Non-Invasive Vagal Nerve Stimulation in Opioid Use Disorders

NCT04556552 | Completed Phase 3 Results FDA Drug FDA Device

• 2 other identifiers: IRB00117320UG3DA048502
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

opioid use disorder; vagus nerve; vagal nerve; neuromodulation; vagus nerve stimulation; OUD

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (1)

• Levels of Interleukin 6 (IL-6)

  Baseline, 2 minutes post-intervention

Study Arms (2)

Active non-invasive Vagal nerve stimulation (VNS)

EXPERIMENTAL

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

Device: Non invasive VN stimulation (nVNS); Drug: Oxygen (15-O) Water

Sham stimulation

SHAM COMPARATOR

Sham stimulation of vagus with opioid cues

Drug: Oxygen (15-O) Water; Device: Sham Stimulation

Interventions

Non invasive VN stimulation (nVNS) 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.

Active non-invasive Vagal nerve stimulation (VNS)

Oxygen (15-O) Water 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.

Also known as: radiolabelled water

Active non-invasive Vagal nerve stimulation (VNS); Sham stimulation

Sham Stimulation 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.

Sham stimulation

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Emory University: lead
• National Institute on Drug Abuse (NIDA): collaborator
• City University of New York: collaborator
• Georgia Institute of Technology: collaborator

Study Sites (1)

Emory University

Atlanta, Georgia, 30322, United States

Location

Related Publications (2)

• 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 Dec;28(8):1396-1407. doi: 10.1016/j.neurom.2025.04.012. Epub 2025 Jun 23.

  PMID: 40548916 DERIVED

• 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.

  PMID: 36041704 DERIVED

MeSH Terms

Conditions

Substance-Related Disorders; Substance Abuse, Intravenous; Opioid-Related Disorders

Interventions

Oxygen; Oxygen-15; Water

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders; Mental Disorders; Narcotic-Related Disorders

Intervention Hierarchy (Ancestors)

Chalcogens; Elements; Inorganic Chemicals; Gases; Hydroxides; Alkalies; Anions; Ions; Electrolytes; Oxides; Oxygen Compounds

Results Point of Contact

• Title: Dr. J. Douglas Bremner
• Organization: Emory University

doug.bremner@emory.edu

404-712-9569

Study Officials

• J Douglas Bremner, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: sham stimulation
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry

Model Details: nVNS versus sham stimulation

Study Record Dates

• First Submitted: September 15, 2020
• First Posted: September 21, 2020
• Study Start: November 13, 2020
• Primary Completion: July 27, 2022
• Study Completion: September 13, 2022
• Last Updated: September 13, 2023
• Results First Posted: September 13, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)