Research Issues Related to Development of Medications for Treatment of Cocaine Addiction.

Draft guidelines for the study of medications for treatment of drug addiction have been developed by the Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research, Division of Anesthetic, Critical Care and Addiction Drug Products. These guidelines are intended to provide a common basis for planning, evaluating and interpreting clinical studies and facilitating development of new and effective drugs for the treatment of dependence. For each class of abusable substances, certain clinical situations stand out as targets for intervention, while others may seem less relevant. The focus of clinical research needs to be tailored to the clinically relevant situations for each drug of abuse. In general, the pharmacotherapies being considered for treatment of abuse and dependence disorders are used to achieve one or more of six major objectives: 1. Reduction in the risk of addiction; 2. Reduction in high-risk behavior; 3. Reduction in morbidity and mortality from addiction; 4. Reduction in drug use and/or induction of abstinence; 5. Relief of symptoms of withdrawal; and 6. Relapse prevention; along with rehabilitation and restoration of functioning. General requirements for outcome measures include measuring drug use, abstinence, withdrawal, and relapse. For all outcomes, both the validity and the meaningfulness must be established. Although considerable neurobiological knowledge relative to cocaine has been acquired, investigation of applicable medications based on these data is still under development. Many studies to date have focused on modifying dopamine function. Because dopamine plays a critical biologic role in motivation, reward and locomotion, modification of its activity may potentially contribute to serious adverse effects. An optimal strategy might require the use of several medications that have different mechanisms of action, or several medications targeted at different aspects of the problem (e.g., relapse craving, etc.). The agonist approach is believed to be potentially problematic because of effects on cardiovascular function and temperature regulation. A substitution model (comparable to methadone for heroin dependence) has not been proposed. The antagonist model is hampered by the fact that reinforcing effects are mediated through dopamine, which, if blocked, might produce a sufficient anhedonic state that compliance with the treatment regimen might be unlikely. Unlike opiates and alcohol, the withdrawal syndrome from cocaine and other stimulants is subtle and usually is not seen as requiring medication intervention.