Non-invasive Vagal Nerve Stimulation in Alcohol Use Disorder

Study Overview
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Brief Summary
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Alcohol use disorder (AUD) is a major health concern amongst Veterans as it causes poor health, lost days at work, impaired psychosocial functioning, and decreased quality of life. Current treatment options for AUD show limited effectiveness, which is exemplified by high relapse rates. Chronic heavy drinking results in psychological and physical distress during abstinence, including anxiety, irritability, and general discomfort, which increases the urge to drink to relieve these symptoms. The hypothesis of this study is that noninvasive vagal nerve stimulation (nVNS) can modify the perception of such inner bodily sensations of distress, and consequently reduces the drive to drink for relief. The aim of this study is to establish feasibility and acceptability of applying nVNS as a rehabilitative treatment for AUD in Veterans. The study will also evaluate the effect of nVNS on functional outcomes, quality of life, distress, and craving, and if nVNS alters neural activation patterns in brain regions involved in the perception and awareness of distress and pain.

Detailed Description
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AUD is a serious mental health disorder that affects more than 40% of US military Veterans, presenting a major burden to this population. Relapse rates of AUD are extremely high; over half of Veterans who complete treatment, relapse within 6 months, highlighting the need for improved treatments or differing treatment targets. Chronic, heavy drinking leads to an imbalance in homeostasis resulting in psychological and physical distress during periods of abstinence, and the urge to drink to relieve these symptoms to restore homeostasis. nVNS is a low-risk form of neuromodulation that has been shown to alleviate anxiety and chronic pain, and to reduce drug and alcohol relapse in animal models. The investigators hypothesize that nVNS attenuates distress-related craving in AUD in humans by modifying the autonomic nervous system and changing the perception of inner bodily sensations of physiological and affective distress. The investigators also hypothesize that nVNS improves functional outcomes and quality of life in Veterans with AUD. The proposed research will include 16 Veterans who meet for a diagnosis of AUD. Subjects will be randomly assigned to receive nVNS or sham stimulation prior to performing a well-validated functional Magnetic Resonance Imaging task designed to assess neural correlates of physical distress (via a heat stimulus). Subjects will then self-administer nVNS/sham at home twice a day for 7 days and return for a follow-up visit, during which all study components will be repeated. Behavioral assessments of functional disability, quality of life, psychological and physiological distress, and craving will be administered at baseline, after stimulation, and at follow-up. The aim of the proposed study is to establish feasibility and acceptability of applying nVNS as a rehabilitative treatment for AUD. In addition, the study will evaluate the preliminary effectiveness of nVNS in improving functional outcomes and quality of life, in reducing distress and craving, and in altering neural activation patterns in brain regions involved in the perception and awareness of distress and pain. The proposed work has the potential to lead to innovative, low-risk treatment options with high promise to significantly improve the care and lives of Veterans as there is a need for alternative treatments for AUD. As such, this novel AUD treatment could be particularly beneficial for Veterans who do not tolerate pharmacotherapy, and who have access or cognitive limitations or stigma concerns that act as barriers to psychotherapy.

Official Title
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Non-invasive Vagal Nerve Stimulation to Improve Functional Outcomes in Veterans With Alcohol Use Disorder

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Device: Cervical transcutaneous vagus nerve stimulation (active comparator)
* Device: Cervical transcutaneous vagus nerve stimulation (sham comparator)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Veteran Male subjects between 21 and 65 years of age Current DSM-5 diagnosis of AUD with at least one functional disability due to alcohol use, current alcohol craving, and current heavy drinking (>4 drinks on any day or >14 drinks per week) Able to forgo consumption of alcohol for 24 hours without any serious discomfort including nausea/vomiting, visual/auditory/tactile hallucinations, or non-essential tremor Exclusion Criteria: Clinical Institute Withdrawal Assessment of Alcohol Scale (CiWA) score >=9 on the day of the scan (symptoms judged to be due to co-existing anxiety or headache disorders will not be counted toward the total). Currently or recently (within last 90 days) enrolled in abstinence-based treatment program. Evidence of a maladaptive pattern of substance use or abuse other than alcohol one month prior to screening visit. Severe mental illness, e.g., psychosis or bipolar disorder At risk for suicide or homicide History of neurological disorder that might be associated with cognitive dysfunction. History of head trauma involving loss of consciousness >24 hours Clinically significant uncontrolled/unstable medical illness or clinically significant surgery within 1 month of the screening visit. MRI-related exclusion criteria: cardiac pacemaker, metal fragments in eyes/skin/body, aortic/aneurysm clips, heart-valve replacement, copper intrauterine device, shunt (ventricular or spinal), neuro/bio-stimulators Vagus nerve stimulation related criteria: history of carotid endarterectomy, severe carotid artery disease (e.g., history of transient ischemic attack (TIA) or stroke], congestive heart failure, cardiac arrhythmia, known severe coronary artery disease or recent myocardial infarction (within 5 years), history of seizure or syncope (within past year), prior neck surgery.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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: Devices include a sham and an active noninvasive vagal nerve stimulator (nVNS). Devices are identical in appearance, and both produce reliable sensation on the skin when applied to the neck area (transcutaneous cervical stimulation). Stimulation duration is approximately 120 seconds for both sham and active devices. Subjects receive the same instructions to self-administer stimulation twice a day for 120 minutes on each side (right and left).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active cervical transcutaneous vagus nerve stimulation<br>Participants will be assigned to active transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. | Device: Cervical transcutaneous vagus nerve stimulation (active comparator)<br>* Active nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that stimulates the vagus nerve.<br>|
| Placebo Comparator: Sham cervical transcutaneous vagus nerve stimulation<br>Participants will be assigned to sham transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. | Device: Cervical transcutaneous vagus nerve stimulation (sham comparator)<br>* Sham nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that does not stimulate the vagus nerve.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Acceptability Questionnaire (TAQ) | The Treatment Acceptability Questionnaire (TAQ) is a self-rating questionnaire used to assess acceptability of a treatment. The TAQ uses a 7-point rating scale ranging from 1 to 7, with lower scores reflecting lower acceptability and a midpoint of 4 indicating neutral acceptability. A rating above the midpoint of the TAQ (i.e., score between 5 and 7) is the established criterion for acceptable to highly acceptable. | Baseline to week 1 of 2x daily intervention (measure only administered at at study completion, i.e., 1 week after baseline) | 
| Measurement of feasibility - Recruitment goal | Treatment feasibility will be evaluated by meeting the recruitment goal of 16 Veterans within 12 months as measured by consented subjects who completed the baseline study visit. | Baseline to week 1 of 2x daily intervention | 
| Measurement of feasibility - Treatment adherence | Treatment feasibility will be evaluated by meeting >75% treatment adherence as documented in checklist/daily diary and interview) and measured as administering nVNS/sham stimulation twice a day for 7 days. | Baseline to week 1 of 2x daily intervention | 
| Measurement of feasibility - Subject retention | Treatment feasibility will be evaluated by meeting >75% subject retention at follow-up as measured by subjects completing the follow-up study visit. | Baseline to week 1 of 2x daily intervention | 
| Measurement of feasibility - Adverse side effects | Treatment feasibility will be evaluated by no serious adverse side effects (as documented in checklist/daily diary and interview). | Baseline to week 1 of 2x daily intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Substance Use Recovery Evaluator (SURE) | The Substance Use Recovery Evaluator (SURE) assesses the following domains of AUD-related functional outcomes: self-care (mental and physical health), relationships, material resources (stability of housing and occupational resources), and outlook of life. The SURE has been developed for use in substance use disorder populations. The SURE is comprised of 21 items, rated on a 3-point scale, but scored using a 3-point scale. Scores range from 21-63. | Baseline to week 1 of 2x daily intervention | 
| WHO Quality of Life assessment (WHOQOL-BREF) | The WHO Quality of Life assessment (WHOQOL-BREF) assesses quality of life across four domains (physical health, psychological, social relationships, and environment) with a total of 26 questions. The rating scale ranges from 1 to 5; score interpretation varies between items. | Baseline to week 1 of 2x daily intervention | 
| Beck Anxiety Inventory (BAI) | The Beck Anxiety Inventory (BAI) is a self-report instrument to measure the severity of anxiety and emotional distress. The BAI is a 21-item questionnaire with a 4-point rating scale, with a higher score reflecting greater anxiety. | Baseline to week 1 of 2x daily intervention | 
| PROMIS Pain Interference | The PROMIS Pain Interference measures self-reported consequences of pain on relevant aspects of one's life, i.e., the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities. This questionnaire has 8 items, rated on a 5-point scale, ranging from not at all to very much. Higher scores reflect higher pain interference. | Baseline to week 1 of 2x daily intervention | 
| Alcohol Urge Questionnaire (AUQ) | The Alcohol Urge Questionnaire (AUQ) is 8-item scale that measures cognitive preoccupation with alcohol on a 7-point rating scale ranging from strongly disagree to strongly agree. Two items are reverse scored. Higher scores reflect greater craving. | Baseline to week 1 of 2x daily intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alcohol use, neuromodulation, neuroimaging, withdrawal, anxiety, quality of life