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.

Managing Opioid Withdrawal Symptoms During the Fentanyl Crisis: A Review

“…There was a more significant reduction in the COWS of the active tAN group than that in the sham group after 30 min of stimulation (reduced by 6.3 compared to 3.7, p = 0.036). 94 …”

“…There was a more significant reduction in the COWS of the active tAN group than that in the sham group after 30 min of stimulation (reduced by 6.3 compared to 3.7, p = 0.036). 94 Two other trials evaluated alternative anatomical locations. Gazi et al investigated transcutaneous cervical vagus nerve stimulation (tcVNS) in individuals with OUD whose last opioid use was at least 8 hours prior.…”

Neuroimmunomodulation of vagus nerve stimulation and the therapeutic implications

“…VNS, vagus nerve stimulation; FDA, Food and Drug Administration; COVID-19, coronavirus disease 2019; ns, non-significant effect on study measure outcome. Reference number , 1 (Addorisio et al, 2019 ), 2 (Arsava et al, 2022 ), 3 (Badran et al, 2020 ), 4 (Chang et al, 2021 ), 5 (Courties et al, 2022 ), 6 (Dawson et al, 2021 ), 7 (De Ridder et al, 2015 ), 8 (Diener et al, 2019 ), 9 (Fisher et al, 2016 ), 10 (Garcia et al, 2021 ), 11 (Gaul et al, 2016 ), 12 (Gazi et al, 2022 ), 13 (Genovese et al, 2020 ), 14 (George et al, 2005 ), 15 (George et al, 2008 ), 16 (Goadsby et al, 2018 ), 17 (Gomolka et al, 2018 ), 18 (Grazzi et al, 2017 ), 19 (Kawai et al, 2017 ), 20 (Kozorosky et al, 2022 ), 21 (Kreuzer et al, 2014 ), 22 (Labar et al, 1999 ), 23 (Lange et al, 2011 ), 24 (Manning et al, 2019 ), 25 (Merchant et al, 2022 ), 26 (Mertens et al, 2022 ), 27 (Morris et al, 2013 ), 28 (Morris and Mueller, 1999 ), 29 (Muthulingam et al, 2021 ), 30 (Najib et al, 2022 ), 31 (Paccione et al, 2022 ), 32 (Redgrave et al, 2018 ), 33 (Rush et al, 2005a ), 34 (Rush et al, 2005b ), 35 (Salama et al, 2020 ), 36 (Shi et al, 2021 ), 37 (Silberstein et al, 2016a ), 38 (Silberstein et al, 2016b ), 39 (Stavrakis et al, 2020 ), 40 (Tassorelli et al, 2018 ), 41 (Tirado et al, 2022 ), 42 (Tornero et al, 2022 ), 43 (Tyler et al, 2017 ), 44 (Verrier et al, 2016 ), and 45 (Wittbrodt et al, 2021 ).…”

“…RAVANS was associated with a significant acute reduction in symptoms of depression and anxiety in women with recurrent major depressive disorder (Garcia et al, 2021 ). Regarding opioid withdrawal syndrome, studies have also demonstrated that tcVNS may decrease subjective opioid withdrawal, reduce distress, and lower the heart rate during acute opioid withdrawal (Gazi et al, 2022 ; Tirado et al, 2022 ). Based on the rationale that VNS can activate the LC and catecholamines in the hippocampus and cortex, VNS undergoes some clinical trials to improve cognitive functions in patients with Alzheimer's disease, but these trials did not achieve a conclusive significance (Vargas-Caballero et al, 2022 ).…”