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Do the benzodiazepines still have a role in the treatment of GAD?
S.17 New treatment strategies in generalized
IS.17.041 Do the benzodiazepines still have a role in the treatment of GAD? M. Lader. Department of Psychiairy, Institute of-psychiatry, Kings College London, UK Generalized Anxiety Disorder (GAD) is a common condition that is mostly seen in the primary care setting. It is essentially a chronic but partially temitting illness with an estimated point prevalence among UK adults of about 3%. Among patients consulting their family physicians, the prevalence is about 15%. Only a small minority - the severely, chronically ill, treatment-resistant - are referred to a psychiatrist. Consequently, the risk/benefit ratio of any treatment must be assessed in the context of primary care and not from the viewpoint of the experienced specialist (Lader, 1994). A second consideration is that the optimum treatment for GAD is now generally considered to be a psychological technique such as CBT or IPT, with medication reserved for those with severe symptoms and/or incapacity, or who have failed an adequate application of a psychological treatment. Manifestly, drug treatment should not interfere with non-drug treatment (and vice-versa): preferably, the two treatments should potentiate each other. The benzodiazepines such as diazepam, lorazepam, alprazolam and clonazepam, are the most widely-available anxiolytic agents. In most countries, they are still the most widely-used. They have a rapid onset of action producing feelings of tranquillity often after a single dose. Their efficacy in short-term use (say, 4-8 weeks) is well-established although the effect size is not large and is superimposed on a substantial placebo effect/natural remission effect. Their efficacy in long-term treatment is less wellestablished, and issues of tolerance and dependence arise. Some patients, however, claim to derive continuing benefit from a dose of benzodiazepine within recommended limits. These drugs are associated with several potential problems including adverse events and dependence. The major ones are: Somatic: dizziness and ataxia, weight gain, rash, menstrual disturbances. Psychological: drowsiness, paradoxical anxiety or hostility. Psychomotor: impaired attention or coordination. Cognitive: amnesia, disrupted consolidation of learning, poor subjective memory. Drug interactions: potentiation of other CNS depressants, particularly alcohol. Tolerance, dependence and abuse: probable waning of efficacy, lessening of psychomotor but not cognitive effects. Low- and highdose physical dependence, abuse, common in association with alcohol or opioids. Most concern has attended the realisation that the benzodiazepines at therapeutic dose induce a state of physical dependence in upto 25% of long-term users (Hallstrom, 1993). The withdrawal syndrome is characterised by anxiety, phobias, insomnia, tremor, perceptual hypersensitivity, shakiness, nausea, loss of appetite and weight, impaired concentration, lethargy, tiredness and malaise, often severe. In most sufferers, the withdrawal syndrome lasts days or weeks but in an unfortunate minority, it may persist. It is difficult to predict who will have problems on discontinuation: the chronically depressed, those with a current or previous alcohol or sedative problem, and those with a “dependent” personality seem to tolerate withdrawal poorly and may revert to the benzodiazepiues, thereafter relying on them lifelong.
anxiety disorder
s173
Thus, benzodiazepines are effective symptomatic remedies in the short term. They are less effective in the long term and in many, but not all, patients their risks come to outweigh their benefits (Lader, 1998). This appraisal has also to be set against credible alternatives. Some sedative drugs such as hydroxyzine have been available for a very long time to treat symptomatic anxiety. Buspirone is a partial ~-HT~A agonist: improvement is slower than with the benzodiazepines. Antidepressants are being used increasingly in the treatment of GAD. Venlafaxine has recently been licensed for this indication in some countries. Other compounds include imipramine and clomipramine,, among the tricyclics, and most of the SSRIs, particularly paroxetine (Rickels et al., 1993). In patients with an admixture of phobic anxiety, the MAOIs have long been favoured by some practitioners despite the major side effects, drug and dietary interactions. The important issue is the relative safety of the antidepressants, particularly the SSRIs, in long term use. Although withdrawal symptoms can supervene, this is generally accepted as rebound rather than dependence. Does this leave a place for the benzodiazepines (Ashton, 1994)? Undoubtedly, if immediate relief is required, as in a severe stress reaction, or a flare-up of GAD symptoms, a benzodiazepine will secure a breathing space while another medication is instituted. The effects of the benzodiazepine are, however, widespread in the sense that the anxiolytic effect is accompanied by sedation and perhaps psychomotor and cognitive impairment. But this may be a worthwhile price to pay. Dosage and duration must be minimised. Patients with previous or current alcohol or sedative problems should not be prescribed benzodiazepines although they may importune for them. When instituting the benzodiazepine, it is important to prepare the patient to expect a short, clearly-defined course of treatment, which the practitioner then adheres to. At the same time, longer term therapy can be started as it may be 2 or more weeks before an adequate response is forthcoming. The drug of choice is probably an SSRI, or, in view of its proven efficacy, venlafaxine. Treatment may have to be long-term but this is justifiable as much long-term data have accrued. Once the anxiety has come under control, an integrated treatment plan should be drawn up combining drug and non-drug therapy. The benzodiazepines may interfere with psychological treatments by impairing learning. The SSRIs and venlafaxine seem innocuous in this respect. A challenging group of benzodiazepine patients are long-term users. Repeated attempts to wean them off the drug have failed and the decision has to be taken to allow them to continue. However, any escalation of dose should be avoided. Also, as the patient ages, tolerance to the benzodiazepine may lessen, with the risk of CNS toxicity. Careful monitoring is essential. In conclusion, the realisation of the adverse effects of the benzodiazepines, together with the advent of efficacious alternatives has continued to restrict their legitimate use. References
VI Ashton, H., 1994. Guidelines for the rational use of benmdiszepines. Drues 48. 2540. C., 1993. Benzodiazepine Dependence, Oxford Medical Publications, Oxford. I31 Lader, M., 1994. Benzodiazepines. A risk-benefit profile. CNS Drugs
PI Hall&o&, ,-
__
1.177-187
141 Lader, M., 1998. The nature and duration, of treatment for GAD. Acta Psychiatry Stand. 98 (supp. 393), 109-l 17. PI Rickels, K., Downing, R., Schweizer, E. et al., 1993. Antidepressants for the treatment of Generalized Anxiety Disorder. Arch. Gen. Psychiatry 50, 884-895.
IS.17.041 Do the benzodiazepines still have a role in the treatment of GAD? M. Lader. Department of Psychiairy, Institute of-psychiatry, Kings College London, UK Generalized Anxiety Disorder (GAD) is a common condition that is mostly seen in the primary care setting. It is essentially a chronic but partially temitting illness with an estimated point prevalence among UK adults of about 3%. Among patients consulting their family physicians, the prevalence is about 15%. Only a small minority - the severely, chronically ill, treatment-resistant - are referred to a psychiatrist. Consequently, the risk/benefit ratio of any treatment must be assessed in the context of primary care and not from the viewpoint of the experienced specialist (Lader, 1994). A second consideration is that the optimum treatment for GAD is now generally considered to be a psychological technique such as CBT or IPT, with medication reserved for those with severe symptoms and/or incapacity, or who have failed an adequate application of a psychological treatment. Manifestly, drug treatment should not interfere with non-drug treatment (and vice-versa): preferably, the two treatments should potentiate each other. The benzodiazepines such as diazepam, lorazepam, alprazolam and clonazepam, are the most widely-available anxiolytic agents. In most countries, they are still the most widely-used. They have a rapid onset of action producing feelings of tranquillity often after a single dose. Their efficacy in short-term use (say, 4-8 weeks) is well-established although the effect size is not large and is superimposed on a substantial placebo effect/natural remission effect. Their efficacy in long-term treatment is less wellestablished, and issues of tolerance and dependence arise. Some patients, however, claim to derive continuing benefit from a dose of benzodiazepine within recommended limits. These drugs are associated with several potential problems including adverse events and dependence. The major ones are: Somatic: dizziness and ataxia, weight gain, rash, menstrual disturbances. Psychological: drowsiness, paradoxical anxiety or hostility. Psychomotor: impaired attention or coordination. Cognitive: amnesia, disrupted consolidation of learning, poor subjective memory. Drug interactions: potentiation of other CNS depressants, particularly alcohol. Tolerance, dependence and abuse: probable waning of efficacy, lessening of psychomotor but not cognitive effects. Low- and highdose physical dependence, abuse, common in association with alcohol or opioids. Most concern has attended the realisation that the benzodiazepines at therapeutic dose induce a state of physical dependence in upto 25% of long-term users (Hallstrom, 1993). The withdrawal syndrome is characterised by anxiety, phobias, insomnia, tremor, perceptual hypersensitivity, shakiness, nausea, loss of appetite and weight, impaired concentration, lethargy, tiredness and malaise, often severe. In most sufferers, the withdrawal syndrome lasts days or weeks but in an unfortunate minority, it may persist. It is difficult to predict who will have problems on discontinuation: the chronically depressed, those with a current or previous alcohol or sedative problem, and those with a “dependent” personality seem to tolerate withdrawal poorly and may revert to the benzodiazepiues, thereafter relying on them lifelong.
anxiety disorder
s173
Thus, benzodiazepines are effective symptomatic remedies in the short term. They are less effective in the long term and in many, but not all, patients their risks come to outweigh their benefits (Lader, 1998). This appraisal has also to be set against credible alternatives. Some sedative drugs such as hydroxyzine have been available for a very long time to treat symptomatic anxiety. Buspirone is a partial ~-HT~A agonist: improvement is slower than with the benzodiazepines. Antidepressants are being used increasingly in the treatment of GAD. Venlafaxine has recently been licensed for this indication in some countries. Other compounds include imipramine and clomipramine,, among the tricyclics, and most of the SSRIs, particularly paroxetine (Rickels et al., 1993). In patients with an admixture of phobic anxiety, the MAOIs have long been favoured by some practitioners despite the major side effects, drug and dietary interactions. The important issue is the relative safety of the antidepressants, particularly the SSRIs, in long term use. Although withdrawal symptoms can supervene, this is generally accepted as rebound rather than dependence. Does this leave a place for the benzodiazepines (Ashton, 1994)? Undoubtedly, if immediate relief is required, as in a severe stress reaction, or a flare-up of GAD symptoms, a benzodiazepine will secure a breathing space while another medication is instituted. The effects of the benzodiazepine are, however, widespread in the sense that the anxiolytic effect is accompanied by sedation and perhaps psychomotor and cognitive impairment. But this may be a worthwhile price to pay. Dosage and duration must be minimised. Patients with previous or current alcohol or sedative problems should not be prescribed benzodiazepines although they may importune for them. When instituting the benzodiazepine, it is important to prepare the patient to expect a short, clearly-defined course of treatment, which the practitioner then adheres to. At the same time, longer term therapy can be started as it may be 2 or more weeks before an adequate response is forthcoming. The drug of choice is probably an SSRI, or, in view of its proven efficacy, venlafaxine. Treatment may have to be long-term but this is justifiable as much long-term data have accrued. Once the anxiety has come under control, an integrated treatment plan should be drawn up combining drug and non-drug therapy. The benzodiazepines may interfere with psychological treatments by impairing learning. The SSRIs and venlafaxine seem innocuous in this respect. A challenging group of benzodiazepine patients are long-term users. Repeated attempts to wean them off the drug have failed and the decision has to be taken to allow them to continue. However, any escalation of dose should be avoided. Also, as the patient ages, tolerance to the benzodiazepine may lessen, with the risk of CNS toxicity. Careful monitoring is essential. In conclusion, the realisation of the adverse effects of the benzodiazepines, together with the advent of efficacious alternatives has continued to restrict their legitimate use. References
VI Ashton, H., 1994. Guidelines for the rational use of benmdiszepines. Drues 48. 2540. C., 1993. Benzodiazepine Dependence, Oxford Medical Publications, Oxford. I31 Lader, M., 1994. Benzodiazepines. A risk-benefit profile. CNS Drugs
PI Hall&o&, ,-
__
1.177-187
141 Lader, M., 1998. The nature and duration, of treatment for GAD. Acta Psychiatry Stand. 98 (supp. 393), 109-l 17. PI Rickels, K., Downing, R., Schweizer, E. et al., 1993. Antidepressants for the treatment of Generalized Anxiety Disorder. Arch. Gen. Psychiatry 50, 884-895.