Vagal Nerve Stimulation for Opioid Use Disorder

(VNS in OUD UH3 Trial)

Recruiting at 6 trial locations

Overseen By James D Bremner, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Emory University

Must not be taking: Methadone, Naltrexone, Suboxone, others

Disqualifiers: Pregnancy, Brain injury, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

103 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how Vagal Nerve Stimulation (VNS) affects withdrawal symptoms in people with Opioid Use Disorders (OUDs). Participants will stay in a research hospital for a week to try this treatment, undergo an MRI scan, and follow up with a call a few months later. The study includes both a real VNS group and a placebo (fake treatment) group for comparison. It suits those diagnosed with OUD who are willing to undergo supervised withdrawal and engage in further treatment after the study. As a Phase 3 trial, this treatment is in the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking therapy for OUD.

Will I have to stop taking my current medications?

The trial requires that participants are not currently being treated with methadone, naltrexone, or Suboxone, or any medications that would conflict with hydromorphone or lofexidine. If you are on these medications, you would need to stop taking them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that transcutaneous cervical vagal nerve stimulation (tcVNS) is generally safe. Earlier studies found that tcVNS reduced withdrawal symptoms in individuals with opioid use disorder (OUD), making it a promising option for those struggling with opioid addiction.

Past research indicates that side effects from tcVNS are usually mild, such as slight skin irritation where the device is placed. No serious side effects were reported in these studies, supporting its safety as a non-invasive treatment.

Since this treatment is in a later stage of research, it has been tested on many people, providing more information about its safety. However, it's important to consider personal health and consult a healthcare provider about any concerns before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for opioid use disorder?

Most treatments for opioid use disorder, like methadone and buprenorphine, involve medication-assisted therapy to reduce cravings and withdrawal symptoms. However, transcutaneous cervical vagal nerve stimulation (tcVNS) offers a unique non-drug approach by using electrical impulses to stimulate the vagus nerve through the skin. This method is exciting because it targets the brain's reward and stress pathways directly, potentially reducing opioid cravings without medication. Additionally, tcVNS is non-invasive and could offer fewer side effects compared to traditional drug therapies, making it a promising option for those seeking alternative treatments.

What evidence suggests that Vagal Nerve Stimulation is effective for Opioid Use Disorder?

Research has shown that transcutaneous cervical vagal nerve stimulation (tcVNS), a treatment available to participants in this trial, can help reduce withdrawal symptoms in people with opioid use disorder (OUD). One study found that this treatment eases both the mental and physical signs of withdrawal. Another study showed that tcVNS affects brain activity, especially in the front part of the brain, during opioid withdrawal. These findings suggest that tcVNS could be a promising non-drug method for managing opioid withdrawal symptoms. ^{1 2 4 6 7}

Who Is on the Research Team?

James D Bremner, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for individuals with Opioid Use Disorders willing to undergo withdrawal and be in a hospital for one week. They must meet criteria based on psychiatric interviews, agree to transition to medication or behavioral management after the study, and not be on certain opioid treatments or have severe non-opioid substance disorders.

Inclusion Criteria

Willing to be transitioned to a MOUD or behavioral management during treatment aftercare

Meet criteria for OUDs based on the DSM5 criteria

I am willing to stop my current treatment under supervision.

Exclusion Criteria

History of head trauma resulting in loss of consciousness (LOC) of greater than one minute where the LOC is not judged to be primarily related to overdose in the judgment of the study physician

Past year moderate to severe non-opioid use disorders that would require separate withdrawal management

Current or lifetime history of schizophrenia, schizoaffective disorder, or bulimia

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Inpatient Stay

Participants undergo Vagal Nerve Stimulation (VNS) testing, psychiatric assessments, physiological monitoring, and brain imaging

1 week

Inpatient stay

Follow-up

Participants receive a follow-up call to monitor safety and effectiveness after the inpatient stay

1-3 months

1 call (virtual)

What Are the Treatments Tested in This Trial?

Interventions

• [F-18]Fallypride
• Sham Stimulation
• Transcutaneous Cervical Vagal Nerve Stimulation

Trial Overview The study tests how Vagal Nerve Stimulation (VNS) affects opioid withdrawal responses. Participants will receive either real VNS or sham stimulation while undergoing MRI scans, physiological monitoring, brain imaging, and completing questionnaires during their stay.

How Is the Trial Designed?

Group I: Transcutaneous Cervical Vagal Nerve Stimulation Device Experimental Treatment 2 Interventions

Stimulation with the tcVNS

Group II: Sham Stimulation Device Placebo Group 2 Interventions

Stimulation with the sham device.

Transcutaneous Cervical Vagal Nerve Stimulation is already approved in United States for the following indications:

Approved in United States as Transcutaneous Cervical Vagal Nerve Stimulation for:

• Opioid withdrawal symptoms

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

Non-invasive Vagal Nerve Stimulation (nVNS) is a promising non-medication treatment for Opioid Use Disorder (OUD), potentially reducing withdrawal symptoms and physiological effects associated with opioid withdrawal.

Preliminary studies suggest that nVNS may work by modulating sympathetic and inflammatory responses in the body, which could help alleviate the distress and pain experienced during opioid withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Vagal Nerve Stimulation for Opioid Use Disorder. Bremner, JD., Gazi, AH., Lambert, TP., et al.[2023]

Transcutaneous cervical vagus nerve stimulation (tcVNS) significantly reduced pain levels in patients undergoing opioid withdrawal, with a notable decrease in pain scores compared to a sham group, indicating its potential as a non-pharmacological pain management strategy.

The study also found a correlation between changes in pain and objective physiological markers, such as heart rate variability and respiration pattern variability, suggesting that tcVNS may influence both pain perception and autonomic nervous system responses during withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pain is reduced by transcutaneous cervical vagus nerve stimulation and correlated with cardiorespiratory variability measures in the context of opioid withdrawal. Gazi, AH., Harrison, AB., Lambert, TP., et al.[2023]

In a study involving 21 patients with opioid use disorder, transcutaneous cervical vagus nerve stimulation (tcVNS) significantly reduced the variability of inspiration time during opioid withdrawal, indicating a potential to alleviate respiratory stress responses associated with withdrawal symptoms.

The results suggest that tcVNS, a non-invasive and easily implemented treatment, could be a promising new therapy for managing symptoms of opioid withdrawal, although further research is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Cervical Vagus Nerve Stimulation Reduces Respiratory Variability in the Context of Opioid Withdrawal. Gazi, AH., Harrison, AB., Lambert, TP., et al.[2023]

Auricular transcutaneous vagus nerve stimulation (atVNS) may enhance the effectiveness of methadone maintenance treatment (MMT) for opioid use disorder (OUD) by improving mood and cognitive control, which are often impaired in individuals with OUD.

atVNS is culturally accepted in China and offers practical advantages such as ease of use and the ability for at-home self-administration, making it a promising adjunct therapy for those undergoing treatment for opioid withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regaining control over opioid use? The potential application of auricular transcutaneous vagus nerve stimulation to improve opioid treatment in China. Colzato, L., Elmers, J., Xu, X., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

In a study involving 15 patients with chronic pelvic pain due to endometriosis, respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) showed a trend towards reducing pain intensity and significantly decreased anxiety compared to nonvagal auricular stimulation (NVAS).

RAVANS demonstrated moderate to large effect sizes in reducing pain and anxiety, suggesting it could be a promising nonpharmacological treatment option for chronic pain disorders, warranting further investigation into its long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Napadow, V., Edwards, RR., Cahalan, CM., et al.[2022]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a safe and effective neuromodulation therapy for a variety of conditions, including epilepsy, depression, and anxiety, indicating its broad therapeutic potential.

Despite its effectiveness, there is currently no standardization among taVNS devices, and further research is needed to clarify the relationship between stimulation parameters and therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. Wang, L., Wang, Y., Wang, Y., et al.[2022]

In a study involving 24 participants, transcutaneous cervical vagus nerve stimulation (tcVNS) was shown to significantly affect cardiovascular biomarkers, with photoplethysmogram amplitude being a more reliable predictor of response than heart rate.

There was a consistent delay of over 5 seconds between the onset of tcVNS and measurable cardiovascular effects, indicating a specific timing in the body's response that could be important for optimizing treatment delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Digital Cardiovascular Biomarker Responses to Transcutaneous Cervical Vagus Nerve Stimulation: State-Space Modeling, Prediction, and Simulation. Gazi, AH., Gurel, NZ., Richardson, KLS., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9588751/

Transcutaneous cervical vagus nerve stimulation reduces ... Transcutaneous cervical vagus nerve stimulation reduces behavioral and physiological manifestations of withdrawal in patients with opioid use disorder.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1094715925001904

Transcutaneous Cervical Vagus Nerve Stimulation ... Transcutaneous Cervical Vagus Nerve Stimulation Modulates Prefrontal Cortex Activity During Opioid Withdrawal in Individuals With Opioid Use ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10699253/

Noninvasive Vagal Nerve Stimulation for Opioid Use Disorder NVNS shows promise as a non-medication approach to OUD, both in terms of its known effect on neurobiology as well as pilot data showing a reduction in ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05834478

Non-invasive Vagal Nerve Stimulation in Opioid Use ... 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.

5. europepmc.org europepmc.org/article/med/40548916

Transcutaneous Cervical Vagus Nerve Stimulation ... The purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on brain response to opioid use cues in patients ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40548916/

Transcutaneous Cervical Vagus Nerve Stimulation Modulates ... tcVNS modulates brain areas implicated in opioid addiction, suggesting a useful role as an adjunctive therapy for OUD.

7. frontiersin.org frontiersin.org/journals/pain-research/articles/10.3389/fpain.2022.1031368/full

Pain is reduced by transcutaneous cervical vagus nerve ... This randomized, double-blind, sham-controlled pilot study provides the first evidence of tcVNS-induced reductions in pain in patients with OUD experiencing ...