A Study of New Treatment for Excessive Alcohol Users by Electric Stimulation of Nerves Around Ear

Study Overview
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Brief Summary
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Alcohol Use Disorders (AUD's) are a major health and social problem. Relapse is a rule rather than an exception in alcohol dependence, leading to poor outcomes. Craving are frequently associated with relapse. Keeping in mind the high burden of disease due to AUD, limited efficacy of available treatment modalities it is important to study new treatment modalities. Vagus nerve stimulation (VNS) is a promising neuromodulation technique with robust evidence in epilepsy and treatment-resistant depression. fMRI studies show that transcutaneous VNS (tVNS) replicates most of the biological effects of VNS with an additional advantage of being non-invasive. Percutaneous Electrical Neural Field Stimulation (PENFS) of auricular branch of vagus nerve is a variant of tVNS which has shown promise in the treatment of opioid withdrawal. The efficacy of PENFS has been evaluated in AUDs in only handful of studies. I propose to employ a double-blind randomized sham-controlled trial where 40 subjects with AUD will be randomized to 2 groups, with 1 group receiving 'Active' auricular PENFS, and another group receiving bilateral 'sham' auricular PENFS. Assessments will be carried out at baseline and after 15 days of advent of PENFS on tasks to assess craving, along with neurohemodynamic changes on functional Magnetic Resonance Image (fMRI). Follow up of patients will be done till the first relapse or till 3 months after the post evaluation, whichever is earlier. The investigator's hypotheses are: Active PENFS will lead to significantly greater improvement in subjective craving and drinking-related outcomes as compared to sham PENFS in patients with AUD over the follow-up period of 3 months. Active PENFS will produce a significantly differential Blood Oxygen Level Dependent (BOLD) activation-deactivation pattern of brain regions (greater activation of dorsolateral prefrontal cortex and anterior cingulate cortex and along with deactivation of insular cortex) associated with craving during a cue-induction paradigm as compared to sham PENFS in patients with AUD. Active PENFS will result in a significant differential change in resting-state functional connectivity (fMRI measured) within and between addiction-related neural networks as compared to sham PENFS as evaluated with a resting state fMRI analysis in patients with AUD.

Detailed Description
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Patients will be recruited into the study after obtaining informed consent. The intervention will be started after completion of detoxification, which will be done with Lorazepam using a front-loading regimen and a drug washout period of 5 half-lives (approx. 3 days) will be given so as not to interfere with the stimulation. Amitriptyline 12.5-25mg will be used as rescue medication for sleep difficulty. All subjects will receive psychosocial interventions related to craving management and relapse prevention as per treatment as usual but will not be prescribed any anti-craving agents during the period of the study.The Drug Relief V 2.0 device will be installed after the detoxification and baseline fMRI scan. After installation, it will automatically provide neurostimulation at regular interval. It will be in situ for the next 15 days. After that, it will be removed temporarily for follow-up fMRI scanning.After completion of scanning a new device will be provided. The current research study will follow standard auricular PENFS procedures with established safety. The battery of the device will last for 15 days. Study subjects will be required to visit NIMHANS (National Institute of mental health and neurosciences) every 15 days to replace the old device for a new one. Till 3 months, all the devices will be provided free of costPatients will be followed up as usual on an outpatient basis, and the recent pattern of alcohol use will be inquired into. The follow-up will be done until the patient has a relapse or a maximum period of three months, whichever is earlier.

Official Title
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Auricular Percutaneous Electrical Neural Field Stimulation in Short-Term Treatment of Alcohol Dependence- Neurohaemodynamic Correlates and Feasibility Study

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Device: Drug Relief V(version) 2.0 Auricular Percutaneous Electrical Neural Field Stimulation (PENFS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Alcohol use disorder (AUD) as per DSM(Diagnostic and Statistical Manual of Mental Disorders)-5 by two psychiatrists working in the department of psychiatry NIMHANS. Male gender. Age not less than 18 years and not more than 50 years. At least, moderately severe AUD as ascertained by a score above 16 in Severity of Alcohol dependence questionnaire (SADQ). Right-handedness as assessed with Edinburgh Handedness Inventory. Informed consent and willingness to come for regular follow-ups (once every two weeks) for three months after recruitment in the study. Exclusion Criteria: Any diagnosis except alcohol dependence syndrome/ Tobacco dependence syndrome (to apply MINI(Mini International Neuropsychiatric Interview) screen). Contra-indications precluding device use- 2.1 patient with cardiac implants or similar biomedical implants, 2.2 during pregnancy unless medically advised, 2.3 patient with haemophilia 2.4 skin pathology 2.5 patient with diminished mental capability or physical competence about the handling of the device Left/ mixed handedness Contraindications to MRI

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Randomized (permuted block randomization, fixed), Parallel Group, Placebo Controlled Trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Arm<br>Active arm: Auricular Percutaneous Electrical Neural Field Stimulation (PENFS) device will stimulate the outer auditory canal. It will deliver with a pulse width of 500 ms. The stimulation frequency pattern is 1.12Hz(hertz), 2.24Hz,4.56Hz, 9.12Hz, 100Hz then 9.12Hz, 4.56Hz,2.28Hz,1.12Hz. This cycle will keep on continuing. An input voltage will be 4.2V(volt). | Device: Drug Relief V(version) 2.0 Auricular Percutaneous Electrical Neural Field Stimulation (PENFS)<br>* This is a Small electronic circuit board with a minimal number of electronic components in it, which is powered by three zinc-air batteries. Each battery consists of 1.4v of charge. From this charge, the circuit produces a maximum voltage of 3.4V under no load condition. The produced Voltage is driven as output by using the three stimulation wires, and the fourth insulated wire acts as a ground. The wires are Bio-compatible and do not have any impact when in contact with the human skin. The wire is attached with a needle to transfer the produced voltage into the nerves of the human ear. The sterilized needle (Titanium) is attached at the end of the wire through a snap fit ring. All the materials used are gone through necessary safety and performance testing including bio-compatibility and sterility testing, wherever necessary.<br>|
| Sham Comparator: Sham Arm<br>Sham arm: Auricular Percutaneous Electrical Neural Field Stimulation (PENFS) device will stimulate centre of the left ear lobe to a pulse width of 500 ms at same pattern of stimulation frequency mentioned in active PENFS with an input voltage of 4.2V | Device: Drug Relief V(version) 2.0 Auricular Percutaneous Electrical Neural Field Stimulation (PENFS)<br>* This is a Small electronic circuit board with a minimal number of electronic components in it, which is powered by three zinc-air batteries. Each battery consists of 1.4v of charge. From this charge, the circuit produces a maximum voltage of 3.4V under no load condition. The produced Voltage is driven as output by using the three stimulation wires, and the fourth insulated wire acts as a ground. The wires are Bio-compatible and do not have any impact when in contact with the human skin. The wire is attached with a needle to transfer the produced voltage into the nerves of the human ear. The sterilized needle (Titanium) is attached at the end of the wire through a snap fit ring. All the materials used are gone through necessary safety and performance testing including bio-compatibility and sterility testing, wherever necessary.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Craving scores | Change in craving scores measured with Penns Alcohol Craving Scale between baseline and equispaced 6 follow-ups (every 15 days) for 3 months. Scale Information: Scale name: Penn Alcohol Craving Scale. It measures craving for alcohol. It is a 5-item scale. Each item score range is 0 to 6. So, Scale's total score range is 0 to 30. Score 0 signifies no craving and score 30 signifies maximum craving. There is no subscale. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cue-induced craving resting state fMRI | Change in Cue-induced craving as measured by the VICE protocol 6-minute Visual Image Induced Craving for Ethanol (VICE) paradigm fMRI and resting state fMRI neurohemodynamic changes in the dorsolateral prefrontal cortex, anterior cingulate cortex (ACC) and insular cortex (IC) after 14 days PENFS. Time-Points are as follows: Time 0 is on the day of recruitment. Time 1 is on Day 14 of recruitment. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol dependence, Peripheral electrical nerve field stimulation (PENFS), Auricular nerve stimulation, Vagus nerve stimulation, relapse prevention