A randomized, sham-controlled clinical trial to evaluate the NET Device™ for reducing withdrawal symptom severity during opioid discontinuation

Abstract

Background: Neuromodulation is a promising approach for opioid discontinuation, as not all patients with opioid use disorder (OUD) seek pharmacotherapy. The NET Device is a non-invasive, battery-powered, portable, device that provides bilateral, transcranial, transcutaneous, alternating current stimulation (tACS) for patients experiencing opioid withdrawal. This clinical trial prospectively evaluated whether NET Device utilization is effective for persons with OUD undergoing opioid discontinuation without medications for OUD (MOUD).

Methods: This randomized, sham-controlled trial was conducted at a single residential treatment center. Persons with OUD undergoing opioid discontinuation were assigned to active or sham device treatment. Clinical Opiate Withdrawal Scale (COWS) total scores were measured prior to and during device use. We tested whether active stimulation would produce a clinically meaningful (≥15%) decrease in COWS score from baseline to 1-hr post-stimulation, compared to sham.

Results: 108 participants (55 sham, 53 active; 59.3% male, 89.8% white; 71.3% fentanyl-positive) form the intent-to-treat dataset. Mean ( ± 1 SD) COWS score in the active device group decreased from baseline (18.1 + 4.4) to 1-hr (7.0 + 4.1); this 61.3% decrease (d=2.14) exceeded the pre-specified 15% criterion. COWS scores decreased more for active (-11.1 ± 5.2) than sham (-8.8 ± 6.3), p<.05, d=-.41. A higher proportion of participants in active vs. sham showed ≥15% reduction in COWS (98.1% vs. 83.6%), p=.016. Device utilization was longer for active than sham, 43.9 + 46.2 vs. 30.0 + 39.2 hours, p=.008, and fewer participants requested MOUD (26% vs. 49%, p<0.02).

Conclusion: The NET Device is effective, safe and well-tolerated for reducing opioid withdrawal symptoms. This device received FDA market clearance in May 2024.

Clinical trial registration: ClinicalTrials.gov, identifier NCT04916600.

Keywords: craving; detoxification; opioid use disorder; tACS; transcranial electrical stimulation; withdrawal.

Figure 1

CONSORT diagram.

Figure 2

Test of efficacy endpoint for reduction of Clinical Opiate Withdrawal Scale (COWS) scores from before (t=0) to 1-hr after device utilization in the active device group (n= 52) and sham control group (n= 55). Comparison of mean ( ± 1 SD) opioid withdrawal symptom severity change from baseline (t= 0 hr) to 1-hr after starting active NET vs. sham device stimulation. Different horizontal color bands indicate the relative ordering in clinical severity for the COWS total score. Active NET stimulation led to significantly greater 1-hr decrease in opioid withdrawal severity than sham, from clinically moderate to mild levels (on average).

Figure 3

Number of participants requesting initiation of Medication for Opioid Use Disorder (MOUD) over inpatient days in the intent-to-treat population.

Figure 4

Mean Clinical Opiate Withdrawal Scale (COWS) scores over inpatient days in the active group, stratified by duration of device utilization (<24 hr vs. ≥24 hr). Group sizes are shown in the accompanying table.

Figure 5

Mean ( ± 1 SD) duration of device utilization. Participants who perceived they were receiving active stimulation, regardless of their device assignment, used the device about 4-fold times longer (36-48 hr on average) than participants who perceived they were receiving sham stimulation (<10 hr on average).

Figure 6

Summary of findings.