Transcutaneous vagus nerve stimulation effects on chronic pain: systematic review and meta-analysis

Abstract

Chronic pain is one of the major causes of disability with a tremendous impact on an individual's quality of life and on public health. Transcutaneous vagus nerve stimulation (tVNS) is a safe therapeutic for this condition. We aimed to evaluate its effects in adults with chronic pain. A comprehensive search was performed, including randomized controlled trials published until October 2023, which assessed the effects of noninvasive tVNS. Cohen's d effect size and 95% confidence intervals (CIs) were calculated, and random-effects meta-analyses were performed. Fifteen studies were included. The results revealed a mean effect size of 0.41 (95% CI 0.17-0.66) in favor of tVNS as compared with control, although a significant heterogeneity was observed (χ² = 21.7, df = 10, P = 0.02, I ² = 53.9%). However, when compared with nonactive controls, tVNS shows a larger effect size (0.79, 95% CI 0.25-1.33), although the number of studies was small (n = 3). When analyzed separately, auricular tVNS and cervical tVNS against control, it shows a significant small to moderate effect size, similar to that of the main analysis, respectively, 0.42 (95% CI 0.08-0.76, 8 studies) and 0.36 (95% CI 0.01-0.70, 3 studies). No differences were observed in the number of migraine days for the trials on migraine. This meta-analysis indicates that tVNS shows promise as an effective intervention for managing pain intensity in chronic pain conditions. We discuss the design of future trials to confirm these preliminary results, including sample size and parameters of stimulation.

Keywords: Chronic pain; Meta-analysis; Neuromodulation; Transcutaneous vagus nerve stimulation.

Figure 1.

PRISMA flow chart displaying the selection process for the inclusion of the studies. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2.

Results of the main analysis. (A) Forest plot showing the comparison of tVNS and control for the outcome of pain intensity in chronic pain conditions, using the random-effects model. (B) Distribution of the true effects. The mean effect size is 0.41, with the true effect size for 95% of comparable populations falling within the interval of −0.31 to 1.14. aNVS, auricular nonvagal stimulation; PNE, pain neuroscience education; tVNS, transcutaneous vagus nerve stimulation.

Figure 3.

Forest plot showing the results of the subanalyses for pain intensity. Random-effects model (95% confidence interval). (A) Sensitivity analysis comparing tVNS with nonactive controls. (B) Subgroup analysis: separate effects of taVNS and tcVNS against control. aNVS, auricular nonvagal stimulation; PNE, pain neuroscience education; tcVNS, transcutaneous cervical vagus nerve stimulation; tVNS, transcutaneous vagus nerve stimulation.

Figure 4.

Forest plot showing the results of the subanalyses for the number of migraine days. Random-effects model (95% confidence interval). (A) Comparison of tVNS and control for the number of migraine days. (B) Sensitivity analysis: comparison of tVNS with sham control only. aNVS, auricular nonvagal stimulation; tVNS, transcutaneous vagus nerve stimulation.

Figure 5.

Funnel plot of SE by standard difference in means for the assessment of publication bias based on the trim-and-fill method. The empty diamond indicates the observed effect size (based on 11 studies). The full diamond indicates the predicted effect size (0.29, 95% CI 0.02-0.56) if the 2 missing studies were included in the analysis.

Figure 6.

Results of the risk of bias and methodological quality assessment, according to the Cochrane Risk of Bias 2.0.