Conditions: Binge Drinking
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

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.

Arms:
arm 1: 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.

Interventions: intervention 1: Naltrexone intervention 2: Bupropion
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
An Open Label Trial of Bupropion and Naltrexone for Binge Drinking 
 
 
 
 
NCT number NCT02842073 
Document Date 05-15-2018 
 
 
 


 
Study Protocol 
 
An Open Label Trial of Bupropion and Naltrexone for Binge Drinking 
 
Overall Concept:  The current proposal represents an innovative pharmacological approach to the 
treatment of binge drinking that derives from preclinical findings from the laboratory of Dr. Todd Thiele, one of 
the proposal’s consultants.  Dr. Thiele found that a melanocortin agonist, melanoton II, potently suppresses 
binge drinking  (Navarro et al, 2015) in a mouse model of binge drinking. Because the antidepressant 
bupropion has been shown to activate melanocortin systems in brain (Greenway et al, 2009) Dr. Thiele's lab 
also studied the effect of bupropion on binge-drinking in their model and showed that bupropion significantly 
reduced binge-drinking at doses that were lower than those that suppress appetite (unpublished 
data).  Because bupropion is a clinically available and FDA approved medication Dr. Thiele initiated a 
discussion with our group to consider a clinical trial of bupropion for binge drinking.  Navarro et al (2015) found 
evidence that using a melanocortin agonist with an opioid antagonist such as naltrexone enhanced the potency 
of the opioid antagonist to suppress binge drinking.   In addition to a direct effect on binge drinking, Dr. Thiele’s 
lab has proposed that modulating the melanocortin system and counteracting binge drinking may have value in 
preventing progression of alcohol use from binge drinking to dependent level drinking (Thiele, 2012; Navarro et 
al, 2015)—potentially, a very important finding for clinical care. 
General Background: Binge drinking is a major public health problem in the United States.  The 
Center for Disease Control (CDC) places alcohol as the number three cause of preventable deaths following 
nicotine use and overweight (Mokdad et al, 2004).  Binge drinking, generally defined as the consumption of five 
or more standard drinks for a man or four or more drinks for a woman in about a two hour period (see Courtney 
and Polich 2009), is a major component of excessive alcohol use and a serious problem for the United States.  
The CDC (2012) report indicated that 17.1% of the adult U.S. population reported one binge drinking episode 
in the past 30 days in 2010--men (23.2%) vs. women (11.4%) with peak ages 18-24 years (28.2%), 25-34 
years (27.9%), and 35-44 years (19.2%).  Men reported an average of 5 binge drinking episodes/month with a 
mean of 9.0 drinks/episode and women 3.2 binge drinking episodes/month at 5.9 drinks/episode. Binge 
drinking leads to multiple problems, e.g. accidental injury (Gmel et al, 2006), aggressive and violent behavior 
(Shepard et al, 2006), and high blood pressure (Fan et al, 2008). Additionally, there is increased risk for 
developing alcohol dependence in individuals that binge drink frequently (Hingson et al, 2006).  Overall, binge 
drinking contributes to more than half of all deaths attributed to alcohol and to three quarters of the economic 
cost of excessive alcohol use—binge drinking is a serious public health problem and one that may exceed 
traditionally defined alcohol dependence in its overall cost to society. 
Binge drinking is a complex construct as it is both a stand-alone phenomenon and also a component of 
alcohol use disorders.  We are focusing on the behavior to allow greater fidelity to the preclinical data where 
the key behavior was consumption of an intoxicating amount of alcohol in a two hour period, a non-dependent 
model (Navarro et al, 2015).  The majority of binge drinkers do not have physical dependence (see Woerle et 
al, 2007), and we are particularly interested in this “developmental” phase towards overt physical dependence 
as the preclinical literature suggests this phase may be a key time for clinical intervention (Thiele  2012).   


Treatment of Binge Drinking with or without Co-Occurring Alcohol Use Disorders 
Despite the significant economic and personal costs associated with binge drinking, efforts to improve 
recognition and treatment of binge drinking have received less attention than efforts directed towards DSM-IV 
defined alcohol dependence though this is beginning to change (Siqueira and Smith, 2015).   A recent 
assessment of screening and brief intervention for patients with risky drinking (where many binge drinkers are 
categorized) and related alcohol-use problems in the primary care setting revealed that a variety of brief 
intervention techniques, e.g. brief advice, motivational interviews, can reduce heavy drinking episodes (12% 
more individuals with no heavy drinking, 95% CI 7-16%) (Jonas et al, 2012).  Unfortunately, the improvements 
were modest and health impacts were unclear highlighting the need for additional approaches such as 
pharmacotherapy. As noted by Hester (2015) “…they [non-dependent drinkers] are an underserved patient 
population associated with significant and growing health care costs.” The availability of medication options for 
binge drinking would increase medical clinicians’ interest in identifying and treating this significant problem.  
Pharmacotherapy approaches to treat binge drinking:  Few clinical trials for binge drinking per se have been 
completed. O’Malley et al (2015) studied 128 young adult college students with heavy drinking (≥ 4 heavy 
drinking days in 4 weeks; ~60% DSM-IV alcohol dependent but without physical dependence) and compared 
25 mg daily + 25 mg targeted naltrexone to be taken in anticipation of a heavy drinking episode to placebo. 
They did not find evidence for an effect on %heavy drinking or %abstinence but naltrexone led to a reduction in 
drinks/drinking day.  They noted, “…the risk-benefit ratio favors offering young adult drinkers naltrexone to 
reduce the amount of alcohol they drink.”  Three trials have been conducted for older heavy drinkers or 
problem drinkers, mean age late 40’s, using the opioid antagonists naltrexone (Kranzler et al 2003, 2009) or 
nalmefene (Karhuvaara et al, 2007).  These trials sought individuals who were problem drinkers or heavy 
drinkers rather than physically dependent on alcohol, though 84-95% met criteria for DSM-IV alcohol 
dependence.  These trials excluded individuals with evidence of more severe alcohol dependence, i.e. >4 
DSM-IV criteria for dependence or having a history of alcohol withdrawal.  All three trials found evidence for 
modest benefit.  Taken together, these studies indicate that medications can be effective in the treatment of 
the milder end of the spectrum of alcohol use disorders where many binge drinkers are categorized. 
Pharmacotherapy for binge drinking is clearly in its infancy, perhaps in a similar state to pharmacotherapy for 
traditionally defined alcohol dependence 20 years ago when naltrexone was first discovered.   
The current proposal will conduct the first human trial to test the novel preclinical finding that activating 
melanocortin systems in brain with/without opioid blockade potently reduces binge drinking.  Identification of a 
potential efficacy signal would be significant as it would not only demonstrate that activation of melanocortin 
systems with/without opioid blockade has potential for therapeutic application for binge drinking in humans but 
would increase awareness of a biomedical component of binge drinking which could positively affect medical 
clinicians’ attitudes and potentially increase identification and treatment efforts. 
Innovation 
The present application is innovative in two major areas:  1) it represents the first clinical test of the exciting 
preclinical finding that activating melanocortin systems potently counteracts binge drinking and 2) it represents 
one of the first clinical trials to investigate the efficacy of pharmacotherapy for binge drinking.  These 
innovations have the potential to affect clinical practice for the binge drinking patient.   


Innovation 1.  First proof of concept trial to translate to humans the preclinical finding that activation of 
melanocortin systems with/without µ-opioid receptor antagonism reduces binge drinking  
Navarro et al (2015) recently demonstrated that activating melanocortin 
systems with/without opioid receptor antagonism in brain produced a 
powerful effect to reduce binge drinking in a mouse model.  The rationale 
to test these systems derived from evidence that activation at the 
melanocortin receptor blunts ethanol intake in animals and that 
melanocortin peptides and the endogenous opioid β-endorphin share a 
common protein precursor and functional relationships (See Navarro et al, 
2015).   
In their study, Navarro et al (2015) used melanotan II (MT-II) to activate 
the melanocortin receptor and naltrexone for opioid blockade.  MT-II 
reduced bring drinking with MT-II being more potent and overall more 
effective than naltrexone (72% decrease in ethanol consumption vs 47% 
decrease), Figure 1.   Furthermore, MT-II increased the effectiveness of 
naltrexone in a synergistic manner. A key aspect of this study was that it 
investigated effects on binge-drinking rather than dependent level 
drinking, as the authors note “…our results specifically speak to the 
possibility that these targets could be useful for curbing excessive binge 
drinking, an approach that may be useful for preventing the transition to 
dependence.”  
Advantageously, for human trials, Bupropion (Wellbutrin®), an FDA approved antidepressant and anti-nicotine 
agent, activates the melanocortin system through proopiomelanocortin neurons likely via norepinephrine and 
dopamine reuptake inhibition (Greenway et al, 2010; Hasegawa et al, 2005).  Thus, we now have access to a 
pharmacological approach, bupropion + naltrexone, approved in humans to test the hypothesis that activation 
of melanocortin systems while blocking the opioid system will significantly reduce binge-drinking-- a true 
translational trial.  
Innovation 2: One of the first clinical trials to investigate the efficacy of pharmacotherapy for binge drinking.   
As noted earlier, there has been very limited effort towards identifying pharmacological agents that help with 
binge drinking, particularly in younger populations.  The O’Malley et al (2015) trial may be the first placebo-
controlled trial in young (18-25 years), heavy drinkers and it did find evidence that naltrexone reduced 
drinks/drinking day. Given that the prevalence of binge drinking peaks in the 18-34 year age range and is 
commonly not associated with physical dependence it is important to conduct clinical trials in populations with 
these characteristics.  The current proposal will therefore focus on subjects ages 21-44 years and will exclude 
those with overt physical dependence on alcohol. 
Targeting the binge drinking population moves the field towards the concept of using pharmacotherapy to treat 
early phases of alcohol use disorders and potentially reduce the likelihood of individuals progressing from 
binge-drinking to overt physical dependence.  While still a theoretical concept this is a highly innovative idea 
and one that could have profound implications for clinical management, see Thiele (2012).  
Research Approach: For this feasibility/tolerability trial, it is important to use doses of bupropion and 
naltrexone that are known to be effective and safe for humans.  For bupropion we have selected a 300 mg/d 
dose of the extended release formulation.  The 300 mg dose of bupropion is approved by the FDA for 
depression and for nicotine dependence.  The extended release 300 mg formulation has a lower estimated risk 
of seizures (0.1%) compared to the 0.4% rate for the immediate release formulation.  The 0.1% risk of seizures 
Figure 1:  Effects of MT-II compared to 
naltrexone on binge drinking in mice 
(Navarro et al, 2015). 


is comparable to the risk reported with other antidepressants such as sertraline and fluoxetine (FDA labels) 
and with acamprosate (FDA label), which is approved for alcohol dependence.  Furthermore, we will be 
studying a binge drinking population without evidence of physical dependence, a history of seizures, or a 
reported history of cocaine use so seizure risk is minimized which has been raised as a concern based on 
animal studies (Silverstone et al, 2008).  For naltrexone, we will use the standard dose of 50 mg/d used for 
alcohol use disorders..  
Participants:  12 men and women between the ages of 21and 44 years of age will be recruited from social 
media, e-mail list serve to UNC students and staff, and local newspaper/radio advertisements.  Key Inclusion 
criteria:  1) A minimum of 5/3 (men/women) or more binge drinking episodes per month over the past three 
months (mean population values, CDC (2012)).  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.  Requiring multiple episodes of 
binge drinking over several months is important to identifying subjects with a consistent pattern of binge-
drinking as shorter time frames may give misleading information (see Courtney and Polich, 2009). Subjects 
may meet DSM-V criteria for mild or moderate alcohol use disorder; 2) BMI ≥18.5 (normal weight or above); 3) 
express a desire to achieve abstinence or to reduce alcohol consumption.  Exclusion criteria:  1) 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); 2) a history of 
bulimia or a seizure disorder; 3) 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); 4) clinically significant psychiatric illness including any psychotic disorder, bipolar disorder, 
anorexia/bulimia, severe depression, or suicidal ideation; 5) other substance abuse or dependence disorder 
other than nicotine or occasional cannabis use ; 6) Concurrent use of anticonvulsants, opioids, varenicline, 
MAOIs, any anti-alcohol medication or any psychotropic medication with the exception of stable doses of 
antidepressants for one month; prior history of adverse reaction to bupropion or naltrexone; 7) AST or ALT > 
3.5 times ULN or bilirubin > 1.5 X ULN; 8) positive urine toxicology screen with the exception of cannabis.  
Individuals with positive cannabis screens will be excluded only if they have a history of a cannabis use 
disorder; 9) pregnancy or breastfeeding.  
Trial Design:  The design is an open-label trial.  We 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. We will see subjects at 
screening and then at Weeks 0, 1, 3, 5, 8 and 12. Subjects will be breathalyzed and receive Medical 
Management (MM) counseling to encourage compliance and progress towards drinking goals. MM is a 
medically oriented brief (10-15') therapy provided by medical personnel (MDs or nursing staff, only MDs in this 
trial). Our medical staff have been trained in MM and have been using it in other trials over the past five years. 
We 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. We will also measure craving for alcohol using the Penn 
Alcohol Craving Scale.. We will assess tolerability by probing for adverse effects and will assess AST and ALT. 
Our key outcomes of interest include tolerability and acceptability, drinking behavior including frequency 
and intensity of binge drinking, and craving for alcohol. 
Recruitment, Telephone Screen, and Full Eligibility Screening:  Subjects will initially be prescreened by 
phone and then at full screening read and sign the informed consent. A breathalyzer test will be administered 
(must be 0.00 gms/dl to give informed consent), height, weight and BMI recorded and a medical history and 
examination completed. Over-the-counter and prescription medication use will be recorded and nicotine use 


documented (Heatherton et al, 1991). CBC with differential; serum bilirubin, AST, ALT, GGT, sodium, 
potassium, chloride, blood urea nitrogen, creatinine, glucose; and urinalysis and urine toxicology Women will 
be given a urine pregnancy test (Uβ-HCG) at screening and at weeks 4, 8, and 12. Trained interviewers will 
conduct the psychiatric screening interview using the M.I.N.I. (Sheehan et al., 1998).  The SCID Substance 
Use Disorders Module to establish DSM-V criteria for alcohol use disorders (First et al, 2016) will be 
administered by either Dr. Garbutt or Dr. Jordan. The study coordinator will conduct the pretreatment 90-day 
Timeline Followback (TLFB) interview to identify amount of alcohol consumed and timeframe of consumption 
(Sobell et al, 1988 and personal communication).  A binge drinking episode requires a minimum of 5/4 
(men/women) standard drinks consumed over about a two hour period, i.e. consuming a bottle of wine over 
five hours would not be coded as a binge drinking day.  The Penn Alcohol Craving Scale (PACS) (Flannery et 
al, 1999) and the University of Rhode Island Change Assessment (URICA) (Diclimente and Hughes, 1990) will 
be completed and treatment goal—abstinence vs. reduction— recorded.   
 
Initial Treatment Visit (within 21 days screening):  Eligible individuals will not be required to abstain from 
drinking alcohol prior to randomization.  The study coordinator will administer a breathalyzer test (BAC must be 
≤0.04 gms/d) and complete assessments as outlined in Table 1, Participants will be given a calendar style 
diary to track pill taking, drinking quantity/timing, intoxication and any side effects.  Finally, participants will 
receive Medical Management from a trained clinician.  
Subsequent Treatment Visits:  See Table 1 for a summary of procedures and assessments.  TLFB and 
PACS are gathered each visit.  Medical monitoring will be conducted by study physicians and will consist of 
review of vital signs, concomitant medication use, and general inquiries into side effects. The physician may 
recommend that medication be held for a period of time to deal with an adverse event, e.g. nausea.   
 
Table 1 Procedures and Assessments 
  
Screen 
Visit 
Initial 
Visit 
Wk 
1 
 
Wk 3 Wk 
5 
Wk 
8 
Wk 
12 
Wk 16 
Follow-up 
 
Informed consent 
X 
 
 
 
 
 
 
 
Physical/Neuro exam 
X 
 
 
 
 
 
 
 
Urine Pregnancy testing 
X 
 
 
 
x 
x 
 
 
CBC & chemistries 
X 
 
 
 
X* 
X* 
X* 
 
Urinalysis/ 
toxicology
 
X 
 
 
 
 
 
 
 
M.I.N.I./SCID-V 
X 
 
 
 
 
 
 
 
DrInC 
X 
 
 
 
 
 
X 
 
CIWA 
 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Bupropion 
 
X 
X 
X 
X 
X 
 
 
Dispense Naltrexone 
 
 
X 
X 
X 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
Collect/provide drinking and 
 
X 
X 
X 
X 
X 
X 
 
Breathalyzer 
X 
X 
X 
X 
X 
X 
X 
 
TLFB 
X 
X 
X 
X 
X 
X 
X 
X 
PACS 
X 
X 
X 
X 
X 
X 
X 
 
MM session 
 
X 
X 
X 
X 
X 
X 
 


 
Medical Management Intervention:  The psychosocial support for the study will be Medical Management 
(MM) (Pettinati et al, 2005). Drs. Kampov, Jordan, Pedersen and Garbutt will conduct MM.  Drs. Kampov and 
Garbutt have been trained in MM by Dr. William Dundon and again by Ms. Gail Kaemf of the University of 
Pennsylvania where Dr. Pedersen was trained as well. Dr. Jordan has been trained in MM by Dr. Garbutt.  MM 
sessions average 10-15 minutes and focus on three main areas: (1) feedback on consequences of drinking; (2) 
encouraging compliance with medication/addressing compliance problems and  (3) encouraging progress 
towards drinking goal— reduction or abstinence are acceptable. 10% of sessions will be audiotaped and 
reviewed to enhance fidelity.  
Medication Compliance Monitoring:  Participants will record their pill taking in calendar-style diaries 
that will be provided and collected at each visit.  Pills will be distributed in blister packs that will be returned to 
the study coordinator to reconcile any unused medication from the returned blister packs with participants’ 
diary records. 
 
Statistical Plan and Data Analysis: The primary outcomes of interest are rates of adverse events, 
reported tolerability and retention.  Frequency and intensity of binge drinking and craving for alcohol will also 
be recorded.  Because this is an open-label feasibility trial, no statistical analyses are proposed but rather an 
overall assessment of tolerability and feasibility will be obtained.  Data will be entered into an Excel database 
and reviewed for accuracy.