Transcutaneous cervical vagus nerve stimulation reduces behavioral and physiological manifestations of withdrawal in patients with opioid use disorder: A double-blind, randomized, sham-controlled pilot study

Fig. 1.. Background and research question. (A) Previous studies of transcutaneous cervical vagus nerve stimulation (tcVNS) found modulated brain activity in regions associated with opioid craving and/or withdrawal. Heart rate reductions during tcVNS were also observed. The hypothesized mechanism of action is shown, where tcVNS is believed to produce afferent signaling to the nucleus tractus solitarius (NTS), followed by neural processing and resultant efferent signaling affecting peripheral organs such as the heart. (B) In this study, we hypothesized that tcVNS would reduce opioid withdrawal symptoms in comparison to sham stimulation in a double-blind, randomized, sham-controlled pilot study.

Fig. 2.. Protocol diagram. The protocol involved neutral videos meant to elicit neutral or positive affect for control purposes; active tcVNS or sham stimulation; and opioid cue audio and videos meant to elicit opioid craving. The protocol lasted approximately 2 h, where each protocol condition block was separated by approximately 5 min. Note that the opioid cue audios were immediately followed by opioid cue videos and stimulation.

Fig. 3.. CONSORT Diagram. Of the 31 patients assessed for eligibility, 23 met inclusion criteria and agreed to participate. These 23 were randomized to exclusively receive either active or sham stimulation. One participant in the active group had unusable data due to equipment malfunctions. Another participant in the active group withdrew from the study.

Fig. 4.. Comparison between active tcVNS and sham stimulation on self-report withdrawal, pain, and distress. Error bars depict 95% confidence intervals (CIs), Δ indicates post-protocol minus baseline changes, and * denotes p < .05. A) The active group's ΔVAS-Withdrawal scores were significantly less than for the sham group. B) The active group's Δ NRS-Pain scores were significantly lower than for the sham group. One patient who received active tcVNS was missing a post-protocol measurement of NRS-pain. C) The active group's Δ SUDS scores were significantly reduced compared to the sham group.

Fig. 5.. Heart rate comparison between the active tcVNS and sham stimulation groups. Δ denotes changes relative to baseline. A) During all stimulation administrations, the active group's mean Δ heart rates in beats per minute (bpm) were significantly lower than the sham group's (p < .05, denoted by *). The error bars show 95% confidence intervals (CIs). The horizontal shift between active and sham data is included solely for the purpose of visualization; measurements were taken equivalently. A light gray background is used for stimulations 3–6 to highlight that opioid cues were presented to participants during this portion of the protocol. The “0” shown represents the baseline used as the initial point to compute differences from for Δ heart rate. B) The mean Δ heart rate response across all stimulations was significantly lower in the active group compared to the sham group (p < .05, denoted by *). Horizontal jitter is used to overlay the participant-specific datapoints.