Baclofen for Treating Anxiety and Alcoholism

Objective:

The selective GABAB receptor agonist baclofen has been identified as a possible medication
able to reduce alcohol craving and intake in alcohol dependent individuals. In keeping with
several preclinical studies, most of the clinical studies have demonstrated baclofen s
effects in reducing alcohol craving and intake and promoting alcohol abstinence. However,
one trial with alcoholics with a low severity of dependence found a robust treatment effect,
but no differences between baclofen and placebo. The inconsistency of baclofen s effects on
alcohol drinking among previous treatment trials suggests that different AD individuals may
respond differently to baclofen. Baclofen has been demonstrated to consistently reduce
anxiety in alcoholic patients, and analyses of positive vs. null findings with baclofen
suggest that alcoholic patients with higher levels of anxiety at baseline may represent a
sub-population particularly responsive to baclofen treatment. Therefore, this study will
systematically test, for the first time, the specific role of baclofen on alcohol-related
outcomes in alcoholic individuals with high anxiety levels. Furthermore, the biobehavioral
mechanisms by which baclofen reduces drinking are not well characterized. A human laboratory
pilot study conducted at Brown University with non-treatment seeking alcohol-dependent
individuals suggests that baclofen reduces alcohol consumption both in the naturalistic
environment as well as in a well-controlled lab setting (using an alcohol
self-administration [ASA] paradigm) and that this could be mediated by baclofen s ability to
alter alcohol-related biphasic effects. An exploratory analysis also revealed that specific
genetic polymorphisms might moderate baclofen s effects, i.e. DRD4 and 5HTTLPR
polymorphisms, although the sample of that pilot study was very small to allow one to draft
definitive conclusions. The present project proposes investigating baclofen using a design
similar to that used in the previous pilot study (thus, an already validated paradigm), thus
representing not only the first study testing baclofen in alcoholic individuals with high
anxiety levels, but also the first study investigating baclofen s biobehavioral mechanisms
in such a population for which baclofen may hypothetically show a very robust effect.

Study population:

Non-treatment seeking alcohol-dependent males and females with high anxiety levels.

Design:

The experimental design is a between-subject randomized double-blind controlled study. The
medication conditions baclofen t.i.d. or placebo represent the between subjects factor. Each
participant will be randomly assigned to one of the two medication conditions and will
receive eight days of the medication, followed by an alcohol laboratory session on Day 8.
The alcohol laboratory session will be conducted in a bar-like room in the NIAAA Outpatient
Clinic of the NIH CRC. The study will be conducted in consecutive phases which will appear
contiguous to volunteers: (1) a one-week screening period; (2) an 8-day period (+ 1-5 days
if needed to permit some participants flexibility in scheduling the laboratory session)
during which participants will take the study medication; (3) an alcohol laboratory session,
including a cue reactivity (CR) test and an alcohol self-administration (ASA) procedure on
Day 8 (last day at the target dose); (4) a 3-day period during which participants will
undergo a dose reduction of the study medication; (5) a 1-week follow-up (including the
tapering phase).

Outcome measures:

Alcohol drinking during the ASA will be measured as the primary outcome. Secondary
objectives include baclofen s effects on alcohol cue-induced responses (urge to drink,
attention to cues, blood pressure, heart rate, saliva), on the subjective effects of alcohol
and on anxiety levels. We will also explore the role of possible moderators of baclofen s
effects, namely family history of alcoholism, early vs. later onset of alcoholism,
pre-treatment anxiety levels and genetic moderators (DRD4, 5-HTTPRL). This study does not
offer direct benefit to participants but is likely to yield generalizable knowledge about
the possible role of baclofen in treating alcoholic individuals with high anxiety levels.
This will markedly facilitate the identification of a novel pharmacotherapy, thus
facilitating the development of novel alcoholism treatments.

- INCLUSION CRITERIA:

- Must be male or female between 21 and 65 years old (inclusive).

- Participants must meet criteria for current DSM-IV-TR diagnosis of alcohol
dependence, supported by the Structured Clinical Interview for DSM-IV-TR Axis I
Disorders (SCID).

- Participants must have a Trait STAI > 39.

- Participants must be in good health as confirmed by medical history, physical
examination, ECG, blood/urine lab tests.

- Females must be postmenopausal for at least one year, surgically sterile, or
practicing an effective method of birth control before entry and throughout the
study; have a negative urine pregnancy test at each visit. Reliable methods of birth
control include oral contraceptives or Norplant ; barrier methods such as diaphragms
with contraceptive jelly, cervical caps with contraceptive jelly, condoms with
contraceptive foam, or intrauterine devices; a partner with a vasectomy; or
abstinence from intercourse.

EXCLUSION CRITERIA:

- Individuals expressing interest in treatment for alcoholism and/or anxiety.

- Pregnancy or breast feeding women or not using an adequate form of birth control

- Unable to provide a negative urine drug screen.

- Individuals diagnosed with a current substance dependence diagnosis, other than
alcohol or nicotine.

- Meet DSM-IV Axis I criteria for a lifetime diagnosis of schizophrenia, bipolar
disorder, or other psychoses.

- An active illness within the past 6 months of Visit 1 that meet the DSM-IV criteria
for a diagnosis of Major Depressive Disorder (MDD). Subjects with a history of
attempted suicide will be excluded.

- Clinically significant medical abnormalities (i.e., unstable hypertension, clinically
significant ECG abnormalities, Creatinine greater than or equal to 2 mg/dL). Although
baclofen has demonstrated a safe profile when administered to alcoholic individuals
with liver cirrhosis, including those with Hepatitis C, this study employs the oral
administration of alcohol. Therefore, individuals with clinically significant liver
problems will be excluded, i.e. liver cirrhosis, AST or ALT > 5 times the upper
normal limit (UNL), and individuals with Hepatitis B and C.

- Current use of psychotropic medications that cannot be discontinued and that may have
an effect on alcohol consumption (thus confounding the results of the study) or that
may interact with baclofen. Specifically, contraindicated medications will include:
naltrexone, acamprosate, alcohol dehydrogenase inhibitors, topiramate, gabapentin,
ondansetron, benzodiazepines, beta-blockers, H2-blockers, and alpha-1 blockers.

- Medical contraindications for use of baclofen.

- A history of adverse reaction or hypersensitivity to baclofen.

- Participants who have significant alcohol withdrawal symptoms, defined as a CIWA-Ar >
8.

- History of epilepsy or alcohol-related seizures.