Brotizolam: review of clinical studies.

It is perhaps in the development of hypnotics that the most critical appraisal of a new drug is likely to be encountered. Considerable expertise is now brought to bear on their assessment from the many disciplines within pharmacokinetics and pharmacodynamics, and many believe that we already have too many, though often the advantage of different drugs in the management of insomnia is not entirely appreciated. Uncertainty concerning the place of hypnotics in the management of sleep difficulties has also arisen because insomnia itself and its many manifestations are little understood. Transient insomnia in an active individual involved in skilled work presents a very different problem from that of recurring insomnia in patients with anxiety, and, as hypnotics have different profiles, it is important that the nature of the sleep disturbance is understood before such drugs are used. As far as transient insomnia is concerned it is necessary to decide whether the sleep disturbance involves difficulty in falling asleep or in staying asleep. The question must also be answered whether a drug will be used only occasionally or whether it may be needed repeatedly, and whether the nature of the daytime work is such that any residual sedative effect must be avoided. Further, in some patients anxiety may be the symptom of primary concern. All these aspects must be borne in mind because appropriate management depends on the clinical picture. Duration of action is particularly relevant to the use of hypnotics, and over the past few years the factors which influence duration of action have become increasingly clear. Hypnotics with persistent activity extending well into the next day have a part to play in the treatment of insomnia-especially if there is an anxiety component-even though they are likely to accumulate with daily ingestion, but there is increasing awareness that hypnotics with a relatively rapid fall in plasma level due either to a sustained distribution phase or to rapid elimination are appropriate to the management of transient insomnia. Drugs which are rapidly eliminated-sometimes called the third generation of hypnotics-include brotizolam. However, even within this group, the various drugs have different rates of decay of plasma levels and so they may sustain sleep to varying degrees. It is in the context of sustaining sleep during the night without residual effects the next day that brotizolam may have a particular place in therapeutics. Brotizolam has high affinity to the benzodiazepine receptor. It is a potent hypnotic which is extensively absorbed and it is metabolised into hydroxylated compounds which are rapidly eliminated. It is free of long-acting metabolites, and with multiple dose treatment there is no tendency for accumulation. Using radio receptor assay the decay of the active hypnotic principle is estimated around 5 h. The elimination half-life is slightly longer in the elderly, but it is still relatively rapid, and so accumulation with daily use is unlikely. There is also no accumulation in renal failure even with creatinine clearances of less than 15 mg min-', and so no dose adjustment is required when brotizolam is used in renal failure. However, in some patients with cirrhosis there may be a decrease in clearance, and lower doses should be used. The initial studies in man were concerned with the activity of brotizolam over the dose range 0.1 to at least 0.5 mg, and subsequent studies on sleep and on performance in healthy subjects have indicated that the most useful dose is likely to be around 0.25 mg. With 0.25 mg, brotizolam reduces sleep onset latency, increases total sleep time, improves the sleep efficiency index, reduces drowsy sleep and the number of awakenings. There is some delay to the first period of rapid eye movement sleep-as is seen with most, if not all, benzodiazepines-but this is without any reduction in the total amount of rapid eye movement sleep and there is no reduction in slow wave sleep. With 0.25 mg there are no residual effects the next day, and there is no evidence of rebound insomnia on withdrawal after repeated ingestion. However, though with a higher dose (0.5 mg) the hypnotic effect may be more pronounced, there is reduced rapid eye movement and slow wave sleep, as well as residual effects the next day and the possibility in some individuals of rebound insomnia on withdrawal. It is therefore clear from studies in both healthy subjects and in insomniacs that the most appropriate dose of brotizolam is 0.25 mg. At this dose it is effective, free of adverse effects on the sleep process, without residual effects the next day and free of accumulation on repeated ingestion and of rebound phenomena on withdrawal. Clinical studies have confirmed these findings. In a long-term study in hospitalized patients complaining of sleep disturbances four-fifths of the patients used 0.25 mg daily over several months, and there was no evidence of a trend towards an increase in dose. Some of the patients required only 0.125 mg. About one-