* Can be taken during the night, up to 5 h before vehicle driving.
dose may be repeated once in 10 min for status epilepticus or in 4 h for severe acute anxiety or agitation: midazolam is a shorter-acting alternative, e.g. for endoscopies. The dose should be titrated according to response, e.g. drooping eyelids, speech, response to commands. • Intramuscular injection of diazepam is absorbed erratically and may be slower in acting than an oral dose: lorazepam and midazolam i.m. are absorbed rapidly.
Tolerance to the anxiolytic effects does not seem to be a problem. In sleep disorders the situation is not so clear; studies of subjective sleep quality show enduring efficacy but about half of the objective (EEG) studies indicate decreased effects after 4-8 weeks, implying that some tolerance develops. That said, the necessity for dose escalation in sleep disorders is rare.
Dependence. Both animal and human research has shown that brain receptors do change in character in response to chronic treatment with benzodiazepines and therefore will take time to return to premedication levels after cessation of medication. Features of withdrawal and dependence vary. Commonly there is a kind of psychological dependence based on the fact that the treatment works to reduce patients' anxiety or sleep disturbance and therefore they are unwilling to stop. If they do stop, there can be relapse, where original symptoms return. There can be a rebound of symptoms, particularly after stopping hypnotics, where there is a worsening of sleep disturbance for one or two nights, with longer sleep onset latency and increased waking during sleep—this is common. In anxiety disorders there may be a few days of increased anxiety and edginess which then resolves, probably in 10-20% of patients. More rarely, there is a longer withdrawal syndrome characterised by the emergence of symptoms not previously experienced, e.g. agitation, headache, dizziness, dysphoria, irritability, fatigue, depersonalisation, hypersensitivity to noise and visual stimuli. Physical symptoms include nausea, vomiting, muscle cramps, sweating, weakness, muscle pain or twitching and ataxia. After prolonged high doses abrupt withdrawal may cause confusion, delirium, psychosis and convulsions. The syndrome is ameliorated by resuming medication but resolves in weeks; in a very few patients it persists, and these people have been the subject of much research, mainly focusing on their personality and cognitive factors.
Withdrawal of benzodiazepines should be gradual after as little as 3 weeks' use but for long-term users it should be very slow, e.g. about 0.125 (1/8) of the dose every 2 weeks, aiming to complete it in 6-12 weeks. Withdrawal should be slowed if marked symptoms occur and it may be useful to substitute a long \}/2 drug (diazepam) to minimise rapid fluctuations in plasma concentrations. Abandonment of the final dose may be particularly distressing. In difficult cases withdrawal may be assisted by concomitant use of an antidepressant.
Adverse effects. In addition to those given above, benzodiazepines can affect memory and balance. Hazards with car driving or operating any machinery can arise from amnesia and impaired psychomotor function, in addition to sleepiness (warn the patient). Amnesia for events subsequent to administration occurs with i.v. high doses, for endoscopy dental surgery (with local anaesthetic), cardioversion, and in these situations it can be regarded as a blessing.5
Women, perhaps as many as 1 in 200, may experience sexual fantasies, including sexual assault, after large doses of benzodiazepine as used in some dental surgery, and have brought charges in law against male staff. Plainly a court of law has, in the absence of a witness, great difficulty in deciding whom to believe. No such charges have yet been brought, it seems, by a man against a woman.
Paradoxical behaviour effects (see above) and perceptual disorders, e.g. hallucinations, occur occasionally. Headache, giddiness, alimentary tract upset, skin rashes and reduced libido can occur. Extrapyramidal reactions, reversible by flumazenil, are rare.
Benzodiazepines in pregnancy. The drugs are not certainly known to be safe and indeed diazepam is teratogenic in mice. The drugs should be avoided in early pregnancy as far as possible. It should be remembered that safety in pregnancy is not only a matter of avoiding prescription after a pregnancy has occurred but that individuals on long-term
5 Although one patient, normally a gentle man, believed he was being lied to when told his endoscopy had been performed. 'He assaulted his physician and was calmed only by a second endoscopy.' Later he was very embarrassed and apologised repeatedly (Lurie Y et al 1990 Lancet 336: 576). Another post-dental surgery patient purchased a bone china teaset and later condemned his wife for extravagance.
therapy may become pregnant. Benzodiazepines cross the placenta and can cause fetal cardiac arrhythmia, and muscular hypotonia, poor suckling, hypothermia and respiratory depression in the newborn.
Interactions. All potentiate the effects of alcohol and other central depressants, and all are likely to exacerbate breathing difficulties where this is already compromised, e.g. in obstructive sleep apnoea.
Overdose. Benzodiazepines are remarkably safe in acute overdose and the therapeutic dose x 10 induces sleep from which the subject is easily aroused. It is said that there is no reliably recorded case of death from a benzodiazepine taken alone by a person in good physical (particularly respiratory) health, which is a remarkable tribute to their safety (high therapeutic index); even if the statement is not absolutely true, death must be extremely rare. But deaths have occurred in combination with alcohol (which combination is quite usual in those seeking to end their own lives) and from complications of prolonged unconsciousness. Flumazenil selectively reverses benzodiazepine effects and is useful in diagnosis and in treatment (see below).
Temazepam is a benzodiazepine that was until recently the most popular hypnotic in the form of a soft gel liquid-filled capsule but, being readily injected, it was widely also abused and the formulation was withdrawn. Temazepam is now classed as a controlled drug; it is available as a tablet, with a much longer absorption time and duration of action making daytime hangover effect more likely. Consequently it is much less often prescribed.
Benzodiazepine antagonist: flumazenil is a competitive antagonist at benzodiazepine receptors and it may have some agonist actions, i.e. it is a partial agonist. Clinical uses include reversal of benzodiazepine sedation after endoscopies, dentistry and in intensive care. Heavily sedated patients become alert within 5 minutes. The t/ of 1 h is much shorter than that of most benzodiazepines (see Table 19.8), so that repeated i.v. administration may be needed. Thus the recovery period needs supervision lest sedation recurs; if used in day surgery it is im portant to tell patients that they may not drive a car home. The dose is 200 micrograms by i.v. injection given over 15 seconds, followed by 100 micrograms over 60 seconds if necessary, to a maximum of 300-600 micrograms. Flumazemil is useful for diagnosis of self-poisoning and also for treatment, when 100-400 micrograms are given by continuous i.v. infusion and adjusted to the degree of wakefulness.
Adverse effects of flumazenil can include brief anxiety, seizures in epileptics treated with a benzodiazepine and precipitation of withdrawal syndrome in dependent subjects. Rarely, vomiting is induced.
Nonbenzodiazepine hypnotics that act at the GABAA-benzodiazepine receptor
Although structurally unrelated to the benzodiazepines, these drugs act on the same macromolecular receptor complex but at different sites from the benzodiazepines; their effects can be blocked by flumazenil, the receptor antagonist. Those described below are all effective in insomnia, have low propensity for tolerance, rebound insomnia, withdrawal symptoms and abuse potential but there are few data of their effects in long-term studies.
Zopiclone is a cyclopyrrolone in structure. It has a fairly fast (about 1 hour) onset of action which lasts for 6-8 hours, making it an effective drug both for initial and maintenance insomnia. It may cause fewer problems on withdrawal than benzodiazepines. Its duration of action is prolonged in the elderly and in hepatic insufficiency. About 40% of patients experience a metallic aftertaste. Care should be taken with concomitant medication that affects its metabolic pathway (see Table 19.2a). The dose is 3.75-7.5 mg p.o.
Zolpidem is an imidazopyridine in structure and has a fast onset (30-60 min) and short duration of action. Patients over 80 years have slower clearance of this drug.
Zaleplon is a pyrazolopyrimidine. It has a fast onset and short duration of action. Studies of psychomotor performance in volunteers have shown that it has no effect on psychomotor skills, including driving skills, when taken at least 5 hours before testing. This means that it can be taken during the night (either when patients have tried getting off to sleep for a long time, or if they wake during the night and cannot return to sleep) without hangover effect.
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