Delivering transcutaneous auricular neurostimulation (tAN) to improve symptoms associated with opioid withdrawal: results from a prospective clinical trial

Abstract

Background: As pharmacological treatments are the primary option for opioid use disorder, neuromodulation has recently demonstrated efficacy in managing opioid withdrawal syndrome (OWS). This study investigated the safety and effectiveness of transcutaneous auricular neurostimulation (tAN) for managing OWS.

Methods: This prospective inpatient trial included a 30-minute randomized, sham-controlled, double-blind period followed by a 5-day open-label period. Adults with physical dependence on opioids were randomized to receive active or sham tAN following abrupt opioid discontinuation. The Clinical Opiate Withdrawal Scale (COWS) was used to determine withdrawal level, and participants were required to have a baseline COWS score ≥ 13 before enrollment. The double-blind period of the study occurred during the first 30-minutes to assess the acute effects of tAN therapy compared to a sham control. Group 1 received active tAN during both the 30-minute double-blind period and the 5-day open-label period. Group 2 received passive sham tAN (no stimulation) during the double-blind period, followed by active tAN during the 5-day open-label period. The primary outcome was change in COWS from baseline to 60-minutes of active tAN (pooled across groups, accounting for 30-minute delay). Secondary outcomes included difference in change in COWS scores between groups after 30-minutes of active or sham tAN, change in COWS scores after 120-minutes of active tAN, and change in COWS scores on Days 2-5. Non-opioid comfort medications were administered during the trial.

Results: Across all thirty-one participants, the mean (SD) COWS scores relative to baseline were reduced by 7.0 (4.7) points after 60-minutes of active tAN across both groups (p < 0.0001; Cohen's d = 2.0), demonstrating a significant and clinically meaningful reduction of 45.9%. After 30-minutes of active tAN (Group 1) or sham tAN (Group 2), the active tAN group demonstrated a significantly greater COWS score reduction than the sham tAN group (41.7% vs. 24.1%; p = 0.036). Participants across both groups achieved an average COWS reduction up to 74.7% on Days 2-5.

Conclusion: Results demonstrate tAN is a safe and effective non-opioid approach for reducing symptoms of OWS. This study supported an FDA clearance.

Clinical trial registration: clinicaltrials.gov/ct2/show/NCT04075214 , Identifier: NCT04075214, Release Date: August 28, 2019.

Keywords: Addiction; Non-opioid treatment; Opioid withdrawal symptoms; Transcutaneous auricular neurostimulation; Trigeminal nerve stimulation; Vagus nerve stimulation.

Conflict of interest statement

NK, SW, DP, CB, HV, MM and AC are employees and have private equity (stock options or other ownership interest) in Spark Biomedical. CT has private equity in and is a paid consultant of Spark Biomedical.

© 2022. The Author(s).

Figures

Fig. 1

Clinical Study Design Diagram

Fig. 2

Form and Fit of tAN Device Around the Ear Neural Structures

Fig. 3

CONSORT Flow Diagram

Fig. 4

COWS Scores Across Time in the Pooled Population Without Data Imputation. Legend: *** denotes p < 0.0001. Timepoints denote the number of minutes from the start of active tAN, which is either at the start or end of the double-blind period, depending on group assignment. Dark blue line indicates the mean COWS score of study participants at each timepoint. Orange lines indicate individual participant COWS score at each timepoint

Fig. 5

Comparison of COWS Scores: Active and Sham tAN at the end of the double-blind period. Legend: P-value; Two-sided independent Welch’s t-test; Data representing the intent-to-treat population. Group 1 received active tAN and Group 2 received sham tAN (no stimulation) during this period. Colored dots indicate individual COWS score percent reductions for the respective treatment groups