Non-Invasive Vagal Nerve Stimulation in Opioid Use Disorders (nVNS in OUDs)

Subjects in this study will be patients with opioid use disorders (OUDs) based on DSM-5 criteria recruited from the greater Atlanta metropolitan region. Recruitment will be from treatment programs in the greater Atlanta Metropolitan Region including the DeKalb Community Service Board residential, detoxification and other treatment programs which with over 30,000 patient visits per year represents the largest treatment program in one of two urban counties in greater Atlanta.

This trial involves a second phase after completing an exploratory study in 20 patients with OUDs to assess different timing parameters of nVNS effects on sympathetic measures and symptoms of craving, as well as modelling to verify and iteratively refine the methods for vagal nerve stimulation. The investigators in this trial will then apply nVNS comparing active (N=10) to sham (N=10) in OUD patients recently started on medication, looking at opioid craving, brain functional response with HR-PET, and cardiovascular and inflammatory biomarker responses to imagery-induced opioid drug craving.

Study Overview

• Status: Completed
• Conditions: Substance-Related Disorders; Substance Abuse, Intravenous; Substance Use Disorders; Opioid Use; Substance Abuse; Opioid-use Disorder; Opioid Use Disorder, Severe; Substance Withdrawal
• Intervention / Treatment: Device: Non invasive VN stimulation (nVNS); Drug: Oxygen (15-O) Water; Device: Sham Stimulation

Detailed Description

Subjects in this study will be patients with opioid use disorders (OUDs) based on DSM-5 criteria recruited from the greater Atlanta metropolitan region. The metropolitan Atlanta area has about 2,623,744 persons age 12 or older. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 109,777 (4.18%) have non-medical use of prescription pain relievers, and 48,302 are estimated to have an opioid use disorder. This DSMP describes the UG3 phase which will study patients with OUDs early in the course of treatment. The Go-No Go criteria listed below have to be met to proceed to the UH3. Recruitment will be from treatment programs in the greater Atlanta Metropolitan Region including the DeKalb Community Service Board residential, detoxification and other treatment programs which with over 30,000 patient visits per year represents the largest treatment program in one of two urban counties in greater Atlanta.

The first UG3 phase will involve an exploratory study in 20 patients with OUDs to assess different timing parameters of nVNS effects on sympathetic measures and symptoms of craving, as well as modelling to verify and iteratively refine our methods for vagal nerve stimulation. The investigators in this trial will then apply nVNS in a pilot study comparing active (N=10) to sham (N=10) in OUD patients recently started on medication, looking at opioid craving, brain functional response with HR-PET, and cardiovascular and inflammatory biomarker responses to imagery-induced opioid drug craving. Brain function will be measured with high resolution positron emission tomography (HR-PET), autonomic function with wearable sensing devices, and biomarkers will be measured in blood, with an assessment of a broad range of stress responsive sympathetic, hormonal and immune markers.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Inclusion Criteria:

Subjects aged 18 and over who meet criteria for OUDs based on the Structured Clinical Interview for DSM-5 (SCID) interview and are stable on medication treatment.

Exclusion Criteria:

1. Positive pregnancy test
2. Meningitis
3. Traumatic brain injury
4. Neurological disorder or organic mental disorder
5. History of loss of consciousness greater than one minute
6. Current pregnancy or breastfeeding for women
7. Current or lifetime history of schizophrenia, schizoaffective disorder, or bulimia, based on the SCID
8. A history of serious medical or neurological illness, such as cardiovascular, gastrointestinal, hepatic, renal, neurologic or other systemic illness
9. Evidence of a major medical or neurological illness that is based on the clinical judgment of the study psychiatrist
10. Active implantable device (i.e. pacemaker)
11. Carotid atherosclerosis
12. Cervical vagotomy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active non-invasive Vagal nerve stimulation (VNS); Active non-invasive Vagal Nerve Stimulation (nVNS) with opioid cues.	Device: Non invasive VN stimulation (nVNS); Stimulation of vagus nerve with active device. Participants will be administered nVNS using the electroCore GammaCore-S non-invasive VNS device. The intensity of the stimulus will be adjusted by the user, to the maximum tolerable level to ensure nVNS without causing excessive pain, the burst frequency to 5 kHz, and the envelope frequency to 25 Hz. The duration of delivery will be 2 minutes, and the beginning will coincide with initiation of acquisition of the HR-PET scan which will be 90 seconds in duration; following an additional 8 minutes, a second VNS delivery will be administered, in conjunction with which another scan will be obtained.; Drug: Oxygen (15-O) Water; Injection of radiolabelled water. H2[15-O] is a radioactive material. Each patient will have eight H2[15-O] blood flow scans. For each O-15 water scan 20 mCi of H2[15O] will be injected as an intravenous bolus.; Other Names: radiolabelled water
Sham Comparator: Sham stimulation; Sham stimulation of vagus with opioid cues	Drug: Oxygen (15-O) Water; Injection of radiolabelled water. H2[15-O] is a radioactive material. Each patient will have eight H2[15-O] blood flow scans. For each O-15 water scan 20 mCi of H2[15O] will be injected as an intravenous bolus.; Other Names: radiolabelled water; Device: Sham Stimulation; Sham stimulation of vagus during opioid cue exposure. Each subject in the "SHAM" group will undergo the action of administering the intervention, but the device will be programmed such that the stimulation will not activate the vagus nerve.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid Craving Using Visual Analogue Scale	Opioid craving will be measured based on Visual Analogue Scale (VAS) VAS consist in 10-point lines anchored with "not at all" on one end and "extremely" on the other where participants report the extent to which they felt any craving for opiates, severity of withdrawal symptoms, and the extent to which the study intervention has helped to ease the cravings. Total possible score ranges from 0 to100, with 100 correlating with worse study outcome.	Baseline, 5 minutes post-intervention
Heart Rate (HR)	Heart rate will be measured after cue. Decreased HR correlates with better outcome.	Baseline, two minutes post-intervention
Pre-ejection Period (PEP)	Pre-ejection Period (PEP) is a marker of cardiac sympathetic tone that is increased with blocked sympathetic function. Higher PEP correlates with better outcome.	Baseline, 2 minutes post-intervention
Photoplethysmography (PPG) Amplitude	Photoplethysmography (PPG) amplitude reflects vasoconstriction in figure blood vessel. PPG amplitude is increased with blocked sympathetic tone and higher PPG correlates with better outcome.	Baseline, 2 minutes post-intervention
Brain Blood Flow in the Anterior Cingulate With VNS Paired With Opioid Use Videos	Brain blood flow measured with Positron Emission Tomography (PET) and radiolabeled water at baseline and 2 min post-intervention during viewing of neutral videos and with active and Sham VNS stimulation paired with opioid use videos. Brain blood flow was measured in mL per 100 g of tissue per minute (mL/100g/min) normalized to a reference of 50 ml/100 g of tissue per minute.	Baseline, 2 minutes post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of Interleukin 6 (IL-6)	IL-6 is an inflammatory marker. Reduced levels of IL-6 correlate with better outcome.	Baseline, 2 minutes post-intervention

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: National Institute on Drug Abuse (NIDA); Georgia Institute of Technology; CUNY
• Investigators: Principal Investigator: J Douglas Bremner, MD, Emory University

Publications and helpful links

General Publications

• Gazi AH, Harrison AB, Lambert TP, Obideen M, Alavi P, Murrah N, Shallenberger L, Driggers EG, Ortega RA, Washington BP, Walton KM, Welsh JW, Vaccarino V, Shah AJ, Tang YL, Gupta R, Back SE, Inan OT, Bremner JD. 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. Brain Stimul. 2022 Sep-Oct;15(5):1206-1214. doi: 10.1016/j.brs.2022.08.017. Epub 2022 Aug 27.

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2020
• Primary Completion (Actual): July 27, 2022
• Study Completion (Actual): September 13, 2022

Study Registration Dates

• First Submitted: September 15, 2020
• First Submitted That Met QC Criteria: September 16, 2020
• First Posted (Actual): September 21, 2020

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: August 23, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: neuromodulation; opioid use disorder; vagus nerve stimulation; vagus nerve; OUD; vagal nerve
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Narcotic-Related Disorders; Substance-Related Disorders; Substance Abuse, Intravenous; Opioid-Related Disorders
• Other Study ID Numbers: IRB00117320; UG3DA048502 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes