Benzodiazepine - History

History

The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting the pharmacology results to be negative and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests. However, the compound showed very strong sedative, anticonvulsant, and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium. Following chlordiazepoxide, diazepam marketed by Hoffmann–La Roche under the brand name Valium in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses.

The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the United Kingdom, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in the British law, making class action law suits more difficult.

In 2010, formerly classified documents from a Medical Research Council (UK) meeting of experts emerged and revealed that the MRC was aware of research 30 years ago that suggested that benzodiazepines could cause brain damage in some people similar to that which occurs from alcohol abuse and failed to follow-up with larger clinical trials. The MRC turned down research proposals in the 1980s by Professor Lader and also proposals by Professor Ashton in 1995 to study whether benzodiazepines had permanent effects on the brain. The MRC responded that it has always been open to research proposals in this area that meet required standards. It was further alleged that the MRC documents were relevant to a large class-action lawsuit, which started in the mid-1980s against drug companies and one solicitor stated that it was strange that the MRC had 'hidden' the documents. Jim Dobbin, MP and chair of the All-Party Parliamentary Group for Involuntary Tranquilliser Addiction, described the documents as a "huge scandal," given the large number of people who experience symptoms such as physical, cognitive, and psychological problems as a result of benzodiazepine use, which can persist even after withdrawing.

Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief have not significantly dropped. For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include zolpidem, zaleplon and eszopiclone. Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.