Opioid Use, Opioid-use Disorder, Opioid Use Disorder, Severe, Substance Abuse, Substance Abuse, Intravenous, Substance-Related Disorders, Substance Use Disorders, Substance Withdrawal
Conditions
Keywords
opioid use disorder, vagus nerve, vagal nerve, neuromodulation, vagus nerve stimulation, OUD
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.
Interventions
DEVICENon 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.
DRUGOxygen (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.
DEVICESham 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.
Sponsors
National Institute on Drug Abuse (NIDA)
City University of New York
Georgia Institute of Technology
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
sham stimulation
Intervention model description
nVNS versus sham stimulation
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Opioid Craving Using Visual Analogue Scale | 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) | Baseline, two minutes post-intervention | Heart rate will be measured after cue. Decreased HR correlates with better outcome. |
| Pre-ejection Period (PEP) | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Levels of Interleukin 6 (IL-6) | Baseline, 2 minutes post-intervention | IL-6 is an inflammatory marker. Reduced levels of IL-6 correlate with better outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Non-invasive Vagal Nerve Stimulation (VNS) Active non-invasive Vagal Nerve Stimulation (nVNS) with opioid cues.
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.
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. | 12 |
| Sham Stimulation Sham stimulation of vagus with opioid cues
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.
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. | 8 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Claustrophobia | 0 | 1 |
| Overall Study | Inability to continue | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Active Non-invasive Vagal Nerve Stimulation (VNS) | Total | Sham Stimulation |
|---|---|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 13.857 | 44.25 years STANDARD_DEVIATION 15.348 | 48.375 years STANDARD_DEVIATION 9.366 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 19 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 8 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 5 Participants |
| Region of Enrollment United States | 12 participants | 20 participants | 8 participants |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 8 |
| other Total, other adverse events | 0 / 12 | 0 / 8 |
| serious Total, serious adverse events | 0 / 12 | 0 / 8 |
Outcome results
Primary
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.
Time frame: Baseline, 2 minutes post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Brain Blood Flow in the Anterior Cingulate With VNS Paired With Opioid Use Videos | Baseline | 56.1 mL/100g/min | Standard Deviation 40.7 |
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Brain Blood Flow in the Anterior Cingulate With VNS Paired With Opioid Use Videos | 2 minutes post-intervention | 40.2 mL/100g/min | Standard Deviation 10.2 |
| Sham Stimulation | Brain Blood Flow in the Anterior Cingulate With VNS Paired With Opioid Use Videos | Baseline | 44.5 mL/100g/min | Standard Deviation 18.1 |
| Sham Stimulation | Brain Blood Flow in the Anterior Cingulate With VNS Paired With Opioid Use Videos | 2 minutes post-intervention | 29.2 mL/100g/min | Standard Deviation 12.2 |
Primary
Heart Rate (HR)
Heart rate will be measured after cue. Decreased HR correlates with better outcome.
Time frame: Baseline, two minutes post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Heart Rate (HR) | Baseline | 64.357 bpm | Standard Deviation 8.275 |
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Heart Rate (HR) | Two minutes post-intervention | 64.192 bpm | Standard Deviation 9.96 |
| Sham Stimulation | Heart Rate (HR) | Baseline | 61.575 bpm | Standard Deviation 10.715 |
| Sham Stimulation | Heart Rate (HR) | Two minutes post-intervention | 59.003 bpm | Standard Deviation 10.182 |
Primary
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.
Time frame: Baseline, 5 minutes post-intervention
Population: Number analyzed in one or more rows differs from overall number analyzed because some data was not collected for technical reasons.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Opioid Craving Using Visual Analogue Scale | Baseline | 3.909 score on a scale | Standard Deviation 3.048 |
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Opioid Craving Using Visual Analogue Scale | 5 min post-intervention | 4.556 score on a scale | Standard Deviation 2.186 |
| Sham Stimulation | Opioid Craving Using Visual Analogue Scale | Baseline | 6 score on a scale | Standard Deviation 2.16 |
| Sham Stimulation | Opioid Craving Using Visual Analogue Scale | 5 min post-intervention | 5.5 score on a scale | Standard Deviation 3.937 |
Primary
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.
Time frame: Baseline, 2 minutes post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Photoplethysmography (PPG) Amplitude | Baseline | 1.411 AU (arbitrary units) | Standard Deviation 1.285 |
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Photoplethysmography (PPG) Amplitude | 2 minutes post-intervention | 1.162 AU (arbitrary units) | Standard Deviation 2.312 |
| Sham Stimulation | Photoplethysmography (PPG) Amplitude | Baseline | 1.684 AU (arbitrary units) | Standard Deviation 0.838 |
| Sham Stimulation | Photoplethysmography (PPG) Amplitude | 2 minutes post-intervention | 1.459 AU (arbitrary units) | Standard Deviation 0.873 |
Primary
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.
Time frame: Baseline, 2 minutes post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Pre-ejection Period (PEP) | Baseline | 0.048 seconds | Standard Deviation 0.033 |
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Pre-ejection Period (PEP) | 2 minutes post-intervention | 0.050 seconds | Standard Deviation 0.032 |
| Sham Stimulation | Pre-ejection Period (PEP) | Baseline | 0.069 seconds | Standard Deviation 0.035 |
| Sham Stimulation | Pre-ejection Period (PEP) | 2 minutes post-intervention | 0.066 seconds | Standard Deviation 0.0312 |
Secondary
Levels of Interleukin 6 (IL-6)
IL-6 is an inflammatory marker. Reduced levels of IL-6 correlate with better outcome.
Time frame: Baseline, 2 minutes post-intervention
Population: Number analyzed in one or more rows differs from overall number analyzed because some data was not collected for technical reasons.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Levels of Interleukin 6 (IL-6) | Baseline | 1.4 pg/ml | Standard Deviation 0.8 |
| Active Non-invasive Vagal Nerve Stimulation (VNS) | Levels of Interleukin 6 (IL-6) | 2 min post-intervention | 2.6 pg/ml | Standard Deviation 2.6 |
| Sham Stimulation | Levels of Interleukin 6 (IL-6) | Baseline | 4.0 pg/ml | Standard Deviation 3.1 |
| Sham Stimulation | Levels of Interleukin 6 (IL-6) | 2 min post-intervention | 3.9 pg/ml | Standard Deviation 3.1 |