RESEARCH STRATEGIES TO ASSESS PHARMACOTHERAPIES FOR ALCOHOLISM

1. The development and implementation of standardized basic and clinic al research strategies is necessary for the discovery and testing of n ew and effective pharmacotherapies for alcohol dependence. While many animal studies have indicated the involvement of central serotonin, en dogenous opioids and dopamine, their exact mehanisms of action have no t been fully discerned. One problem is the use of various animal model s, making it difficult to compare or replicate results from different laboratories. 2. Once a drug appears to decrease alcohol intake in ani mals, assessing its effects in humans can be even more challenging. 3. Most drugs were developed and may be even registered for another indi cation, so Phase I trials must be repeated in heavy alcohol users in c ase the drug has behavioural, pharmacokinetic or pharmacodynamic inter actions with alcohol. 4. Phase II trials, assessing the effects of the drug on alcohol intake, are usually radically different from the anim al models: most are long (>6 months), use varied designs, and accept o nly abstinence as successful outcome. Moderately dependent alcoholics, who comprise the majority of patients, prefer a goal of nonhazardous drinking. 5. In Phase III multicentre trials, especially international ones, it is almost impossible to control for potentially confounding variables, such as patient characteristics and concomitant psychosocia l treatment. 6. Also, research in pharmacotherapies for alcoholism is influenced by external factors such as sources of funding and other re sources. Thus, this methodical progression from Phase I to Phase III c linical trials is often abbreviated. 7. The authors developed a brief early Phase II clinical paradigm to assess pharmacotherapies for moder ately dependent alcoholics, and conducted 3 studies with the serotonin uptake inhibitors, citalopram and fluoxetine, and a serotonin antagon ist, ritanserin. This paradigm, which includes a short (1 to 2 weeks) outpatient phase and two experimental drinking sessions, measures alco hol intake, desire to drink, alcohol's subjective effects, and intoxic ation. While it may have limited relevance to a goal of abstinence, it is efficient and economical to screen drug effects on alcohol intake and suggest mechanisms (desire to drink, subjective effects). It is al so the only human model concordant with results in animals. 8. Develop ment of new pharmacotherapies for alcoholism may benefit from acceptan ce of both abstinence and moderation of drinking as acceptable treatme nt goals.