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Transcutaneous auricular vagus nerve stimulation (TVNS) improved sleep quality significantly in a small, sham-controlled trial, substantially expanding a growing body of evidence supporting its safety and efficacy for chronic insomnia.

On the primary endpoint of improvement in the Pittsburgh Sleep Quality Index (PSQI), the benefit of TVNS was documented at the end of an 8-week treatment period as well through follow-up lasting an additional 12 weeks, new data showed.

The study was published online on December 16 in JAMA Network Open.

Large Effect Size

The study included 72 participants who had at least a 3-month history of insomnia as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Patients with more complicated forms of insomnia, including sleep apnea, narcolepsy, and restless leg syndrome were excluded.

Although all patients were required to have a PSQI score of at least 8 (scale 0-21 with 8 signifying poor sleep quality) at entry, they were not necessarily refractory to prior treatment, study investigator Yu Wang, MD, PhD, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China, noted.

“Our team has not conducted investigations on patients with insomnia who do not respond to other therapies,” Wang told Medscape Medical News, but he acknowledged this group “merits further exploration in our future studies.” 

Both active treatment and sham-controlled participants received electrical stimulation delivered to the bilateral auricular and cymba conchae for 30 minutes twice per day on 5 consecutive days for 8 weeks. However, at 0.1 mA, the current intensity in the sham group was considered to be below the therapeutic threshold.

The higher intensity stimulation in the active treatment group was adjusted to the patient’s maximum tolerable levels. Treatments were self-administered or by a family member at home.

With a 2.5-point reduction in the PSQI considered to be a minimal clinically important change, both groups achieved a statistically significant and clinically meaningful reduction in insomnia from baseline at 8 weeks. But the 4.2-point greater mean change in the TVNS group (−8.2 vs −3.9; P < .001) represented a large effect size.

In addition, the difference between groups favoring TVNS was already significant at 4 weeks, and the advantage was persistent from the end of the 8-week treatment through an additional 12 weeks of follow-up. Indeed, the PSQI remained essentially unchanged over follow-up in the active treatment group, whereas scores climbed modestly over time in the sham group.

Mechanism of Benefit Unclear

The same or very similar relative benefit from TVNS relative to sham was seen across most secondary outcome measures that included the Insomnia Severity Index (ISI), the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale, the Flinders Fatigue Scale, and the Epworth Sleepiness Scale (ESS).

In each scale, scores improved in both groups, in all but ESS, there was a significantly greater improvement by week 4 in the TVNS group and generally no loss of response in the TVNS group from the end of treatment to the end of follow-up.

For ISI and HAM-D, there was a modest increase in the advantage of TVNS at the end of 20 weeks because of a return toward baseline in the sham group. On ESS, the curves separated quickly and favored TVNS until the end of follow-up, but the differences did not reach statistical significance at any timepoint.

The proportion of patients with adverse events were similar in the TVNS and sham groups (13.9% vs 11.1%, respectively). Clamping pain was reported by 4 patients in the TVNS group and 3 patients in the sham group. In both, the pain resolved with kneading of the clamping spot.

There are numerous published studies associating TVNS with benefit against insomnia, including insomnia from specific etiologies. For example, a 2024 sham-controlled study associated TVNS with improved sleep depth and stability in armed service veterans with post-traumatic stress disorder (PTSD).

Delivered in various doses and for various periods, TVNS has also been associated with activity against depression, migraine, and epilepsy, although the mechanism of benefit is not fully understood for any potential indication, said Wang.

Noting that the 8-week course of TVNS in this study was relatively long, Wang said these findings “align with previous research suggesting that prolonged treatment is relevant to achieving and prolonging the benefit.”

A Small but Important Study

Commenting on the findings for Medscape Medical News, Emerson Wickwire, PhD, who heads a Sleep Medicine Unit at the University of Maryland School of Medicine, Baltimore, noted that insomnia “is the most common sleep disorder seen in clinical practice,” adding that there’s “a dramatic unmet need for insomnia treatments that are safe, effective, and convenient.” 

Despite the availability of FDA-approved insomnia medications and proven benefit from such interventions as cognitive behavior therapies (CBT), Wickwire pointed out that there is a need for more options, including nondrug therapies and treatments that are less time-consuming and costly than CBT.

The newly published study is “small,” but it is “important,” Wickwire added.

“Relative to sham control, TVNS was found to reduce insomnia severity as well as daytime symptoms of depressed mood and sleepiness over 20 weeks,” he said, indicating that these are meaningful findings. However, he indicated that they are not definitive.

“Future studies will be required to replicate these findings, examine the impact of TVNS on a broader range of daytime symptoms, and determine the potential economic benefit of this approach,” he said.

Wang reported no potential conflicts of interest. Wickwire reported financial relationships with Eisai, Idorsia, and Merck.

Ted Bosworth is a medical journalist based in New York City.