Efficacy and Safety of High Dose Baclofen for Alcohol Dependence

Alcohol dependence (AD) is a common problem with significant health consequences. Treatment
of AD is evolving to include both counseling methods and medications. Several medications
have been discovered, that show efficacy in AD, e.g. naltrexone, acamprosate. However, the
overall effect of existing medications is modest leaving a clear need for the development of
new pharmacotherapies. The gamma-aminobutyric acid (GABA)-B receptor agonist baclofen has
attracted attention as a potential new medication for AD based on preclinical data and early
clinical trials. Baclofen is an FDA approved medication with an excellent safety profile even
for patients with liver cirrhosis—a not uncommon consequence of AD. Questions have arisen
with regards to the efficacy of baclofen and whether higher doses of baclofen are safe and
more effective than the prior tested dose of 30 mg/ day. There is emerging evidence that
severity of dependence is positively associated with baclofen response. The main goal of the
present proposal is to test the efficacy and safety of 30 mg/d and 90 mg/d of baclofen
compared to placebo controlling for severity of dependence as assessed by drinks/drinking
day. A primary secondary goal will examine for an anxiolytic effect of baclofen. The study
proposes to enroll 120 men and women with AD in a randomized, placebo-controlled trial to
include at least 60 individuals with more severe AD (≥14 drinks/drinking day for men; ≥10
drinks/drinking day for women) with randomization to baclofen or placebo balanced for this
variable. Baclofen will be titrated to 10 mg t.i.d over 3 days and to 30 mg t.i.d over 12
days and maintained at that level for 12 weeks and then downtitrated for a total study time
of 16 weeks. Medical Management will be provided to encourage progress towards drinking goals
and to enhance retention and compliance. Drinking patterns, anxiety levels, sleep patterns,
craving for alcohol, gamma-glutamyl transferase (GGT) and carbohydrate deficient transferring
(CDT) will be assessed. Trough blood levels of R & S-baclofen will be assessed in all
individuals at week 4.

In summary, the present proposal is innovative and of clinical significance as it will test
and compare standard and high-dose baclofen for efficacy and safety in individuals with AD.
The proposal is adequately powered to test the primary hypothesis and provides good power to
assess whether drinks/drinking day is predictive of baclofen response. Adequate power is also
present to examine the anxiolytic effect of baclofen. Ascertaining the effects of standard
and high-dose baclofen, the predictive value of heavy drinking on baclofen response and the
anxiolytic effect of baclofen are important goals towards determining whether baclofen has
true value for the clinical management of the patient with alcohol dependence.

Inclusion Criteria:

1. Men and women between the ages of 18 and 65 meeting Diagnostic and Statistical Manual
(DSM)-IV criteria for current alcohol dependence.

2. More than 14 drinks (women) or 21 drinks (men) per week including at least 2 heavy
drinking days (men > 5 drinks/day; women > 4 drinks/day) per week in the 30-day period
prior to screening. In addition we will recruit 50% of individuals who have a mean of
≥14 drinks/drinking day (men) or ≥10 drinks/drinking day (women) in the 30 days prior
to screening.

3. Ability to understand and sign written informed consent.

4. Must have a 0.0 gms/dL breathalyzer reading on the day of screening and 0.0 gms/dL on
the day of randomization.

5. Express a desire to achieve abstinence or to greatly reduce alcohol consumption

6. Must have a stable residence and be able to identify an individual who could contact
participant if needed.

Exclusion Criteria:

1. 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, severe
depression, or suicidal ideation.

2. Other substance abuse or dependence disorder other than nicotine or alcohol or
cannabis abuse.

Occasional use of cocaine is acceptable.

3. 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. Concurrent use of anticonvulsants,
insulin, or oral hypoglycemics.

4. Prior history of adverse reaction to baclofen.

5. Creatinine level > Upper Limit of Normal (ULN) or Estimated Glomerular Filtration Rate
< age norm.

6. aspartate aminotransferase (AST), or alanine transaminase (ALT) > 5 times ULN or
bilirubin > 1.5 X ULN.

7. 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.

8. 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).

9. Women who are breastfeeding.

10. Individuals requiring inpatient treatment or more intense outpatient treatment for
their alcohol dependence.

11. Participation in any clinical trial within the past 60 days.

12. Court-mandated participation in alcohol treatment or pending incarceration.