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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the treatment Vagal Nerve Stimulation for Opioid Use Disorder?

Research shows that transcutaneous cervical vagus nerve stimulation (tcVNS) can reduce pain and respiratory stress during opioid withdrawal, which are key challenges in recovery. This non-invasive treatment has been shown to lower pain levels and improve physiological markers, suggesting it could be a helpful addition to opioid use disorder treatment. ^{1 2 3 4 5}

Is vagal nerve stimulation safe for humans?

Vagal nerve stimulation, including transcutaneous auricular and cervical methods, is generally considered safe for humans, with mild and temporary side effects like ear pain, headache, and tingling. No severe adverse events have been causally linked to these treatments. ^{2 3 6 7 8}

How is transcutaneous cervical vagal nerve stimulation (tcVNS) different from other treatments for opioid use disorder?

Transcutaneous cervical vagal nerve stimulation (tcVNS) is unique because it is a non-invasive treatment that reduces pain and respiratory stress during opioid withdrawal without using medication. Unlike traditional drug treatments, tcVNS works by stimulating the vagus nerve in the neck, which can help manage withdrawal symptoms and improve physiological responses. ^{1 2 3 4 5}

Research Team

James D Bremner, MD

Principal Investigator

Emory University

Eligibility Criteria

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

I am not on methadone, naltrexone, Suboxone, or drugs that clash with hydromorphone or lofexidine.

Positive pregnancy test or breastfeeding for women

I do not have any serious illness that would stop me from joining the study.

Timeline

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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 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]

References

1. United States 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. [2023]

2. Switzerland 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. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Noninvasive Vagal Nerve Stimulation for Opioid Use Disorder. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Transcutaneous Cervical Vagus Nerve Stimulation Reduces Respiratory Variability in the Context of Opioid Withdrawal. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]

8. Canada pubmed.ncbi.nlm.nih.gov

Digital Cardiovascular Biomarker Responses to Transcutaneous Cervical Vagus Nerve Stimulation: State-Space Modeling, Prediction, and Simulation. [2023]