A Phase 3 interventional study of Transcutaneous Cervical Vagal Nerve Stimulation and Sham Stimulation in Withdrawal Symptoms, Opioid Use Disorder and Opioid Use, sponsored by Emory University. Recruiting at 6 sites in United States. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2026-03-27.
Sponsored by Emory University · Phase 3, Interventional, and Treatment
This study is being done to answer the question: what is the effect of Vagal Nerve Stimulation (VNS) dosing on opioid withdrawal responses in individuals with a history of Opioid Use Disorders (OUDs)? Eligible participants will be in the study for one week in an inpatient research hospital stay, have an MRI scan, and have a follow-up call 1-3 months after their inpatient stay. Participants will complete several psychiatric questionnaires/interviews, physiological monitoring with several devices, brain imaging, and VNS testing.
The purpose of this study is to look at Opioid Use Disorders (OUDs) and Vagal Nerve Stimulation (VNS). OUDs are conditions involving misuse or addiction to opiate-containing prescription pain medications or opioid-containing substances including heroin. OUDs are associated with symptoms of withdrawal upon discontinuation of the substance, which can include problems with concentration and sleep, irritability, rapid heart rate, and craving for opioids. Vagal Nerve Stimulation (VNS) is a procedure where the vagus nerve, which is in the neck, is electrically stimulated, much like a pacemaker is used to stimulate the heart. Branches of the vagus nerve travel throughout the brain and the body. Vagal nerve stimulation is felt to have positive effects on the brain and body by blocking the sympathetic (adrenaline) response that occurs with withdrawal from opioids, as well as changes in the brain that drive a craving for opioids. A surgically implantable VNS has been approved by the Food and Drug Administration (FDA) for the treatment of both epilepsy and severe depression. Studies have shown that VNS stimulation is helpful for both conditions. Researchers are using a non-invasive hand-held VNS device made by a company called ElectroCore. It is applied directly to the neck and does not require surgery. It is approved in Europe for the treatment of epilepsy, anxiety, depression, headaches, and other conditions, and in the US by the FDA for the treatment of headaches. Investigators have studied its use at Emory for PTSD and have found it to be well tolerated and there have been no adverse events or untoward effects with the device. The research team conducted two initial studies in patients with OUDs and found that it was safe and that it reduced opioid craving and withdrawal as well as blocking the sympathetic (adrenaline) response to withdrawal. It has not yet been approved in the US by the FDA for the treatment of OUDs and is considered investigational in this study.
This study will enroll individuals that have been diagnosed with Opioid Use Disorder (OUD). The main purpose of this study is to look at the effects of VNS on behavior as well as the body and brain's responses to craving in patients with OUDs. Study procedures include a screening, mental health assessment, medical assessment, lab work, brain imaging (MRI and PET), and a follow-up call. It is possible that participants may not have brain imaging (MRI and PET) during the study. The study will be completed in around a week depending on the scheduling of the MRI visit. This might be completed during the inpatient stay or could be a separate visit. The research team will also plan to call and follow up with participants 1-3 months after the inpatient stay.
74 studies on the registry are indexed under Substance Withdrawal Syndrome; 7 are open to participants now.
This study's planned enrollment of 103 is above the median of 64 across 55 interventional studies indexed under Substance Withdrawal Syndrome.
Browse Substance Withdrawal Syndrome studies →Emory University is the lead sponsor of 1,405 studies on the registry; 225 are open to participants now.
Of its 237 completed or terminated interventional studies of FDA-regulated products, 178 (75%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Stimulation with the tcVNS
Device: Transcutaneous Cervical Vagal Nerve Stimulation · Drug: [F-18]Fallypride
Stimulation with the sham device.
Device: Sham Stimulation · Drug: [F-18]Fallypride
Participants will receive stimulation of the vagus nerve with the non-invasive transcutaneous cervical Vagal Nerve Stimulation (tcVNS), which does not require surgery or implantation, and electrically stimulates the vagus nerve as it passes through the neck, dampening the sympathetic nervous system and modulating brain regions to a single side of the neck with the GammaCore device. Participants will be trained on self-stimulation and from days 1-7 patients undergo four times daily self-stimulation with tcVNS first for two minutes on one side, followed by a one-minute pause, then two minutes on the same side. The intensity of the stimulus (i.e. the current amplitude) will be adjusted by the user, to the maximum tolerable level without causing excessive pain \[typically 10-30 V and 60milliamperes (mA) (peak)\], with an alternating current (AC) signal consisting of five 5 kilohertz (kHz) pulses 200 microseconds in duration, repeating at a rate of 25 Hz (about once every 40 milliseconds).
Also known as: tcVNS
Participants will have the same procedures as with the tcVNS but will instead receive a device that appears identical to the active tcVNS device in look, weight, visual and audible feedback, and also in user controls. The Sham device looks and sounds like an active device but does not deliver an electric current.
Also known as: Sham stimulation of vagus nerve
\[F-18\]Fallypride is a radioactive material. Each patient will have two \[F-18\]Fallypride PET scans. For each scan \[F-18\]Fallypride will be injected as an intravenous bolus. The radiation dose to body organs in this study is well within the Food and Drug Administration (FDA) national guidelines for radiation exposure for human research studies and less than the total amount that is permitted for research studies in one year.
Also known as: Radiolabeled material
Change in Peak Subjective Opiate Withdrawal Scale (SOWS) Score
All participants will complete the Subjective Opiate Withdrawal Scale (SOWS). The total score on each day will be compared between active tcVNS versus sham stimulation. The SOWS is performed four times daily. The total SOWS score is the sum of the individual item scores and ranges from 0 to 64, with a higher score indicating greater withdrawal severity.
Time frame: Day 2, Day 3
Safety of tcVNS use
Defined as the absence of device related adverse events.
Time frame: Up to 7 days after study initiation
Study retention
Study retention as defined by taking a single dose of Medication for Opioid Use Disorders (MOUD) (Suboxone, methadone, or naltrexone) within ten days of study initiation.
Time frame: Baseline, Up to 10 days after study initiation
Treatment adherence
Defined by adherence to Medication for Opioid Use Disorders (MOUD)
Time frame: 3 months
Change in brain dopamine D1 and D2/3 receptor regional binding potentials
Brain dopamine D1 and D2/3 receptor regional binding potentials will be measured with the brain imaging of the dopamine system with \[F-18\]fallypride with high-resolution positron emission tomography (HR-PET). Brain imaging of the dopamine system with \[F-18\]fallypride occurs at rest on day 2 and with active tcVNS or sham stimulation on day 3 while watching videos paired with tcVNS or sham stimulation.
Time frame: Day 2, Day 3
Change in heart rate
Participants will be outfitted with ambulatory monitors to measure multiple peripheral physiological signals representative of cardiac electrophysiology.
Time frame: Baseline, Day 2, Day 3
Change in inflammatory biomarkers
Interleukin 6 (IL-6) will be measured by having participants undergo blood sampling before and during exposure to neutral and pleasant videos paired with tcVNS or sham stimulation at specified study time points.
Time frame: 15 minutes before stress and up to 180 minutes post-stress
Change in catecholamines concentration
Catecholamines concentration will be measured by drawing blood sampling during exposure to neutral and pleasant videos paired with tcVNS or sham stimulation at specified study time points.
Time frame: Baseline, Day 2, Day 3
Squares analysis of SOWS score
Measured on each of day two and three based on the peak Subjective Opiate Withdrawal Scale (SOWS) Total score on each day compared between active tcVNS versus sham stimulation. The SOWS is performed four times daily.
Time frame: Day 1, Day 7
Time to Rescue Medication
Patients receiving rescue medication with clonidine will have last observation carried forward.
Time frame: Up to 7 days after study initiation
Change in Peak Clinical Opiate Withdrawal Scale (COWS) Scores
All participants will complete the Clinical Opiate Withdrawal Scale (COWS). This tool can be used in both inpatient and outpatient settings to reproducibly rate common signs and symptoms of opiate withdrawal and monitor these symptoms over time. The summed score for the complete scale can be used to help clinicians determine the stage or severity of opiate withdrawal and assess the level of physical dependence on opioids.
Time frame: Day 2, Day 3
Transition to MOUD Treatment or Behavioral Management
The research team will monitor the time for participants to require MOUD and/or behavioral management.
Time frame: Up to 7 days after study initiation
Change in Brain-derived Neurotrophic Factor (BDNF)
Participants will undergo blood sampling to measure BDNF during exposure to neutral and pleasant videos paired with tcVNS or sham stimulation at specified study time points.
Time frame: 5 minutes before stress and up to 180 minutes post-stress
Change in Calcium-binding Protein B (S100B)
Participants will undergo blood sampling to measure S100B during exposure to neutral and pleasant videos paired with tcVNS or sham stimulation at specified study time points.
Time frame: 5 minutes before stress and up to 180 minutes post-stress
Plan to share: Yes — At the conclusion of the trial, the data will be stripped of identifiers prior to release for sharing and will be made available in de-identified form to other investigators and other sites.
Access criteria: Investigators will make the data and associated documentation available to users only under a data-sharing agreement that provides for (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.
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Substance Withdrawal Syndrome →