Zolpidem for insomnia

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

The objectives of the review are:

  1. to determine the effectiveness of zolpidem for insomnia treatment in comparison with placebo and active comparators;

  2. to determine the safety profile of zolpidem in comparison with placebo and active comparators; and

  3. to compare zolpidem with other new-generation hypnotics in terms of effectiveness and safety.


Description of the condition

Affecting between 5% to 20% of the adult population in Western countries, insomnia is a major public health issue (Ohayon 2002) because of its high prevalence and its impact on physical and psychosocial well-being. About one-third of adults report sleeping problems and between 6% and 10% meet the criteria for a diagnosis of insomnia (Ohayon 2002; Roth 2003; Morin 2006; Ohayon 2009).

The predominant symptom of insomnia is difficulty initiating sleep (sleep-onset insomnia), maintaining sleep (sleep-maintenance insomnia) or a poor and non-restorative quality of sleep (Ohayon 2001). For a diagnosis of insomnia, commonly used diagnostic systems like the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (American Psychiatric Association 2000), the International Classification of Diseases (ICD-10) (World Health Organization 1992) and the International Classification of Sleep Disorders (ICSD) (American Academy of Sleep Medicine 2005) require that these sleeping problems i) persist over a period of at least one month, ii) cause next-day impairments including social, occupational or other important areas of functioning, and iii) do not result from mental disorders (e.g. major depression, generalised anxiety disorder), substance abuse (e.g. alcohol, medications, illegal drugs) or other sleep disorders (e.g. narcolepsy, breathing-related sleep disorder). The ICD-10 diagnosis of insomnia in addition demands a frequency of sleeping problems of at least three times a week and the occurrence of preoccupation with sleepiness and excessive concern.

Most models of insomnia refer to a common framework proposed by Spielman 1991, distinguishing between predisposing, precipitating and perpetuating factors. While predisposing factors such as maladaptive coping stress strategies, cognitive-emotional hyperarousal and older age make individuals more vulnerable to sleeping problems (Fernández-Mendoza 2010), increased life-stress, irregular sleep habits and poor sleep hygiene further precipitate their occurrence (Bastien 2004). If sleep is repeatedly disturbed, a further perpetuation of the problem results from the selective attention directed towards the inability to fall asleep, creating a vicious cycle that often leads to chronicity. The neurocognitive model of insomnia (Perlis 2007) emphasises the role of hyperarousal, including an increased level of somatic, cognitive and cortical activity, which is enforced through classical conditioning and which promotes abnormal levels of sensory and information processing, thought to render the insomniac individual especially vulnerable to perturbation by environmental or other stimuli (Riemann 2009). The inhibition model developed by Espie 2002 conceptualises insomnia as the failure to inhibit wakefulness rather than the inability to induce sleep and underscores the originally functional role of wakefulness in the presence of stressors. If the 'threat' is not eliminated, attention is increasingly focused on sleep and motivational processes such as the conscious intent to fall asleep are activated, both interfering with the otherwise automatic response of inhibiting wakefulness.

Insomnia is not a trivial complaint. Besides causing psychological distress during the night, insomnia leads to next-day cognitive and psychomotor impairments, irritability and decreased job performance (Metlaine 2005). In the longer term, reduced sleep increases the risk of substance abuse (Johnson 2001; Falcón 2009) and psychiatric comorbidity (Riemann 2007), and reduces life quality (Zammit 1999; Rosekind 2010) and longevity (Roth 2009). Untreated insomnia does usually not remit with time (Angst 1989; Leshner 2005), underscoring the need for effective and safe treatment interventions.

Description of the intervention

Even though recommended as first-line treatments for chronic insomnia (Hajak 1997; Ramakrishnan 2007), non-pharmacological treatment strategies such as sleep restriction, stimulus control, relaxation techniques and cognitive behavioral therapy (CBT) are rarely used in clinical practice. Benzodiazepines are effective for short-term treatment of insomnia (Buscemi 2007), but carry the risk of rebound insomnia, physical and psychological dependence, serious withdrawal symptoms (Royal College of Psychiatrists 1997; Lader 1999; Ballenger 2000) and next-day hangover effects, responsible for traffic and machine operation accidents (Barbone 1998), self injuries and hip fractures, commonly seen in elderly patients (Bolton 2008; Woolcott 2009).

In the 1980s and early 1990s, a new group of hypnotic agents, known as new-generation hypnotics, non-benzodiazepine hypnotics, benzodiazepine receptor agonists or 'z-drugs' were introduced to the markets. Meanwhile, zolpidem, zopiclone, zaleplon and eszopiclone, four different non-benzodiazepine hypnotic compounds have been developed and introduced as insomnia therapies (Nutt 2010). In 1992, the Food and Drug Administration (FDA) approved zolpidem, a non-benzodiazepine hypnotic of the imidazopyridine class for the short-term treatment of insomnia. Today, zolpidem is the most widely prescribed hypnotic drug in the USA and is one of the most frequently used drugs used for insomnia treatment worldwide (Verster 2007; Greenblatt 2012). Approved doses of zolpidem in its standard immediate-release form are 10 mg for adults and 5 mg for elderly patients (Greenblatt 2012). Zolpidem is rapidly absorbed (maximum plasma concentration (Tmax) ˜ 2 hours) and rapidly eliminated (elimination half-life time (t½) ˜ 2 to 3.5 hours), while there is high interindividual variability in plasma levels (de Haas 2010; Nutt 2010; Greenblatt 2012). Furthermore, zolpidem does not have active metabolites and does not accumulate during repeated administration (Fraisse 1996).

Since 2005, besides the immediate-release tablet preparation, zolpidem has also been provided as an extended-release formulation in the USA, prepared as two-layer tablets with a biphasic release profile, releasing the first layer immediately and the second layer at a slower rate. This maintains plasma concentrations for a longer period of time than immediate-release zolpidem formulations (Barkin 2007). In 2008, the FDA approved an aerosolised form of zolpidem, which delivers an approved dose into the oral cavity. In 2009, a sublingual formulation of zolpidem was approved for the US market, assumed to be more rapidly absorbed after dosing without altering the absolute bio-availability of the drug (Roth 2008).

How the intervention might work

Similar to benzodiazepines, new-generation hypnotics develop their sedative properties through activity at the gamma-aminobutyric acid-A (GABA-A) receptor, whose endogenous ligand, GABA, is the major inhibitory neurotransmitter in the central nervous system, involved in anxiolysis, sedation, seizure suppression and muscle relaxation (Bateson 2004; Rudolph 2011). The GABA-A receptor is composed of five protein subunits and at least 19 distinct subunit isoforms, mediating different behavioural and pharmacological responses (Drover 2004; Dündar 2004b; Sieghart 2006; Dolder 2007). Alpha 1 subunits of the GABA-A receptor are thought to be mainly responsible for the mediation of sedative drug effects, alpha 2 and alpha 3 subunits for anxiolytic and antidepressant drug activities and alpha 5 receptor subunits for cognitive effects including memory and learning (Lingford-Hughes 2002; Nutt 2010). While benzodiazepines modulate different subunits of the GABA-A receptor, most new-generation hypnotics selectively bind to the alpha 1-containing receptor subtypes responsible for sedation. Accordingly, new-generation hypnotics are assumed to produce an advantageous clinical profile compared to benzodiazepines, particularly with respect to the residual effects as well as the development of tolerance and dependence (Follesa 2002; Drover 2004). Among new-generation hypnotics, zolpidem has the highest affinity to alpha 1-containing receptor subtypes and in contrast comparatively low affinity to other alpha 2, 3 and 5 subtypes (Nutt 2010), suggesting that zolpidem has specific sedative properties and a reduced propensity to produce cognitive and motor impairments (Nutt 2010; Greenblatt 2012). Nevertheless, even though evidence from ex-vivo and animal studies confirms its specific profile of effectiveness, evidence from clinical studies with zolpidem is not consistent (Greenblatt 2012).

Further differences in the clinical effects of new-generation hypnotics are assumed to be associated with their unique pharmacokinetic profiles, including the bioavailability of the drug, the volume of distribution and the elimination half-life time (Drover 2000). With a comparatively rapid onset of action and a relatively short brain receptor occupancy, standard immediate-release zolpidem appears to be particularly beneficial for patients with sleep-onset insomnia (Drover 2000; Nutt 2010). In contrast to immediate-release formulations of zolpidem, extended-release formulations were shown to maintain plasma concentration over a longer period of time and thus - unlike original zolpidem - are indicated for both sleep-onset and sleep-maintenance insomnia (Barkin 2007; Lieberman 2007).

Why it is important to do this review

Based on the assumption that new-generation hypnotics are just as effective as benzodiazepines while having a lower risk for abuse and dependence, new-generation hypnotics have continuously replaced benzodiazepines as the most commonly prescribed hypnotic drugs and have emerged as the first-line drug for insomnia treatment (Erman 2005; Siriwardena 2008; Hausken 2009; Hoffmann 2009; NHS Prescribing Service 2010). In fact, various reviews (Montplaisir 2003; Drover 2004; Dündar 2004a; Dündar 2004b; Zammit 2009), post-marketing surveillance studies (Delahaye 1990) and case study reports (Lader 1999; Soyka 2000; Hajak 2003) conclude that because of their pharmacokinetic and pharmacodynamic properties, new-generation hypnotics have some important advantages over benzodiazepine hypnotics, including a lower risk for next-day impairments and a lower potential for abuse and dependence. Nevertheless, the evidence is not entirely consistent. Two studies comparing subjective and performance-related effects of new-generation hypnotics (zolpidem, zaleplon) and a short-acting benzodiazepine (triazolam) indicated similar pharmacologic-behavioural profiles of the tested hypnotics (Rush 1999a; Rush 1999b). Studies with baboons showed even higher self injection rates for zolpidem than for benzodiazepines and the occurrence of withdrawal symptoms after zolpidem was substituted with saline, indicating reinforcing properties of the drug as well as its potential to cause physical dependence (Griffiths 1992; Weerts 1998). Following a recommendation of the World Health Organization (WHO) in 2002, zolpidem was added to Schedule IV of the UN Convention on Psychotropic Substances (United Nations 1971).

When therapeutic decisions about the pharmacological treatment of insomnia are made, safety issues including a drug's potential for tolerance, abuse and dependence, as well as the risk for next-day residual effects, have to be considered (Lieberman 2007). Thus, an integration of the available evidence on zolpidem appears to be indispensable to provide best evidence to practising physicians and health decision-makers. This review will form part of a suite of four reviews on new-generation hypnotics for insomnia; the other three will assess the effectiveness and safety of zopiclone (Rösner 2013a), zaleplon (Rösner 2013b) and eszopiclone (Rösner 2013c).


The objectives of the review are:

  1. to determine the effectiveness of zolpidem for insomnia treatment in comparison with placebo and active comparators;

  2. to determine the safety profile of zolpidem in comparison with placebo and active comparators; and

  3. to compare zolpidem with other new-generation hypnotics in terms of effectiveness and safety.


Criteria for considering studies for this review

Types of studies

Parallel randomised controlled trials (RCTs), which compare zolpidem with either placebo or active control in its effectiveness to improve sleep and/or in their potential to cause adverse events, withdrawal symptoms or rebound insomnia. Run-out phases will be included if controlled with placebo. Cross-over trials will not be included in the review due to the risk of medium- or long-term therapeutic benefits, which can hardly be controlled by wash-out intervals and thus might cause carry-over effects.

Types of participants

Individuals with primary insomnia as diagnosed with a standardised diagnostic system such as the DSM (American Psychiatric Association 2000), the ICD (World Health Organization 1992) or the ICSD (American Academy of Sleep Medicine 2005), irrespective of any other characteristics. Patients with transient insomnia (duration of sleeping problems of less than four weeks) and secondary insomnia (insomnia that was explicitly diagnosed in the primary study as a symptom of another medical problem or condition)* will be excluded.

* The distinction between primary and secondary insomnia is considered in the inclusion criteria as it has important implications for treatment: while treatment of primary insomnia focusses on the improvement of sleep, therapy of secondary insomnia should eliminate the causative medical problem (and if treated successfully, the insomnia will disappear as well).

Types of interventions

Experimental intervention: zolpidem as monotherapy.

Comparator interventions: placebo, other new-generation hypnotics, short-/intermediate-/long-acting benzodiazepines; other active controls. Any treatment setting (in- and outpatient) and any formulation will be included. Drugs that were withdrawn from the market or on which research or development has been discontinued, will not be considered in the review.

Types of outcome measures

We have selected the primary and secondary outcomes of the review with regard to the availability of outcome criteria, their clinical relevance and the avoidance of conceptual overlaps. The study endpoints of the primary outcomes are considered essential to determine the effectiveness and safety conclusions of the review, while secondary effectiveness outcomes have only complementary value in the interpretation of results. All types of measurement including objective measures (e.g. polysomnography) and patient-reported sleep measures will be considered. If both objective and subjective measures are provided in a study publication, subjective measures will be included in the meta-analysis and we will examine the impact of the type of measurement with sensitivity analyses (see Sensitivity analysis). For the assessment of adverse events (withdrawal symptoms and next-day alertness) any types of outcome measures will be included.

Primary outcomes
Effectiveness outcomes
  1. Sleep onset latency (SOL)

  2. Wake time after sleep onset (WASO)

Treatment effectiveness is assessed through two outcomes: 'sleep onset latency' (SOL), defined as the length of time (in minutes) after lights-out until sleep onset and 'wake time after sleep onset' (WASO), defined as the length of time (in minutes) of wakefulness after the onset of persistent sleep. The consideration of two effectiveness outcomes is reasoned by their conceptual distinctiveness, with SOL measuring a drug's impact on sleep onset, and WASO measuring the potential to improve sleep maintenance; the former reflecting its suitability for the treatment of sleep-onset insomnia and the latter for sleep-maintenance insomnia (see Description of the condition).

Discontinuation effects
  1. Withdrawal symptoms

  2. Rebound insomnia

Discontinuation effects are assessed through withdrawal symptoms, comprising adverse symptoms during the placebo run-out period that appear for the first time during this period or which already appeared during treatment, but deteriorated during the placebo run-out interval; and/or rebound insomnia, defined as the temporary worsening of sleep relative to baseline following the discontinuation of the hypnotic and is assessed through the examination of sleep data (SOL, WASO or total sleep time (TST)) relative to baseline during the placebo run-out period. The consideration of two variables to assess effects of drug discontinuation are based on the fact that most studies provide data on either one or the other outcome.

Secondary outcomes
  1. Total sleep time (TST)

  2. Next-day alertness

  3. Adverse events (AEs)

'Total sleep time' (TST) is the total time (in minutes) a person spent sleeping during the in-bed interval. TST is a common outcome measure in insomnia treatment, but to avoid conceptual overlaps with the primary efficacy outcomes, SOL and WASO (TST is time in bed minus SOL and minus WASO (Schutte-Rodin 2008)), it is only considered as a secondary outcome of the review. 'Next-day alertness' reflects the state of vigilance the day after hypnotics have been taken. 'Adverse events' (AEs) are all types of unfavourable symptoms that occur during the course of the study.

Search methods for identification of studies

Electronic searches

The Cochrane Depression, Anxiety and Neurosis Group's Trials Search Co-ordinator (TSC) will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 onwards), EMBASE (1980 onwards) and PsycINFO (1987 onwards) (Appendix 2). Search strategies will be developed comprehensively to simultaneously address different new-generation hypnotic compounds (zolpidem, zopiclone, zaleplon and eszopiclone) and we will then analyse the results of the search for different compounds separately (the results for zopiclone, zaleplon and eszopiclone will be presented in Rösner 2013a, Rösner 2013b and Rösner 2013c respectively). We will run a complementary search on PSYNDEX (in English and German).

The WHO trials portal and ClinicalTrials.gov will be searched to identify any ongoing or completed trials with unpublished results.

Searching other resources

We will contact key informants, experts, public sponsors and drug manufacturers with the request to indicate further studies of potential relevance. For this purpose, we will provide reference lists with identified studies and the criteria for inclusion and exclusion in the review. Finally, we will handsearch the reference lists of included studies and current reviews to complete and to verify the preceding searches. All eligible studies identified with the search will be included irrespective of language, publication type or status.

Data collection and analysis

Selection of studies

We will assess the eligibility and relevance of trials on the basis of their abstracts retrieved from the electronic searches. For studies that appear to meet the inclusion criteria according to the abstract information, we will obtain full-text versions for closer inspection. Two review authors will assess the relevance and eligibility of studies independently. We will outline the process of study identification and its results as flow diagrams according to the PRISMA statement (Moher 2009).

Data extraction and management

Two review authors will extract all relevant outcome data independently onto pre-specified data extraction forms and compare data value by value. In case of disagreements, we will undertake the following sequential procedures in descending order:

  1. comparison of published and extracted information to identify transcription and comprehension errors;

  2. explanation of the coding decisions by each review author, followed by consensus discussion and arbitration.

Finally, after comparisons and corrections are concluded, we will enter data into the Review Manager software (RevMan 2012).

For meta-analyses, we will compare zolpidem individually with either placebo or active control. We will group benzodiazapine active control drugs according to their duration of action into short-acting (less than five hours), intermediate-acting (five to 24 hours) and long-acting (more than 24 hours) agents (Greenblatt 1981), potentially generating the following comparisons:

a) zolpidem versus placebo;

b) zolpidem versus other new-generation hypnotics;

c) zolpidem versus short-acting benzodiazepines;

d) zolpidem versus intermediate-acting benzodiazepines;

e) zolpidem versus long-acting benzodiazepines;

f) zolpidem versus other active controls (compounds to be specified at a later date).

Assessment of risk of bias in included studies

We will assess the risk of bias in accordance with The Cochrane Collaboration's 'Risk of bias' assessment tool (Higgins 2008). We will consider the equivalence of baseline characteristics and the equivalence of treatment utilisation as further bias risks in the rating of the item 'free of other bias'. We will judge the general susceptibility to bias effects in consideration of the objectivity of outcome information and rate this separately for measures of sleep and next-day functioning.

Two review authors will complete 'Risk of bias' tables independently. The criteria considered as constitutive for the rating of bias risks are outlined in Appendix 1.

Measures of treatment effect

We will measure treatment effects for dichotomous effectiveness outcomes using risk ratio (RR). We will measure adverse events using risk difference (RD); this measure can also be calculated in cases where there are no events in either group (Deeks 2008). For continuous outcomes, we will assess treatment effects using the mean differences (MD) for outcomes measured on the same scale (WASO, SOL, TST) and the standardised mean difference (SMD) for outcomes measured on different scales (next-day alertness), the latter being justified by the fact that trials appear not to differ considerably in study designs and criteria for inclusion. For subjective measures of next-day functioning, higher scores indicate a more positive state; if not provided in the primary study, scales need to be reversed in their polarity. We will calculate all treatment effects within 95% confidence intervals (CIs). If effects on binary outcomes reach statistical significance, we will calculate the number needed to treat for an additional beneficial outcome (NNTB) for effectiveness outcomes and the number needed to treat for an additional harmful outcome (NNTH) for side effects. A P value of 0.05 and below has been chosen to indicate statistical significance of effects.

Unit of analysis issues

Only individually randomised trials with the individual participant constituting the unit of analysis will be included in the review, so cluster-randomised trials will not be considered. To control unit of analysis errors in studies with multiple treatment groups, we will combine interventions to create single-pair comparisons; in multi-arm studies with different dose schedules, only the most common dose group will be considered.

Dealing with missing data

Outcome statistics will be included in the review as provided by the study publications, irrespective of how missing individuals were handled in the primary analysis. We will impute sample sizes for continuous outcomes which are not explicitly provided in the trial publication by the size of treatment-received samples or - if not available - by the size of the randomised sample. An exception will be if samples are from analyses explicitly specified as completer analyses, which exclusively report on patients who completed the trial. Missing standard deviations are obtained from standard errors (SEs) or CIs for group means. For differences in means, missing SEs are obtained from standard deviations (SDs), CIs or t values and P values. If only the medians are provided in the trial publications, the outcome statistics will not be included in the meta-analyses, but we will insert the information on the significance of effects (yes, no) into tables and describe qualitatively in the discussion of results.

Assessment of heterogeneity

We will quantify inconsistency across studies with the I2 statistic (Higgins 2003), using threshold values for substantial heterogeneity as outlined by Deeks 2008. The Tau2 statistic will additionally be considered to provide an estimate of between-study variance (Rücker 2008) independent of the sample size.

Assessment of reporting biases

If there are more than 10 included studies, we will graphically illustrate the risk of publication bias with the funnel plot method (Light 1984; Egger 1997).

Data synthesis

For synthesising aggregate outcome measures, we will use a random-effects model (DerSimonian 1986), with study effects being weighted using the Mantel-Haenszel approach (Mantel 1959). For outcomes with low effect heterogeneity (I2 < 30%), we will additionally apply a fixed-effect model within the scope of sensitivity analyses (see Sensitivity analysis). 

Subgroup analysis and investigation of heterogeneity

Due to age-related changes in the architecture of sleep and pharmacokinetic changes, elderly patients are repeatedly shown to respond differently to hypnotic drugs than younger people (Dolder 2007). We will conduct subgroup analyses including only samples of age groups over 65 years to determine the effectiveness of zolpidem in patients in the older age group.

Sensitivity analysis

We will conduct sensitivity analyses to determine the influence of the following variables on the primary effectiveness outcomes (SOL, WASO):

  • the underlying statistical model, by comparing effect sizes for low heterogeneity outcomes (I2 < 30%) based on random-effects models versus fixed-effect models;

  • the method of measurement, by comparing effect sizes measured by polysomnography versus effect sizes measured by patient self reports.


CRG Funding Acknowledgement:
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Depression, Anxiety and Neurosis Group.

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.


Appendix 1. Criteria for bias assessment








Sequence generationIs the method used for randomisation adequate?YesThe method used for sequence generation constitutes a random process, in which every study participant has an equal chance to be assigned to each of the treatment conditions (e.g. allocation by random number table, computer random number generator, coin tossing, shuffling cards or envelopes, throwing dice)
  NoThe method used for sequence generation allows the prediction of assignments to treatment groups (e.g. allocation by date of birth, date of admission, hospital or clinic record number etc.)
  UnclearInsufficient information about the sequence generation process to permit judgement of 'Yes' or 'No'
Allocation concealmentWas the treatment allocation concealed?Yes

At least one of the following measures was undertaken to ensure allocation concealment:

- randomisation or drug preparation were performed centralised and remote from the patient recruitment centres

- sequentially numbered, opaque, sealed envelopes (SNOSE) were used for enclosing assignments

- all of the drug containers were tamper-proof, equal in weight and similar in appearance

  NoMethods for allocation were used that allow un-concealment such as an open random allocation schedule, assignment envelopes without appropriate safeguards, alternation or rotation
  UnclearInsufficient information about measures to ensure allocation concealment to permit judgement of 'Yes' or 'No'
BlindingWas knowledge of the allocated interventions adequately prevented during the study?




At least one of the following measures were undertaken to ensure blinding:

- patients and research staff were explicitly mentioned to be included in the blinding procedures; AND active medication and placebo were of identical appearance, odour* and taste*

- the integrity of blinding was checked and confirmed at the end of the treatment.

*Only required for drugs with a typical inherent taste or odour such as eszopiclone and valerian

  NoEvidence that indicates an unmasking of blinding by either patients, treatment providers or research staff such as significant group differences in the perception of appearance, odour or taste or significant group differences in guessing the affiliation to treatments as demonstrated by inquiries on blinding integrity
  UnclearInsufficient information about blinding to permit judgement of 'Yes' or 'No'
Handling of incomplete outcome dataWere incomplete outcome data adequately addressed?




At least one of the following procedures were undertaken to ensure adequate incomplete outcome data handling:

All randomised patients (intention-to-treat analysis) or those who have received at least one dose of treatment (treatment received analysis) were analysed in the group they had been allocated to by randomisation

Drop-outs were excluded from the analyses (available case analysis), but those who were excluded were shown not to differ from trial completers

  NoDrop-outs were excluded from the analyses (available case analysis) and shown to differ from trial completers

Drop-outs were excluded from the analyses (available case analysis) without testing if those who dropped out differ from trial completers OR

Insufficient reporting of drop-out rates or drop-out handling to permit judgement of 'Yes' or 'No'

Selective reportingAre reports of the study free of suggestion of selective outcome reporting?Yes

The reporting of outcomes in the trial publication fulfils both of the following criteria:

- all outcomes listed in the methods section of the publication were adequately reported in the results section

- the primary and secondary endpoints represent an adequate diversity of outcome criteria including at least one indicator of sleep induction, sleep maintenance, rebound insomnia* and withdrawal symptoms*

*Only required in studies with treatment duration of 3 weeks or longer


One or more outcomes listed in the study protocol or the methods section of the publication were not adequately reported in the results section OR

The outcomes of the study are of limited diversity

  UnclearOutcomes were not explicitly stated in the study protocol or the methods section of the trial publication
Other bias: equivalence of baseline characteristicsAre groups equivalent at baseline?Yes

The testing of baseline age, gender and sleep fulfils at least one of the following conditions:

- baseline equivalence between groups was confirmed for age, gender AND at least one indicator of sleep (e.g. sleep induction, sleep maintenance, insomnia duration)

- baseline differences between groups were demonstrated, but adequately controlled in the statistical analyses

  NoDifferences between groups in one or more relevant baseline characteristics became evident, but were not controlled in the statistical analyses
  UnclearInsufficient reporting of baseline equivalence or its testing to permit judgement of 'Yes' or 'No'
Other bias: equivalence of treatment utilisationAre groups equivalent in the utilisation of treatments?Yes

Treatment utilisation fulfils at least one of the following conditions:

- the equivalence of medication compliance* and the use of adjuvant treatments known to affect sleep** was tested and confirmed

- differences in medication compliance* or the use of adjuvant medications known to affect sleep were demonstrated, but adequately controlled in the statistical analyses

*A priori considered as fulfilled in laboratory studies
**A priori considered as fulfilled if the use of adjuvant medications known to affect sleep was prohibited in the study protocol (see criteria of exclusion)

  NoDifferences between groups in one or more of the potentially effect-determining baseline characteristics or in treatment attendance became evident and were not controlled in the statistical analyses
  UnclearInsufficient reporting of treatment attendance (medication compliance and the concomitant use of adjuvant medications) to permit judgement of 'Yes' or 'No'
General susceptibility to bias effects 1: quantitative measures of sleepIs the validity of sleep outcomes ensured?Yes

The assessment of quantitative sleep outcomes fulfils one of the following conditions:

(1) the quantitative sleep outcomes of the study are exclusively based on objective measures (e.g. PSG, electroencephalogram (EEG))

(2) the quantitative sleep outcomes of the study are based on patient self reports and confirmed by objective measures, meaning that both types of measures come to consistent significance conclusions

  NoObjective measures and patient self reports come to different significance conclusions

No objective measures were considered in the study

Objective measures and patient self reports were considered in the study, but it is unclear whether these come to consistent significance conclusions

General susceptibility to bias effects 2: next-day functioningIs the validity of next-day functioning ensured?Yes

The assessment of next-day functioning fulfils one of the following conditions:

(1) indicators of next-day functioning are exclusively based on objective measures (e.g. objective testes of psychomotor co-ordination, attention, vigilance, reaction time)

(2) next-day functioning was assessed by subjective measures (visual analogue scale (VAS), Likert scale, etc.) and objective tests, both coming to consistent significance conclusions

  NoObjective measures and patient self reports come to different significance conclusions

No objective measures were considered in the study

Objective measures and patient self reports were considered in the study, but it is unclear whether these come to consistent significance conclusions

Appendix 2. Search strategies: CENTRAL, MEDLINE, EMBASE, PsycINFO

The Cochrane Central Register of Controlled Trials (CENTRAL) will be searched using the following terms:

#1. (generation NEAR hypnotic*)
#2. (nonbenzodiazepin* or "non benzodiazepin*" or non-benzodiazepin*)
#3. (imidazopyridin* or cyclopyrrolon*)
#4. (eszopiclon* or zaleplon or zolpidem or zopiclon*)
#5. (z NEXT hypnotic*) or (z NEXT drug*)
#6. (#1 or #2 or #3 or #4 or #5)
#7. insomn*
#8. sleep*
#9. MeSH descriptor Sleep Initiation and Maintenance Disorders explode all trees
#10. MeSH descriptor Sleep Disorders, this term only
#11. MeSH descriptor Sleep, this term only
#12. MeSH descriptor Sleep Stages, this term only
#13. MeSH descriptor Wakefulness, this term only
#14. (#7 or #8 or #9 or #10 or #11 or #12 or #13)
#15 (#6 and #14)

OVID MEDLINE will be searched using the following terms:

  1. ((new generation or third generation) adj3 hypnotic*).tw.

  2. (nonbenzodiazepin* or non benzodiazepin*).tw.

  3. (imidazopyridin* or cyclopyrrolon*).tw.

  4. (eszopiclon* or zaleplon or zolpidem or zopiclon*).mp.

  5. (z hypnotic* or z drug*).tw.

  6. or/1-5

  7. insomnia*.tw.

  8. insomn*.ot.

  9. sleep*.tw.

  10. exp Sleep Initiation and Maintenance Disorders/

  11. Sleep Disorders/

  12. Sleep/ or Sleep Stages/

  13. Wakefulness/

  14. or/7-13

  15. randomized controlled trial.pt.

  16. controlled clinical trial.pt.

  17. randomi#ed.ti,ab.

  18. randomly.ab.

  19. placebo.ab.

  20. drug therapy.fs.

  21. trial.ab.

  22. groups.ab

  23. (control$ adj3 (trial or study)).ab,ti.

  24. ((singl$ or doubl$ or tripl$ or trebl$) adj3 (blind$ or mask$ or dummy$)).mp.

  25. (animals not (humans and animals)).sh.

  26. or/15-24

  27. 26 not 25

  28. 6 and 14 and 27

OVID EMBASE will be searched using the following terms:

  1. ((new generation or third generation) adj3 hypnotic*).tw.

  2. (nonbenzodiazepin* or non benzodiazepin*).tw.

  3. (imidazopyridin* or cyclopyrrolon*).tw.

  4. (eszopiclon* or zaleplon or zolpidem or zopiclon*).mp.

  5. Eszopiclone/ or Zaleplon/ or Zolpidem/ or Zopiclone/

  6. (z hypnotic* or z drug*).tw.

  7. or/1-6

  8. insomnia*.tw.

  9. insom*.ot.

  10. exp Insomnia/

  11. sleep*.tw.

  12. Sleep/ or Sleep Induction/ or Sleep Pattern/ or Sleep Stage/ or Sleep Time/ or Sleep Waking Cycle/

  13. Sleep Parameters/

  14. Sleep Disorder/

  15. Wakefulness/

  16. or/8-15

  17. randomized controlled trial.de.

  18. randomization.de.

  19. placebo.de.

  20. placebo.ti,ab.

  21. randomi#ed.ti,ab.

  22. randomly.ab.

  23. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp.

  24. factorial$.ti,ab.

  25. allocat$.ti,ab.

  26. assign$.ti,ab.

  27. volunteer$.ti,ab.

  28. crossover procedure.de.

  29. (crossover$ or cross over$).ti,ab.

  30. (quasi adj (experimental or random$)).mp.

  31. (control$ adj3 (trial$ or study or studies or group$)).ti,ab.

  32. ((animal or nonhuman) not (human and (animal or nonhuman))).de.

  33. or/17-31

  34. 33 not 32

  35. 7 and 16 and 34

OVID PsycINFO will be searched using the following terms:

  1. ((new generation or third generation) adj3 hypnotic*).tw.

  2. (nonbenzodiazepin* or non benzodiazepin*).tw.

  3. (imidazopyridin* or cyclopyrrolon*).tw.

  4. (eszopiclon* or zaleplon or zolpidem or zopiclon*).mp.

  5. (z hypnotic* or z drug*).tw.

  6. or/1-6

  7. insomnia*.tw.

  8. insomn*.ot.

  9. Insomnia/

  10. sleep*.tw.

  11. (insomnia or sleep).tm.

  12. Sleep/ or Sleep Onset/ or Sleep Wake Cycle/

  13. Sleepiness/

  14. Sleep Disorders/

  15. Wakefulness/

  16. or/7-15

  17. treatment effectiveness evaluation.sh.

  18. clinical trials.sh.

  19. mental health program evaluation.sh.

  20. placebo.sh.

  21. placebo.ti,ab.

  22. randomly.ab.

  23. randomi#ed.ti,ab.

  24. trial.ti,ab.

  25. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp.

  26. (control$ adj3 (trial$ or study or studies or group$)).ti,ab.

  27. factorial$.ti,ab.

  28. allocat$.ti,ab.

  29. assign$.ti,ab.

  30. volunteer$.ti,ab.

  31. (crossover$ or cross over$).ti,ab.

  32. (quasi adj (experimental or random$)).mp.

  33. "2000".md.

  34. or/17-33

  35. (6 and 16 and 34)

Contributions of authors

Susanne Rösner:

  • protocol elaboration

  • study selection

  • data extraction

  • data management

  • analysis of data (MAL)

  • interpretation and discussion of results

  • writing of the review

  • securing funding

Christian Englbrecht:

  • study selection

  • data extraction

Renate Wehrle:

  • study selection

  • data extraction

Göran Hajak:

  • protocol elaboration

  • interpretation and discussion of results

Michael Soyka:

  • protocol elaboration

  • interpretation and discussion of results

  • securing funding

Declarations of interest

Rösner S: no conflict of interest known

Englbrecht C: no conflict of interest known

Wehrle R: no conflict of interest known

Hajak G: received speaker/consultancy/advisory board honoraria from Actelion, Astra-Zeneca, Bristol-Meyers Squibb, Boehringer Ingelheim, Cephalon, EuMeCom, GlaxoSmithKline, Janssen-Cilag, Lilly, Lundbeck, Novartis, Organon, Pfizer, Sanofi-Aventis, Servier, Takeda, Wyeth. Advisory Boards: Actelion, Astra-Zeneca, Bristol-Meyers Squibb, Janssen-Cilag, Lilly, Lundbeck, Neurocrine, Organon, Pfizer, Sanofi-Aventis, Sepracor, Servier, Takeda, Wyeth. Industrie-Drittmittel: Actelion, Affectis, Astra-Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Lundbeck, Novartis, Organon, Sanofi-Aventis, Sepracor, Servier, Takeda

Soyka M: received speaker/consultancy/advisory board honoraria from Lipha Pharmaceuticals, Forest Laboratories, Sanofi-Aventis, Essex Pharma, Eli Lilly, Prempharm, Lundbeck and AstraZeneca

Sources of support

Internal sources

  • Ludwig Maximilian University of Munich, Germany.

    Provision of infrastructure and related services

External sources

  • Federal Ministry of Education and Research, Germany.

    Financial support/salary