A rticles in the Update series Les articles de la rubrique give a concise, authoritative. Le point fournissent un and up-to-date wurvev of the bhilan concis et fiable de la present position in the se- I .ituation actuelle dans le lected fields, and, over a domaine considere. Des ex- ,/t a e period of years, will cover perts couvriront ainsi .vucl- man v different aspe ts of cessivement de nombreux the biomedical sciences aspects des sciences bio- L e p ointt atid public health. .Mo.st oJf mdicales et de la sante the articles will be writ- publique. La plupart de ces ten, by invitation. bv ic- articles auront donc ete A/nowledged experts on the rediges stir demande par les subject. specialistes les plus autorises. Bulletin ofthe World Health Organization, 61 (4): 551 - 562 (1983) © World Health Organization 1983 Use and abuse of benzodiazepines* WHO REVIEW GROUP Benzodiazepines are widely used for the treatment of anxiety, insomnia, and certain neuromuscular and convulsive disorders. However, their widespread avail- ability has given rise to fears that they are over-prescribed. The problem is compounded by the fact that there is no universal agreement among medical prac- titioners as to the clinical indications warranting the use of these drugs. Although most industrialized countries exercise control over the sale and manufacture of benzodiazepines, many developing countries do not have sufficient control of these drugs. As a result, information on drug utilization and associated problems is diffi- cult to obtain and there is a lack ofcomparative data on drug consumption in differ- ent countries. The present article describes the current knowledge on the pharmacological, clinical, and epidemiological characteristics of benzodiazepines, and the problems associated with their use, and indicates areas where more research is needed. Recom- mendations are made forfuture work. The use and misuse of benzodiazepines represents a particularly complex problem, since there is no universal agreement among medical practitioners as to the clinical indications warranting their use. Although it is clear that the drugs are safe and effective in the treat- ment of anxiety, insomnia, and certain neuromuscular and convulsive disorders, their widespread availability has given rise to fears that they are over-prescribed. Further, reports of illegal diversion of various benzodiazepines to street use has been reported by various countries. Unfortunately, many countries do not have adequate drug surveillance operations, and it is therefore difficult to obtain reliable comparative data on drug use in different parts of the world. The present article summarizes knowledge on the pharmaco- logical, clinical, and epidemiological properties of the benzodiazepines, and the problems associated with their use, and indicates areas where more research is needed. * This article is based on the report of a Review Group which met in Geneva on 6-10 September 1982 (WHO unpublished document, MNH/82.44, 1982). The participants in the meeting are listed on pages 561-562. Requests for reprints should be addressed to Division of Mental Health, World Health Organization, 1211 Geneva 27, Switzerland. A French translation of this article will be published in a later issue of the Bulletin. 4314 -551 552 WHO REVIEW GROUP PHARMACOLOGY The benzodiazepines in current clinical use have a generally similar pharmacological profile; they produce sedative-hypnotic, anti-anxiety, anticonvulsant effects and induce muscle relaxation with minimal interference with locomotion. The behavioural effects of the benzodiazepines in laboratory animals are similar to those of barbiturates. Benzodiazepines are notable for their anti-aggressive effects. Studies using operant conditioning procedures have shown that benzodiazepines have different effects on positively and negatively reinforced behaviour, i.e., behaviour maintained by food delivery is generally reinforced by benzodiazepines while, at the same doses, there is reduced control of behaviour by noxious stimuli. The ability of the benzodiazepines to promote behaviour that has been suppressed by punishment is clearly documented and is of therapeutic relevance. Drug discrimination procedures have been shown to be useful in the characterization of drug classes,a and show promise for elucidating distinctive behavioural effects of the benzodiazepines. In drug discrimination procedures, animals are first trained to respond to a particular drug. The test drug is then administered, and is judged to produce discrim- inative stimuli similar to those produced by the training drug if it induces the drug-appro- priate response. The procedure provides information analogous to a human testing situ- ation in which subjects categorize drugs according to their subjective effects. It has thus been possible to train animals to discriminate a benzodiazepine from saline. When other drugs have been substituted in diazepam- or chlordiazepoxide-trained animals, the drug- appropriate response has occurred for all other benzodiazepines tested and for most other sedative-hypnotic drugs, but not for neuroleptics, thus indicating some specificity of effect. Although pentobarbital- and alcohol-trained animals also react to benzodiazepines under the drug discrimination procedure, animals can be trained to discriminate chlor- diazepoxide from pentobarbital. Thus, evidence exists for some differential, as well as common, attributes of the sedative-hypnotic drugs. Systematic comparison of 22 clinically used benzodiazepines was carried out in a series of pharmacological tests in animals, covering assessment of gross behavioural effects, anticonvulsant activity, potentiation of barbiturate-induced sleeping time, and sup- pression of righting reflex; the relative potency of the compounds was found to vary widely depending on the test used. Although definitive conclusions await further research, these results suggest that there may be important differences among benzodiazepines in their pharmacological effects. Benzodiazepines decrease sleep latency, increase time spent in sleep, increase rapid eye movement (REM) sleep latency, and reduce REM sleep. Sleep is less restless. There is an increase in stage 2 sleep while stages 3 and 4 are usually shortened. The drug withdrawal rebound phenomenon associated with many hypnotics is less frequently seen with benzo- diazepines. In animals and man, benzodiazepines prevent the subcortical spread of seizure activity. They strongly inhibit pentetrazol- and picrotoxin-induced seizures, but are less effective against the seizure activity induced by strychnine or electroshock therapy. In experimental models of epilepsy, all benzodiazepines suppress the spread of seizure activity produced by epileptogenic foci in the cortex, thalamus, and limbic structures but do not abolish the abnormal discharge of the focus. Benzodiazepines also suppress polysynaptic reflexes in the spinal cord and decrease neuronal activity in the mesencephalic reticular system. Benzodiazepines have no significant influence on respiration or cardiovascular function, when administered to human subjects in therapeutic doses by the oral route. However, a WHO Technical Report Series, No. 618, 1978. BENZODIAZEPINES 553 when administered intravenously, these drugs can cause respiratory depression. None of the benzodiazepines exerts a direct effect on the gastrointestinal tract. Benzodiazepines are generally well absorbed from the gastrointestinal tract but vary in their rate of absorption, systemic bioavailability, extent and pattern of metabolism and elimination, clearance, volume of distribution, and the rate at which they enter the brain. Certain benzodiazepines (e.g., clorazepate, halazepam) are relatively inactive prodrugs until converted in the body to more active forms. Such pharmacokinetic differences deter- mine the onset and duration of pharmacological effects. Compounds with a relatively slow onset of effect (e.g., halazepam, oxazepam, prazepam) are probably less likely to be abused than those with a more rapid onset (e.g., diazepam). Benzodiazepines vary in their pattern and rate of metabolism. Some, such as diazepam, are metabolized by N-desmethylation and hydroxylation; others, such as oxazepam, are conjugated with glucuronic acid to form water-soluble derivatives. Benzodiazepines vary widely in their plasma half-lives, diazepam having a half-life of 50 hours or more, triazolam having a half-life of a few hours. Furthermore, some have active metabolites (e.g., N-desmethyldiazepam) and others (e.g., oxazepam) do not. The effects of benzo- diazepines are usually prolonged in the elderly, partly because of slowed elimination. Two recent discoveries are potentially of great importance in elucidating the mechanism of action of benzodiazepines: the first was the close relationship between benzodiazepines and the GABAergic system, and the demonstration of specific high-affinity binding sites for the benzodiazepines. The physiological and clinical significance of these sites is shown by the high correlation between the behavioural effects and binding affinities of these compounds. More recently, several subtypes of receptors have been found with different distributions in the brain. Benzodiazepines vary in their relative affinities for these receptors and it has been suggested that this may be reflected in different pharmacological profiles. Some of the binding sites are in close proximity to the GABAergic system and have a functional relationship with GABAergic receptor-chloride