The history of benzodiazepines.

After more than 50 years of experience with benzodiazepines, the American health care system has a love-hate relationship with them. In 1955, Hoffmann-La Roche chemist Leo Sternbach serendipitously identified the first benzodiazepine, chlordiazepoxide (Librium). By 1960, Hoffmann-La Roche marketed it as Librium, and it pursued molecular modifications for enhanced activity. Valium (diazepam) followed in 1963. Hoffmann-La Roche's competitors also began looking for analogues. Initially, benzodiazepines appeared to be less toxic and less likely to cause dependence than older drugs. A specific improvement was their lack of respiratory depression, a safety concern with barbiturates. Medical professionals greeted benzodiazepines enthusiastically at first, skyrocketing their popularity and patient demand. In the mid-to-late 1970s, benzodiazepines topped all "most frequently prescribed" lists. It took 15 years for researchers to associate benzodiazepines and their effect on gamma-aminobutyric acid as a mechanism of action. By the 1980s, clinicians' earlier enthusiasm and propensity to prescribe created a new concern: the specter of abuse and dependence. As information about benzodiazepines, both raising and damning, accumulated, medical leaders and legislators began to take action. The result: individual benzodiazepines and the entire class began to appear on guidelines and in legislation giving guidance on their use. Concurrently, clinicians began to raise concerns about benzodiazepine use by elderly patients, indicating that elders'lesser therapeutic response and heightened sensitivity to side effects demanded prescriber caution. The benzodiazepine story continues to evolve and includes modern-day issues and concerns beyond those ever anticipated.