Appraisal Consultation Document: Zaleplon, zolpidem and zopiclone for the management of insomnia


Appraisal Consultation Document

Zaleplon, zolpidem and zopiclone for the management of insomnia

The Department of Health and the National Assembly for Wales have asked the National Institute for Clinical Excellence (NICE or the Institute) to conduct an appraisal of zaleplon, zolpidem and zopiclone and provide guidance on their use to the NHS in England and Wales. The Institute was specifically asked to advise on the clinical and cost effectiveness of zaleplon, zolpidem and zopiclone relative to the benzodiazepines that are used for the management of insomnia. The Appraisal Committee has held its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of zaleplon, zolpidem and zopiclone.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consulteesfor this appraisal are listed on the NICE website).

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. (For further details, see the Guide to the Technology Appraisal Process on the Institute's website).

  • The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
  • At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
  • After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
  • Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: 11 November 2003
Second Appraisal Committee meeting: 26 November 2003

Details of membership of the Appraisal Committee are given in Appendix A and a list of the sources of evidence used in the preparation of this document is given in Appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.
1 Appraisal Committee's preliminary views
1.1 When, after due consideration and appropriate use of non-pharmacological measures, hypnotic drug therapy is considered appropriate for the management of severe insomnia interfering with normal daily life, it is recommended that hypnotics should be prescribed for short periods of time only, in strict accordance with their licensed indications.
1.2 It is recommended that, because of the lack of compelling evidence to distinguish between zaleplon, zolpidem, zopiclone or the short-acting benzodiazepine hypnotics, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed. The drugs with higher acquisition costs should only be prescribed if an individual is intolerant to the first-line choice.
1.3 It is recommended that switching from one of these hypnotics to another should only occur if an individual proves to be intolerant to a specific agent. Individuals who have not responded to one of these hypnotic drugs should not be prescribed any of the others.
2 Clinical need and practice
2.1 Insomnia is a disturbance of normal sleep patterns commonly characterised by difficulty in initiating sleep (sleep onset latency) and/or difficulty maintaining sleep (sleep maintenance). However, insomnia is highly subjective and although most healthy adults typically sleep between 7 and 9 hours per night, patterns vary greatly between individuals, and in any given individual there are variations from night to night.
2.2 Insomnia can have a number of different causes: primary insomnia can be differentiated from insomnia secondary to other factors such as personal circumstances, physical or psychiatric co-morbidities, concomitant drug treatments or substance abuse (drugs, nicotine, alcohol or caffeine). A 1996 World Health Organisation survey indicated that 52% of individuals reporting a sleep problem had a well-defined mental health disorder and 54% reported a physical disorder.
2.3 The published estimates of the prevalence of insomnia vary from 10-38%. This variation can be attributed to the epidemiological surveys utilising different definitions, classification systems and diagnostic criteria. A recent systematic review of the epidemiological literature suggested that, whilst 30-48% of individuals reported the presence of insomnia symptoms and 8-18% reported dissatisfaction with sleep quality or quantity, only 6% met the criteria for a diagnosis of insomnia. Although 1 in 20 individuals are believed to present to healthcare professionals with insomnia-related symptoms, it is thought that many individuals do not seek medical help.
2.4 The prevalence of insomnia has been reported to be higher in women and to increase with age. However, the age-related increase has been attributed to the fact that older people have more co-morbidities and sleep less efficiently, which leads to daytime sleepiness, fatigue and frequent napping during the day.
2.5 Sleep disturbance and the resultant daytime fatigue cause distress and impairment of daytime functioning, both social and occupational, which have been associated with reduced quality of life. Individuals with insomnia have been shown to have higher rates of mental health problems, drug and alcohol abuse, cardiac morbidity and healthcare utilisation, and to be at increased risk of accidents and overall mortality. It is however difficult to differentiate the effects of insomnia from the effects of its cause, for example co-morbidities.
2.6 The electrophysiological parameters of sleep can be objectively assessed using polysomnography (PSG), which monitors sleep architecture by using electrodes applied to the scalp. However, insomnia is however very subjective and there is great variation in sleep parameters both between individuals and in individuals on different nights. Therefore, although objective data on sleep parameters (for example time taken to get to sleep, duration of sleep and number of awakenings) can be collected, such data are difficult to interpret and do not fully capture the impact of the condition. More subjective evaluations can be made using generic and disease-specific quality of life instruments and self-report measures such as sleep diaries and sleep quality indices.
2.7 The choice of management strategy for insomnia is dependent on the duration and nature of the presenting symptoms. Appropriate management of existing co-morbidities may relieve the symptoms. A vital component of the overall management strategy is the provision of advice on relaxation techniques and appropriate sleep hygiene, for example avoiding stimulants and maintaining regular sleeping hours with a suitable environment for sleep. Other non-pharmacological interventions such as cognitive behavioural therapies and self-hypnosis have also been shown to be effective. However, although GPs can deliver sleep hygiene education and advice about relaxation techniques, access to many non-pharmacological therapies is restricted through a combination of a lack of trained providers, cost and a poor understanding of available options.
2.8 A drug used to induce sleep is termed a 'hypnotic'. Although hypnotics can provide relief from the symptoms of insomnia, they do not treat any underlying cause. Many individuals with insomnia (up to a reported 40%) self-medicate with hypnotics available, without prescription, from pharmacies (for example sedative antihistamines). It is difficult to ascertain how many prescriptions for hypnotics are written annually because benzodiazepines, which are commonly prescribed for insomnia, are also prescribed for other conditions.
2.9 There are a number of hypnotic agents available for the treatment of insomnia, including the benzodiazepines and zaleplon, zolpidem and zopiclone (Z-drugs). The British National Formulary (BNF) 44th edition lists six benzodiazepines (nitrazepam, flunitrazepam, flurazepam, loprazolam, lormetazepam and temazepam) in Section 4.4.1 on hypnotics. They are all available in generic form except for flunitrazepam and flurazepam, which are 'blacklisted' and cannot be prescribed within the NHS. A further two benzodiazepines, diazepam and lorazepam, are licensed for both insomnia and anxiety and are listed in the anxiolytic section of the BNF (Section 4.1.2). The BNF notes that nitrazepam has a prolonged duration of action and may give rise to residual effects on the following day and that repeated doses tend to be cumulative.
2.10 Benzodiazepines are a group of structurally related compounds that enhance the effects of gamma (y)-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system. The effects of specific benzodiazepines are dependent on the dose administered and the pharmacokinetic profile. In general, benzodiazepines induce sleep when given in high doses at night and provide sedation and reduce anxiety when given in low divided doses during the day. Benzodiazepines with a longer elimination half-life tend to have prolonged effects and if used as hypnotics, have a greater tendency to have next-day residual effects. This may affect mental function and cause psychomotor impairment, which may interfere with activities such as driving and working with machinery.
2.11 One of the key concerns about the use of benzodiazepines is that many people develop tolerance to their effects, become dependent on them (both physically and psychologically), and suffer a withdrawal syndrome when they stop taking them. The withdrawal syndrome may be prolonged and may develop at any time up to 3 weeks after cessation of a long-acting benzodiazepine, or a few hours after cessation of a short-acting one. The syndrome includes anxiety, depression, nausea and perceptual changes. 'Rebound insomnia' also occurs, characterised by a worsening of the original insomnia symptoms. There are also problems with individuals abusing benzodiazepines as they enhance and often prolong the 'high' obtained from other drugs and alleviate their withdrawal effects.
2.12 Estimates suggest that 10-30% of chronic benzodiazepines users are physically dependent on them and 50% of all users suffer withdrawal symptoms. Factors potentially associated with an increased risk of developing dependency include short duration of action, long-term use, high dose, high potency, alcoholism and other drug dependency, personality disorders and use without medical supervision. The concerns over dependence led the Committee on Safety of Medicines to recommend that the use of benzodiazepines should be restricted to severe insomnia and that treatment should be at the lowest dose possible and not be continued beyond 4 weeks.
3 The technologies
3.1 Zaleplon, zolpidem and zopiclone (the Z-drugs) are non-benzodiazepine hypnotics. They were developed with the aim of overcoming some of the adverse events associated with benzodiazepines - primarily dependence and withdrawal. Although the Z-drugs differ structurally from the benzodiazepines, they are also agonists of the GABA receptor complex and therefore enhance GABA-mediated neuronal inhibition.
3.2 Zaleplon is a pyrazolopyrimidine with an elimination half-life of 1 hour. It is licensed for the treatment of patients with insomnia who have difficulty falling asleep. It is indicated only when the disorder is severe, disabling or subjecting the individual to extreme distress. The Summary of Product Characteristics (SPC) specifies that treatment should be as short as possible with a maximum duration of 2 weeks.
3.3 Zolpidem is an imidazopyridine and has an elimination half-life of 2.5 hours. It is licensed for the short-term treatment of insomnia in situations where the insomnia is debilitating or is causing severe distress for the patient. The SPC states that the duration of treatment should usually vary from a few days to 2 weeks with a maximum of 4 weeks, including tapering off where appropriate.
3.4 Zopiclone is a cyclopyrrolone and has an elimination half-life of 3.5-6.5 hours. It is licensed for the short-term treatment of insomnia (including difficulties in falling asleep, nocturnal awakening and early awakening, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances) in situations where the insomnia is debilitating or is causing severe distress for the patient. The SPC states that long-term continuous use is not recommended, that a course of treatment should employ the lowest effective dose, and a single period of treatment should not exceed 4 weeks including any tapering off. The SPC also states that the duration of treatment should be 2-5 days for transient insomnia and 2-3 weeks for short-term insomnia.
3.5 In common with the benzodiazepines, the sedative effects of the Z-drugs may persist the next day. The SPCs for all three Z-drugs carry warnings about their potential to cause tolerance, dependency and withdrawal symptoms. For full details of side effects and contraindications, see the SPC.
3.6 The current acquisition costs for an adult dose are zaleplon (10 mg) £0.29, zolpidem (10mg) £0.16 and zopiclone (7.5 mg) £0.16 (excluding VAT; British National Formulary45th edition).
4 Evidence and interpretation
  The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B). The remit given to NICE by the Department of Health/ Welsh Assembly Group was to advise on the clinical and cost effectiveness of zaleplon, zolpidem and zopiclone relative to benzodiazepines. The evidence appraised was therefore restricted to comparisons of the Z-drugs with benzodiazepines that are approved for the treatment of insomnia and may be prescribed within the NHS (diazepam, nitrazepam, loprazolam, lorazepam, lormetazepam and temazepam).
4.1 Clinical effectiveness
4.1.1 The Assessment Report reviewed data from 24 randomised controlled trials (RCTs) that compared the Z-drugs with either a benzodiazepine or with another Z-drug. In total, 11 different comparisons were made between benzodiazepines and zolpidem (4 RCTs) or zopiclone (13 RCTs). No RCTs were identified that compared zaleplon with a benzodiazepine. Six RCTs were reviewed that compared zaleplon with zolpidem and one that compared zolpidem with zopiclone.
4.1.2 The duration of the studies ranged from 1 night to 6 weeks. Ten studies included a follow-up period, which ranged from 3 to 11 days. The number of patients included in the trials ranged from 10 to 615. The most common comparator used in the RCTs was nitrazepam, which has a prolonged duration of action and may give rise to residual effects on the following day. None of the trials compared the Z-drugs against the standard dose of temazepam which, in clinical practice, is regarded as the most appropriate comparator. One of the ten studies used objective PSG recordings; the remaining nine relied on reports from patients.
4.1.3 Five RCTs restricted their inclusion criteria to individuals of 60 years of age or older. Although it is recommended that the doses of both the Z-drugs and the benzodiazepine hypnotics should be reduced in older people, only three of the five RCTs used recommended doses for this age group. The inclusion criteria of an additional 12 RCTs, which compared standard dose hypnotics (benzodiazepines and Z-drugs), permitted the inclusion of adults over the age of 60.
4.1.4 The Assessment Group reported that it was difficult to compare the results of individual studies because of methodological problems and variations in the definitions used. In addition direct statistical comparisons between the hypnotics included in individual RCTs were not always made, and often insufficient data were reported to permit further analysis. There was also evidence of multiple testing of outcomes, with selective reporting of significant findings.
4.1.5 Although in the individual RCTs there were some statistically significant differences between the Z-drugs and the benzodiazepines for some of the efficacy outcome measures, the differences were not consistent across the trials. In addition, in most cases the absolute difference was small and the clinical significance of the differences was difficult to ascertain. The Assessment Group concluded that there was no consistent pattern of superiority of one drug over another.
4.1.6 Six RCTs compared zaleplon with zolpidem. One RCT found that 10 mg zaleplon per night resulted in statistically significant shorter sleep onset latency than 5 mg zolpidem (median time 31 minutes versus 42 minutes). Pooled data from three RCTs indicated the sleep was of less quality (odds ratio [OR] 0.66; 95% confidence interval [CI]: 0.51 to 0.87) and the median sleep time was statistically significantly less with 5 mg zaleplon per night compared with 5 mg zopiclone (291 minutes versus 309 minutes). Compared with 7.5 mg zopiclone, 10 mg zolpidem per night was associated with shorter sleep onset latency (OR 1.72; 95% CI: 1.04 to 2.84) in the 2?week trial identified. There were no statistically significant differences in the global impression of treatment.
4.1.7 There were no significant differences in the rates of treatment emergent adverse events associated with any of the comparisons of Z-drugs versus benzodiazepines. There was little consistency in the reporting of adverse events, which prevented comparison of individual event rates or meta-analysis.
4.1.8 In the comparisons between the Z-drugs and benzodiazepines, no data were identified on the rates of symptoms associated with withdrawal or dependency.
4.1.9 The Assessment Group also searched for studies of other designs that specifically evaluated rates of dependency and withdrawal symptoms following treatment with the Z-drugs. Six studies were identified, four of which evaluated patients after extended treatment periods. Two placebo-controlled studies examined relative rates of withdrawal symptoms after individuals receiving zolpidem were switched to placebo after 3 or 4 weeks' treatment. One study found no patient in either group reported more than one symptom after 4 weeks treatment with 10 mg zolpidem or placebo; the second found that three older patients who had received zolpidem, at doses of 10-20 mg experienced adverse events. In addition, information on cases of dependency reported to the Committee on Safety of Medicines was sought and 16 case reports were identified in the literature relating to zolpidem (11) and zopiclone (5). There are problems with the interpretation of such reports, as rates of reporting are dependent on the publicity and awareness of certain adverse reactions and the pattern of use of the drugs.
4.1.10 In addition to the RCTs conducted in individuals with insomnia, the manufacturers submitted evidence from 15 RCTs and cross-over studies that were conducted in healthy volunteers in whom insomnia had been induced. Most studies had very small sample sizes (less than 30 individuals) or were of very short duration (for example 1-3 nights). The largest study was conducted in 630 individuals and compared 10 mg zolpidem with 15 mg temazepam, 0.25 mg triazolam or placebo. Data were collected from multiple outcome measures few of which indicated any significant differences; although subjects receiving zolpidem reported greater ease in falling asleep, more sleep time and less wake time than those receiving temazepam, they also reported a significant reduction in next day performance.
4.1.11 A manufacturer submitted evidence from two RCTs that compared continuous zolpidem use (10 mg per night) with intermittent use. Data for each night were not reported but the submission reported that there were no significant differences in the sleep efficacy outcomes, other than the investigators assessment of sleep onset latency, which was significantly greater in the continuous zolpidem group. No similar studies were located for benzodiazepines.
4.1.12 In summary the Assessment Group did not find any RCTs that appropriately compared the Z-drugs with benzodiazepines, used at appropriate doses. In the RCTs that were reviewed, there were no consistent differences between the drugs, which were attributed in part to the poor quality of reporting.
4.2 Cost effectiveness
4.2.1 None of the submissions contained an economic evaluation that compared the costs and effects of the short-term use of Z-drugs with benzodiazepines. In addition, the Assessment Group was unable to identify any in the health economics literature. No comparative data on the health-related quality of life associated with Z-drugs and benzodiazepines using generic health status measures were identified, and there was no evidence to link the clinical end-points from the trials with quality of life.
4.2.2 The manufacturer of zaleplon submitted two models based upon the key assumption that zaleplon does not cause 'mental impairment' the day after administration. The first model consisted of a cost-consequence algorithm comparing the costs and additional road traffic accidents (RTAs) associated with the residual effects of zopiclone and zaleplon. This model was based on a study mapping residual effects of zopiclone and zaleplon to RTAs using data from three other studies. The first stage of the mapping procedure was to estimate the impact of the residual effects of the Z-drugs on driving performance. This was taken from a double-blind study of 28 healthy volunteers given zaleplon, zopiclone or placebo in the evening. The volunteers were woken in the middle of the night and given either placebo (those who had earlier taken active medication) or zaleplon, zopiclone or placebo (those who had earlier taken placebo). Participants undertook a series of tests the following morning including a driving performance test, which estimated the deviation of the car from the lateral position. An equipment failure during the study resulted in 17 tests being rendered invalid - these were repeated later in the morning following completion of the rest of the tests. The results found that driving performance was significantly worse in the zopiclone group, and performance after zaleplon was similar to that for placebo. These results were linked to data from a similar study designed to measure the driving performance associated with differing levels of blood alcohol content. Driving performance was estimated after blinded healthy volunteers had ingested varying amounts of alcohol on two separate days. Driving performance whilst sober was measured on a separate day. From these data, a relationship between deviation of the car from the lateral position and blood alcohol content was estimated. The relationship between blood alcohol content and the residual effects of the Z-drugs was then estimated. The relationship between relative risk of RTAs and blood alcohol content was estimated using a 1964 US case-control study. The results of the model suggest that the expected excess accident costs per person over a 2?week period were $71 for 10 mg zaleplon and $92 for 10 mg zopiclone. In support of the economic model, the manufacturer also cited other published evidence, including a UK based study which examined a sample of drivers involved in RTAs and compared the odds of having an accident whilst exposed or not exposed to specified drugs. The study found that zopiclone and anxiolytic benzodiazepines, but not hypnotic benzodiazepines, were associated with increased risk of RTAs. The manufacturer also cited a Canadian study estimating the relationship between hypnotic drugs and RTAs in older people. The study found that benzodiazepines with a long half-life were associated with an increased risk of RTAs, but that those with a short-half life were not. Concern was expressed regarding this study at the time of publication, particularly with regard to the failure to adequately control for confounding effects and the lack of distinction between benzodiazepines used as hypnotics and those used as anxiolytics. Another study was also cited in support of this evidence, but was only available as an abstract. The manufacturer also submitted a model designed to estimate the costs associated with hip fractures caused by falls as a result of the residual effects of zolpidem, nitrazepam, temazepam and zaleplon. The model assumed treatment on a basis of 2 weeks on therapy followed by 2 weeks off therapy over a one-year period and did not take into account benefits relating to treatment. This model was based on a published retrospective study, which examined the use of sedative-hypnotics using Medicare data in a sample of older patients. Each case, defined as a patient who underwent surgical care for hip fracture, was matched by four age-gender matched controls from the Medicare database. Confounding factors are likely to bias results in studies of this type, particularly as insomnia may be a result of co-morbid conditions, which in turn could increase the risk of falls. Attempts to reduce confounding were made by adjusting crude odds ratios by a number of factors, including a measure of co-morbid illness severity. The study found that zolpidem use and benzodiazepine use were associated with a significant increase in the risk of hip fracture. The model used the adjusted odds ratios from this study to represent the increased risk of hip fracture. The manufacturer assumed no additional risk of hip fracture was associated with zaleplon (i.e. adjusted OR 1.0), although this drug had not been evaluated in the published study. The results of the model suggest that per year zolpidem, nitrazepam and temazepam therapy were more expensive than zaleplon when treating a cohort of 10,000 patients by £821,000, £129,000 and £111,000, respectively.
4.2.3 The Assessment Group reanalysed the hip fractures model after correcting some errors and adding illustrative quality-adjusted life year (QALY) values, but retaining the key assumption that zaleplon was not associated with increased risk of hip fractures. The Assessment Group concluded from the results of the amended model that at current acquisition costs, after taking into account the uncertainty surrounding all of the model inputs, the drugs included in the analysis appeared similarly cost effective compared with no treatment.
4.2.4 A manufacturer of zolpidem submitted a discussion of a model to estimate the costs of long-term zolpidem treatment compared with temazepam treatment. The model used estimates of dependency based on national prescribing data and concluded that despite having higher costs per dependent and non-dependent patient, zolpidem was shown to cost less on average because of its lower likelihood of high-cost dependency. However the manufacturer stated that, "in the absence of robust data on the incidence of dependency, the author had to rely on a weak surrogate indicator of dependence in the form of continuous use".
4.2.5 In summary, the manufacturers suggest that the additional acquisition costs of Z-drugs would be offset by reduced consumption of other healthcare resources or lead to an improvement in health outcomes as a result of decreased dependency or reduced residual effects.
4.3 Consideration of the evidence
4.3.1 The Committee reviewed the evidence available on the clinical and cost effectiveness of zaleplon, zolpidem and zopiclone, having considered evidence on the nature of the condition and the value placed by users on the benefits of zaleplon, zolpidem and zopiclone from people with insomnia, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.
4.3.2 The Committee heard testimony that insomnia is generally not managed appropriately and that there is a lack of availability of training for healthcare providers in this field. It was advised that, despite national recommendations and restrictions specified in the SPCs, hypnotic agents are commonly used for minor degrees of insomnia and also prescribed for long periods, which has been associated with increased likelihood of dependency.
4.3.3 The Committee heard evidence that some non-pharmacological strategies, including simple techniques such as improved sleep hygiene and relaxation techniques, had been shown to be effective in the management of insomnia. The Committee considered that although it was likely that such strategies could replace some of the current prescribing of hypnotics, the evidence base for them had not been appraised and further research was required to determine their clinical and cost effectiveness.
4.3.4 The Committee appreciated that there were differences in the pharmacokinetics of the individual hypnotics (both Z-drugs and benzodiazepines) which may confer different clinical characteristics. For example a hypnotic that is rapidly absorbed and rapidly cleared will inevitably result in shorter sleep onset latency, but it may not extend the total sleep duration as its effects will rapidly wear off. The Committee was not however persuaded that this resulted in any overall benefit for the patient in terms of perceived quality of sleep, daytime functioning or quality of life. The Committee was also informed that there was no difference between the Z-drugs and the benzodiazepines in their potential to be abused.
4.3.5 The Committee considered that the RCTs available did not reflect current practice: none of the Z-drugs had been compared with appropriate hypnotic doses of temazepam and the most common comparator used in the RCTs was nitrazepam, which has a prolonged duration of action and may give rise to residual effects on the following day. The Committee also appreciated that the effects of both the Z-drugs and the benzodiazepines were dose-related and that inappropriate comparisons, particularly in older patients, would confound the results of the RCTs.
4.3.6 The Committee was made aware by the patient organisation that warnings regarding potential dependency associated with extended use of hypnotics are often not passed onto patients. The Committee was particularly concerned that patients may be preferentially prescribed Z-drugs or transferred from benzodiazepines to the Z-drugs because of the unsubstantiated belief that they are less likely to induce dependency than the benzodiazepines.
4.3.7 The Committee considered the economic models submitted by one of the manufacturers. The Committee fully discussed the basis of the manufacturer's models and recognised that they were based on the premise that the use of individual Z-drugs in preference to other Z-drugs or benzodiazepines would prevent road traffic accidents or hip fractures caused by falls. The Committee did not accept these models as it considered that the evidence used in them was not robust and the additional assumptions underpinning the models were not appropriate. Additionally the Committee considered that there was no reliable evidence to support the claim that the higher acquisition costs of the Z-drugs would be offset by the reductions in the use of other health service resources.
4.3.8 In summary, given the lack of compelling evidence on any clinically useful differences between the Z-drugs and the benzodiazepines, the Committee concluded that, unless an individual was intolerant to a specific hypnotic, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be used in preference to more expensive alternatives.
5 Proposed recommendations for further research
5.1 Although RCTs to assess the relative clinical effectiveness, and cost effectiveness of the Z-drugs and the short-acting benzodiazepines could potentially clarify some of the uncertainty, it is unlikely that they would be a cost effective use of NHS resources. Efforts should therefore be concentrated on determining the effectiveness and cost effectiveness of pharmacological treatments relative to non-pharmacological interventions, including their relative roles in the long-term management of insomnia.
5.2 Previous trials have concentrated on the use of sleep-specific measures of outcomes, which have not been directly related to improvements in daytime functioning and quality of life. Further research should therefore include the impact of hypnotics and any resultant improvement in sleep quality, on daytime functioning and health-related quality of life.
5.3 There is limited evidence on the risk of dependency associated with the Z-drugs and benzodiazepines. In particular, the risk of dependency should be examined with respect to intermittent use of hypnotics, and the relationship between risk of dependency and length of treatment.
5.4 National information leaflets should be developed through consultation with appropriate professional and user organisations. The leaflets should be produced in formats and languages that make them accessible to a wide range of service users. In addition to information on hypnotics and the risks associated with their use, the leaflets should include general information on insomnia and non-pharmacological management strategies, including relaxation techniques and good sleep hygiene practice.
6 Preliminary views on the resource impact for the NHS
6.1 This section outlines the Appraisal Committee's preliminary assessment concerning the likely impact on NHS resources if the recommendations in Section 1 were to be implemented. When guidance is issued, this section is intended to assist NHS planners and managers in its implementation. Therefore the Institute particularly welcomes comments and information from those who would be involved in the implementation of the guidance so that this section can be made as helpful and robust as possible.
6.2 It is likely that this guidance will result in the preferential prescription of hypnotics with lower acquisition costs and possibly lead to a reduction in the overall prescribing of hypnotics. It is therefore expected that there will be savings in terms of costs directly associated the prescription of hypnotics. In 2002, a total of 3.9 million prescriptions were written for Z-drugs with a net ingredient cost of £15.9 million. If all of the individuals currently being prescribed a Z-drug were transferred to temazepam, the potential cost savings are approximately £10.5 million. The overall effect on NHS resources will however depend on any reduction in overall hypnotic prescribing, the proportion of patients prescribed more expensive hypnotics as a result of intolerance to the cheaper alternatives and the uptake of any non-pharmacological alternatives that are potentially more resource intensive. It is also likely that there may be an increased demand for appropriate training for healthcare practitioners.
7 Proposals for implementation and audit
  This section presents proposals for implementation and audit based on the preliminary recommendations for guidance in Section 1.
7.1.1 NHS organisations and clinicians who prescribe treatment for people with insomnia should review their current practice and policies and the current patterns of prescribing hypnotic drugs, as reported in high-level performance indicators, to take account of the guidance set out in Section 1.
7.2 Local guidelines, protocols or care pathways that refer to the care of people with insomnia should incorporate the guidance in Section 1.
7.3 To measure compliance locally with the guidance, the following criteria could be used. Further details on suggestions for audit are presented in Appendix C.
7.3.1 Hypnotic drug therapy is used for the management of severe insomnia interfering with normal daily life only after consideration and appropriate use of non-pharmacological measures.
7.3.2 When hypnotic drug therapy is used, the drugs are prescribed for short periods of time only, in strict accordance with the licensed indications.
7.3.3 When hypnotic drug therapy with short-acting benzodiazepine hypnotics, zaleplon, zolpidem or zopiclone is prescribed, the drug with the lowest purchase cost is chosen.
7.3.4 An individual is switched from one of these hypnotic drugs to another only if he or she proves to be intolerant to the hypnotic first prescribed.
7.3.5 An individual who has not responded to one of these hypnotic drugs is not prescribed any of the others.
8 Related guidance
8.1 There is no specific related NICE guidance for the management of insomnia.
9 Proposed date for review of guidance
9.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.
9.2 It is proposed that the guidance on this technology is reviewed in October 2006
Andrew Stevens
Chair, Appraisal Committee
October 2003
Appendix A. Appraisal Committee members
NOTE The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into two branches, with the chair, vice-chair and a number of other members attending meetings of both branches. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.
Dr A E Ades
Senior Scientist, MRC Health Services Research Collaboration, University of Bristol
Professor Ron Akehurst
Dean, School of Health Related Research, University of Sheffield
Dr Tom Aslan
General Practitioner, Stockwell, London
Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester
Dr Karl Claxton
Health Economist, University of York
Dr Richard Cookson
Senior Lecturer, Health Economics, School of Health Policy and Practice, University of East Anglia, Norwich
Professor Gary A Ford
Professor of Pharmacology of Old Age/Consultant Physician, Newcastle upon Tyne Hospitals NHS Trust
Ms Bethan George
Interface Liaison Pharmacist, Tower Hamlets PCT and Royal London Hospital, Whitechapel
Dr Trevor Gibbs
Head, Global Clinical Safety & Pharmacovigilance, GlaxoSmithKline, Greenford
Mr John Goulston
Director of Finance, Barts and the London NHS Trust
Professor Robert Kerwin
Professor of Psychiatry and Clinical Pharmacology, Institute of Psychiatry, London
Professor Philip Home
Professor of Diabetes Medicine, University of Newcastle upon Tyne
Mr Muntzer Mughal
Consultant Surgeon, Lancashire Teaching Hospitals NHS Trust, Chorley
Mrs Kathryn Roberts
Nurse Practitioner, Hyde, Cheshire
Professor Philip Routledge
Professor of Clinical Pharmacology, College of Medicine, University of Wales, Cardiff
Ms Anne Smith
Lay Representative; Trustee, Long-Term Medical Conditions Alliance
Professor Andrew Stevens (Vice-Chair)
Professor of Public Health, University of Birmingham
Dr Cathryn Thomas
General Practitioner, & Senior Lecturer, Department of Primary Care & General Practice, University of Birmingham
Dr Norman Vetter
Reader, Department of Epidemiology, Statistics and Public Health, College of Medicine, University of Wales, Cardiff
Dr David Winfield
Consultant Haematologist, Royal Hallamshire Hospital, Sheffield
NICE Project Team
Each appraisal of a technology is assigned to a Health Technology Analyst and a Technology Appraisal Project Manager within the Institute.
Sarah Garner
Technical Lead, NICE project team
Louise Longworth
Technical Lead, NICE project team
Joanna Richardson
Technical Lead, NICE project team
Kathleen Dalby
Project Manager, NICE project team
Appendix B. Sources of evidence considered by the Committee
The following documentation and opinion was made available to the Committee:

The assessment report for this appraisal was prepared by the Liverpool Reviews and Implementation Group.

Newer hypnotic drugs for the management of insomnia, August 2003


The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope and assessment report. They are also invited to comment on the ACD and consultee organisations are provided with the opportunity to appeal against the FAD.

I Manufacturer/sponsors:

  • Aventis
  • Generics (UK)
  • Lagap Pharmaceuticals
  • Pliva Pharma
  • Sanofi Synthelabo
  • Wyeth

II Professional/specialist and patient/carer groups:

  • Age Concern Cymru
  • Age Concern England,
  • British Association for Service to the Elderly
  • British Geriatrics Society
  • British Sleep Society
  • Council for Involuntary Tranquilliser Addiction
  • Royal College of General Practitioners
  • Royal College of Psychiatrists
  • Royal Pharmaceutical Society of Great Britain
  • Royal Society of Medicine, Sleep Medicine Section
  • Sleep Matters, Medical Advisory Service

    III Other groups:

  • Department of Health
  • Kingston Primary Care Trust
  • Welsh Assembly Government

    IV Commentator organisations (without the right of appeal):

  • British National Formulary (BNF)
  • Loughborough Sleep Research Centre
  • NHS Confederation
  • NHS Quality Improvement Scotland
  • Sleep Assessment and Advisory Service
  • Sleep Research Centre, University of Glasgow

The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on zaleplon, zolpidem and zopiclone for the management of insomnia by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

  • Ms Pam Armstrong, Clinical Nurse Specialist & Advisor, Council for Involuntary Tranquilliser Addiction
  • Professor Heather Ashton, Emeritus Professor of Clinical Psychopharmacology, Division of Psychiatry, University of Newcastle upon Tyne
  • Mrs Helen Kay, on behalf of Council for Involuntary Tranquilliser Addiction
  • Dr Adrian Williams, Consultant Physician and Director, Sleep Disorders Centre, St Thomas' Hospital, London


Appendix C. Detail on criteria for audit of the use of zaleplon, zolpidem and zopiclone for the management of insomnia
Possible objective for an audit
An audit could be carried out on the appropriateness of use of zaleplon, zolpidem and zopiclone.
Possible patients to be included in the audit

An audit could be carried out on all patients treated for insomnia for a suitable time period for audit, for example, 3 to 6 months.

Alternatively, an audit could be carried out on all people for whom hypnotic drug therapy is prescribed over a suitable time period for audit, for example, 3 to 6 months.

Measures that could be used as a basis for an audit
The measures that could be used in an audit of zaleplon, zolpidem and zopiclone for the management of insomnia are as follows.
Definition of Terms
1. Non-pharmacological measures are considered and used before the prescription of drug therapy for insomnia 100% of people being treated for insomnia None Clinicians will need to agree on how non-pharmacological measures are defined for audit purposes. They can include appropriate management of existing co-morbidities; provision of advice on relaxation techniques and appropriate sleep hygiene, for example, avoiding stimulants and maintaining regular sleeping hours with a suitable environment for sleep; cognitive behavioural therapies; or self-hypnosis. Drug therapy for insomnia can include zaleplon, zolpidem, zopiclone orthe short-acting benzodiazepine hypnotics (nitrazepam, loprazolam, lormetazepam, temazepam, diazepam and lorazepam).
2. When hypnotic drug therapy is used, the drug used is prescribed for a short period of time only, in strict accordance with the licensed indications 100% of people for whom hypnotic drug therapy is prescribed None See above for a list of hypnotic drugs. For audit purposes, clinicians will need to agree locally on how to define the duration of a prescription. The maximum duration of a prescription for zaleplon is 2 weeks and for zolpidem and zopiclone is 4 weeks. Also for audit purposes, clinicians will need to agree locally on how to define and measure the consistency of prescriptions with licensed indications for each drug.
3. When hypnotic drug therapy is prescribed, the drug with the lowest purchase cost is chosen 100% of people for whom hypnotic drug therapy is prescribed A. The individual is intolerant to the drug that was the first-line choice The lowest purchase cost takes into account the daily required dose and the product price per dose.Clinicians will need to agree locally on the source of cost information, for audit purposes.
4. An individual is switched from one hypnotic drug to another 0% of people for whom hypnotic drug therapy is prescribed The individual proves to be intolerant to the hypnotic drug first prescribed Clinicians will need to agree locally on how intolerance to a specific drug is documented for audit purposes.

An audit on all people for whom hypnotic drug therapy is prescribed could be carried out using the measures above.

Calculation of compliance with the measure
Compliance (%) with each measure described in the table above is calculated as follows.

Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed

    X 100

Number of patients to whom the measure applies

Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.

This page was last updated: 30 March 2010