Aripiprazole for Prevention of Relapse to Cocaine Use in Methadone-Maintenance Patients

Background. Though methadone effectively treats opioid dependence in polydrug users, some
abstinent patients relapse to maladaptive use of cocaine during treatment. Relapse may be
triggered by cocaine-associated cues. Work in a rodent relapse model has demonstrated that
the atypical neuroleptic drug aripiprazole (Abilify), a partial agonist at dopamine D2
receptors, can block relapse to cocaine use induced by cocaine-associated environmental
stimuli or by priming doses of cocaine.

Scientific goals. To determine whether aripiprazole prevents relapse to cocaine use more
effectively than placebo in cocaine-abstinent patients maintained on methadone.

Participant population. A total of up to 275 opioid-dependent outpatients abusing cocaine and
opioids (110 evaluable) will be enrolled. Target enrollment will include 40% women and 60%
minorities (mostly African-American).

Experimental design and methods. The study will be a randomized double-blind clinical trial
with two treatment groups (55 per group): aripiprazole (15 mg oral daily) and placebo. All
patients will receive standard treatment (methadone daily and individual counseling weekly)
for 39 weeks. To establish abstinence prior to aripiprazole induction, contingent vouchers
will be given for each cocaine-negative urine specimen during the first 12 weeks (weeks
1-12). Participants who are abstinent from cocaine during weeks 11 and 12 will be randomized
to receive aripiprazole or aripiprazole placebo in weeks 13 through 27 (induction, weeks 13
and 14; taper, week 27). From weeks 28-33, participants will receive methadone and counseling
only, and then will be offered assistance to transfer to another program; those who do not
transfer will undergo an 8-week methadone detoxification. The primary outcome measures will
be time to relapse and longest duration of cocaine abstinence. Secondary objectives include
evaluating whether the treatment groups differ in self-reported changes in drug use and
proportion of drug-negative urine specimens. In addition, drug use, drug craving, stress, and
HIV-risk behaviors such as injection practices will be assessed via electronic diaries
(ecological momentary assessment, EMA).

Benefits to participants and/or society. Participants will receive methadone, drug
counseling, and contingency-management therapy. The methadone, counseling, and voucher
interventions are likely to reduce participants use of heroin and cocaine and HIV risk
behaviors. Aripiprazole may reduce the incidence of relapse to cocaine use.

Risks to participants. Participants may experience side effects from aripiprazole and
methadone and discomfort during withdrawal from methadone and aripiprazole. Methadone could
raise serum levels of aripiprazole via inhibition of CYP2D6 metabolic pathways. The EMA
component of the study may generate some assessment burden.

- INCLUSION CRITERIA:

1. Age between 18 and 60

2. Evidence of physical dependence on opioids (determined by self-report, urine
screen, and physical exam)

3. Evidence of (a) current cocaine use (determined by self-report and urine screen)
or (b) cocaine dependence (DIS interview for DSM-IV criteria).

4. Lifetime drug-use duration of at least 1 year and current cocaine use on at least
3 days of the last 30.

5. Seeking treatment for opiate and cocaine use.

6. Able to attend methadone clinic 7 days/week.

EXCLUSION CRITERIA:

1. Any medical illness that in the view of the investigators would compromise
participation in research (determined by Self-Reported Medical History; Physical
Examination; Blood and Urine Laboratory tests; see details under Screening measures
below), including, but not limited to:

- cardiovascular disease

- cerebrovascular disease

- unexplained history of syncope

- history of seizures, except for febrile seizures at childhood

- chronic renal failure, as estimated by Cr > 2.0

- diabetes mellitus

- hyperlipidemia

2. Allergy, hypersensitivity, or intolerance to either methadone or aripiprazole
(determined by Self-Reported Medical History)

3. AIDS, CD4 <200, or evidence of severely compromised immune system (determined by Blood
Laboratory tests; see details under Screening measures below)

4. Pregnancy or breastfeeding (Urine Pregnancy Test; self report)

5. Orthostatic hypotension (i.e., upon standing for 3 minutes, a 20 mm Hg decrease in
systolic blood pressure or a 10 mmHg decrease in diastolic blood pressure, accompanied
by an increase by 20 bpm in heart rate) on two separate readings during physical
examination.

6. Marked, sustained high blood pressure (SBP >160 mm Hg, DBP >100 mm Hg) on two or more
readings at a single visit and confirmed with two readings on a follow-up visit. If a
participant is started on antihypertensive drugs at the start of the study, the
participant may be cleared, but will not be started on aripiprazole until confirmation
that the hypertension is well controlled (systolic blood pressure < 150, diastolic
blood pressure < 100 mm Hg) on two readings at least 3 days apart.

7. ECG abnormalities including QTc interval > 450 ms or changes suggesting acute
ischemia, second or third degree heart block, left bundle branch block, atrial
fibrillation, or other clinically important arrhythmias. ECGs may be sent to an
outside cardiologist for manual reading.

8. Contraindicated medications (Self-Reported Medical History):

- Alpha-1 receptor blockers (e.g., doxazin, terazosin)

- Anti-epileptic medications (e.g., carbamazepine)

- Tricyclic antidepressants

- SSRIs

- Neuroleptics

- Quinidine

- Antifungals (e.g., ketoconazole)

- Ranolazine

- CYP3A4 inhibitors or inducers (other than methadone)

- CYP2D6 inhibitors or inducers (other than methadone)

9. Family history (Self-Reported Medical History):

- Family history of sudden death of unexplained causes

- Sudden cardiac death

- Aneurysm

- Myocardial infarction below the age 50 years

10. Psychiatric history:

A) Cognitive impairment severe enough to preclude informed consent or valid responses
on questionnaires (Shipley Institute of Living scale estimated full-scale IQ less than
80)

B) History of schizophrenia or any other DSM-IV psychotic disorder (Self-Reported
Medical History; Diagnostic Interview Schedule for the DSM-IV (DIS IV))

C) History of bipolar disorder (Self-Reported Medical History; DIS IV)

D) Current Major Depressive Disorder (Self-Reported Medical History; DIS IV)

E) Previous suicide attempts or ideation (Self-Reported Medical History; DIS-IV)

F) Dementia (DIS-IV; Clinical Interview; Shipley Institute of Living scale)

11. Current physical dependence on alcohol or sedative-hypnotics, e.g. benzodiazepines
(self-report; ASI; alcohol CAGE questions; and pattern of positive drug screens or BAL
for alcohol)

12. Body Mass Index (BMI) over 40

13. Failure to agree to use a medically effective form of contraception while in the study
(in women who are sexually active with a male partner and able to get pregnant).
Acceptable forms of contraception for this study include:

- hormonal contraceptives (birth control pills, injectable hormones, vaginal ring
hormones),

- surgical sterility (tubal ligation or hysterectomy)

- IUD

- Diaphragm with spermicide

- Condom with spermicide