Transcutaneous Cervical Vagus Nerve Stimulation Reduces Respiratory Variability in the Context of Opioid Withdrawal

Opioid withdrawal's physiological effects are a major impediment to recovery from opioid use disorder (OUD). Prior work has demonstrated that transcutaneous cervical vagus nerve stimulation (tcVNS) can counteract some of opioid withdrawal's physiological effects by reducing heart rate and perceived symptoms. The purpose of this study was to assess the effects of tcVNS on respiratory manifestations of opioid withdrawal - specifically, respiratory timings and their variability. Patients with OUD (N = 21) underwent acute opioid withdrawal over the course of a two-hour protocol. The protocol involved opioid cues to induce opioid craving and neutral conditions for control purposes. Patients were randomly assigned to receive double-blind active tcVNS (n = 10) or sham stimulation (n = 11) throughout the protocol. Respiratory effort and electrocardiogram-derived respiration signals were used to estimate inspiration time (T_i), expiration time (T_e), and respiration rate (RR), along with each measure's variability quantified via interquartile range (IQR). Comparing the active and sham groups, active tcVNS significantly reduced IQR(T_i) - a variability measure - compared to sham stimulation (p = .02). Relative to baseline, the active group's median change in IQR(T_i) was 500 ms less than the sham group's median change in IQR(T_i). Notably, IQR(T_i) was found to be positively associated with post-traumatic stress disorder symptoms in prior work. Therefore, a reduction in IQR(T_i) suggests that tcVNS downregulates the respiratory stress response associated with opioid withdrawal. Although further investigations are necessary, these results promisingly suggest that tcVNS - a non-pharmacologic, non-invasive, readily implemented neuromodulation approach - can serve as a novel therapy to mitigate opioid withdrawal symptoms.