Exploring the dark side of the moon: the treatment of benzodiazepine tolerance

The use of benzodiazepines (BZDs) has a history of more than 50 years. The first BZD, chlordiazepoxide, was approved in 1960, primarily to treat anxiety and insomnia. The 1960s saw a rapid diffusion of the use of this drug, followed soon by the still popular diazepam and, gradually, by several others. As early as the 1970s diazepam became the best-selling drug in the UK and the USA [1]. Soon after its introduction, however, reports of BZD tolerance and dependency emerged. BZD tolerance has been reported as early as 1961 [2], but this and other reports during the 1960s and 1970s were obscured by the enthusiastic easy management in the use of these barbiturates replacement drugs. Many countries now have recommendations for a short term use of BZD (2–4 weeks) [1]. Unfortunately these recommendations are largely disregarded by patients and doctors themselves. Misuse of BZD can cause deficits in learning, attention, memory, depression and injurious falls, traffic and other accidents [3]. Overall, the prevalence of long term use in the general population is approximately 2–7.5%, with estimates for long term use among BZD users ranging from 25% to 76% [4]. The problem of use of BZDs is also related to the use of high doses [5–7]. A cross-sectional study with 520 000 patents, estimated that 1.6% used BZDs in very high doses, exceeding the maximal recommended daily dose more than two-fold [8]. Surveys from France, Germany, Italy and the UK showed that 3.9% and 3.2% of current hypnotic and anxiolytic users have been taking a dose higher than the recommended therapeutic range [9]. Few studies evaluated the quality of life in long term users and even less among patients who use BZD at high doses.