Landmark drugs: The discovery of benzodiazepines and the adverse publicity that followed
No other landmark drug in this series has been associated with as much adverse publicity as Valium (diazepam) and the extended family of benzodiazepines which it spawned.
Even today, nearly five decades after the first benzodiazepine was launched, and almost 30 years since the Department of Health warned against long-term use, an estimated 1.5 million people are addicted to benzodiazepines.1 Indeed, when the Medical Defence Union (MDU) reported in May 2009 that repeat prescriptions were responsible for more medication errors requiring financial settlements to patients than any other aspect of prescribing, benzodiazepines were among the culprits.2
“The cost of defending such cases will continue to spiral until the MDU refuses to defend GPs who prescribe benzodiazepines for longer periods than those stipulated in the data sheets, without due cause,” predicts Malcolm Lader, emeritus professor of clinical psychopharmacology at the Institute of Psychiatry, King’s College, London.
Newly qualified when Valium was introduced in 1963, Professor Lader recalls the welcome it received from the medical profession and from anxiety-laden patients.
“From the start, there was enthusiasm for Librium and then Valium for anxiety because, until then, most patients were treated with barbiturates, which were addictive, required increasing dosages, and carried a risk of overdose and interactions with other medications,” he explains. “In contrast, we saw good results with Librium and Valium, they were pleasant to take, and we were assured that there was no risk of dependence with the low doses we were prescribing.”
A class apart
Diazepam was discovered in Roche’s New Jersey laboratories by organic chemist Leo Sternbach, who had worked for the company in Basel before the 1939–45 war. In 1957, he found that a benzheptoxdiazine derivative, chlordiazepoxide, left over from an earlier project, had unexpected sedative, anticonvulsant and muscle-relaxing properties in animal studies and, untrammelled by the requirements of modern drug testing, Roche was able to market the drug as Librium just three years later.3
In the years that followed, Sternbach went on to make diazepam and some of its successors, including nitrazepam, flunitrazepam and clonazepam. Such was the instant success of Valium — dubbed “mother’s little helper” in a 1966 hit for the Rolling Stones — that other pharmaceutical companies quickly set about developing rival benzodiazepines.
They exert their anxiolytic and sedative effects by potentiating the inhibitory effects of gamma aminobutyric acid (GABA) on neuronal excitation via synaptic GABAA receptor complexes. The group is generally divided into short, intermediate and long-acting agents on the basis of their half life, with triazolam being among the shortest acting, while lorazepam and temazepam are intermediate acting, and chlordiazepoxide and diazepam are long acting.
By the mid-1970s, over 40 million benzodiazepine prescriptions were being written each year, but there had been hints of dependence and reports of psychiatric side effects of treatment almost from the start.
Professor Lader explains that doctors were aware that dependence had been seen with high doses of chlordiazepoxide used in a study in a US prison, but they understood that this was not the case with the lower doses of chlordiazepoxide and diazepam that were being used in everyday practice.
Even when it became clear that some patients did not want to stop taking their benzodiazepines, says Professor Lader, pharmaceutical companies offered reassurance that the drugs could not be addictive because patients were not demanding their doses be increased, which is the usual sign of addiction.
In 1980, the Committee for the Review of Medicines (CRM) warned against long-term use of benzodiazepines, highlighted the potential for withdrawal symptoms, such as anxiety, apprehension, tremor, insomnia and vomiting, and recommended that therapy should be withdrawn slowly when treatment was being stopped.4
The following year, two UK papers clearly demonstrated the withdrawal problems associated with stopping benzodiazepine treatment even when patients had been taking normal doses.5,6 But a survey of tranquilliser users carried out for the popular “That’s life” TV programme in 1984 showed that over 90 per cent of respondents had taken the drugs for periods of four months or more — the duration for which, the CRM noted, there was little evidence of efficacy.
In 1988, the Committee on Safety of Medicines (CSM) issued a warning to all doctors that, for anxiety, benzodiazepines should only be used for “short-term relief (two to four weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness”. For insomnia, it recommended that benzodiazepines should be used to treat symptoms that are severe, disabling, or subjecting the individual to extreme distress, and it advised that treatment should not continue beyond four weeks.
Of the large family of benzodiazepines that ultimately reached the market, four members have run into particular difficulties.
When triazolam was launched in 1979, it was claimed to have advantages over other sleeping pills because of its rapid onset and short half-life. But psychiatric side effects, such as memory loss and depression, proved more common than with rival compounds, and the CSM suspended the drug’s licence in 1991.
Flunitrazepam has become infamous as the “date-rape” drug. Soluble in alcohol, it also causes amnesia, leaving victims whose drinks have been spiked with the drug unable to remember what happened to them. In the US, it is classified as an illegal drug.
Lorazepam is a powerful anxiolytic but carries a higher risk of withdrawal problems than other benzodiazepines. It is favoured by patients subject to panic attacks associated with phobias, such as fear of flying, owing to its amnesic potential. It was one of two drugs — along with propofol — recently named as most likely to have been implicated in the death of Michael Jackson, although diazepam and midazolam were also found in the singer’s blood.
Temazepam remains the most popular sleeping tablet in the UK, but its intravenous use to potentiate the effects of heroin has caused deaths among drug abusers.
Benzodiazepine prescribing has fallen steadily in the past 20 years, although over 11 million prescriptions were issued in England in 2007 (nearly five million for diazepam and over three million for temazepam). Professor Lader points out that, even now, about a third of a million patients nationwide are started on these drugs annually. But the testimonies of patients dependent on the drugs or experiencing withdrawal problems continue to fill the websites of UK and international support groups. Tried-and-tested methods to wean patients off benzodiazepines have been published,7–9 but many continue to struggle.
Lesser of two evils
As a long-term critic of the way benzodiazepines have been used, does Professor Lader wish they had never been discovered?
“Compared with barbiturates, benzodiazepines were the lesser of two evils. For short-term treatment of sleep problems for up to two weeks, and anxiety for up to four weeks, they probably do more good than harm. But patients with mild to moderate symptoms should be getting psychological help and not taking drugs at all,” he says.
Professor Lader adds that it is the unpredictability of dependence problems that has been the undoing of the benzodiazepines. Although it is well established that alcohol abusers are more likely to have withdrawal problems, it has proved impossible to predict the other 10 per cent of benzodiazepine users who are at high risk of dependence.
He explains: “If benzodiazepine use had been controlled from the start, we might not have run into so many problems. We need to learn some lessons from the experience of benzodiazepines, but I’m not very optimistic that we won’t keep making the same mistakes.”
1. All-Party Parliamentary Drugs Misuse Group. An inquiry into physical dependence and addiction to prescription and over-the-counter medication. Available at www.drugscope.org.uk (PDF 700K)(accessed 11 September 2009).
2. Long–term prescribing tops list of medication error claims reveals MDU. Available at www.mdu.com (accessed 11 September 2009).
3. Sternbach LH. The benzodiazepine story. Journal of Medicinal Chemistry 1979;22:1–7.
4. Committee on the Review of Medicines. Systematic review of the benzodiazepines. BMJ 1980;280:910–2.
5. Tyrer P, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. The Lancet 1981;1:520–2.
6. Petursson H, Lader MH. Withdrawal from long-term benzodiazepine treatment. BMJ 1981;283:643–5.
7. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009;23:19–34.
8. Ashton H. The diagnosis and management of benzodiazepine dependence. Current Opinion in Psychiatry 2005;18:249–55.
9. Lader M. Tranquillizers and antidepressants: when to take them, how to stop. London: Sheldon Press; 2008.
Citation: The Pharmaceutical Journal URI: 10978453
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