Managing Alcoholism in People Who Do Not Respond to Naltrexone

Naltrexone has been established as an efficacious medication to treat alcohol dependence but
studies thus far have focused mostly on the acute phase of treatment rather than long-term
management and have not offered alternative treatment strategies when patients do not respond
to an initial course of naltrexone. For these initial non-responders to naltrexone, it is
unclear what adjustments to treatment should be made to increase the likelihood of treatment
success. We are unaware of previous research focused specifically on naltrexone non-response.
Pilot data from ongoing trials at our center, however, suggest that up to a third of patients
fail to respond to naltrexone. Moreover, these non-responsive patients go on to have the
worst outcomes during the next 6 months of treatment if maintained on the same combination of
naltrexone and medication management (MM). We propose to augment medication management with a
combination of motivational enhancement therapy and cognitive behavioral therapy (combined
behavioral intervention - CBI) and to test the benefits of continued/discontinued treatment
with naltrexone in a randomized placebo-controlled trial. Clinical strategies for second line
treatments often favor switching treatments rather than augmentation. However, there may be
synergies between naltrexone and CBI that were not apparent with medication management.
Specifically, CBI may have advantages in motivating patients to greater medication adherence
(a leading cause of naltrexone treatment failure) and CBI may address psychosocial factors
that limited or attenuated the effects of naltrexone.

Inclusion Criteria:

- 18 years of age or older

- Current DSM-IV diagnosis of alcohol dependence using the MINI.

- Meets the following drinking criteria as measured by the Timeline Followback (TLFB): *
drank within 30 days of randomization; * reports a minimum of 48 standard alcoholic
drinks (avg. 12 drinks/wk.) in a consecutive 30-day period over the 90-day period
prior to intake; and * has 2 or more days of heavy drinking (defined as over 5 drinks
per day in males and over 4 drinks per day in females) in this same pre-treatment
period, prior to intake.

- Prior to starting NTX, scores below 8 on the Clinical Inventory of Withdrawal from
Alcohol (CIWA), and at least 3 consecutive days of abstinence (2 days abstinence will
be permitted with approval by the principal investigator) directly prior to
randomization, as determined by Subject report and breathalyzer measures

- Speaks, understands and prints in English.

Exclusion Criteria:

- Has abused or been dependent on opiates in the past 12 months, or evidence of opiate
use in month prior to treatment, as assessed by subject report and intake urine drug
screen. Use of prescription opioids prior to treatment entry is allowed at the
discretion of the investigator. However, subjects must be free from use at the time of
randomization.

- Meets DSM IV criteria for current dependence, abuse, or dependence in partial
remission on any substance other than alcohol (except nicotine and marijuana).
Subjects who test positive on the urine drug screen (with the exception of THC) at the
initial visit (a repeat UDSis permitted in cases that are not clear. The repeat UDS
should be at least 5 days after the initial test)

- Has a lifetime DSM-IV diagnosis of schizophrenia or any psychotic disorder. Has a
current DSM-IV diagnosis of post-traumatic stress disorder (PTST) or bipolar disorder,
or any disorder that may interfere with study participation, at the discretion of the
investigator.

- Hepatocellular disease indicated by elevations of SGPT (ALT) and SGOT (AST) of at
least 5 times normal, or elevated bilirubin (of 1.3 or higher), as evidenced by the
most recent lab results prior to randomization. (documentation of Gilberts syndrome
will not constitute an exclusion despite elevated bilirubin).

- Has evidence of significant hematological, pulmonary, endocrine, cardiovascular, renal
or gastrointestinal disease that the principal investigator considers a risk to
participation.

- Has taken any psychotropic medications (or disulfiram) regularly within the last seven
days prior to randomization or needs immediate treatment with a psychotropic
medication (with the exception of detoxification medications or benadryl used
sparingly for sleep). The required washout period for fluoxetine (Prozac®) is 14 days
prior to randomization, and the required washout period for other psychotropic
medications is 7 days prior to randomization.

- Has taken any detoxification medication on the day of randomization.

- Tests positive on a pregnancy test, is contemplating pregnancy in the next 12 months,
is nursing, or is not using an effective contraceptive method if the subject is of
child-bearing potential.