Levetiracetam (Keppra) Tolerability in Cocaine Abusing Methadone-maintained Patients.

This 12-week open-label clinical trial will provide treatment for 15 cocaine-dependent
opioid dependent patients. Participants, aged 18-65 years, will receive levetiracetam 3000
mg/day while concurrently receiving treatment with methadone. Baseline cocaine use will be
determined during the first week of treatment participation.

The study design will have three overlapping phases that are summarized below: 1) A one week
methadone fixed induction (week 1) and flexible stabilization phase (weeks 2-9); 2) an
8-week "treatment" phase (weeks 2-9), consisting of slow titration and stabilization on
study medication; and 3) a four week "taper, detoxification or transfer" phase (weeks 9-12).

During the first week of induction onto methadone, participants will be administered fixed
increasing doses of methadone starting at 30 mg daily and increased 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. 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 receive levetiracetam 500mg/day 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 8.

At the end of week 8, participants will undergo detoxification from methadone over a 4-week
period (weeks 8-12) 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 reported
medication side effects (medication tolerability), and reduction in cocaine use, as assessed
by self-report and thrice-weekly urinalyses. Secondary outcomes will include weeks in
treatment (retention), 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:

1. Between the ages of 18-65 years.

2. Participants must demonstrate current opioid dependence as determined by study
physician, 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.

3. 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 (Kaye & Darke
2002).

4. 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:

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

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

3. 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.

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

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