Substance-Related DisordersPhase 3nVNS in OUDsNCT04556552
Non-Invasive Vagal Nerve Stimulation in Opioid Use Disorders
A Phase 3 study testing Non invasive VN stimulation (nVNS) and Oxygen (15-O) Water in people with Substance-Related Disorders and Substance Use Disorders, run by Emory University at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Substance-Related Disorders, Substance Use Disorders, Substance Abuse, Intravenous
- What is being tested?
- Non invasive VN stimulation (nVNS) and Oxygen (15-O) Water
- Type of treatment
- Injection or infusion, Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- 13 Nov 2020to 13 Sep 2022
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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
- Being tested
- Non invasive VN stimulation (nVNS), Oxygen (15-O) Water, Sham Stimulation
- Keywords
- opioid use disorder, vagus nerve, vagal nerve, neuromodulation, vagus nerve stimulation, OUD
- Medical subject headings
- Substance-Related Disorders, Substance Abuse, Intravenous, Opioid-Related Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
Oxygen (15-O) WaterDrug
Also called radiolabelled 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.
Sham StimulationDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| Active non-invasive Vagal nerve stimulation (VNS) | Experimental | Active non-invasive Vagal Nerve Stimulation (nVNS) with opioid cues. Receives: Device: Non invasive VN stimulation (nVNS); Drug: Oxygen (15-O) Water |
| Sham stimulation | Sham comparator | Sham stimulation of vagus with opioid cues Receives: Drug: Oxygen (15-O) Water; Device: Sham Stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline, 5 minutes post-intervention
Heart Rate (HR)
Heart rate will be measured after cue. Decreased HR correlates with better outcome.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, 2 minutes post-intervention
Secondary outcomes (1)
Levels of Interleukin 6 (IL-6)
IL-6 is an inflammatory marker. Reduced levels of IL-6 correlate with better outcome.
Measured: Baseline, 2 minutes post-intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2020
- Study start13 Nov 2020
- Primary completion27 Jul 2022
- Study completion13 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Substance-Related DisordersStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- nVNS versus sham stimulation
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA), City University of New York, Georgia Institute of Technology
- Responsible party
- Principal investigator, James Douglas Bremner, Emory University
- Investigators
- J Douglas Bremner, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04556552
- Sponsor's protocol ID
- IRB00117320
- Other IDs
- UG3DA048502
- Acronym
- nVNS in OUDs
- Status last verified
- Aug 2023
- First submitted
- 15 Sep 2020
- Last updated
- 13 Sep 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 40548916Gazi 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.
PubMed 36041704
Study at a glance
From the registry record, last updated by the sponsor on 13 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Non-Invasive Vagal Nerve Stimulation in Opioid Use Disorders
- ClinicalTrials.gov ID
- NCT04556552
- Acronym / sponsor ID
- nVNS in OUDs / IRB00117320
- Conditions
- Substance-Related Disorders, Substance Use Disorders, Substance Abuse, Intravenous, Substance Withdrawal, Substance Abuse, Opioid-use Disorder
- Keywords
- opioid use disorder, vagus nerve, vagal nerve, neuromodulation, vagus nerve stimulation, OUD
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Emory UniversityUniversity, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA), City University of New York, Georgia Institute of Technology
- Study start
- 13 Nov 2020 (actual)
- Primary completion
- 27 Jul 2022 (actual)
- Study completion
- 13 Sep 2022 (actual)
- First posted
- 21 Sep 2020 (actual)
- Results
- Posted 13 Sep 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- nVNS versus sham stimulation
| Arm | Type | Receives |
|---|---|---|
| Active non-invasive Vagal nerve stimulation (VNS) | Experimental | Device: Non invasive VN stimulation (nVNS), Drug: Oxygen (15-O) WaterActive non-invasive Vagal Nerve Stimulation (nVNS) with opioid cues. |
| Sham stimulation | Sham comparator | Drug: Oxygen (15-O) Water, Device: Sham StimulationSham stimulation of vagus with opioid cues |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (12 listed)
- Positive pregnancy test
- Meningitis
- Traumatic brain injury
- Neurological disorder or organic mental disorder
- History of loss of consciousness greater than one minute
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Device | Active non-invasive Vagal nerve stimulation (VNS) |
| Oxygen (15-O) WaterAlso: radiolabelled waterInjection 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. | Drug | Active non-invasive Vagal nerve stimulation (VNS), Sham stimulation |
| Sham StimulationSham 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. | Device | Sham stimulation |
Primary outcome
Opioid Craving Using Visual Analogue Scale
Time frame: Baseline, 5 minutes post-intervention
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.
Heart Rate (HR)
Time frame: Baseline, two minutes post-intervention
Heart rate will be measured after cue. Decreased HR correlates with better outcome.
Pre-ejection Period (PEP)
Time frame: Baseline, 2 minutes post-intervention
Pre-ejection Period (PEP) is a marker of cardiac sympathetic tone that is increased with blocked sympathetic function. Higher PEP correlates with better outcome.
Photoplethysmography (PPG) Amplitude
Time frame: Baseline, 2 minutes post-intervention
Photoplethysmography (PPG) amplitude reflects vasoconstriction in figure blood vessel. PPG amplitude is increased with blocked sympathetic tone and higher PPG correlates with better outcome.
Brain Blood Flow in the Anterior Cingulate With VNS Paired With Opioid Use Videos
Time frame: Baseline, 2 minutes post-intervention
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.
1 secondary outcome
Levels of Interleukin 6 (IL-6)
Time frame: Baseline, 2 minutes post-intervention
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40548916Rahman 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.
- Derived from this study: PubMed 36041704Gazi 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
J Douglas Bremner, MD principal investigator
Emory University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Non invasive VN stimulation (nVNS) and Oxygen (15-O) Water in people with Substance-Related Disorders and Substance Use Disorders, run by Emory University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Sep 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Opioid Craving Using Visual Analogue Scale (time frame: Baseline, 5 minutes post-intervention). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04556552, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2023.