2.5.4 Dependence
Dependence on benzodiazepine hypnotics can develop if the drugs are taken regularly for several weeks.[4] Many long term users are reluctant to withdraw the drugs because of rebound insomnia. Withdrawal from benzodiazepine hypnotics in dependent users may also give rise to anxiety and other typical withdrawal symptoms.[31-35]
2.5.5 Respiratory Depression
Benzodiazepines can cause respiratory depression and decrease the ventilatory response to hypercapnia[34] and increase hypopnoeic episodes during; sleep.[35] Like other drugs which depress respiration they should be avoided in patients with severe chronic obstructive airways disease.
2.6 Choice of Benzodiazepine Hypnotic
For an hypnotic drug, a rapid onset combined with a medium duration of action is usually desirable. Temazepam, loprazolam and lormetazepam meet these criteria (Table II). Temazepam tablets act as rapidly as when the drug is administered in soft gelatine capsules. The tablets also have less abuse potential and can be cut in half to minimise dosage.
Rapidly eliminated benzodiazepines, such as triazolam, can impair memory the next day,[26,28] give rise to daytime anxiety,[25] and probably carry a greater dependence risk.[1] Oxazepam is not recommended as it has a relatively slow onset of action. Nitrazepam is only slowly eliminated. Diazepam acts rapidly and, although slowly eliminated, does not have a prolonged action when used in single doses.
Doses should be minimised to avoid residual effects (especially important for drivers, airline pilots, and machinery operators) and the patient should be warned about additive effects with alcohol and other depressants. Recommended dosage schedules are shown in Table II.
2.6.1 The Elderly
The elderly are especially vulnerable to adverse effects of hypnotic drugs. Rates of metabolism of benzodiazepines that are oxidised (diazepam, nitrazepam) decline with age.[35,36] Elderly patients are also more susceptible to CNS depression and may develop confusional states and ataxia, leading to falls and fractures.[37] They are sensitive to respiratory depression and prone to sleep apnoea and other sleep disorders.[38]
However, insomnia is particularly common in this age group and regular hypnotics may sometimes be indicated if sleep disturbance is distressing. Temazepam, lormetazepam and loprazolam (which do not have pharmacologically active metabolites) remain suitable choices. but dosage should be adjusted, usually to half the recommended adult dose.
2.6.2 The Young
Hypnotics are generally contraindicated for children. Sedative antihistamines are commonly used if sedation is required, but a single dose of a benzodiazepine, with suitable dosage reduction, may be more effective.
2.6.3 Pregnancy and Lactation
Regular use of hypnotics in pregnancy is contraindicated as the drugs readily traverse the placenta. Intermittent doses of relatively rapidly eliminated benzodiazepines have been shown to be safe during breastfeeding.
2.6.4 Disease States
Benzodiazepines are rarely helpful in insomnia due to organic disease and may depress respiration in chronic pulmonary disease. However, in terminal conditions, the possibility of drug dependence becomes less important and regular use of hypnotics should not be denied if they provide symptomatic relief.
2.6.5 Withdrawal of Benzodiazepine Hypnotics
Many patients who have taken benzodiazepine hypnotics nightly for years can have the drugs withdrawn successfully (see section 3.5.2). Often there is surprisingly little sleep disturbance if withdrawal is carried out sufficiently slowly. Many patients find they actually sleep better without the drugs. The use of liquid preparations of temazepam, nitrazepam or diazepam facilitates small dosage reductions. However, unmotivated patients (often elderly patients who have taken hypnotics for years) should not be forced to withdraw these agents against their will simply because they are dependent. Long term prescriptions (in minimal dosage) are sometimes necessary.
2.6.6 Alternatives to Benzodiazepines
Benzodiazepines compare favourably with other hypnotics in efficacy and safety. They have fewer adverse effects than chlormethiazole and chloral derivatives and are more efficacious than sedative antihistamines.[4] Zopiclone, which has a similar mechanism of action, is expensive and is not free of dependence liability and other adverse effects.[39,40] Although antidepressants and antipsychotics may improve sleep in patients with depression or psychosis, they are more toxic than benzodiazepines and should not be used as general hypnotics, but reserved for patients with disorders for which these drugs are specifically indicated.
3. Rational Use of Benzodiazepines for Anxiety
Official recommendations on the use of benzodiazepines in anxiety are similar to those for insomnia. The UK Committee on Safety of Medicines[2] advised that they 'are indicated for the short term relief (2-4 weeks only) of anxiety that is severe, disabling or causing unacceptable distress'. To a considerable extent this advice appears to have been heeded and yearly prescriptions for benzodiazepine anxiolytics have decreased in the UK from a peak of 18 million in 1978 to less than 10 million at present. There is no doubt that benzodiazepines can be highly efficacious in anxiety. The indications for their rational use in different types of anxiety disorders have become clearer in recent years. [41,42]
3.1 Prevalence of Anxiety
Anxiety symptoms are common in the general population. Uhlenuth et al.[43] estimated the prevalence of generalised anxiety disorder among US adults to be 6.4%, while another 3.5% experienced panic, agoraphobia and other phobias. Prevalence (often elderly patients who have taken hypnotics for years) should not be forced to withdraw these agents against their will simply because they are dependent. Long term prescriptions (in minimal dosage) are sometimes necessary.
3.2 Classification of Anxiety
There is still some controversy about how anxiety states should be classified. Anxiety disorders recognised on the DSM-III-R criteria [45] include generalised anxiety disorder, panic disorder, agoraphobic disorder, social phobia, simple phobia and post-traumatic stress disorder. Generalised anxiety is the most common of the disorders, but Tyrer [46,47] stresses the considerable overlap of symptoms between different anxiety disorders, as well as the co-occurrence of depressive symptoms. He argues for a simple descriptive term, the generalised neurotic syndrome, to encompass most categories.
Acute stress reactions and post-traumatic stress disorder, which may persist as adjustment disorders, are clearly precipitated by major life events, but the reasons for anxiety in generalised anxiety disorder, panic and phobias is usually not known.[47] Vulnerability to stress may be linked with genetic factors[48] and environmental influences. Most patients with anxiety symptoms have a long history of high anxiety levels going back to childhood.
Management of anxiety conditions, however classified or caused, usually calls for nondrug measures that may range from simple counselling to specific psychological techniques. The latter may include anxiety management training, behaviour or cognitive therapy. Drug treatment may also be indicated and the range of effective drugs includes benzodiazepines, antidepressants, antipsychotics and (ß-blockers, each with its own advantages, disadvantages and specific indications.[47] Possible alternatives include buspirone and some newer anxiolytics likely to be introduced soon (alpidem, suriclone and others).[49,50]
3.3 Effects of Benzodiazepines on Anxiety
Benzodiazepines are potent anxiolytic agents and are effective both in otherwise-healthy patients undergoing stress and in anxious patients. Anxiolytic effects are exerted in doses that cause minimal sedation, although the hypnotic, muscular relaxant and perhaps amnesic actions may all contribute to relief of associated tension and insomnia. The relatively selective effect on anxiety is probably related to the fact that benzodiazepines suppress activity in many limbic and other brain areas involved in anxiogenesis, including the septal area, amygdala, hippocampus, hypothalamus, locus coeruleus and raphé nuclei. They also decrease the turnover of acetylcholine, norepinephrine (noradrenaline), serotonin (5-hydroxy-tryptamine, 5-HT) and dopamine in these areas.[51] Suppression of noradrenergic and/or serotonergic pathways appears to be of particular importance in relation to anxiolytic effects.
The major clinical advantage of benzodiazepines as anxiolytics is the rapid onset of action, usually apparent after a single dose. This immediate effect contrasts with the delayed anxiolytic effects of antidepressants, buspirone and psychological treatments. In addition, benzodiazepines are relatively non-toxic and safer than most of the alternative drugs. Their immediate efficacy and safety combine to make benzodiazepines the drugs of first choice for rapid relief of anxiety that is unacceptably distressing, whatever the cause.
As in insomnia, benzodiazepines provide only symptomatic treatment for anxiety; they do not cure the underlying disorder. Nevertheless they can provide valuable short term cover, allowing time for more specific treatments to take effect, and can alleviate exacerbations of anxiety which are often self-limiting.
3.4 Disadvantages of Benzodiazepine Anxiolytics
3.4.1 Tolerance
Tolerance to the anxiolytic effects of benzodiazepines seems to develop more slowly and less completely than to the hypnotic effects. There is, however, little evidence that they retain their effectiveness after 4 months of regular treatment.[52,53] While some studies indicate that anxiolytic effects are maintained for at least 22 weeks in chronic anxiety states,[54] clinical observations of long term recipients of these agents suggest that the prolonged benzodiazepine use over years does little to control and may even aggravate anxiety states.[55]
The question remains controversial.[44,56] but there is general agreement that benzodiazepine use in most anxiety states should be limited where possible to short term (ideally not more than 4 weeks) or intermittent courses.[2,41,42,47]
![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")
