Non-Invasive Vagal Nerve Stimulation in Opioid Use Disorders

Study Overview
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Brief Summary
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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
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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.

Official Title
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Non-Invasive Vagal Nerve Stimulation in Opioid Use Disorders

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

Intervention / Treatment
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* Device: Non invasive VN stimulation (nVNS)
* Drug: Oxygen (15-O) Water
* Device: Sham Stimulation


Participation Criteria
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Eligibility Criteria
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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: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: nVNS versus sham stimulation
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active non-invasive Vagal nerve stimulation (VNS)<br>Active non-invasive Vagal Nerve Stimulation (nVNS) with opioid cues. | Device: Non invasive VN stimulation (nVNS)<br>* 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.<br>Drug: Oxygen (15-O) Water<br>* 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.<br>* Other names: radiolabelled water;|
| Sham Comparator: Sham stimulation<br>Sham stimulation of vagus with opioid cues | Drug: Oxygen (15-O) Water<br>* 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.<br>* Other names: radiolabelled water;Device: Sham Stimulation<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OUD, opioid use disorder, vagus nerve, vagal nerve, neuromodulation, vagus nerve stimulation