Efficacy of Levetiracetam in Cocaine-Abusing Methadone Maintained Patients

This 17-week double-blind, placebo controlled randomized pilot clinical trial will provide
treatment for 40 cocaine-dependent opioid dependent patients. Participants, aged 18-65 years,
will be randomized to receive levetiracetam 3000 mg/day or placebo while concurrently
receiving treatment with methadone. Baseline cocaine use will be determined during the first
week of treatment participation. (Gossop et al., 1997) The study design will have three
overlapping phases that are summarized below: 1) A one week methadone fixed induction (week
1) and flexible methadone stabilization phase (weeks 2-13); 2) an 12-week "treatment" phase
(weeks 2-13), consisting of slow titration and stabilization on study medication; and 3) a
four week "taper, detoxification or transfer" phase (weeks 13-17).

During the first week of induction onto methadone, participants will be administered
increasing doses of methadone starting at 30 mg daily and increased up to 60 mg daily by the
end of the first week. This methadone dose will be adjusted for stabilization of opiate
withdrawal symptoms using a flexible dosing from 40 mg up to 150 mg between weeks 2 to 12.
This range has been found to be adequate for the vast majority of patients receiving
methadone in our program and is designed to accommodate participants who may not be able to
tolerate the higher maintenance doses or may still experience withdrawal symptoms,
respectively. We may increase or decrease this amount on a case-by-case basis based on
physician assessment of self-reported and observed symptoms.

Starting on week 2 subjects will start study medication in one of two randomly assigned
experimental groups: levetiracetam 3000 mg /day (active medication) or placebo (inactive
medication). Concurrent with the stabilization on methadone, levetiracetam will be increased
from 500mg/day on week 2 and this dose will be slowly titrated to a total of 3000mg/day or
maximum tolerated dose (MTD). Subjects will remain on their full dosage through week 13.

At the end of week 13, participants will undergo detoxification from methadone over a 4-week
period (weeks 13-17) and discontinuation from levetiracetam over a concurrent 2-week period.

All participants will receive weekly 1-hour of individual psychotherapy (Cognitive Behavioral
Treatment) with experienced clinicians specifically trained to deliver the therapy and who
will receive ongoing supervision. The primary outcomes will be reduction in cocaine use, as
assessed by self-report and thrice-weekly urinalyses. Secondary outcomes will include weeks
in treatment (retention), reported medication side effects (medication tolerability), and
change in measures of: cocaine craving, anxiety symptoms and opiate withdrawal symptoms. This
study will occur at the Outpatient Treatment Research Program in Building 36 at the VA CT
Healthcare System.

Inclusion Criteria:

- Between the ages of 18-65 years.

- Participants must demonstrate current opioid dependence as determined by study
physician or APRN, self-reported history of opioid dependence for one year and a
positive urine of opiates. Participants may be transferred from other methadone
maintenance programs, including the WHVA methadone program.

- Participants also must be current users of cocaine with self-reported use of cocaine >
1 time/week in at least one month preceding study entry, cocaine-positive urine screen
and score over 3 as assessed with the Severity Dependence Scale.

- Women of childbearing age are eligible to be included in the study if they have a
negative pregnancy test at screening, agree to adequate contraception to prevent
pregnancy, to have monthly pregnancy tests, and they understand the risk of fetal
toxicity due to medication and cocaine.

Exclusion Criteria:

- Current diagnosis of other drug or alcohol dependence (other than opiates, cocaine or
tobacco).

- Patients with serious medical illness (e.g., major cardiovascular, renal, endocrine,
hepatic, and serious neurological disorders including any history of seizures).

- Patients with current serious psychiatric illness or history of psychosis,
schizophrenia, bipolar type I disorder and subjects with suicidal or homicidal
thoughts or taking psychotropic medications.

- Women who are pregnant, nursing or refuse to use a reliable form of birth control or
refuse monthly testing.

- Screening liver function tests (SGOT or SGPT) greater than 3 times normal and renal
function test (creatinine) greater than 1.5 mg/dl.