An Open Label Trial of Bupropion and Naltrexone for Binge Drinking

Study Overview
=================
Brief Summary
-----------------
This is an open-label Phase IIa pilot study of the tolerability and effects on binge drinking of bupropion and naltrexone for binge drinkers.

Detailed Description
-----------------
This is an open-label Phase IIa pilot study of the tolerability and effects on binge drinking of bupropion and naltrexone for binge drinkers. Participants: Investigators will recruit 12 men or women ages 21-34 years who exhibit a minimum of 5/3 (men/women) or more binge drinking episodes per month over the past three months. A binge drinking episode is defined as the consumption of 5/4 (men/women) standard drinks ( 12 gms ethanol) in about a two hour period. Subjects may meet DSM-V criteria for mild or moderate alcohol use disorder. Subjects with overt physical dependence on alcohol, significant medical problems including seizures or bulimia, other substance use disorder except for occasional marijuana (based on toxicology screen) or significant psychiatric illness will be excluded. Procedures (methods): As a first step in human trials investigators will give open label bupropion + naltrexone to active binge drinking subjects. The primary goal here is to assess tolerability and acceptability though changes in binge drinking and subjective sense of effect will be gathered as well. Investigators will also test cortical adaptation to binge drinking by completing tactile sensory testing and comparing the results to controls and individuals with overt physical dependence on alcohol. Investigators will recruit subjects using the e-mail listserve for UNC students, faculty and staff. Investigators will use standard clinical doses of bupropion-XL 300 mg/d (lower seizure risk) and naltrexone 50 mg/d dispensed by the UNC Investigational Drug Services. Bupropion XL will be initiated at 150 mg/d on Days 1-4 and increased to 300 mg/d for Days 5-84. Naltrexone will be initiated at 25 mg/d from Days 7-9 and then go to 50 mg/d for Days 10-84. Subjects will be seen at screening and then at Weeks 0, 1, 3, 5, 8 and 12. Subjects will be breathalyzed and receive Medical Management counseling to encourage compliance and progress towards drinking goals. Investigators will use the Time Line Follow-Back approach to assess alcohol consumption history modified to include time taken to consume alcohol and define a binge. They will also measure craving for alcohol and will assess tolerability by probing for adverse effects. Key outcomes of interest include tolerability and acceptability, drinking behavior including frequency and intensity of binge drinking, and craving for alcohol. Because this is an open-label trial without a placebo comparison group no formal statistics will be completed and efficacy will not be assessed. Instead, this pilot study will inform investigators about the recruitment of binge drinkers, the tolerability and acceptability of bupropion/naltrexone in this population and potential efficacy signals.

Official Title
-----------------
Assessing Changes in the Brain Melanocortin System and Sensory Processing in Response to Alcohol to Advance Our Understanding of the Pathophysiology and Psychopharmacology of Binge Drinking

Conditions
-----------------
Binge Drinking

Intervention / Treatment
-----------------
* Drug: Naltrexone
* Drug: Bupropion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women between the ages of 21 and 34 years. A minimum of 5/3 (men/women) or more binge drinking episodes per month over the past three months. A binge drinking episode is defined as the consumption of 5/4 (men/women) standard drinks ( 12 gms ethanol) in about a two hour period. Subjects may meet DSM-V criteria for mild or moderate alcohol use disorder. Ability to understand and sign written informed consent. Must have a 0.0 gms/dl breathalyzer reading on the day of screening and 0.0 gms/dl on the day of randomization. Must have a stable residence and be able to identify an individual who could contact participant if needed. Have a goal of sobriety or significantly reducing alcohol intake. Exclusion Criteria Presence of physical dependence on alcohol as assessed by clear tolerance to alcohol or alcohol withdrawal symptoms based on SCID interview or a Severe Alcohol Use Disorder (>5 SCID DSM-V symptoms). Bupropion is contraindicated in individuals with a history of bulimia or a seizure disorder and naltrexone is contraindicated in acute liver disease and in patients using or misusing opioids. Clinically significant medical disease that might interfere with the evaluation of the study medication or present a safety concern (e.g., renal insufficiency, cirrhosis, unstable hypertension, diabetes mellitus, seizure disorder). Clinically significant psychiatric illness including any psychotic disorder, bipolar disorder, anorexia/bulimia, severe depression, or suicidal ideation. Other substance abuse or dependence disorder other than nicotine or cannabis abuse. Concurrent use of anticonvulsants. Concurrent use of any psychotropic medication including antidepressants, mood stabilizers, antipsychotics, anxiolytics, stimulants, or hypnotics with the exception of stable doses of antidepressants for one month. Bupropion is commonly added to antidepressants for augmentation so the use of another antidepressant does not represent a safety concern. Prior history of adverse reaction to bupropion or naltrexone. AST or ALT > 3.5 times ULN or bilirubin > 1.5 X ULN. Positive urine toxicology screen with the exception of cannabis. Individuals with positive cannabis screens will be excluded only if they have a history of cannabis dependence. Pregnant women and women of childbearing potential who do not practice a medically acceptable form of birth control (oral or depot contraceptive, or barrier methods such as diaphragm or condom with spermicidal). Women who are breastfeeding. Individuals requiring inpatient treatment or more intense outpatient treatment for their alcohol problems. Participation in any clinical trial within the past 60 days that would have safety concerns for the trial. Court-mandated participation in alcohol treatment or pending incarceration.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 34 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naltrexone and Buproprion<br>Investigators will use standard clinical doses of bupropion-XL 300 mg/d (lower seizure risk) and naltrexone 50 mg/d dispensed by the UNC Investigational Drug Services. Bupropion XL will be initiated at 150 mg/d on Days 1-4 and increased to 300 mg/d for Days 5-84. Naltrexone will be initiated at 25 mg/d from Days 7-9 and then go to 50 mg/d for Days 10-84. | Drug: Naltrexone<br>* Standard clinical doses of naltrexone 50 mg/d dispensed by the UNC Investigational Drug Services. Naltrexone will be initiated at 25 mg/d from Days 7-9 and then go to 50 mg/d for Days 10-84.<br>Drug: Bupropion<br>* Standard clinical doses of bupropion-XL 300 mg/d (lower seizure risk) dispensed by the UNC Investigational Drug Services. Bupropion XL will be initiated at 150 mg/d on Days 1-4 and increased to 300 mg/d for Days 5-84.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Associated Adverse Events | Tolerability assessed by specifically probing for intervention-associated adverse effects. | 12 weeks | 
| Number of Participants Discontinuing Subsequent to Defined Intolerance | Retention was evaluated indirectly by accounting for those participants who discontinued either naltrexone or bupropion or study participation itself due to intolerance. | Throughout study, a total of approximately 12 weeks | 
| Number of Binge Drinking Days During Treatment | The number of binge drinking days during treatment with bupropion + naltrexone | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Final Penn Alcohol Craving Scale (PACS) Score | Craving for alcohol will be assessed using the Penn Alcohol Craving Scale (PACS) The PACS is a five-item self-administered instrument for assessing craving. Frequency, intensity, and duration of thoughts about drinking are assessed along with ability to resist drinking. The final item asks the responder to provide an average rating of his/her craving over the course of the past week. The questions on the PACS use descriptors coupled with numerical ratings ranging from 0 to 6 with the highest possible total score of 30. Higher scores reflect a higher level of craving. This outcome measure is the final PACS total score obtained in the trial. | 12 weeks | 
| Mean Number of Drinks/Binge Drinking Day During Treatment |  | 12 weeks |