The Effects of Doxazosin on the Cardiovascular and Subjective Effects of Cocaine

Condition(s) targeted: Cocaine Addiction

Intervention: Sugar Pill (Drug); Doxazosin (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Baylor College of Medicine

Official(s) and/or principal investigator(s):
Thomas Newton, MD, Principal Investigator, Affiliation: Baylor College of Medicine

Overall contact:
Thomas Newton, MD, Phone: 877-228-5777, Email: SARP@bcm.edu

Human Laboratory Trial of Doxazosin for Cocaine Dependence: Accumulating evidence implicates noradrenergic (NE) systems in mediating the effects of stimulants (1-8). Mice lacking NE £\

- 1 receptor mice show reduced sensitivity to cocaine and amphetamine (8, 9). Local depletion

of prefrontal cortex (PFC) NE reduced rewarding effects of amphetamine and reduced amphetamine-induced dopamine (DA) release in the PFC and accumbens (7), suggesting that PFC NE contributes to the rewarding effects of stimulants. Treatment with the NE ƒÑ-1 antagonist prazosin has been shown to antagonize a variety of effects produced by cocaine and amphetamine. In rats, prazosin (1-2 mg/kg) significantly attenuated the locomotor activating effects produced by cocaine (10-12) and for amphetamine (4, 13, 14). Similar findings have been observed for the discriminative stimulus effects produced by cocaine and amphetamine in mice (15) and for food-maintained responding in pigeons (16). More recently, prazosin (0. 3 mg/kg) reduced reinstatement of extinguished cocaine-seeking behavior in rats without affecting responding for food, suggesting that prazosin my blunt the motivational effects of drug cues (5). Clinical Experience with Alpha-1 Adrenergic Antagonists: Prazosin is a prototypical antagonist at NE £\-1 receptors. When first released the medication was thought to produce relaxation of smooth muscles in the vasculature. Since then however it has been determined that prazosin antagonizes norepinephrine and this mediates the antihypertensive effect (17). The medication has been assessed extensively for the treatment of hypertension (18). The initial dose is 1mg two or three times per day. The usual dose range is 6mg/day to 15mg/day, with some patients requiring up to 40mg/day in divided doses. The most common side effects are: dizziness 10. 3%, headache 7. 8%, drowsiness 7. 6%, lack of energy 6. 9%, weakness 6. 5%, palpitations 5. 3%, and nausea 4. 9%. In most instances side effects have disappeared with continued therapy or have been tolerated with no decrease in dose of drug. More recently, prazosin has been successfully used to treat post traumatic stress disorder (19, 20). For this indication, prazosin was initiated at 1mg at bedtime and increased as needed to control symptoms to up to 15mg at bedtime by day 28. This approach resulted in no change in systolic and diastolic blood pressure compared to pretreatment measurements. Several subjects reported transient dizziness upon standing (9/14 in the prazosin group and 6/15 in the placebo group), but none reported syncope. Prazosin has a relatively short elimination half-life of 3. 5 h (21). Longer-lasting cogeners (e. g. terazosin and doxazosin) are available, but there is no experience using these medications as treatments for cocaine dependence. The purpose of this study is to evaluate the effects of doxazosin on the cardiovascular and subjective effects of cocaine in a human laboratory study. Doxazosin was selected because it has a longer elimination half-life (22h) compared to terazosin (12h). The side-effect profile of doxazosin closely resembles that of prazosin.

Official title: The Effects of Doxazosin on the Cardiovascular and Subjective Effects of Cocaine

Study design: Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Health Services Research

Primary outcome: Determine the safety of treatment with doxazosin in cocaine-dependent volunteers by examining hemodynamic and subjective effects of administration of ascending doses of cocaine (0, 20mg, and 40mg) and a placebo dose during treatment with doxazosin

Secondary outcome: To evaluate the effect of doxazosin on the pharmacokinetics of intravenously administered cocaine • To determine effects of treatment with doxazosin, as compared to placebo, on subjective effects produced by administration of cocaine or placebo

Minimum age: 18 Years. Maximum age: 64 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Be English-speaking volunteers who are not seeking treatment at the time of the study; 2. Be between 18-55 years of age; 3. Meet DSM-IV TR criteria for cocaine dependence; participants may or may not meet criteria for nicotine dependence. Nicotine dependence is allowed but not required because most cocaine users smoke cigarettes. 4. Have a self-reported history of using cocaine by the smoked or IV route; 5. Have vital signs as follows: supine blood pressure > 100/65 mm Hg, a seated blood pressure of > 90/60 mm Hg and < 150/90 mm Hg, and an orthostatic change < 20 mm Hg systolic or <10 mm Hg diastolic on standing. Resting pulse must be < 90 bpm. 6. Have hematology and chemistry laboratory tests that are within normal (+/- 10%) limits with the following exceptions: a) liver function tests (total bilirubin, ALT, AST, and alkaline phosphatase) < 3 x the upper limit of normal, and b) kidney function tests (creatinine and BUN) within normal limits; 7. Have a baseline EKG that demonstrates clinically normal sinus rhythm, clinically normal conduction, and no clinically significant arrhythmias; 8. Have a medical history and brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician and the principal investigator.

Exclusion Criteria:

1. Meet DSM IV TR criteria for dependence on drugs other than cocaine or nicotine. 2. Have any history or evidence suggestive of seizure disorder or brain injury; 3. Have any previous medically adverse reaction to cocaine, including loss of consciousness, chest pain, or epileptic seizure; 4. Have neurological or psychiatric disorders, such as: • psychosis, bipolar illness or major depression as assessed by MINI; • organic brain disease or dementia assessed by clinical interview; • history of any psychiatric disorder which would require ongoing treatment or which would make study compliance difficult; • history of suicide attempts within the past year and/or current suicidal ideation/plan; 5. Have evidence of clinically significant heart disease or hypertension, as determined by the PI; 6. Have evidence of untreated or unstable medical illness including: neuroendocrine, autoimmune, renal, hepatic, or active infectious disease; 7. Have symptomatic HIV or are taking antiretroviral medication; 8. Be pregnant or nursing. Other females must either be unable to conceive (i. e., surgically sterilized, sterile, or post-menopausal) or be using a reliable form of contraception (e. g., abstinence, birth control pills, intrauterine device, condoms, or spermicide). All females must provide negative pregnancy urine tests before study entry, upon hospital admission, and at the end of study participation; 9. Have asthma or currently use theophylline or other sympathomimetics; 10. Have any other illness, condition, or use of psychotropic medications, which in the opinion of the PI and/or the admitting physician would preclude safe and/or successful completion of the study.

Criteria for Discontinuation Following Initiation Participants will be discharged if they have a positive breath test indicating use of alcohol or a urine test indicating illicit use of drugs while in the MED-VAMC, if they do not comply with study procedures, or if they do not tolerate the study drugs. Stopping criteria are detailed below.

Stopping Criteria Cocaine administration will not be initiated if there are clinically significant arrhythmias or if vital signs are outside of acceptable ranges, which are resting pulse < 130 bpm and blood pressure below 165mm Hg systolic and 100mm Hg diastolic. In addition, repeated doses of cocaine will not be administered (and the study physician will halt continued cocaine delivery) if there are behavioral manifestations of cocaine toxicity (agitation, psychosis, inability to cooperate with study procedures).

Stopping Criteria for Further Participation Subject participation will be terminated if any of the following events occur: 1. Systolic BP greater than 180 mm Hg sustained for 5 minutes or more; 2. Diastolic BP greater than 120 mm Hg sustained for 5 minutes or more;

3. Heart rate greater than (220 - age x 0. 85) bpm sustained for 5 minutes or more. Note:

if a single value exceeding the values above is detected, the readings will be repeated until it is determined whether or not the stopping criteria have been met.

Subject Selection Criteria Rationale Route of administration. Participants are required to have used cocaine by the IV or smoked route to avoid exposing participants to drugs by routes of administration that produce more intensive interoceptive effects than usually used by the participants. Prior experience with smoked cocaine is allowed (rather than restricting the population to those with experience with IV cocaine) because smoked cocaine reaches brain sites of action as rapidly as does intravenously administered cocaine and smoked cocaine produces effects that are comparable to IV cocaine. Speed of administration (and rate of delivery to brain) of stimulant drugs likely impacts subjective and cardiovascular effects, so smoked and intravenously administered cocaine produce similar subjective effects (22-26).

Thomas Newton, MD, Phone: 877-228-5777, Email: SARP@bcm.edu

Michael Debakey VA Medical Center, Houston, Texas 77030, United States; Recruiting
Thomas Newton, MD, Principal Investigator

Starting date: January 2010
Last updated: March 3, 2010