Deficiencies of clinical trials of alcohol withdrawal.

Eighty-one therapeutic trials of alcohol withdrawal were found that have been published in English since 1954; controls were randomized in 29 (RCTs). Two thousand three hundred thirteen patients were randomized. Variable pretreatment description prevented estimates of delirium tremens and convulsion prevalence, but only four deaths were reported. Endpoints were thus entirely subjective in these moderately ill patients. Protocol quality of the RCTs was graded by a previously developed system for evaluating adequacy of descriptions, blinding, and essential measurements. Mean score obtained was .49 +/- .03 (1 SE). (A perfect paper would score 1.00.) Data presentations and statistical analyses scored .18 +/- .03. There was little evidence of improvement of scores over time. Papers lacked confidence intervals, proper handling of dropouts, and adequate details of side effects. In five RCTs, six comparisons showed that benzodiazepines are clearly superior to placebo (p less than .001), but conclusions about comparisons with other drugs were not possible. In none of eight "negative" comparisons was the probability of a type II error (beta) considered. Discovery of more effective symptomatic agents or methods of reducing the death rate will require more rigid protocols and analyses as well as larger studies to allow the use of more critical endpoints such as occurrence of delirium tremens, convulsions, or death.