Transcutaneous Auricular Vagus Nerve Stimulation For Radiotherapy-Related Neuropathic Pain in Patients With Head and Neck Cancer: The RELAX Randomized Clinical Trial

Background: Rapid relief of radiotherapy-related neuropathic pain (RRNP) in head and neck cancer (HNC) survivors is challenging when relying solely on pharmacologic treatments, especially in the early stages of medication. Whether transcutaneous auricular vagus nerve stimulation (taVNS) can effectively and rapidly control the RRNP in HNC survivors remains uncertain. Methods: RELAX trial is a randomized, double-blind, parallel, sham-controlled trial, which was conducted at four centres of China, with study enrollment from September 2022 to December 2023. We randomly assigned (1:1) HNC survivors with moderate-to-severe RRNP (as defined by Numeric Rating Scale [NRS] score of ≥4) to receive taVNS or sham stimulation for 30 minutes twice daily over 7 days. All patients also received a basal dose of pregabalin (75 mg twice daily). The primary outcome was pain intensity reduction, as measured by the change of NRS scores from baseline to day 7. This trial is registered at ClinicalTrials.gov, NCT 05543239. Findings: Among 116 patients who were randomized (mean age, 50.8 [SD, 8.8] years; 40 [34.5%] were women), all patients completed NRS score at baseline and day 7, and 112 (96.6%) completed 80% or more of the intervention course. The pain intensity at baseline was 5.79 (SD, 1.59) in the taVNS group and 5.66 (SD, 1.54) in the control group. At day 7, pain intensity decreased by 2.43 (SD, 2.19) in the taVNS group and 1.12 (SD, 1.64) in the Control group; between-group difference, 1.31 points (95% CL, 0.60 to 2.02; P<0.001). The most common adverse event (AE) related to taVNS was mild, transient local skin irritations at the electrode site (8.6% vs. 1.7%, p = 0.21), and no serious AE were associated with the device. Interpretation: In this trial, taVNS for 7 days at the initial stage of pregabalin treatment resulted in significantly better pain relief in HNC survivors with moderate-to-severe RRNP with no serious AE.