Anxiety is a commonly experienced emotion that becomes a clinical disorder when it is too severe, too protracted, or too pervasive for the subject to bear. Insomnia is a failure to experience satisfying sleep, together with a feeling of tiredness during the day. Many compounds, the anxiolytics and hypnotics, are used to treat these conditions, but the two groups of drugs overlap.

The classical antianxiety drugs (anxiolytics) are alcohol, the opioids, and the barbiturates. For the past 45 years, the benzodiazepines, such as diazepam and lorazepam, have dominated the field. They are effective anxiolytics in the short term but their long-term efficacy remains in dispute. Their disadvantages include cognitive and psychomotor impairment, paradoxical reactions, tolerance, and dependence, and they are major drugs of abuse.

Other anxiolytics act on the 5-hydroxytryptamine (5-HT; serotonin) systems of the brain and include buspirone and the selective serotonin reuptake inhibitors (SSRIs). Newer compounds are still being introduced that lie outside these groups.

The use of benzodiazepine and benzodiazepine-like hypnotics, by contrast, continues apace. Some switching to the shorter-acting benzodiazepines has occurred, together with the introduction of the ‘z-compounds’, zopiclone, zolpidem, and zaleplon. These drugs tend to have fewer residual effects the next day than the benzodiazepines, and are claimed to be less likely to induce rebound and dependence than equivalent benzodiazepines. Particular care is needed in prescribing such hypnotics to the elderly.

The rational use of both anxiolytics and hypnotics requires minimal dosage, short durations of use, and simultaneous exploitation of non-pharmacological methods.

‘Sedative’ originally meant a substance that has the property of allaying anxiety. However, it has now come to denote feelings of drowsiness or torpor. This state was originally called ‘oversedation’, and was often noted with the barbiturates and other older drugs such as chloral. Next, the term ‘tranquillizer’ was introduced 40 or more years ago in an attempt to distinguish between the older sedatives and the newer drugs, supposedly non-sedative, such as the benzodiazepines. But this distinction is artificial as, apart from safety in overdosage, the benzodiazepines closely resemble the barbiturates in pharmacological and clinical properties. The term ‘anxiolytic’ is now generally favoured.

Anxiety-allaying drugs have been used for thousands of years, dating back to the discovery that, among its psychotropic properties, alcohol could induce sedation. The nineteenth century saw the development of inorganic and, later, organic chemical compounds. Bromides were introduced as sedatives and became widely used despite their poor effectiveness, toxicity, and potential abuse. Organic chemists in the second half of the nineteenth century introduced sedatives such as chloral and paraldehyde.

The first barbiturate was introduced over a 100 years ago. This group of drugs is divisible into the ultrashort-acting (e.g. anaesthetic-induction agents such as thiopentone and methohexital), short-acting (e.g. secobarbital), medium-acting (e.g. butobarbital), and long-acting (e.g. phenobarbital) barbiturates. Most of the rest are of medium duration with half-lives of 16 h or so. The disadvantages of the barbiturates include drowsiness, tolerance to their effects, dangers of overdose, and possible physical and psychological dependence with severe withdrawal syndromes.⁽¹⁾ Meprobamate was introduced as the first of the ‘tranquillizers’, but its advantages over the barbiturates proved minimal.

The benzodiazepines were first synthesized in the 1930s, but not developed until 2 years later. The prototype, chlordiazepoxide, was evaluated in the clinic, found effective, and soon introduced into medical practice. More than 1000 benzodiazepines and related compounds have been synthesized, including diazepam, the most widely used of all. Anxiolytic and hypnotic, as well as muscle-relaxant and anticonvulsant properties are licensed indications. However, the distinction between anxiolytic and hypnotic uses often seems to owe more to commercial expediency than to scientific rationale; some compounds, such as lorazepam, are marketed for both indications.

The main groups of drugs used in the modern treatment of insomnia are the benzodiazepines, and the newer compounds, zopiclone, eszopiclone, zolpidem, and zaleplon. The pharmacology of these benzodiazepines is essentially the same as that of the anxiolytic compounds.

Nitrazepam is a long-acting benzodiazepine with an elimination half-life ranging between 25 and 35 h, but it is longer in the elderly. Because of this, it is likely to produce residual effects and to accumulate. Flunitrazepam is more potent, but is somewhat shorter acting with a half-life of 10 to 20 h. It has a rapid redistribution phase, which can result in a short duration of intense action. It has earned an undeserved reputation as the ‘date-rape’ drug. Flurazepam is still widely used in the United States. It has a very long-acting metabolite, which can produce psychological impairment on regular dosage, especially in the elderly. Of the intermediateacting compounds, temazepam has a half-life of 10 to 15 h, without active metabolites. At modest dose (10-15 mg daily), it results in few residual effects and is fairly well tolerated by the elderly. Major problems with abuse have limited its popularity, but it is still widely prescribed worldwide. Lormetazepam is slightly shorter acting, loprazolam has a fairly short half-life, but its absorption may be slow and erratic.

Triazolam is the archetypal short-acting benzodiazepine, with a mean half-life of around 3 to 4 h, and no clinically significant metabolites. Daytime sedation is seen after high doses (0.5 mg daily), but not usually with lower ones. These higher doses have also been associated with an increased incidence of anterograde amnesia and unusual behaviours, including depressive reactions and hostility.

Zopiclone is a cyclopyrrolone derivative believed to bind close to, but not exactly at, the benzodiazepine receptor. It has a half-life of about 5 h in younger subjects and about 8 h in the elderly. Its sedative and hypnotic effects are similar to those of the benzodiazepines, but its side effect profile is generally superior with fewer central nervous system effects such as oversedation, confusion, and memory impairment. Rebound and withdrawal problems also seem to be less.

Eszopiclone is the S-enantiomer of zopiclone, which is a racemic mixture. It is licensed for the long-term treatment of insomnia in the United States, following successful clinical trials.

Zolpidem is an imidazopyridine compound that binds selectively to one subtype of the benzodiazepine receptor. It is rapidly absorbed and has a short elimination half-life of 0.7 to 3.5 h (mean 2.4 h). It decreases sleep-onset latency but has less consistent effects on total sleep time.⁽⁵⁾ Residual effects are minimal, as are memory disturbances. Rebound and withdrawal are uncommon but have been documented.

Zaleplon is also a selective compound with a very short half-life averaging only 1 h. It shortens sleep onset without usually prolonging total sleep time. Residual effects are absent, and memory is minimally disturbed.

Although the usual licensed indications are generalized anxiety and panic disorder,^(6,7) the main practical application of the benzodiazepines is to aid in the symptomatic management of anxiety and stress-related conditions.⁽⁸⁾ These indications are often so wide as to be difficult to define in terms of recognized disorders. Instead the symptoms of anxiety, in whatever context, are the main indication.
Thousands of comparative trials among the benzodiazepines have been carried out, but few differences with respect to risk-benefit ratios have been found.

Antianxiety medications are difficult to assess. Anxiety disorders are very varied in their natural history; some resolve over a few weeks, whereas others become chronic for no apparent reason, with subsequent acute-on-chronic exacerbations. The patients with chronic, severe unresponsive illnesses tend to be referred to psychiatric outpatient departments. Uncontrolled observations on family practice patients will give a more encouraging impression of antianxiety drugs than will assessment of the more chronic patients attending psychiatric clinics. Even in the latter type of patient, useful symptomatic relief is often obtained without complete resolution of the illness.

Drugs such as diazepam have a long elimination half-life so that once daily or nightly dosage is sufficient. Nevertheless, many patients prefer to take a divided dosage during the day, often claiming that they can detect further antianxiety activity after each dose and are thereby reassured. For episodic anxiety, shorter-acting compounds such as lorazepam can be used, taken 30 min or so before entering the anxiety-provoking situation. If the panic has already started, lorazepam can still be given and will exert a fairly prompt action. Lorazepam is also invaluable in the emergency management of the acutely anxious and disturbed psychotic patient.

Antipanic actions have been claimed for the benzodiazepines, in particular alprazolam, acting to prevent the episodes rather than aborting them. However, although suppression of the panic attack is often quite effective, relapse, and even rebound may occur when the benzodiazepine is discontinued, even if it is tapered off.⁽⁹⁾ Because of this SSRI antidepressants are generally preferred.⁽⁷⁾

The short-acting benzodiazepines are also used as adjuncts to relaxation therapy, preoperative medication, and deep sedation for minor operative procedures such as dentistry. The drugs render the patient calm, conscious, and cooperative, with often total anterograde amnesia for the operation.