- Email: [email protected]
Restrictions on benzodiazepine use: Do they make sense?
SlO8
S.21 A review of the place of the benzodiazepines
in males, genetic loading, and grossly normal neuroanatomy observed in this disorder. This presentation will suggest that abnormalities in the neural pathways for either oxytocin or vasopressin could account for many and perhaps all of these aspects of autism. Animal studies with these neuropeptides have demonstrated their importance for social bond formation, memory, and species-typical motor patterns. In addition, vasopressin appears sexually dimorphic with greater levels of gene expression in males. Recent studies of the genes for oxytocin and vasopressin receptors suggest that the promoter regions of these genes are highly variable across species and may show variation within human populations, providing a potential model for individual differences in social or cognitive b&on. The available data suggest that these neurpeptide systems may be reasonable candidates for further study in autistic patients and their families. References [l] Insel TR, O’Brien D, L&man J. Oxytocin, vasopressin, a connection? Biological Psychiatry, in press.
Each mention of a medication to be administered alone or as part of a combination was counted. Medications were grouped by class. The table below displays the percentage of drug mentions for a disorder attributable to each drug class shown, by year. The major findings are: Mentions of tricyclic antidepressants (TCAs) as a preferred first-line pharmacotherapy for anxiety disorders declined by about half from 1992 to 1997. Selective serotonin reuptake blockers (SSRls) were mentioned as a preferred first-line pharmacotherapy for anxiety disorders 3 to 8 times more often in 1997 than in 1992. Mentions of benzodiazepines (Benzos) as a preferred first-line pharmacotherapy for anxiety disorders hardly changed in frequency from 1992 to 1997. Benzodiazepines were mentioned more often than any other class of drugs as a preferred first-line pharmacotherapy for anxiety disorders, except obsessive-compulsive disorder.
and autism: Is there Year
Dw class
Panic disorder
GAD
phobia
42 16 4 34 39 39
40 20 6 35 44 40
30 15 3 26 47 43
Agora-
S.21 A review of the place of the
benzodiazepines Is.21.Ol 1Trends
in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997
E.H. Uhlenhuth, M.B. Balter, T.A. Ban, K. Yang. Unioersity of New Mexico, School of Medicine, Department of Psychiatry, Albuquerque, NM, USA Objectives: In our view, the 3 factors that have the greatest impact on treatment with psychotherapeutic medications are the findings of clinical research, governmental regulations, and personal clinical experience. The first 2 are well recognized and form the basis for officially approved clinical practice. However, clinical experience, which is at least of equal importance, remains greatly underutilized because it has not been systematically gathered, quantitatively analyzed, and widely disseminated. These considerations led us to conduct an international survey study of expert judgment on the therapeutic use of benzodiazepines and other psychotherapeutic medications. The specific aims of this study were to: . Provide a representative body of expert judgment on the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. . Focus principally on the pharmacotherapy of the anxiety disorders. Method: A panel of psychiatrists was constituted by a peer nomination process. The criteria for nomination to the panel were “theprofessionally most respected physicians of the world with extensive experience and howledge in the pharmacotherapy of anxiety and depressive disorders.” The process began with leading clinical psychopharmacologists in 44 countries as initial nominators, and the final panel included 73 experts from 25 countries. The data were collected in 1991-1992 by means of a self-administered questionnaire, sent in the mail. It covered a wide variety of issues in the pharmacotherapy of anxiety disorders and required at least 4 hours to complete. There was no prior communication with the experts, and their names were kept strictly confidential until the initial results were published. Each respondent was paid $750 after the questionnaire was completed and returned. The response rate was 90% (66/73). In 1997, a short follow-up questionnaire was sent to the original 66 participants to assess whether their recommendations for treating anxiety disorders had changed during the 5 year interval, a period when many new antidepressants came into widespread use. The follow-up questionnaire included 7 case vignettes from the original study depicting typical anxiety disorders, each followed by questions on recommendations for management. Fifty-one of the original 66 panelists participated, for a response rate of 77%. Results: The results presented here are based on responses to a question about the preferred first-line pharmacotherapy for each case.
TCAs SSRlS Benzos
I992 1991 I992 1997 1992 I997
Social phobia
Discrete OCD phobia
Adjustment
IO 5 3 25 25 26
I5 II II 30 53 44
14 3 3 8 71 79
64 38 19 52 II 9
Conclusions: Over the past 5 years, selective serotonin reuptake inhibitors displaced tricyclic antidepressants as the experts’ choices for tit-line pharmacotherapy of anxiety disorders. . According to the experts’ judgements, the benzodiazepines remain a mainstay of pharmacotherapy for anxiety disorders, except obsessivecompulsive disorder.
??
References [1] Balter MB, Ban TA, Uhlenhuth EH (1993). International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications. 1. Current concerns. Human Psychophunnacology 8: 253-261. [2] Uhlenhuth EH, Baker MB, Ban TA, Yang K (1995). International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications. II. Pharmacotherapy of anxiety disorders. J Afictive
Disord 35: 153-162. [3] Uhlenhuth EH, Baiter MB, Ban TA, Yang K (1995). International
study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications. III. Clinical features affecting experts’ therapeutic recommendations in anxiety disorders. Psychopharmacol Bull 3 I: 289-296.
-1
Restrictions sense?
on benzodiarepine
use: Do they make
M. Lader. Institute of Psychiatry London SE5, UK The benzodiazepines, once the most widely-prescribed of all medications, have fallen into increasing disfavour. Two indications will be examined, anxiety disorders and insomnia. Restrictions on the usage of benzodiazepine in clinical practice relate to the indication, dose and duration of use. Thus, the indication is generally taken to refer to anxiety or insomnia which is “severe, disabling or subjecting the individual to extreme unacceptable distress”. The duration is “short-term” (24 weeks) in anxiety and “as short as possible” (a few days to two weeks) for a hypnotic. The dosage should be the “lowest to control symptoms”. These restrictions refer to UK Data Sheets but other countries have similar caveats. In addition, the benzodiazepines are controlled drugs, a reflection of their abuse potential that has been recognised internationally. Such restrictions can be evaluated initially in terms of the risk/benefit characteristics of the benzodiazepines in relation to the severity and
S.21 A review of the place of the benzodiazepines chronic@ of anxiety and insomnia indications (Lader, 1994). The last can be viewed in terms of symptomatic distress and social and occupational handicaps. The efficacy of benzodiazepine anxiolytics and hypnotics is wellestablished for short-term use, although the non-specific effects such as the placebo response are substantial. However, after a few nights’ use as an hypnotic and a few weeks’ use as an anxiolytic, efficacy wanes although its evaluation becomes confounded by discontinuation phenomena. Long-term efficacy is thus debatable. The unwanted effects of the benzodiazepines are well-catalogued and comprise subjective sedation together with objective psychological impairment. This translates into real-life problems such as increased risk of accidents. Tolerance occurs to most of these side-effects with the notable exception of memory disturbances (Curran, 1991). These risks are strongly dose-related. Less frequent and predictable are paradoxical reactions with heightened anxiety and aggression. Drug interactions mainly relate to other sedative compounds, in particular, alcohol. Even the safety in overdose of the benzodiazepines has been questioned. Discontinuation phenomena comprise rebound of insomnia and anxiety, particularly noticeable with short acting hypnotics. This merges into withdrawal in which newly-emergent symptoms, typically perceptual, plague a proportion (upto a half) of patients discontinuing normal therapeutic doses (Michelini et al, 1996). Again this problem is strongly closerelated and withdrawal may be protracted. Relapse of the underlying condition may complicate the picture. Although the risk/benefit ratio of the benzodiazepines appears favourable, at least in the short-term, wider issues are involved and must be addressed. The & potential IS of increasing concern (Griffiths & Weerts, 1997). Therapeutic use can escalate, although not commonly, to high dose use. Withdrawal is then much more difficult and may be attended by fits or by a psychotic reaction. Polydrug abusers often use benzodiazepines, taken orally, by sni&ing, or by injection. The last incurs the risk of blood borne viruses such as hepatitis B and C and HIV, and of local trauma and sepsis, and of overdose. Also, benzodiazepines can be abused as the drug of preference. They can have a marked disinhibiting effect and may result in gratuitous violence. Benzodiazepines are generally scheduled in a fairly non-restrictive way, the exception being flunitrazepam which causes the most problems worldwide. The benzodiazepines are notorious for inappropriate use. Some groups of patients are particularly at risk. Examples include the elderly who can become unsteady with the risk of falls and fractures, or can develop confusional states. Patients with alcohol problems are prone to incur benzodiazepine dependence and abuse. Benzodiazepines may be used on their own inappropriately to treat depression or psychotic conditions. Or cases of only mild or transient anxiety or insomnia are given a benzodiazepine unnecessarily and perhaps recklessly. Conversely, benzodiazepines may be withheld when they would be appropriate in cases of severe anxiety or insomnia. The most inappropriate use is when short-term use develops into long-term use because of inadequate monitoring. The problem is the difficulty in predicting the minority of patients who have problems discontinuing short-term use because of rebound or relapse. Alternatives to henzodiazepines are of increasing importance. Within the class, long-acting compounds may be preferred to short-acting ones to treat anxiety, and vice-versa for insomnia. In some indications such as Panic Disorder, more effective compounds such as the SSRIs are preferable. However, some alternatives such as buspirone are slower in onset of action, and do not provide the immediate gratifying response to the anxiolytic benzodiazepines. Non-drug therapies comprise a vast range from analytic-based psychotherapies to counselling. The efficacy of many of these strategies is largely unproven. The current favourite is cognitive-behavioural therapy (CBT). Some therapists believe that benzodiazepines interfere with their non-drug treatments. Finally, the economics of benzodiazepine use need addressing but in as wide a context as possible (Lyons et al., 1992). It is not sufficient to compare the costs of a non-drug therapy such as CBT, or a newer SSRI agent with say, generic diazepam. The entire costs to society need quantification. For example, someone withdrawing from a benzodiazepine
s109
may need hospitalisation for a fit or an elderly person on a hypnotic may stand up, be ataxic, fall over and break the neck of femur. These costs will be substantial and can cancel out the use of an inexpensive therapeutic manoeuvre in many patients. Furthermore, the cost to society of illicit use needs to be added to the equation. In conclusion, benzodiazepines resemble many other therapeutic interventions, in being effective in short-term clinical trials, with an acceptable safety profile. In longer-term use, particularly under the exigencies of the usual health-care systems, significant problems concerning safety arise. These particularly involve issues of withdrawal. With doubts about long-term efficacy, the risk/benefit ratio turns adverse around 2 weeks for hypnotic use and 4 weeks for anxiolytics. The widespread availability of these compounds leads to inappropriate use and abuse. The crux of the matter is limiting usage to the short-term: this should give every prescriber pause for thought. References [I] Curran, H.V. (1991). Benzodiazepines. memory and mood: a tevrew. Psychopharmacology 105: I-8. [2] Griffiths, R.R. and Weeits, E.M. (1997). Benzodiazepmes self-administration in humans and laboratory animals - implications for problems of long-term use and abuse. Psychopharmacology 134: l-37. [3] Lader, M. (1994). Benzodiazepines. A risk-benefit profile. CNS Drugs I : 377387. [4] Lyons, J.S., Larson, D.B. and Hromco, J. (1992). Clmical and economic evaluation of benzodiazepines. A value analysis. PhannacoEconomics 2: 397407.
-1
The use of benzodiarepines disorders
in anxiety and other
D.J. Nutt. University of Bristol, Psychopharmacoiogv Unit, School qf Medical Sciences, University Walk, Bristol BS8 I TD, UK The benzodiazepines have a long tradition in the treatment of the anxiety disorders. For over 30 years they have proved the mainstay of treatment for acute situational (stress) reactions and for GAD. Some (especially high potency drugs such as alprazolam and clonazepam) have also been shown to be also have utility in other disorders such as panic and social phobia. The only drug to seriously compete with the benzodiazepines in the treatment of GAD is buspirone, although in recent years there has been a growing interest in the use of antidepressants, especially the SSRls, in this condition. The use of non-benzodiazepine drugs in anxiety raises interesting issues about their comparative modes of action, which in turn raises issues about the underlying causes of anxiety. The main differences between the benzodiazepines and the other drugs are listed in Table 1 which also serves to emphasize the relative merits and drawbacks of each class. Although the benzodiazepines were licensed before there was a need to clearly specify between the anxiety disorders some of these drugs have been tested in specific conditions and indeed licensed for these. In addition the benzodiazepines have utility in other diseases both psychiatric and neurological (see Table 2). Advantages and Disadvantages The benzodiazepines have several main positive attributes. They work quickly, ohen producing symptom relief within minutes. Therapeutic benefits tend to continue to improve over several weeks and in general therapeutic gains are maintained for weeks or months without significant tolerance developing. However tolerance does develop to some of the unwanted actions of the benzodiazepines such as sedation, ataxia and memory impairment although this may never be complete. The only areas in which tolerance develops to the therapeutic actions of the benzodiazepines is epilepsy where breakthrough seizures can occur after weeks or months. In anxiety disorders tolerance appears not to develop, and in many cases patients find they can reduce dosing after a while. Patients who require increasing doses of benzodiazepines should be carefully evaluated for evidence of drug abuse or dependence.
S.21 A review of the place of the benzodiazepines
in males, genetic loading, and grossly normal neuroanatomy observed in this disorder. This presentation will suggest that abnormalities in the neural pathways for either oxytocin or vasopressin could account for many and perhaps all of these aspects of autism. Animal studies with these neuropeptides have demonstrated their importance for social bond formation, memory, and species-typical motor patterns. In addition, vasopressin appears sexually dimorphic with greater levels of gene expression in males. Recent studies of the genes for oxytocin and vasopressin receptors suggest that the promoter regions of these genes are highly variable across species and may show variation within human populations, providing a potential model for individual differences in social or cognitive b&on. The available data suggest that these neurpeptide systems may be reasonable candidates for further study in autistic patients and their families. References [l] Insel TR, O’Brien D, L&man J. Oxytocin, vasopressin, a connection? Biological Psychiatry, in press.
Each mention of a medication to be administered alone or as part of a combination was counted. Medications were grouped by class. The table below displays the percentage of drug mentions for a disorder attributable to each drug class shown, by year. The major findings are: Mentions of tricyclic antidepressants (TCAs) as a preferred first-line pharmacotherapy for anxiety disorders declined by about half from 1992 to 1997. Selective serotonin reuptake blockers (SSRls) were mentioned as a preferred first-line pharmacotherapy for anxiety disorders 3 to 8 times more often in 1997 than in 1992. Mentions of benzodiazepines (Benzos) as a preferred first-line pharmacotherapy for anxiety disorders hardly changed in frequency from 1992 to 1997. Benzodiazepines were mentioned more often than any other class of drugs as a preferred first-line pharmacotherapy for anxiety disorders, except obsessive-compulsive disorder.
and autism: Is there Year
Dw class
Panic disorder
GAD
phobia
42 16 4 34 39 39
40 20 6 35 44 40
30 15 3 26 47 43
Agora-
S.21 A review of the place of the
benzodiazepines Is.21.Ol 1Trends
in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997
E.H. Uhlenhuth, M.B. Balter, T.A. Ban, K. Yang. Unioersity of New Mexico, School of Medicine, Department of Psychiatry, Albuquerque, NM, USA Objectives: In our view, the 3 factors that have the greatest impact on treatment with psychotherapeutic medications are the findings of clinical research, governmental regulations, and personal clinical experience. The first 2 are well recognized and form the basis for officially approved clinical practice. However, clinical experience, which is at least of equal importance, remains greatly underutilized because it has not been systematically gathered, quantitatively analyzed, and widely disseminated. These considerations led us to conduct an international survey study of expert judgment on the therapeutic use of benzodiazepines and other psychotherapeutic medications. The specific aims of this study were to: . Provide a representative body of expert judgment on the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. . Focus principally on the pharmacotherapy of the anxiety disorders. Method: A panel of psychiatrists was constituted by a peer nomination process. The criteria for nomination to the panel were “theprofessionally most respected physicians of the world with extensive experience and howledge in the pharmacotherapy of anxiety and depressive disorders.” The process began with leading clinical psychopharmacologists in 44 countries as initial nominators, and the final panel included 73 experts from 25 countries. The data were collected in 1991-1992 by means of a self-administered questionnaire, sent in the mail. It covered a wide variety of issues in the pharmacotherapy of anxiety disorders and required at least 4 hours to complete. There was no prior communication with the experts, and their names were kept strictly confidential until the initial results were published. Each respondent was paid $750 after the questionnaire was completed and returned. The response rate was 90% (66/73). In 1997, a short follow-up questionnaire was sent to the original 66 participants to assess whether their recommendations for treating anxiety disorders had changed during the 5 year interval, a period when many new antidepressants came into widespread use. The follow-up questionnaire included 7 case vignettes from the original study depicting typical anxiety disorders, each followed by questions on recommendations for management. Fifty-one of the original 66 panelists participated, for a response rate of 77%. Results: The results presented here are based on responses to a question about the preferred first-line pharmacotherapy for each case.
TCAs SSRlS Benzos
I992 1991 I992 1997 1992 I997
Social phobia
Discrete OCD phobia
Adjustment
IO 5 3 25 25 26
I5 II II 30 53 44
14 3 3 8 71 79
64 38 19 52 II 9
Conclusions: Over the past 5 years, selective serotonin reuptake inhibitors displaced tricyclic antidepressants as the experts’ choices for tit-line pharmacotherapy of anxiety disorders. . According to the experts’ judgements, the benzodiazepines remain a mainstay of pharmacotherapy for anxiety disorders, except obsessivecompulsive disorder.
??
References [1] Balter MB, Ban TA, Uhlenhuth EH (1993). International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications. 1. Current concerns. Human Psychophunnacology 8: 253-261. [2] Uhlenhuth EH, Baker MB, Ban TA, Yang K (1995). International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications. II. Pharmacotherapy of anxiety disorders. J Afictive
Disord 35: 153-162. [3] Uhlenhuth EH, Baiter MB, Ban TA, Yang K (1995). International
study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications. III. Clinical features affecting experts’ therapeutic recommendations in anxiety disorders. Psychopharmacol Bull 3 I: 289-296.
-1
Restrictions sense?
on benzodiarepine
use: Do they make
M. Lader. Institute of Psychiatry London SE5, UK The benzodiazepines, once the most widely-prescribed of all medications, have fallen into increasing disfavour. Two indications will be examined, anxiety disorders and insomnia. Restrictions on the usage of benzodiazepine in clinical practice relate to the indication, dose and duration of use. Thus, the indication is generally taken to refer to anxiety or insomnia which is “severe, disabling or subjecting the individual to extreme unacceptable distress”. The duration is “short-term” (24 weeks) in anxiety and “as short as possible” (a few days to two weeks) for a hypnotic. The dosage should be the “lowest to control symptoms”. These restrictions refer to UK Data Sheets but other countries have similar caveats. In addition, the benzodiazepines are controlled drugs, a reflection of their abuse potential that has been recognised internationally. Such restrictions can be evaluated initially in terms of the risk/benefit characteristics of the benzodiazepines in relation to the severity and
S.21 A review of the place of the benzodiazepines chronic@ of anxiety and insomnia indications (Lader, 1994). The last can be viewed in terms of symptomatic distress and social and occupational handicaps. The efficacy of benzodiazepine anxiolytics and hypnotics is wellestablished for short-term use, although the non-specific effects such as the placebo response are substantial. However, after a few nights’ use as an hypnotic and a few weeks’ use as an anxiolytic, efficacy wanes although its evaluation becomes confounded by discontinuation phenomena. Long-term efficacy is thus debatable. The unwanted effects of the benzodiazepines are well-catalogued and comprise subjective sedation together with objective psychological impairment. This translates into real-life problems such as increased risk of accidents. Tolerance occurs to most of these side-effects with the notable exception of memory disturbances (Curran, 1991). These risks are strongly dose-related. Less frequent and predictable are paradoxical reactions with heightened anxiety and aggression. Drug interactions mainly relate to other sedative compounds, in particular, alcohol. Even the safety in overdose of the benzodiazepines has been questioned. Discontinuation phenomena comprise rebound of insomnia and anxiety, particularly noticeable with short acting hypnotics. This merges into withdrawal in which newly-emergent symptoms, typically perceptual, plague a proportion (upto a half) of patients discontinuing normal therapeutic doses (Michelini et al, 1996). Again this problem is strongly closerelated and withdrawal may be protracted. Relapse of the underlying condition may complicate the picture. Although the risk/benefit ratio of the benzodiazepines appears favourable, at least in the short-term, wider issues are involved and must be addressed. The & potential IS of increasing concern (Griffiths & Weerts, 1997). Therapeutic use can escalate, although not commonly, to high dose use. Withdrawal is then much more difficult and may be attended by fits or by a psychotic reaction. Polydrug abusers often use benzodiazepines, taken orally, by sni&ing, or by injection. The last incurs the risk of blood borne viruses such as hepatitis B and C and HIV, and of local trauma and sepsis, and of overdose. Also, benzodiazepines can be abused as the drug of preference. They can have a marked disinhibiting effect and may result in gratuitous violence. Benzodiazepines are generally scheduled in a fairly non-restrictive way, the exception being flunitrazepam which causes the most problems worldwide. The benzodiazepines are notorious for inappropriate use. Some groups of patients are particularly at risk. Examples include the elderly who can become unsteady with the risk of falls and fractures, or can develop confusional states. Patients with alcohol problems are prone to incur benzodiazepine dependence and abuse. Benzodiazepines may be used on their own inappropriately to treat depression or psychotic conditions. Or cases of only mild or transient anxiety or insomnia are given a benzodiazepine unnecessarily and perhaps recklessly. Conversely, benzodiazepines may be withheld when they would be appropriate in cases of severe anxiety or insomnia. The most inappropriate use is when short-term use develops into long-term use because of inadequate monitoring. The problem is the difficulty in predicting the minority of patients who have problems discontinuing short-term use because of rebound or relapse. Alternatives to henzodiazepines are of increasing importance. Within the class, long-acting compounds may be preferred to short-acting ones to treat anxiety, and vice-versa for insomnia. In some indications such as Panic Disorder, more effective compounds such as the SSRIs are preferable. However, some alternatives such as buspirone are slower in onset of action, and do not provide the immediate gratifying response to the anxiolytic benzodiazepines. Non-drug therapies comprise a vast range from analytic-based psychotherapies to counselling. The efficacy of many of these strategies is largely unproven. The current favourite is cognitive-behavioural therapy (CBT). Some therapists believe that benzodiazepines interfere with their non-drug treatments. Finally, the economics of benzodiazepine use need addressing but in as wide a context as possible (Lyons et al., 1992). It is not sufficient to compare the costs of a non-drug therapy such as CBT, or a newer SSRI agent with say, generic diazepam. The entire costs to society need quantification. For example, someone withdrawing from a benzodiazepine
s109
may need hospitalisation for a fit or an elderly person on a hypnotic may stand up, be ataxic, fall over and break the neck of femur. These costs will be substantial and can cancel out the use of an inexpensive therapeutic manoeuvre in many patients. Furthermore, the cost to society of illicit use needs to be added to the equation. In conclusion, benzodiazepines resemble many other therapeutic interventions, in being effective in short-term clinical trials, with an acceptable safety profile. In longer-term use, particularly under the exigencies of the usual health-care systems, significant problems concerning safety arise. These particularly involve issues of withdrawal. With doubts about long-term efficacy, the risk/benefit ratio turns adverse around 2 weeks for hypnotic use and 4 weeks for anxiolytics. The widespread availability of these compounds leads to inappropriate use and abuse. The crux of the matter is limiting usage to the short-term: this should give every prescriber pause for thought. References [I] Curran, H.V. (1991). Benzodiazepines. memory and mood: a tevrew. Psychopharmacology 105: I-8. [2] Griffiths, R.R. and Weeits, E.M. (1997). Benzodiazepmes self-administration in humans and laboratory animals - implications for problems of long-term use and abuse. Psychopharmacology 134: l-37. [3] Lader, M. (1994). Benzodiazepines. A risk-benefit profile. CNS Drugs I : 377387. [4] Lyons, J.S., Larson, D.B. and Hromco, J. (1992). Clmical and economic evaluation of benzodiazepines. A value analysis. PhannacoEconomics 2: 397407.
-1
The use of benzodiarepines disorders
in anxiety and other
D.J. Nutt. University of Bristol, Psychopharmacoiogv Unit, School qf Medical Sciences, University Walk, Bristol BS8 I TD, UK The benzodiazepines have a long tradition in the treatment of the anxiety disorders. For over 30 years they have proved the mainstay of treatment for acute situational (stress) reactions and for GAD. Some (especially high potency drugs such as alprazolam and clonazepam) have also been shown to be also have utility in other disorders such as panic and social phobia. The only drug to seriously compete with the benzodiazepines in the treatment of GAD is buspirone, although in recent years there has been a growing interest in the use of antidepressants, especially the SSRls, in this condition. The use of non-benzodiazepine drugs in anxiety raises interesting issues about their comparative modes of action, which in turn raises issues about the underlying causes of anxiety. The main differences between the benzodiazepines and the other drugs are listed in Table 1 which also serves to emphasize the relative merits and drawbacks of each class. Although the benzodiazepines were licensed before there was a need to clearly specify between the anxiety disorders some of these drugs have been tested in specific conditions and indeed licensed for these. In addition the benzodiazepines have utility in other diseases both psychiatric and neurological (see Table 2). Advantages and Disadvantages The benzodiazepines have several main positive attributes. They work quickly, ohen producing symptom relief within minutes. Therapeutic benefits tend to continue to improve over several weeks and in general therapeutic gains are maintained for weeks or months without significant tolerance developing. However tolerance does develop to some of the unwanted actions of the benzodiazepines such as sedation, ataxia and memory impairment although this may never be complete. The only areas in which tolerance develops to the therapeutic actions of the benzodiazepines is epilepsy where breakthrough seizures can occur after weeks or months. In anxiety disorders tolerance appears not to develop, and in many cases patients find they can reduce dosing after a while. Patients who require increasing doses of benzodiazepines should be carefully evaluated for evidence of drug abuse or dependence.