Oxytocin Treatment of Alcohol Withdrawal

Study Overview
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Brief Summary
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Purpose: Test whether intranasal administration of the neuropeptide, oxytocin, is effective in decreasing alcohol withdrawal symptoms, the number of bouts of withdrawal requiring standard medication treatment (lorazepam) and the amount of lorazepam required to control withdrawal bouts in individuals undergoing medical detoxification. Also, determine rates of subject recruitment and retention in the inpatient setting. Participants: 80 alcohol dependent patients, 18-65 years of age, admitted for medical detoxification. Procedures (methods): Subjects will be inpatients undergoing medical detoxification from alcohol. Oxytocin or placebo will be administered in a nasal spray twice daily in a randomized, double blind manner for three days. Withdrawal symptoms will be measured routinely at q4 hours and prn for length of hospital stay. Lorazepam will be given whenever withdrawal symptoms increase above specific parameters.

Detailed Description
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Study Design: This will be a double-blind, placebo controlled comparison of the efficacy of twice daily intranasal administration of oxytocin and placebo (saline) in reducing alcohol withdrawal symptoms, the number of bouts of withdrawal during which symptoms are of sufficient magnitude requiring prn lorazepam treatment (see definitions below) and the amount of lorazepam required to resolve withdrawal bouts. Treatment group assignment will be random within each sex. Subjects will be patients admitted to (University of North Carolina (UNC) Hospitals or the Dix Clinical Research Unit (CRU) for medical detoxification. Each treatment group will be composed of up to 40 subjects. Dr. Hamer, the study statistician, will construct a randomization plan to randomize 80 subjects to 2 groups of 40 subjects each with a blocksize of 4. This will be a permuted blocksize as this is a blind study. Procedures: Most patients who are admitted to the UNC Neuroscience Hospital Crisis Stabilization Unit, UNC Hospitals Family Practice or Hospitalist Services, or the Dix CRU for medical detoxification from alcohol will come in through the UNC Hospitals Emergency Department or Dorothea Dix Screening and Admissions during the late evening or early morning. Physical examination, medical and psychiatric history and lab tests (including complete blood count [CBC], magnesium, sodium, potassium, [blood urea nitrogen] BUN, creatinine, glucose, albumin, liver functions tests [ALT, AST, LDH, GGT], throid-stimulating hormone (TSH), B12, folate, urinalysis, urine toxicology screen and pregnancy test) are routinely obtained by the emergency department (ED)/ Dorothea Dix Screening and Admissions and/or inpatient unit during the admission process. Possibly in the UNC Hospitals ED/ Dorothea Dix Screening and Admissions and definitely after admission to these units, patients will have their vital signs (VSs) measured and their withdrawal symptoms quantified using the revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar scale, Sullivan et al 1989) on the schedule in the standard alcohol detoxification order set in the UNC Hospital electronic medical records system (CPOE) system. The CRU at Dorothea Dix will use a hard copy version of the CIWA used in the CPOE at UNC Hospitals. After consent is obtained, subjects will be randomly assigned to a treatment group (oxytocin or placebo). Prior to receiving their first intranasal treatment, an ECG will be obtained and blood drawn to obtain serum for assay of cytokine and allopregnanolone concentrations. Subjects also will rate their symptoms using the Alcohol Withdrawal Symptom Checklist (AWSC, Pittman et al 2007) prior to receiving their first test dose. These procedures will be done/overseen by research nurses or physicians. Subjects will usually receive their first intranasal test dose between 1000 and 1200 hours and will consist of 6 insufflations of Syntocinon Spray (approximately 24 IU) or placebo, with each insufflation given 30 seconds apart and alternating between nostrils. Test doses will be taken again at 1700 hr later that day (Admission Day 1) and at 0900 and 1700 hr on Admission Days 2 and 3. Oxytocin test treatments will be administered from 5 ml intranasal spray vials designed to deliver 0.1 ml metered volume per insufflation. The placebo treatments will be administered from 60 ml intranasal spray vials (each containing 30ml of solution) also designed to deliver 0.1ml metered volume per insufflation. Vials containing oxytocin and placebo spray will be blind labeled by the UNC Investigational Drug Service or the Dorothea Dix Hospital pharmacy. Research nurses or physicians will oversee subject self-administration of all intranasal test doses. After enrollment on admission day 1 and in the morning on admission days 2 and 3, subjects will be given multiple copies of the AWSC questionnaire and requested to complete one each time the unit nurses do CIWA ratings. These questionnaires will be retrieved by research staff the following morning. Shortly after the morning test dose on admission days 2 and 3, subjects will complete the Alcohol Craving Visual Analog Scales (ACVAS), the Penn Alcohol Craving Scale, and the Profile of Mood States (McNair et al, 1971). On these same admission days, research nurses will also draw (and subsequently process) blood serum samples to assay cytokine and allopregnanolone concentrations shortly after the morning test dose. Additional blood will be drawn after the morning test dose on admission day 2 to obtain serum for tests to be run in McLendon Laboratories (magnesium, chloride, calcium, sodium, potassium, BUN, creatinine, and liver function tests). Another electrocardiogram (ECG) will also be obtained shortly after the morning test treatment on admission day 2. Research staff will retrieve on a daily basis CIWA ratings and vital sign measurements obtained on each subject from their electronic medical record. In all subjects, PRN lorazepam doses will be administered by mouth (PO) or intravenously (IV) (if subjects cannot take medication PO) whenever CIWA ratings are > 14 per the protocol in the standard alcohol detoxification order set in the UNC Hospital CPOE system. Lorazepam doses (1 - 4 mg) and frequency (q 2 -6 h) will be adjusted based on the severity of withdrawal symptoms. This same order set will be employed at the Dorothea Dix CRU.

Official Title
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Oxytocin Treatment of Alcohol Withdrawal

Conditions
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Alcohol Withdrawal

Intervention / Treatment
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* Drug: intranasal oxytocin spray
* Other: intranasal spray without oxytocin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Daily consumption of 6 or more alcohol drinks/day for at least 2 weeks prior to admission. Only one of the following two conditions must be met: At least one prior episode 2 days or longer in duration which the subject experienced withdrawal symptoms that caused significant incapacitation. At least one prior inpatient or outpatient medical detoxification during which the subject exhibited withdrawal symptoms that sedative-hypnotic or anticonvulsant medication was required at least once on 2 consecutive days after cessation of or reduction in the use of alcohol following 2 weeks or more of heavily daily consumption (6 or more drinks/day). Exclusion Criteria: Low literacy as indicated by an inability to read and understand the consent form. Dependence on substances other than alcohol, nicotine, caffeine or cannabis. History of alcohol withdrawal-related seizures, delirium tremens or hallucinations. Current or past alcohol-related medical complications (e.g. cirrhosis of the liver, esophageal varices, severe gastritis, hemoptysis, hematochezia or melena). Current delirium, disorientation to place or persons, seizures, acute or unstable psychosis or mania. Suicidal or homicidal ideation with strong intent, plans or recent attempt. Debilitating medical conditions (including AIDS, seizure disorder, emphysema, cancer and not well-controlled diabetes/hypertension) [HIV infection, diabetes, hypertension and asthma will not be grounds for exclusion] Diagnosis of amnesia, dementia, cognitive impairment or significant neurological symptoms. Low body weight (BMI<17). History of anorexia nervosa or bulimia in the past 2 years. Significant trauma, self injurious behavior or surgery in the previous 2 months Pregnancy; giving birth or breast-feeding in the past 6 months. Ingestion during the 2 weeks prior to this admission of much more alcohol/day than during previous drinking binges that preceded the onset of alcohol withdrawal symptoms. Ingestion of more than 450 ml of alcohol/day. Chronic treatment with benzodiazepines, barbiturates, anticonvulsants or stimulants Treatment/ingestion in the 72 hours prior to enrollment in the study with long half-life benzodiazepines or sedative hypnotic drugs. A blood alcohol level upon admission > 300 mg/dl. Well-documented history of inadequately treated baseline hypertension or tachycardia (SBP>150 or DBP>100 or P>110).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: intranasal spray without oxytocin<br>Twice daily intranasal spray without oxytocin. | Other: intranasal spray without oxytocin<br>* 6 insufflations (0.1 metered dose/insufflation) twice daily<br>|
| Experimental: intranasal oxytocin spray<br>Twice daily intranasal oxytocin spray | Drug: intranasal oxytocin spray<br>* 6 insufflations (24 IU of oxytocin total) given twice daily for 3 days<br>* Other names: Syntocinon Spray;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Lorazepam Dosage (in Milligrams) | Total lorazepam (in milligrams) required per subject to complete detoxification | Days 1 to 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CIWA-Ar Scores | Clinical Institute Withdrawal Assessment for Alcohol (CIWA) scale modified to include vital sign measurements. The CIWA scale measures each of 10 alcohol withdrawal symptoms between 0 and 6 (least to worst). Also in the modified CIWA score are ratings of body temperature (0-3, normal range to increasingly elevated), pulse (0-6), respirations (0-2), and diastolic blood pressure (0-6). So the range of possible total scores on the modified CIWA is 0-77. | days 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxytocin, alcohol withdrawal, lorazepam, alcoholism, intranasal administration, CIWA-Ar