In summary, it is proposed that the more frequent or severe side effects associated with the newer triazolo-benzodiazepines are related to an interaction of several factors, including rapid elimination, high receptor-binding affinity, and unique chemical properties. Among benzodiazepine hypnotics, triazolam has a unique side effect profile for CNS adverse reactions in regard to type, frequency, and severity. All of the three factors mentioned contribute to this side effect profile: rapid elimination (the shortest half-life among benzodiazepine anxiolytics and hypnotics); high receptor-binding affinity (the highest among benzodiazepine anxiolytics and hypnotics); and unique chemical properties as a triazolo-benzodiazepine. Given these three factors, the drug's side effects can be understood as follows: Hyperexcitability states (daytime anxiety during drug administration and rebound insomnia following withdrawal) are related primarily to its rapid elimination and secondarily to the other two factors, whereas cognitive impairments (amnesia, confusion, and psychiatric symptoms) are related to the high binding affinity and unique chemical properties as well as to its rapid elimination. In contrast, benzodiazepines that are slowly eliminated and have only relatively moderate receptor-binding affinity (flurazepam) are unlikely to produce daytime anxiety and rebound insomnia and CNS adverse reactions such as cognitive impairment. The most common side effect, daytime sedation, is easily recognized and can be managed by dose reduction and/or intermittent use. This safety profile combined with the drug's high degree of efficacy both initially and with continued use provides a high benefit-risk ratio in using the drug in the adjunctive pharmacologic treatment of insomnia. Similarly, temazepam, which has relatively weak receptor-binding affinity produces very few CNS adverse reactions. Furthermore, temazepam (15 mg) is more efficacious than triazolam (0.25 mg). However, temazepam is not as effective as flurazepam, because it is slowly absorbed and therefore has limited efficacy for sleep induction. On the other hand, triazolam's safety profile of frequent and severe adverse reactions combined with the lack of efficacy for the current dose of 0.25 mg limits the drug's usefulness. In fact, the 0.25-mg dose has such a poor benefit-to-risk ratio that there is a real question as to whether the drug should remain on the market.(ABSTRACT TRUNCATED AT 400 WORDS)