JOP271110.1177/0269881113503509Journal of PsychopharmacologyBaldwin et al. 5035092013 Commentary Benzodiazepines: Risks and benefits. A reconsideration Journal of Psychopharmacology 27(11) 967 –971 © The Author(s) 2013 David S Baldwin1, Katherine Aitchison2, Alan Bateson3, Reprints and permissions: 4 5 6 7 sagepub.co.uk/journalsPermissions.nav H Valerie Curran , Simon Davies , Brian Leonard , David J Nutt , DOI: 10.1177/0269881113503509 David N Stephens8 and Sue Wilson7 jop.sagepub.com Abstract Over the last decade there have been further developments in our knowledge of the risks and benefits of benzodiazepines, and of the risks and benefits of alternatives to benzodiazepines. Representatives drawn from the Psychopharmacology Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology together examined these developments, and have provided this joint statement with recommendations for clinical practice. The working group was mindful of widespread concerns about benzodiazepines and related anxiolytic and hypnotic drugs. The group believes that whenever benzodiazepines are prescribed, the potential for dependence or other harmful effects must be considered. However, the group also believes that the risks of dependence associated with long-term use should be balanced against the benefits that in many cases follow from the short or intermittent use of benzodiazepines and the risk of the underlying conditions for which treatment is being provided. Keywords Benzodiazepines, pharmacology, risks, withdrawal, benefits The Royal College of Psychiatrists has previously provided guid- Pharmacological properties of ance on the risks and benefits of benzodiazepines, in March 1988 and January 1997. Over the last decade there have been further benzodiazepines developments in our knowledge of the risks and benefits of Benzodiazepines are ‘allosteric modulators’ of GABAA receptors benzodiazepines, and of the risks and benefits of alternatives to (GABA is the widely distributed inhibitory neurotransmitter benzodiazepines. In addition, the licensing of some selective sero- gamma-aminobutyric acid). A GABAA receptor comprises five tonin reuptake inhibitors and serotonin-noradrenaline reuptake transmembrane glycoprotein subunits arranged around a central inhibitors for treatment of a broad range of anxiety disorders chloride channel. Benzodiazepines bind to a specific site on the (and the licensing of pregabalin for generalized anxiety disor- GABAA receptor membrane complex, which is distinct from the der) has increased choice among potential pharmacological and GABA binding site. The GABAA receptor has multiple additional psychological interventions. Representatives drawn from both binding sites, including those for benzodiazepines, barbiturates the Psychopharmacology Special Interest Group of the Royal and neurosteroids. It is controversial whether alcohol interacts College of Psychiatrists and the British Association for directly or only indirectly with the receptor. Different GABAA Psychopharmacology together examined these developments, and subunits are combined together to produce a variety of receptor have provided this joint statement with its recommendations for clinical practice. 1Faculty of Medicine, University of Southampton, Southampton, UK The working group was mindful of widespread concerns about 2Department of Psychiatry, University of Alberta, Edmonton, Canada benzodiazepines and related anxiolytic and hypnotic drugs. The 3 Department of Pharmacology, Ross University School of Medicine, group believes that whenever benzodiazepines are prescribed, the Roseau, Commonwealth of Dominica potential for dependence or other harmful effects must be consid- 4Faculty of Brain Sciences, University College London, London, UK ered. However, the group also believes that the risks of depend- 5 Centre for Addiction and Mental Health, University of Toronto, ence associated with long-term use should be balanced against the Toronto, Canada benefits that in many cases follow from the short or intermittent 6National University of Ireland, Galway, Ireland use of benzodiazepines and the risk of the underlying conditions 7Faculty of Medicine, Imperial College London, London, UK 8 for which treatment is being provided. The balance of risks and School of Psychology, University of Sussex, Brighton, UK benefits with benzodiazepines or alternative interventions in an Corresponding author: individual patient can be hard to assess, and is ultimately a matter David Baldwin, Department of Psychiatry, University of Southampton, of clinical judgment. The group contends that benzodiazepine pre- Academic Centre, College Keep, 4-12 Terminus Terrace, Southampton, scribing, like other aspects of clinical practice, should be based on SO14 3DT, UK. thoughtful consideration of the likely risks and benefits of benzo- Email: [email protected] diazepines, and of the risks and benefits of alternative interven- Joint Report from a Working Group drawn from the Royal College of tions. This consideration should be made in conjunction with the Psychiatrists Psychopharmacology Special Interest Group and the British patient, and their carers, where appropriate. Association for Psychopharmacology Downloaded from jop.sagepub.com by guest on November 21, 2013 968 Journal of Psychopharmacology 27(11) subtypes, which have distinct distributions within the central for Health and Care Excellence (NICE), the British Association nervous system as well as specific pharmacological properties. for Psychopharmacology and other bodies suggests that other Binding of a benzodiazepine to its site on the receptor increases approaches should be used in preference to benzodiazepines, the affinity of the receptor for GABA, which in turn leads to a which are generally reserved for patients who do not respond to greater likelihood of the receptor ‘opening’ to allow the passage of other treatments. Benzodiazepines do not have an antidepressant chloride ions through the membrane. This normally results in neu- effect when used alone, which is a disadvantage in patients with ronal hyper-polarization and reduced excitability of the target cell. anxiety disorders who are also depressed, but they may sometimes Unlike barbiturates at high doses, benzodiazepines do not mimic be used to cover the period of illness before antidepressants the effects of GABA and do not activate chloride channels directly. become effective (typically a few weeks) and to reduce possible The benzodiazepines can be divided into different groups exacerbations of anxiety during this period. based on their chemical structure and pharmacokinetic properties, Benzodiazepine anxiolytics should be prescribed primarily although all share a common mechanism of action and produce a either for the short-term relief of severe anxiety symptoms, or range of similar clinical effects. There are other compounds of where anxiety disorders are disabling and severe and causing both unrelated structure that also bind to the benzodiazepine site on the significant personal distress and substantial impairment of daily GABAA receptor and share some, but not all, of the pharmaco- activities. Where the rationale for treating anxiety symptoms does logical properties of benzodiazepines. Currently these are the not meet either of these criteria, psychological or pharmacological ‘Z-drugs’ (zaleplon, zolpidem and zopiclone), which are used as treatments with an evidence base for long-term use are more hypnotics only. They show subtle differences in pharmacology suitable. from the benzodiazepines as well as having an improved kinetic To reduce the risk of dependence on benzodiazepines they profile for sleep induction with reduced ‘hangover’. The general should generally not be prescribed as a regularly administered principles that apply to benzodiazepine prescribing also apply to medication for longer than four weeks. Ideally they should be the Z-drugs. given on an ‘as required’ basis and intermittently every few days The benzodiazepines differ in their potency, time to effect and during this period. Benzodiazepines may exert beneficial effects duration of action, with some needing repeated daily dosing and within a few days of starting treatment, and may offer the prospect others once-daily dosing to achieve their desired clinical effects. of symptom relief while other treatments such as cognitive– Many benzodiazepines (for example, diazepam) have longer- behavioural therapy have yet to be started or before antidepressant lasting active metabolites, which can accumulate with repeated drugs have had time to act. dosing, especially in elderly patients and those with physical There are clinical circumstances in which longer-term prescrip- health problems, or those with genetic variants leading to low or tion of benzodiazepines might be considered desirable because the absent activity of relevant cytochrome P450 enzymes. alternatives are probably worse than the continued use of benzodi- azepines. This may be the case in conditions such as chronic treat- ment-resistant anxiety disorders or in patients who have established Beneficial effects of benzodiazepines dependence and who have not been able to stop treatment success- fully. In rare instances longer-term prescriptions of benzodiaz- The beneficial effects of benzodiazepines include the reduction of epines may be seen as a form of harm reduction in patients who anxiety, the induction and maintenance of sleep, muscle relaxa- would otherwise consume illicit benzodiazepines