock Photo.

References
Neuromodulation in trigeminal autonomic cephalalgias: 11-year experience of non-invasive vagus nerve stimulation.
Fernandes et al.
Cephalalgia. 2025 Sep;45(9):3331024251370339.

Vagus nerve stimulation for trigeminal autonomic cephalalgias: Evidence, challenges and future directions.
Moisset X.
Cephalalgia. 2025 Sep;45(9):3331024251370318.