Non-Invasive Vagal Nerve Stimulation in Opioid Use Disorders

NCT ID: NCT04556552

Last Updated: 2023-09-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-13
• Study Completion Date: 2022-09-13

Brief Summary

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.

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.

Conditions

Substance-Related Disorders; Substance Use Disorders; Substance Abuse, Intravenous; Substance Withdrawal; Substance Abuse; Opioid-use Disorder; Opioid Use Disorder, Severe; Opioid Use

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Active non-invasive Vagal nerve stimulation (VNS)

Active non-invasive Vagal Nerve Stimulation (nVNS) with opioid cues.

Group Type: EXPERIMENTAL

Non invasive VN stimulation (nVNS)

Intervention Type: DEVICE

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.

Oxygen (15-O) Water

Intervention Type: DRUG

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.

Sham stimulation

Sham stimulation of vagus with opioid cues

Group Type: SHAM_COMPARATOR

Oxygen (15-O) Water

Intervention Type: DRUG

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.

Sham Stimulation

Intervention Type: DEVICE

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.

Interventions

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.

Intervention Type: DEVICE

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.

Intervention Type: DRUG

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.

Intervention Type: DEVICE

Other Intervention Names

radiolabelled water

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Drug Abuse (NIDA)

NIH

Sponsor Role: collaborator

City University of New York

OTHER

Sponsor Role: collaborator

Georgia Institute of Technology

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: lead

Responsible Party

James Douglas Bremner

Professor of Psychiatry

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

J Douglas Bremner, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Emory University

Atlanta, Georgia, United States

Countries

United States

References

Rahman FN, Nawar A, Nye JA, Choi J, Lambert TP, Robinson M, Gazi AH, Abbaraju V, Tomic N, Harrison AB, Jaquemet N, Mermin-Bunnell K, Mesfin H, Gray TA, Welsh JW, Dunn KE, Bikson M, Vaccarino V, Shah AJ, Inan OT, Bremner JD. Transcutaneous Cervical Vagus Nerve Stimulation Modulates Prefrontal Cortex Activity During Opioid Withdrawal in Individuals With Opioid Use Disorder. Neuromodulation. 2025 Jun 23:S1094-7159(25)00190-4. doi: 10.1016/j.neurom.2025.04.012. Online ahead of print.

Reference Type: DERIVED

PMID: 40548916 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36041704 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

UG3DA048502

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB00117320

Identifier Type: -

Identifier Source: org_study_id