Newer Hypnotic Drugs for the Short-Term Management of Insomnia: a Systematic Review and Economic Evaluation

Health Technology Assessment 2004; Vol. 8: No. 24

Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation

Y Dündar, A Boland, J Strobl, S Dodd, A Haycox, A Bagust, J Bogg, R Dickson and T Walley

June 2004

Health Technology Assessment NHS R&D HTA Programme HTA HTA

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The website also provides information about the HTA Programme and lists the membership of the various committees. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation

Y Dündar,1 A Boland,1 J Strobl,1 S Dodd,2 A Haycox,1 A Bagust,1 J Bogg,3 R Dickson1* and T Walley1

1 Liverpool Reviews and Implementation Group, University of Liverpool, UK 2 Centre for Medical Statistics and Health Evaluation, Faculty of Medicine, University of Liverpool, UK 3 Department of Clinical Psychology, University of Liverpool, UK

* Corresponding author

Declared competing interests of authors: none. Tom Walley is HTA Programme Director, although he was not involved in the editorial processes for this report.

Published June 2004

This report should be referenced as follows:

Dundar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation. Health Technol Assess 2004;8(24).

Health Technology Assessment is indexed in Index Medicus/MEDLINE and Excerpta Medica/ EMBASE. NHS R&D HTA Programme

he research findings from the NHS R&D Health Technology Assessment (HTA) Programme directly Tinfluence key decision-making bodies such as the National Institute for Clinical Excellence (NICE) and the National Screening Committee (NSC) who rely on HTA outputs to help raise standards of care. HTA findings also help to improve the quality of the service in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’ that is being developed to improve the evidence of clinical practice throughout the NHS. The HTA Programme was set up in 1993. Its role is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care. The HTA programme commissions research only on topics where it has identified key gaps in the evidence needed by the NHS. Suggestions for topics are actively sought from people working in the NHS, the public, consumer groups and professional bodies such as Royal Colleges and NHS Trusts. Research suggestions are carefully considered by panels of independent experts (including consumers) whose advice results in a ranked list of recommended research priorities. The HTA Programme then commissions the research team best suited to undertake the work, in the manner most appropriate to find the relevant answers. Some projects may take only months, others need several years to answer the research questions adequately. They may involve synthesising existing evidence or designing a trial to produce new evidence where none currently exists. Additionally, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme is able to commission bespoke reports, principally for NICE, but also for other policy customers, such as a National Clinical Director. TARs bring together evidence on key aspects of the use of specific technologies and usually have to be completed within a limited time period.

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The research reported in this monograph was commissioned and funded by the HTA Programme on behalf of NICE as project number 02/22/01. The authors have been wholly responsible for all data collection, analysis and interpretation and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme, NICE or the Department of Health. HTA Programme Director: Professor Tom Walley Series Editors: Professor John Gabbay, Dr Chris Hyde, Dr Ruairidh Milne, Dr Rob Riemsma and Dr Ken Stein Managing Editors: Sally Bailey and Caroline Ciupek

ISSN 1366-5278 © Queen’s Printer and Controller of HMSO 2004 This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NCCHTA, Mailpoint 728, Boldrewood, University of Southampton, Southampton, SO16 7PX, UK. Published by Gray Publishing, Tunbridge Wells, Kent, on behalf of NCCHTA. Printed on acid-free paper in the UK by St Edmundsbury Press Ltd, Bury St Edmunds, Suffolk. T Health Technology Assessment 2004; Vol. 8: No. 24

Abstract

Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation Y Dündar,1 A Boland,1 J Strobl,1 S Dodd,2 A Haycox,1 A Bagust,1 J Bogg,3 R Dickson1* and T Walley1

1 Liverpool Reviews and Implementation Group, University of Liverpool, UK 2 Centre for Medical Statistics and Health Evaluation, School of Health Sciences, University of Liverpool, UK 3 Department of Clinical Psychology, University of Liverpool, UK * Corresponding author

Objectives: To assess the clinical and cost- limited data provided. The existing published economic effectiveness of zaleplon, zolpidem and zopiclone literature in this area is very limited. No relevant (Z-drugs) compared with benzodiazepines. economic evaluations were identified for inclusion in Data sources: Electronic databases, reference lists of the review. The industry submissions did not include retrieved articles and pharmaceutical company detailed evidence of cost-effectiveness. Given the lack submissions. of robust clinical evidence, no economic model Review methods: Randomised controlled trials (RCTs) describing the costs and benefits of the newer hypnotic that compared either benzodiazepines to the Z-drugs drugs for insomnia was developed. The systematic or any two of the non-benzodiazepine drugs in patients review provided in this report suggests that an agnostic with insomnia were included in the review. Data on the approach to cost-effectiveness is required at this stage. following outcome measures were considered: sleep In the short-term, no systematic evidence is available onset latency, total sleep duration, number of concerning significant outcome variations between awakenings, quality of sleep, adverse effects and either the different classes of drugs or between rebound insomnia. A search was also undertaken for individual drugs within each class. Within this short- any study designs that evaluated issues related to term horizon, the one element that does vary adverse events (e.g. dependency and withdrawal significantly is the acquisition cost of the individual symptoms). Full economic evaluations that compared drugs. two or more options and considered both costs and Conclusions: The short-acting drugs seem equally consequences including cost-effectiveness, cost–utility effective and safe with minor differences that may lead analysis or cost–benefit analysis undertaken in the a prescriber to favour one over another in different context of high-quality RCTs were considered for patients. There is no evidence that one is more cost- inclusion in the review. effective than any other. Analysis of the additional costs Results: Twenty-four studies, involving a total study to the NHS, depending on the rate of change from population of 3909 patients, met the inclusion criteria. benzodiazepine prescriptions to Z-drug prescriptions, These included 17 studies comparing a Z-drug with a at current levels of hypnotic prescribing, range from benzodiazepine and seven comparing a Z-drug with £2 million to £17 million per year. There are clear another Z-drug. The diversity of possible comparisons research needs in this area; in particular, none of the and the range of outcome measures in the review may existing trials adequately compare these medications. It be confusing. Outcomes were rarely standardised and, is suggested that further consideration should be given even when reported, differed in interpretation. In to a formal trial to allow head-to-head comparison of addition, variations in assessment and variety in the some of the key drugs in a double-blind RCT lasting at level of information provided make study comparisons least 2 weeks, and of sufficient size to draw reasonable difficult. As a result, meta-analysis has been possible on conclusions. We would also recommend that any such only a small number of outcomes. However, some trial should include a placebo arm. It should also collect broad conclusions might be reached based on the good-quality data around sleep outcomes and in iii

particular quality of life and daytime drowsiness. We do recurring course, the short-term trial of medication and not believe that any formal study of risk of dependency lack of long-term follow-up undermine attempts to is feasible at present. Finally, the management of long- develop evidence-based guidelines for the use of term insomnia is suggested for further investigation: hypnotics in this condition, or indeed for its whole considering the frequency of this symptom and its management.

iv Health Technology Assessment 2004; Vol. 8: No. 24

Contents

Glossary and list of abbreviations ...... vii 6 Economics: response to industry submission ...... 45 Executive summary ...... ix Critique of industry economic submissions ...... 45 1 Review aims...... 1 Industry submissions ...... 45 Sanofi-Synthelabo Ltd submission ...... 45 2 Background ...... 3 Wyeth submission ...... 45 Normal sleep ...... 3 Conclusion ...... 48 Insomnia ...... 3 Treatment options ...... 6 7 Budget impact analysis ...... 49 Outcome measures ...... 7 Introduction ...... 49 Adverse events ...... 8 Trends in volume of prescriptions and Current service provision ...... 12 spending on hypnotics ...... 49 Current market share ...... 50 3 Methods ...... 13 Budget impact analysis ...... 51 Methods for reviewing clinical effectiveness ...... 13 8 Conclusions ...... 57 Extended review on dependence and withdrawal symptoms ...... 13 Acknowledgements ...... 61 Methods for reviewing cost-effectiveness ...... 15 References ...... 63

4 Results ...... 17 Appendix 1 Search strategies and Clinical effectiveness ...... 17 search results ...... 69 Measures of psychomotor performance and memory ...... 28 Appendix 2 Quality assessment Review of dependency and withdrawal ...... 30 checklists ...... 73 Discussion ...... 34 Appendix 3 Clinical data tables ...... 75 5 Results: economic analysis ...... 39 Introduction ...... 39 Appendix 4 Clinical: included and Economic impact of insomnia ...... 40 excluded references ...... 121 Costs of insomnia within the framework of economic evaluation ...... 41 Health Technology Assessment reports Health outcomes of insomnia within published to date ...... 127 the framework of economic evaluation ...... 42 Health Technology Assessment Conclusion ...... 43 Programme ...... 137

Health Technology Assessment 2004; Vol. 8: No. 24

Glossary and list of abbreviations

Technical terms and abbreviations are used throughout this report. The meaning is usually clear from the context, but a glossary is provided for the non-specialist reader. In some cases, usage differs in the literature, but the term has a constant meaning throughout this review.

Glossary

Abuse potential Tendency of a drug to Rebound insomnia Worsening of sleep induce improper use. compared with pretreatment levels on abrupt discontinuation of a hypnotic agent Drug dependence A state, psychic and sometimes also physical, resulting from the Sleep onset latency The amount of time interaction between a living organism and a required to fall asleep. drug, characterised by behavioural and other Short-term insomnia Insomnia lasting up to responses that always include a compulsion to 3–4 weeks. take the drug on a continuous or a periodic basis in order to experience its psychic effects, Subjective assessment Evaluation of and sometimes to avoid the discomfort of its treatment based on the perceived effect absence (WHO definition). reported by patient and/or investigator. Nocturnal awakening Waking up during the Tolerance Reduction in response to the drug night. after repeated administration. Non-benzodiazepine hypnotic A hypnotic Total sleep duration Actual time spent asleep. that is a benzodiazepine receptor agonist. Transient insomnia Insomnia that lasts less Objective assessment Evaluation of than 1 week and does not reoccur. treatment based on the quantitative Withdrawal syndrome A complex of clinical measurement of defined outcomes. manifestations (insomnia, compulsive episodes, Primary insomnia Insomnia that is not irritability, anxiety) that occur when the drug caused by a known physical or mental administration in a physically dependent condition and persists for at least 1 month. person is abruptly discontinued.

List of abbreviations

ADQ average daily quantity CNS central nervous system

CBA cost–benefit analysis CSM Committee on Safety of Medicines CBT cognitive–behavioural therapy CUA cost–utility analysis CEA cost-effectiveness analysis

CFF critical flicker fusion DDD defined daily dose

CI confidence interval EEG electroencephalographic

CMA cost-minimisation analysis continued vii

List of abbreviations continued

HRQoL health-related quality of life RCT randomised controlled trial ITT intention-to-treat REM rapid eye movement NAWs number of awakenings RR relative risk NIC net integrated cost RTA road traffic accident NICE National Institute for Clinical SF-36 Short Form with 36 Items Excellence STAR-PU specific therapeutic area- OR odds ratio prescribing unit OTC over-the-counter STM short-term memory PPA Prescription Pricing Authority VAS visual analogue scale PSG polysomnography WHO World Health Organization QALY quality-adjusted life-year Z-drugs zaleplon, zolpidem and zopiclone QoL quality of life

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.

viii Health Technology Assessment 2004; Vol. 8: No. 24

Executive summary

Objectives including the identification of clinical and economic studies, application of inclusion criteria, To assess the clinical and cost-effectiveness of quality assessment of included studies and data zaleplon, zolpidem and zopiclone (Z-drugs) extraction and analysis. compared with the benzodiazepines licensed and approved for use in the UK for the short-term management of insomnia. Inclusion criteria

Specifically the review includes comparisons of: Randomised controlled trials that compared either benzodiazepines to the Z-drugs or any two of the G zaleplon, zolpidem or zopiclone with non-benzodiazepine drugs in patients with benzodiazepines (diazepam, loprazolam, insomnia were included in the review. Data on the lorazepam, lormetazepam, nitrazepam, following outcome measures were considered: temazepam) sleep onset latency, total sleep duration, number G any two of the three non-benzodiazepine drugs of awakenings, quality of sleep, adverse effects and (zaleplon, zolpidem or zopiclone) rebound insomnia.

The review team also carried out an extended Background search to identify other study designs that evaluated issues related to adverse events (e.g. Insomnia is a common complaint of dependency and withdrawal symptoms). dissatisfaction with the quantity or quality of sleep. The estimates of population prevalence vary Full economic evaluations that compared two or between 10 and nearly 38%. Although there is more options and considered both costs and evidence of effectiveness of non-pharmacological consequences including cost-effectiveness, treatments, benzodiazepines are often prescribed. cost–utility analysis or cost–benefit analysis Non-benzodiazepine hypnotics (Z-drugs) were undertaken in the context of high-quality introduced for short-term treatment of insomnia randomised controlled trials were considered for in the late 1980s and 1990s. They were introduced inclusion in the review. as an alternative which might overcome some of these adverse effects associated with benzodiazepines, including tolerance, dependency, Clinical findings withdrawal symptoms and decreased psychomotor performance. In 2002, the UK Prescription Twenty-four studies, involving a total study Pricing Authority recorded over 6 million population of 3909 patients, met the inclusion prescriptions for benzodiazepines and 4 million criteria. These included 17 studies comparing a for the Z-drugs. Z-drug with a benzodiazepine and seven comparing a Z-drug with another Z-drug. The development and introduction of these newer hypnotic drugs have made it necessary to examine The diversity of possible comparisons and the the available research evidence to establish the range of outcome measures in the review may be clinical and cost-effectiveness of older and newer confusing. This is compounded by the fact that agents used for short-term management of outcomes were rarely standardised and, even when insomnia to inform national guidance. reported, differed in interpretation. In addition, variations in assessment and variety in the level of information provided make study comparisons Methods difficult. As a result, meta-analysis has been possible on only a small number of outcomes. The review was conducted following accepted However, some broad conclusions might be guidelines for conducting systematic reviews, reached based on the limited data provided. ix

1. Concerning zolpidem: model describing the costs and benefits of the (a) Zolpidem with nitrazepam (n = 2). One newer hypnotic drugs for insomnia was developed. study reports statistically significantly fewer Although we accept that the burden of disease awakenings with zolpidem. imposed by insomnia is significant for both (b) Zolpidem with temazepam (n = 2). One individuals and the NHS, the available evidence study reports significantly favourable results does not give a basis on which we can provide any for sleep latency and sleep quality in the firm guidance with regard to the comparative zolpidem group. cost-effectiveness of different drugs in this area. (c) Zolpidem with zopiclone (n = 1). Results from the only study in this comparator The systematic review provided in this report group suggest a statistically significant suggests that an agnostic approach to cost- difference in favour of zolpidem for sleep effectiveness is required at this stage. In the short- latency, rebound insomnia of sleep latency term, no systematic evidence is available concerning and adverse events. significant outcome variations between either the 2. Concerning zopiclone: different classes of drugs or between individual (a) Zopiclone with lormetazepam (n = 1). Only drugs within each class. Within this short-term one study in this group reports that horizon, the one element that does vary significantly lormetazepam results in shorter sleep onset is the acquisition cost of the individual drugs. latency than zopiclone. (b) Zopiclone with nitrazepam (n = 8). There is no convincing evidence of any differences Implications for the NHS in the outcomes measured between zopiclone and nitrazepam (one study Analysis of the additional costs to the NHS, suggests sleep latency is significantly depending on the rate of change from shorter with zopiclone and another with benzodiazepine prescriptions to Z-drug nitrazepam; one study reports significant prescriptions, at current levels of hypnotic improvements in sleep quality for prescribing, range from £2 million to £17 million zopiclone). Results from four studies per year. suggest a statistically significant difference in favour of zopiclone in daytime alertness. (c) Zopiclone with temazepam (n = 4). There Recommendations for further is no convincing evidence of any differences research in the outcomes measured between zopiclone and temazepam (only one study There are clear research needs in this area; in reports that rebound insomnia of sleep particular, none of the existing trials adequately latency is significantly worse following compare these medications. We would urge, zopiclone than after temazepam). therefore, that further consideration should be 3. Concerning zaleplon: given to a formal trial to allow head-to-head (a) Zaleplon with zolpidem (n = 6). Some comparison of some of the key drugs in a double- evidence suggests that zaleplon results in blind randomised controlled trial lasting at least 2 shorter sleep latency than zolpidem but weeks, and of sufficient size to draw reasonable zolpidem results in longer sleep duration conclusions. We would also recommend that any than zaleplon. Evidence suggests that such trial should include a placebo arm. It should zolpidem is statistically significantly more also collect good-quality data around sleep likely to improve sleep quality than zaleplon. outcomes and in particular quality of life and Evidence suggests that withdrawal is less daytime drowsiness. We do not believe that any likely and rebound insomnia significantly less formal study of risk of dependency is feasible at likely on zaleplon compared to zolpidem. present.

Finally, the major research issue is perhaps not Economic evaluation around the management of short-term insomnia, but around the management of long-term The existing published economic literature in this insomnia: considering the frequency of this area is very limited. No relevant economic symptom and its recurring course, the short-term evaluations were identified for inclusion in the trial of medication and lack of long-term follow-up review. The industry submissions did not include undermine attempts to develop evidence-based x detailed evidence of cost-effectiveness. Given the guidelines for the use of hypnotics in this lack of robust clinical evidence, no economic condition, or indeed for its whole management. Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 1 Review aims

o assess the clinical and cost-effectiveness of Specifically the review includes comparisons of: T zaleplon, zolpidem and zopiclone compared with benzodiazepines licensed and approved for G zaleplon, zolpidem or zopiclone with use in the UK for the short-term management of benzodiazepines (diazepam, loprazolam, insomnia. lorazepam, lormetazepam, nitrazepam, temazepam) G any two of the three non-benzodiazepine drugs (zaleplon, zolpidem or zopiclone).

Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 2 Background

Normal sleep remain asleep or a lack of feeling refreshed upon waking. Insomnia is also very variable and marked If questioned, most individuals would agree that night-to-night variations complicate the process of the perfect sleep is one in which you fall asleep diagnosis. Specific diagnosis of insomnia is complex. quickly and easily (sleep latency), stay asleep (total Insomnia can be classified by duration, severity or sleep time and number of awakenings) and awake comorbidity or by quantity and/or quality of sleep. refreshed and alert (daytime alertness). Individuals The definitions vary substantially across the may experience differences in these parameters on classification systems. The various components of a day-to-day basis and between individuals the accepted classification criteria are presented in differences may also be large.1 These within- and Table 1. Previous definitions also included duration between-individual variations limit the development of insomnia. However, it has been argued that the of definitions for the precise parameters of good concept of diagnosis by duration is in fact done quality sleep and assessment of existing research only retrospectively (especially in the case of indicates that there are limited data available transient insomnia) and is therefore clinically regarding the stability of these measures over time.2 unhelpful. (Morgan K, University of Loughborough personal communication, 2003) However, objective and subjective methods have been developed to assess the quality of various There is also a need to differentiate whether the aspects of the sleep experience. Objective measures insomnia is the primary syndrome or a symptom of sleep include the use of polysomnography of some other disease process.11 It is well known (PSG). This includes the monitoring of multiple that many patients complaining of insomnia suffer electrophysiological parameters including significant comorbidities, such as depression, parameters such as electroencephalographic other mental health problems or organic (EEG) and electromyographic activity and eye disorders. The WHO 1996 survey report12 movements.3 Data from these assessments provide indicates that internationally 27% of patients a picture of sleep architecture, which includes the reported some form of sleep problem. Of these, cyclic nature of sleep, various stages of sleep and 52% also had a well-defined mental health assessment of rapid eye movement (REM) and disorder and 54% reported a physical disorder. non-REM sleep. These data also allow for the evaluation of quantitative sleep measures such as Given these variations in classification and sleep onset latency, total sleep time and number of symptom presentation, there is a lack of consistency awakenings (NAWs). in the use of diagnostic criteria. Recommendations for the assessment of patients presenting with However, “while such objective assessments can insomnia vary, but the majority require a measure the quantity of sleep, they can only comprehensive history that includes definition of provide information on the theoretical quality of the sleep disorder including a description of actual sleep”.4 Numerous subjective tools have been sleep patterns, consideration of possible concurrent developed to assess the quality of sleep (e.g. sleep medical conditions, substance use (caffeine, diaries, sleep quality index).5 Debate continues nicotine or alcohol), psychiatric disorders and any regarding the correlation of the objective and other physical or psychological factors that may be subjective measures related to both the qualitative affecting the person’s ability to sleep.7,11,13,14 and quantitative measures applicable to sleep.6 Researchers have attempted to address the issues related to the diagnosis of insomnia. A 2003 Insomnia consensus document from Spain provides an extensive list of issues to be addressed when Classification and diagnosis of insomnia considering diagnosis.15 A similar Canadian In general terms, insomnia is defined as document actually goes on to say that the diagnosis dissatisfaction with the quantity or quality of sleep.7 of primary insomnia needs to be made by This may include the ability to fall asleep or to exclusion: by ruling out other conditions that may 3

TABLE 1 Classifications/clinical features of insomnia

Severity Comorbidity Quantity and/or quality of sleep (ICSD)8 (DSM-IV)9 (ICD-10)10

Mild: occurring almost every night Primary insomnia Difficulty falling asleep or maintaining with a minimum or no evidence of sleep, or of poor quality of sleep impairment of quality of life

Moderate: occurring every night, Insomnia related to another mental Occurrence of sleep disturbance >3 mild to moderate impairment with disorder (non-organic) (e.g. major times/week for <1 month associated symptoms depressive disorder, generalised anxiety disorder)

Severe: occurring every night, Insomnia related to a general medical Preoccupation with the sleeplessness, severe impairment with significant condition (organic) excessive concern over its consequences associated symptoms (irritability, fatigue, anxiety, etc.)

Substance-induced insomnia Unsatisfactory quantity and/or quality of sleep either causing marked distress or interfering with ordinary activities

Adapted from Holbrook and colleagues.7

be causing the sleep disturbance, a decision can be identified 9% of the population with ‘severe made that the primary problem is the insomnia.16 insomnia’. They found a higher prevalence in Presenting the issues from a public health women. In Norway, Pallesen and colleagues23 perspective, Dement and Pelayo13 provided detailed conducted a telephone survey using DSM-IV recommendations for the evaluation of insomnia criteria and report a prevalence of 12% with including differential diagnosis, and a European seasonal variations and increased sleep disorders consensus document related to diagnosis and reported in the winter months. management outlines the importance of the problem and the apparent lack of attention being From a more pragmatic perspective, Simon and paid to the diagnosis and treatment.17 VonKorff24 analysed the WHO data on patients under 65 years old within their health Epidemiology maintenance organisation in the USA. Prevalence Epidemiological reports related to insomnia utilise rates were 10% and assessment of patient data differing definitions, classification systems and indicated the patients with insomnia had greater diagnostic criteria and therefore are often not functional impairment, lower productivity and an directly comparable.18 As a result, the estimates of excess of healthcare utilisation. population prevalence of insomnia have, unsurprisingly, varied from 10% to as high as A recent systematic review of epidemiological 38%.7,19,20 literature provides an excellent summary of the problems of measurement and reporting of these In a survey of five European countries, Chevalier data.18 This report details insomnia data from four and Los21 conducted face-to-face interviews in the perspectives: general population using DSM-IV criteria. They reported a prevalence of insomnia of 4–9% in G insomnia symptoms Germany, Sweden, Ireland and Belgium, whereas G insomnia symptoms accompanied with daytime 22% of the population in the UK were affected. consequences This figure for the UK is slightly lower than the G dissatisfaction with sleep quality or quantity individual UK data reported in the WHO report,12 G insomnia diagnosis. where any sleep problem was reported by 32% of those patients surveyed. The review is based on the analysis of available epidemiological data and provides estimates Leger and colleagues22 surveyed more than 12,000 within each of these categories. The summary of 4 people in France using ‘strict’ DSM-IV criteria and this analysis is presented in Figure 1. Health Technology Assessment 2004; Vol. 8: No. 24

of the individual to the symptoms or the response Insomnia symptoms of the healthcare providers to individuals • Presence: 30–48% presenting for treatment. • At least 3 nights/week or often or always: 16–21% In the first instance, there may be an individual • Moderately to extremely: 10–28% underestimation of the problem and subsequent Insomnia symptoms + lack of presentation for treatment. Only one in daytime consequence 20 individuals are believed to present to healthcare 9–15% professionals with insomnia-related symptoms.28 Dissatisfaction with sleep This may reflect an individual preference to quality or quantity self-treat using alternative treatments which are 8–18% not included in the true costs of insomnia such as antihistamines or alcohol.27 There may also be an Insomnia association of insomnia as a stigma and therefore a diagnosis 6% reticence to present for treatment even when the severity of symptoms significantly impacts on quality of life (QoL).29

FIGURE 1 Average prevalence of insomnia symptoms and In the area of healthcare provision, there may be a diagnoses (adapted from Ohayon18) lack of comprehensive assessment and treatment of symptoms. A failure to include questions regarding sleep and sleep quality in routine health visits The prevalence of insomnia has historically been limits the case detection rates and therefore the reported to be higher in women and to increase prevalence and effect of insomnia can never be with age.18 Multi-variant analysis of French adequately assessed.29 Hypotheses that explain the population data25 identified that low family lack of comprehensive assessment of insomnia have income, being female, being >65 years of age and been put forward but not researched. They include being separated, divorced or widowed were issues related to health professionals’ knowledge significantly associated with sleep difficulty. Recent and training regarding the diagnosis and research cited by Holbrook and colleagues7 treatment of insomnia, a lack of belief in an ability suggests that insomnia may be less correlated with to provide effective care and time constraints.30 age and more closely related to other physiological conditions and treatment of these Assessment tools have been developed to assess conditions. Regression analysis carried out by the impact of insomnia (and treatment) on QoL.31 Pallesen and colleagues23 in a Norwegian survey Some of the tools are general health measures revealed that somatic and psychiatric health were [e.g. Short Form with 36 items (SF-36)] whereas in fact the strongest predictors of insomnia. Given others have been specifically designed to assess that physiological complaints increase with age, it insomnia and may or may not have been could be expected that prevalence of insomnia validated.32 In some studies, a combination of would also increase. Overall prevalence of tools have been utilised.31 Leger and colleagues,33 insomnia among older people living in the in an evaluation of the SF-36 in relation to community varies from 12 to 39.8%.26 insomnia, point out that surprisingly few studies have investigated QoL related to insomnia and go Pallesen and colleagues23 also stated that 6.9% of on to say that they were able to identify only four the population reported using hypnotics. This rate studies that included QoL as an outcome. Leger of use of hypnotics is similar to the results of a and colleagues33 indicated that QoL is decreased French survey25 that identified 10% of the in those individuals suffering from insomnia and population who were taking sleep medication and that degradation of QoL was correlated with the that for most, consumption had been long term. severity of the insomnia. However, they go on to Of those taking medication, 82% had been using point out that the original cause of the insomnia hypnotics for more than 6 months and 31% had may have a significant effect on their findings. been using them for more than 5 years. This is discussed specifically in relation to general health status of the individuals suffering from Burden of illness insomnia. For instance, if the initial problem It is difficult to estimate the impact of insomnia. leading to insomnia is a chronic disease, it is not Some argue that insomnia is undertreated.13,27 possible to differentiate the effects of the disease Reasons for this may be attributed to the response from the effects of the insomnia on the QoL. 5

The difficulties experienced in differentiating 59 studies that examined the effectiveness of between effects of recurrent, persistent or multiple non-pharmacological interventions to improve health problems and insomnia in relation to QoL sleep onset, maintenance or mixed insomnia. They are also experienced when attempting to assess the concluded that non-pharmacological interventions effects of insomnia on measures such as disability are effective in producing reliable and durable and healthcare utilisation. Epidemiological surveys changes in sleep patterns in patients with chronic consistently report higher levels of physical illness insomnia. A more recent systematic review by Petit and disability and healthcare utilisation in and colleagues5 that examined diagnosis and respondents reporting insomnia.21,24,25,33 As stated treatment of insomnia in the elderly recommended by Leger and colleagues33 “we could conclude only the initial use of non-pharmacological that insomnia was related to a worse health status interventions. Consensus statements such as one and not whether it was a cause or consequence of published in Canada16 recommend the use of this worse health status”. non-pharmacological interventions as first-line treatment for insomnia. In general, the systematic In a similar context, it is difficult to measure the reviews indicate that behavioural interventions impact of insomnia on daily alertness and appear to be as effective as pharmacotherapy in productivity. As an example, one company the short term37–39 and in some cases are reported submission34 included extensive discussion as superior in the long term.40 The limited use of regarding sleepiness and the incidence of road these interventions has been highlighted in a traffic accidents (RTAs). Although there may well systematic review carried out by Perlis and be data to support a causal link between RTAs and colleagues,39 who discuss causes as a lack of sleepiness, such data does not directly link to trained providers, cost, lack of third-party insomnia. reimbursement and lack of understanding of the treatment methods. Treatment options Pharmacological treatment Pharmacological agents are generally accepted as Treatment may vary depending on the presenting effective in reducing sleep latency, increasing total symptoms and other coexisting health problems. sleep time and reducing periods of awakening, In cases of primary insomnia, the treatment will although the extent of the benefit is questioned by aim to reduce insomnia symptoms alone, whereas some.41 Benzodiazepines have been the treatment in cases where insomnia symptoms are linked to of choice for insomnia since the mid 1960s.16 other general health complaints (physical or They act at specific benzodiazepine receptors to mental), the treatment will aim to address the enhance the binding of the inhibitory more complex combination of symptoms. neurotransmitter GABA. There are a variety of benzodiazepines licensed in the UK as hypnotics, Ideally, effective treatment for insomnia should and others are licensed as sedatives or anxiolytics. normalise sleep patterns but, importantly, not There is little real difference in the effects of these impair next-day function. However, the use of drugs: the decision as to whether a drug is an prescribed medication will be influenced to a great anxiolytic or a hypnotic is partly based on its extent by the patient’s perception of efficacy and pharmacokinetics, but is largely a commercial the absence of what could be considered adverse decision. A recent systematic review by Holbrook effects, such as impact on mood and daytime and colleagues in Canada41 of their use concluded function. that “the use of benzodiazepines in the treatment of insomnia is associated with an increase in sleep Non-pharmacological treatment duration, but this is countered by a number of Non-pharmacological treatments include adverse effects”. The adverse effects include interventions such as sleep hygiene measures and tolerance, dependence, rebound insomnia and a variety of behavioural activities such as cognitive impairment of daytime functioning.16 therapies, relaxation and sleep restriction. In the UK, guidelines for these were published in 1992.35 Zaleplon, zolpidem and zopiclone (Z-drugs) are non-benzodiazepine hypnotics introduced in the A number of systematic reviews have compared the late 1980s and 1990s and are only licensed for effectiveness of non-pharmacological interventions short-term (2–4 weeks) use for the treatment of to pharmacotherapy and reported similar results. insomnia in the UK. Although not chemically In a systematic review by Morin and colleagues benzodiazepines, they interact with the 6 published in 1994,36 the authors identified benzodiazepine receptors or with some particular Health Technology Assessment 2004; Vol. 8: No. 24

types of benzodiazepine receptors. It was hoped behavioural effects of zolpidem with that these drugs might avoid some of the adverse benzodiazepines and concluded that there was not effects of benzodiazepines, such as tolerance, enough research to draw firm conclusions. dependency and withdrawal symptoms. Zopiclone belongs to the cyclopyrrolone group Zaleplon, the most recently approved drug, is a and, like benzodiazepines, is less selective in its pyrazolopyrimidine compound and binds binding. A general review of this agent indicates selectively to the omega-1 site of the receptor. Two that compared with placebo, it is effective in published reviews with slightly different inclusion decreasing sleep latency, increasing sleep duration criteria examined the effectiveness of zaleplon and decreasing number of awakenings.49 This versus placebo.42,43 The reviews included studies same report in addition to a summary by Terzano that evaluated both patients with insomnia and and collegues,50 indicates that the drug may cause healthy volunteers and came to slightly differing some next-day impairment, especially in higher conclusions. doses.

Eight studies summarised by Maidment42 report a Table 2 gives the hypnotic agents currently listed in 6–16-minute decrease in sleep latency with the BNF, March 2003,51 for the short-term zaleplon. Results related to symptoms of rebound management of insomnia and included in this insomnia were mixed, but consistently indicated review. less hangover effect from use of the drug compared with placebo. Patat and colleagues43 Although pharmokinetic parameters are identified 16 studies comparing zaleplon with important, as we shall see, the elimination half-life placebo of which nine assessed the administration is a poor guide to duration of action, particularly of twice the normal dose of the drug. The primary as some of these drugs have active metabolites. focus of the review was the effect on psychomotor performance. Data on sleep latency and duration Several other benzodiazepines used for the were discussed but not presented. The authors treatment of insomnia are not included in this concluded that the recommended dose of 10 mg review. These are flunitrazepam and flurazepam, did not impair psychomotor and memory which hold a UK marketing authorisation but are performance but that administration of double the not approved for use in the NHS, and triazolam, dose was found to impair participant for which marketing authorisation has been performance. A third review by Dooley and withdrawn in the UK. Plosker44 also included a comparison of zaleplon with placebo and, consistent with the other There are other drugs licensed as hypnotics, such reviews, identified a decrease in sleep latency. as chloral hydrate and its derivatives and Insufficient data were available at the time of that clomethiazole, but these are considered less review to compare the effectiveness of zaleplon suitable because of the dangers of overdose and of with those of the other two Z-drugs. dependency, and are little used. These are not considered further in this report. Zolpidem is an imidazopyridine that binds selectively to only one (omega-1) receptor subtype Other drug therapies include over-the-counter of benzodiazepine. A review examining the safety (OTC) drugs available through pharmacies of zolpidem45 included reports on postmarketing without prescription. These have a limited efficacy surveillance, rebound insomnia and safety of use and safety database in this indication. The extent in the elderly. The authors conclude that there was of their use is not clear but a recent report raises a low incidence of adverse events, no statistically concerns that perhaps as many as half of the users significant rebound insomnia and a minimal risk of such drugs are using them in an inappropriate of abuse when the drug is prescribed as manner.52 These drugs are not considered further recommended and used in short-term treatment. in this report. Unden and Schechter46 included 30 trials in a systematic review assessing the next-day effects of zolpidem and concluded that there were limited Outcome measures next-day effects but that use of the drug was recommended when the individual could get a full Sleep measures night’s sleep prior to resuming next-day activities. As noted earlier, the assessment of sleep can be A review by Holm and Goa47 drew the same subjective or objective. Subjective measures may conclusions. A review by Rush48 compared include the use of patient diaries that report 7

TABLE 2 Pharmacological agents included in this review

b Pharmaceutical agent Product name Dose (mg) tmax (h) Elimination (Supplier)a half-life (h)

Diazepam Tablets* 5–15 0.5–1.5 24–48 Tensium® Rimapam® Oral solution: Dialar®

Loprazolam Tablets* 1, increased to 1.5 or 2; elderly (or debilitated), 0.5–12–44–11

Lorazepam Tablets* 1–2210–20

Lormetazepam Tablets* 0.5–1.5; elderly (or debilitated), 500g1–1.5 11

Nitrazepam Tablets* 5–10; elderly (or debilitated) 2.5–5 1.5–224–30 Remnos® Mogadon® Oral suspension: Somnite®

Temazepam Tablets* 10–20, up to 30–40; elderly Oral solution* (or debilitated), 10, up to 20 0.3–0.7 8–15

Zaleplon Capsules: Sonata® 10; elderly, 5 1 1 (Wyeth)

Zolpidem Tablets*: Stilnoct® 10; elderly (or debilitated), 5 <3 2.5 (Sanofi-Synthelabo)

Zopiclone Tablets*: Zimovane® 7.5; elderly, initially 3.75, increased (Rhone-Poulenc Rorer) if necessary 2 3.5–6.5

a An asterisk indicates availability as non-proprietary. b Time to peak plasma concentration

perceived quality and quantity of sleep, and Table 3 outlines the primary measures and scoring reports of feelings of well-being the next day. tools used to assess psychomotor functioning, Objective measures include evaluation of the memory, mood and sleep quality. quantitative aspects of sleep and may include sleep latency (how long it takes to get to sleep), total sleep time (how long you stay asleep) and number Adverse events of awakenings after falling asleep. Other less common measures assess the amount of time it Dependency, withdrawal and tolerance takes the individual to return to sleep if they wake Perhaps the adverse effects of these drugs which and whether they wake earlier than desired and give rise to greatest concern are their potential to are unable to return to sleep. lead to the related phenomena of dependency, withdrawal and tolerance. Drug dependency is not Psychomotor, mood and memory only a function of the drug, but also of the user – outcomes not all users of hypnotics become dependent, as Measures of mood and sleep quality are normally described by Tyrer,54 and careful patient selection undertaken via self-reported measures. The can reduce the risk of dependency. efficacy and correlation of self-reported measures for postsleep questionnaires have been reported53 The WHO (quoted in Lader,55 p. 54) defines drug and validated mood questionnaires are available. dependency as “A state, psychic and sometimes Self-reported measures often use a visual analogue also physical, resulting from the interaction 8 scale (VAS) or Likert scale to obtain scores. between a living organism and a drug, Health Technology Assessment 2004; Vol. 8: No. 24

TABLE 3 Measures and scoring mechanisms of measures

Measure Test Scoring mechanism

Spiegal sleep questionnaire Quality of sleep Likert scale, score range 1–5, i.e. morning Morning condition disposition: 1 very bad, 2 bad, 3 as usual, 4 good, 5 excellent

Norris mood rating scale Mood 18-item VAS, e.g. alert/drowsy, calm/excited, attentive/dreamy, elated/depressed

Hamilton rating scale for anxiety Anxiety Likert scale

Tolouse–Peron attention test Graphic symbols Interval

Sleep questionnaire/diary Sleep quality VAS or Likert scale (unspecified) Daytime arousal VAS or Likert scale Sleep quality VAS or Likert scale Morning alertness VAS or Likert scale

Patient rating of efficacy Sleep quality VAS or Likert scale (unspecified)

Patient questionnaire Sleep quality VAS or Likert scale

Memory test (unspecified) Graphic symbols Interval

Alertness (unspecified) Cancellation test Interval

Psychomotor tests Symbol copying Interval (unspecified) Digit symbol substitution Interval Tapping rate Interval Auditory reaction time Interval

Syndrom Kurztest Nine subscales test short-term Interval memory and concentration

Leeds psychomotor tester Choice reaction time Interval Critical flicker fusion Interval

Cancellation test (unspecified) Letter cancellation Interval

Short-term memory (unspecified) Number recall Interval Cued recall Interval Implicit recall Interval Alertness Interval

Long-term memory (unspecified) Sustained attention Interval Divided attention Interval

Mood question (study designed) Seven questions (all unspecified) Likert scale (probable but not specified)

Life events (unspecified) Unspecified Unspecified

characterised by behavioural and other responses In a systematic review, Linsen and colleagues57 that always include a compulsion to take the drug identified a large degree of disagreement between on a continuous or a periodic basis in order to definitions of dependency used in studies of experience its psychic effects, and sometimes to benzodiazepines. The most consistently used avoid the discomfort of its absence.” This concept criteria for physical dependency included specific of dependency has caused confusion when withdrawal syndromes or symptoms after researchers begin to refer to either physical or discontinuation of the drug. Many consider the psychological dependency.56 most important adverse effect of hypnotic use to 9

be physical dependence58 which the WHO defines (rather than the general population), poor as “the development of an altered physiological compliance in discontinuation studies, the state which requires continued administration of a required length of observation, particularly for drug to prevent the appearance of a characteristic longer acting drugs, and the inconsistency in illness, the abstinence syndrome” (quoted in defining and measuring withdrawal, in addition to Lader,55 p. 54). the overlap between withdrawal symptoms and symptoms for which the drug was taken.58,61,62 Researchers define the withdrawal syndrome in different ways. In Lader’s view,59 withdrawal Tolerance is generally defined as a decrease in a syndrome is generally accepted to include a drug’s effect with continued administration, which minimum of three new symptoms emerging after results in the need to increase the dose of the withdrawal of the drug (i.e. symptoms not present drug.59 A progressive decrease in pharmacological before treatment). He lists the typical withdrawal effects of a drug with repeated administration is symptoms as perceptual hypersensitivity with an indication of the development of tolerance (see photophobia, hyperacusis and hyperalgesia, and Lader,63 p. 136). systemic symptoms such as anorexia, malaise and bodyweight loss. Further psychological symptoms, Benzodiazepines such as insomnia or anxiety, may be difficult to Dependency can occur after discontinuation of identify and distinguish from symptoms present therapeutic doses of benzodiazepines.64,65 It has prior to treatment. This same phenomena is called been suggested that the proportion of chronic ‘discontinuation syndrome’ by Nutt and may be users who are physically dependent on their linked to physical symptoms that were not originally treatment may be as high as 10–30%, even on associated with a need for the drug (Nutt D, therapeutic doses.66 Noyes and colleagues61 noted University of Bristol: personal communication, that controlled studies of long-term use of 2003). In the case of benzodiazepines, this may benzodiazepines (over 1 year) report an incidence include sensations such as metallic taste or of withdrawal syndromes (equated with hypersensitivity to light or sound.60 dependency) in nearly half of the patients.

Nutt explains these phenomena as follows: It has been suggested that shorter acting “Physical dependency manifests itself through the benzodiazepines may be more likely than expression of a withdrawal syndrome that is long-acting ones to induce dependence.62 thought to occur as a consequence of adaptive However, Woods and colleagues65 were not able to changes developing to attenuate or compensate conclude from their literature review that there for the actions of a drug. These lead to a change was a difference between different in physiological activity when the drug is stopped. benzodiazepines with regard to their potential to Such withdrawal syndromes come in two distinct induce physical dependency. forms that I suggest should be called rebound and discontinuation syndromes.” Nutt goes on to Gudex58 suggested that slowly eliminated drugs define rebound as the worsening of the condition show milder rebound insomnia than rapidly for which the drug was originally prescribed. This eliminated benzodiazepines. Lader59 concurs with may include increased sleep latency, decreased this view, whereas Woods and colleagues65 total sleep time or an increase in the number of conclude more optimistically that long-acting nocturnal awakenings. He also points out that benzodiazepines do not appear to produce these rebound symptoms may be so severe that in rebound insomnia. However, a systematic review of fact patients experience worse symptoms than sleep laboratory studies by Soldatos and those for which they were originally treated – a colleagues67 examined the issue from a slightly process he describes as ‘overshoot’ (Nutt D, different perspective and concluded that one University of Bristol: personal communication, rapidly eliminated benzodiazepine (triazolam) has 2003). It has been suggested that the study of more pronounced tolerance and rebound rebound phenomena is complicated by the fact symptoms than zolpidem. that blinding of subjects and assessors in a trial is difficult to maintain in a withdrawal phase.1 Long-term use, high doses, high potency, alcoholism and other drug dependencies, There are several methodological problems in personality disorders and use without medical studying withdrawal. These include a lack of supervision have been suggested to be major risk double-blind comparisons, the selection of subjects factors for developing dependency when using 10 already having difficulty discontinuing their drugs benzodiazepines.68 Woods and colleagues65 Health Technology Assessment 2004; Vol. 8: No. 24

reported that there is no clear relationship between caution in using higher doses. A relatively recent either dose or duration and the development of meta-analysis of sleep laboratory trials and dependency on benzodiazepines. Others, however, before–after studies assessed tolerance and disagree61 and point to the clear dose–effect rebound insomnia following the use of rapidly relationship for the occurrence of rebound eliminated hypnotics, and concluded that there insomnia following benzodiazepine withdrawal. was evidence of only marginal tolerance and mild However, Lader63 concluded that there appears to rebound insomnia following cessation of zolpidem, be no relationship between rebound insomnia and compared with clear tolerance and intense duration of treatment with benzodiazepines. rebound insomnia after triazolam Petursson and Lader64 suggested that some degree discontinuation.67 of tissue tolerance or adaptation might occur in most patients using benzodiazepines, but this does Zopiclone not equate to dependency since most patients The incidence of withdrawal symptoms after maintain constant doses. zopiclone discontinuation is suggested to be considerably lower than that of benzodiazepine Zaleplon comparators.71 Hajak71 indicated that nearly all There are reports from placebo-controlled studies reports of zopiclone dependency concerned of withdrawal symptoms including rebound patients with a history of other drug abuse. insomnia following zaleplon discontinuation, but Lader63 concluded that the risk of dependency the incidence is suggested to be low.44,69 Reviews after normal doses is negligible. However, caution of trials and follow-up studies involving zaleplon with the use of both zopiclone and zolpidem is concluded that no significant rebound events had recommended, given an as yet “unclear been identified following zaleplon dependence potential”.50,72 discontinuation,42,44 although some trials have identified rebound insomnia (see review by Bianchi and Musch73 reviewed 25 laboratory Maidment42). A review by Dooley and Plosker44 sleep studies and clinical trials observing noted that there is no evidence of tolerance in the zopiclone discontinuation, 20 of which were available small number of trials and longer-term performed on insomniacs. No rebound effect on non-comparative follow-up studies. sleep variables and few withdrawal effects were observed after zopiclone. For the purpose of their The WHO Expert Committee on Drug review, any signs or symptoms during withdrawal Dependence56 reviewed zaleplon at its September were counted as withdrawal effects, whereas 2002 meeting in Geneva. The Committee noted rebound was defined as a statistically significant that zaleplon produces a benzodiazepine-type worsening of sleep variables during withdrawal withdrawal syndrome and considers its abuse compared with baseline. Anxiety and vertigo were potential to be similar to that of zolpidem and the main withdrawal symptoms reported after triazolam. Nevertheless, the Committee stopped zopiclone use. short of recommending a critical review, because of insufficient evidence as yet of an associated Several authors have concluded that zopiclone significant public health and social problem. shows a potential to cause rebound,1 but much less likelihood to do so than benzodiazepine Zolpidem comparators.59,63 It has been suggested, however, The WHO Expert Committee on Drug that pill discontinuation per se may cause rebound Dependence in 2000 recommended zolpidem be insomnia, as demonstrated in a placebo group.71 placed in Schedule IV of the 1971 Convention. Similarly, Lader63 suggested that most studies The Committee observed that “rates of actual show no evidence for tolerance developing during abuse and dependency on zolpidem appear to be treatment with zopiclone. similar to those of other hypnotic benzodiazepines currently listed in Schedule IV. In terms of the The WHO Expert Committee on Drug numbers of cases for abuse, dependency and Dependence56 reviewed zopiclone again at its withdrawal syndrome reported to the WHO September 2002 meeting in Geneva and Adverse Drug Reaction database, less than 10 recommended the substance for “critical review”. benzodiazepines are ranked higher than The Committee noted zopiclone’s capacity to zolpidem” (WHO,70 p. 15). produce withdrawal syndrome and abuse potential, as evidenced by the adverse drug Lader59 notes that there is little evidence for reaction reports to the international drug rebound after zolpidem 10 mg, but suggested monitoring programme. 11

Current service provision general concern about the misuse of these drugs in medical practice (in addition to concern about The Committee on Safety of Medicines has, since their diversion to illicit use). 1988, had clear guidance on containing the use of these drugs to no more than 4 weeks,51 and this is Reflecting this, Prodigy79 (Department of echoed by the Royal College of Psychiatrists.74 The Health/NICE funded computer decision support BNF51 now stipulates that hypnotics should not be system for general practitioners) outlines prescribed for more than 3 weeks and preferably guidelines on the use of hypnotics which are in for intermittent use. They should therefore be effect a consensus statement and these state: reserved for short courses for acutely distressed patients. Despite this advice, long-term use of 1. Use non-drug treatments where possible, these drugs is common: in a recently published including simple advice and counselling. study conducted in The Netherlands and Sweden, 2. If the insomnia is severe, disabling or one-third of patients prescribed benzodiazepines subjecting the individual to extreme distress, had continued use over 8 years follow-up.75 More consider prescribing a hypnotic as an adjunct recent survey data from the UK indicate that to non-drug treatment: chronic (≥4 years) hypnotic use was common (a) Use the lowest effective dose for a among older patients.76 maximum of 1 week. (b) Consider using intermittently (e.g. once In the second quarter of 2002, the UK Prescription every other day, every third day). Pricing Authority77 recorded over 1.5 million items of benzodiazepines (i.e. temazepam, nitrazepam, The National Service Framework on Mental loprazolam, and lormetazepam, with over 1 million Health80 contains a number of recommendations items for temazepam alone) having been prescribed around monitoring benzodiazepine use in local at a net ingredient cost (NIC) of over £2.39 audit (and, although not explicitly stated, usually million. In the case of benzodiazepines it is not taken to include the newer hypnotics). Although possible to differentiate whether the drugs were there are no explicit recommendations on standards prescribed for hypnotics or anxiolytic purposes. for this audit, it is implicit that high usage of these The three Z-drugs accounted for £3.86 million drugs would be considered bad prescribing. (NIC) for over 940,000 items, with zopiclone accounting for over 80% of the prescribed items. Against this background, this report considers the clinical and economic evidence around the Data from the DIN-LINK network4 and the comparative benefits of newer medicines General Practice Research Database78 suggest that compared with the older drugs. We have not at any given time ~0.5–1.4 million people are considered how appropriate it is that these drugs using hypnotics in the UK. The extent of this use should ever be used, as this is outside our remit, is discussed in Chapter 7. However, there is but this is clearly an important issue.

12 Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 3 Methods

Methods for reviewing clinical retrieved. Full-text copies of the selected papers effectiveness were obtained and each assessed independently by at least two reviewers for inclusion (YD, JS, RD). Search strategy The search included a number of strategies. The Details of inclusion and exclusion criteria are electronic databases were searched for the period presented in Table 4. from 1966 to March 2003 (see Table 4). The search had no language restrictions. Search terms for Data extraction electronic databases included a combination of Data extraction was carried out by four reviewers index terms (e.g. sleep initiation and maintenance (YD, RD, JS, SD). Individual study data relating to disorders or insomnia) and free text words (e.g. study design and findings were extracted and insomnia or sleeplessness) combined with specific checked by two reviewers using a pretested data drug terms (e.g. zaleplon or Sonata, zolpidem or extraction form. Data from baseline and first night Stilnoct, zopiclone or Zimovane). Details of the after discontinuation of treatment were extracted search strategies used and the number of where more than one data point was available. references retrieved for each search are provided in Table 20, Appendix 1. Quality assessment At least two reviewers (YD, RD, JS, SD) Reference lists of retrieved articles and independently evaluated the included studies for pharmaceutical company submissions were methodological quality. This involved searched to identify further studies. Recent issues methodological assessment for clinical (October 2002 to June 2003) of relevant journals effectiveness based on the Centre for Reviews and 81 that might not yet have been indexed in electronic Dissemination, York, Report 4 (see Appendix 2). databases were handsearched; the journals Any discrepancies were resolved through consensus. searched included European Psychiatry, Human Psychopharmacology: Clinical and Experimental, International Clinical Psychopharmacology, Psycho- Extended review on dependence pharmacology, Sleep, Sleep Medicine, Sleep Medicine and withdrawal symptoms Reviews, The British Journal of Psychiatry and The Journal of Clinical Psychiatry. Internet resources Drug trials are usually too short to be able to (including industry-supported websites) were assess the development of drug dependence. examined for information on clinical trials. Therefore, the research group conducted an extended search to identify studies of other An advisory panel was established to guide the designs which might help address the question of review process. The role of the advisory panel was the relative potential of the comparison drugs to to comment on the review protocol, to answer induce drug dependence and withdrawal. specific questions as the review progressed and to comment on an early draft of the review, including Search strategy and inclusion and identifying missed or ongoing studies. exclusion criteria Search terms for this expanded search included a All references were exported to the EndNote reference combination of index terms (e.g. withdrawal database, Version 6.0, ISI ResearchSoft, Berkeley syndrome, drug tolerance, drug withdrawal) and CA, USA. free text words (e.g. withdrawal, dependency, tolerance, rebound) combined with specific drug Inclusion and exclusion criteria names including zaleplon or Sonata, zolpidem or The identified citations were assessed for inclusion Stilnoct, zopiclone or Zimovane. Search strategies through two stages and disagreements were resolved did not include filters that would limit results to by discussion at each stage. Two reviewers (YD, JS) specific publication types or study designs. Only independently scanned all the titles and abstracts English-language reports were identified because and identified the potentially relevant articles to be of time restrictions. Details of the search strategies 13

TABLE 4 Databases searched and inclusion and exclusion criteria for clinical and cost-effectiveness

Clinical effectiveness Extended review: Cost-effectiveness dependency and withdrawal symptoms

Electronic MEDLINE (1966–2003) MEDLINE MEDLINE (1987–2003) databases EMBASE (1980–2003) EMBASE EMBASE (1987–2003) PsycINFO (1966–2003) PsycINFO PsycINFO (1974–2003) SCI//Web of Science SCI//Web of Science (1981–2003) (1987–2003) SCI/ISI Proceedings (1990–2003) SCI/ISI Proceedings (1990–2003) The Cochrane Library 20031 The Cochrane Library 20031

Study design RCT RCT RCT Case–control studies Economic analyses Case series Case reports Cohort studies Surveys

Patient population Individuals with insomnia Individuals with insomnia Individuals with insomnia

Interventions Zaleplon, zolpidem, zopiclone: Zaleplon, zolpidem, zopiclone: Zaleplon, zolpidem, zopiclone: • compared with • compared with • compared to benzodiazepinesa • benzodiazepines • benzodiazepinesa • compared with each other • compared with each other • individually or compared • with each other

Outcomes Sleep latency Dependency Cost per increase in sleep Sleep duration Withdrawal symptoms duration Number of awakenings Cost per decrease in sleep Sleep quality latency Daytime alertness Cost per adverse effect avoided Tolerance Cost per quality-adjusted Rebound life-year gained Abuse potential Adverse effects including dependency and withdrawal

Exclusion criteria RCTs that: RCTs that: Papers were excluded if: • provide data on a subgroup • provide only unplanned, • the main source of clinical • of the enrolled patients • interim findings • efficacy data was from a • provide only unplanned, • provide data on a subgroup • non-RCT or not explicitly stated • interim findings • of the enrolled patients • there was no attempt to • are continuing to recruit • are continuing to recruit • synthesise costs and benefits • patients • patients • they were letters, editorials, • include volunteer subjects • include individuals without • commentaries or • that do not report symptoms • symptoms of insomnia • methodological papers • of insomnia in their study • population • compares benzodiazepines • not currently licensed for • use in the management of • insomnia in the UK

a The BNF51 refers to the following benzodiazepines for the short-term management of insomnia: diazepam, loprazolam, lorazepam, lormetazepam, nitrazepam and temazepam.

used and the number of references retrieved for Data extraction each search are provided in Table 21 in Appendix 1. Data extraction was carried out by two reviewers Electronic databases searched and inclusion and (YD, JS). Individual study data relating to study 14 exclusion criteria are detailed in Table 4. design and findings were extracted independently Health Technology Assessment 2004; Vol. 8: No. 24

by one reviewer into a predesigned data extraction All the references were exported to the Endnote form and checked by a second reviewer. reference database, Version 6.0. Meta-analysis of results Methods for reviewing The outcomes that were considered in the cost-effectiveness identified studies were:

Search strategy G sleep onset latency A comprehensive review of the literature was G total sleep duration undertaken to identify all published articles that G number of awakenings could provide evidence with regard to the cost- G quality of sleep effectiveness of newer hypnotic drugs for the G adverse effects management of insomnia. G rebound insomnia (sleep onset latency, total sleep duration, number of awakenings, quality The search included a number of strategies. of sleep). Search terms for electronic databases included a combination of index terms (e.g. sleep initiation The studies identified were grouped and and maintenance disorders or insomnia) and free presented according to the following comparisons: text words (e.g. insomnia or sleeplessness) combined with specific drug terms (e.g. zaleplon 1. Z benzodiazepine comparisons or Sonata, zolpidem or Stilnoct, zopiclone or (a) zolpidem versus nitrazepam Zimovane). Clinical terms were combined with (b) zolpidem versus temazepam economic terms (e.g. cost or economic). (c) zopiclone versus lormetazepam (d) zopiclone versus nitrazepam Reference lists of retrieved articles and (e) zopiclone versus temazepam. pharmaceutical company submissions were also 2. Z Z comparisons searched to identify further studies. (a) zaleplon versus zolpidem (b) zolpidem versus zopiclone Electronic databases searched are presented in Table 4. Search strategies and results of the Meta-analyses were carried out when possible searches undertaken are provided in Table 22, between studies that compared the same drugs. If Appendix 1. extracted data were unsuitable for combination using meta-analysis, data were shown in a Forest Inclusion and exclusion criteria plot. Scales used to assess outcomes differed The aim of the economic review was to identify between studies and, therefore, to avoid problems economic evaluations informed by clinical data in interpretation when scale direction differed from randomised controlled trials (RCTs). After also, mean values were negated when a decreased scanning the abstracts, all papers that appeared to score indicated improvement. This was carried out be of potential value to the study were obtained. to create a uniform direction of improvement on Using explicit, predetermined criteria (see the Forest plots, so that an increase in mean score Table 4), two reviewers (AB, AH) independently indicated improvement. Crossover trials with less identified studies for inclusion in the than two nights’ washout were excluded from the cost-effectiveness review process. Disagreements analysis. Data were pooled using a fixed-effect were resolved through discussion. The inclusion model (as there was no evidence of statistical and exclusion criteria used in the review are heterogeneity) with odds ratio (OR) and 95% presented below. confidence intervals (CI).

Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 4 Results

Clinical effectiveness RCTs and assessing the efficacy and safety of zaleplon 5 and 10 mg with zolpidem 5 mg and Selection of included studies placebo in a large population of elderly A total of 72 references were identified to which outpatients (986 patients) with insomnia. One the inclusion criteria were applied. Of these, additional RCT was identified within a previously 24 studies met the inclusion criteria (Table 5). published review.44 It compared zaleplon 10 and These included 17 studies comparing a Z-drug 20 mg, zolpidem 10 mg and a placebo in patients with a benzodiazepine82–98 and seven (reported in with primary insomnia (130 patients). A request to six reports) comparing a Z-drug with another the author revealed that the study was part of a Z-drug.99–104 Reports of studies which did not fulfil pan-European multicentre study initiated by the the inclusion criteria are available in Appendix 4. pharmaceutical company Wyeth Ayerst. The The reason for exclusion is given for each of these author did not have access to the data. excluded references. Identification of this study occurred in the final stages of the preparation of this report. It has not Twenty studies were assessed from reports yet been possible to ascertain if the data from published in peer-reviewed journals. The these studies are already included in this review. remainder were published abstracts of conference proceedings.89,99,103 Of these, two studies are Study characteristics reported in one abstract.103 The 24 included studies involved a total study population of 3909 patients, ranging in size from Four studies86,88,91,92 were published in Japanese 10 patients90 to 615 patients.100 Thirteen studies language journals. A Japanese native speaker had fewer than 100 patients in total; only three assisted the review team with data extraction and studies100–102 had over 500 patients. interpretation, but we were not able to extract data related to specific measures used to assess Fifteen of the included studies were multicentred. psychomotor, memory and mood outcomes. Of these, six were conducted in Europe,83–85,89,94,99 five in Japan,86,88,91,92,104 three in the USA,82,101,102 The review team identified two reports (presented and one in Canada and Europe.100 The remainder as conference posters) from one of the Industry were single centred. Five were carried out in Submissions to the National Institute of Clinical Europe,87,90,93,97,98 two (published in one report) Excellence (NICE).4 One105 was a pooled analysis in the USA103 and one each in Malaysia95 and of three RCTs evaluating global assessment of the Canada.96 efficacy of zaleplon 5, 10 and 20 mg and zolpidem 10 mg, compared with a placebo in the treatment The majority of studies incorporated key of outpatients (1840 patients) with insomnia. The characteristics of the DSM-IV criteria for the other106 was also a pooled analysis including two diagnosis of insomnia. One study did not state

TABLE 5 Summary of included clinical studies

Zolpidem/ Zolpidem/ Zopiclone/ Zopiclone/ Zopiclone/ Zaleplon/ Zolpidem/ nitrazepam temazepam lormetazepam nitrazepam temazepam zolpidem zopiclone

Kazamatsuri, Kerkhof, 199689 Ansoms, 199183 Agnoli, 198984 Ngen, 199095 Allain, 200199 Tsutsui, 199386 Leppik, 199782 Anderson, 198785 Stip, 199996 Ancoli-Israel, 2001104 Kudo, 199388 Jovanovic, 198390 van der Kleijn, 1999102 Klimm, 198787 198997 Elie, 1999100 Ohtomo 1, 198591 Wheatley, 198598 Fry, 2000101 Ohtomo 2, 198592 Zammit 1, 2000103 Pull, 198393 Zammit 2, 2000103 Tamminen, 198794 17

insomnia criteria93 and three listed only that randomisation to allocate participants to a study participants experienced sleep difficulties.98,99,104 group, but only one study reported the method of randomisation or whether the allocation sequence Seven studies82,95,97,98,100–102 acknowledged was concealed.95 funding from a pharmaceutical company for the trial and one104 stated they received the drugs The baseline comparability for each treatment used in the trial from a pharmaceutical company. group was adequately or partially presented in In 10 of the included studies, at least one of the 16 studies and adequately or partially achieved in co-authors was an employee of a pharmaceutical 10 studies. All studies presented the participant company.83,85,87,90,93,94,99–102 eligibility criteria but co-interventions were not reported in any of the included studies. Study duration varied and ranged from from one night93 to 6 weeks.94 In 10 All included studies were described as double studies82,85,89,90,96,97,100–102,104 clinical follow-up blind but made no mention of methods of after the end of the study was available, ranging blinding or reported assessment of the blinding from 3100,101 to 11 days.89 procedure. Fifteen studies reported the number of and reason for withdrawals. Only four Details of study characteristics are provided in studies87,90,98,99 appeared to include an Table 23 in Appendix 3. intention-to-treat (ITT) analysis. Participant characteristics Clinical results and analysis Patients were primarily female. The lowest Results have been grouped by treatment with proportion of females was seen in the study by results from the studies examining Z-drugs versus Ansoms and colleagues83 (zopiclone group 37%, benzodiazepines first, followed by head-to-head lormetazepam group 28%) and the highest was in comparisons of Z-drugs. the study by Klimm and colleagues (80%).87 The mean age of patients (reported in 15 studies) In assessment of sleep outcomes, 10 studies varied across the trials, ranging between 30.190 included placebo groups and compared active and 73.2 years.87 treatment with placebo alone, assessing significance of change from baseline within each Three studies82,91,92 included only patients over group. Direct comparisons between active 60 years of age and two studies87,102 included treatments were not always presented. We report those aged over 65 years. Six studies included all significant findings when direct between- patients diagnosed with a psychiatric disorder. Of treatment comparisons in the studies were made. these, four84,96,100,101 included patients with mild However, the findings should be interpreted with non-psychotic psychiatric disorders, one93 only caution: there is evidence of multiple significance included patients hospitalised for depression, testing of data in most studies, which increases the schizophrenia or alcoholism and one86 only chance of spurious findings. In cases where direct included those with schizophrenia and between-treatment comparisons were not made by manic-depressive psychosis. One study83 only authors and insufficient data were available for us included alcoholic patients who had undergone a to assess formally between-treatment differences, withdrawal period. the results are described in a qualitative manner to allow the detection of any trends. Data from the Participant characteristics are presented in Table 24 run-in baseline period and final week of treatment in Appendix 3. were extracted to determine the efficacy of the treatments. None of the studies reported sample Quality assessment size calculations, which may be an indication of The methodological quality of the included studies insufficient power. is presented in Table 6 using the criteria based on the CRD Report No.4 (see Appendix 2).81 The Sleep efficacy outcomes reported include patients’ CRD checklist includes key aspects of RCT design estimates of sleep onset latency, total sleep and quality. duration, number of awakenings and quality of sleep, recorded from post-sleep questionnaires and Overall, the methodological quality of the from sleep diaries in all but three studies. The included studies was poor. The studies varied in study by Jovanovic and Dreyfus90 and two studies the level of detail for reporting outcomes. Of the by Zammit103 used PSG tracings in a sleep 18 24 included studies, 21 reported that they used laboratory to establish sleep outcomes. In all Health Technology Assessment 2004; Vol. 8: No. 24 s ITT NA NA NA ✗✗ ✗✗✗ ✗✗ ✗✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗✗ ✗ ✗ ✗ ✗ ✗ ✗✗ Withdrawals analysis NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS assessed in final stated final assessed in NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS ✗✗ ✗ ✗ ✗ ✗ ✗ criteria identified specified Baseline Blinding NS NS NS NS comparability NA NA NA NA NANA NA NA ✗ ✗✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗✗ ✗ ✗✗ ✗ ✗ ✗ ✗✗ ✗ ✗ ✗ ✗ ✗✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ , no (item not adequately addressed), / partially addressed); NA, applicable, NS, stated. Randomisation ✗ ✗✗ NSNSNSNS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NSNS NS NS NS NS NS NS NS NS NS NS NS NS NS NS Truly AllocationTruly Number Presented Achieved Eligibility Co-interventions AssessorsReason Administration>80% Participants Procedure random concealment stated 97 102 86 91 92 94 85 90 98 89 83 82 104 87 84 99 95 88 96 1996 93 100 101 Quality assessment of included studies a 103 2001 a 2000 Yes (item adequately addressed); Yes a Quality assessment based on conference abstract only. Zammit 1 and Study Allain, Agnoli, 1989 2, a Ancoli-Israel, 1999 Anderson, 1987 Ansoms, 1991 Elie, 1999 2000 Fry, Jovanovic, 1983 1993 Kazamatsuri, Kerkhof, Klimm, 1987 1993 Kudo, Leppik, 1997 Ngen, 1990 Ohtomo 2, 1985 Pull, 1983 Stip, 1999 1987 Tamminen, 2001 Tsutsui, van der Kleijn, 1989 1985 Wheatley, Ohtomo 1, 1985

TABLE 6 TABLE 19

studies, a variety of rating scales were used for Quality of sleep reporting quality of sleep. Kudo and colleagues88 reported results in favour of zolpidem over nitrazepam regarding improvement Reporting of adverse events was not consistent in the quality of sleep, but did not make a direct across the studies. Some studies reported on all statistical comparison of this difference using a adverse effects whereas others reported significance test. Overall, 66.7% of patients taking treatment-emergent adverse events, which were zolpidem reported an improvement in sleep defined as new events that began after the first quality compared with 37.5% on nitrazepam. dose of active treatment or events that worsened during therapy. These generally include central Adverse events nervous system (CNS)-related events (e.g. dizziness, Both studies86,88 reported data concerning daytime drowsiness, nervousness, light-headedness, side-effects (e.g. dizziness, sleepiness, insomnia, headache and fatigue) and those not related to the fatigue, headache). Meta-analysis of binary data in CNS (e.g. gastrointestinal symptoms). this group was possible, and the difference between treatments was not statistically Key outcomes extracted from the included studies significant with an OR for side-effects on are presented in Table 25 in Appendix 3. The zolpidem compared with nitrazepam of 0.70 (95% summary of results related to the key outcomes is CI 0.37 to 1.30). provided in Table 7. Daytime alertness Ten trials had a period of post-treatment Neither study reported a statistically significant follow-up. These data offer some information difference between active treatment groups regarding rebound insomnia, or temporary regarding mental and physical status on worsening from baseline (see Table 26, in awakening and during the day. Appendix 3). All data are self-reported except in the Jovanovic and Dreyfus study.90 Global impression of treatment Kudo and colleagues88 reported a global Forest plots of the meta-analysis are included in improvement rate of 65.6% in the zolpidem group Figures 2–4. Summary details describing the and 52.2% in the nitrazepam group and psychomotor, memory, mood and patient Kazamatsuri and colleagues86 reported a rate of satisfaction outcomes and the specific measures 58.9% in the zolpidem group and 58.1% in the utilised in the included studies are provided in nitrazepam group. Neither of these differences Table 27 in Appendix 3. was statistically significant (2 test).

Zolpidem versus nitrazepam Zolpidem versus temazepam Two studies, by Kazamatsuri and colleagues86 and Two studies compared these agents. In Leppik and Kudo and colleagues88 compared zolpidem (10 colleagues82 (comparing zolpidem 5 mg with mg) with nitrazepam (5 mg). temazepam 15 mg), sleep onset latency data were reported as being skewed and therefore sleep Sleep onset latency duration data were likely to be skewed also (i.e. the Both studies reported data on sleep latency. No distribution of measurements is asymmetric and significant differences were found between therefore not appropriate for meta-analysis). treatments by Kazamatsuri and colleagues.86 Kudo Kerkhof and colleagues89 compared zolpidem and colleagues88 reported a non-significant 10 mg with temazepam 20 mg. improvement, with 68.4% of patients on zolpidem experiencing an improvement in sleep onset Sleep onset latency latency during the trial compared with 56.4% on Leppik and colleagues82 reported no significant nitrazepam. differences between zolpidem and temazepam with regard to sleep latency, whereas Kerkhof and Total sleep duration colleagues89 reported significantly favourable results Kazamatsuri and colleagues86 reported on sleep for sleep latency in the zolpidem group (after 10 duration, indicating no significant differences days’ treatment and 11 days’ follow-up: zolpidem between the two drugs. 38.8 minutes, temazepam 61.6 minutes, p = 0.05).

Number of awakenings Total sleep duration Kazamatsuri and colleagues86 reported significantly Leppik and colleagues82 presented data on sleep 20 fewer awakenings with zolpidem (p = 0.031). duration but direct comparisons between treatments Health Technology Assessment 2004; Vol. 8: No. 24

were not reported. Zolpidem resulted in a slightly Sleep outcomes larger increase in sleep duration from baseline Data were extracted on sleep onset latency, total than temazepam, but the statistical significance of sleep duration, number of awakenings, quality of this difference could not be assessed from the sleep and adverse events. Medians were calculated extracted data, as the variable was skewed. from raw data given in the paper. All outcomes were measured on a five-point ordinal scale. Quality of sleep Lormetazepam resulted in shorter sleep onset Kerkhof and colleagues89 reported significant latency than zopiclone, and this was the only improvements with regard to subjective estimates statistically significant difference between of sleep quality for the zolpidem group compared treatments (p = 0.013). with the temazepam group (p = 0.03). However, the measurement scale was not defined. Adverse events The percentage of patients who reported adverse Adverse events effects was similar in both groups (26% in the Leppik and colleagues82 reported very similar zopiclone group compared with 28% in the proportions of subjects experiencing lormetazepam group). treatment-emergent adverse events (63% on zolpidem, 67% on temazepam). The resultant OR Global impression of treatment of 0.87 (95% CI 0.46 to 1.64) indicates that this The study utilised a four-point categorical scale difference was not statistically significant. (excellent, good, fair and poor), rated by the investigator, to assess medication efficacy and Tolerance tolerability (overall safety) after active treatment, Leppik and colleagues82 reported data for sleep but no significant difference was found between onset latency and duration on a weekly basis. Both treatment groups. zolpidem and temazepam showed improvements in those outcomes from week 1 to week 4, except Zopiclone versus nitrazepam for sleep duration, which decreased insignificantly Eight studies compared zopiclone with from week 1 to week 4 in the temazepam group. nitrazepam. Agnoli and colleagues,84 Anderson and colleagues,85 Jovanovic and Dreyfus,90 Klimm Rebound insomnia and colleagues,87 Ohtomo and colleagues91 and Leppik and colleagues82 reported that, for sleep Tamminen and Hansen94 compared zopiclone latency and duration, no rebound effects were 7.5 mg with nitrazepam 5 mg; Ohtomo92 found in each of the active treatment groups and compared zopiclone 5 mg with nitrazepam 5 mg the only observed significant differences from and Pull and colleagues93 compared two doses of baseline were improvements. Sleep quality zopiclone (7.5 and 15 mg) with nitrazepam (5 and deteriorated on the first night after withdrawal 10 mg). Of these, the studies by Agnoli and compared with baseline in both treatment groups. colleagues84 and Pull and colleagues93 were crossover trials. However, there was no washout Daytime alertness period in the study by Pull and colleagues, so the Leppik and colleagues82 used a morning results were not included in the meta-analysis. questionnaire to assess morning sleepiness and Agnoli and colleagues84 presented data from each ability to concentrate. The study reports that treatment pooled over both sequence groups, so statistically significant differences were within subject paired comparisons were not “sporadically noted” for these, in addition to other possible. secondary outcomes (ease of falling asleep, number of awakenings, wake time after sleep onset, sleep Sleep onset latency quality). However, no consistent pattern was noted. Data on sleep onset latency were extracted from six trials, but only Agnoli and colleagues,84 Global impression of treatment Tamminen and Hansen94 and Klimm and In Leppik and colleagues82 a global impression of colleagues87 reported both means and standard therapy was elicited but no direct comparisons for deviations. Data from Tamminen and Hansen and active treatment groups were undertaken. colleagues94 were skewed and therefore excluded from the Forest plots. Klimm and colleagues87 Zopiclone versus lormetazepam presented data from a scale of 0 (fast) to 100 Only one study, by Ansoms and colleagues, (slow) in terms of means and standard deviations compared zopiclone (7.5 mg) and lormetazepam of changes from baseline, whereas Agnoli and (1 mg).83 colleagues84 presented means and standard 21

deviations at baseline and the end of treatment increased doses of zopiclone and nitrazepam separately. Sleep onset latency data from Agnoli resulted in more favourable results for sleep onset and colleagues84 were extracted from a graph and latency, but no significant differences were indicated actual latency time in minutes. Means observed in sleep onset latency between from both studies were negated for the Forest nitrazepam (10 mg) and zopiclone (15 mg) and plots, as a decreased mean denoted improvement between nitrazepam (5 mg) or zopiclone (7.5 mg). in sleep onset latency. Meta-analysis of this data However, results from this trial should be was not possible, as the units of measurement interpreted with caution, given the lack of washout differed between studies, and it was decided that period between treatments and the small sample change scores and final values should not be size (acknowledged by the authors). combined in a meta-analysis of standardised mean differences. Tamminen and Hansen94 reported a trend in favour of zopiclone in terms of sleep latency Klimm and colleagues87 reported mean (>30 minutes, zopiclone 38%, nitrazepam 44.4%, differences between the first day of the active after active treatment, p = 0.07). treatment and the last day of the placebo run-in period for sleep latency and the Spiegel sleep Total sleep duration questionnaire was used to assess sleep onset Klimm and colleagues87 used the Spiegel sleep latency. The authors found only one significant questionnaire to assess duration of sleep and difference between the two groups: nitrazepam reported no significant difference between resulted in a greater reduction in sleep onset treatment groups. In the studies by Agnoli and latency on the fifth day (out of seven) of treatment colleagues84 and Tamminen and Hanson,94 no than zopiclone (p < 0.001). significant differences in duration of sleep between treatments were found. In the crossover study, Agnoli and colleagues84 reported that sleep latency was significantly Jovanovic and Dreyfus90 observed a trend in shorter after zopiclone was administered favour of zopiclone in a change from the baseline, (p < 0.001) than after nitrazepam. but the authors did not report the difference between treatment groups as being significant. Data regarding sleep onset latency were extracted from a graph given by Anderson and colleagues.85 In the study by Pull and colleagues93 increased However, direct comparisons between treatment doses of zopiclone and nitrazepam resulted in groups were not made in the paper, and no formal increased sleep duration. However, the differences statistical testing could be carried out using the in sleep duration between nitrazepam (10 mg) and extracted data. Nevertheless, nitrazepam was zopiclone (15 mg) and between nitrazepam (5 mg) observed to lead to a slightly greater reduction in or zopiclone (7.5 mg) were not statistically sleep onset latency from baseline compared with significant. zopiclone. Two Japanese studies by Ohtomo91,92 reported on In the sleep laboratory study, Jovanovic and sleep duration, but only the first91 observed a Dreyfus90 reported a borderline statistically statistically significant difference (p < 0.05) significant difference (p < 0.08) between the between treatments in favour of zopiclone. groups during the early period of active treatment with patients taking zopiclone having shorter Number of awakenings sleep latency than those taking nitrazepam. Six of the included studies in this comparison However, they also acknowledged that, as 50 group reported on the number of awakenings. statistical tests were carried out in this study and Klimm and colleagues87 used the Spiegel sleep the number of statistically significant differences questionnaire to assess the number of awakenings they obtained between the groups was in the range but found no significant difference between of that expected purely by chance, great emphasis treatment groups. In the crossover studies by should not be placed on this result. Agnoli and colleagues84 and Tamminen and Hansen,94 the difference in the number of Pull and colleagues93 compared two doses of nocturnal awakenings between treatments was not zopiclone (7.5 and 15 mg) with nitrazepam (5 and statistically significant. 10 mg) in a crossover trial with no washout between treatments. There appears to be a In the study by Pull and colleagues,93 increased 22 dose–response relationship in both drugs, as doses of zopiclone and nitrazepam resulted in Health Technology Assessment 2004; Vol. 8: No. 24

more favourable results for the number of side-effects on zopiclone compared with awakenings, but neither of the differences in the nitrazepam, 1.46 (0.65 to 3.30)]. number of awakenings between nitrazepam (10 mg) and zopiclone (15 mg) or between nitrazepam Tolerance (5 mg) and zopiclone (7.5 mg) were statistically The 6-week trial by Tamminen and Hansen94 significant. presented week 2 and week 6 data on sleep onset latency and quality of sleep for zopiclone and Two Japanese studies91,92 reported on the number nitrazepam. There was a 24% deterioration of awakenings. Both trials reported no significant between weeks 2 and 6 in sleep quality but a slight differences between treatment groups regarding improvement in sleep onset latency in the the number of awakenings. nitrazepam group. In the zopiclone group, both outcomes showed improvements from week 2 to Quality of sleep week 6. Seven studies reported on sleep quality. Klimm and colleagues,87 Agnoli and colleagues84 and Data on tolerance could not be statistically Tamminen and Hansen94 reported no difference assessed, as standard deviations were not provided in quality of sleep measures. for the changes between initial and final treatment periods. Only Tamminen and Hansen94 and Klimm and colleagues87 reported both means and standard Rebound insomnia deviations. Tamminen and Hansen94 indicated Two included studies, which compared zopiclone final scores from a scale from 0 (good) to 100 with nitrazepam, included post-treatment follow-up, (bad) but the data were skewed and therefore not which allowed assessment of rebound insomnia. shown on the Forest plot. Klimm and colleagues87 The study by Anderson85 reported no significant presented changes from baseline from a scale from change in sleep measures between baseline and 0 (bad) to 100 (good). follow-up placebo week in either the zopiclone or nitrazepam group. Data extracted on sleep latency Data regarding quality of sleep were extracted and quality show an improvement in both groups from a graph given in the study by Anderson,85 in the follow-up week compared with baseline. but no direct comparisons were made between the Jovanovic and Dreyfus90 reported average data for active treatment arms. Although no formal the first three nights post-treatment. No statistical testing could be carried out using the deteriorations from baseline were observed for extracted data, it was observed that the use of either zopiclone or nitrazepam in the main sleep zopiclone resulted in a slightly greater efficacy outcomes. Nights 9 and 10 after improvement in quality of sleep from baseline withdrawal showed a statistically significant compared with nitrazepam. deterioration in the number of awakenings for nitrazepam patients relative to baseline, but no In the study by Pull and colleagues93 increased other deteriorations were observed in either doses of zopiclone and nitrazepam resulted in treatment group on nights 9 and 10 relative to more favourable results for quality of sleep, but baseline. neither of the differences in sleep quality between nitrazepam (10 mg) and zopiclone (15 mg) or Formal between-treatment assessment of these between nitrazepam (5 mg) and zopiclone (7.5 mg) data could not be carried out as the authors were reported as being statistically significant. presented means only.

Two Japanese studies91,92 reported on quality of Alertness sleep. Of these, in the first study Ohtomo91 Alertness/feeling upon awakening. Two Japanese reported a significant difference between treatment studies91,92 measured mental and physical groups in favour of zopiclone (p < 0.05), whereas alertness on awakening. The first study91 found a no significant difference between treatment groups significant difference (p < 0.05) in favour of was detected in the second.92 zopiclone for both mental and physical alertness, but no significant difference was found in the Adverse events second study.92 Only two studies91,92 comparing zopiclone with nitrazepam provided data regarding adverse The study by Agnoli and colleagues84 reported a event rates. The difference between treatments significantly better quality of daytime arousal after was not statistically significant [OR (95% CI) for zopiclone (p < 0.01). 23

Tamminen and Hansen94 reported no significant Global impression of treatment difference between the groups in feeling upon Ohtomo in a first study91 reported a significantly awakening. higher global improvement rate (p < 0.05) with zopiclone compared with nitrazepam, but in a Daytime alertness. Two Japanese studies91,92 second study92 reported no significant difference measured next-day mental and physical condition. in global improvement between treatments. The first study91 reported a significant difference (p < 0.05) in favour of zopiclone for next-day Anderson,85 Pull and colleagues93 and Tamminen mental condition and a trend in favour of and Hansen94 reported no difference in global zopiclone (p < 0.1) for next-day physical assessment of efficacy between treatments. condition. The second study92 found no significant difference in these outcomes between groups. Zopiclone versus temazepam Four trials95–98 compared zopiclone and Agnoli and colleagues84 assessed daytime alertness temazepam. Van der Kleijn97 and Wheatley98 were levels evaluated by the Toulouse–Pieron attention crossover trials. Data provided by Wheatley were test and found significant differences in favour of not included in the meta-analysis, as there was no zopiclone at the end of treatment (omitted items, washout period reported. The trial by Stip and p < 0.05; execution time, p < 0.01). colleagues96 compared temazepam 30 mg with zopiclone 7.5 mg, whereas the remaining three In the study by Anderson,85 a subjective trials compared zopiclone 7.5 mg with temazepam assessment of residual effects was carried out each 20 mg. day by patients shortly after rising. Patients on zopiclone judged themselves to be significantly Sleep onset latency more wide-awake in the morning than did those Ngen and Hassan,95 van der Kleijn,97 Stip and on nitrazepam. colleagues96 and Wheatley98 all reported data on sleep onset latency. In the study by Klimm and colleagues,87 the comparison between the two active treatment Ngen and Hassan95 did not compare zopiclone groups showed only two significant differences: and temazepam directly. Comparisons were made patients on zopiclone felt more alert in the with baseline only. Although the sleep latency morning than those receiving nitrazepam on two results from the last week of the trial favour out of seven active treatment days (day 9, temazepam (mean sleep latency: 64.5 minutes for p < 0.02; day 11, p < 0.01). The Syndrom zopiclone and 26.1 minutes for temazepam), it Kurztest was used to assess short-term memory should be noted that there was a great imbalance (STM) and concentration and the authors between mean sleep latency in the two groups at reported no significant differences in these baseline (122.8 minutes for zopiclone and outcomes between active treatment groups. 50.4 minutes for temazepam) and that the two treatments resulted in very similar relative In the study by Pull and colleagues93 a reduction in sleep latency (47% reduction in the cancellation test was used to assess vigilance and zopiclone group compared with 48% in the awakening, but no statistically significant temazepam group). difference was found between groups. A memory test showed a trend (p < 0.1) in favour of Both van der Kleijn97 and Wheatley98 report no zopiclone. significant treatment differences related to latency of sleep onset. However, van der Kleijn97 reports a Tamminen and Hansen94 used psychomotor tests trend favouring zopiclone (p = 0.106). Results (symbol copying, digit symbol substitution, tapping from Wheatley98 should be interpreted with rate and auditory reaction time) to assess residual caution, however, as there was no washout period effects but no significant differences were found in this crossover study. Stip and colleagues96 between groups. However, a trend in favour of collected data on sleep onset latency but only zopiclone (p = 0.1) was found on assessment of comparisons with the placebo were made. tapping rate scores. Baseline scores for the reaction time test were very imbalanced between groups; Total sleep duration on average, patients in the zopiclone group scored In Ngen and Hassan’s study,95 comparisons were much higher. This meant that despite the dramatic made against baseline only. However, zopiclone decrease in reaction time in the zopiclone group, resulted in a greater improvement from baseline 24 final scores were similar between groups. in duration of sleep (average increase of Health Technology Assessment 2004; Vol. 8: No. 24

99 minutes) compared with temazepam (average crossover study by van der Kleijn,97 data on the increase of 42 minutes) (p < 0.01). last placebo run-in and first placebo follow- up/washout night could be compared. Extracted Wheatley98 reported a statistically non-significant data suggest that there is worsening in both sleep between-drug difference of sleep duration quality and sleep onset latency following treatment (396 minutes for both zopiclone and temazepam), with zopiclone compared with baseline. The but there was no washout period in this crossover temazepam group experienced less deterioration study so the results should be interpreted with from baseline in sleep quality and none in sleep caution. onset latency. The authors state that, following zopiclone, sleep onset latency was significantly Number of awakenings worse than after temazepam. Number of awakenings was reported by Ngen and Hassan,95 Stip and colleagues,96 and Wheatley.98 Data given by Stip and colleagues96 indicate that the mean score relating to quantity of nocturnal The study by Ngen and Hassan95 did not compare awakenings had deteriorated in the temazepam zopiclone and temazepam directly; comparisons group in the follow-up week compared with were made against baseline only and mean values baseline, but the deterioration was not reported as were given. Zopiclone resulted in a smaller statistically significant. Scores on nocturnal improvement in number of awakenings (average awakenings for patients on zopiclone had not 0.33 fewer awakenings) compared with temazepam deteriorated. (average decrease of 0.72 awakenings). Alertness Wheatley98 reported that the between-drug No significant differences between active difference in the number of awakenings was not comparator groups were found in this comparator statistically significant, but there was no washout group for daytime alertness. period in this crossover study so the results should be interpreted with caution. Ngen and Hassan95 assessed psychomotor function using the Leeds psychomotor tester In the study by Stip and colleagues,96 no direct [choice reaction time and critical flicker fusion comparisons between treatments were made by the (CEF)] and a letter cancellation test but no direct authors but extracted data indicated a trend in comparisons were made. favour of zopiclone. Stip and colleagues96 assessed memory, alertness, Quality of sleep attention and concentration and found no Van der Kleijn97 and Wheatley98 presented data on statistically significant differences between groups. quality of sleep. Van der Kleijn97 reported a trend favouring zopiclone (average mean scores over In van der Kleijn’s study97 no statistically 5 days: zopiclone 3.9, temazepam 3.8; p = 0.1) significant difference was found between groups whereas Wheatley98 reported no significant on awakening. difference between drugs. Wheatley98 assessed state on awakening and Adverse events condition at work, with others and driving. No Only van der Kleijn97 and Wheatley98 presented statistically significant differences were found for data regarding adverse side-effects. Van der any of these outcomes between groups. Kleijn97 did not make a formal comparison of adverse event rates but presented rates in favour Global impression of treatment of temazepam [26% of patients on zopiclone Global assessment of efficacy was compared reported side-effects (headache, perspiration, between groups but no statistically significant trembling/shaking, lightheadedness and difference was found. nervousness) compared with 17% on temazepam]. Wheatley98 reported a statistically non-significant Zaleplon versus zolpidem between-drug difference in terms of adverse Six studies compared zaleplon with zolpidem.99–103 events (e.g. daytime drowsiness, migraine). Of these, two100,101 compared three doses of zaleplon (5, 10 and 20 mg) with zolpidem (10 mg), Rebound insomnia one100 compared two doses of zaleplon (5 and Two included studies,96,97 included follow-up data 10 mg) with zolpidem (5 mg) and three99,103 which could be compared with baseline. From the compared zaleplon (10 mg) with zolpidem (10 mg). 25

Sleep onset latency Ancoli-Israel and colleagues102 reported results in Comparisons made in the two studies by terms of median sleep quality and the percentage Zammit103 were with placebo only. No sleep of patients with improved sleep quality relative to latency data were available to compare the effects baseline for each week of treatment. There was no of the active treatments in these studies or in the consistent trend observed between zaleplon groups study by Allain and colleagues99 (available only as and therefore the results from the zaleplon groups abstracts). Elie and colleagues100 and Fry and were pooled from three studies for the meta- colleagues101 did not make direct comparisons analysis. Patients on zaleplon were significantly between active treatments, but a significant less likely to experience an improvement in sleep dose–response trend with increasing doses of quality than those on zolpidem. The OR when zaleplon was reported in both studies: the higher zaleplon is compared with zolpidem for the dose, the shorter was the sleep onset latency. improvement at the end of treatment compared to Ancoli-Israel and colleagues102 reported that baseline is 0.66 (95% CI 0.51 to 0.87). sleep latency was significantly shorter with zaleplon (10 mg) than zolpidem (5 mg) during Allain and colleagues99 stated that there was a both weeks of treatment (p < 0.001). In real statistically significant improvement in quality of terms, this is derived from a reported median sleep favouring zolpidem as measured on both sleep latency with zaleplon (10 mg) of 31 minutes the VAS and the Leeds Sleep Evaluation and with zolpidem (5 mg) of 42 minutes. A similar Questionnaire (LSEQ) (p < 0.0001 on both VAS trend was observed in Elie and colleagues’ study, and LSEQ). However, data are not provided to where zolpidem (10 mg) resulted in a longer sleep evaluate this result. onset latency throughout the 4 weeks of treatment. Adverse events Total sleep duration Three studies100–102 reported the frequency of Six studies99–103 in this group evaluated total sleep treatment-emergent adverse events, but only Elie duration. Comparisons made in the two studies by and colleagues100 and Fry and colleagues101 Zammit103 were with placebo only, and no sleep reported sufficient data for inclusion in duration data were available to compare the effects meta-analysis. No dose-response trend was of active treatments. evident among the zaleplon treatment groups and data from these groups were again pooled for the No direct comparisons were made between active meta-analysis. Treatment with zaleplon was less treatment arms in Elie and colleagues100 and Fry likely to result in treatment-emergent adverse effects and colleagues.101 However, Ancoli-Israel and but this difference was not statistically significant. colleagues102 reported that the median sleep time Subjects seemed to be more likely to suffer was significantly less in the zaleplon (5 mg) group treatment-emergent adverse events on zolpidem than the zolpidem (5 mg) group during both but this was not statistically significant. The OR weeks of treatment (290.7 and 308.57 minutes, for adverse events when zaleplon is compared with respectively; p < 0.05). In the studies by Elie and zolpidem is 0.86 (95% CI 0.62 to 1.20). colleagues100 and Fry and colleagues,101 a similar trend is observed, as the change in median values Withdrawal symptoms from baseline is greater in the zolpidem group None of the included studies reported any than in the zaleplon groups. assessment of dependence. Elie and colleagues100 and Fry and colleagues101 formally assessed the Allain and colleagues,99 state that no significant occurrence of withdrawal symptoms following the differences were observed between the treatment discontinuation of therapy with zaleplon (5, 10 or arms related to total sleep duration (8.3 hours for 20 mg), zolpidem (10 mg) or placebo. Both studies zolpidem and 8 hours for zaleplon). used the benzodiazepine withdrawal symptom questionnaire (a listing of 20 commonly reported Number of awakenings symptoms) by Tyrer and colleagues.107 Both studies Two studies in this group100,101 reported data on reported the incidence of withdrawal symptoms on the median number of awakenings, but direct nights 1, 2, and 3 after the discontinuation of comparisons were not made. treatment (when placebos were administered). Elie and colleagues100 reported the incidence of three Quality of sleep or more new withdrawal symptoms and Fry and Four studies evaluated sleep quality.99–102 Of these, colleagues101 reported the incidence of three or Elie and colleagues,100 Fry and colleagues101 and more new or more severe withdrawal symptoms. 26 Health Technology Assessment 2004; Vol. 8: No. 24

Direct comparisons of the incidence of Daytime alertness withdrawal symptoms were not made between the Two studies by Zammit103 were the only ones in active treatments in either study. Instead, the this comparator group to assess subjective incidence in each active treatment group was measures of sedation and psychomotor compared with that in the placebo group. Data on performance. However, no direct comparisons withdrawal could be formally assessed only from were made between active treatments. the first night of the placebo run-out phase of Fry and colleagues.101 Patients taking zaleplon Global impression of treatment were statistically significantly less likely to suffer In the crossover study by Allain and colleagues,99 withdrawal symptoms than those on zolpidem it was reported that 62.3% of patients favoured [OR 0.2 (95% CI 0.05 to 0.72), p = 0.01]. There zolpidem compared with 37.7% who favoured does appear to be a general trend favouring zaleplon (p = 0.08) when asked to choose between zaleplon from all three nights of the run-out drugs. phase from both studies, as patients taking zolpidem tended to be at least 50% more likely to Zolpidem versus zopiclone suffer withdrawal as those on zaleplon. The Only one study, by Tsustsui,104 provided data percentage of patients reporting withdrawal comparing zolpidem (10 mg) with zopiclone symptoms in each group was far higher in the (7.5 mg). study by Elie100 than in that by Fry and colleagues,101 but the relative differences between Sleep onset latency zaleplon and zolpidem were greater in the study Tsutsui104 reported data regarding sleep onset by Fry and colleagues.101 latency as percentages with improvement from baseline (scale 1–5). Improvement of one grade or Tolerance more in sleep onset latency at the end of Two included studies100,101 involved a minimum of treatment was significantly higher with zolpidem 4 weeks of active treatment and could therefore be than with zopiclone [85.8 versus 77.5% used to extract data on tolerance. Data on sleep respectively, OR 1.72 (95% CI 1.04 to 2.84)]. efficacy outcomes from the first available and final weeks of treatment were extracted. All relevant Adverse events data were self-report data. Tsutsui104 reported a statistically significantly lower proportion of patients in the zolpidem group Fry and colleagues101 observed no evidence of experiencing adverse events ‘related’, ‘possibly tolerance in any of the active treatment groups on related’ or ‘probably related’ to treatment with sleep onset latency, duration quality, or number of those in the zopiclone group [OR 0.55 (95% CI awakenings, comparing week 1 and week 4 data 0.37 to 0.81), p = 0.004]. (minor deterioration in two of the 16 data points, compared with 13 improvements and one Rebound insomnia identical result). The data in the study by Elie and The incidence of rebound in terms of deterioration colleagues100 presented a very similar picture, with at the end of a maximum 1-week follow-up relative only improvements (or identical results) being to baseline was reported. The proportion of reported between the first and final readings on patients who experienced deterioration from all four outcomes. baseline in sleep onset latency was statistically significantly different between treatment groups Rebound insomnia [4.5 and 15.4% after treatment with zolpidem or Two studies100,101 reported the percentage of zopiclone, respectively; OR 0.28 (95% CI 0.13 to patients in each group experiencing rebound 0.60), p = 0.005], but none of the other changes insomnia after the first placebo run-out night in in sleep parameters differed significantly between terms of sleep latency, duration and number of the treatment groups. Overall, sleep onset latency, awakenings. In all groups, some patients duration and the number of awakenings remained experienced rebound. Subjects on zaleplon were significantly better in both treatment groups at the statistically significantly less likely to experience end of follow-up relative to baseline. rebound insomnia of sleep onset latency, sleep duration and number of awakenings compared Dependency with those on zolpidem [OR 0.27 (95% CI 0.17 to An assessment of dependence took place in the 0.44), 0.25 (95% CI 0.15 to 0.41) and 0.34 (95% study by Tsutsui104 at the end of the treatment and CI 0.18 to 0.61), respectively]. follow-up, but no specific data were reported. 27

(i) Sleep onset latency*

Comparison: Zopiclone benzodiazepine Outcomes: Sleep onset latency

Study Zopiclone 7.5 mg Benzodiazepine WND (fixed) Weight WMD (fixed) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Zopiclone Nitrazepam Klimm, 198787 36 18.20 (48.20) 36 15.60 (49.50) 4.48 2.60 (–19.99 to 25.19) Agnoli, 198984 20 –8.00 (5.70) 20 –12.00 (9.60) 95.52 4.00 (–0.89 to 8.89)

Zopiclone Temazepam van der Kleijn, 198997 53 3.80 (1.46) 53 3.70 (1.46) 100.00 0.10 (–0.46 to 0.66) –10 –50 510 Favours BZD Favours zopiclone * Agnoli: minutes multiplied by –1; Klimm: change from baseline; scale 0 fast, 100 slow; multiplied by –1, van der Kleijn: scale 1 slow, 5 fast

(ii) Number of awakenings*

Comparison: Zopiclone benzodiazepine Outcomes: Number of awakenings

Study Zopiclone 7.5 mg Benzodiazepine WND (fixed) Weight WMD (fixed) N Mean (SD) N Mean (SD) 95% CI % 95% CI Zopiclone Temazepam Stip, 199996 19 6.80 (2.05) 16 5.80 (1.96) 100.00 1.00 (–0.33 to 2.33) –10 –50 510 Favours BZD Favours zopiclone * Stip: scale unknown, but increase indicates improvement

(iii) Quality of sleep*

Comparison: Zopiclone benzodiazepine Outcomes: Quality of sleep

Study Zopiclone 7.5 mg Benzodiazepine WND (fixed) Weight WMD (fixed) N Mean (SD) N Mean (SD) 95% CI % 95% CI Zopiclone Nitrazepam Klimm, 198787 36 24.00 (45.60) 36 23.10 (37.80) 100.00 0.80 (–18.45 to 20.25)

Zopiclone Temazepam van der Kleijn, 198997 53 3.90 (1.46) 53 3.80 (1.53) 100.00 0.10 (–0.47 to 0.67) –10 –50 510 Favours BZD Favours zopiclone * Klimm: change from baseline, scale 0 bad, 100 good; van der Klejn: scale 1 bad, 5 good

FIGURE 2 Z versus benzodiazepines

Daytime alertness 61.6% in the zopiclone group. However, this The study assessed daytime physical condition, but difference was not statistically significant. no direct comparison was made.

Global impression of treatment Measures of psychomotor The study reported that 69.7% of patients in the performance and memory zolpidem group were rated by the investigator as “at least moderately improved” using the modified A summary of the results of the assessment of the 28 Clinical Global Impression Scale compared with quality of sleep has been reported in the section Health Technology Assessment 2004; Vol. 8: No. 24

(iv) Treatment-emergent adverse events

Comparison: Zolpidem temazepam Outcomes: Adverse events

Study Zolpidem 5 mg Temazapam 15 mg OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Leppik, 199782 52/82 56/84 100.00 0.87 (0.46 to 1.64) 0.1 0.2 0.5 1 2 5 10 Favours zolpidem Favours temazepam (v) Adverse events

Comparison: Zolpidem nitrazepam Outcomes: Adverse events

Study Zolpidem Nitrazepam OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Kazamatsuri 7/82 12/79 47.31 0.52 (0.19 to 1.40) Kudo, 199388 13/79 15/80 52.69 0.85 (0.38 to 1.93)

Total (95% CI) 161 159 100.00 0.70 (0.37 to 1.30) Total events: 20 (treatment), 27 (control) Test for heterogeneity: 2 = 0.57, df = 1 (p = 0.45), I2 = 0% Test for overall effect: Z = 1.13 (p = 0.28) 0.1 0.2 0.5 1 2 5 10 Favours zolpidem Favours nitrazepam Comparison: Zopiclone nitrazepam Outcomes: Adverse events

Study Zopiclone Nitrazepam OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Ohlomo 1, 198591 5/64 7/64 66.37 0.69 (0.21 to 2.30) Ohlomo 2, 198592 10/66 4/71 33.63 2.99 (0.89 to 10.06)

Total (95% CI) 130 135 100.00 1.46 (0.65 to 3.30) Total events: 15 (zopiclone), 11 (nitrazepam) Test for heterogeneity: 2 = 2.83, df = 1 (p = 0.09), I2 = 64.7% Test for overall effect: Z = 0.92 (p = 0.36) 0.1 0.2 0.5 1 2 5 10 Favours zopiclone Favours nitrazepam

FIGURE 2 Z versus benzodiazepines (cont’d)

‘Clinical results and analysis’ (p. 18). In this Studies varied considerably in the level of section we present the other measures used to information provided. The majority of studies assess sleep quality and sequelae as reported in (14/16) did not reference or provide enough detail the included trials. A summary of the specific for study methodology. Owing to the variations in measures utilised and their results are presented measurement tools and/or lack of detail, direct in Table 27 in Appendix 3. Data from non-English comparisons across studies were not possible. papers were not extracted for this component of the review. A number of different psychomotor tests were reported in the studies that compared Of the 16 studies, one90 did not include any benzodiazepines with the Z-drugs, but most were measures of mood, psychomotor performance, not described and validated. Details of the exact memory or satisfaction with sleep quality. In the nature of the test ranged from the measure being remaining 15 studies, 28 questionnaires were used cited as a memory test (unspecified), with the scale to measure these outcomes. described as a graphic symbols test (unspecified), 29

(i) Quality of sleep (%, with improvement at week 4 compared to baseline)

Comparison: Zaleplon zolpidem Outcomes: Improved quality of sleep

Study Zaleplon Zolpidem OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Ancoli-Isreal, 1999102 168/325 72/109 38.92 0.55 (0.35 to 0.86) Elie, 1999100 189/303 66/99 27.97 0.83 (0.51 to 1.34) Fry, 2000101 158/304 61/98 33.11 0.66 (0.41 to 1.05)

Total (95% CI) 932 306 100.00 0.66 (0.51 to 0.87) Total events: 515 (zaleplon), 199 (zolpidem) Test for heterogeneity: 2 = 1.50, df = 2 (p = 0.47), I2 = 0% Test for overall effect: Z = 3.00 (p = 0.003) 0.1 0.2 0.5 1 2 5 10 Favours zolpidem Favours zaleplon (ii) Treatment-emergent adverse events

Comparison: Zaleplon zolpidem Outcomes: Adverse events

Study Zaleplon Zolpidem OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Elie, 1999100 234/365 78/122 55.36 1.01 (0.66 to 1.54) Fry, 2000101 272/355 96/116 44.64 0.68 (0.40 to 1.17)

Total (95% CI) 720 238 100.00 0.86 (0.62 to 1.20) Total events: 506 (zaleplon), 174 (zolpidem) Test for heterogeneity: 2 = 1.23, df = 1 (p = 0.27), I2 = 18.5% Test for overall effect: Z = 0.87 (p = 0.38) 0.1 0.2 0.5 1 2 5 10 Favours zaleplon Favours zolpidem

FIGURE 3 Zaleplon versus zolpidem

to fully specified measures and scales (i.e. Leeds time the Z-drugs were developed it was considered psychomotor test). It is possible that the studies unethical to use long-acting benzodiazepine incorporated validated tests. However, only two comparators as the negative daytime effects were studies provided references for the measures so feared as to make the long-acting drugs almost used.87,93 unusable (Nutt D, University of Bristol: personal communication, 2003). Variations in assessment and variety in the level of information provided make study comparisons difficult. Differences in mood, psychomotor Review of dependency and function and memory have been reported. Only withdrawal one study104 assessed mood and noted improvements with both zaleplon and zolpidem. The RCTs included in the main clinical None of the studies that directly compared effectiveness review did not provide data related to Z-drugs with each other assessed memory or dependency and withdrawal. The research team psychomotor performance. extended the search to other study designs that evaluated the use of the non-benzodiazepines. Available data do not provide enough information Specifically, the team sought to identify any or appropriate comparisons to allow for valid studies reporting the assessment of dependence or assessment of the effectiveness of the Z-drugs withdrawal symptoms following discontinuation of versus benzodiazepines. An explanation provided insomnia treatment with the three non- 30 by a member of the review panel is that by the benzodiazepine hypnotics assessed in this review. Health Technology Assessment 2004; Vol. 8: No. 24

(iii) Withdrawal symptoms

Comparison: Zaleplon zolpidem Outcomes: Withdrawal

Study Zaleplon Zolpidem OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Fry, 2000101 4/265 6/84 100.00 0.20 (0.05 to 0.72) 0.1 0.2 0.5 1 2 5 10 Favours zaleplon Favours zolpidem (iv) Rebound insomnia concerning sleep onset latency

Comparison: Zaleplon zolpidem Outcomes: Rebound insomnia: sleep onset latency

Study Zaleplon Zolpidem OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Elie, 1999100 20/290 15/92 39.46 0.38 (0.19 to 0.78) Fry, 2000101 17/290 23/96 60.54 0.20 (0.10 to 0.39)

Total (95% CI) 580 188 100.00 0.27 (0.17 to 0.44) Total events: 37 (Zaleplon), 38 (zolpidem) Test for heterogeneity: 2 = 1.69, df = 1 (p = 0.19), I2 = 40.9% Test for overall effect: Z = 5.28 (p = 0.00001) 0.1 0. 2 0.5 1 2 5 10 Favours zaleplon Favours zolpidem (v) Rebound insomnia concerning sleep duration

Comparison: Zaleplon zolpidem Outcomes: Rebound insomnia: sleep duration

Study Zaleplon Zolpidem OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Elie, 1999100 19/293 15/94 38.33 0.37 (0.18 to 0.75) Fry, 2000101 17/294 27/95 61.67 0.18 (0.09 to 0.36)

Total (95% CI) 587 189 100.00 0.25 (0.15 to 0.41) Total events: 36 (Zaleplon), 39 (zolpidem) Test for heterogeneity: 2 = 1.92, df = 1 (p = 0.17), I2 = 48.0% Test for overall effect: Z = 5.55 (p = 0.00001) 0.1 0. 2 0.5 1 2 5 10 Favours zaleplon Favours zolpidem

(vi) Rebound insomnia concerning number of awakenings

Comparison: Zaleplon zolpidem Outcomes: Rebound insomnia: number of awakenings

Study Zaleplon Zolpidem OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Elie, 1999100 8/185 12/63 53.16 0.19 (0.07 to 0.50) Fry, 2000101 18/208 11/69 46.84 0.50 (0.22 to 1.12)

Total (95% CI) 393 132 100.00 0.34 (0.18 to 0.61) Total events: 26 (zaleplon), 23 (zolpidem) Test for heterogeneity: 2 = 2.27, df = 1 (p = 0.13), I2 = 55.9% Test for overall effect: Z = 3.56 (p = 0.0004) 0.1 0. 2 0.5 1 2 5 10 Favours zaleplon Favours zolpidem

FIGURE 3 Zaleplon versus zolpidem (cont’d) 31

(i) Sleep onset latency*

Comparison: Zolpidem zopiclone Outcomes: Decreased sleep onset latency

Study Zolpidem 10 mg Zopiclone 7.5 mg OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Tsutsui, 2001104 179/209 170/219 100.00 1.72 (1.04 to 2.84) 0.1 0.2 0.5 1 2 5 10 Favours zopiclone Favours zolpidem * %, showing an improvement in sleep latency of 1+ grade (scale 1–5) at week 2 compared with baseline

(ii) Drug related adverse events

Comparison: Zolpidem zopiclone Outcomes: Adverse events

Study Zolpidem 10 mg Zopiclone 7.5 mg OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Tsutsui, 2001104 66/211 102/225 100.00 0.55 (0.37 to 0.01) 0.1 0.2 0.5 1 2 5 10 Favours zolpidem Favours zopiclone

(iii) Rebound insomnia concerning sleep onset latency*

Comparison: Zolpidem zopiclone Outcomes: Rebound insomnia: sleep onset latency

Study Zolpidem 10 mg Zopiclone 7.5 mg OR (fixed) Weight OR (fixed) n/Nn/N 95% CI % 95% CI Tsutsui, 2001104 9/191 31/205 100.00 0.28 (0.13 to 0.60) 0.1 0.2 0.5 1 2 5 10 Favours zolpidem Favours zopiclone * %, with a worsening of sleep onset latency by 1+ grade at the end of follow-up (2 weeks treatment, max. 1 week follow-up) relative to baseline

FIGURE 4 Zolpidem versus zopiclone

Trials and cohort studies A total of 194 patients were randomised to either Two RCTs108,109 and one open single-group zolpidem (10 mg) or a placebo for a 4-week study110 assessed withdrawal symptoms following treatment phase, after which 153 patients entered zolpidem discontinuation. One open single-group a 1-week placebo follow-up period (75 of the study examined withdrawal following the use of zolpidem group). The researchers assessed a zopiclone.111 A further paper112 reported two potential withdrawal reaction by DSM-IV criteria RCTs investigating the gradual withdrawal of and reported that no patient in either group zolpidem or zopiclone after long-term use experienced more than one symptom constituting (minimum 3 months) (see Tables 28 and 29 in criterion B of a sedative/hypnotic withdrawal Appendix 3). None of these studies met the symptom (criterion B: autonomic hyperactivity; inclusion criteria of the main clinical effectiveness increased hand tremor; insomnia; nausea and review and therefore a formal assessment of their vomiting; transient visual, tactile, or auditory quality was not carried out. No studies assessing hallucinations or illusions; psychomotor agitation; withdrawal following zaleplon discontinuation anxiety; grand mal seizures).9 were identified. The second trial, by Shaw and colleagues,109 Zolpidem compared zolpidem and a placebo in a double- Asnis and colleagues108 included patients treated blind RCT involving 80 elderly psychiatric 32 for depression with serotonin reuptake inhibitors. patients aged between 65 and 85 years. Patients Health Technology Assessment 2004; Vol. 8: No. 24

were randomised to two groups on relatively high group (97 patients), respectively (p = 0.008). No doses of zolpidem (10 and 20 mg) or placebo significant difference was reported when sleep treatment for a double-blind period of 3 weeks, complaints were excluded. Neither the Ashton followed by a 1-week placebo period. The authors scale113 nor the Tyrer questionnaire107 recorded a reported that zolpidem was tolerated without any significant difference in withdrawal signs between withdrawal symptoms, but reported a small the two groups. number of adverse events including daytime aggression (one patient), day time restlessness One single-group, open study followed 10 (of (one patient), increased sedation and confusion originally 11) chronic insomniac patients after (one patient) during the post-treatment phase. 54 nights of treatment with zopiclone (7.5 mg) for a further 2-week withdrawal period on a placebo.111 The single-group open study by Maarek and EEG recordings and subjective ratings were used to colleagues110 tested zolpidem in 96 insomniac evaluate drug effectiveness. One patient reported patients over 180 days, with the option to carry on significant daytime anxiety and hyperventilation for another 180 days. The initial dose was 10 mg on the first withdrawal day, whereas another but could be adjusted as needed to 20 mg. After patient experienced rebound insomnia, anxiety the first 180 days, patients could choose to and general weakness 6 days after withdrawal. discontinue treatment. Nineteen of the 21 patients who discontinued treatment were followed up for Case reports 20–30 days. Those patients reported no A total of 16 English-language case reports were withdrawal symptoms, but there is an indication identified, including 11 on zolpidem114–124 and that at least some of them withdrew from five on zopiclone,125–129 but none on zaleplon treatment gradually. The method of measurement (sees Tables 30 and 31, Appendix 3). of withdrawal symptoms was not specified. Most reports stem from Western European Lemoine and colleagues112 reported two RCTs, one countries with two reported cases of zolpidem of which involved 193 patients who had received abuse in the USA. All case studies involved zolpidem (10 mg) for a median of 7.4 months and excessive doses of the drugs, which had been were thereafter randomised to continue the gradually increased by patients themselves, at treatment for a further 3 weeks or to be withdrawn times with the intention of re-enforcing the gradually over the same time (1 week each of full, experienced positive effects of the drug. The half and no dose). Patient files reporting adverse maximum dose of zolpidem used by patients events, dropouts or a score of ≥3 on the Tyrer and ranged from 40 to 600 mg per day and that of colleagues107 benzodiazepine withdrawal symptom zopiclone from 22.5 to 380 mg per day. questionnaire were reviewed to judge whether events might be related to drug withdrawal. The Patients were between 26 and 55 years old, apart incidence of such events was 38 and 24% in the from two 67-year-olds, one each on zolpidem and withdrawal and continuation group respectively zopiclone (Sikdar and Ruben128 did not report the (p = 0.049), but no significant difference was ages of six patients). In nine case studies, a history found when sleep complaints were excluded. of substance abuse was reported, and in Similarly, the Ashton scale113 (a list of withdrawal 12 studies, patients had a concomitant or previous symptoms formalised into a rating scale) recorded diagnosis of depression. an increase in the withdrawal group but no change in the continuation group. No difference was Reported withdrawal symptoms from case studies recorded between the two groups on the Tyrer of dependent patients vary across the studies and questionnaire scores. include epileptic seizures (four patients on zolpidem, one on zopiclone), psychomotor Zopiclone agitation, restlessness, anxiety, confusion and sleep The RCT reported by Lemoine and colleagues112 disturbances. For some patients, no explicit involved 201 patients who had received zopiclone withdrawal symptoms were reported, usually (7.5 mg) for a median of 9.1 months and were because withdrawal had been managed through thereafter randomised to continue the treatment gradual dose tapering. for a further 3 weeks or to be withdrawn gradually over the same time (1 week each of full, half and We sought data from the Committee on Safety of no dose). The incidence of events possibly related Medicines (CSM) related to the numbers of cases to drug withdrawal was 38 and 20% in the of dependency reported via the yellow card withdrawal group (102 patients) and continuation system. These data are always confounded by 33

several factors – reporting of yellow cards is more (b) Zopiclone with nitrazepam (n = 8) common now than in the 1970s when problems There is no convincing evidence of any with benzodiazepines were greatest, and will also differences in the outcomes measured be influenced by the publicity around adverse between zopiclone and nitrazepam (one effects (dependency on benzodiazepines is more study suggests sleep latency is significantly likely to be diagnosed now than in the past, but shorter with zopiclone and another with less likely to be reported since it is well recognised) nitrazepam; one study reports significant and changing patterns of use of these drugs – improvements in sleep quality for probably fewer long-term users now, although no zopiclone). Results from four studies direct comparative data exist. suggest a statistically significant difference in favour of zopiclone in daytime alertness. The yellow card data show distortion as a result of (c) Zopiclone with temazepam (n = 4) these factors – there are, for instance, 40 reports There is no convincing evidence of any of drug dependency on zopiclone, one on differences in the outcomes measured zolpidem and none on zaleplon compared with between zopiclone and temazepam (only three on nitrazepam, two on temazepam and one one study reports that rebound insomnia of on lormetazepam. The figures clearly sleep latency is significantly worse following underestimate the problem and the relative zopiclone than after temazepam). contributions of each drug to the problem. We did 3. Concerning zaleplon not feel that any more detailed data would add (a) Zaleplon with zolpidem (n = 6) anything useful to this analysis. Some evidence suggests that zaleplon results in shorter sleep latency than zolpidem but zolpidem results in longer Discussion sleep duration than zaleplon. Evidence suggests that zolpidem is statistically The diversity of possible comparisons and the significantly more likely to improve sleep range of outcome markers in the review may be quality than zaleplon. Evidence suggests confusing. This is compounded by the fact that that withdrawal is less likely and rebound outcomes are rarely standardised and, even when insomnia significantly less likely on reported, may differ in exact interpretation. Also, zaleplon than zolpidem. the quality of reporting is poor and as a result meta-analysis has been possible on only a small It must be remembered that these comparisons are number of studies. It is therefore difficult to limited and that it was possible to undertake interpret the results. The results related to the key meta-analysis with data from only a small subset of outcomes on the data provided from comparisons the papers included in the review. Many papers in the studies are presented in Table 7 and did not make direct comparisons between the summarised in the following text. active treatments and reported only comparisons with placebos, often with insufficient data to allow 1. Concerning zolpidem direct comparisons to be made. Studies frequently (a) Zolpidem with nitrazepam (n = 2) reported a statistical difference in end-points One study reports statistically significantly between drugs, but did not report enough data to fewer awakenings with zolpidem. allow evaluation of the clinical importance of this (b) Zolpidem with temazepam (n = 2) difference. One study reports significantly favourable results for sleep latency and sleep quality in There was also evidence of multiple testing of the zolpidem group. outcomes, with selective reporting of significant (c) Zolpidem with zopiclone (n = 1) findings, which meant that many of the results Results from the only study in this that were reported might have been spurious. The comparator group suggest a statistically extent of the multiple testing was not always clear significant difference in favour of zolpidem and not accounted for in statistical analysis. A for sleep latency, rebound insomnia of related issue is that of the power of the studies – sleep latency and adverse events. most were too small to detect any difference 2. Concerning zopiclone between therapies, and none have power (a) Zopiclone with lormetazepam (n = 1) calculations which support the size of the study. Only one study in this group reports that Issues of the differences between studies designed lormetazepam results in shorter sleep onset to show equivalence or difference between 34 latency than zopiclone. therapies do not seem to have been considered. Health Technology Assessment 2004; Vol. 8: No. 24 c = 4) = 1) = 2) = 1) = 2) = 3) = 3) No data NDC ( n NS ( n NDC NS ( n NS ( n b = 2) NDC ( n = 1) b n = 2) Zop > N ( n = 1) NS ( n n n = 1) No data < 0.001). shows statistically significant difference; NDC, no p = 1) NS ( n = 2) NDC ( = 1) NDC ( = 1) T > Zop ( = 2) No data = 3) Zal > Zol ( n NDC ( n NS ( n NS Zol > Zop Zol > Zop Adverse events insomnia Rebound Daytime alertness d = 2) = 1) d = 1) NS ( n = 1) NS ( n = 1) NS ( n = 5) = 2) = 2) NS ( n NDC ( n Zop > N ( n NS ( n NS . = 1) NDC ( n = 2) Zol > Zal ( n = 2) = 6) NS ( n = 1) NS ( n awakenings NS No data No data = 1) NDC ( n = 1) = 1) No data Zol > T( n = 1) NDC ( n = 4) = 6) NS ( n = 1) NS ( n = 1) = 1) Zol > N ( n NDC ( n NS a = 1) Zol > Zal ( n = 1) Zop > N ( n = 1) = 1) NDC ( n n = 1) = 4) NS ( n = 2) NDC ( n = 3) NS ( n = 1) = 2) NS ( n = 2) NS ( n Zop > N ( n NDC ( n NDC ( n NDC ( n N > Zop ( n NS ( n Sleep latency Sleep duration Number of Quality of sleep Summary of results = 1) = 8) = 2) = 2) = 6) = 4) = 1) = Na of studies Rebound insomnia of sleep latency only. insomnia of sleep latency only. Rebound Nitrazepam resulted in a greater reduction sleep onset latency on the 5th day (out of seven) treatment than zopiclone ( Meta-analysis of three these studies is significantly in favour zolpidem. One study reports significant differences on two out of seven active treatment days only ( n Zopiclone vs nitrazepam( n NS ( n ( n Zopiclone vs lormetazepam L > Zop Zaleplon vs zolpidem Zal > Zol ( n ( n Zolpidem vs temazepam Zol > T ( Zopiclone vs temazepam NS ( n ( n ( n Zolpidem vs zopiclone Zol > Zop No data Comparison n Zolpidem vs nitrazepam NS ( n ( n temazepam; L, lormetazepam; Zop, zopiclone; Zal, zaleplon; NS, no statistical significance; >, Zol, zolpidem; N, nitrazepam; T, direct comparisons. a b c d

TABLE 7 TABLE 35

The very nature of insomnia will have led to had concerns, however, about the quality of many skewed data in many of the papers considered. of the placebo-controlled or comparator studies Although they were often correctly reported using on which we would have been dependent, and the median data, this made any form of meta-analysis quality of their reporting: the direction of their impossible. Other problems included limited effect would probably have been similar, but the availability of data from abstracts,89,99,103 and data power of these studies would have been small and that were not normally distributed and required an extensive systematic review and meta- comparisons made only with a placebo.100–102 In analysis for each comparison. There are some studies, the data were not adequately substantial heterogeneities in the populations labelled in the study report83,84,89 and there was studied, many of whom were normal volunteers excessive use of multiple comparisons.82,84,87,93 rather than insomniacs. Nevertheless, this would Three studies93,97,98 did not have appropriate have been an interesting adjunct to the current washout periods (e.g. at least 1 week), so the data study but was not included in the protocol at the must be interpreted with caution. time of writing.

These factors in part arise from the era in which The results of this review must be interpreted with most of these trials were undertaken (10 studies considerable caution. Zaleplon gives shorter sleep reported before 1990). The conduct and reporting latency than zolpidem, but shorter duration of of trials during that time were less standardised sleep. This largely seems to be the result of the and published studies were not required to meet pharmacological profile of the drug and in what are now accepted as standard quality particular its rapid absorption and short half-life criteria.130 in contrast to the other drugs such as zolpidem or zopiclone or even the relatively short acting The research question provided to the review team benzodiazepines (see Table 1). was based on an assumption of the effectiveness of each of the groups of drugs – that is, the team was There are some differences between drugs, but it asked to compare the effectiveness of the is difficult to quantify these or their clinical interventions with each other. importance. Zolpidem may give rise to less rebound insomnia and shorter sleep latency than The use of indirect comparisons, of drug A with zopiclone, but not convincingly compared with the placebo and of drug B with placebo (or with some benzodiazepines. Zaleplon gives shorter sleep common comparator, e.g. triazolam), to draw latency than zolpidem, but a shorter duration and comparisons between A and B has been quality of sleep and less rebound. It might seem, recommended in cases where either there is no therefore, that zaleplon might be a slightly better direct comparison or where the comparison drug than zolpidem for patients with problems of depends on limited evidence, such as only one falling asleep, but not for those who tend to wake RCT. In the past, there were concerns that indirect during the night or suffer from early morning comparisons may carry greater bias than direct awakening. In absolute terms, however, the benefit comparisons and may overestimate the efficacy of in sleep latency seems small and therefore the one or other drug. This is the case for naive or value of zaleplon over zolpidem may be open to unadjusted comparisons, but Song and question (the WHO came to a similar conclusion). colleagues131 have recently described methods for Zaleplon has not been adequately compared with adjusting such comparisons that may avoid these the benzodiazepines used in the UK. problems. In 44 direct and indirect comparisons, they found similar results in all but three: the There may be differences in the drugs where they reasons for these discrepancies vary but a key issue are used outside their licence. This is regrettably was that the studies in the indirect comparisons common, as will be discussed later. The RCTs should be as similar as possible, and this aspect included in this review all used no more than needed careful attention. 6 weeks of therapy and, therefore, it is difficult to make comments on the risks of tolerance and Song and colleagues131 suggested that the results dependency. It has been argued that drugs with a of indirect comparisons can be quantitatively shorter half-life may encourage dependency by combined to increase the statistical power if there causing the rapid onset of withdrawal symptoms, is no discrepancy between the two. Use of such so encouraging the patient to continue taking the methods might have allowed us to make indirect drug. However, this is probably less likely to be the comparisons between more drugs, in particular case for a hypnotic than for an anxiolytic. 36 between zaleplon and other benzodiazepines. We Although initially heavily marketed as ‘non- Health Technology Assessment 2004; Vol. 8: No. 24

benzodiazepines’ at a time when benzodiazepines It is claimed that intermittent use of drugs may were under a considerable cloud with increased also be useful in avoiding dependency; this seems awareness of their propensity to cause probable and is encouraged, but we found no dependency, in practice it seems that drugs such studies describing this form of use of the drugs as zopiclone and zolpidem may also cause within our inclusion criteria. The manufacturers of dependency. It is difficult to detect this in RCTs zolpidem reported such studies and claim its and we are dependent on case reports. We could effectiveness is proven in this situation, unlike find no case–control studies to allow us to derive a other drugs. The BNF51 also recommends this use comparative incidence. No case reports were for benzodiazepines. The use of short-acting drugs found for zaleplon; this may be a reflection of how as ‘rescue’ therapy of a failure to sleep on one or the drug is licensed, that is, for use for no more two nights per week is also described, but than 2 weeks (but not necessarily how it is used), comparative studies are not available. to the fact of its short half-life and clearance, or simply because the drug is not long on the market. A final factor to be considered which may decrease The SPC (Summary of Product Characteristics)132 the value of the studies included is publication states clearly that zaleplon may also give rise to bias. We were unable to identify any ongoing dependency and should therefore be used with studies which may have shown inconclusive or caution and for no longer than the licensed even unfavourable results to a study sponsor. Most period. This seems to us to be sound advice. studies in this area were conducted with Theoretically, a drug with such a short duration of pharmaceutical company involvement; such action seems less likely to cause dependency, but studies in the past have been shown to contain a there is no firm evidence to substantiate or reject bias towards the drugs of the sponsor in other this view. therapeutic areas.

Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 5 Results: economic analysis

Introduction therapies, benzodiazepine or non-benzodiazepine medication (i.e. zopiclone) for the management of In this chapter, we explore the published literature chronic insomnia in the elderly], based on the on the costs and benefits of hypnotics for the published literature and expert opinion. The management of insomnia. We begin with the results appeared to demonstrate that if there is no results of a literature search on the economics of underlying health problem, non-pharmacological different hypnotic drugs for the management of therapies should be the first line of treatment for insomnia. The next section goes on to describe the insomnia. However, gains and savings appear to significant economic impact of insomnia be small. When non-pharmacological therapies are worldwide from both a health service and societal compared with benzodiazepines for the average perspective. Finally, key issues associated with patient, the quality-adjusted life-year (QALY) gain economic evaluation of newer hypnotic drugs for was estimated to be 0.37 QALYs, and savings are the management of insomnia are summarised and estimated to be US$2781 over 10 years. relevant implications for the NHS are discussed. Unfortunately, it has not been possible to obtain the full version of this paper in order to determine Review of economic literature its relevance to the review. We conducted a systematic search for comparative economic evidence concerning hypnotic drugs. A second paper, an HTA report due for publication The aim of the review was to identify published later this year, investigated psychological treatments cost-effectiveness analyses (CEAs) of newer in chronic hypnotic drug users.134 The economic hypnotic drugs (zaleplon, zolpidem and zopiclone) evaluation was based on the results of an RCT and for the management of insomnia that are based on concludes that “in routine general practice clinical evidence from drug versus drug RCTs. settings, psychological treatment for insomnia can improve sleep quality, reduce hypnotic drug use Identification of studies and improve health-related quality of life at a One reviewer (A Boland) examined the titles and favourable cost among long-term hypnotic users abstracts of the 929 papers identified by the with chronic sleep difficulties”. The authors electronic search. In addition, another reviewer estimated that the total cost of service provision (YD) looked through all of the articles identified was ~£150 per patient. The mean incremental by the clinical effectiveness search strategies in the cost per QALY gained at 6 months was ~£3500. search for economic studies. The authors claim that the positive benefits associated with this treatment last for at least Quantity and quality of research 12 months if patients comply with their treatment. available No full economic evaluations based on clinical Although of considerable importance in relation evidence from RCTs were identified, either to the use of hypnotics outside their therapeutic between drug groups (Z-drugs versus licence, this paper was not a drug versus drug benzodiazepines) or within drug groups. Although comparison and was outside the scope of this a large number of papers were identified by the review. cost-effectiveness search strategies, only a small number were assessed for inclusion in the review, Finally, only one intra-Z-drug economic study was none of which met the inclusion criteria. identified. Menzin and colleagues135 compared the costs and benefits (risk of RTAs) of zaleplon and We did identify two studies which looked at the zopiclone. The study, part funded by the economic evaluation of hypnotics versus other Wyeth-Ayerst Global Health Outcomes Assessment therapies or no therapy for chronic insomnia. Group, was not based on data comparing the One133 was in the form of an abstract and drugs at all, but on data comparing effects of included a cost–utility analysis (CUA). The authors various blood alcohol concentrations on the risk of compared different therapeutic options [do RTAs, and an extrapolation of the ‘blood alcohol nothing approach, suggest non-pharmacological equivalent’ effects of each drug. This extrapolation 39

leads to a conclusion that compared with zaleplon, treatment for insomnia, and they are under a the use of zopiclone over 14 days in France might cloud, then patients may be relabelled as anxious/ lead to 503 excess accidents per 100,000 drivers at depressed rather than primarily insomniac, and an extra cost of US$31 per person (at 1996 values). treated accordingly. If individuals do not seek out The extrapolations in Menzin and colleagues the usual medical treatments to manage their paper135 seem extreme and improbable. This insomnia, e.g. if they do not go to their GP, then study was excluded from the economic review of they might be using alternative treatments which the literature, as it was not based on any direct are not included in the estimated costs of comparative data. However, further discussion of insomnia, such as antihistamines or alcohol.27 this study is presented later. Indeed, only one in 20 individuals with insomnia are believed to present to healthcare professionals Commentary with insomnia-related symptoms.28 Finally, another Despite the large volume of published explanation for the under-treatment (and/or pharmacoeconomic evaluations that exist, we non-diagnosis) of insomnia is because healthcare were unable to identify any that explored the professionals might not ask patients about it.29 cost-effectiveness of different hypnotic drugs for the short-term management of insomnia based on Third, the management of insomnia is associated RCT data. None of the studies identified by the with a range of diverse costs. These costs are often review process included economic evaluations categorised as direct (medical and non-medical), comparing benzodiazepines with Z-drugs, nor indirect and intangible. The direct costs of were any found that included intra-Z-group drug insomnia include prescription drugs, over-the- comparisons. Most of the papers on cost and/or counter remedies, GP consultations, tests and economic issues that were identified tended to investigations, inpatient and outpatient hospital focus on the quantification of the public health visits and referrals to hospital specialists. Indirect consequences of insomnia using cost-of-illness costs include the cost of lost earnings to the analyses. Most of these papers on costs were individual from having to take time off work owing written for American and Canadian audiences. to sleep-related illnesses. Also, workers suffering from insomnia who are able to work might not be as productive as those who do not suffer from Economic impact of insomnia insomnia, and this has a knock-on effect on the productivity of the workforce. Insomnia is It is very difficult to estimate the true costs of associated with an incalculable cost in terms of insomnia, and estimates vary from country to human suffering as a result of poor personal and country and also within countries. There are professional relationships.20 These intangible costs several reasons for these variations in estimates. might include the breakdown of marital First, there are conflicting estimates of how many relationships and impaired intellectual function. people suffer from insomnia. Some authors suggest that 5–10% of the adult population136 is Despite these difficulties, some authors have affected whereas others suggest that the size of the attempted to estimate the cost impact of insomnia. problem is much greater. Stoller20 suggests that The role of such burden of illness studies is always insomnia affects approximately one-third of the debated – health economists would argue that population and is of global concern. As described unless there is something that can be changed, in Chapter 2, definitions of insomnia differ from there is little point in evaluating it. On the other study to study, and this in turn might help to hand, for healthcare planners a realisation of explain why the prevalence of insomnia appears to where money is spent and where disease needs are vary from country to country.136,137 can bring about a change in resource allocation, or can promote further research. Second, some authors argue that insomnia is under-recognised and under-treated.27 This might Insomnia is said to be the most frequently be because the individual does not perceive reported sleep problem in industrialised nations him/herself to be affected by insomnia and worldwide138 and to be associated with significant therefore does not report the symptoms to the GP. mortality and morbidity.20 Estimates of the The individual may prefer to self-treat or might economic impact of insomnia are therefore high in not want to be associated with the stigma of many countries. In 1995, the direct costs of insomnia despite having severe symptoms. Disease insomnia (‘the cost of medical care or self-treatment may also be defined by the availability of borne by patients, organised healthcare providers, 40 treatment – so if benzodiazepines are the only insurance companies or by the government’) in Health Technology Assessment 2004; Vol. 8: No. 24

the USA were estimated to be US$13.9 billion.139 relaxation techniques and cognitive therapy This total cost was made up of substances used to components. These packages are certainly not treat insomnia (US$1.97 billion) and healthcare inexpensive and cost substantially more than services (US$11.96 billion). If indirect (reduced short-term benzodiazepines alone, although they productivity) costs are included in the total, then may be cost-effective compared with the adverse the total annual cost is estimated to be much consequences of long-term benzodiazepines. higher. Another US estimate in 1994 was higher still, at approximately US$100 billion.20,140 In Current national guidance focuses on the France, the total direct cost of insomnia in 1995 non-pharmacological treatment of insomnia.79 was estimated to be approximately US$2 billion The National Service Framework for Mental and included substances used for insomnia, Health reflects concerns about over-use of outpatient visits and sleep specialist hypnotics and states that the “prescribing rates of investigations.141 benzodiazepines should be monitored and reviewed within the local clinical audit There are no comparable estimates of the direct programme”.80 In the report Medicines and older costs of insomnia in the UK. However, we do know people: implementing the medicines-related aspects of the that in 2002 approximately £25 million was spent NSF for older people,142 the guidelines, which apply on zolpidem, zopiclone, zaleplon, nitrazepam, to all other National Service Frameworks and temazepam, loprazolam and lormetazepam.77 vulnerable users, recommend that primary care agencies should both invite patients to ‘come off ’ long-term hypnotics and provide support for them Costs of insomnia within the to do so. framework of economic evaluation Costs to the health service The direct drug treatment costs of insomnia As in any costing study, when estimating the costs have been outlined above. It is argued that other associated with insomnia and hypnotics, it is very costs associated with insomnia are typically important to be explicit about the perspective insomnia-related accidents (e.g. motor vehicle, adopted for the analysis. For example, if the work-related and catastrophic accidents).20 Indeed, analyst explicitly states that the viewpoint is that of Leger143 suggests that 41–54% of all RTAs are the NHS, then the costs of lost productivity due to fatigue related. Accidents are not only related to insomnia-related ill health are no longer the disease per se, but also to drug treatments for considered in the calculation of total costs. insomnia. In particular, some hypnotics have been However if we extend the perspective to that of linked to RTAs,144,145, falls in the elderly146 and publicly funded social services, these costs may be deliberate self-harm147 (see Table 8). In many of included. Definition of the study viewpoint is these observational studies, there was insufficient crucial as the health implications of insomnia and use of newer drugs such as zolpidem or zaleplon insomnia treatments are wide-ranging and do not to make any comment. fall on one single sector of the economy. A study by Menzin and colleagues135 discusses the In practice, the total treatment costs of insomnia link between zaleplon and zopiclone and RTAs but are often difficult to define and are made up of a is, as described above, controversial. The number of different items. Many patients are attribution of costs to accidents is also prescribed hypnotics in the short term after only a controversial, as they are based on strong single GP consultation. Even for long-term users assumptions (e.g. what proportion of the cost of a of hypnotics, there are few consultations related to car accident is a direct result of sleepiness?).143 the hypnotic use, as both parties use the repeat Careful consideration of the techniques used in prescribing systems to avoid confrontation and measuring costs is therefore required. discussion of sensitive issues. Drug costs may seem to dominate the costs of insomnia, but the costs of Costs to society accidents or injuries might also be considered. Similarly, some argue that the highest costs associated with insomnia are the indirect costs Hypnotics can be sometimes prescribed as part of incurred by society,27 due either to lost a cognitive-behavioural therapy (CBT) package for productivity or to accidents. The balance between insomnia.134 This package might include all or lost productivity or accidents due to insomnia20,143 some of the following: information leaflets, advice or to the treatment of insomnia is, however, on sleep hygiene, stimulus control programme, unclear, and gives scope for much speculation. 41

TABLE 8 Selected studies

Study Outcome Study details Included benzodiazepines and non-benzodiazepines

Barbone, 1998144 Car accident Case–control study Alprazolam, bromazepam, chlordiazepoxide, clorazepate hydrochloride, diazepam, lorazepam, oxazepam, flunitrazepam, flurazepam, loprazolam, lormetazepam, nitrazepam, temazepam, zopiclone

Menzin, 2001135 Car accident Extrapolation from Zaleplon, zopiclone alcohol-related accidents

Neutel, 1995145 Car accident Cohort study Triazolam, flurazepam, lorazepam, diazepam, oxazepam

Neutel, 2002146 Falls (1) Descriptive study Benzodiazepines including lorazepam and oxazepam (2) Case-crossover study

Neutel, 1997147 Self-harm Population-based Triazolam, flurazepam, lorazepam, diazepam, oxazepam cohort study

Health outcomes of insomnia kind of economic evaluation might be most within the framework of appropriate to compare these drugs. economic evaluation Cost-minimisation analysis (CMA) Not only are there many types of costs associated CMA requires that the health outcomes of interest with insomnia in the literature, there is also a vast be proven identical for the healthcare interventions range of reported health outcomes.28 In the under scrutiny. Although the clinical review has published literature, health outcomes of interest in not found significant evidence of major differences the short term can be divided into (1) sleep between drugs, there are some differences, for efficacy outcomes, (2) rebound and tolerance instance, shorter sleep latency on zaleplon outcomes, (3) adverse effects and (4) withdrawal. compared with zolpidem, but longer duration of Sleep efficacy outcomes include sleep onset sleep on zolpidem. We believe that to claim latency, total sleep duration, number of equivalence on the basis of the poor data available awakenings, adverse events and quality of sleep. would be inappropriate. For many of the health Rebound and tolerance outcomes are related to outcomes, as the results of the meta-analysis show sleep onset latency, total sleep duration, number (see Chapter 4), there appear to be no major of awakenings and quality of sleep. Non-sleep- differences between the drugs. We therefore believe related adverse effects range from the that using a cost-minimisation approach to assess insignificant, such as indigestion, to the the costs and benefits of the newer hypnotics for significant, such as severe allergic reaction. Other the management of insomnia is not valid. important outcomes of interest include morning disposition (e.g. how does the individual feel on Cost-effectiveness analysis (CEA) awakening?) and daytime performance (e.g. does In order to conduct a CEA, a clear unidimensional the patient feel tired or sleepy during the day?). outcome of interest is a prerequisite. As discussed, These outcomes are often labelled as the residual there is no single outcome of interest from the or hangover effects of the drug. Assessment of review that would be applicable to all sufferers. QoL is also of interest. Much of the published Some people might prefer to fall asleep quickly literature in this area focuses on zopiclone and/or (sleep onset latency) whereas others might prefer to measures the QoL of insomniacs compared with sleep for more than 6.5 hours (total sleep duration). good sleepers.31,32,148 In the long term, health Individuals might be prepared to accept that they outcomes are focused on dependency and will feel a little bit drowsy the next day if they have withdrawal symptoms. uninterrupted sleep (no awakenings) whereas others might not. Recent developments in the techniques In general, in the assessment of health outcomes of economic evaluation have led to the use of associated with hypnotics, the systematic review discrete choice experiments to examine patient suggests that in terms of most sleep efficacy preferences between treatments that have different measures, there are no major differences between levels of specified attributes (e.g. insomnia-related 42 any of the drugs. This leaves us to consider what outcomes might include sleep onset latency and Health Technology Assessment 2004; Vol. 8: No. 24

total sleep duration). The use of such methods to Conclusion evaluate these outcomes could alleviate some of the problems associated with multiple outputs and This chapter has discussed the published literature facilitate CEAs. However, there are no relevant on the costs and benefits associated with published data for use by the review team at this treatments for insomnia. Results of the literature time. Given the nature of the outcomes associated review have indicated that little evidence is with benzodiazepines and non-benzodiazepines, a available on the economics of different hypnotic CEA to assess newer hypnotics for the drugs for the management of insomnia. Although management of insomnia is not recommended. we accept that the burden of disease imposed by insomnia is significant for both individuals and Cost–utility analysis (CUA) the NHS, the available evidence does not provide CUA is the only economic evaluation method that a basis on which we can give any firm guidance combines the effects of healthcare interventions in with regard to the comparative cost-effectiveness terms of both quality and quantity of life. Although of different drugs in this area. Although a large it is unlikely that any of the hypnotics will impact number of papers have been published in this directly on length of life, these drugs may affect therapeutic area, none were found to provide QoL to different extents and perhaps for different sufficient evidence to inform our analyses. There periods of time. For example, zopiclone is reported is a need for robust clinical data to allow such to improve QoL as compared with a placebo.31 analyses to be undertaken. QoL is a multidimensional health outcome that would enable the many different unidimensional From a longer term perspective, there is an equal health outcomes to be combined. CUA is therefore lack of compelling evidence with regard to the an appropriate approach to adopt in the light of comparative value of individual drugs and drug the nature of the health outcomes. However, there classes and the prevention of drug dependence. are no reliable comparative data on changes in Although it appears that those suffering from QoL associated with any of the drugs, and insomnia are more at risk of falls and RTAs, again therefore no utility values. We found no data to we have no compelling evidence with regard to the allow us to undertake such a study and the extent to which each of the drugs being compared collection of new data was beyond our remit and is likely to lead to beneficial changes in the profile resources. However, the recent cost–utility study134 of such accidents. In such a data vacuum, it conducted as part of the HTA report on cognitive becomes impossible to choose a structure for the and behavioural therapies may provide a valuable economic evaluation. In particular, to use CMA framework for such work in the future. would imply that we had evidence that the drugs or drug classes being compared had been proven Cost–benefit analysis (CBA) to be equivalent. This is not the case. We have CBA requires that all costs and benefits be identified an absence of evidence of incremental presented in monetary units. Given that many of benefit, which is not necessarily equivalent to the health outcomes associated with hypnotics and evidence of an absence of effect. Until the clinical insomnia are intangible, such as drowsiness or efficacy data come up with more compelling breakdown of personal relationships, a CBA would conclusions, the economic modelling must be be very difficult. However, if time and resources placed in abeyance. were unconstrained, then this approach would yield both useful and interesting results.

Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 6 Economics: response to industry submission

Critique of industry economic the clinical evidence presented. A formal budget submissions impact analysis was not presented.

Our review of the economic evidence on Z-drugs and benzodiazepines for the short-term Sanofi-Synthelabo Ltd submission management of insomnia reveals that no up-to-date evidence of cost-effectiveness exists in the published Short-term model literature. No economic evaluations of any of the No formal short-term economic model was Z-drugs compared with the benzodiazepines were presented in the industry submission. identified by the literature search. However, the industry economic submissions do, to some extent, Long-term model address the issue of cost-effectiveness. We appraise In their discussion of cost-effectiveness issues, the the economic models as presented in the industry authors allude to a long-term modelling exercise submissions and comment on the underlying model carried out on the issue of dependency risks, but assumptions and parameter values. We did not state that there was too much uncertainty attempt to build a decision-analytic cost-effectiveness concerning these risks to allow any robust results model given the limitations of both the clinical to be generated. In particular, the authors and economic data available to us at this time. highlight the fact that there is a “lack of robust Finally, we discuss the relative cost-effectiveness of data on which to establish the probability of newer hypnotic drugs for the short-term dependency and its increased burden to the health management of insomnia based on systematic and care provider” (Sanofi-Synthelabo Ltd submission, 4 objective consideration of the clinical and p. 49). We agree with this view. economic evidence base. In addition, the intended scope of the modelling exercise is unclear from the description of the Industry submissions model. However, it appears to have been largely restricted to cost effects, and therefore does not Submissions to NICE were received from the address issues of QoL and utility effects, nor following manufacturers/sponsors: does it reflect the licensed indications for the use of the drug. G Sanofi-Synthelabo Ltd: zolpidem G Wyeth Pharmaceutical: zaleplon. To summarise, given the lack of detailed information regarding this long-term model, it has No submissions from the manufacturers/sponsors not been possible to undertake a formal critique of of zopiclone were received. the modelling exercise.

The submission from Sanofi-Synthelabo Ltd4 explicitly states that no formal short-term Wyeth submission cost-effectiveness assessment is included within the submission. They do, however, discuss the Short-term models cost-effectiveness of non-benzodiazepines versus In the Wyeth submission, two short-term cost benzodiazepines in the long-term treatment of effectiveness models are presented and discussed. insomnia within the framework of economic The first deals with RTAs and the second with falls modelling. Sanofi-Synthelabo Ltd4 also included a in the elderly. budget impact analysis and explored the potential additional costs to the NHS of using or switching Road traffic accidents model to zolpidem. This is a cost–consequence algorithm which claims that, compared with zaleplon, zopiclone is The submission from Wyeth34 includes a short- associated with extra costs because of a risk to term cost-effectiveness model which supplements drivers from drug-induced drowsiness. The 45

argument that zopiclone compared with zaleplon calculate the additional cost of hip fractures and leads to excess driving accidents is based on the additional mortality from using zolpidem, results of a study by Menzin and colleagues,135 the nitrazepam and temazepam versus zaleplon. The basis of which has already been criticised in economic analysis is based on the use of hypnotic Chapter 5. drugs for a 1-year period. However, patients do not receive continual therapy; they receive 2 weeks The algorithm is based on the assumption that ‘on therapy’ followed by 2 weeks ‘off therapy’. “zaleplon does not interfere with mental function the day following administration for insomnia” In summary, the weaknesses of the model can be (Wyeth submission p. 28),34 in contrast to outlined as follows. First, there is a limited zopiclone. However, our results from the review of conceptual framework offered, and the authors do clinical evidence suggest that there is currently not provide a comprehensive description of the little evidence from published RCTs to prove any model in terms of its scope or perspective. statistically significant differences in terms of Second, the comparisons considered within the residual effects between these two drugs. model are not stated explicitly or fully described. Therefore, this assumption and the relationship to Finally, the spreadsheets themselves contain errors drowsiness induced by various blood alcohol and some of the key values are inadequately concentrations underlying the Wyeth analysis of referenced. RTAs must be open to question. As a result, the review team attempted to correct There are therefore reasonable grounds for and, in places, rebuild parts of the model in an considering that this issue is not of central attempt to obtain more detailed cost-effectiveness concern in estimating cost-effectiveness from the results. The structure is shown in Figure 5. NHS perspective. The model begins with a representative Falls and hip fractures in the elderly population of 10,000 people over 60 years old, In the submission, the model is described either as split into four age bands (60–64, 65–74, 75–84, ‘simple’ or ‘simplistic’. The model sets out to 85+ years) for each sex in proportion to their

10,000 patients aged 60+

Odds ratio (Wang) Johansen

Estimated number Estimated number of fractures p.a. of hip fractures p.a.

Standard mortality rates

Estimated number Estimated number of hip fractures related of non-hip fractures p.a. deaths p.a.

1.7 Relative standard £843 £12,124 mortality rates

Adjusted number Estimated cost Estimated cost of hip fractures-related of non-hip fractures p.a. of hip fractures p.a. deaths p.a.

46 FIGURE 5 Structure Health Technology Assessment 2004; Vol. 8: No. 24

representation in the UK population. These are or not it is appropriate to include these costs. then multiplied by the annual incidence rates for In addition, the social costs are largely made all fractures and for hip fractures to estimate the up of long-stay hospital care for 1 year and, in annual number of fracture cases (total and hip) to the paper, this is estimated to be twice the cost be expected per 10,000 elderly persons. The of long-stay residential care. The review team non-hip fractures are calculated as a simple believes that this assumption leads to an difference. For scenarios involving zolpidem or overestimation of costs in the Wyeth benzodiazepines, ORs from Wang and submission34 because recent changes in colleagues149 are applied in the calculation of the reimbursement mean that, currently, the cost of number of hip fractures. The model assumes no long-stay hospital care is ~20% more expensive increases in hip fractures above baseline in than residential care. This means that the mean patients taking zaleplon. cost of a hip fracture used in the submission is likely to be an overestimate. Also, recent Standard age/sex mortality rates are then applied changes to improving patient discharge, with to the number of hip fractures to estimate the intermediate care and better social support, expected number of deaths in these patients. mean that this scenario is less likely to take These figures are then uplifted by 70% on the place in today’s NHS. basis of excess mortality in 12 months following 5. In calculating the cost of treatment over the hip surgery as described in the study by Richmond course of 1 year (assuming treatment for and colleagues.150 The estimated costs of treating 2 weeks out of every 4), the authors assume hip and non-hip fractures are calculated using four GP visits per year for all patients on drug simple averages of £12,124 and £843, respectively. treatments, but consider that patients not assigned drug therapy will not consult their GP Spreadsheet problems again. This seems unreasonable since we must In addition to several calculation errors, there presume that sleep dysfunction continues appear to be some technical problems and throughout the period. unexplained aspects of the model that could distort the model results. Conceptual issues Implicitly, this model is based on the assumption 1. Donaldson and colleagues151 and Johansen and of equal efficacy between all treatments as far as Stone152 quote two sources for fracture inducing sleep is concerned. The model is only incidence rates, but it was chosen to use the concerned with minimising the cost of a single higher values from Johansen and Stone without consequence of one adverse effect – falls leading justification. Use of the lower figures would to hip fractures (in some cases with fatal outcome) substantially reduce the claimed differences. due to drowsiness. It does not address the 2. The authors employ the ORs from Wang and important issue of possible drug dependency and colleagues’ paper149 as though they were does not attempt to evaluate the utility gains from relative risk (RR) values. RR is always less than successful treatment of sleep disturbance. This OR and varies depending on the underlying means that within the original model, it is difficult baseline risk level. This means that the excess to calculate meaningful cost-effectiveness ratios or risk of fractures for benzodiazepines and cost–utility ratios. Indeed, the summary table is zolpidem is overstated. unclear, presenting measures and ratios that have 3. Although a source is given for the very large little relevance to assessing cost-effectiveness. mean cost of treating a hip fracture, none is offered for the mean cost of treating other Adjusted model types of fracture in the elderly (£843) – the The model has been amended and corrected in differential between these figures may be several ways to provide more meaningful results overstated. (albeit still subject to some of the aforementioned 4. In order to verify the mean cost of treating a shortcomings). The changes are as follows: hip fracture used in the submission, the review team obtained the original article. The mean 1. All detected calculation or transcription errors cost estimated by Dolan and Torgerson153 have been corrected. includes social costs and these make up ~60% 2. ORs have been replaced by age-related RRs. of the mean cost of treating a hip fracture. 3. Patients not on drug therapy are assumed to Given that the perspective of the economic see their GP twice yearly. analysis is not stated in the Wyeth submission, 4. Illustrative QALY values have been assigned [a the review team cannot comment on whether gain of 0.1 in health-related quality of life 47

TABLE 9 Results obtained from adjusted Wyeth model (i.e. no increases in falls on zaleplon but increases in falls on other drugs)

AB CD

Primary therapy Incremental analysis Zolpidem Nitrazepam Temazepem No drug

Zaleplon Inc. cost –£767920 –£111371 –£93171 +£836801 Inc. QALY +78.18 +38.54 +38.54 +500.00 Inc. cost/QALY Dominates Dominates Dominates £1674

Zolpidem Inc. cost +£656549 +£674749 +£1604721 Inc. QALY –39.64 –39.64 +421.82 Inc. cost/QALY Dominated Dominated £3804

Nitrazepam Inc. cost +£18200 +£948172 Inc. QALY 0.00 +461.46 Inc. cost/QALY N/A £2055

Temazepem Inc. cost +£929972 Inc. QALY +461.46 Inc. cost/QALY £2015

(HRQoL) for 26 weeks of the year for other primary concern is the risk of successful therapy, a loss of 0.5 in HRQoL for dependency/withdrawal syndrome. What effect 13 weeks per hip fracture and loss of 5 year’s does this have on QoL and on health costs? life expectancy per death consequent on a hip fracture]. Long-term model 5. Ten pairwise therapy comparisons have been No formal long-term economic model is presented carried out to yield illustrative incremental in the industry submission. cost/QALY gained ratios.

Results obtained from the adjusted model, based Conclusion on Wyeth assumptions, are shown in Table 9. Sanofi-Synthelabo Ltd did not submit a formal Therefore if the Wyeth data and assumptions are short-term model. Given the authors’ explicit accepted, the re-analysis suggests that all the recognition of the uncertainty around their long- drugs of interest in the analysis are similarly cost- term model, no formal critique was therefore effective compared with not treating these elderly undertaken by the review group. patients (see column D), and that the apparent differences between drugs appear to be relatively Wyeth presented two short-term models and no minor. Based on Wyeth data and assumptions, long-term model. The RTA model was not zaleplon seems to dominate the other therapies, presented in sufficient detail to allow a detailed that is, zaleplon is more effective and less critique of it to be performed. Critique of the falls expensive than the comparators (zolpidem, model was limited by calculation errors and nitrazepam, temazepam and no drug). technical problems, and heavily dependent on assumptions which favour Wyeth’s product but Other considerations which do not seem supported by the clinical The impact of sleep disorders on HRQoL is not analysis in Chapter 4. considered in any of the Wyeth short-term models. Addressing HRQoL is fundamental to economic In summary, careful scrutiny of the models assessment, and we have estimated an HRQoL presented has reinforced the view that there is a score to allow meaningful comparison between the paucity of clinical and economic evidence available drugs. Equally, there is no information to indicate regarding the comparison of benzodiazepine and the degree of risk/adverse outcome associated with non-benzodiazepine drugs for the management of untreated or imperfectly treated disorder. The short-term insomnia.

48 Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 7 Budget impact analysis

Introduction diazepam and lorazepam are not included in the analysis. A significant proportion of diazepam and This section describes current trends in the lorazepam prescribing is for the treatment of volume of prescriptions and spending on anxiety and to include this data would distort the hypnotics in general practice in England during results of the budget impact analysis. The budget the period 1993–2002. We also project future impact analysis is based on data from the volumes of prescriptions and spending over the Prescription Pricing Authority (PPA). period 2003–07. Throughout this chapter, the benzodiazepine drug group includes nitrazepam, temazepam, loprazolam and lormetazepam. Data Trends in volume of prescriptions on diazepam or lorazepam use have not been and spending on hypnotics included in any of the analyses, since although licensed as hypnotics, they are not defined as As shown in Figure 6, the total number of hypnotics in the BNF51 nor widely used for this prescriptions in general practice in England purpose. The Z-drug group includes zolpidem, during the period 1993–2002 has changed little zopiclone and zaleplon. This covers the group of over the whole period, with a gradual increase drugs defined as ‘hypnotics’ by the BNF,51 taking place from 1995 onwards. Approximately subsection 4.1.1, with the exception of 10 million prescriptions are issued for hypnotics clomethiazole and choral and its derivatives. every year.77 There has been a steady change in the mix of benzodiazepines and Z-drugs within In line with current trends in spending, a budget this group. Large numbers of prescriptions for impact analysis is carried out in order to estimate benzodiazepines are still being prescribed, but the the costs associated with switching prescribing volume of benzodiazepine prescribing has fallen from benzodiazepines to Z-drugs. Again, substantially over this period. In contrast, there

12 Zolpidem, zopiclone, zaleplon

Nitrazepam, temazepam, loprazolam, lormetazepam

4 Number of prescriptions (millions)

0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year

FIGURE 6 Trends in volume of prescriptions in general practice in England (1993–2002) 49

has been a steady rise in the number of Z-drug TABLE 10 Current market shares prescriptions and approximately 4 million prescriptions for these newer hypnotics were Market share (%) dispensed in 2002. Hypnotic By volume of By spending prescriptions The change in the mix of the drugs has led to an annual increase in total spending on hypnotics Zolpidem 6 10 over this period. Indeed, total spending on these Zopiclone 32 51 Zaleplon 1 1 hypnotics has more than doubled since 1994. All Z-drugs 38 62 Figure 7 shows that since 1994, there has been a Nitrazepam 17 9 steady rise in spending on Z-drugs compared with Temazepam 41 22 spending on benzodiazepines. Spending on Z-drugs Loprazolam 2 4 has risen substantially, with only £2 million being Lormetazepam 2 3 spent in 1994 compared with over £15 million All benzodiazepines 62 38 being spent in 2002. The dip in total spending on Z-drugs during the period 1993–94 was due to the company decision to drop the price in the face of up 38% of the total market share based on volume a threat by the then Health Secretary to blacklist of prescriptions. Within the Z-drugs, zopiclone is zopiclone. At this point, zopiclone made up all by far the most frequently prescribed (82%). spending on Z-drugs, so any change in price had a Temazepam is the most commonly prescribed significant impact on total spend in this group. benzodiazepine (22%) and makes up almost The more recent dip in the costs for two-thirds of the benzodiazepine market. This benzodiazepines is due to correction following percentage has fallen since a change in the generic price setting by the Department of Health. regulations in 1995 when temazepam became a controlled drug in an attempt to limit the risk of ‘non-medical’ abuse. As a controlled drug, Current market share temazepam carries some of the usual prescribing restrictions. Table 10 lists current market shares for each of the drugs in 2002 by volume of prescriptions and by If current market share is based on spending, total cost to the NHS. Currently the Z-drugs make using net ingredient cost data, market share of the

30 Zolpidem, zopiclone, zaleplon

Nitrazepam, temazepam, loprazolam, lormetazepam 25

10 Net ingredient cost (£ millions)

0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year

50 FIGURE 7 Trends in spending on hypnotics in general practice in England (1993–2002) Health Technology Assessment 2004; Vol. 8: No. 24

drugs is reversed. Sixty per cent of the total Volume of prescriptions amount spent is on Z-drugs. Within the Z-drugs, The volume of prescriptions is taken directly from zopiclone accounts for 82% of the amount spent. data made available by the PAA.77 In order to Within the benzodiazepines group, spending on estimate cost per prescription for each of the drugs, temazepam is ~60%. an estimate of prescription length is required. Two estimates of the length of the prescription are used in the budget impact analysis. As all of the Budget impact analysis drugs are licensed for short-term use, it seems appropriate to use a uniform 14-day period to There is a paucity of robust and comparable estimate the cost of a single prescription for each published evidence on the costs and benefits of of the drugs. However, in practice, both the newer hypnotics (zaleplon, zopiclone and benzodiazepines and Z-drugs could be prescribed zolpidem) for the management of insomnia. for more than a 14-day period. In order to Therefore, in this report, the budget impact estimate the typical length of a prescription for analysis is simply a pragmatic exercise whose each of the drugs, we used data on the defined purpose is to highlight the possible financial daily dose (DDD) of the drugs.155 The DDD is implications of changes in the mix of considered a typical adult dose but may not benzodiazepine and Z-drug prescriptions. This is a represent the actual prescribed daily dose in any stand-alone exercise and the assumptions therein individual country. An estimate of treatment days are not derived from the clinical or economic based on typical usage can then be calculated for evidence set out in this report. each of the drugs (total number of doses/number of prescriptions). Based on this information, the In order to carry out a budget impact assessment, prescription length for each of the drugs is accurate information is required on the estimated to vary from 16 to 39 days. comparative cost of the hypnotic drugs, total number of prescriptions for each of the drugs and In England, the average daily quantity (ADQ) is typical length of prescription. reported by the PPA77 – this is an arbitrary figure based on the average prescribed daily dose and on Cost of the drugs what preparations are available.156 For the most Table 11 presents the list prices of the part, ADQs are similar to DDDs. We chose not to benzodiazepines and the Z-drugs of interest to this use the ADQs in our calculations since the ADQ is 51 report as quoted in the BNF. Note that zaleplon is 5 mg for zolpidem – this would give an unusually licensed only for a 14-day course, unlike the other long duration of each prescription and is out of Z-drugs, which are licensed for up to 28 days, so for keeping with other hypnotics, so we have used the comparability of prices we have used 14 days as the DDD of 10 mg for zolpidem as suggested by the duration, although in practice most benzodiazepine WHO.155 All of our estimated days of average prescriptions are for longer (see later). treatment are based on DDD data.

51 List prices as published in the BNF and total net Table 12 shows the estimated days of treatment 77 ingredient costs from PPA data are used in the based on typical usage as calculated from the PPA budget impact analysis. Total net ingredient costs dataset,77 and compared with the data provided in refer to the total cost of the drug before discounts the Sanofi-Synthelabo Ltd submission. The and do not include any dispensing fees or costs.154 TABLE 12 Estimated mean days of treatment per prescription

TABLE 11 Cost of the drugs Estimated mean days of treatment per prescription Product 2002 BNF list price (£) for a 14-day period (defined daily dose) Product PPA data Sanofi-Synthelabo

Zolpidem 2.24 (10 mg/day) Zolpidem 22 26 Zopiclone 2.24 (7.5 mg/day) Zopiclone 24 28 Zaleplon 4.04 (10 mg/day) Zaleplon 16 17 Nitrazepam 0.41 (5 mg/day) Nitrazepam 39 36 Temazepam 0.75 (20 mg/day) Temazepam 22 34 Loprazolam 2.23 (1 mg/day) Loprazolam 26 36 Lormetazepam 0.72 (1 mg/day) Lormetazepam 30 35 51

number of days of treatment per prescription with 60–80% of scripts were issued to patients taking zaleplon is shorter than for other drugs, in the drugs for over 2 years. keeping with its licence. For nitrazepam, the estimated days of treatment is higher: this The Prescribing Support Unit calculates specific suggests that it is being used at doses higher than therapeutic area-prescribing units (STAR-PUs) for its DDD or that prescriptions for chronic users are Z-drugs and benzodiazepine hypnotics.157 These of extended duration. are based on prescribing patterns and cost in approximately 200 UK practices, and are an There are limited data on the actual length of approximation of the relative use of the drugs prescriptions issued. Data submitted by Sanofi- according to patient age. It is possible, therefore, Synthelabo Ltd4 suggest a longer duration of knowing the age–sex profile of the practice, to prescription but unfortunately they have been estimate whether it is an above or below average unable to provide further details or describe the spender or user of these drugs. Data reflect the methodology used in more detail. In particular, it age/sex profile of hypnotic users, and the relative would have been interesting to define duration of costs of benzodiazepines and Z-drugs. Analysis use in new users of hypnotics and the likelihood of shows that hypnotics of all types are predominantly repeat prescriptions, and whether this differed prescribed for older patients, and for women with different drugs. generally more than men (Tables 14 and 15).

Sanofi-Synthelabo Ltd has also calculated the Finally, data from General Practice Research mean number of days of therapy received per year Database (GPRD)78 define the absolute rates of for each type of drug (but unfortunately, cannot use of all hypnotics (about two-thirds of the total) provide information on the range or separate out and anxiolytics (about one-third of the total) over new users) (Table 13). In general, it seems that 1 year. It is clear that the heaviest use is in the users of drugs such as nitrazepam or loprazolam elderly, who are most at risk from adverse effects, are receiving the drug almost permanently. Audit and for females more than male (Table 16). data from one Primary Care Trust (Gateshead) suggest that nitrazepam and loprazolam account Current cost to the NHS for around 35% of all benzodiazepine/Z-drug There are a number of ways to estimate the cost of prescriptions and that, depending on the practice, hypnotics to the NHS. Depending on the assumptions made, different estimates of total

TABLE 13 Estimated mean days of treatment per patient per year TABLE 15 STAR-PU values (Z-drugs only)

Product Estimated mean days of treatment Age group (years) Male Female per patient (Sanofi-Synthelabo) 0–4 0.0 0.0 Zolpidem 111 5–14 0.0 0.0 Zopiclone 145 15–24 0.1 0.0 Zaleplon 51 25–34 0.2 0.1 Nitrazepam 299 35–44 0.2 0.2 Temazepam 215 45–54 0.3 0.4 Loprazolam 290 55–64 0.3 0.5 Lormetazepam 194 65–74 0.3 0.5 75 0.5 0.7

TABLE 14 STAR-PU values (hypnotics excluding Z-drugs) TABLE 16 Percentage of patients prescribed hypnotics or Age group (years) Male Female anxiolytics by age and sex

0–4 0.0 0.0 Age group (years) Male Female 5–14 0.0 0.0 15–24 0.1 0.0 0–4 0.26 0.2 25–34 0.3 0.2 5–14 0.18 0.19 35–44 0.3 0.3 15–34 1.63 2.23 45–54 0.4 0.6 35–54 3.26 5.54 55–64 0.5 0.9 55–74 5.8 10.8 65–74 0.7 1.3 75+ 15.2 22.4 75 1.2 1.5 Average 2.2 4.8 52 Health Technology Assessment 2004; Vol. 8: No. 24

TABLE 17 Cost to the NHS (2002)

Hypnotic Total prescriptions Cost per prescription Net ingredient cost (£) taken directly (2002) per day (£) from PPA dataset (2002)

Zolpidem 631,710 0.16 2,483,959 Zopiclone 3,213,805 0.16 13,078,162 Zaleplon 58,443 0.29 316,128 Total Z-drugs 3,903,958 15,878,249

Nitrazepam 1,773,187 0.03 2,180,660 Temazepam 4,128,277 0.05 5,662,938 Loprazolam 17,0273 0.16 974,863 Lormetazepam 18,4389 0.05 801,395 Total benzodiazepines 6,256,126 9,619,855

Total (approx.) 10,000,000 25,000,000 spending are obtained. Table 17 presents the cost TABLE 18 Additional cost of switching from benzodiazepines to to the NHS by drug, based on total net ingredient Z-drugs costs for Z-drugs and benzodiazepines. Switch (%) Based on a Based on 14-day prescription estimated Short-term shift from benzodiazepines (£ million) average days to Z-drugs of treatment Current professional advice, e.g. Prodigy,79 favours (£ million) the prescription of benzodiazepines unless there is a clear clinical reason to favour Z-drugs. However, 20 2 3 50 5 8 it is evident from an analysis of prescribing 80 8 13 patterns that a switch from benzodiazepines to Z-drugs is slowly happening. This may be due to a cohort effect – the large numbers of patients who were given benzodiazepines at the height of their Table 18, using 2002 data, shows the additional use in the 1970s, and who have been using them annual cost of switching from benzodiazepines to ever since, are slowly dying off. Or it may be due Z-drugs. In this scenario, the reduction in the to doctor preference to prescribe the newer number of benzodiazepine prescriptions Z-drugs, either because of their perceived clinical (n = 1,251,225) is shared between the Z-drugs benefits, advertising or simply because the newer according to their 2002 market share of Z-drug Z-drugs are not benzodiazepines. Tables 18 and 19 prescriptions. Clearly, any increase in the number illustrate the cost to the NHS of switching of Z-drug prescriptions is accompanied by prescriptions from benzodiazepines to Z-drugs. substantial increased costs. Additional costs range from £3 million to £13 million depending on the The budget impact analysis recognises that the size of the switch. An important unknown is volume of benzodiazepine prescriptions is whether what will change will be simply numbers decreasing and, following the current trend, will of prescriptions or length of prescriptions – for continue to decrease. Following the current trend, example, will a long prescription for nitrazepam it appears likely that the proportion of be replaced by a short prescription of zaleplon or prescriptions for Z-drugs will continue to rise. other Z-drugs. This seems unlikely.

TABLE 19 Additional annual cost of switching from benzodiazepines to individual Z-drugs

Based on a 14-day Based on estimated prescription (£ million) treatment days (£ million)

Switch (%) Zolpidem Zopiclone Zaleplon Zolpidem Zopiclone Zaleplon

20 2 2 4 3 3 4 50 5 5 10.5 7 8 10.5 80 8 8 17 11 13 17 53

Table 19, using 2002 data, depicts the additional patterns, by the end of the year 2005, it may be annual cost to the NHS if a reduction in expected that Z-drug prescribing will overtake that benzodiazepine prescriptions leads to an increase of benzodiazepine (Figure 9). in the number of zolpidem or zopiclone or zaleplon prescriptions. For example, if a reduction As the total volume of hypnotic prescriptions in 20% (1.2 million) of benzodiazepine continues to rise, the cost to the NHS will be prescriptions leads to a 1.2 million increase in considerable. Initial estimates of total cost by the zolpidem prescriptions, then the additional cost to year 2007 range from £17 million to £33 million the NHS is £2 million or £3 million depending on depending on the method used. Detailed the method used. Clearly, the results of the budget estimates of future spending have not been analysis must be interpreted in the light of the calculated given the many underlying assumptions made; the lowest estimate of total uncertainties governing this market such as additional cost (£2 million) to the NHS is very potential relative price changes of the drugs, the different from the largest estimate (£17 million). effect of reducing benzodiazepine prescriptions on the volume of Z-drug prescriptions and availability Long-term shift from benzodiazepines of new techniques and treatments for insomnia. to non-benzodiazepines To forecast future NHS expenditure on hypnotics, it Limitations and conclusion is necessary to estimate the size of future volumes of The budget impact analysis clearly shows that any prescriptions from the perspective of the NHS. In decrease in the volume of benzodiazepine order to do this, the trend in historic prescription prescribing, if associated with increased data from 1995 onwards was modelled using a prescribing of Z-drugs, will be very costly to the quadratic function to allow projection of the volume NHS. of prescriptions for a 5-year period. Figure 8 indicates that the total volume of prescriptions for In this pragmatic budget impact analysis, a switch hypnotics is actually projected to increase slightly, from benzodiazepine to Z-drug prescribing has reaching almost 10.5 million per year by 2008. been used to estimate the likely total cost of Each of the data points on the graph is based on hypnotics in the NHS. Although there is no rolling quarterly data. clinical evidence from RCTs to justify this switch, by adopting a pragmatic approach the budget On closer analysis, it is clear that the number of impact analysis has recognised that the number of prescriptions for benzodiazepines may continue to prescriptions for benzodiazepines is falling and fall and the number of prescriptions for Z-drugs may continue to do so. It is unlikely that a may continue to rise. Given current prescribing reduction in the number of benzodiazepine

PPA data Projected trendline 9 Total prescriptions per annum (millions) Total

8 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Year

54 FIGURE 8 Projecting future trends in volumes of prescriptions Health Technology Assessment 2004; Vol. 8: No. 24

9 Non-benzodiazepine prescriptions

8 Benzodiazepine prescriptions

Total prescriptions per annum (millions) Total 2

0 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Year

FIGURE 9 Projecting future trends: benzodiazepines versus Z-drugs prescriptions will lead to savings in the NHS. G That advice given about non-drug therapies for What is more likely is that the prescriptions for insomnia for every new and repeat prescription other insomnia treatments will rise. Given current of benzodiazepines is documented. trends in prescribing, it seems appropriate, in the G That appropriate advice given about the risk of budget impact analysis, to assume that benzodiazepine use, including the potential for prescriptions for Z-drugs will rise. dependency, is documented.

However, it may not be the case that a reduction Although not specifically stated, this advice is in benzodiazepine prescriptions will only be usually extended to include the Z-drugs, where the accompanied by an increase in the number of evidence of dependency for two of these drugs is Z-drugs prescribed. Current guidance is focused not different to that of benzodiazepines. If it is on the non-pharmacological treatment of demonstrated that some of the Z-drugs have fewer insomnia and it may be the case that a reduction problems of dependency and withdrawal than in the number of benzodiazepine prescriptions is benzodiazepines when misused, then it may be the linked to both an increase in prescriptions of case that increases in initial spending are Z-drugs and other non-pharmacological somewhat off-set in future years; typical days of treatments. If so, then the budget impact analysis treatment will be shorter and fewer individuals will may over- or underestimate the total cost of require NHS care to manage their dependency. hypnotics in the NHS. One final limitation to the budget impact In recognition of the fact that misuse of analysis is that it is carried out from the benzodiazepines is linked to problems of long-term perspective of the NHS. The impact of insomnia dependency and withdrawal, the National Service and its treatment has consequences not only for Framework for Mental Health80 recommends that the NHS but also for society as a whole and this the prescribing of benzodiazepines be audited must be recognised. regularly within a local clinical audit programme. It has been recommended that the following In conclusion, a reduction in the number of should be audited: benzodiazepine prescriptions, if accompanied by an increase in Z-drug prescribing, will be very G That new benzodiazepine prescriptions are costly to the NHS. Whether or not the switch from issued for short-term relief (less than 4 weeks) benzodiazepines to Z-drugs is merited on clinical of insomnia. and/or economic grounds is unclear. 55

Health Technology Assessment 2004; Vol. 8: No. 24

Chapter 8 Conclusions

his review has examined the comparative of all patients received these for more than 4 T effectiveness of the newer hypnotics to weeks. Of all hypnotic prescriptions in this study, benzodiazepines in the short-term treatment of 30% were for more than 6 months. insomnia. A key issue is that it does not evaluate the broader question of the appropriateness of It is therefore striking that the use of hypnotics as using hypnotics in the first place and of the a whole has not declined and indeed is increasing effectiveness of hypnotics versus placebo or non- slightly. This may be a source of concern for the pharmacological interventions. Questions also future, if these drugs continue to be considered remain about the long-term effectiveness of these inappropriate for widespread or prolonged use. drugs when used for periods beyond 4–6 weeks and their role in a condition which has a variable To summarise the results, there are minor course and which is typically relapsing. These are differences between the drugs. Some of these vitally important questions, but are outside the relate to the pharmacology of the drugs; for remit of this study. instance, zaleplon is rapidly absorbed and rapidly cleared – this results in shorter sleep latency, but The systematic review identified a relatively small no extension in duration of sleep compared with number of studies comparing one hypnotic with zolpidem. The question of which of these is the another. Most of these studies were old and ‘better’ hypnotic may depend on what aspects of conducted at a time when the quality of study sleep are problematic for the patient – not falling reporting and publication were lower than they asleep or excessive awakenings. There are are at present and, as a result, many of the studies therefore trade-offs between different aspects of have been of very poor methodological quality. sleep. Some drugs show less daytime drowsiness Furthermore, the studies reported many different than others, usually again a function of the outcomes, and it has been difficult to extract and pharmacokinetics of the drugs, with drugs with a compare data from the studies to address the long half-life such as nitrazepam apparently the review question. worst offenders in this regard.

A further issue is that the remit of this review was The lack of any major evidence of difference in to consider these drugs with respect to their terms of clinical effectiveness or utility, or indeed licensed indications. However, it is clear from the even within well-defined areas such as sleep latency prescribing and other data that many of these or duration, may be due to the poor design on drugs are prescribed completely outside their reporting of trials, which undermines attempts to current licence. Some of this is historical in origin combine results from different studies. Most of the and represents treatments which were started many studies were commercially sponsored. Many years ago. We were unable to obtain data on how perceived differences between benzodiazepines many new patients were becoming chronic users of and Z-drugs may be the results of the historical hypnotics and whether this differed between drugs. time at which they came to the market. Anecdotally, although it still happens, this appears to be far less than in previous years. For instance, There is, however, no consistent pattern of the prescribing of nitrazepam is declining, superiority of one drug over any other, even within presumably owing to a cohort effect as older well-defined areas. Many of the comparisons patients, who were prescribed this drug for many between drugs which we would like to have years, gradually die. Primary Care Trust evaluated have never been made, for example prescribing advisers report anecdotally (personal between zaleplon and many benzodiazepines. communications) that one of the leading sources of chronic prescriptions of hypnotics today are Broad guidance on what constitutes good use of patients seen by consultant psychiatrists rather hypnotics has been produced by the BNF.51 It than a GP; this is borne out by a recent study158 in recommends short-term use – no more than a mental health trust which showed that 31% of all 3 weeks, and intermittent dosing is preferable; a patients were prescribed hypnotics, and that 10% rapidly eliminated drug is generally (more) 57

appropriate, and names temazepam, lormetazepam drugs. Falls, especially in the elderly, may be an or loprazolam as drugs that fit this description. issue, but again the evidence in this area to argue The Z-drugs are also considered satisfactory. that one drug is superior to another is weak.

The question of intermittent use has not been Much was made in the industry submissions of the examined in this review: there is evidence to improved functioning of individuals during the support the use of zolpidem in this way but similar day as a consequence of the use of the more trials do not seem to exist for benzodiazepines or expensive drugs with shorter half-lives. Again, we other Z-drugs. It is assumed that such a await further evidence for both the existence of prescribing pattern should limit the development this and its importance. We found limited of tolerance and the risks of dependency, but evidence of statistically significant differences in more research on this is needed. There are no daytime function, either mental or physical, comparative studies between drugs in this area. resulting from the use of the different drugs. This is obviously a crucial area for future research which In summary, the short-acting drugs seem equally will greatly improve the ability of the economic effective and safe with minor differences that may analysis to undertake a meaningful assessment. lead a prescriber to favour one over another in different patients. There is no evidence that one is Although we examined the health economics of more cost-effective than any other. this area, we found insufficient data to allow us to undertake an economic evaluation. We have A key issue has been the question of drug reworked one economic evaluation submitted by a dependency. This mainly applies when the drug is company and corrected some of its errors, but used outside its licence, and has been difficult to point out that this is dependent on a key address because of the lack of adequate research in supposition, namely that falls are related to this area. In the past, benzodiazepines were used at hypnotic use and that one drug will be superior – higher doses and for prolonged periods and this a contention not so far supported by the trial resulted in large numbers of dependent patients evidence or indeed by the observational data. and reports of dependency. By contrast, the newer hypnotics have come on to the market at a later The systematic review provided in this report time, when attitudes towards the use of hypnotics suggests that an agnostic approach to cost- and sedatives in general have changed. They are effectiveness is required at this stage. In the short therefore perhaps less likely to be used in the same term, no systematic evidence is available way and for the same prolonged periods. Although concerning significant outcome variations between there are reports of dependency on these drugs, either the different classes of drugs or between they are more limited than on benzodiazepines. individual drugs within each class. Within this Some argue that there is a difference in short-term horizon, the one element that does vary dependency potential among hypnotics when they significantly is the acquisition cost of the individual are used for inappropriately long periods. At drugs. In such circumstances, and in the absence present, it may be more appropriate to be on the of further evidence of their clinical superiority, it side of caution, and restrict use of these drugs to seems difficult to justify the use of more expensive the terms of the BNF recommendations, including drugs and there seems no reason to alter restriction to use in disabling insomnia. traditional recommendations of choice of drug (i.e. to use short-acting benzodiazepines as first With regard to other potential adverse effects such choice). as amnesia and next-day drowsiness, our review has not found any consistent differences between There are clear research needs in this area: in the drugs, in part because of the poor quality of particular, none of the existing trials adequately reporting. compare these medications. We would urge, therefore, that further consideration should be Issues raised in the pharmaceutical company given to a formal trial to allow head-to-head submissions involved whether particular drugs comparison of some of the key drugs in a double- might be less likely to lead to falls and to RTAs. blind RCT lasting at least 2 weeks, and of There are described associations between some sufficient size to draw reasonable conclusions. We hypnotics and both of these events. With regard to would also recommend that any such trial should driving, evidence that long-acting drugs such as include a placebo arm. It should also collect good- nitrazepam are more harmful exists, but there is quality data around sleep outcomes and in 58 no clear distinction between the shorter acting particular QoL and daytime drowsiness. We do not Health Technology Assessment 2004; Vol. 8: No. 24

believe that any formal study of risk of insomnia: considering the frequency of this dependency is feasible at present. symptom and its recurring course, the short-term trial of medication and lack of long-term follow-up Finally, the major research issue is perhaps not undermine attempts to develop evidence-based around the management of short-term insomnia, guidelines for the use of hypnotics in this but around the management of long-term condition, or indeed for its whole management.

Health Technology Assessment 2004; Vol. 8: No. 24

Acknowledgements

About home unit and also data analysis and interpretation. All The Liverpool Reviews and Implementation contributors took part in the editing and Group (LRIG) was established within the production of this report. Department of Pharmacology and Therapeutics in April 2001. It is a multidisciplinary research group List of Review Panel members whose purpose, in the first instance, is to conduct (provided feedback to the team during systematic reviews commissioned by the NHS R&D the review process) HTA Programme. G Dr M Gabbay, Senior Lecturer, Department of Primary Care, University of Liverpool Contributions of authors G Dr A Holbrook, Director, Clinical Mr Adrian Bagust (Senior Research Fellow, Health Pharmacology, Department of Medicine, Economics) conducted the analysis of economic McMaster University and Senior Scientist, models. Dr Jan Bogg (Lecturer, Health Centre for Evaluation of Medicines, St Joseph’s Psychology) conducted the review of memory, Hospital, Hamilton, Ontario, Canada mood and psychomotor measures used in clinical G Professor K Morgan, Professor of Gerontology, studies. Ms Angela Boland (Research Fellow, University of Loughborough Health Economics) conducted the review of G Professor D Nutt, Professor of economic effectiveness, carried out budget impact Psychopharmacology, Department of Clinical analysis and prepared the results for publication. Medicine, School of Medical Sciences, Ms Rumona Dickson (Director, Liverpool Reviews University of Bristol and Implementation Group) participated in G Professor PJ Tyrer, Head of Department of assessing the scope and the development of the Psychological Medicine, Imperial College review protocol, assessed studies for inclusion, (Charing Cross Campus), London cross-checked data and assisted in drafting the results for publication. Ms Susanna Dodd Peer reviewers (Research Associate, Medical Statistics) data G Professor D Cohen, Professor of Health extracted information from clinical studies, served Economics, University of Glamorgan, Pontypridd as statistical advisor for data analysis and assisted G Professor I Hindmarch, Head of Human in drafting the results for publication. Dr Yenal Psychopharmacology Research Unit (HPRU), Dündar (Research Fellow, Clinical Effectiveness) Medical Research Centre, Guildford coordinated the review production, conducted the G Professor M Lader, Emeritus Professor of Clinical review of clinical effectiveness and prepared the Psychopharmacology, Institute of Psychiatry, results for publication. Dr Alan Haycox (Senior London Lecturer, Health Economics) provided support and supervision for the economic review. This report was commissioned by the NHS R&D Ms Judith Strobl (Research Fellow, Clinical HTA programme. The views expressed in this Effectiveness) assisted in development of search report are those of the authors and not necessarily strategies, data extracted information from clinical those of the review panel, peer reviewers, the HTA studies and prepared the results for publication. programme, National Institute for Clinical Professor Tom Walley (Professor, Pharmacology Excellence or the Department of Health. Any and Therapeutics) supervised the review activities errors are the responsibility of the authors.

Health Technology Assessment 2004; Vol. 8: No. 24

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Appendix 1 Search strategies and search results

TABLE 20 Search for clinical-effectiveness studies: summary

Database Years Search strategy References identified

MEDLINE 1966–2003 See the accompanying text 244 EMBASE 1980–2003 See the accompanying text 416 PsycINFO 1966–2003 See the accompanying text 61 Science Citation 1981–2003 [(insomnia* or sleep*) and (zaleplon or sonata or 481 Index/Web of Science zolpidem or stilnoct or zopiclone or zimovane or zileze)] Science Citation 1990–2003 As above 37 Index/ ISI Proceedings Cochrane Trials Register 2003 (1) As above 260 Cochrane Database 2003 (1) As above 8 of Systematic Reviews HTAa 1994–2003 As above 0 DAREa 1994–2003 As above 5 Total references identified 1504 Duplicates 699 Total 805

a Note that these databases have retrospective coverage of the literature a few years prior to the start dates given. Also, the HTA used to be included as part of the DARE.

Search strategy for clinical 19. human.sh. effectiveness (MEDLINE 20. 18 not (18 and 19) 21. 17 not 20 1966–2003) 22. (zaleplon or sonata).af 1. randomized controlled trial.pt. 23. (zolpidem or stilnoct).af 2. randomized controlled trials.sh. 24. (zopiclone or zimovane or zileze).af 3. random allocation.sh. 25. or/22-24 4. double blind method.sh. 26. exp “Sleep Initiation and Maintenance 5. single blind method.sh. Disorders”/ or exp SLEEP/ 6. clinical trial.pt. 27. (insomnia or sleeplessness).tw 7. clinical trials.sh. 28. 26 or 27 8. controlled clinical trials.sh. 29. 21 and 25 and 28 9. (clin$ adj25 trial$).ti,ab. 10. ((singl$ or doubl$ or trial$) adj25 (blind$ or mask$)).ti,ab. Search strategy for clinical 11. random$.ti,ab. effectiveness (EMBASE 12. research design.sh. 1980–2003) 13. exp Evaluation Studies/ 14. follow up studies.sh. 1. randomised controlled trial/ 15. prospective studies.sh. 2. controlled study/ 16. (control$ or prospective$ or volunteer$).ti,ab. 3. randomisation/ 17. or/1-16 4. exp double blind procedure/ 18. animal.sh. 5. exp single blind procedure/ 69

6. clinical trial/ 3. exp drug tolerance 7. random$.ti,ab. 4. tolerance.mp 8. methodology/ 5. rebound.mp 9. evaluation/ 6. exp substance withdrawal syndrome 10. follow up/ 7. exp “dependency (Psychology)” 11. prospective study/ 8. (zaleplon or sonata).af 12. (control$ or prospective$ or volunteer$).ti,ab. 9. (zolpidem or stilnoct).af 13. or/1-12 10. (zopiclone or zimovane or zileze).af 14. (zaleplon or sonata).af 11. or/1-7 15. (zolpidem or stilnoct).af 12. or/8-10 16. (zopiclone or zimovane or zileze).af 13. 11 and 12 17. or/14-16 14. limit to 13 to human 18. exp insomnia/ or (insomnia or sleeplessness).tw. 19. exp sleep/ 20. 18 or 19 Search strategy for dependency 21. 13 and 17 and 20 and withdrawal (EMBASE 22. limit 21 to human 1980–2003)

1. withdraw$.mp Search strategy for clinical 2. dependenc$.mp effectiveness (PsycINFO 3. exp drug tolerance 1966–2003) 4. tolerance.mp 5. exp withdrawal syndrome/ or exp drug 1. random$ controlled trial.mp. withdrawal 2. random$.ti.ab. 6. rebound.mp 3. (clin$ adj25 trial$).ti,ab. 7. (zaleplon or sonata).af 4. ((singl$ or doubl$ or trial$) adj25 (blind$ or 8. (zolpidem or stilnoct).af mask$)).ti,ab. 9. (zopiclone or zimovane or zileze).af 5. (control$ or prospective$ or volunteer$).ti,ab. 10. or/1-6 6. (zaleplon or sonata).af 11. or/7-9 7. (zolpidem or stilnoct).af 12. 10 and 11 8. (zopiclone or zimovane or zileze).af. 14. limit to 12 to human 9. or/1-5 10. or/6-8 11. exp insomnia/ or (insomnia or sleeplessness).tw. Search strategy for dependency 12. and/9-11 and withdrawal (PsycINFO 13. limit 12 to (human and year=1966-2003) 1966–2003)

1. withdraw$.mp Search strategy for dependency 2. dependenc$.mp and withdrawal (MEDLINE 3. exp drug tolerance 1966–2003) 4. tolerance.mp 5. rebound.mp 1. withdraw$.mp 6. exp drug withdrawal 2. dependenc$.mp 7. exp drug dependency

TABLE 21 Search strategies for dependency and withdrawal

Database Years Search strategy References identified

MEDLINE 1966–2003 See the accompanying text 192 EMBASE 1980–2003 See the accompanying text 399 PsycINFO 1966–2003 See the accompanying text 67 Total references identified 658 Duplicates 195 Total 463 70 Health Technology Assessment 2004; Vol. 8: No. 24

TABLE 22 Search for cost-effectiveness studies: summary

Database Years Search strategy References identified

MEDLINE 1966–2003 See the accompanying text 148 EMBASE 1980–2003 See the accompanying text 440 PsycINFO 1974–2003 See the accompanying text 38 Science Citation 1981–2003 (cost or quality of life) and insomnia 209 Index/Web of Science Science Citation 1981–2003 (cost or quality of life) and insomnia 26 Index/ ISI Proceedings Cochrane Database 2003 (1) (cost and insomnia) 46 of Systematic Reviews NHS EEDa 1994–2003 (insomnia or sleep) 63 HTAa 1994–2003 (insomnia or sleep) 7 DAREa 1994–2003 (insomnia or sleep) 124 Health Economic 1995–2003 ((benzodiazepine or zaleplon or 9 Evaluations Database zolpidem or zopiclone) and cost) Total references identified 1110 Duplicates 171 New total 939

a Note that these databases have retrospective coverage of the literature a few years prior to the start dates given. Also, the HTA used to be included as part of the DARE.

8. exp drug tolerance 12. quality of life.mp. or exp Quality of Life/ 9. (zaleplon or sonata).af 13. exp Life Expectancy/ or quality adjusted life 10. (zolpidem or stilnoct).af year.mp. or exp Decision Making/ or exp 11. (zopiclone or zimovane or zileze).af Quality-Adjusted Life Years/ or exp Cost- 12. or/1-8 Benefit Analysis/ or exp Quality of Life/ 13. or/9-11 14. (1 or 2 or 3 or 4) and (5 or 6 or 7) and (8 or 9 14. 12 and 13 or 10 or 11 or 12 or 13) 15. limit 14 to human EMBASE cost-effectiveness MEDLINE cost-effectiveness search strategy (1980–2003) search strategy (1966–2003) 1. benzodiazepine$.mp. or exp benzodiazepines/ 1. benzodiazepine$.mp. or exp benzodiazepines/ 2. (zalepon or sonata).af 2. (zalepon or sonata).af 3. (zolpidem or stilnoct).af 3. (zolpidem or stilnoct).af 4. (zopiclone or zimovane or zileze).af. 4. (zopiclone or zimovane or zileze).af. 5. exp sleep/ 5. exp sleep/ 6. insomnia.mp or exp “sleep initiation and 6. insomnia.mp or exp “sleep initiation and maintenance disorders”/ maintenance disorders”/ 7. (insomnia or sleeplessness).tw 7. (insomnia or sleeplessness).tw 8. cost.mp or exp “Costs and Cost Analysis”/ 8. cost.mp or exp “Costs and Cost Analysis”/ 9. cost$.mp 9. cost$.mp 10. model$.mp 10. model$.mp 11. economic$.mp or exp ECONOMICS/ or exp 11. economic$.mp. or exp ECONOMICS, HEALTH ECONOMICS/ NURSING/ or exp ECONOMICS, DENTAL/ 12. quality of life.mp. exp quality of life or exp ECONOMICS/ or exp ECONOMICS, 13. Health Care Delivery/ or quality adjusted life HOSPITAL/ or exp ECONOMICS, year.mp. or Cost Effectiveness Analysis/ or PHARMACEUTICAL/ Health Status/ or Economics/ or Economic 71

Aspect/ or Quality of Life/ or Cost Benefit 3. (zolpidem or stilnoct).af Analysis/ or Quality Adjusted Life Year/ or 4. (zopiclone or zimovane or zileze).af. Life Expectancy 5. exp sleep/ 14. (1 or 2 or 3 or 4) and (5 or 6 or 7) and (8 or 9 6. (insomnia or sleeplessness).tw or 10 or 11 or 12 or 13) 7. cost.mp or exp “Costs and Cost Analysis”/ 8. cost$.mp 9. model$.mp PsycINFO cost-effectiveness 10. quality of life.mp. or exp Quality of Life/ search strategy (1974–2003) 11. (1 or 2 or 3 or 4) and (5 or 6) and (7 or 8 or 9 or 10) 1. benzodiazepine$.mp. or exp benzodiazepines/ 2. (zalepon or sonata).af

72 Health Technology Assessment 2004; Vol. 8: No. 24

Appendix 2 Quality assessment checklists

Quality assessment checklist for G Were the individuals who were administered the clinical studies intervention blinded to the treatment allocation? Studies of clinical effectiveness will be assessed G Were the participants who received the using the following criteria, based on CRD Report intervention blinded to the treatment allocation? No. 4, University of York.81 G Was the success of the blinding procedure assessed? G Was the method used to assign participants to G Were at least 80% of the participants originally the treatment groups really random? included in the randomisation process, followed (Computer-generated random numbers and random up in the final analysis? number tables will be accepted as adequate, whereas G Were the reasons for any withdrawals stated? inadequate approaches will include the use of G Was an ITT analysis included? alternation, case record numbers, birth dates or days of the week.) Items graded as: , yes (item adequately G Was the allocation of treatment concealed? addressed); , no (item not adequately (Concealment will be deemed adequate where addressed); / partially, (item partially randomisation is centralised or pharmacy controlled, addressed); NA, not applicable; NS, not stated. or where the following are used: serially numbered containers, on-site computer-based systems where assignment is unreadable until after allocation, other Quality assessment checklist for methods with robust methods to prevent foreknowledge cost-effectiveness studies159 of the allocation sequence to clinicians and patients. Inadequate approaches will include: the use of G Well-defined question. alternation, case record numbers, days of the week, G Comprehensive description of competing open random number lists and serially numbered alternatives. envelopes even if opaque.) G Effectiveness established. G Was the number of participants who were G All important and relevant costs and randomised stated? consequences for each alternative identified. G Were details of baseline comparability presented G Costs and consequences measured accurately. in terms of treatment-free interval, disease bulk, G Costs and consequences valued credibly. number of previous regimens, age, histology G Costs and consequences adjusted for differential and performance status? timing. G Was baseline comparability achieved for G Incremental analysis costs and consequences. treatment free interval, disease bulk, number of G Sensitivity analyses to allow for uncertainty in previous regimens, age, histology and estimates of costs or consequences. performance status? G Study results/discussion include all issues of G Were the eligibility criteria for study entry concern to users. specified? G Were any co-interventions identified that may The scores used for each dimension were as influence the outcomes for each group? follows: , dimension appropriately addressed; G Were the outcome assessors blinded to the /, dimension partially/maybe addressed; N/A, treatment allocation? dimension not applicable.

Health Technology Assessment 2004; Vol. 8: No. 24

Appendix 3 Clinical data tables

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued None None None Other None None 11 days 1 week 1 week 10 nights Patients in Patients which sleep pattern could not be ascertained in Patients which sleep pattern unclear, inappropriate drug use Not stated Age 16 – 70 Insomniacs with schizophrenia and manic-depressive psychosis sleep disturbance >3 days/week Age 16 – 70 Chronic primary insomnia sleep difficulties >3 days/week Not stated Japan Multicentre Japan Multicentre The Netherlands Multicentre and centres criteria criteria Duration Follow-up comparators Sleep latency, quality of sleep, sleep duration, feeling NAWs, on waking up and during safety, day, anxiety Sleep latency, quality of sleep, sleep duration, feeling NAWs, on waking up and during safety, day, anxiety PSG parameters, motor activity, subjective estimates of sleep times and sleep quality Not stated Not stated Not stated support Majority inpatients Mostly outpatients Not stated RCT DB parallel RCT DB parallel RCT DB parallel n = 73 = 74 = 64 = 67 Nitrazepam 5 mg n Nitrazepam 5 mg n Zolpidem 10 mg n Zolpidem 10 mg n Zolpidem 10 mg 17 in analysis Temazepam 20 mg 13 in analysis drug and design dose, 88 Study characteristics 86 89 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercial Study Inclusion Exclusion Study Interventions: Kudo, 1993 Kudo, Kazamatsuri, 1993 76 Kerkhor, 1996 TABLE 23 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued = 85 = 84 Triazolam n Placebo n None Other 4 days None 4 weeks 5 nights Mental illness, organic conditions, previous drug use, known allergy, substance abuse, shift workers and individuals with changing sleep schedules Mental illness, previous drug use, history of drug abuse, shift workers Age 60 – 85 Chronic insomnia >3 months, SSL of 30 minutes, SSD of 4 – 6/night, impairment of daytime func, deprivation, stable mental and physical health Age 21 – 55 Need daily hypnotic for alcohol withdrawal, sleep latency >30 minutes, several nocturnal awakenings, waking up too trouble early, during the day because of lack sleep at night USA Multicentre Belgium 2 centres and centres criteria criteria Duration Follow-up comparators Primary: SSL, Primary: SSD Secondary: ease of falling asleep, NAWs, wake time after sleep onset, quality of sleep, morning sleepiness, ability to concentrate Hypnotic efficacy, behaviour and mood at awakening, overall evaluation of tolerability and efficacy Acknowledged Lornex Pharmaceuticals, Skokie, IL, USA Rh ô ne-Poulenc Inc., Rorer, Brussels, Belgium (co-author) support Not stated Unclear ’ d) RCT DB parallel RCT DB parallel = 54 n n = 82 = 82 = 27 in = 25 in Temazepam Temazepam 15 mg n analysis Lormetazepam 1 mg n analysis Overall : Zolpidem 5 mg n Zopiclone 7.5 mg n drug and design dose, 82 Study characteristics (cont 83 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion Leppik, 1997 Ansoms, 1991 77 TABLE 23 TABLE

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued = unknown None Placebo n Other None 1 week 2 weeks 2 weeks Mental illness, organic conditions, concomitant antidepressive, anxiolytic or neuroleptic drug use, effectiveness of placebo Mental illness, organic condition, substance abuse, previous drug use, hypersensitivity, night shift workers Age 20 – 50 Generalised anxiety disorder (Hamilton rating <20), absence of factors related to onset or persistence of insomnia Age 20 – 69 Unable to fall asleep within 45 minutes, or >2 nocturnal awakenings with difficulty returning to sleep, no known cause, or sleeping <6 hours per night. Italy 3 centres UK Multicentre and centres criteria criteria Duration Follow-up comparators Quality of daytime arousal, time of sleep induction, number of nocturnal arousals, quality of sleep, duration of sleep Sleep latency, nocturnal awakenings, duration of sleep, quality of sleep, feeling on awakening, adverse events. None reported May & Baker, Ltd., Essex, UK (author) support Not stated General practice ’ d) RCT DB crossover (1 week washout) RCT DB parallel n = 119 Zopiclone 7.5 mg Nitrazepam 5 mg Overall: n (No. per group not reported) Zopiclone 7.5 mg Nitrazepam 5 mg Overall: n = 20 drug and design dose, 84 Study characteristics (cont 85 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion Agnoli, 1989 78 Anderson, 1987 TABLE 23 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued None None Other 10 nights (first week on placebo) None 1 week 14 nights Painful conditions, contraindications to benzodiazepines, substance misuse, drug treatment liable to affect metabolism, unable to complete trial or already in other trial, unlikely to cooperate Acute illness, severe chronic diseases, substance abuse, mental retardation and epilepsy, organic condition (pregnancy), history of drug reaction Age 21 – 49 At least 3 of the following symptoms over at least 2 months without improvement: sleep onset longer than 45 minutes, sleep duration shorter than 6 h, at least 3 nocturnal awakenings, waking up in the morning at least 2 h before expected, poor morning conditioning Age >65 Any two of the following criteria: hypnotics 5 per week for 3 months, sleep latency >1 h, sleep duration <6 h, waking >3 times per night; IQ and memory test within normal range for age Germany Single centre Germany Single centre and centres criteria criteria Duration Follow-up comparators Total sleep Total time, NAWs Sleep onset quality latency, of sleep, feeling on awakening, duration of sleep, nocturnal awakenings, condition in the morning, general evaluation Rh ô ne-Poulenc Sant é , Courbevoie, France (co-author) Rh ô ne-Poulenc Sant é , Courbevoie, France (2 co-authors) support Sleep lab. Community residence ’ d) RCT DB parallel RCT DB parallel = 74 n n = 5 = 5 (No. per group not reported) Nitrazepam 5 mg n Zopiclone 7.5 mg n Zopiclone 7.5 mg Nitrazepam 5 mg Overall: drug and design dose, 87 Study characteristics (cont 90 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion Jovanovic, 1983 Klimm, 1987 79 TABLE 23 TABLE

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued None None None Other None None None 1 week 1 week 1 night Mental illness, organic condition, known allergy Mental illness, organic condition, known allergy Expected hospitalisation <5 days or change in basic treatment, need for psychotropic medication or psychotherapy after 13.00 h, patients expected not to comply with abstinence from certain substances, non- psychotropic somatic treatment or non-stabilised disorder possibly influencing sleep, pregnancy 1 ≥ 3 days/week Age >60 Difficulty with sleeping ≥ Age >60 35 – 81 kg, difficulty with sleeping day/week Age 18 – 65 Hospitalised for depression, schizophrenia, alcoholism, stabilised, but suffering from insomnia Japan Multicentre Japan 14 centres Luxembourg Single centre and centres criteria criteria Duration Follow-up comparators Sleep latency, sleep NAWs, side- quality, effects Sleep latency, sleep NAWs, side- quality, effects Quality of sleep, including sleep onset latency, total sleep time, NAWs, vigilance after awakening, feeling after awakening, side- memory, effects Not stated Not stated Rh ô ne-Poulenc Sant é , Courbevoie, France (co-author) support Hospital In- and outpatients In- and outpatients ’ d) RCT DB parallel RCT DB parallel RCT DB crossover (no washout period) = 40 n n = 54 = 74 = 66 = 71 Nitrazepam 5 mg n Nitrazepam 5 mg n Zopiclone 7.5 mg n Zopiclone 5 mg n Zopiclone 7.5 mg Zopiclone 15 mg Nitrazepam 5 mg Nitrazepam 15 mg Overall: drug and design dose, 93 Study characteristics (cont 91 92 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion 80 Ohtomo 1, 1985 Ohtomo 2, 1985 Pull, 1983 TABLE 23 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued = 20 Placebo n None Other None None 2 weeks 6 weeks Mental illness, organic condition, known allergy, previous drug use, substance abuse, night shift work Mental illness, organic condition, known allergy, previous drug use, substance abuse 2 ≥ 2 of 3 months, ≥ weeks: >45 minutes sleep >2 latency, nocturnal awakenings every night without known cause and difficulty returning to sleep, sleep duration <6 h Age 18 – 70, insomnia ≥ Age 18 – 70 One of the following symptoms for the following: latency of sleep onset >30 minutes, total sleep duration <6.5 h, nocturnal awakenings >2 per night, time to fall asleep after at least one nocturnal awakening >30 minutes, awakening >2 h before scheduled time Finland, Denmark, Norway 7 centres Malaysia Single centre and centres criteria criteria Duration Follow-up comparators ’ s Sleep onset quality latency, of sleep, sleep questionnaire, investigator global evaluation, general morning condition, working somatic ability, complaints Sleep latency, total NAWs, sleep duration, psychomotor performance, and physician global assessment Rh ô ne-Poulenc Pharma Norden, Birkerod, Denmark (co-author) Acknowledged Rh ô ne-Poulenc support Outpatients Home- based (unclear) ’ d) RCT DB parallel RCT DB parallel n = 49 = 45 = 130 = 20 = 20 Nitrazepam 5 mg n Overall: n Only 94 included in analysis Temazepam 20 mg n Zopiclone 7.5 mg n Zopiclone 7.5 mg n drug and design dose, 95 Study characteristics (cont 94 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion Tamminen, 1987 Ngen, 1990 81 TABLE 23 TABLE

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued = 15 Placebo n Other 1 week 3 weeks None stated Adult patients insomnia Primary or insomnia associated with mild non- psychotic psychiatric disorders (DSM III-R) daytime fatiguability, diminished power of concentration and at least two of the following: latency >30 minutes, sleep duration <5 h, >2 awakenings per night, early wake- up in the morning Canada Single centre and centres criteria criteria Duration Follow-up comparators Primary: cognitive functioning Secondary: sleep anxiety, onset, duration, quality NAWs, of sleep, residual effects, memory, attention and concentration None stated support Not stated ’ d) RCT DB parallel = 60 n n (No. randomised per group not reported) Zopiclone 7.5 mg 30 Temazepam mg Overall: drug and design dose, 96 Study characteristics (cont Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion 82 Stip, 1999 TABLE 23 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Placebo None Other (1 week placebo) None 5 nights following 2 nights washout 1 week (no washout between crossover phases) Non- benzodiazepine hypnotics prior use of to study, psychotropic drugs for the first time or change of such medication, high-dose hypnotic use prior to study, organic conditions, unable to complete questionnaire, substance misuse, mental illness, physical stress situations likely to fluctuate, shift-workers Not stated 18 1 week ≥ ≥ Age 18 – 70 One of the following: latency of sleep onset >30 minutes, waking too early, several nocturnal awakenings with difficulty in returning to sleep, bothered during day by unsatisfactory sleep Age Difficulty sleeping for The Netherlands Single centre UK Single centre and centres criteria criteria Duration Follow-up comparators Sleep quality, latency of onset, status after awakening, mood and behaviour during the day, somatic symptoms and side-effects Sleep latency, nocturnal awakenings, duration, and quality of sleep, state on waking, at work, with others, driving and side- effects. Acknowledged Rh ô ne-Poulenc Pharma Acknowledged May & Baker support Outpatients Not stated ’ d) DB crossover (2 night washout) RCT DB crossover (no washout) = 60 = 36 n n n = 17 = 19 Zopiclone 7.5 mg Temazepam 20 mg Overall: Temazepam Temazepam 20 mg n Overall: Zopiclone 7.5 mg n drug and design dose, Study characteristics (cont 97 98 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion van der Kleijn, 1989 Wheatley, 1985 83 TABLE 23 TABLE

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued = 107 = 126 None Placebo n Placebo n Other None 1 week 3 days 2 nights (no information on washout between treatment periods) 2 weeks 4 weeks None specified (except for ban on hypnotic use for 1 week prior to study entry) Pre-existing medical condition that would affect the study results, sleep apnea or restless legs syndrome Organic conditions, mental illness, previous drug use, substance abuse 30 ≥ 6.5 h 65 ≤ ≥ 6.5 h or Age: not stated Untreated insomnia characterised by difficulties falling asleep, no other criteria mentioned Age Age 18 – 65 insomnia Primary or insomnia associated with mild non-psychotic disorders (DSM- III-R), sleep latency minutes, daytime impairment due to sleep disturbance, and either mean sleep duration ≤ prolonged or frequent nocturnal awakenings Sleep latency >30 minutes, awakenings on average per night >3, total sleep time France (12 GPs recruited patients) USA 35 centres Canada and Europe 39 centres and centres criteria criteria Duration Follow-up comparators Quality of sleep, drug preference, diurnal awakeness, quality of sleep onset, quality of sleep, duration of sleep Subjective assessments of sleep latency, total sleep time, NAWs, sleep quality, rebound insomnia Sleep latency, sleep maintenance, sleep quality, rebound insomnia, withdrawal effects. Sanofi- Synthelabo (2 co-authors) Wyeth-Ayerst Research, PA, Radnor, USA (2 co-authors) Wyeth-Ayerst Research, PA, Radnor, USA (2 co-authors) support General practice Outpatients Outpatients ’ d) RCT DB crossover RCT DB parallel RCT DB parallel = 53 n n = 166 = 165 = 111 = 122 = 121 = 124 = 122 Zaleplon 10 mg Zolpidem 10 mg Overall: Zaleplon 5 mg n Zaleplon 10 mg n Zolpidem 5 mg n Zaleplon 5 mg n Zaleplon 10 mg n Zaleplon 20 mg n Zolpidem 10 mg n drug and design dose, 99 100 Study characteristics (cont 102 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion Ancoli-Israel, 1999 Elie, 1999 84 Allain, 2001 TABLE 23 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued = 119 Placebo n Placebo Placebo Other 3 days None None 4 weeks 2 nights 2 nights Transient insomnia, situational insomnia, substance abuse, major mental illness Pregnancy Pregnancy 30 ≥ 6.5 h, or Age 18 – 65 Objectively verified sleep maintenance insomnia Age 16 – 85 insomnia Primary or insomnia associated with mild non- psychotic psychiatric disorders, sleep latency minutes, daytime impairment due to sleep disturbance, average total sleep duration/night ≤ prolonged or frequent nocturnal awakenings Age 18 – 65 Objectively verified sleep maintenance insomnia USA Single centre USA 27 centres USA Single centre and centres criteria criteria Duration Follow-up comparators Primary: SSL Primary: Secondary: subjective assessments of total sleep time, NAWs, sleep quality, rebound, withdrawal effects, adverse effects Next-day residual sedation, sleep total latency, sleep time Next-day residual sedation, sleep total latency, sleep time Wyeth-Ayerst Research, PA, Radnor, USA (co-author) None reported None reported support Outpatients Sleep lab. Sleep lab. ’ d) RCT DB parallel RCT DB crossover RCT DB crossover = 42 = 37 n n n = 118 = 120 = 121 = 117 Zaleplon 10 mg n Zaleplon 20 mg n Zolpidem 10 mg n Zaleplon 5 mg n Zaleplon 10 mg Zolpidem 10 mg Overall: Zaleplon 10 mg Zolpidem 10 mg Overall: drug and design dose, Study characteristics (cont 101 103 103 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion Zammit 1, 2000 Fry, 2000 Fry, Zammit 2, 2000 85 TABLE 23 TABLE

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 None Other 1 week 2 weeks Mental illness, organic conditions, symptoms interfering with sleep (pain, fever, etc.), known allergy, previous drug use, history of drug dependence Age: not stated Chronic primary insomnia (i.e. experiencing non- restorative sleep or difficulty initiating or maintaining sleep >1 month), sleep difficulties >3 times/week Japan 95 centres and centres criteria criteria Duration Follow-up comparators ’ s . impression of treatment efficacy, investigator assessment of the usefulness of the treatment, adverse events, dependence, sleep quality, physical condition parameters Primary: global Primary: improvement of sleep disorders (rated by investigators) Secondary: patient ’ s Drugs supplied by Fujisawa Pharmaceutical Co. Ltd (Japan); Rh ô ne-Poulenc Inc. Rorer, (Japan) support Home- based vs lab.-based? ’ d) RCT DB parallel n = 231 = 218 Zolpidem 10 mg n Zopiclone 7.5 mg n drug and design dose, Study characteristics (cont 104 Study Interventions: Study SettingCommercial OutcomesLocationSettingCommercialStudy Interventions: Study Inclusion Exclusion DB, double-blind; SSD, self-reported sleep duration; SSL, latency 86 Tsutsui, 2001 TABLE 23 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued 10 days Patients suffer from Patients schizophrenia and manic-depressive psychosis Those in post- alcoholism withdrawal period of ≥ included disorders(s) Concomitant For primary psychiatric disorder drugs 62% 64% Use of study medication within 30 days prior to study prohibited, as was regular use of medication that could interfere with assessment of hypnotics, and previous use of zolpidem on Patients benzodiazepine tranquillisers or with history of drug abuse before study period excluded 1 month 1 month 3 months 27% of patients >6 months; 30% ≤ 52% of patients >6 months; 21% ≤ Chronic insomnia of ≥ Duration of illness drug use Prior Concomitant 63 61 36 36 70 63 37 28 10% >60 11% >60 25% >60 31% >60 69 (range 59 – 85) (total) 44.2 (8.8) 43.6 (8.1) (years) a Zolpidem 10 mg 20 mg Temazepam Zolpidem 10 mg Nitrazepam 5 mg Zolpidem10 mg Nitrazepam 5 mg Zolpidem 5 mg 15 mg Temazepam Zopiclone 7.5 mg Lormetazepam 1 mg 83 89 82 88 Participant characteristics Participant 86 Zolpidem versus nitrazepam Zolpidem versus temazepam Zopiclone versus lormetazepam Study name Intervention Age, mean (SD) (female) % Sex Kazamatsuri, 1993 1993 Kudo, 1996 Kerkhof, Leppik, 1997 Ansoms, 1991

TABLE 24 TABLE 87

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued Generalised anxiety disorder (DSM III-R) 71 patients had concomitant diseases including arthritis, circulatory disorders, hypertension and All cardiac insufficiency. were free from severe organic and psychiatric disorders disorders(s) Concomitant No psychotropic or centrally active drugs were given during washout period and treatment drugs Use of benzodiazepines in 8 patients reported medication Regular providing sedation or analgesia and centrally acting antihypertensives were not permitted Drug addiction and previous medication medications Regular continued unchanged Chronic (mean duration 31.7 days) Minimum 2 months Chronic Duration of illness drug use Prior Concomitant 60 40 60 80 57.8 56.2 30.1 (total) 38.2 (9.4) 73.2 (1.54) (total) (years) (cont ’ d) a Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 5 mg Nitrazepam 5 mg 87 84 Participant characteristics Participant 90 91 85 92 Zopiclone versus nitrazepam Study name Intervention Age, mean (SD) (female) % Sex Jovanovic, 1983 Ohtomo 1, 1985 Agnoli, 1989 Anderson, 1987 Klimm, 1987 Ohtomo 2, 1985

88 24 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Only those hospitalised for depression, schizophrenia or alcoholism included. The psychiatric episode was stabilised at the beginning of the trial disorders(s) Concomitant Associated psychotropic medication including antidepressants (22 cases), minor tranquillisers (23 cases) and major tranquillisers (7 cases) remained unchanged during trial Mild non-psychotic psychiatric disorders (DSM III-R) also included drugs Patients on hypnotics Patients 54% of zopiclone and 47% of nitrazepam patients were previously treated with hypnotics (mainly benzodiazepines) Not reported having Patients received hypnotics with long life received lorazepam for 1 week prior to washout Most patients known regular hypnotic users Not reported Untreated 3 months 26 patients considered as chronic Sleep disturbance of ≥ Minimum 2 weeks <3 months in 69% of patients Duration of illness drug use Prior Concomitant 77 Not stated Not stated 60 60 70 61 49 53.2 (12.6) (total) 47 (range 26 – 71) (total) 38.4 36.2 38.4 (9.9) 42.9 (12.0) 53 (range 23 – 69) (total) 52.2 (total) (years) (cont ’ d) a Zopiclone 7.5 mg 20 mg Temazepam Zopiclone 7.5 mg Zopiclone 15 mg Nitrazepam 5 mg Nitrazepam 10 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg 30 mg Temazepam Zopiclone 7.5 mg 20 mg Temazepam Zaleplon 10 mg Zolpidem 10 mg Zopiclone 7.5 mg 20 mg Temazepam 95 99 96 93 Participant characteristics Participant 94 97 98 Zopiclone versus temazepam Zaleplon versus zolpidem Study name Intervention Age, mean (SD) (female) % Sex Tamminen, 1987 Ngen, 1990 van der Kleijn, 1989 Pull, 1983 Stip, 1999 Wheatley, 1985 Allain, 2001

TABLE 24 TABLE 89

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 Insomnia associated with mild non- psychotic psychiatric disorders also included Insomnia associated with mild non- psychotic psychiatric disorders also included Psychiatric disorders Psychiatric excluded disorders(s) Concomitant 2 Intake of psychotropic agents necessary for the primary diseases and use of antihistamines, H receptor antagonists, xanthines and other drugs reported to induce drowsiness or insomnia allowed provided the dosage unchanged drugs CNS medications (discontinued before placebo washout period) CNS-active medications (discontinued before placebo washout period) CNS medications, theophylline, corticosteroids, antihistamines, diet pills (discontinued before placebo washout period) Zopiclone intake within 3 months prior to study was prohibited, as was hypnotic use in doses exceeding standard single dose 1 month 1 month ≥ ≥ Chronic primary insomnia Duration of illness drug use Prior Concomitant 69 54 61 54 58 64 70 67 58 58 57 65 71.51 (5.3) 71.61 (4.84) 72.1 (5.2) 42.5 (12.9)) 42.6 (12.5) 42.6 (12.2) 44.3 (12.5) 43 (12) 40 (10) 41 (13) 42 (11) 41.1 (12.6) 43.2 (12.7) (years) (cont ’ d) a Zaleplon 5 mg Zaleplon 10 mg Zolpidem 5 mg Zaleplon 5 mg Zaleplon 10 mg Zaleplon 20 mg Zolpidem 10 mg Zaleplon 5 mg Zaleplon 10 mg Zaleplon 20 mg Zolpidem 10 mg Zaleplon 10 mg Zolpidem 10 mg Zaleplon 10 mg Zolpidem 10 mg Zolpidem 10 mg Zopiclone 7.5 mg 104 100 Participant characteristics Participant 101 103 103 102 Blank cells indicate no data reported. Zolpidem versus zopiclone Study name Intervention Age, mean (SD) (female) % Sex a Elie, 1999 Zammit 1, 2000 2001 Tsutsui, Ancoli-Israel, 1999 2000 Fry, Zammit 2, 2000

90 24 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Withdrawal 7/82 (8.5) 12/79 (15.2) 13/79 (16.5) 15/80 (18.8) (number/total, %) = 13) = 17) ( n ( n Scale unknown but increase indicates improvement. result is post Final 11-day follow-up period BaselineFinal 6.46 6.66 66.7 37.5 improvement (%) Total BaselineFinal 7.76 9.22 17.8 (none) 35.6 (1) 43.8 (2 – 4) 2.8 (5+) 13.5 (none) 25.7 (1) 45.9 (2 – 4) 14.9 (5+) %, (number of awakenings) awakenings, mean Number of Quality of sleep, Adverse events 360 (108) 366 (120) Mean (SD) (minutes), mean mean = 13) = 17) ( n ( n 4.1 (<15 min) Final result is post Final 11-day follow-up period BaselineFinal 57.7 61.6 24.7 (15 – 30 min) 41.1 (30 – 60 min) 30.1 (>60 min) 10.8 (<15 min) 24.3 (15 – 30 min) 33.8 (30 – 60 min) 31.1 (>60 min) % (amount of time needed to fall asleep) 68.4 56.4 improvement (%) Total BaselineFinal 52.2 38.8 latency (minutes), duration mean Zolpidem 10 mg Nitrazepam 5 mg Zolpidem 10 mg Nitrazepam 5 mg Zolpidem 10 mg 20 mg Temazepam Outcomes 88 89 86 Zolpidem versus nitrazepam Zolpidem versus temazepam Study Interventions Sleep onset sleep Total Kudo, 1993 Kerkhof, 1996 Kazamatsuri, 1993

TABLE 25 TABLE 91

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued Withdrawal 52/82 (63.4) 56/84 (66.7) Treatment-emergent adverse events 7/27 (26) [*6/25 (24)] 7/25 (28) [*5/25 (20)] Any side-effects (*side- effects related to drug) (number/total, %) = 25) = 25) = 25) = 26) Calculated from raw data; scale: 1 = bad, 5 = good Final 4 ( n Baseline 3 ( n Final 3 ( n Baseline 3 ( n = 25) = 25) = 25) = 26) Calculated from raw data; scale: 1 = frequent, 5 = never Final 4 ( n Baseline 3 ( n Final 3 ( n Base. 3 ( n awakenings, mean Number of Quality of sleep, Adverse events = 25) = 25) = 25) = 26) = 82) = 77) = 84) = 76) ( n ( n ( n ( n Medians calculated from raw data; scale: 1 = short, 5 long Final 3 ( n Baseline 3 ( n Final 3 ( n Baseline 294.5 (62.5) FinalChange 362.8 (64.9) 70.0 (64.9) Baseline 312.4 (49.5) FinalChange 375.3 (58.4) 61.8 (55.8) Mean (SD) Skewed variable, not included in meta analysis Baseline 3 ( n (minutes), mean mean = 25) = 25) = 25) = 26) = 82) = 77) = 84) = 76) ( n ( n – 39.7 (41.2) ( n ( n – 39.4 (41.0) Medians calculated from raw data; scale: 1 = long, 5 short Final 4 ( n Baseline 2 ( n Final 3 ( n Baseline 2 ( n FinalChange 40.5 (27.2) FinalChange 38.0 (26.2) Baseline 78.1(47.1) Baseline 74.1(44.9) Mean (SD) Skewed variable, not included in meta analysis latency (minutes), duration mean Zolpidem 5 mg 15 mg Temazepam Zopiclone 5 mg Lormetazepam 1 mg Outcomes (cont ’ d) 83 82 Study Interventions Sleep onset sleep Total Ansoms, 1991 Leppik, 1997 Zopiclone versus lormetazepam

92 25 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Withdrawal (number/total, %) .0 67.3 65 BaselineFinal Data estimated from 43.5 graph; scale 0 = bad, 100 = good BaselineFinal 41.3 = 5) = 5) 0 = 5) 0 = 5) 0 Final 0.05 ( n Baseline 1.1 ( n Final 0.1 ( n Baseline 1.5 ( n awakenings, mean Number of Quality of sleep, Adverse events = 5) = 5) = 5) = 5) n n Final 441.9 ( n Baseline 376.6 ( Final 465.7 ( n Baseline 351.8 ( (minutes), mean mean .0 .0 60 64 = 5) = 5) = 5) = 5) = 20) = 20) = 20) = 20) ( n ( n ( n ( n Mean (SD), data estimated from graph Final 24.1 ( n Final 12 (9.6) Baseline 83.4 ( n Baseline 33 (1.9) Final 17.5 ( n Final 8 (5.7) BaselineFinal Baseline 42.5 Final Data estimated from 35.5 graph; scale: 0 = long, 100 = short Baseline 97.8 ( n Baseline 36 (1.5) latency (minutes), duration mean Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Outcomes (cont ’ d) 84 85 90 Study Interventions Sleep onset sleep Total Agnoli, 1989 Anderson, 1987 Jovanovic, 1983 Zopiclone versus nitrazepam

TABLE 25 TABLE 93

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued Withdrawal 5/64 (7.8) 7/64 (10.9) (number/total, %) = 36) = 36) ( n ( n 1.6 (worse) 3.1 (very effective) 0 (worse) Mean (SD) of differences between first day of active treatment and last day of placebo run-in period; scale: 0 = bad, 100 =good Change from Baseline 23.1 (37.8) Change from Baseline 24 (45.6) effective) 25 (very 31.3 (effective) 18.8 (little effective) 23.4 (no change) 34.4 (effective) 32.8 (little effective) 29.7 (no change) %; scale: very effective to worse 9.4 (very effective) 0 (worse) 7.8 (very effective) 0 (worse) 25 (effective) 23.4 (little effective) 42.2 (no change) 26.6 (effective) 28.1 (little effective) 37.5 (no change) %; scale: very effective to worse awakenings, mean Number of Quality of sleep, Adverse events 1.6 (worse) 1.6 (very effective) 3.1 (worse) 10.9 (very effective) 31.3 (effective) 29.7 (little effective) 26.6 (no change) 26.6 (effective) 25.0 (little effective) 43.8 (no change) %; scale: very effective to worse (minutes), mean mean = 36) = 36) ( n ( n Mean (SD) of differences between first day of active treatment and last day of placebo run-in period; scale: 0 = fast, 100 = slow Change from Baseline 15.6 (49.5) Change from Baseline 18.2 (48.3) latency (minutes), duration mean Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Outcomes (cont ’ d) 91 87 Study Interventions Sleep onset sleep Total Ohtomo 1, 1985 Klimm, 1987

94 25 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Withdrawal 10/66 (15.2) 4/71 (5.6) (number/total, %) = 49) = 45) ( n ( n 1.6 (excellent) 4.9 (worse) 0 (worse) FinalBaseline 33.8 (24.4) 49.9 (30.7) FinalMean (SD); scale: 34.0 (27.8) 0 = good, 100 bad 3.0 2.4 3.5 2.5 Data estimated from graph; scale: lower score = better quality of sleep Baseline 55.8 (33.7) 32.8 (good) 29.5 (O.K.) 31.1 (not good) 10.3 (excellent) 32.4 (good) 35.3 (O.K.) 22.1 (not good) %; scale: excellent to worse 3.3 (excellent) 3.3 (worse) 3.3 (excellent) 3.3 (worse) 2.93 2.3 2.95 2.35 Data estimated from graph; scale: smaller score = fewer awakenings Baseline 63.3 FinalBaseline 18.4 75.6 Final% with >2 nocturnal 24.4 awakenings 11.7 (good) 31.7 (O.K.) good) 50 (not 16.9 (good) 26.2 (O.K.) 50.8 (not good) %; scale: excellent to worse awakenings, mean Number of Quality of sleep, Adverse events 6.9 (excellent) 3.4 (worse) 3.0 (excellent) 6.1 (worse) 2.8 3.6 2.6 3.7 Data estimated from graph; scale: larger score = longer sleep duration Baseline 75 FinalBaseline 37.5 73.3 Final% with duration of 37.7 sleep <6.5 h 25.9 (good) 25.9 (O.K.) 37.9 (not good) 19.7 (good) 28.8 (O.K.) 42.4 (not good) %; scale: excellent to worse (minutes), mean mean = 49) = 45) ( n ( n FinalBaseline 31.5 (27.2) 52.5 (33.7) FinalMean (SD); scale: 32.7 (29.4) 0 = fast, 100 slow Baseline 58 (31.2) 3.5 2.8 4.2 3.2 Data estimated from graph; scale: smaller score = shorter onset latency latency (minutes), duration mean Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Zopiclone 15 mg Nitrazepam 5 mg Nitrazepam 10 mg Zopiclone 5 mg Nitrazepam 5 mg 93 Outcomes (cont ’ d) 94 92 Study Interventions Sleep onset sleep Total Pull, 1983 Tamminen, 1987 Ohtomo 2, 1985

TABLE 25 TABLE 95

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued Withdrawal 26 17 (number/total, %) = 53) = 53) ( n ( n Baseline 3.0 (1.31) FinalBaseline 3.9 (1.46) 3.0 (1.31) FinalMean (SD), data 3.8 (1.53) estimated from graph; scale: 1 = bad, 5 = good = 13) = 13) = 13) = 13) = 19) = 16) ( n ( n ( n ( n ( n ( n Final 1.28 Baseline 2 Final 0.62 Baseline 0.95 Baseline 4.8 (1.96) FinalBaseline 6.8 (2.05) 5.1 (2.4) FinalMean (SD), scale 5.8 (1.96) (likely) larger score = fewer awakenings awakenings, mean Number of Quality of sleep, Adverse events = 13) = 13) = 13) = 13) ( n ( n ( n ( n Final 337.2 Baseline 295.2 Final 361.8 Baseline 262.8 (minutes), mean mean = 13) = 13) = 13) = 13) ( n ( n ( n ( n (n = 53)* (n = 53)* Note: very poorly balanced groups at baseline Final 26.1 Baseline 50.4 Final 64.5 Baseline 122.8 Baseline 2.8 (1.82) FinalBaseline 3.8 (1.46) 2.8 (1.82) FinalMean (SD), data 3.7 (1.46) estimated from graph; scale: 1 = long, 5 = short latency (minutes), duration mean Zopiclone 7.5 mg 30 mg Temazepam Zopiclone 7.5 mg 20 mg Temazepam Zopiclone 7.5 mg 20 mg Temazepam 96 Outcomes (cont ’ d) 95 97 Study Interventions Sleep onset sleep Total Ngen, 1990 Stip, 1999 Zopiclone versus temazepam van der Kleijn, 1989

96 25 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Withdrawal 9/35 (26) 5/32 (16) Side-effects 56 59 63 %, treatment-emergent adverse events (number/total, %) = 32) = 36) = 35) = 36) = 32 ( n ( n ( n ( n = 35 on = 36 at n n Assume baseline, zopiclone and n on temazepam (by calculation from No. (%) given under Side-effects); scale 0 = good, 4 bad Final 0.87 Baseline 2.1 Final 0.93 Baseline 2.1 82/162 (51) 86/163(53) 72/109 (66) Number/total (%) with improvement at week 4 in sleep quality from baseline/total = 32) = 36) = 35) = 36) = 32 ( n ( n ( n ( n = 35 on = 36 at n n Assume baseline, zopiclone and n on temazepam (by calculation from No. (%) given under Side- effects) Final 0.66 Baseline 1.9 Final 0.75 Baseline 1.9 awakenings, mean Number of Quality of sleep, Adverse events = 32) = 36) = 35) = 36) = 32 = 150) = 151) = 105) ( n ( n ( n ( n ( n ( n ( n = 35 on = 36 at n n Assume baseline, zopiclone and n on temazepam (by calculation from No. (%) given under Side- effects) Final 396 Baseline 300 Final 396 Baseline 300 480 498 Baseline 290.71 FinalBaseline 325 316.14 FinalBaseline 348 308.57 FinalMedians, estimated 360 from graph (minutes), mean mean = 32) = 36) = 35) = 36) = 32 = 148) = 150) = 101) ( n ( n ( n ( n ( n ( n ( n = 35 on = 36 at n n zopiclone and n on temazepam (by calculation from No. (%) given under Side- effects) Assume baseline, Final 29.1 Baseline 82.9 Final 30.8 Baseline 82.9 Baseline 75.75 FinalBaseline 38 62.5 FinalBaseline 31 58.75 FinalMedians, estimated 42 from graph latency (minutes), duration mean Zopiclone 7.5 mg 20 mg Temazepam Zaleplon 10 mg Zolpidem 10 mg Zaleplon 5 mg Zaleplon 10 mg Zolpidem 5 mg Outcomes (cont ’ d) 102 98 99 Zaleplon versus zolpidem Study Interventions Sleep onset sleep Total Ancoli-Israel, 1999 Wheatley, 1985 Allain, 2001

TABLE 25 TABLE 97

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued (8) (9) (10) (16) (%) with 3+ withdrawal symptoms first night after discontinuation of treatment; data estimated from graph Withdrawal 71/121 (59) 87/120 (73) 76/124 (61) 78/122 (64) Treatment-emergent adverse events (number/total, %) 66/101 (65.3) 59/100 (59.0) 64/102 (62.7) 66/99 (66.7) Number with improvement at week 4 in sleep quality from baseline/total (%) = 112) = 87) = 111) = 82) = 114) = 86) = 114) = 84) BaselineFinal 2 ( n 2 ( n BaselineFinal 2 ( n 2 ( n BaselineFinal 2 ( n 1 ( n BaselineFinal 2 ( n 2 ( n Medians awakenings, mean Number of Quality of sleep, Adverse events = 113) = 102) = 112) = 99) = 116) = 103) = 115) = 100) ( n ( n ( n ( n ( n ( n ( n ( n Baseline 313 Final 372 Baseline 331 Final 384 Baseline 328 Final 385 Baseline 330 Final 400 Medians (minutes), mean mean = 113) = 112) = 116) = 115) ( n ( n ( n ( n Baseline 66 Final 31 Baseline 57 Final 28.8 Baseline 55 Final 27.5 Baseline 64 Final 36.5 Medians, data extracted from graph latency (minutes), duration mean Zaleplon 5 mg Zaleplon 10 mg Zaleplon 20 mg Zolpidem 10 mg 100 Outcomes (cont ’ d) Study Interventions Sleep onset sleep Total Elie, 1999

98 25 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued 1/91 (1.1) 1/83 (1.2) 2/91 (2.2) 6/85 (7.1) (%) with 3+ withdrawal symptoms first night after discontinuation of treatment Withdrawal 90/118 (76) 89/120 (74) 93/117 (79) 96/116 (83) Treatment-emergent adverse events (number/total, %) 49/101 (48.5) 52/102 (51.0) 57/101 (56.4) 61/98 (62.2) Number with improvement at week 4 in sleep quality from baseline/total (%); data extracted from graph = 90) = 115) = 114) = 90) = 117) = 91) = 112) = 89) ( n ( n ( n ( n ( n Baseline 2 ( n Final 1.71 Baseline 1.86 Final 1.57 Baseline 2 ( n Final 1.6 ( n Baseline 2.14 Final 1.67 Medians awakenings, mean Number of Quality of sleep, Adverse events = 98) = 115) = 101) = 116) = 102) = 119) = 101) = 118) ( n ( n ( n ( n ( n ( n ( n ( n Medians Final 392.9 Baseline 334.3 Final 377.5 Baseline 343.0 Final 376.3 Baseline 334.3 Final 360.0 Baseline 334.3 (minutes), mean mean = 98) = 115) = 101) = 116) = 102) = 119) = 101) = 118) ( n ( n ( n ( n ( n ( n ( n ( n Medians Final 34.3 Baseline 60.7 Final 30.0 Baseline 61.1 Final 35.0 Baseline 62.5 Final 45.6 Baseline 69.3 latency (minutes), duration mean Zaleplon 5 mg Zaleplon 10 mg Zaleplon 20 mg Zolpidem 10 mg Outcomes (cont ’ d) 101 Study Interventions Sleep onset sleep Total Fry, 2000 Fry,

TABLE 25 TABLE 99

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 Withdrawal 66/211 (31.3) 102/225 (45.3) Drug-related adverse events (number/total, %) awakenings, mean Number of Quality of sleep, Adverse events (minutes), mean mean 179/209 (85.8) 170/219 (77.5) Number/total (%) with improvement of 1+ scale: from baseline (scale: 1 – 5); numbers estimated from percentage latency (minutes), duration mean Zaleplon 10 mg Zolpidem 10 mg Zaleplon 10 mg Zolpidem 10 mg Zolpidem 10 mg Zopiclone 7.5 mg Outcomes (cont ’ d) 103 103 104 Zammit 1, 2000 Zammit 2, 2000 Tsutsui, 2001 Study Interventions Sleep onset sleep Total Zolpidem versus zopiclone

100 25 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued awakenings, sleep awakenings, Tolerance = 82) = 77) = 83) = 76) ( n ( n ( n ( n Initial 353.4 (55.2) Final 362.8 (64.9) Initial 375.0 (63.8) Final 375.3 (58.4) Mean (SD). Skewed variable; therefore not included in MA mean Total sleep Total Number of Quality of = 82) = 77) = 83) = 76) ( n ( n ( n ( n Initial 44.7 (27.2) Final 40.5 (27.2) Initial 43.1 (29.2) Final 38.0 (26.2) Mean (SD). Skewed variable; therefore not included in MA mean (minutes), mean mean latency duration sleep, Rebound insomnia Rebound Total sleep Total Number of mean Quality of Sleep onset (minutes), mean mean latency duration awakenings, latency duration Zolpidem 10 mg Nitrazepam 5 mg Zolpidem 10 mg Nitrazepam 5 mg Zolpidem 10 mg 20 mg Temazepam Zolpidem 5 mg 15 mg Temazepam Zopiclone 7.5 mg Lormetazepam 1 mg 82 88 Outcomes: rebound insomnia and tolerance 86 89 83 Study InterventionsZolpidem versus nitrazepam Sleep onset Zolpidem versus temazepam Zopiclone versus lormetazepam Kazamatsuri, 1993 1993 Kudo, Kerkhof, 1996 Leppik, 1997 Ansoms, 1991

TABLE 26 TABLE 101

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued awakenings, sleep awakenings, Tolerance mean Total sleep Total Number of Quality of mean (minutes), mean mean latency duration BaselinePost-TRT 41.3 51.5 BaselinePost-TRT 43.5 51.3 Data estimated from graph; scale 0 = bad, 100 = good sleep, = 5) = 5) = 5) = 5) ( n ( n ( n ( n Baseline 1.5 0.7 Post-TRT Baseline 1.1 Post-TRT 0.7 taken as Post-TRT first 3 nights after treatment = 5) = 5) = 5) = 5) ( n ( n ( n ( n Rebound insomnia Rebound ’ d) Baseline 351.8 Post-TRT 432.6 Baseline 376.6 Post-TRT 422.2 Total sleep Total Number of mean Quality of Sleep onset = 5) = 5) = 5) = 5) ( n ( n ( n ( n BaselinePost-TRT 42.5 50 BaselinePost-TRT 35.5 48 Data estimated from graph; scale: 0 = long, 100 = short Baseline 97.8 Post-TRT 49 Baseline 83.4 Post-TRT 52.6 taken as Post-TRT first 3 nights after treatment (minutes), mean mean latency duration awakenings, latency duration Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Nitrazepam 5 mg 87 84 Outcomes: rebound insomnia and tolerance (cont 85 90 91 Study InterventionsZopiclone versus nitrazepam Sleep onset Anderson, 1987 Jocanovic, 1983 Ohtomo 1, 1985 Agnoli, 1989 Klimm, 1987

102 26 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Initial 37.1 (25.2) Final 33.8 (24.4) Initial 27.4 (23.3) Final 34.0 (27.8) Mean (SD); scale: 0 = good, 100 = bad awakenings, sleep awakenings, Tolerance mean Total sleep Total Number of Quality of Initial 34.1 (25.9) Final 31.5 (27.2) Initial 35.5 (30.7) Final 32.7 (29.4) Mean (SD); scale: 0 = fast, 100 = slow mean (minutes), mean mean latency duration sleep, = 19) = 16) ( n ( n Baseline 4.8 (1.96) Post-TRT 5.1 (2.27) Baseline 5.1 (2.4) Post-TRT 4.4 (0.56) SD = 2.24 Scale unknown as yet; likely that larger score = fewer awakenings Rebound insomnia Rebound ’ d) Total sleep Total Number of mean Quality of Sleep onset (minutes), mean mean latency duration awakenings, latency duration Zopiclone 5 mg Nitrazepam 5 mg Zopiclone 7.5 mg Zopiclone 15 mg Nitrazepam 5 mg Nitrazepam 10 mg Zopiclone 7.5 mg Nitrazepam 5 mg Zopiclone 7.5 mg 20 mg Temazepam Zopiclone 7.5 mg 30 mg Temazepam 95 Outcomes: rebound insomnia and tolerance (cont 96 93 92 94 Study Interventions Sleep onset Stip, 1999 Ohtomo 2, 1985 Pull, 1983 Ngen, 1990 Tamminen, 1987 Zopiclone versus temazepam

TABLE 26 TABLE 103

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued awakenings, sleep awakenings, Tolerance mean Total sleep Total Number of Quality of mean (minutes), mean = 53) = 53) ( n ( n mean latency duration Baseline 3.0 (1.31) Post-TRT 2.0 (0.73) Baseline 3.0 (1.31) Post-TRT 2.7 (1.46) Mean (SD). Data estimated from graph; first night before treatment compared with first night after treatment; scale: 1 = bad, 5 good sleep, (3) (4.5) (6.5) (%) with Total rebound insomnia; data estimated from graph Rebound insomnia Rebound ’ d) (6.5) (9) 28/104 (27) Number/total (%) with rebound insomnia; data estimated from graph Total sleep Total Number of mean Quality of Sleep onset = 53) = 53) ( n ( n Baseline 2.8 (1.82) (8.5) (9) 20/100 (20) Number/total (%) with rebound insomnia; data estimated from graph Post-TRT 2.0 (1.67) Baseline 2.8 (1.82) Post-TRT 2.8 (1.82) Mean (SD). Data estimated from graph; first night before treatment compared with first night after treatment; scale: 1 = long, 5 short (minutes), mean mean latency duration awakenings, latency duration Zopiclone 7.5 mg 20 mg Temazepam Zopiclone 7.5 mg 20 mg Temazepam Zaleplon 5 mg Zaleplon 10 mg Zolpidem 5 mg Zaleplon 10 mg Zolpidem 10 mg 99 Outcomes: rebound insomnia and tolerance (cont 97 98 102 Study Interventions Sleep onset Zaleplon versus zolpidem van der Kleijn, 1989 Wheatley, 1985 Allain, 2001 Ancoli-Israel, 1999

104 26 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 = 113) = 102) = 112) = 100) = 116) = 103) = 115) = 100) ( n ( n ( n ( n ( n ( n ( n ( n continued Initial 4.1 Final 3.8 Initial 3.9 Final 3.7 Initial 3.8 Final 3.6 Initial 3.7 Final 3.4 Scale: 1 = good, 7 = bad = 104) = 87) = 101) = 82) = 103) = 86) = 100) = 84) ( n ( n ( n ( n ( n ( n ( n ( n awakenings, sleep awakenings, Initial 2 Final 2 Initial 2 Final 2 Initial 2 Final 1 Initial 2 Final 2 Medians Tolerance = 113) = 102) = 112) = 99) = 116) = 103) = 115) = 100) ( n ( n ( n ( n ( n ( n ( n ( n Initial 351 Final 372 Initial 370 Final 384 Initial 370 Final 385 Initial 379 Final 400 Medians mean Total sleep Total Number of Quality of InitialFinal 42.5 31 InitialFinal 36 28.8 InitialFinal 33 27.5 InitialFinal 45 36.5 Medians; data estimated from graph mean (minutes), mean mean latency duration sleep, 3/61 (5) 2/57 (4) 3/67 (4) 12/63 (19) Number/total (%) with rebound insomnia; data estimated from graph Rebound insomnia Rebound ’ d) 5/99 (5) 3/95 (3) 11/99 (11) 15/94 (16) Number/total (%) with rebound insomnia; data estimated from graph mean Total sleep Total Number of Quality of Sleep onset 5/99 (5) 4/94 (4) 11/97 (11) 15/92 (16) Number/total (%) with rebound insomnia; data estimated from graph (minutes), mean mean latency duration awakenings, latency duration Zaleplon 5 mg Zaleplon 10 mg Zaleplon 20 mg Zolpidem 10 mg Outcomes: rebound insomnia and tolerance (cont 100 Study Interventions Sleep onset Elie, 1999

TABLE 26 TABLE 105

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 = 118) = 101) = 119) = 102) = 116) = 101) = 115) = 98) ( n ( n ( n ( n ( n ( n ( n ( n continued Initial 3.43 Final 3.38 Initial 3.57 Final 3.54 Initial 3.43 Final 3.29 Initial 3.38 Final 3.15 Scale: 1 = good, 7 = bad = 108) = 90) = 112) = 91) = 109) = 90) = 108) = 89) ( n ( n ( n ( n ( n ( n ( n ( n awakenings, sleep awakenings, Initial 1.93 Final 1.71 Initial 1.69 Final 1.57 Initial 1.75 Final 1.60 Initial 1.59 Final 1.67 Medians Tolerance = 118) = 101) = 119) = 102) = 116) = 101) = 115) = 98) ( n ( n ( n ( n ( n ( n ( n ( n Initial 360 Final 360 Initial 360.6 Final 376.3 Initial 368.6 Final 377.5 Initial 377.1 Final 392.9 Medians mean Total sleep Total Number of Quality of = 101) = 102) = 101) = 98) ( n ( n ( n ( n InitialFinal 45.4 45.6 InitialFinal 40.7 35.0 InitialFinal 35.7 30.0 InitialFinal 45.7 34.3 Medians mean (minutes), mean mean latency duration sleep, 6/72 (8) 7/64 (11) 5/72 (7) 11/69 (16) Number/total (%) with rebound insomnia; data estimated from graph Rebound insomnia Rebound ’ d) 5/97 (5) 7/100 (7) 5/97 (5) 24/95 (25) Number/total (%) with rebound insomnia; data estimated from graph Total sleep Total Number of mean Quality of Sleep onset 5/95 (5) 4/100 (4) 8/95 (8) 23/96 (24) Number/total (%) with rebound insomnia; data estimated from graph (minutes), mean mean latency duration awakenings, latency duration Zaleplon 5 mg Zaleplon 10 mg Zaleplon 20 mg Zolpidem 10 mg Outcomes: rebound insomnia and tolerance (cont 101 Study Interventions Sleep onset Fry, 2000 Fry,

106 26 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 awakenings, sleep awakenings, Tolerance mean Total sleep Total Number of Quality of mean (minutes), mean mean latency duration sleep, Rebound insomnia Rebound Total sleep Total Number of mean Quality of Sleep onset 9/191 (4.5) 31/205 (15.4) Number/total (%) with aggravation of sleep onset latency by 1+ grade at end of follow-up relative to baseline; numbers estimated from percentage (minutes), mean mean latency duration awakenings, latency duration Zaleplon 10 mg Zolpidem 10 mg Zolpidem 10 mg Zopiclone 7.5 mg Outcomes: Rebound insomnia and tolerance (cont ’ d) 103 104 Study Interventions Sleep onset Zolpidem versus zopiclone Zammit 1 and 2, 2000 Tsutsui, 2001

TABLE 26 TABLE 107

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued b No consistent pattern of differences noted No direct comparisons were made between treatment groups No significant differences between groups for any of the items Significant reduction of anxiety levels after zopiclone Significant improvement of attentive capacity after zopiclone for some items, of the time Significantly better quality of daytime arousal after zopiclone S S S M M S S Mood/ a Test type Test motor satisfaction findings Reported Mem Anxiety Attention Sleep quality Daytime arousal Quality of sleep Quality of sleep Ability to concentrate Sleep quality Sleep improvement Overall feeling Quality of sleep Morning disposition Mood Specific measurement of Memory Psycho- Non-English Spiegel sleep questionnaire Norris mood rating scale Hamilton rating scale for anxiety – Pieron attention Toulouse test Sleep questionnaire (unspecified) Non-English Groningen sleep scale Morning questionnaire (unspecified) Global impression of therapy Global impression of treatment 83 89 82 84 88 Overview of studies, measures used and psychomotor, memory, mood and patient satisfaction outcomes memory, Overview of studies, measures used and psychomotor, 86 AuthorZolpidem versus nitrazepam Name of measure Zolpidem versus temazepam Zopiclone versus lormetazepam Zopiclone versus nitrazepam Kudo, 1993 Kudo, 1996 Kerkhof, Leppik, 1987 Ansoms, 1991 Agnoli, 1989 Kazamatsuri, 1993

108 27 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued b Zopiclone group more wide awake than nitrazepam group No differences were reported between treatment groups Zopiclone group felt more alert in the morning than nitrazepam group on 2 of 7 active treatment days No difference between treatment groups on any subscale of Syndrom-Kurztest – S S – S S S S Mood/ ’ d) a (cont Test type Test – P P P P P P P P P motor satisfaction findings Reported Mem Mem Mem Mem Mem Mem Mem – 10 numbers ascending order duplicate set appears in a list of 126 symbols BA substitution 1 test 1 objects from a set of 48 Sleep quality Morning alertness sleep quality VAS alertness on awakening VAS Quality of sleep Morning condition 9 subscales test short-term memory and concentration: 1. object naming: 2. object recall 3. read a series of 4. arrange same numbers in 5. find missing number using a 6. count n times a symbol 7. interference test – AB to 8. object recall of items in test 9. object recognition – find None Specific measurement of Memory Psycho- Sleep questionnaire (unspecified) Global assessment of efficacy Sleep diary (unspecified) Spiegel sleep questionnaire Syndrom-Kurztest None 87 Overview of studies, measures used and psychomotor, memory, mood and patient satisfaction outcomes memory, Overview of studies, measures used and psychomotor, 85 90 Author Name of measure Anderson, 1987 Jovanovic, 1983 Klimm, 1987

TABLE 27 TABLE 109

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued b No significant differences between groups in feeling upon awakening No significant difference between treatment groups No significant difference between treatment groups A trend in favour of zopiclone was found on assessment of tapping rate scores No significant difference between treatment groups No difference in global assessment of efficacy between treatments Calm/excited: nitrazepam 10 mg > calm score Contented/discontented: zopiclone 15 mg > contentment score zopiclone 7.5 and 10 mg Troubled/tranquil: nitrazepam 10 mg > tranquil score nitrazepam 10 mg and zopiclone Tense/relaxed: 15 mg > relaxed score No significant differences, tendency in favour of zopiclone No significant differences found between groups M M S S Mood/ ’ d) a (cont Test type Test P P P P P motor satisfaction findings Reported Mem Mood Graphic symbols Cancellation test Mood Symbol copying Digit symbol substitution rate Tapping Auditory reaction time Sleep quality working ability VAS Specific measurement of Memory Psycho- ’ s global Non-English assessment of efficacy Norris mood rating scale Memory test (unspecified) Vigilance + awakening (unspecified) Norris mood rating scale tests Psychomotor (unspecified) Sleep questionnaire (unspecified) Investigator 93 Overview of studies, measures used and psychomotor, memory, mood and patient satisfaction outcomes memory, Overview of studies, measures used and psychomotor, 91,92 94 Author Name of measure Ohtomo 1 and 2, 1985 Pull, 1983 Tamminen, 1987

110 27 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued b No direct comparisons were made between groups No significant difference between groups No significant difference between groups No significant difference between groups No significant difference between groups No significant difference between groups No significant difference between groups No significant difference between groups No significant difference between groups on awakening No differences between groups Stated that the majority of participants did not report any life events M S M S S O Mood/ ’ d) a (cont Test type Test P P P P P P motor satisfaction findings Reported Mem Mem Mem Mem Mem Mem – word – visual reaction Choice reaction time Critical flicker fusion Letter cancellation test Anxiety Number recall – increasing complexity Cued recall – word Sleep quality Seven questions cited but not specified Sleep quality Feeling on waking Unspecified time Sustained attention – visual reaction time Divided attention – number recall combined with simultaneous moving target pursuit task completion Alertness Implicit recall Specific measurement of Memory Psycho- Leeds psychomotor tester Cancellation test (unspecified) Sleep questionnaire (unspecified) Mood question (study designed) Hamilton scale for anxiety Short-term memory (unspecified) Long-term memory (unspecified) questionnaire Patient (unspecified) Life events (unspecified) 95 96 Overview of studies, measures used and psychomotor, memory, mood and patient satisfaction outcomes memory, Overview of studies, measures used and psychomotor, 97 98 Stip, 1999 Wheatley, 1985 Ngen, 1990 van Der Kleijn, 1989 AuthorZopiclone versus temazepam Name of measure

TABLE 27 TABLE 111

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 b No direct comparisons reported for next-day sedation and psychomotor performance No direct comparisons reported for daytime physical condition No statistically significant differences reported between treatment groups 0.05. Any identified trends are reported. ≤ M S S S S S Mood/ ’ d) a (cont Test type Test motor satisfaction findings Reported , other. Daytime sedation performance Psychomotor Daytime mood (questions unspecified) Physical condition (questions unspecified) Sleep quality Sleep quality Sleep quality (question/s unspecified) Sleep quality Sleep quality (question/s unspecified) Specific measurement of Memory Psycho- Sleep latency test and subjective assessments Measures of psychomotor performance (not specified) Sleep questionnaire (unspecified) rating of efficacy Patient (unspecified) Clinical global impression scale Sleep questionnaire (LSEQ) VAS Sleep questionnaire (unspecified) Sleep questionnaire (unspecified) Sleep questionnaire (unspecified) 104 99 100 Overview of studies, measures used and psychomotor, memory, mood and patient satisfaction outcomes memory, Overview of studies, measures used and psychomotor, 101 103 102 Satisfaction outcomes reported and compared in results section of the report. All significant differences at p Mem, memory; S, self-report satisfaction; M, mood; O Allain, 2001 Ancoli-Israel, 1999 Elie, 1999 2000 Fry, 2001 Tsutsui, AuthorZaleplon versus zolpidem Name of measure Zammit 1 and 2, 2000 Zolpidem versus zopiclone a b

112 27 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Placebo (96 included in analysis) None 3 months ’ treatment in previous trial 4 weeks 3 weeks following ≥ Hamilton Rating Scale for Depression (HAM-D) score >12, history of suicide attempt, psychotropic treatment other than selective serotonin reuptake inhibitors (SSRI), insomnia secondary to other conditions (shift work, substance abuse, anxiety disorder) History or current episode of depression or psychiatric severe disorder, and evolving physical illness, dementia, alcoholism, drug abuse, acute pain, use of psychotropic drugs within previous 2 weeks, pregnancy or likelihood breast thereof, feeding 3 months Age 18 – 66 years, experiencing insomnia and currently treated for a depressive all disorder, patients major depressive disorder, dysthymic disorder or minor depressive disorder (DSM-IV) Age 18 – 65 years (all patients were included in previous trials involving ≥ treatment with the study drug) Inclusion criteria Exclusion criteria Duration of Other treatment comparators 14 centres, USA and Canada France, multicentre centres Hypnotic impact efficacy, on daytime function, QoL, safety Withdrawal symptoms, withdrawal syndrome (adverse events), quality of sleep – study characteristics Primary Primary Secondary Locations and 75 Zolpidem 93, zopiclone 102, all on gradual withdrawal (1 week each on full, half and no dose) withdrawal entering outcomes outcomes period RCT, DB RCT, 2 separate RCTs, DB randomising patients after trial to continuation or gradual withdrawal = 201, 3 months ≥ = 193, of Zolpidem 10 mg (94 included in analysis) (Overall 194 randomised) Patients treated Patients for randomised to 3 weeks ’ continuation of treatment or withdrawal: zolpidem 10 mg ( n which 93 withdrawal), zopiclone 7.5 mg ( n of which 102 withdrawal) No. of patients Dependency and withdrawal review: trials observational studies 108 112 Asnis, 1999 Lemoine, 1995 Study Intervention/ Study design No. of patients

TABLE 28 TABLE 113

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 continued None None 180 days 54 nights Use of other psychotropic drugs, benzodiazepines, or other hypnotics, malignant disease History of drug abuse or addiction, hypersensitivity to benzodiazepines, psychotic disorder, mental epilepsy, retardation, recent severe head trauma, severe organic illness, pain interfering with sleep, pregnancy, breast feeding, inadequate contraception 1 month Age >40 years, minimum one defined symptom of insomnia Sleep problems (defined) for ≥ Inclusion Exclusion Duration of Other criteria criteria treatment comparators ’ d) France, 10 GPs France, Canada, number of centres unclear centres Sleep onset NAW, latency, time awake during night, duration of sleep, wake-up time, quality of sleep, feeling on awakening Sleep onset sleep latency, time, wake sleep NAWs, morphology, psychomotor performance – study characteristics (cont Primary Primary Secondary Locations and 20 10 withdrawal entering outcomes outcomes period Single-group open study Single-group open study = 96) = 11) Zolpidem 10/20 mg (10 in 65% of patients at end of study) ( n Zopiclone 7.5 mg ( n No. of patients Dependency and withdrawal review: trials observational studies 111 110 Pecknold, 1990 Maarek, 1992 Study Intervention/ Study design No. of patients

114 28 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 = 39) Placebo ( n 21 nights Serious systemic medical condition, transient or situational insomnia, insomnia associated with use of drugs or alcohol, or related to respiratory impairment, history of alcohol abuse, concomitant use of benzodiazepines or hypnotics 2 ≥ 2 criteria Age 65 – 85 years, insomnia weeks, fulfilling ≥ (defined) Inclusion Exclusion Duration of Other criteria criteria treatment comparators ’ d) England, number of centres unclear centres Sleep onset duration, latency, total NAWs, time awake, quality of sleep, status on following morning – study characteristics (cont Primary Primary Secondary Locations and Zolpidem 10 mg, 39; zolpidem 20 mg, 36 withdrawal entering outcomes outcomes period RCT, DB, parallel RCT, = 40) = 40) Zolpidem 10 mg ( n Zolpidem 20 mg ( n No. of patients Dependency and withdrawal review: trials observational studies 109 Shaw, 1992 Study Intervention/ Study design No. of patients DB, double-blind.

TABLE 28 TABLE 115

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 2 of the symptoms B criterion dropped out during withdrawal phase owing to rebound insomnia) sedative/hypnotic withdrawal syndrome (DSM-IV). 2 patients reported moderate symptoms: anxiety and hyperventilation, anxiety and general weakness (only 9 patients completed withdrawal phase – 1 patient No report of withdrawal symptoms No patient had ≥ Incidence of events, possibly related to gradual discontinuation of active treatment, was higher in the withdrawal groups than in the treatment group (zolpidem: 38 and 24%, respectively; zopiclone: 20%, respectively); if sleep complaints were excluded, no statistical difference remained. No in Tyrer questionnaire score; Ashton scale (of withdrawal symptoms) showed significantly more withdrawal symptoms in the zolpidem withdrawal group compared with the zolpidem continuation group (no differences between the two zopiclone groups) No withdrawal symptoms reported on zolpidem; adverse events during follow-up reported: 10 mg group, daytime aggression (1 patient); 20 mg group, restlessness 5 days after treatment (1 patient), increased sedation and confusion 4 days after treatment (1 patient) 8 patients were taking benzodiazepines within 1 month of entering study – 79% of patients required hypnotics before study Patients had used Patients study drug for a median of 9.1 months (zopiclone) or 7.4 months (zolpidem) 85% of patients previously on treatment of insomnia Previous use Previous Withdrawal symptoms Major depressive disorder, dysthymic disorder or minor depressive disorder None reported None reported None reported Dementia (50%), schizophrenia (27%), depression (11%). Majority of patients institutionalised diagnoses of hypnotics None Excluded None reported None None reported – patient characteristics and withdrawal symptoms Fluoxetine, paroxetine, sertraline Not reported None reported None reported Antipsychotics, antidepressants, treatment of movement disorders, cardiovascular conditions, etc. Concomitant History of Other 63.6 78.9 69.8 Not reported 10 mg: 77.5 20 mg: 57.5 41.6 56.8 43.9 10 mg: 74.9 20 mg: 72.9 Not reported (years) female (%) treatment substance abuse Zolpidem 10 mg Zolpidem 10/20 mg (at end of study 65% patients used 10 mg) Zopiclone 7.5 mg Zolpidem 10 mg, Zopiclone 7.5 mg Zolpidem 10 mg Zolpidem 20 mg Dependency and withdrawal review: trials observational studies 109 108 110 111 112 Maarek, 1992 Shaw, 1992 Asnis, 1999 Lemoine, 1995 Pecknold, 1990 Study Intervention Age (mean) and Sex

116 29 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 continued Patient increased dose to combat jet Patient lag Patient tried to reinforce anxiolytic Patient effect The paper reports a second case of withdrawal symptoms after the drug being described for a personality disorder Withdrawal symptoms present despite treatment with benzodiazepine Dose increase because of tolerance to hypnotic effect Notes Restlessness, disturbed sleep, Restlessness, vegetative symptoms Generalised tonic – clonic seizure, drug craving, recurrence of apathy, depressive mood Mild withdrawal syndrome (anxiety, agitation, restlessness, poor concentration, insomnia) psychomotor agitation, facial Tremor, flushing, anxiety Low mood, nightmares, sweating, tremors, panic attacks, confusion Epileptic seizures Abstinence phenomena during the day included sweating, tachycardia, muscular tremors, severe anxiety, twitches and myoclonic jerks Idiopathic Parkinson syndrome, organic delusional syndrome Major depression Obesity, hypertension None reported Major depression Depression, anxiety Depression Other Withdrawal symptoms Benzodiazepines, alcohol, clomethiazole None None reported None reported Benzodiazepines (diazepam, flunitrazepam, bromazepam) None reported Alcohol, barbiturate, benzodiazepine dependence drug abuse substance/ diagnoses – zolpidem Germany Italy Germany USA Italy USA UK 39 M 43 F 33 M 53 M 31 F 67 F 55 F sex Zolpidem (40 mg) Zolpidem (280 mg) Zolpidem (450 – 600 mg) Zolpidem (140 mg) Zolpidem (80 mg) Zolpidem (100 mg) Zolpidem (200 mg) dose) (max. daily (years), Dependency and withdrawal review: case reports 119 120 114 115 116 117 118 Study Intervention Age Location History of Madrak, 2001 Ravishankar, 1998 Aragona, 2000 Bottlender, 1997 Cavallaro, 1993 Gericke, 1994 Golden, 2000

TABLE 30 TABLE 117

© Queen’s Printer and Controller of HMSO 2004. All rights reserved. Appendix 3 ‘ odd ’ behaviour under No withdrawal symptoms reported on previous discontinuation, patient exhibited effect of zolpidem Patient increased dose because of Patient perceived tolerance increased dose as tolerance Patient developed Dose increases were without marked effect The paper reports a fourth case of withdrawal symptoms, but it is unclear whether the drug was originally used for insomnia Notes Rebound insomnia, anxiety, agitation, insomnia, anxiety, Rebound tremors, seizures Epileptic seizures Confusion, psychomotor agitation Craving feelings still on gradual withdrawal Depression Depression None Histrionic personality disorder Borderline personality disorder Borderline personality disorder, dysthymia Other Withdrawal symptoms Repeated zolpidem abuse None None Benzodiazepines Alcohol Cannabis drug abuse substance/ diagnoses – zolpidem Greece Spain Greece Greece 44 F 33 M 43 F 30 F 26 F 33 M sex Zolpidem (300 mg) Zolpidem (300 – 400 mg) Zolpidem (600 mg) Zolpidem (400 – 500mg) Zolpidem (160 – 200mg) Zolpidem (120mg) dose) (max. daily (years), Dependency and withdrawal review: case reports 121 122 123 124 Sakkas, 1999 Sanchez, 1996 Tripodianakis, 2003 Vartzopoulos, 2000 Study Intervention Age Location History of

118 30 TABLE Health Technology Assessment 2004; Vol. 8: No. 24 Admitted for controlled withdrawal Clients reported knowing of many other fellow addicts abusing zopiclone Notes Grand-mal-type convulsions sweating, tremor, Tachycardia, rebound insomnia tremors, Strong craving, anxiety, sweats, flushes Severe rebound insomnia, anxiety Sweating, palpitations, tremor, anxiety Hyperactivity with tachycardia, hand tremor and weakness, panic attacks Rebound insomnia, feeling edgy, very insomnia, feeling edgy, Rebound strong craving Depression Major depression and compulsive personality disorder Pneumothorax None reported Depression Bipolar affective disorder Depressive disorder Not reported Other Withdrawal symptoms Alcohol, flurazepam Nitrazepam, trimipramine, promazine, beer None reported None reported None reported Benzodiazepine dependency None reported Temazepam, heroin, cocaine; now on methadone maintenance drug abuse substance/ diagnoses – zopiclone Finland Wales Switzerland Ireland England 36 M 29 M 26 M 49 F 36 F 67 M six patients (4 M, 2 F) 36 M sex Zopiclone (90 mg) Zopiclone (22.5 mg) Zopiclone (30 mg) Zopiclone (22.5 mg) Zopiclone (30 mg) Zopiclone (337.5 mg) Zopiclone (45 mg) Zopiclone (380 mg) dose) (max. daily (years), 128 126 Dependency and withdrawal review: case reports 125 127 129 Aranko, 1991 Jones, 1998 Kuntze, 2002 1996 Sikdar, Thakore, 1992 Study Intervention Age Location History of

TABLE 31 TABLE 119

Health Technology Assessment 2004; Vol. 8: No. 24

Appendix 4 Clinical: included and excluded references

Included studies

Study Reference(s)

Zolpidem versus nitrazepam Kazamatsuri, 199386 Kazamatsuri H, Sato M, Mori A, Toru M, Kaneno S, Murasaki M, et al. Clinical evaluation of zolpidem on insomnia of patients with schizophrenia and manic-depressive psychosis – double-blind trial in comparison with nitrazepam [in Japanese]. Rinsho Iyaku 1993;9:107–36. Kudo, 199388 Kudo Y, Kawakita Y, Saito M, Nishimura T, Nakajima T, Ogawa N, et al. Clinical efficacy and safety of zolpidem on insomnia: a double-blind comparative study with zolpidem and nitrazepam [in Japanese]. Rinsho Iyaku 1993;9:79–105.

Zolpidem versus temazepam Kerkhof, 199689 Kerkhof G, van Vianen BG, Kamphuisen HAC. A comparison of zolpidem and temazepam in psychophysiological insomniacs. Eur Neuropsychopharmacol 1996;6(Suppl 4):155–6. Leppik, 199782 Leppik IE, Roth Schechter GB, Gray GW, Cohn MA, Owens D. Double-blind, placebo- controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug Dev Res 1997;40:230–8. Ochs R, Fillingim J, Cutler N, Leppik I, Lucas E, Cohn M, et al. The effect of zolpidem in elderly patients with chronic insomnia. Sleep Res 1992;1(Suppl 1):164.

Zopiclone versus lormetazepam Ansoms, 199183 Ansoms S, Lebon O, Pelc I, Cabri C, Poels R. Zopiclone or lormetazepam in the treatment of insomnia and the effect on behavior and mood in patients during the post alcoholism withdrawal period. Curr Ther Res Clin Exp 1991;49:54–64.

Zopiclone versus nitrazepam Agnoli, 198984 Agnoli A, Manna V, Martucci N. Double-blind study on the hypnotic and antianxiety effects of zopiclone compared with nitrazepam in the treatment of insomnia. Int J Clin Pharmacol Res 1989;9:277–81. Anderson, 198785 Anderson AA. Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice. Sleep 1987;10 (Suppl 1):54–62. Klimm, 198787 Klimm HD, Dreyfus JF, Delmotte M. Zopiclone versus nitrazepam – a double-blind comparative study of efficacy and tolerance in elderly patients with chronic insomnia. Sleep 1987;10:73–8. Jovanovic, 198390 Jovanovic UJ, Dreyfus JF. Polygraphical sleep recordings in insomniac patients under zopiclone or nitrazepam. Pharmacology 1983;27(Suppl 2):136–45. Ohtomo 1, 198591 Ohtomo E. The clinical efficacy of zopiclone for insomnia in geriatric subjects in the field of internal medicine: comparison with nitrazepam by the double-blind method [in Japanese]. Geriatr Med 1985;22:971–2. Ohtomo 2, 198592 Ohtomo E. The clinical efficacy of zopiclone for insomnia in geriatric subjects: comparison with nitrazepam by the double-blind method [in Japanese]. Geriatr Med 1985;23:399–419. Pull, 198393 Pull CB, Dreyfus JF, Brun JP. Comparison of nitrazepam and zopiclone in psychiatric patients. Pharmacology 1983;27(Suppl 2):205–9. Tamminen, 198794 Tamminen T, Hansen PP. Chronic administration of zopiclone and nitrazepam in the treatment of insomnia. Sleep 1987;10(Suppl 1):63–72.

continued 121

Study Reference(s)

Zopiclone versus Temazepam Ngen, 199095 Ngen CC, Hassan R. A double-blind placebo-controlled trial of zopiclone 7.5 mg and temazepam 20 mg in insomnia. Int Clin Psychopharmacol 1990;5:165–71. Stip, 199996 Stip E, Furlan M, Lussier I, Bourgouin P, Elie R. Double-blind, placebo-controlled study comparing effects of zopiclone and temazepam on cognitive functioning of insomniacs. Hum Psychopharmacol 1999;14:253–61. van der Kleijn, 198997 van der Kleijn E. Effects of zopiclone and temazepam on sleep, behaviour and mood during the day. Eur J Clin Pharmacol 1989;36:247–51. Wheatley, 198598 Wheatley D. Zopiclone: a non-benzodiazepine hypnotic. Controlled comparison to temazepam in insomnia. Br J Psychiatry 1985;146:312–14.

Zaleplon versus zolpidem Allain, 200199 Allain H, Le Breton S, Kleinermans D, Lavoisy J, Klausner J, Gandon JM. Assessment of patients’ preferences between two hypnotics, zolpidem (10 mg) vs. zaleplon (10 mg). Sleep 2001;24(Abstr Suppl):A332. Ancoli-Israel, 1999102 Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M. Zaleplon, a novel nonbenzodizepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care 1999;1:114–20. Elie, 1999100 Elie R, Ruther E, Farr I, Emilien G, Salinas E. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. J Clin Psychiatry 1999;60:536–44. Fry, 2000101 Fry J, Scharf M, Mangano R, Fujimori M, Berkowitz D, Bielksi R, et al. Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Int Clin Psychopharmacol 2000;15:141–52. Zammit 1 and 2, 2000103 Zammit G. Zaleplon vs zolpidem: differences in next-day residual sedation after middle-of- the-night administration. J Sleep Res 2000;9(Suppl 1):214.

Zolpidem versus zopiclone Tsutsui, 2001104 Tsutsui S. A double-blind comparative study of zolpidem versus zopiclone in the treatment of chronic primary insomnia. J Int Med Res 2001;29:163–77.

References excluded from the review

Reference Reason for exclusion

Aeschbach D, Dijk DJ, Trachsel L, Brunner DP, Borbely AA. Dynamics of slow-wave activity and Healthy subjects spindle frequency activity in the human sleep EEG – effect of midazolam and zopiclone. Midazolam Neuropsychopharmacology 1994;11:237–44.

Allain H, Patat A, Lieury A, LeCoz F, Janus C, Menard G, et al. Comparative study of the effects Healthy subjects of zopiclone (7.5 mg), zolpidem, flunitrazepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics. Eur Psychiatry 1995;10:S129–35.

Allen D, Curran HV, Lader M. The effects of single doses of CL284,846, lorazepam, and placebo Healthy subjects and psychomotor and memory function in normal male volunteers. Eur J Clin Pharmacol 1993;45:313–320.

Begg EJ, Robson RA, Frampton CM, Campbell JE. A comparison of efficacy and tolerance of the Comparator: short acting sedatives midazolam and zopiclone. N Z Med J 1992;105:428–9. midazolam

Biondi F, Casadei GL. Results of a multicenter trial with the hypnotic zolpidem in 1152 insomniac Zolpidem only patients. Curr Ther Res Clin Exp 1994;55:262–74.

continued 122 Health Technology Assessment 2004; Vol. 8: No. 24

Reference Reason for exclusion

Bocca ML, Le Doze F, Etard O, Pottier M, L’Hoste J, Denise P. Residual effects of zolpidem 10 mg Healthy subjects and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades. Psychopharmacology 1999;143:373–9.

Campbell RD, Grace MGA, Bourgouin J, Forget JP. Efficacy and safety of zopiclone in the Zopiclone only treatment of insomnia. Curr Ther Res Clin Exp 1987;42:665–70.

Cluydts R, Deroeck J, Cosyns P, Lacante P. Antagonizing the effects of experimentally-induced Healthy subjects sleep disturbance in healthy volunteers by lormetazepam and zolpidem. J Clin Psychopharmacol 1995;15:132–7.

Danjou P, Paty I, Fruncillo R, Worthington P, Unruh M, Cevallos W, et al. A comparison of the Healthy subjects residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening. Br J Clin Pharmacol 1999;48:367–74.

Darwish M, Paty I, Patat A, Troy S. Comparison of psychomotor and memory impairment with Non-RCT zaleplon versus other hypnotics: an integrated analysis (poster).

Dietrich B, Emilien G, Salinas E. Zaleplon improves sleep efficiency in a phase-advance model of Healthy subjects transient insomnia. Presented at XXIst Collegium Internationale Neuropsychopharmacologicum, Glasgow, 12–16 July 1998.

Drover D, Lemmens H, Naidu S, Cevallos W, Darwish M, Stanski D. Pharmacokinetics, Healthy subjects pharmacodynamics, and relative pharmacokinetic/pharmacodynamic profiles of zaleplon and zolpidem. Clin Ther 2000;22:1443–61.

Elie R. Zaleplon is effective in reducing time to sleep onset. European College of Non-RCT Neuropsychopharmacology, poster 047; 1999.

Erman MK, Erwin CW, Gengo FM, Jamieson AO, Lemmi H, Mahowald MW, et al. Comparative Healthy subjects efficacy of zolpidem and temazepam in transient insomnia. Hum Psychopharmacol 2001;16:169–76.

Gremion G, Sutter-Weyrich C, Rostan A, Forster A. Physical performance and sedation: Healthy subjects comparative study of the effects of a benzodiazepine (temazepam) and a non-benzodiazepine hypnotic (zolpidem). [in French]. Schweiz Z Sportmed 1992;40(3):113–18.

Grobler LA, Schwellnus MP, Trichard C, Calder S, Noakes TD, Derman WE. Comparative effects Healthy subjects of zopiclone and loprazolam on psychomotor and physical performance in active individuals. Clin J Sport Med 2000;10:123–8.

Harrison C, Subhan Z, Hindmarch I. Residual effects of zopiclone and benzodiazepine hypnotics Healthy subjects on psychomotor performance related to car driving. Drugs Exp Clin Res 1985;11:823–9.

Hemmeter U, Muller M, Bischof R, Annen B, Holsboer-Trachsler E. Effect of zopiclone and Healthy subjects temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers. Psychopharmacologia 2000;147:384–96.

Hindmarch I. Immediate and overnight effects of zopiclone 7.5 mg and nitrazepam 5 mg with Healthy subjects ethanol, on psychomotor performance and memory in healthy volunteers. Int Clin Psychopharmacol 1990;5 (Suppl 2):105–13.

Hindmarch I, Patat A, Stanley N, Paty I, Rigney U. Residual effects of zaleplon and zolpidem Healthy subjects following middle of the night administration five hours to one hour before awakening. Hum Psychopharmacol Clin Exp 2001;16:159–67.

Jobert M, Poiseau E, Jahnig P, Gaillard P, Schulz H. ECG activity in the sleep of insomniac patients Outcomes under the influence of lormetazepam and zopiclone. Neuropsychobiology 1995;31:204–9.

Lader M, Fricka G. Subjective effects during administration and on discontinuation of zopiclone Healthy subjects and temazepam in normal subjects. Pharmacopsychiatry 1987;20:67–71.

continued 123

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Lemoine P, Allain H, Janus C, Sutet P. Gradual withdrawal of zopiclone (7.5 mg) and zolpidem Non-RCT (10 mg) in insomniacs treated for at least 3 months. Eur Psychiatry 1995;10:S161–5.

Maillard D, Thiercelin JF, Fuseau E, Rosenzweig P, Attali P. Effects of zolpidem versus diazepam Outcomes and placebo on breathing control parameters in healthy-human subjects. Int J Clin Pharmacol Res 1992;12:27–35.

Momose T. Effectiveness of zopiclone as a preoperative hypnotic. Int Pharmacopsychiatry Not insomniacs 1982;17(Suppl 2):196–204.

Nair NP, Schwartz G, Dimitri R, Le Morvan P, Thavundayil JX. A dose-range finding study of 1 Comparator: zopiclone in insomniac patients. Int Clin Psychopharmacol 1990;5(Suppl 2):1–10. furazepam

Nakajima T, Takazawa S, Hayashida S, Nakagome K, Sasaki T, Kanno O. Effects of zolpidem and Healthy subjects zopiclone on cognitive and attentional function in young healthy volunteers: an event-related potential study. Psychiatry Clin Neurosci 2000;54:37–40.

Parrino L, Boselli M, Spaggiari MC, Smerieri A, Terzano MG. Multidrug comparison (lorazepam, Healthy subjects triazolam, zolpidem, and zopiclone) in situational insomnia: polysomnographic analysis by means of the cyclic alternating pattern. Clin Neuropharmacol 1997;20:253–63.

Patat A, Coz FL, Thebault C, Allain H, Gandon JM. Effects of zopiclone, zolpidem and Healthy subjects flunitrazepam on nocturnal psychomotor and cognitive functions in normal young subjects Conference Abstract, XXth Collegium Internationale Neuropsychopharmacologicum, Melbourne, Australia. 23–27 June 1996.

Ranlov PJ, Nielsen SP. Effect of zopiclone and diazepam on ventilatory response in normal Healthy subjects human subjects. Sleep 1987;10 (Suppl 1):40–7.

Rettig HC, De Haan P, Zuurmond WWA, Leeuwen VL. Effects of hypnotics on sleep and Not insomniacs psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone. Anaesthesia 1990;45:1079–82.

Scharf MB, Mendels J, Thorpy M, Weiss B. Safety of long-term zolpidem treatment in patients Comparator: with insomnia. Curr Ther Res Clin Exp 1994;55:1100–11. flurazepam

Shapiro CM, Sherman D, Peck DF. Withdrawal from benzodiazepines by initially switching to Zopiclone only zopiclone. Eur Psychiatry 1995;10:S145–51.

Stone BM, Turner C, Mills SL, Paty I, Patat A, Darwish M, et al. Noise-induced sleep maintenance Healthy subjects insomnia: hypnotic and residual effects of zaleplon. Br J Clin Pharmacol 2002;53:196–202.

Suzuki M, Uchiumi M, Murasaki M. Effects of a single dose of zolpidem, a novel benzodiazepine Healthy subjects omega1 receptor-related hypnotic, on human memory: a comparative double-blind study with triazolam and nitrazepam. Jpn J Neuropsychopharmacol 1993;15:375–89.

Trachsel L, Dijk D J, Brunner DP, Klene C, Borbely AA. Effect of zopiclone and midazolam on sleep Healthy subjects, and EEG spectra in a phase-advanced sleep schedule. Neuropsychopharmacology 1990;3:11–18. midazolam

Troy SM, Lucki I, Unruh MA, Cevallos WH, Leister CA, Martin PT, et al. Comparison of the Healthy subjects effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance. J Clin Psychopharmacol 2000;20:328–37.

Uchiumi M, Isawa S, Suzuki M, Murasaki M. The effects of zolpidem and zopiclone on daytime Healthy subjects sleepiness and psychomotor performance. Jpn J Psychopharmacol 2000;20:123–30.

Vera F, Luna-Villegas G, Fernandez-Mas R, Navarro JF, Fernandez-Guardiola A. Effect of the Healthy subjects administration of gabaergic agonists of the GABA(A)/BDZ receptor on sleep in human subjects. Salud Mental 1999;22:5–13. continued 124 Health Technology Assessment 2004; Vol. 8: No. 24

Reference Reason for exclusion

Vermeeren A, Danjou PE, O’Hanlon JF. Residual effects of evening and middle-of-the-night Healthy subjects administration of zaleplon 10 and 20 mg on memory and actual driving performance. Hum Psychopharmacol 1998;13(Suppl 2):S98–107.

Vermeeren A, Riedel WJ, Van Boxtel MPJ, Darwish M, Paty I, Patat A. Differential residual effects Healthy subjects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 2002;25:224–31.

Versiani M, Hojaij CR, Nardi AE, Mundin FD, Drach AR, Cocarelli T. Treatment of chronic Comparator: insomnia: comparative clinical trial zopiclone x midazolam [in Portuguese]. Arq Bras Med midazolam 1993;67:131–6.

Verster JC, Volkerts ER, Schreuder A, Eijken EJE, Van Heuckelum JHG, Veldhuijzen DS, et al. Healthy subjects Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol 2002;22:576–83.

Voderholzer U, Riemann D, Hornyak M, Backhaus J, Feige B, Berger M, et al. A double-blind, Healthy subjects randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin Neurosci 2001;251:117–23.

Whitehead C, Sanders L, Appadurai I, Power I, Rosen M, Robinson J. Zopiclone as a preoperative Not insomniacs night hypnotic: a double-blind comparison with temazepam and placebo. Br J Anaesth 1994;72:443–6.

Whitaker T, Mangano R, Entsuah R, Emilien R, Salinas E, Fujimori M. Zaleplon safely improves Non-RCT sleep in elderly patients with insomnia (poster).

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Yamadera H, Kato M, Tsukahara Y, Brandeis D, Okuma T. Zopiclone versus diazepam effects on Healthy subjects EEG power maps in healthy volunteers. Acta Neurobiol Exp 1997;57:151–5.

Outcomes: reports involving outcomes, which were not considered in this review.

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Health Technology Assessment Programme

Prioritisation Strategy Group Members

Chair, Professor Bruce Campbell, Dr John Reynolds, Clinical Professor Tom Walley, Consultant Vascular & General Director, Acute General Director, NHS HTA Programme, Surgeon, Royal Devon & Exeter Medicine SDU, Radcliffe Department of Pharmacology & Hospital Hospital, Oxford Therapeutics, Professor Shah Ebrahim, Dr Ron Zimmern, Director, University of Liverpool Professor in Epidemiology Public Health Genetics Unit, of Ageing, University of Strangeways Research Bristol Laboratories, Cambridge

HTA Commissioning Board Members

Programme Director, Professor John Brazier, Director Professor Peter Jones, Head of Professor Mark Sculpher, Professor Tom Walley, of Health Economics, Department, University Professor of Health Economics, Director, NHS HTA Programme, Sheffield Health Economics Department of Psychiatry, Centre for Health Economics, Department of Pharmacology & Group, School of Health & University of Cambridge Institute for Research in the Therapeutics, Related Research, Social Services, University of York University of Liverpool University of Sheffield Professor Sallie Lamb, Research Professor in Physiotherapy/Co- Professor Martin Severs, Chair, Dr Andrew Briggs, Public Director, Interdisciplinary Professor in Elderly Health Professor Shah Ebrahim, Health Career Scientist, Health Research Centre in Health, Care, Portsmouth Institute of Professor in Epidemiology of Economics Research Centre, Coventry University Medicine Ageing, Department of Social University of Oxford Medicine, University of Bristol Professor Julian Little, Dr Jonathan Shapiro, Senior Fellow, Health Services Professor Nicky Cullum, Professor of Epidemiology, Department of Medicine and Management Centre, Deputy Chair, Director of Centre for Evidence Therapeutics, University of Birmingham Professor Jenny Hewison, Based Nursing, Department of Professor of Health Care Aberdeen Health Sciences, University of Ms Kate Thomas, Psychology, Academic Unit of York Professor Stuart Logan, Deputy Director, Psychiatry and Behavioural Director of Health & Social Medical Care Research Unit, Sciences, University of Leeds Dr Andrew Farmer, Senior Care Research, The Peninsula University of Sheffield School of Medicine Lecturer in General Practice, Medical School, Universities of Department of Primary Health Exeter & Plymouth Professor Simon G Thompson, Care, University of Oxford Director, MRC Biostatistics Dr Jeffrey Aronson Professor Tim Peters, Professor Unit, Institute of Public Health, Reader in Clinical Professor Fiona J Gilbert, of Primary Care Health Services Cambridge Pharmacology, Department of Professor of Radiology, Research, Division of Primary Ms Sue Ziebland, Clinical Pharmacology, Department of Radiology, Health Care, University of Senior Research Fellow, Radcliffe Infirmary, Oxford University of Aberdeen Bristol Cancer Research UK, Professor Ann Bowling, Professor Adrian Grant, Professor Ian Roberts, Professor University of Oxford Professor of Health Services Director, Health Services of Epidemiology & Public Research, Primary Care and Research Unit, University of Health, Intervention Research Population Studies, Aberdeen Unit, London School of University College London Hygiene and Tropical Medicine Professor F D Richard Hobbs, Professor Andrew Bradbury, Professor of Primary Care & Professor Peter Sandercock, Professor of Vascular Surgery, General Practice, Department of Professor of Medical Neurology, Department of Vascular Surgery, Primary Care & General Department of Clinical Birmingham Heartlands Practice, University of Neurosciences, University of Hospital Birmingham Edinburgh

137 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.ncchta.org)

Diagnostic Technologies & Screening Panel Members

Chair, Professor Adrian K Dixon, Mr Tam Fry, Honorary Dr Margaret Somerville, Dr Ron Zimmern, Director of Professor of Radiology, Chairman, Child Growth Director of Public Health, the Public Health Genetics Unit, Addenbrooke’s Hospital, Foundation, London Teignbridge Primary Care Trust Strangeways Research Cambridge Laboratories, Cambridge Dr Edmund Jessop, Professor Lindsay Wilson Dr David Elliman, Medical Adviser, Turnbull, Scientific Director, Consultant in Community National Specialist Centre for MR Investigations & Commissioning Advisory Group Ms Norma Armston, Child Health, London YCR Professor of Radiology, (NSCAG), Department of Freelance Consumer Advocate, University of Hull Health, London Bolton Professor Glyn Elwyn, Primary Medical Care Professor Martin J Whittle, Professor Max Bachmann Research Group, Dr Jennifer J Kurinczuk, Head of Division of Professor Health Swansea Clinical School, Consultant Clinical Reproductive & Child Health, Care Interfaces, University of Wales Epidemiologist, University of Birmingham Department of Health Swansea National Perinatal Policy and Practice, Epidemiology Unit, Dr Dennis Wright, Consultant University of East Anglia Dr John Fielding, Oxford Biochemist & Clinical Director, Consultant Radiologist, Pathology & The Kennedy Professor Rudy Bilous Dr Susanne M Ludgate, Medical Radiology Department, Galton Centre, Northwick Park Professor of Clinical Medicine & Director, Medical Devices Royal Shrewsbury Hospital & St Mark’s Hospitals, Consultant Physician, Agency, London Harrow The Academic Centre, Dr Karen N Foster, Clinical South Tees Hospitals Dr William Rosenberg, Senior Lecturer, Dept of General NHS Trust Lecturer and Consultant in Practice & Primary Care, Medicine, University of Dr Paul Cockcroft, University of Aberdeen Southampton Consultant Medical Microbiologist/Laboratory Professor Antony J Franks, Dr Susan Schonfield, CPHM Director, Public Health Deputy Medical Director, Specialised Services Laboratory, St Mary’s Hospital, The Leeds Teaching Hospitals Commissioning, Croydon Portsmouth NHS Trust Primary Care Trust

Pharmaceuticals Panel Members

Chair, Dr Christopher Cates, GP and Mrs Sharon Hart, Managing Professor Jan Scott, Dr John Reynolds, Clinical Cochrane Editor, Bushey Health Editor, Drug & Therapeutics Professor of Psychological Director, Acute General Centre Bulletin, London Treatments, Medicine SDU, Oxford Institute of Psychiatry, Dr Christine Hine, Consultant in Radcliffe Hospital Professor Imti Choonara, University of London Professor in Child Health, Public Health Medicine, University of Nottingham, Bristol South & West Primary Mrs Katrina Simister, New Derbyshire Children’s Hospital Care Trust Products Manager, National Prescribing Centre, Liverpool Mr Charles Dobson, Special Professor Stan Kaye, Professor Tony Avery, Projects Adviser, Department of Professor of Medical Oncology, Professor of Primary Health Dr Richard Tiner, Medical Health Consultant in Medical Care, University of Nottingham Oncology/Drug Development, Director, Association of the The Royal Marsden Hospital British Pharmaceutical Industry Professor Stirling Bryan, Dr Robin Ferner, Consultant Professor of Health Economics, Physician and Director, West Ms Barbara Meredith, Dr Helen Williams, Health Services Midlands Centre for Adverse Project Manager Clinical Consultant Microbiologist, Management Centre, Drug Reactions, City Hospital Guidelines, Patient Involvement Norfolk & Norwich University University of Birmingham NHS Trust, Birmingham Unit, NICE Hospital NHS Trust Mr Peter Cardy, Chief Dr Karen A Fitzgerald, Dr Frances Rotblat, CPMP Executive, Macmillan Cancer Pharmaceutical Adviser, Bro Taf Delegate, Medicines Control Relief, London Health Authority, Cardiff Agency, London

138 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.ncchta.org) Health Technology Assessment 2004; Vol. 8: No. 24

Therapeutic Procedures Panel Members

Chair, Mr Matthew William Cooke, Ms Bec Hanley, Freelance Professor James Neilson, Professor Bruce Campbell, Senior Clinical Lecturer and Consumer Advocate, Professor of Obstetrics and Consultant Vascular and Honorary Consultant, Hurstpierpoint Gynaecology, Dept of Obstetrics General Surgeon, Royal Devon Emergency Department, and Gynaecology, & Exeter Hospital University of Warwick, Coventry Ms Maryann L. Hardy, University of Liverpool, & Warwickshire NHS Trust, Lecturer, Liverpool Women’s Hospital Division of Health in the Division of Radiography, Community, Centre for Primary University of Bradford Dr John C Pounsford, Consultant Physician, North Health Care Studies, Coventry Professor Alan Horwich, Bristol NHS Trust Dr Carl E Counsell, Senior Director of Clinical R&D, The Lecturer in Neurology, Institute of Cancer Research, Dr Vimal Sharma, Dr Mahmood Adil, Head of University of Aberdeen London Consultant Psychiatrist & Hon Clinical Support & Health Snr Lecturer, Dr Phillip Leech, Principal Protection, Directorate of Dr Keith Dodd, Consultant Mental Health Resource Centre, Medical Officer for Primary Health and Social Care (North), Paediatrician, Derbyshire Victoria Central Hospital, Care, Department of Health, Department of Health, Children’s Hospital Wirrall London Manchester Professor Gene Feder, Professor Dr L David Smith, Consultant of Primary Care R&D, Barts & Dr Simon de Lusignan, Dr Aileen Clarke, Cardiologist, Royal Devon & the London, Queen Mary’s Senior Lecturer, Primary Care Reader in Health Services Exeter Hospital School of Medicine and Informatics, Department of Research, Public Health & Dentistry, University of London Community Health Sciences, Policy Research Unit, Professor Norman Waugh, St George’s Hospital Medical Professor of Public Health, Barts & the London School of Professor Paul Gregg, School, London Medicine & Dentistry, Professor of Orthopaedic University of Aberdeen Institute of Community Health Surgical Science, Department of Dr Mike McGovern, Senior Sciences, Queen Mary, Orthopaedic Surgery, Medical Officer, Heart Team, University of London South Tees Hospital NHS Trust Department of Health, London

139 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.ncchta.org) Health Technology Assessment Programme

Expert Advisory Network Members

Professor Douglas Altman, Professor Nicky Cullum, Professor Robert E Hawkins, Dr Andrew Mortimore, Director of CSM & Cancer Director of Centre for Evidence CRC Professor and Director of Consultant in Public Health Research UK Med Stat Gp, Based Nursing, University of York Medical Oncology, Christie CRC Medicine, Southampton City Centre for Statistics in Research Centre, Christie Primary Care Trust Medicine, University of Oxford, Dr Katherine Darton, Hospital NHS Trust, Manchester Dr Sue Moss, Institute of Health Sciences, Information Unit, MIND – The Professor F D Richard Hobbs, Associate Director, Cancer Headington, Oxford Mental Health Charity, London Professor of Primary Care & Screening Evaluation Unit, Professor Carol Dezateux, Professor John Bond, General Practice, Department of Institute of Cancer Research, Professor of Paediatric Director, Centre for Health Primary Care & General Sutton Epidemiology, London Practice, University of Services Research, Professor Jon Nicholl, Birmingham University of Newcastle upon Mr John Dunning, Director of Medical Care Tyne, School of Population & Consultant Cardiothoracic Professor Allen Hutchinson, Research Unit, School of Health Health Sciences, Surgeon, Cardiothoracic Director of Public Health & and Related Research, Newcastle upon Tyne Surgical Unit, Papworth Deputy Dean of ScHARR, University of Sheffield Hospital NHS Trust, Cambridge Department of Public Health, Mr Shaun Brogan, Mrs Julietta Patnick, University of Sheffield Chief Executive, Ridgeway Mr Jonothan Earnshaw, National Co-ordinator, NHS Primary Care Group, Aylesbury Consultant Vascular Surgeon, Dr Duncan Keeley, Cancer Screening Programmes, Gloucestershire Royal Hospital, General Practitioner (Dr Burch Sheffield Mrs Stella Burnside OBE, Gloucester & Ptnrs), The Health Centre, Chief Executive, Professor Robert Peveler, Thame Office of the Chief Executive. Professor Martin Eccles, Professor of Liaison Psychiatry, Trust Headquarters, Professor of Clinical Dr Donna Lamping, University Mental Health Altnagelvin Hospitals Health & Effectiveness, Centre for Health Research Degrees Programme Group, Royal South Hants Social Services Trust, Services Research, University of Director & Reader in Psychology, Hospital, Southampton Altnagelvin Area Hospital, Newcastle upon Tyne Health Services Research Unit, Professor Chris Price, Londonderry London School of Hygiene and Professor Pam Enderby, Visiting Chair – Oxford, Tropical Medicine, London Ms Tracy Bury, Professor of Community Clinical Research, Bayer Project Manager, World Rehabilitation, Institute of Mr George Levvy, Diagnostics Europe, Confederation for Physical General Practice and Primary Chief Executive, Motor Cirencester Therapy, London Care, University of Sheffield Neurone Disease Association, Ms Marianne Rigge, Northampton Director, College of Health, Mr John A Cairns, Mr Leonard R Fenwick, London Professor of Health Economics, Chief Executive, Newcastle Professor James Lindesay, Health Economics Research upon Tyne Hospitals NHS Trust Professor of Psychiatry for the Dr Eamonn Sheridan, Unit, University of Aberdeen Elderly, University of Leicester, Consultant in Clinical Genetics, Professor David Field, Leicester General Hospital Genetics Department, Professor of Neonatal Medicine, Professor Iain T Cameron, St James’s University Hospital, Child Health, The Leicester Professor Rajan Madhok, Professor of Obstetrics and Leeds Gynaecology and Head of the Royal Infirmary NHS Trust Medical Director & Director of Public Health, Directorate of Dr Ken Stein, School of Medicine, Mrs Gillian Fletcher, Clinical Strategy & Public Senior Clinical Lecturer in University of Southampton Antenatal Teacher & Tutor and Health, North & East Yorkshire Public Health, Director, President, National Childbirth Dr Christine Clark, & Northern Lincolnshire Health Peninsula Technology Trust, Henfield Medical Writer & Consultant Authority, York Assessment Group, Pharmacist, Rossendale Professor Jayne Franklyn, University of Exeter Professor David Mant, Professor of Medicine, Professor Collette Mary Clifford, Professor of General Practice, Professor Sarah Stewart-Brown, Department of Medicine, Professor of Nursing & Head of Department of Primary Care, Director HSRU/Honorary University of Birmingham, Research, School of Health University of Oxford Consultant in PH Medicine, Queen Elizabeth Hospital, Sciences, University of Department of Public Health, Edgbaston, Birmingham Birmingham, Edgbaston, Professor Alexander Markham, University of Oxford Director, Molecular Medicine Birmingham Ms Grace Gibbs, Unit, St James’s University Professor Ala Szczepura, Deputy Chief Executive, Professor Barry Cookson, Hospital, Leeds Professor of Health Service Director for Nursing, Midwifery Director, Research, Centre for Health & Clinical Support Servs, Dr Chris McCall, Laboratory of Healthcare Services Studies, University of West Middlesex University General Practitioner, Associated Infection, Warwick Hospital, Isleworth The Hadleigh Practice, Health Protection Agency, Castle Mullen Dr Ross Taylor, London Dr Neville Goodman, Senior Lecturer, Consultant Anaesthetist, Professor Alistair McGuire, Department of General Practice Professor Howard Stephen Cuckle, Southmead Hospital, Bristol Professor of Health Economics, and Primary Care, Professor of Reproductive London School of Economics University of Aberdeen Epidemiology, Department of Professor Alastair Gray, Paediatrics, Obstetrics & Professor of Health Economics, Dr Peter Moore, Mrs Joan Webster, Gynaecology, University of Department of Public Health, Freelance Science Writer, Consumer member, HTA – Leeds University of Oxford Ashtead Expert Advisory Network

140 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.ncchta.org)

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The National Coordinating Centre for Health Technology Assessment, Mailpoint 728, Boldrewood, University of Southampton, Southampton, SO16 7PX, UK. Fax: +44 (0) 23 8059 5639 Email: [email protected] http://www.ncchta.org ISSN 1366-5278