Stress and Medication Effects on Cocaine Cue Reactivity

Stress and cocaine cues produce craving and ultimately relapse in cocaine dependent
individuals. This is a randomized, double-blind, placebo-controlled study evaluating the
effects of either guanfacine (Tenex) or modafinil (Provigil) on stress and cue induced
craving in cocaine dependent individuals. Cocaine dependence will be assessed in adults (ages
18-65) as defined by DSM-IV criteria. If the subject signs the consent form, meets the study
criteria and does not meet the exclusion criteria they will be included in the study.
Subjects will report to the General Clinical Research Center (GCRC) at the Medical University
of South Carolina (MUSC), for an outpatient visit and will receive their first dose of study
medication. The following day subjects will return to the GCRC and admitted for the duration
of the study (two days and one night). There will be a one-week and a one-month follow-up
visit. Subjects will be randomly assigned to one of two treatment groups (guanfacine or
placebo). Each subject will also be randomly assigned to either a stress or no-stress
subgroup. On the test day (day 3) subjects in the stress group will be asked to perform a
speech and a math problem in front of an audience (Trier Social Stress Test, TSST), while the
no-stress group will be asked to sit quietly and read. Following these tasks, each subject
will be exposed to neutral (control) cues and immediately afterwards the subjects will be
exposed to cocaine cues (cocaine paraphernalia). Craving/mood, physiological activity, and
endocrine responses, will be assessed at pre-set intervals throughout the testing procedure.
The cue reactivity protocol will be repeated on the one-week follow-up visit.

Inclusion Criteria:

Subjects must be able to provide informed consent and function at an intellectual level
sufficient to allow accurate completion of all assessment instruments.

Subjects must consent to remain abstinent from all drugs of abuse (except nicotine) during
the GCRC admission.

Because of the high comorbidity of alcohol and marijuana use and cocaine dependence,
individuals meeting dependence for alcohol and marijuana will be included. Individuals
requiring medical detox from alcohol will be excluded.

Subjects must consent to random assignment to stress vs. no stress and drug treatment
conditions.

Exclusion Criteria:

Women who are pregnant, nursing or of childbearing potential and not practicing an
effective means of birth control. Modafinil inhibits metabolism of steroidal contraceptives
via CYP3A4 and can reduce the effectiveness of this type of birth control, female subjects
must use one of the following methods of birth control: barrier methods (diaphragm or
condoms with spermicide or both), surgical sterilization, use of an intra-uterine
contraceptive device, or complete abstinence from sexual intercourse.

Subjects with evidence of or a history of significant hematological, endocrine,
cardiovascular (including but not limited to left ventricular hypertrophy (unless a
cardiologist deems that it is not clinically significant), mitral valve prolapse, left
bundle branch block, myocardial infarction, and angina), pulmonary, renal,
gastrointestinal, or neurological disease including diabetes, as these conditions may
affect HPA axis function.

Subjects with any liver function test (LFTs) of greater than two times normal, as
compromised liver function can interfere with HPA axis activity (Williams and Dluhy 1987)
and may affect drug metabolism.

Subjects with Addison's disease, Cushing's disease or other diseases of the adrenal cortex
likely to affect HPA axis function.

Subjects with a history of or current psychotic disorder or bipolar affective disorder as
these may interfere with HPA function.

Subjects with current major depressive disorder or post-traumatic stress disorder as these
disorders are associated with characteristic changes in HPA axis function.

Subjects receiving synthetic glucocorticoid therapy, any exogenous steroid therapy, or
treatment with other agents that interfere with HPA axis function within one month of the
time of testing.

Subjects taking any psychotropic medications, opiates or opiate antagonists because these
may affect HPA axis function.Participants taking SSRI's will be included.

Subjects required to take medications that could adversely interact with study medications,
including, but not limited to, azole type antifungals, cyclosporine, warfarin,
theophylline, or carbamazepine. Any medications that induce or inhibit CYP3A4 pathways are
excluded, as modafinil is metabolized through this enzyme system.

Subjects with any acute illness or fever as this may affect HPA axis activity. Individuals
who otherwise meet study criteria will be rescheduled for evaluation for participation.

Subjects who are grossly obese (BMI > 39), as this may interfere with HPA axis function.

Subjects who are unwilling or unable to maintain abstinence from alcohol and other drugs of
abuse (except nicotine) prior to the stress task procedure.

Subjects meeting DSM-IV criteria for substance dependence (other than nicotine, cocaine,
alcohol or marijuana) within the past 60 days.