Drug Class Review - OHSU

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sleep, insomnia, trials, drugs, zolpidem, were, with, studies, newer, Newer, latency, Table, adverse, placebo-controlled, that, zaleplon, included, outcomes, adults, head-to-head, other, eszopiclone, Drug, Sleep, from, Review, Insomnia, Effectiveness, Zolpidem, There

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Drug Class Review
on Newer Drugs for Insomnia
Final Report
July 2006
The Agency for Healthcare Research and
Quality has not yet seen or approved this report
The purpose of this report is to make available information regarding the
comparative effectiveness and safety profiles of different drugs within
pharmaceutical classes. Reports are not usage guidelines, nor should they be
read as an endorsement of, or recommendation for, any particular drug, use or
approach. Oregon Health & Science University does not recommend or endorse
any guideline or recommendation developed by users of these reports.
Susan Carson, MPH
Po-Yin Yen, MS
Marian S. McDonagh, PharmD
Oregon Evidence-based Practice Center
Oregon Health & Science University
Mark Helfand, MD, MPH, Director
Copyright © 2006 by Oregon Health & Science University
Portland, Oregon 97239. All rights reserved.
TABLE OF CONTENTS
INTRODUCTION............................................................................................................. 4
Scope and Key Questions ....................................................................................................................... 4
METHODS ...................................................................................................................... 6
Literature Search ..................................................................................................................................... 6
Study Selection ........................................................................................................................................ 6
Data Abstraction ...................................................................................................................................... 7
Validity Assessment................................................................................................................................. 7
Data Synthesis......................................................................................................................................... 7
RESULTS ....................................................................................................................... 8
Overview of included studies ................................................................................................................... 8
Key Questions 1 and 2. What is the comparative effectiveness, safety, and tolerability of newer drugs
in treating adults and children with insomnia?....................................................................................... 11
Summary of the Evidence...................................................................................................................... 11
Detailed Assessment ............................................................................................................................. 13
Zolpidem vs Zaleplon........................................................................................................................ 13
Zolpidem vs Zopiclone...................................................................................................................... 20
Zolpidem vs Eszopiclone.................................................................................................................. 22
Zolpidem extended release vs other newer drugs for insomnia....................................................... 26
Eszopiclone vs Zaleplon................................................................................................................... 27
Zaleplon vs Zopiclone....................................................................................................................... 27
Ramelteon vs newer sedative hypnotics .......................................................................................... 28
Summary by Drug and Outcome ...................................................................................................... 30
Newer insomnia drugs vs benzodiazepines ..................................................................................... 32
Newer insomnia drugs vs trazodone ................................................................................................ 33
Long-term Effectiveness................................................................................................................... 33
Long-term Safety .............................................................................................................................. 34
Abuse and Dependence ................................................................................................................... 35
Key Question 3. Are there subgroups of patients based on demographics (age, racial groups, gender),
other medications, or co-morbidities for which one newer insomnia drug is more effective or
associated with fewer adverse events? ................................................................................................. 35
Summary of the Evidence...................................................................................................................... 35
Detailed Assessment ............................................................................................................................. 36
Older adults ...................................................................................................................................... 36
Gender and Racial Groups............................................................................................................... 37
Use in Pregnancy ............................................................................................................................. 37
Patients with Comorbid Conditions................................................................................................... 37
Overall Summary......................................................................................................... 38
REFERENCES.............................................................................................................. 42
FIGURES
Figure 1. Newer drugs for insomnnia: Results of literature search .......................................................9
Figure 2. Rebound sleep latency: head-to-head comparison of zolpidem vs zaleplon ........................18
Figure 3. Sleep latency at one week in placebo-controlled trials of zolpidem and zaleplon ................20
Figure 4. Sleep latency at one week in placebo-controlled trials of zolpidem vs zopiclone .................21
Figure 5. Objective WASO: head-to-head comparison of eszopiclone vs zolpidem ............................22
Figure 6. Sleep outcomes at one week in placebo-controlled trials of zolpidem and eszopiclone.......23
Figure 7. Sleep outcomes at one month in placebo-controlled trials of zolpidem vs eszopiclone .......25
Figure 8. Sleep latency at one week in placebo-controlled trials of eszopiclone and zaleplon............27
Figure 9. Sleep latency at one week in placebo-controlled trials of zaleplon and zopiclone................28
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TABLES
Table 1. Newer drugs for insomnia.........................................................................................................5
Table 2. Total numbers of head-to-head trials of newer drugs for insomnia ........................................10
Table 3. Median sleep latency (time to sleep onset) in studies of zolpidem vs zaleplon (difference from
placebo, minutes)...................................................................................................................................14
Table 4. Median sleep duration in trials of zaleplon versus zolpidem (difference from placebo,
minutes) .................................................................................................................................................15
Table 5. Median number of awakenings in studies of zaleplon vs zolpidem........................................17
Table 6. Adverse events in head-to-head studies of zaleplon vs zolpidem..........................................19
Table 7. Objective wake time after sleep onset (WASO) in placebo controlled trials of eszopiclone
(mean difference; 95% CI) .....................................................................................................................26
Table 8. Objective sleep latency over 2 days in placebo-controlled trials of ramelteon, zolpidem, and
eszopiclone ............................................................................................................................................29
Table 9. Subjective sleep outcomes in a placebo-controlled trial of ramelteon in older adults ............29
Table 10. Summary of short-term efficacy by drug and outcome.........................................................31
Table 11. Results of 6-month placebo-controlled trial of eszopiclone 3 mg.........................................33
Table 12. Summary of the evidence by key question...........................................................................39
APPENDICES
Appendix A. Literature search strategies..............................................................................................53
Appendix B. Quality assessment methods for drug class reviews for the Drug Effectiveness Review
Project ....................................................................................................................................................54
Appendix C. Excluded Trials.................................................................................................................58
Appendix D. Summary of results of trials of newer insomnia drugs versus benzodiazepines .............87
EVIDENCE TABLES – Published in a separate document
Funding:
The funding source, the Center for Evidence-based Policy, is supported by 17 organizations, including 15
state Medicaid programs. These organizations selected the topic and had input into the Key Questions for
this review. The content and conclusions of the review are entirely determined by the Evidence-based
Practice Center researchers. The authors of this report have no financial interest in any company that
makes or distributes the products reviewed in this report.
Suggested citation for this report:
Carson S, Yen P-Y, McDonagh MS. Drug Class Review on Newer Drugs for Insomnia. 2006.
http://www.ohsu.edu/drugeffectiveness/reports/final.cfm
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INTRODUCTION
Insomnia is a serious health problem that affects millions of people. Population surveys
have estimated the prevalence of insomnia to be about 30% to 50% of the general population, but
estimates vary depending on the methods and definitions used to define insomnia.1 About threefourths of those who have trouble sleeping say that the problem is ‘‘occasional,’’ averaging
about six nights per month. The other 25% have frequent or chronic insomnia, averaging about
16 nights per month.2 Individuals with insomnia most often report a combination of difficulty
falling asleep and intermittent wakefulness during sleep.3 The most common symptoms of
insomnia include waking up feeling unrefreshed and being awake often during the night. The
symptoms of difficulty falling asleep and waking up too early are less common, but still
experienced at least a few nights a week by about one-fourth of adults with insomnia.1 The risk
of sleep disorders increases with age, affecting approximately 20% to 40% of older adults at least
a few nights per month.2
Consequences of insomnia can include an increased risk of depression, poor memory,
reduced concentration, and poor work performance. Insomnia has been associated with poor
general health, greater healthcare utilization, lower quality of life, socioeconomic status and
poorer social relationships, memory, mood and cognitive function. 4 Insomnia can occur in an
acute, transient setting, and can also be a more chronic problem when associated with underlying
psychiatric or medical illness.
Treatment of insomnia involves behavioral changes such as minimizing daily habits that
interfere with sleep (e.g., drinking coffee or engaging in stressful activities in the evening),4 and
pharmacotherapy using sedating antidepressants (e.g., trazodone), sedating antihistamines,
anticholinergics, benzodiazepines, or non-benzodiazepine hypnotics. The benzodiazepines and
the newer sedative hypnotics zolpidem, zaleplon, zopiclone, and eszopiclone work through the
Gamma-aminobutyric acid (GABA) receptors. Ramelteon, a hypnotic approved by the FDA in
July 2005, is a selective melatonin receptor (MT1 and MT2) agonist.
The newer drugs for insomnia differ from each other in their pharmacokinetics (see Table
1), which could be expected to affect different aspects of insomnia. For example, drugs with a
shorter half-life might be effective for sleep latency but less effective for sleep duration.5
In general, short-term use of insomnia drugs is recommended, however it is recognized
that some individuals may require longer-term treatment.4
Newer non-benzodiazepine drugs have been sought for multiple reasons, including but
not limited to the risk of tolerance, dependence and abuse associated with the benzodiazepine
class.
Scope and Key Questions
The purpose of this review is to help policymakers and clinicians make informed choices
about the use of newer drugs for insomnia. Our goal is to summarize comparative data on
efficacy, effectiveness, tolerability, and safety.
The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying
the populations, interventions, and outcomes of interest, and based on these, the eligibility
criteria for studies. These key questions were reviewed and revised by representatives of
organizations participating in the Drug Effectiveness Review Project (DERP). The participating
organizations of DERP are responsible for ensuring that the scope of the review reflects the
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populations, drugs, and outcome measures of interest to both clinicians and patients. The
participating organizations approved the following key questions to guide this review:
1. What is the comparative effectiveness of newer drugs for insomnia in treating adults and
children with insomnia?
2. What is the comparative tolerability and safety of newer drugs when used to treat adults
and children with insomnia?
3. Are there subgroups of patients based on demographics (age, racial groups, gender), other
medications, or co-morbidities for which one newer drug for insomnia is more effective
or associated with fewer adverse events?
Included populations
We included studies in adults or children with insomnia of any duration. We did not
exclude studies that did not specify a definition of insomnia as part of enrollment criteria, but
most studies specified a DSM-IV diagnosis of primary insomnia. The DSM-IV criteria for the
diagnosis of primary insomnia are “a complaint of difficulty initiating or maintaining sleep or of
nonrestorative sleep that lasts for at least one month and causes clinically significant distress or
impairment in social, occupational, or other important areas of functioning. The disturbance in
sleep does not occur exclusively during the course of another sleep disorder or mental disorder
and is not due to the direct physiological effects of a substance or a general medical condition.”3
Included interventions
Six nonbenzodiazepine drugs for insomnia have been introduced since 1992 (Table 1).
Five are available in the US (eszopiclone, ramelteon, zaleplon, zolpidem and zolpidem extended
release) and two in Canada and other countries (zaleplon and zopiclone).
The recommended starting dose in older adults is half the recommended adult dose for all
of these drugs except ramelteon because of the theoretical risk of increased adverse events such
as somnolence. This is generally based on increased bioavailability observed in older adults.
Table 1. Newer drugs for insomnia
Active ingredient Brand name Initial dose
(given at bedtime)
Half-life
(hours)
Pediatrics Adults Older
adults
eszopiclone Lunesta NA 2 mg 1 mg 6
ramelteon Rozerem NA 8 mg 8 mg 1-2.6
zaleplon Sonata NA 10 mg 5 mg 1
zolpidem Ambien NA 10 mg 5 mg 2.5
zolpidem extended
release
Ambien CR NA 12.5 mg 6.25 mg 2.8
zopiclone (Canada) Imovane NA 5 to 7.5 mg 3.75 mg 5
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Included outcomes
Improvement in insomnia is measured in several ways. Effectiveness outcomes included
sleep latency, sleep duration, number of awakenings, sleep quality, daytime alertness, rebound
insomnia, and quality of life. Safety outcomes included tolerance, adverse effects, abuse
potential, withdrawal symptoms, and dependency.
Sleep latency is the time period taken by a person to fall asleep. Sleep duration is the
time period a person remains asleep. The number of awakenings during the night is also
frequently measured in insomnia trials. A measure used in some studies is wake time after sleep
onset (WASO). This is the total time that a person is awake between sleep onset and final wakeup.
These outcomes can be measured subjectively (e.g., using patient sleep diaries), or
objectively, using polysomnography (PSG), the testing of sleep cycles and stages through the use
of continuous recordings of brain waves and other measures in a sleep laboratory. Most studies
report subjective outcomes. While objective measures may give a more accurate indication of
sleep duration and other outcomes, subjective outcomes may be more important to patients.
Sleep quality is usually measured by patient questionnaire using a Likert or visual
analogue scale (e.g., 0=poor to 10=excellent). Similarly, daytime alertness and other next-day
effects are usually measured by patient self-report.
Rebound insomnia is worsening of insomnia from baseline (prior to pharmacotherapy)
upon treatment discontinuation. This can be measured using any of the outcomes above.
Quality of life includes influence upon physical, psychological, and social aspects of the
patient.
METHODS
Literature Search
To identify relevant citations, we searched the Cochrane Central Register of Controlled
Trials (4th Quarter 2005), Cochrane Database of Systematic Reviews, DARE, MEDLINE (1996
to November Week 3 2005), PsycINFO (1985 to December Week 4 2005) using terms for
included drugs, indications, and study designs (see Appendix A for complete search strategies).
To identify additional studies, we also searched reference lists of included studies and reviews,
FDA information (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/), and dossiers
submitted by pharmaceutical companies. All citations were imported into an electronic database
(EndNote 9.0).
Study Selection
For assessment of efficacy and effectiveness, we included English-language reports of
randomized controlled trials of adults or children with insomnia. Interventions included one
newer hypnotic compared with another newer hypnotic, another active comparator, or placebo.
Trials that evaluated one newer insomnia drug against another (“head-to-head” trials) provided
direct evidence of comparative efficacy and adverse event rates. Trials with other comparators
provided indirect evidence. We included trials that were published in abstract or poster form
only if they provided sufficient information to assess their validity.
For adverse effects, in addition to randomized controlled trials, we included observational
studies and case reports. Clinical trials are often not designed to assess adverse events, and may
select low-risk patients (in order to minimize dropout rates) or utilize inadequately rigorous
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methodology for assessing adverse events. Observational studies designed to assess adverse
event rates may include broader populations, carry out observations over a longer time period,
utilize higher quality methodological techniques for assessing adverse events, or examine larger
sample sizes.
Data Abstraction
We abstracted the following data from included studies: study design, setting, population
characteristics (including sex, age, ethnicity, diagnosis), eligibility and exclusion criteria,
interventions (dose and duration), comparisons, numbers screened, eligible, enrolled, and lost to
followup, method of outcome ascertainment, and results for each outcome. Data were abstracted
by one reviewer and checked by a second. We recorded intention-to-treat results if available and
the trial did not report high overall loss to followup.
Validity Assessment
We assessed the internal validity (quality) of trials based on the predefined criteria listed
in Appendix B. These criteria are based on those developed by the US Preventive Services Task
Force and the National Health Service Centre for Reviews and Dissemination (UK).6, 7 We rated
the internal validity of each trial based on the methods used for randomization, allocation
concealment, and blinding; the similarity of compared groups at baseline; maintenance of
comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and
contamination; loss to followup; and the use of intention-to-treat analysis. We rated the quality
of observational studies of adverse events based on non-biased selection of patients, low loss to
followup, non-biased and accurate ascertainment of events, and control for potential confounding
factors.
Studies that had a fatal flaw in one or more categories were rated poor quality; studies
which met all criteria, were rated good quality; the remainder were rated fair quality. As the
“fair quality” category is broad, studies with this rating vary in their strengths and weaknesses:
the results of some fair quality studies are likely to be valid, while others are only probably valid.
A “poor quality” study is not valid—the results are at least as likely to reflect flaws in the study
design as the true difference between the compared drugs. External validity of studies was
assessed based on whether the publication adequately described the study population, how
similar patients were to the target population in whom the intervention will be applied, and
whether the treatment received by the control group was reasonably representative of standard
practice. We also recorded the funding source.
Data Synthesis
We constructed evidence tables showing study characteristics, quality ratings and results
for all included studies.
When possible, we calculated the weighted mean difference between treatments for
continuous outcomes and displayed results in forest plots using RevMan (v4.2, Update
Software). Meta-analysis was performed when possible (i.e., when populations and
interventions were similar and when significant heterogeneity did not exist among trials), also
using RevMan. Statistical heterogeneity was assessed using the chi-squared test; a level of 0.10
was considered significant. A fixed effects model was used.
To assess the overall strength of evidence for a body of literature about a particular key
question, we examined the consistency of study designs, patient populations, interventions, and
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results. Consistent results from good-quality studies across a broad range of populations suggest
a high degree of certainty that the results of the studies were true (that is, the entire body of
evidence would be considered “good-quality.”) For a body of fair-quality studies, however,
consistent results may indicate that similar biases are operating in all the studies. Unvalidated
assessment techniques or heterogeneous reporting methods for important outcomes may weaken
the overall body of evidence for that particular outcome or make it difficult to accurately
estimate the true magnitude of benefit or harm. Poor-quality studies are not considered in the
assessment of the overall body of evidence.
RESULTS
Overview of included studies
We identified 2,246 citations from literature searches, reviews of reference lists, and
citations from dossiers submitted by three pharmaceutical manufacturers: Sanofi-Aventis
(zolpidem and zolpidem extended release), Sepracor (eszopiclone), and Takeda (ramelteon).
After applying the eligibility and exclusion criteria to the titles and abstracts, we obtained the full
text of 315 publications. After re-applying the criteria for inclusion, we included 175
publications. The flow of study inclusion and exclusion is detailed in Figure 1.
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Figure 1. Newer drugs for insomnnia: Results of literature search
Numbers in parentheses indicate new studies added in Update 1
324 (69) retrieved for full-text evaluation
181 (40) publications included:
91 (9) trials in 90 publications
8 (1) head-to-head trials
44 (0) active-controlled trials
39 (8) placebo-controlled trials
(3 FDA documents)
18 (1) observational studies
53 (24) case reports
4 (1) systematic review
10 (4) background
2,255 (299) citations identified through
searches
2,015 (230) excluded at title/abstract level
465 (69) wrong outcome 334 (46) wrong or combination therapy
260 (20) wrong population
61 (2) wrong design
881 (79) wrong publication type (letter,
editorial, non-systematic review, etc.)
(14) foreign language
145 (29) excluded at full-text level
2 (0) duplication
10 (3) abstract only
18 (1) foreign language
13 (5) wrong outcome
8 (0) wrong or combination therapy
36 (6) wrong population
31 (0) wrong design
22 (14) wrong publication type (letter,
editorial, non-systematic review, etc.)
5 (0) unable to locate
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We excluded studies for the following reasons: study contained no original data, outcome
measure not included, study design not included, drug not included or combined drug therapy
where the effect of the hypnotics could not be distinguished, patient population not included, and
language other than English. A list of excluded trials is reported in Appendix C.
We included eight head-to-head trials (Table 2).8-15 One trial is published as a poster
presentation only;14 additional details were provided by the manufacturer and in the FDA review
of eszopiclone.16 Details of these trials are presented in Evidence Table 1 (efficacy), Evidence
Table 2 (rebound insomnia), and Evidence Table 3 (adverse events).
Table 2. Total numbers of head-to-head trials of newer drugs for insomnia
Zaleplon
Zolpidem
Zolpidem
extended
release
Zopiclone
Eszopiclone
Ramelteon
Zaleplon
*********
Zolpidem
4
**********
Zolpidem
extended
release
0 0 **********
Zopiclone
0
3
0
**********
Eszopiclone
0
1
0
0
**********
Ramelteon
0 0 0 0 0 **********
To supplement information from head-to-head trials, we attempted to make indirect
comparisons of newer insomnia drugs from active- and placebo-controlled trials.
We included 44 trials in 45 publications of newer insomnia drugs versus
benzodiazepines.17-61 Most of the active-controlled studies included a placebo arm and reported
efficacy and safety outcomes by comparing to placebo instead of comparing the two active
drugs. Appendix D summarizes the efficacy, safety, and rebound insomnia results of these
studies. Details of the populations, interventions, and outcomes are provided in Evidence Tables
4 through 12. Details of the quality assessment of all trials are provided in Evidence Table 16.
We identified two trials of a sedative hypnotic compared with trazodone; one (versus
zaleplon)48 was rated poor quality and the other (versus zolpidem)57 was rated fair.
Thirty-four placebo-controlled trials in 35 publications were also included.62-96
Four good-quality systematic reviews (see Appendix B for quality criteria) of newer
sedative hypnotics were included.1, 97-99 The most relevant review to this report is a comparative
review conducted by the National Institute for Clinical Excellence (NICE).97 The others were
not designed specifically to compare the sedative hypnotics head-to-head. One meta-analysis
examined the risks and benefits of sleep agents, including newer sedative hypnotics, in older
people with insomnia.99
We included 18 observational studies (Evidence Table 17)100-117 and 53 case reports
(Evidence Table 18)118-148149-170 of adverse events associated with newer drugs for insomnia.
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Key Questions 1 and 2. What is the comparative effectiveness, safety, and
tolerability of newer drugs in treating adults and children with insomnia?
Summary of the Evidence
Short-term Effectiveness and Safety
• We identified no effectiveness studies; trials assessed efficacy only.
• There are no randomized controlled trials of newer insomnia drugs in children.
Zolpidem vs zaleplon
• There is evidence from four head-to-head trials that zaleplon is more efficacious than
zolpidem for sleep latency, but zolpidem is more efficacious than zaleplon for sleep
duration and sleep quality.
• The drugs were similar for number of awakenings and daytime alertness.
• Zolpidem caused more rebound insomnia on the first night after discontinuation.
• Short-term adverse events and withdrawals due to adverse events were similar.
Zolpidem vs zopiclone
• One fair-quality head-to-head trial found that zolpidem and zopiclone were similar in
efficacy on patient-rated sleep outcomes and investigator’s global assessment of
improvement. Zopiclone caused more rebound sleep latency insomnia than
zolpidem.Overall adverse events and effects of withdrawal were similar in another study
designed to measure withdrawal effects.There is limited indirect evidence that zopiclone
was more effective for sleep latency at one week.
Zolpidem vs eszopiclone
• In one head-to-head trial, zolpidem and eszopiclone had similar objective sleep latency
and Wake Time After Sleep Onset as measured by polysomnography after two nights of
treatment.
• There was no difference between zolpidem and eszopiclone on subjective measures of
next-day effects, including morning sleepiness, daytime alertness, and daytime ability to
function.
• Indirect comparisons based on placebo-controlled trials provide evidence that the drugs
were similar for sleep latency and number of awakenings, but eszopiclone was more
effective for increasing sleep duration. Comparisons were limited due to differences in
populations across placebo-controlled studies.
Zolpidem extended release vs other newer drugs for insomnia
• There are no trials of zolpidem extended release compared to other newer insomnia
drugs, benzodiazepines, or trazodone.
• No placebo-controlled trial has been fully published.
• Two placebo-controlled trials of 3 weeks’ duration, one in adults and one in older adults,
are available as poster presentations. An FDA review is not yet available.
- According to data in these posters, zolpidem extended release was more
effective than placebo on objective and subjective sleep outcomes, and caused
rebound insomnia on the first night after discontinuation.
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- It is not possible to make indirect comparisons from these trials because of
limitations in reporting of the data.
Eszopiclone vs zaleplon
• There are no head-to-head trials.
• Limited indirect comparisons suggest the drugs are similar for sleep latency at one week.
Indirect comparisons for other sleep outcomes are not possible.
Zaleplon vs zopiclone
• There are no head-to-head trials
• Limited indirect comparisons suggest the drugs are similar for sleep latency at one week.
Indirect comparisons for other sleep outcomes are not possible.
Ramelteon vs newer sedative hypnotics
• There are no trials of ramelteon compared to newer sedative hypnotics, benzodiazepines,
or trazodone in adults or children with insomnia.
• One placebo-controlled crossover trial of 2 nights of treatment in adults has been fully
published. Its similar design, outcome measure, and population to a trial of zolpidem vs
eszopiclone vs placebo allows an indirect comparison of objective sleep latency.
- Objective sleep latency was 4 to 8 minutes longer with ramelteon compared
with zolpidem and eszopiclone.
- Confidence intervals for the differences from placebo for the 3 drugs
overlapped, however.
- There was no difference between ramelteon 8 mg and placebo on any subjective
sleep measure. Sleep latency at the 16 mg dose was shorter than placebo (-13.1
minutes; 95% CI –24.3, –1.9).
• A five-week, placebo-controlled study in older adults found ramelteon 4 mg and 8 mg
improved subjective sleep latency and total sleep time at some time points. There was no
difference from placebo on other subjective sleep outcomes, including number of
awakenings, ease of falling back to sleep after awakening, and sleep quality. There was
no rebound insomnia on days 1 through 7 after discontinuation of ramelteon.
• Abstracts of additional placebo-controlled trials of ramelteon do not provide sufficient
information to assess internal validity and are not included.
Long-term efficacy and safety
• Evidence about long-term safety is limited; there is no comparative evidence.
• Two placebo-controlled trials provide evidence that eszopiclone 3 mg is efficacious for up
to 6 months. One of these is currently available only as a poster presentation.
- Withdrawal symptoms were not observed after discontinuation.
- There was no evidence of rebound insomnia in one trial; rebound insomnia was
not assessed in the other.
- These trials do not add any information about the comparative long-term efficacy
and safety of eszopiclone versus other newer drugs for insomnia.
• In a 6-month open-label extension of one 6-month placebo-controlled trial of eszopiclone
3 mg, improvements in sleep outcomes were sustained; 3.8% of patients discontinued due
to adverse events. Withdrawal effects and rebound insomnia were not assessed.
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• A one-year open-label extension study of zaleplon 5 mg in older adults found most
adverse events were mild. Sleep outcomes worsened after discontinuation, indicating
rebound insomnia, but did not approach baseline levels. The most frequent adverse events
were headache (27%) and infection (13%). The most frequent adverse events resulting in
discontinuation were pain (5%), somnolence or dizziness (4%), and gastrointestinal
disturbances (2%).
• There are case reports of dependence with zolpidem and zopiclone.
Newer insomnia drugs vs benzodiazepines
- There are no studies of eszopiclone or ramelteon versus benzodiazepines
- Most comparisons found the newer sedative hypnotics to be similar to benzodiazepines
in efficacy and short-term adverse events
- Some studies found less rebound insomnia with newer sedative hypnotics.
Newer insomnia drugs vs trazodone
- We identified one fair-quality, short-term trial of zolpidem versus trazodone.
- Sleep latency was shorter with zolpidem after 1 week of treatment, but the difference
was not significant at week 2.
- Sleep duration, number of awakenings, sleep quality, and patients’ global impressions
of treatment were similar for the drugs at weeks 1 and 2.
- More patients reported daytime somnolence with trazodone. Withdrawals due to
adverse events and overall adverse events were similar between the drugs.
-
Detailed Assessment
Zolpidem vs Zaleplon
Direct comparisons
Four fair-quality head-to-head studies compared zolpidem to zaleplon and placebo.8, 10, 11, 13
Two of these were conducted in adults under age 65 and had identical designs.10, 11 Another was
conducted in older adults.8 The fourth head-to-head study13 was a small, single-dose crossover
trial that measured patient preference as a primary outcome. All were funded by the
manufacturer of zaleplon. Comparisons between zaleplon and placebo were the primary
comparisons; published reports do not provide a head-to-head analysis of the two active drugs.
More complete reporting and head-to-head analyses would facilitate direct comparisons from
these studies.
Sleep latency. Sleep latency (time to sleep onset) was the primary outcome in two
studies in adults (Table 3).10, 11 Both compared zaleplon at three fixed doses (5 mg, 10 mg, or 20
mg) to zolpidem 10 mg for 4 weeks. A placebo arm was also included, and analyses are
presented for the comparison to placebo. Neither publication provided a head-to-head analysis
of zolpidem versus zaleplon, but a head-to-head analysis is provided in the FDA statistical
review of zaleplon5 for one trial.11
At weeks 1 through 4,11 there was no difference between zaleplon 5 mg or 10 mg and
zolpidem 10 mg on the median number of minutes to sleep onset. The only significant
difference between the drugs on this outcome was a shorter latency with zaleplon 20 mg
compared to zolpidem 10 mg. There was no zolpidem 20 mg arm in this trial. There was no
difference in the comparison of recommended starting doses zaleplon 10 mg and zolpidem 10
mg. These results are not intention-to-treat.
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For the second trial,10 intention-to-treat results using the last observation carried forward
method (LOCF) are presented in the FDA review of zaleplon.5 Analyses were conducted versus
placebo. Results in this study were mixed. Zaleplon at all three doses had a shorter latency than
placebo at all time points, with the exception of 5 mg at week 4. For zolpidem 10 mg, latency at
weeks 2 and 3 was significantly shorter than placebo, but was not significantly different at week
4. At week 1, there was a trend for shorter latency, but this was not significant (-10 minutes;
p=0.07).
Table 3. Median sleep latency (time to sleep onset) in studies of zolpidem vs zaleplon
(difference from placebo, minutes)
Study
Week 1
Week 2
Week 3
Week 4
Withdrawal day +1
(rebound)
Fry
(not
ITT)5
Zaleplon
(p vs zolpidem)
5 mg: -12
(0.764)
10 mg: -17
(0.490)
20 mg: -22
(0.003)
Zolpidem
10 mg: -12
Zaleplon
(p vs zolpidem)
5 mg: -6
(0.959)
10 mg: -13
(0.183)
20 mg: -18
(<0.001)
Zolpidem
10 mg: -3
Zaleplon
(p vs zolpidem)
5 mg: -4
(0.323)
10 mg: -9
(0.110)
20 mg: -15
(<0.001)
Zolpidem
10 mg: -0.7
Zaleplon
(p vs zolpidem)
5 mg: -2
(0.124)
10 mg: -12
(0.988)
20 mg: -17
(<0.037)
Zolpidem
10 mg: -13
Zaleplon
(p vs zolpidem)
5 mg: 0
(0.012)
10 mg: -2
(0.008)
20 mg: -11
(<0.001)
Zolpidem
10 mg: +20
Elie
(LOCF
analysi
s)5
Zaleplon
(p vs placebo)
5 mg: -8
(0.02)
10 mg: -14
(0.001)
20 mg: -17
(<0.001)
Zolpidem
(p vs placebo)
10 mg: -5
(0.07)
Zaleplon
(p vs placebo)
5 mg: -12
(0.01)
10 mg: -16
(0.008)
20 mg: -17
(<0.001)
Zolpidem
(p vs placebo)
10 mg: -11
(0.05)
Zaleplon
(p vs placebo)
5 mg: -9
(0.04)
10 mg: -11
(0.02)
20 mg: -13
(<0.001)
Zolpidem
(p vs placebo)
10 mg: -5
(0.04)
Zaleplon
(p vs placebo)
5 mg: -6
(0.37)
10 mg: -9
(0.04)
20 mg: -10
(0.004)
Zolpidem
(p vs placebo)
10 mg: -3
(0.55)
Zaleplon
(p vs placebo)
5 mg: +9
(0.37)
10 mg: +9
(0.14)
20 mg: +2
(0.99)
Zolpidem
(p vs placebo)
10 mg: +22
(0.003)
AncoliIsrael
1999*8
Zaleplon
(p vs zolpidem)
5 mg: +4**
(NS)
10 mg: -17**
(0.001)
Zolpidem
(p vs placebo)
5 mg: -7 **
Zaleplon
(p vs zolpidem)
5 mg: -18**
(NS)
10 mg: -26**
(0.001)
Zolpidem
(p vs placebo)
5 mg: -16**
-- -- Zaleplon
(p vs placebo)
5 mg: -14
(NS)
10 mg: +1
(NS)
Zolpidem
(p vs placebo)
5 mg: +16
(<0.01)
*patients > age 65
**estimated from graphL
OCF=Last observation carried forward analysis; ITT=intention-to-treat analysis
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Table 3 also shows results of a 2-week head-to-head trial of zaleplon 5 mg or 10 mg
versus zolpidem 5 mg conducted in 549 older adults (65 years or older).8 Results were similar to
those of the trials in younger patients: there was no difference in sleep latency for zaleplon 5 mg
versus zolpidem 5 mg, but zaleplon at a higher dose (10 mg) was associated with a shorter
latency than zolpidem 5 mg. Zolpidem, but not zaleplon, was associated with rebound sleep
latency on the first night of discontinuation.
Sleep duration. Duration of sleep was a secondary outcome in three head-to-head trials
of zaleplon versus zolpidem.8, 10, 11 Table 4 shows outcomes for weeks 1 through 4 and rebound
on the first day after the end of treatment. Zolpidem 5 mg and 10 mg increased sleep duration
more than placebo in all three studies. In two studies in adults, zaleplon 5 mg and 10 mg were
no different from placebo on this outcome at any time period. Zaleplon 20 mg was more
effective than placebo at weeks 1 and 3, but not weeks 2 and 4.
Table 4. Median sleep duration in trials of zaleplon versus zolpidem (difference from
placebo, minutes)
Study Week 1
Week 2 Week 3 Week 4 Withdrawal day +1
(rebound)
Fry
(not
ITT)5
Zaleplon
(p vs placebo)
5 mg: +13
(NS)
10 mg: +14
(NS)
20 mg: +22
(<0.05)
Zolpidem
(p vs placebo)
10 mg: +30
(<0.001)
Zaleplon
(p vs placebo)
5 mg: +6
(NS)
10 mg: +4
(NS)
20 mg: +9
(NS)
Zolpidem
(p vs placebo)
10 mg: +24
(<0.05)
Zaleplon
(p vs placebo)
5 mg: -5
(NS)
10 mg: +11
(NS)
20 mg: +20
(<0.05)
Zolpidem
(p vs placebo)
10 mg: +26
(<0.01)
Zaleplon
(p vs placebo)
5 mg: -4
(NS)
10 mg: +12
(NS)
20 mg: +13
(NS)
Zolpidem
(p vs placebo)
10 mg: +29
(<0.05)
Zaleplon
(p vs placebo)
5 mg: 0
(NS)
10 mg: 0
(NS)
20 mg: 0
(NS)
Zolpidem
(p vs placebo)
10 mg: -30
(P<0.05)
Elie
(LOCF
analysi
s)5
Zaleplon
(p vs placebo)
5 mg: 0
(0.92)
10 mg: +19
(0.11)
20 mg: +19
(0.04)
Zolpidem
(p vs placebo)
10 mg: +28
(<0.001)
Zaleplon
(p vs placebo)
5 mg: 0
(0.28)
10 mg: +8
(0.24)
20 mg: +13
(0.01)
Zolpidem
(p vs placebo)
10 mg: +29
(<0.001)
Zaleplon
(p vs placebo)
5 mg: +10
(0.26)
10 mg: +10
(0.43)
20 mg: +9
(0.07)
Zolpidem
(p vs placebo)
10 mg: +21
(<0.001)
Zaleplon
(p vs placebo)
5 mg: +13
(0.47)
10 mg:+15
(0.10)
20 mg: +23
(0.02)
Zolpidem
(p vs placebo)
10 mg: +39
(<0.001)
Zaleplon
(p vs placebo)
5 mg: 0
(NS)
10 mg: 0
(NS)
20 mg: 0
(NS)
Zolpidem
(p vs placebo)
10 mg: 0
(<0.05 using F test)
AncoliIsrael
1999*10
1
Zaleplon
(p vs placebo)
5 mg: NR
(NS)
10 mg: +27
(0.05)
Zolpidem
(p vs placebo)
5 mg: +42
(<0.001)
Zaleplon
(p vs placebo)
5 mg: NR
(NS)
10 mg: NR
(NS)
Zolpidem
(p vs placebo)
5 mg: +34
(<0.01)
-- -- Zaleplon
(p vs placebo)
5 mg: +12.5
(NS)
10 mg: -2.5
(<0.05)
Zolpidem
(p vs placebo)
5 mg: -17.5
(<0.001)
ITT= intention-to-treat analysis; LOCF=last observation carried forward analysis
Number of awakenings. The difference from placebo in the median number of
awakenings during the night was another secondary outcome in head-to-head trials (Table 5). In
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one trial,10 there was no difference from placebo for any dose of either zaleplon or zolpidem at
any time period. The other trial in adults,11 had mixed results. Zaleplon 5 mg and 10 mg was no
different from placebo, zaleplon 20mg was more effective than placebo at weeks 2, 3, and 4, and
zolpidem 10 mg was better than placebo at weeks 1, 2, and 3. In older adults, only zolpidem 5
mg was more effective than placebo.8
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Table 5. Median number of awakenings in studies of zaleplon vs zolpidem
Study
Week 1
Week 2
Week 3
Week 4
Withdrawal day +1
(rebound)
Fry
(not
ITT)11
Zaleplon
(p vs placebo)
placebo: 1.71
5 mg: 1.93
(NS)
10 mg: 1.69
(NS)
20 mg: 1.75
(NS)
Zolpidem
(p vs placebo)
10 mg: 1.59
(<0.01)
Zaleplon
(p vs placebo)
placebo: 2.00
5 mg: +6
(NS)
10 mg: +4
(NS)
20 mg: +9
(<0.001)
Zolpidem
(p vs placebo)
10 mg: +24
(<0.001)
Zaleplon
(p vs placebo)
placebo: 2.00
5 mg: 1.67
(NS)
10 mg: 1.69
(NS)
20 mg: 1.50
(<0.001)
Zolpidem
(p vs placebo)
10 mg: 1.50
(N<0.001)
Zaleplon
(p vs placebo)
placebo: 1.86
5 mg: 1.71
(NS)
10 mg: 1.71
(NS)
20 mg: 1.43
(<0.05)
Zolpidem
(p vs placebo)
10 mg: 1.71
(NS)
Zaleplon
(p vs placebo)
placebo: 2.00
5 mg: 2.00
(NS)
10 mg: 2.00
(NS)
20 mg: 2.00
(NS)
Zolpidem
(p vs placebo)
10 mg: 2.00
(<0.05 by F test)
Elie
(not
ITT)10
Zaleplon
(p vs placebo)
placebo: 2
5 mg: 2
(NS)
10 mg: 2
(NS)
20 mg: 2
(NS)
Zolpidem
(p vs placebo)
10 mg: 2
(NS)
Placebo: 2.0
Zaleplon
(p vs placebo)
placebo: 2
5 mg: 2
(NS)
10 mg: 2
(NS)
20 mg: 2
(NS)
Zolpidem
(p vs placebo)
10 mg: 2
(NS)
Placebo: 1.9
Zaleplon
(p vs placebo)
placebo: 2
5 mg: 2
(NS)
10 mg: 2
(NS)
20 mg: 1
(NS)
Zolpidem
(p vs placebo)
10 mg: 2
(NS)
Zaleplon
(p vs placebo)
placebo: 2
5 mg: 2
(NS)
10 mg: 2
(NS)
20 mg: 1
(NS)
Zolpidem
(p vs placebo)
10 mg: 2
(NS)
Zaleplon
(p vs placebo)
placebo:1
5 mg: 2
(NS)
10 mg: 2
(NS)
20 mg: 1
(NS)
Zolpidem
(p vs placebo)
10 mg: 2
(<0.01)
Placebo: 2
AncoliIsrael8
Zaleplon
(p vs placebo)
5 mg: 1.8
(NS)
10 mg: 1.8
(NS)
Zolpidem
(p vs placebo)
5 mg: 1.7
(p<0.01)
Zaleplon
(p vs placebo)
5 mg: 1.9
(NS)
10 mg: 1.7
(NS)
Zolpidem
5 mg: 1.6
(p<0.05)
-- -- Zaleplon
(p vs placebo)
5 mg: 2
(NS)
10 mg: 2
(NS)
Zolpidem
5 mg: 2
(NS)
Sleep Quality. In a pooled analysis of three trials of zaleplon versus zolpidem8, 10, 11, the
NICE review97 found that patients on zaleplon were less likely to experience improvement in
sleep quality at the end of treatment than patients taking zolpidem (OR 0.66; 95% CI 0.51 to
0.87).
Rebound insomnia. Two head-to-head trials found zolpidem 10 mg to be associated with
more rebound insomnia than zaleplon as measured by median sleep latency on the first night
after discontinuation.10, 11 Zolpidem 10 mg was associated with a 20- to 22-minute increase in
sleep latency versus placebo on the first night of discontinuation. Rebound sleep latency was not
seen with zaleplon at any dose. Figure 2 shows the mean difference between zolpidem and
zaleplon for rebound sleep latency, measured on the first day after withdrawal after 4 weeks of
treatment in one of these studies.10 Zaleplon at all doses (5 mg, 10 mg, and 20 mg) was less
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likely to cause rebound sleep latency than zolpidem 10 mg. The mean difference for zolpidem
10 mg versus zaleplon 10 mg was 34 minutes (95% CI, 10.5 to 57.5 minutes).
Figure 2. Rebound sleep latency: head-to-head comparison of zolpidem vs zaleplon
Review: Sedative hypnotics Comparison: 06 Rebound insomnia
Outcome: 01 Rebound sleep latency zolpidem vs zaleplon
Study zolpidem zaleplon WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 zolpidem 10 mg vs zaleplon 5 mg
Elie 1999 115 91.60(100.40) 113 51.70(56.57) 39.90 [18.79, 61.01]
02 zolpidem 10 mg vs zaleplon 10 mg
Elie 1999 115 91.60(100.40) 112 57.60(79.10) 34.00 [10.52, 57.48]
03 zolpidem 10 mg vs zaleplon 20 mg
Elie 1999 115 91.60(100.40) 116 50.40(77.70) 41.20 [18.03, 64.37]
Subtotal (95% CI)
-100 -50 0 50 100
Favors zolpidem Favors zaleplon
Head-to-head studies also found zolpidem to be associated with rebound decrease in
sleep duration on the first night of discontinuation. Zaleplon was not associated with rebound on
this outcome, except at the 10 mg dose in older adults.
In two studies in adults,10, 11 zolpidem, but not zaleplon, was associated with an increase
in awakenings compared to placebo on the first night after withdrawal. In older adults, neither
drug was associated with rebound insomnia on this measure.8
Other Outcomes. A small (N=53) single-dose crossover study of zolpidem 10 mg versus
zaleplon 10 mg was designed to measure patient preference for a drug as a primary outcome.13
This was measured by a questionnaire filled in by the patient the evening following
administration of the drug. More patients preferred zolpidem, but the difference was not
statistically significant (62% vs 32%; p=0.81).
Secondary outcomes were mean scores on the Leeds sleep evaluation questionnaire
(LSEQ), and “day quality,” a visual analogue scale (0-100, higher is better) measuring 7 factors
on the day following the administration of the drug. Zolpidem patients improved more on two of
four factors on the LSEQ (Getting to Sleep and Quality of Sleep); there was no difference
between drugs on the other two factors (Ease of Waking Up and Behavior Following
Wakefulness). Only one of 7 factors on the “day quality” measure was significantly different
between drugs. Zolpidem patients reported better quality of sleep (mean score 68.8 vs 50.2,
p<0.0001), but there were no differences on other factors.
Short-term adverse events. Table 6 shows the total withdrawals and withdrawals due to
adverse events reported in short-term head-to-head trials of zaleplon versus zolpidem. Rates of
overall adverse events and withdrawals due to adverse events were similar for both drugs and
increased with longer duration of the trials.
The most common treatment-emergent adverse events were headache and dizziness. In a
2-week trial in older adults,8 somnolence was significantly more common (p<0.05) with
zolpidem 5 mg (10%) than with placebo (2%) or zaleplon 5 mg (4%). In one of two 4-week
trials in adults,11 dizziness was significantly more frequent in 10 mg and 20 mg treatment groups
than placebo (p<0.001), occurring in 8% of patients in the placebo group, 3% in the zaleplon 5
mg group, 9% in the zaleplon 10 mg group, 14% in the zaleplon 20 mg group, and 14% in the
zolpidem 10 mg group.
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In the single-dose study conducted in 53 general practice patients,13 3 adverse events
occurred in the zolpidem 10 mg group (sluggish tongue, impaired concentration, leg complaints),
and 4 in the zaleplon 10 mg group (cephalgia requiring analgesic treatment, headache, abdominal
fullness, vertigo).
Table 6. Adverse events in head-to-head studies of zaleplon vs zolpidem
Incidence of adverse events
Withdrawals due to
adverse events
Comparison
(duration)
N
Percent
Risk difference
(95% CI)
Percent
Risk
difference
(95% CI)
Zaleplon 5 mg vs zolpidem 10
mg10, 11
(4 weeks)
476 67% vs 73% -6%
(-14% to 2%)
2% vs 6% -4%
(-7% to 0%)
Zaleplon 10 mg vs zolpidem 10
mg10, 11
(4 weeks)
476 74% vs 73% 0%
(-8% to 8%)
5% vs 6% -1%
(-5% to 3%)
Zaleplon 20 mg vs zolpidem 10
mg10, 11
(4 weeks)
477 70% vs 73% -3%
(-11% to 5%)
5% vs 6% -1%
(-5 to 3%)
Zaleplon 5 mg vs zolpidem 5 mg8
(2 weeks)
331 56% vs 63% -7%
(-18% to 4%)
Not
reported
Not reported
Zaleplon 10 mg vs zolpidem 5 mg
(2 weeks)
276 59% vs 63% -4%
(-16% to 7%)
Not
reported
Not reported
Indirect comparisons
Figure 3 shows results of two placebo-controlled trials of zolpidem and zaleplon for the
outcome of sleep latency at one week. At one week, only zaleplon 10 mg was significantly
better than placebo for sleep latency (mean difference, -11.75 minutes; 95% CI –20.41 to –3.09
minutes). There was no difference between placebo and zolpidem 10 mg or zaleplon 20 mg.
Indirect comparisons that can be made from these studies are limited. Placebo group sleep
latency rates varied considerably in these studies (63 minutes for zaleplon vs 37 minutes for
zolpidem), indicating that the populations may have had different baseline severity, which could
account for differences in response rates.
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Figure 3. Sleep latency at one week in placebo-controlled trials of zolpidem and
zaleplon
Study Treatment Placebo WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
02 zaleplon 10 mg
FDA 307 242 51.51(41.38) 153 63.26(43.67) -11.75 [-20.41, -3.09]
03 zaleplon 20 mg
FDA 307 242 55.10(45.73) 153 63.26(43.67) -8.16 [-17.16, 0.84]
04 zolpidem 10 mg
Dorsey 2004 68 33.00(4.18) 73 37.00(2.45) -4.00 [-5.14, -2.86]
-100 -50 0 50 100
Favors treatment Favors placebo
Zolpidem vs Zopiclone
Direct comparisons
Two fair-quality studies compared zolpidem to zopiclone.9, 12 One was designed to
assess the effect of withdrawal in patients already taking the drugs for insomnia and did not
report efficacy outcomes.9
A third head-to-head study measured next-day simulated driving performance as the
primary outcome, and reported subjective sleep parameters as secondary outcomes.15 This study
was rated poor quality because no baseline demographic or clinical data are reported, so it cannot
be determined if groups were comparable at baseline, and there is no information about
withdrawals, so it is impossible to determine if an intention-to-treat analysis was conducted.
A two-week, double-blind trial in 479 patients at multiple centers in Japan12 is the only
head-to-head trial of zolpidem versus zopiclone in which efficacy is the primary outcome. The
funding source is not reported.
Global assessment of improvement. The primary outcome was the investigator’s global
assessment of improvement, based on patient sleep diaries and reported as the proportion of
patients who were “moderately improved” or “markedly improved.” At the end of treatment,
there were no significant differences between treatment groups in the number of patients
“markedly improved” (18.7% zolpidem vs 16.4% zopiclone) or “moderately improved” (49.3%
zolpidem vs 45.2% zopiclone). Patients’ ratings of treatment efficacy were similar and did not
differ between treatment groups. Sleep outcomes (sleep onset latency, frequency of awakening,
sleep duration, daytime mood, and daytime physical condition) were improved from placebo to a
similar extent in both treatment groups, but data are not reported.
Rebound insomnia. Rebound insomnia was defined as the percentage of patients with an
aggravation of sleep onset latency by one grade or more after 2 weeks of treatment.12 More
patients who took zopiclone had rebound insomnia by this definition than those who took
zolpidem (15.4% vs 4.5%, p<0.005).
Short-term adverse events. More patients in the zopiclone group than the zolpidem group
had an adverse event “related”, “probably related”, or “possibly related” to treatment (31.3% vs
45.3%; p=0.004). There were no significant differences in the proportion of patients who
withdrew due to any adverse event (8.5% zolpidem vs 10.2% zopiclone) or due to a drug-related
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adverse event (6.6% vs 8.9%). The frequency of specific adverse events was similar between
groups, with the exception of bitter taste, which occurred in 3% of patients in the zolpidem
group, and 31% of those in the zopiclone group.
Effects of withdrawal. The study designed to assess the effect of withdrawing from
zolpidem or zopiclone was not a head-to-head trial, but 2 trials with the same design conducted
simultaneously.9 The comparison in each trial was the effect of withdrawal of treatment versus
continuing treatment. During the 2 weeks following withdrawal from treatment, the incidence of
adverse events was higher in the withdrawal groups compared to continued treatment groups, but
was similar for zolpidem and zopiclone (38% vs 41%, respectively). Most events were sleeprelated.
Indirect comparisons
In placebo-controlled trials, sleep latency was significantly shorter with zopiclone 7.5 mg
than with placebo (mean difference –18.00 minutes; 95% CI –20.36 to –15.64 minutes), but there
was no difference between zolpidem 10 mg and placebo (-4.00 minutes; -5.14 to –2.86 minutes)
(Figure 4). No head-to-head trial reported data on sleep latency, so it is not possible to compare
these results to direct evidence.
Figure 4. Sleep latency at one week in placebo-controlled trials of zolpidem vs
zopiclone
Review: Sedative hypnotics Comparison: 01 Sleep latency
Outcome: 07 Sleep latency at 1 week zolpidem vs zopiclone
Study Treatment Placebo WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
04 zolpidem 10 mg
Dorsey 2004 68 33.00(4.18) 73 37.00(2.45) -4.00 [-5.14, -2.86]
06 zopiclone 7.5 mg
Chaudoir 1983 25 31.10(4.00) 25 49.10(4.50) -18.00 [-20.36, -15.64]
-100 -50 0 50 100
Favors treatment Favors placebo
Trials comparing zolpidem and zopiclone to benzodiazepines do not add additional
comparative information regarding zolpidem versus zopiclone. Outcomes were reported
differently, so it is not possible to make indirect comparisons.
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Zolpidem vs Eszopiclone
Direct comparisons
There is one head-to-head trial of eszopiclone versus zolpidem. This study has not yet
been fully published. It has been reported in a poster presentation,14 and additional information
is provided in the FDA statistical review of eszopiclone.16 The primary efficacy outcome was
latency to persistent sleep as measured by polysomnography. The study compared 4 doses of
eszopiclone (1 mg, 2 mg, 2.5 mg, 3 mg) to placebo and zolpidem 10 mg in a crossover design
over 2 nights of treatment. Subjective sleep outcomes are not available for this study.
Both drugs were more effective than placebo for PSG-measured sleep latency and total
sleep time. Eszopiclone 2.5 mg and 3 mg were more effective than placebo for objective
WASO, but there was no difference from placebo for eszopiclone at other doses or for zolpidem
10 mg.
Objective sleep latency was slightly shorter for zolpidem 10 mg compared to eszopiclone
1 mg (mean difference 8.6 minutes; 95% CI 1.68 to 15.52 minutes), but there was no difference
between zolpidem 10 mg and eszopiclone 2 mg or 3 mg. There was no difference between
zolpidem 10 mg and any dose of eszopiclone on objective WASO (figure 5).
Figure 5. Objective WASO: head-to-head comparison of eszopiclone vs zolpidem
Review: Sedative hypnotics Comparison: 05 WASO
Outcome: 01 Objective Wake Time after Sleep Onset (WASO)
Study Eszopiclone Zolpidem WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 1 mg vs zolpidem 10 mg
FDA 190-045 63 41.40(26.50) 64 39.30(28.50) 2.10 [-7.47, 11.67]
02 eszopiclone 2 mg vs zolpidem 10 mg
FDA 190-045 63 36.00(25.00) 64 39.30(28.50) -3.30 [-12.62, 6.02]
03 eszopiclone 3 mg vs zolpidem 10 mg
FDA 190-045 64 35.90(31.70) 64 39.30(28.50) -3.40 [-13.84, 7.04]
-100 -50 0 50 100
Favors eszopiclone Favors zolpidem
Next-day effects
There was no difference between zolpidem and eszopiclone on subjective measures of
next-day effects, including morning sleepiness, daytime alertness, and daytime ability to
function.16
Indirect comparisons
Figure 6 shows outcomes at one week in placebo-controlled trials of eszopiclone and
zolpidem. The studies are not directly comparable because the doses varied and populations
differed in age and baseline severity of insomnia. In two studies in older adults, both zolpidem 5
mg and eszopiclone (1 mg and 2 mg) were more effective than placebo in reducing subjective
sleep latency. In two studies in adults, eszopiclone 3 mg, but not zolpidem 10 mg, was more
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effective than placebo. These studies varied considerably in their placebo response rates (37
minutes in the zolpidem 10 mg study vs 85 minutes in the eszopiclone 3 mg study), so they
cannot be used to draw conclusions about comparative efficacy. Results for sleep duration were
similar. On number of awakenings, zolpidem 10 mg and eszopiclone 3 mg were more effective
than placebo, but eszopiclone 1 mg and 2 mg (in older adults) were not.
Figure 6. Sleep outcomes at one week in placebo-controlled trials of zolpidem and
eszopiclone
Review: Sedative hypnotics Comparison: 01 Sleep latency
Outcome: 10 Sleep latency at 1 week including elderly: zolpidem vs eszopiclone
Study Treatment Placebo W MD (fixed) W MD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 1 mg
Scharf 2005 (older adults) 72 60.80(72.00) 80 97.50(115.00) -36.70 [-66.89, -6.51]
02 eszopiclone 2 mg
Scharf 2005 (older adults) 79 49.50(61.00) 80 97.50(115.00) -48.00 [-76.57, -19.43]
03 eszopiclone 3mg
Krystal (1909-049) 595 48.20(56.40) 196 85.40(81.10) -37.20 [-49.42, -24.98]
04 zolpidem 5 mg
Leppik 1997 (older adults) 82 44.70(3.00) 83 63.40(4.70) -18.70 [-19.90, -17.50]
05 zolpidem 10 mg
Dorsey 2004 68 33.00(4.18) 73 37.00(2.45) -4.00 [-5.14, -2.86]
-100 -50 0 50 100
Favors treatment Favors placebo
Review: Sedative hypnotics Comparison: 02 Sleep duration
Outcome: 03 Sleep duration at 1 week including elderly
Study Treatment Control W MD (fixed) W MD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 1 mg
Scharf 2005 (older adults) 72 345.80(80.00) 80 316.40(102.00) 29.40 [0.40, 58.40]
02 eszopiclone 2 mg
Scharf 2005 (older adults) 79 372.90(76.00) 80 316.40(102.00) 56.50 [28.56, 84.44]
03 eszopiclone 3 mg
Krystal (190-049) 595 372.50(85.70) 196 322.30(73.80) 50.20 [37.78, 62.62]
05 zolpidem 5 mg
Leppik 1997 (older adults) 82 353.40(6.10) 83 347.40(7.20) 6.00 [3.96, 8.04]
06 zolpidem 10 mg
Lahmeyer 1997 43 316.00(86.00) 52 315.00(83.00) 1.00 [-33.20, 35.20]
-100 -50 0 50 100
Favours control Favours treatment
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Review: Sedative hypnotics Comparison: 03 Number of awakenings
Outcome: 03 Number of awakenings at 1 week including elderly
Study Treatment Placebo WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 1 mg
Scharf 2005 (older adults) 72 2.20(1.20) 80 2.00(1.00) 0.20 [-0.15, 0.55]
02 eszopiclone 2 mg
Scharf 2005 (older adults) 79 1.80(1.00) 80 2.00(1.00) -0.20 [-0.51, 0.11]
03 eszopiclone 3 mg
Krystal 595 2.20(1.70) 196 2.80(2.10) -0.60 [-0.92, -0.28]
04 zolpidem 10 mg
Dorsey 2004 68 1.50(0.11) 73 2.30(0.11) -0.80 [-0.84, -0.76]
Lahmeyer 1997 45 1.20(0.13) 54 2.10(0.19) -0.90 [-0.96, -0.84]
Test for heterogeneity: Chi² = 7.21, df = 1 (P = 0.007), I² = 86.1%
-4 -2 0 2 4
Favors treatment Favors placebo
Figure 7 shows sleep outcomes at one month in placebo-controlled trials of zolpidem and
eszopiclone. Sleep latency was reported in 5 trials. One trial of zolpidem 5 mg was conducted
in older adults. Sleep latency was significantly shorter than placebo (mean difference –17.4
minutes; 95% CI –18.8 to –16.0 minutes). Eszopiclone 3 mg was significantly better than
placebo but eszopiclone 2 mg was not. Zolpidem 10 mg had mixed results in two studies. There
was no difference from placebo in one study in which placebo sleep latency was 31 minutes, but
in another study with more severe patients (placebo sleep latency 72.5 minutes), zolpidem 10 mg
was more effective than placebo (mean difference –34.9 minutes, 95% CI –57.6 to –12.2
minutes). This study was comparable to a study of eszopiclone 3 mg, where the placebo sleep
latency was 71.3 minutes and mean difference versus placebo was –27 minutes (95% CI –35.9 to
–18.1 minutes).
Two studies reported mean sleep duration and number of awakenings. Eszopiclone 3 mg
increased sleep duration more than placebo, but zolpidem 10 mg did not. For number of
awakenings, eszopiclone 3 mg and zolpidem 10 mg were more effective than placebo, but
eszopiclone 2 mg was not.
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Figure 7. Sleep outcomes at one month in placebo-controlled trials of zolpidem vs
eszopiclone
Review: Sedative hypnotics Comparison: 01 Sleep latency
Outcome: 11 Sleep latency at 1 month zolpidem vs eszopiclone including elderly
Study Treatment Placebo WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 2 mg
Zammit 2004 104 24.00(35.80) 99 30.20(28.20) -6.20 [-15.04, 2.64]
02 eszopiclone 3 mg
Krystal 595 44.30(36.50) 196 71.30(59.80) -27.00 [-35.87, -18.13]
Zammit 2004 105 18.10(26.10) 99 30.20(28.20) -12.10 [-19.57, -4.63]
Test for heterogeneity: Chi² = 6.34, df = 1 (P = 0.01), I² = 84.2%
03 zolpidem 5 mg
Leppik 1997 (older adults) 77 40.50(3.10) 75 57.90(5.60) -17.40 [-18.84, -15.96]
04 zolpidem 10 mg
Dorsey 2004 68 29.00(2.64) 73 31.00(2.90) -2.00 [-2.91, -1.09]
Scharf 1994 26 37.60(22.40) 24 72.50(52.60) -34.90 [-57.64, -12.16]
Test for heterogeneity: Chi² = 8.03, df = 1 (P = 0.005), I² = 87.5%
-100 -50 0 50 100
Favors treatment Favors placebo
Review: Sedative hypnotics Comparison: 02 Sleep duration
Outcome: 02 Sleep duration at 1 month
Study Treatment Control WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 3 mg
Krystal 2003 595 373.90(67.50) 196 331.10(69.80) 42.80 [31.62, 53.98]
02 zolpidem 10 mg
Scharf 1994 24 356.00(78.00) 26 340.00(68.00) 16.00 [-24.71, 56.71]
-100 -50 0 50 100
Favours control Favours treatment
Review: Sedative hypnotics Comparison: 03 Number of awakenings
Outcome: 02 Number of awakenings at 1 month
Study Treatment Placebo WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 2 mg
Zammit 2004 104 7.30(4.00) 99 6.50(4.50) 0.80 [-0.37, 1.97]
02 eszopiclone 3 mg
Krystal 2003 595 2.10(1.40) 196 2.80(2.60) -0.70 [-1.08, -0.32]
Zammit 2004 105 6.40(3.60) 99 6.50(4.50) -0.10 [-1.22, 1.02]
Subtotal (95% CI) 700 295 -0.64 [-1.00, -0.28]
Test for heterogeneity: Chi² = 0.98, df = 1 (P = 0.32), I² = 0%
03 zolpidem 10 mg
Dorsey 2004 68 1.40(0.12) 73 1.80(0.12) -0.40 [-0.44, -0.36]
Lahmeyer 1997 45 1.40(0.17) 54 1.70(0.20) -0.30 [-0.37, -0.23]
-4 -2 0 2 4
Favous treatment Favors placebo
Two placebo-controlled trials of eszopiclone also reported WASO, measured
polysomnographically. Results at different time periods are shown in Table 7 below.
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Table 7. Objective wake time after sleep onset (WASO) in placebo controlled trials of
eszopiclone (mean difference; 95% CI)
Drug, dose 1 day 1 week
Eszopiclone 2 mg –14.7 minutes
(–23.4 to –6.0)
--
Eszopiclone 3 mg –15.4 minutes
(–24.1 to –6.7)
–20.8 minutes
(–39.6 to –2.0)
Zolpidem extended release vs other newer drugs for insomnia
Direct comparisons
There are no head-to-head trials of zolpidem extended release compared to other newer
drugs for insomnia.
Indirect comparisons
No trial of zolpidem extended release has been fully published. The FDA review of
Ambien-CR is not yet publicly available. FDA approval was based on two placebo-controlled
trials of 3 weeks’ duration, one in adults95 and one in older adults.96
Information about placebo-controlled trials is limited to poster presentations.95, 96 Both
trials were rated fair-quality based on the information provided in these posters. Intention-totreat analyses were not conducted; analyses was performed on all patients who received at least
one dose of double-blind study treatment with at least one post-baseline data point. In the study
in adults, 9.4% of patients overall withdrew (8.8% of those taking zolpidem, 10% of those taking
placebo); in the study in older adults, 3.4% of patients overall withdrew (5.0% of those taking
zolpidem, 1.9% of those taking placebo). Neither poster reports the number analyzed, or at what
point these patients withdrew. In the study in older adults,96 there appear to be differences at
baseline in sleep data for zolpidem versus placebo patients. For example, the number of
awakenings in the placebo group was 4.1, compared with 6.2 in the zolpidem group. Baseline
sleep outcomes are controlled for in the analysis, however.
A placebo-controlled trial of zolpidem extended release 12.5 mg was conducted in 212
adults with primary insomnia.95 This study included 2 nights of PSG recording, 12 nights of
outpatient treatment, 2 more nights of PSG recording, 5 nights of outpatients treatment, and a 2night placebo run-out to measure rebound.
On objective measures (mean WASO, number of awakenings, sleep latency, and sleep
duration, all baseline-adjusted) patients improved compared with placebo on both 2-night PSG
assessment periods (nights 1-2 and nights 15-16).95
Subjective sleep outcomes are reported as the percentage of patients who reported
improvements on day 2, night 15, and night 22. Significantly more zolpidem extended releasetreated patients reported improvements on sleep latency, total time slept, sleep quality, and the
statement, “treatment helped me sleep.” Detailed data (e.g., difference from placebo in minutes)
is not reported in the poster. There was a rebound effect shown on the first night after
discontinuation (night 22) on sleep latency, sleep duration, and WASO; by night 23 the effect
was not seen.
Results of a placebo-controlled trial of zolpidem extended release 6.25 mg in 205 older
adults are available in a poster presentation.96 This trial had an identical design to the trial in
adults.95 Objective WASO, sleep latency, and sleep duration all improved on both 2-night PSG
assessment periods.
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On subjective sleep outcomes, there was significant improvement versus placebo in
patient global impression items on day 2, night 15, and night 22. The actual percentage of
patients who reported improvement is not presented in the poster, and the patient global
impression items are not specified. Subjective sleep quality was significantly improved on day
1-2. Subjective sleep quality at other endpoints is not reported.
There was a rebound effect in both studies after discontinuation on the first night after
discontinuation (night 22), but not on night 23.
Because the objective sleep data are baseline-adjusted, and subjective data are either
given only as the percentage of patients improved or not reported, it is not possible to make
indirect comparisons about the efficacy and safety of zolpidem extended release and other newer
insomnia drugs from these trials.
Eszopiclone vs Zaleplon
Direct comparisons
There are no head-to-head trials of eszopiclone versus zaleplon.
Indirect comparisons
Indirect comparisons from placebo-controlled trials are available only for the outcome of
sleep latency at one week for eszopiclone versus zaleplon (Figure 8). Both drugs were more
effective than placebo. There was more of a difference from placebo in the eszopiclone study,
but confidence intervals overlap. Additionally, the placebo sleep latency rate was higher in the
eszopiclone study than in the zaleplon study (85.4 minutes vs 63.3 minutes), indicating the
populations differed in severity and limiting conclusions that can be drawn from comparing these
studies.
Figure 8. Sleep latency at one week in placebo-controlled trials of eszopiclone and
zaleplon
Review: Sedative hypnotics Comparison: 01 Sleep latency
Outcome: 09 Sleep latency at 1 week eszopiclone vs zaleplon
Study Treatment Placebo WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 eszopiclone 3mg
Krystal 2003 595 48.20(56.40) 196 85.40(81.10) -37.20 [-49.42, -24.98]
595 196
02 zaleplon 10 mg
FDA 307 242 51.51(41.38) 153 63.26(43.67) -11.75 [-20.41, -3.09]
03 zaleplon 20 mg
FDA 307 242 55.10(45.73) 153 63.26(43.67) -8.16 [-17.16, 0.84]
-100 -50 0 50 100
Favors treatment Favors placebo
Zaleplon vs Zopiclone
Direct Comparisons
There are no head-to-head studies of zaleplon versus zopiclone.
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Indirect comparisons
Indirect comparisons of zaleplon versus zopiclone from placebo-controlled trials are
available only for the outcome of sleep latency at one week (Figure 9). Confidence intervals for
the mean difference from placebo overlapped, indicating the drugs were similarly effective.
Figure 9. Sleep latency at one week in placebo-controlled trials of zaleplon and
zopiclone
Review: Sedative hypnotics Comparison: 01 Sleep latency
Outcome: 04 Sleep latency at 1 week zaleplon versus zopiclone
Study Treatment Placebo WMD (fixed) WMD (fixed)
or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
02 zaleplon 10 mg
FDA 307 242 51.51(41.38) 153 63.26(43.67) -11.75 [-20.41, -3.09]
Subtotal (95% CI)
03 zaleplon 20 mg
FDA 307 242 55.10(45.73) 153 63.26(43.67) -8.16 [-17.16, 0.84]
06 zopiclone 7.5 mg
Chaudoir 1983 25 31.10(4.00) 25 49.10(4.50) -18.00 [-20.36, -15.64]
-100 -50 0 50 100
Favors treatment Favors placebo
One trial compared zaleplon to triazolam25 and two compared zopiclone to triazolam.34, 55
On sleep outcomes (time to sleep onset and duration of sleep), both zaleplon and zopiclone were
similarly efficacious to triazolam 0.25 mg. It is difficult to draw conclusions about the
comparative efficacy of zaleplon versus zopiclone from active-control studies, however, because
the duration of treatment and populations differed.
Ramelteon vs newer sedative hypnotics
Direct Comparisons
There are no head-to-head studies of ramelteon versus newer sedative hypnotics.
Indirect comparisons
Ramelteon has been compared to placebo in patients with chronic insomnia in 5 placebocontrolled trials.171 Two of these have been fully published; one in adults and one in older
adults.94, 172 Abstracts of two other trials173, 174 are available, but these reports do not contain
enough information to assess internal validity and are not included in this report.
A fair-quality crossover trial was conducted in 107 adults ages 18 to 64 years,
randomized to placebo or ramelteon 4 mg, 8 mg, 16 mg, or 32 mg.94 The primary outcome
measure was sleep latency, measured using PSG in a sleep laboratory after 2 days of treatment.
The design of this study is similar to that of a study of eszopiclone and zolpidem.14 Table
8 (first 2 rows) shows results of the primary outcome from the ramelteon study.94 The remaining
rows show results from a study of eszopiclone vs zolpidem. These studies are similar in their
designs, outcome measures, and placebo response rates, so they allow indirect comparisons of
ramelteon, zolpidem, and eszopiclone for the outcome of objective sleep latency. Objective
sleep latency was 4 to 8 minutes longer with ramelteon compared with zolpidem and
eszopiclone. Confidence intervals for the difference from placebo overlapped, however,
indicating that the drugs were similar on this outcome.
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Table 8. Objective sleep latency over 2 days in placebo-controlled trials of ramelteon,
zolpidem, and eszopiclone
Study, year
Drug, dose
Objective LPS
(mean), treatment
Objective LPS
(mean), placebo
Mean difference
vs placebo
(minutes)
Erman 200694 Ramelteon 8 mg 24.3 37.7 -13.7 (-20.4, -7.0)
Erman 200694 Ramelteon 16
mg 24.0 37.7 -13.4 (-20.0, -6.7)
Erman 200514 Zolpidem 10mg 16.6 37.8 -21.2 (-29.6, -12.8)
Erman 200514 Eszopiclone 2
mg 20.1 37.8 -17.7 (-26.5, -8.9)
Erman 200514 Eszopiclone 3
mg 18.3 37.8 -19.2 (-28.1, -10.3)
LPS, latency to persistent sleep
Subjective sleep outcomes (sleep latency, total sleep time, and sleep quality) were also
measured in the trial of ramelteon.94 There was no difference from placebo on any subjective
measure, with the exception of sleep latency at the 16 mg dose of ramelteon (-13.1 minutes; 95%
CI –24.3, –1.9). There were no significant next-day effects on alertness or ability to concentrate
associated with ramelteon.
A fair-quality, placebo-controlled trial of ramelteon 4 mg and 8 mg in 829 older adults
has also been published (Evidence Table 13).172 The primary outcome was sleep latency as
measured by patient sleep diaries; outcomes were reported for weeks 1, 3, and 5. Patients taking
ramelteon showed improvements in sleep latency at week 1 and week 5 (Table 9). At week 3,
the ramelteon 8 mg group was improved over placebo, but not the 4 mg group. Total sleep time
was increased in both ramelteon groups compared with placebo at week 1 and with the 4 mg
dose at week 3, but there was no difference with either dose at week 5.
Table 9. Subjective sleep outcomes in a placebo-controlled trial of ramelteon in older
adults
Outcome Ramelteon 4 mg
(p vs placebo)
Ramelteon 8 mg
(p vs placebo)
Placebo
Sleep latency
Week 1
Week 3
Week 5
70.2 minutes (p=0.008)
64.9 minutes (p=0.142)
63.4 minutes (p=0.028)
70.2 minutes (p=0.008)
60.3 minutes (p=0.003)
57.7 minutes (p<0.001)
78.5 minutes
69.3 minutes
70.6 minutes
Total sleep time
Week 1
Week 3
Week 5
324.6 minutes (p=0.004)
336.0 minutes (p=0.007)
337.5 minutes (p=0.104)
321.1 minutes (p=0.055)
332.1 minutes (p=0.071)
334.4 minutes (p=0.347)
313.9 minutes
324.3 minutes
330.1 minutes
There were no differences from placebo on other sleep outcomes, including number of
awakenings, ease of falling back to sleep after awakening, and sleep quality (data not reported).
There was no evidence of rebound insomnia or withdrawal effects, as measured on days 1
through 7 after discontinuation using a placebo run-out.
An unpublished trial in adults in which the primary outcome was subjective sleep latency
found no difference between ramelteon and placebo.171 It is not possible to assess this evidence
until the study is fully published with more details.
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Summary by Drug and Outcome
Table 10 summarizes the comparative evidence for short-term efficacy by drug and
outcome. Although there are some differences between the drugs on some outcomes no one drug
appeared to be consistently superior.
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Table 10. Summary of short-term efficacy by drug and outcome
Outcome Shorter sleep latency Longer sleep duration
Fewer number
of awakenings
Improved
sleep quality Daytime alertness
Less rebound
insomnia
Direct
evidence
Similar to zolpidem*
Similar to
zolpidem*
Similar to zolpidem
Eszopiclone Indirect
evidence
Similar to zolpidem Better than
zolpidem
Direct
evidence
Better than zolpidem Similar to
zolpidem
Similar to zolpidem Better than zolpidem
Zaleplon Indirect
evidence
Better than zolpidem
Similar to zopiclone
Direct
evidence
Similar to eszopiclone*
Better than
zaleplon
Similar to
zaleplon and
zopiclone
Better than
zaleplon
Similar to
eszopiclone and
zaleplon
Better than zopiclone
Zolpidem
Indirect
evidence
Similar to eszopiclone
Direct
evidence
Zolpidem
extended
release Indirect
evidence
Direct
evidence
Similar to zolpidem*
Similar to
zolpidem
Similar to
zolpidem
Zopiclone Indirect
evidence
Similar to zaleplon
Better than zolpidem
Direct
evidence
Ramelteon Indirect
evidence
Similar to zolpidem*
and eszopiclone*
*measured via PSG in a sleep laboratory
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Newer insomnia drugs vs benzodiazepines
Appendix D summarizes results of good or fair quality studies of newer drugs compared
with benzodiazepines in the general population of adults and older adults with insomnia. Details
of the populations, interventions, and outcomes of these trials are provided in Evidence Tables 4
through 8. We also included six active-control trials in subgroups of patients with comorbid
conditions; these are detailed in Evidence Tables 10 through 12.
There are no trials of eszopiclone, ramelteon, or zolpidem extended release versus
benzodiazepines, and the evidence for zaleplon versus benzodiazepines is limited to two fairquality trials versus triazolam. 25, 58
Zolpidem. We included one study of zolpidem versus flurazepam,28 two versus
temazepam,36, 56 and four versus triazolam.36, 40, 46, 49
In one study of zolpidem 10 mg or 20 mg versus flurazepam 30 mg, zolpidem was more
effective for sleep outcomes.28 Adverse events were similar for zolpidem 10 mg vs flurazepam,
but zolpidem 20 mg was associated with more adverse events.
Two studies of zolpidem versus temazepam,36, 56 found the drugs similar in efficacy and
rebound insomnia.
In two studies comparing zolpidem 10 mg to triazolam 0.25 mg,46, 49 sleep outcomes were
similar for the two drugs, but triazolam caused more rebound insomnia. There was also more
rebound insomnia with triazolam 0.25 mg compared to zolpidem 5 mg,46 and with triazolam 0.5
mg compared to zolpidem 10 mg.40
The NICE review97 presents an analysis of two studies of zolpidem versus nitrazepam
that were excluded from our review because they are not English language.(Kazamatsuri, 1993
and Kudo, 1993) There were no significant differences between drugs in sleep latency or
duration. In one study, more patients reported improved sleep quality with zolpidem (66.7% vs
37.5%, p=0.031),(Kudo, 1993) and there were fewer awakenings with zolpidem in the
other.(Kazamatsuri, 1993} There were no differences in adverse event rates (OR 0.70, 95% CI
0.37 to 1.30), and no difference in daytime alertness or global impression of treatment in either
study.
Zaleplon. In two trials of zaleplon compared to triazolam, the drugs were similar on most
sleep outcomes and short-term adverse events.25, 58 In one study, triazolam 0.25 mg was
associated with more nausea than zaleplon 5 mg.58 However, this outcome was with a low dose
of zaleplon (5 mg). In the same study, there was no difference between zaleplon 10 mg and
triazolam 0.25 mg.58
Zopiclone. Zopiclone has been compared to four benzodiazepines (flurazepam,
nitrazepam, temazepam, and triazolam). In five studies of zopiclone versus flurazepam,22, 27, 39,
41, 50 most comparisons found the two drugs to be similar in efficacy and adverse effects.
Zopiclone and triazolam were similar in efficacy and adverse events.24, 33, 34 For rebound
insomnia, results were mixed in two studies, with one finding triazolam causing more rebound29
and the other finding no difference.32
In studies of zopiclone versus nitrazepam,18, 35 efficacy and safety were similar, but
nitrazepam was associated with more rebound insomnia.
The NICE review97 presents an analysis of four studies of zopiclone versus temazepam.
No significant differences were found in the two studies that made direct comparisons on sleep
outcomes (sleep latency, sleep duration, number of awakenings, and sleep quality). Adverse
events were similar in the one study that made a direct comparison.
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Newer insomnia drugs vs trazodone
We identified one short-term, fair-quality study of zolpidem 10 mg versus trazodone 50
mg.57 Sleep latency was shorter with zolpidem after 1 week of treatment (48.2 vs 57.7 minutes,
p=0.037), but the difference was not significant at week 2 (48.1 vs 54.5 minutes, p not reported).
Sleep duration, number of awakenings, sleep quality, and patients’ global impressions of
treatment were similar for the drugs at weeks 1 and 2. The total numbers of adverse events and
withdrawals due to adverse events were similar between the drugs. More patients reported
somnolence with trazodone (16% vs 23%).
A trial of trazodone versus zaleplon, conducted in psychiatric inpatients, was rated poor
quality and does not provide additional comparative information about newer insomnia drugs
versus trazodone.48
Long-term Effectiveness
A fair-quality, 6-month placebo-controlled trial of eszopiclone 3 mg in 788 adults is the
longest-term trial of a newer insomnia drug.76 Results of this trial are summarized in Table 11.
Table 11. Results of 6-month placebo-controlled trial of eszopiclone 3 mg
Outcome
(difference
from
placebo)
Week 1 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6
Sleep
latency
(median,
minutes)
-30
(p<0.0001)
-21
(p<0.0001)
-20
(p<0.0001)
-15
(p<0.0001)
-15
(p<0.0001)
-14
(p<0.0001)
-15
(p<0.0001)
Sleep
duration
(median,
minutes)
+45
(p<0.0001)
+38
(p<0.0001)
+40
(p<0.0001)
+34
(p<0.0001)
+19
(p<0.0001)
+42
(p<0.0001)
+38
(p<0.0001)
Number of
awakenings
(median)
0
(p=0.0013)
-0.5
(p<0.0001)
-0.4
(p<0.0001)
-0.3
(p<0.0001)
-0.6
(p<0.0001)
-0.5
(p<0.0001)
-0.4
(p<0.0001)
Sleep
quality
(scale 1-10,
higher is
better)
+2.0
(p<0.0001)
+1.0
(p<0.0001)
+1.0
(p<0.0001)
+1.0
(p<0.0001)
+0.8
(p<0.0001)
+1.0
(p<0.0001)
+1.0
(p<0.0001)
Daytime
alertness
(scale 1-10,
higher is
better)
+1.0
(p<0.0001)
+0.5
(p<0.0001)
+0.6
(p<0.0001)
+0.8
(p<0.0001)
+0.7
(p<0.0001)
+0.7
(p<0.0001)
+0.8
(p<0.0001)
Eszopiclone 3 mg was more effective than placebo at all time periods through 6 months
on sleep latency, sleep duration, number of awakenings, sleep quality, and daytime alertness.
Rebound insomnia was not measured in this trial.
Although this trial provides evidence that eszopiclone 3 mg is efficacious versus placebo
for up to 6 months, it does not provide any information about the comparative efficacy and safety
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of eszopiclone versus other newer drugs for insomnia. There are no long-term trials of
eszopiclone at lower doses, although 2 mg is the recommended initial dose.
A second 6-month placebo-controlled trial of eszopiclone is currently available only as a
poster presentation.175 This trial also showed eszopiclone 3 mg was more effective than placebo
for sleep latency, WASO, total sleep time, number of awakenings, and sleep quality for each
month up to 6 months. There was no evidence of rebound insomnia or discontinuation effects
(results are reported graphically only).
Long-term Safety
There is limited evidence about the long-term safety of newer drugs for insomnia, and no
direct evidence about their comparative long-term safety. Results of observational studies of
adverse events are shown in Evidence Table 17.
Zaleplon. A one-year, open-label extension of a head-to-head trial8 was conducted to
assess the longer-term safety of zaleplon 5 mg in older patients.101 In order to qualify for the
extension phase, patients were required to have completed the trial and a placebo run-out period
of 7 days without adverse effects, so this study is limited to a highly selected sample of patients
less likely to experience discontinuation effects. Sixty-four percent of those completing the 2week trial enrolled in the extension study. Results of this open-label extension are reported in
combination with another extension study of a different, unpublished trial, also conducted in
older people. The most frequent adverse events were headache (27%) and infection (13%). The
most frequent adverse events resulting in discontinuation were pain (5%), somnolence or
dizziness (4%), and gastrointestinal disturbances (2%). There was a significant increase in
rebound sleep latency, number of awakenings, and reduced total time slept on the first night after
discontinuation, but these did not approach original baseline levels.
Zolpidem. Two open-label studies in general practice patients in France assessed the
safety of 6 months of treatment with zolpidem.110, 115
In an open-label study of zolpidem 10 mg or 20 mg,110 96 patients over age 40 in general
practice in France were followed for 6 months. Forty-nine patients continued treatment for an
additional 6 months. Patients were evaluated every 30 days. About 70% of patients used the 10
mg dose. In the first 6 months, 7.3% of patients withdrew due to adverse events considered
related to the drug, including a feeling of strangeness (1 patient), feeling of drunkenness (1
patient), anterograde amnesia (2 patients), nausea (1 patient), confusional episode (1 patient),
malaise (1 patient), vertigo (4 patients), daytime drowsiness (2 patients), unpleasant awakening
(1 patient), and diplopia (1 patient). Four of the 49 patients who continued treatment after 180
days withdrew (8%); two experienced nightmares, but these were not considered to be related to
the study drug. There were no reports of withdrawal or rebound phenomena.
Zopiclone. We identified no prospective studies that assessed the long-term safety of
zopiclone.
Eszopiclone. In a 6-month placebo-controlled trial of eszopiclone 3 mg,76 rates of serious
adverse events were 2.9% for eszopiclone and 1.0% for placebo. The most common serious
adverse events were gastrointestinal disorder (0.5% per group) and chest pain (0.5% per group).
Following discontinuation of the drug, there were similar overall rates of “new” events (defined
as those not seen during the treatment period, or a worsening of an event) in the placebo (10.7%)
and eszopiclone (11.2%) groups. There were no reports of seizures, hallucinations, or
perceptual-disturbance events. There was one report of anxiety in the eszopiclone group.
Adverse events occurred in 81.1% of the eszopiclone group versus 70.8% of the placebo group.
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The most common adverse event was unpleasant taste (26.1% eszopiclone vs 5.6% placebo).
Over 6 months, the rate of discontinuation due to adverse events was 12.8% in the eszopiclone
group and 7.1% in the placebo group. The most common reasons for discontinuation were
somnolence (2.2% eszopiclone vs 1.5% placebo), depression (2.0% vs 0%), unpleasant taste
(1.7% vs 0.5%), headache (0% vs 2%), asthenia (1% vs 1.5%), and insomnia (0% vs 1.5%).
A 6-month, open-label extension study of this trial has also been conducted.176 All
patients who completed the double-blind phase were eligible to participate in the open-label
extension. Of the 788 patients enrolled in the 6-month double-blind phase, 471 patients
continued into the 6-month open-label extension study (59.8%), and 382 completed a full 12
months of treatment (48.5%). Improvements in sleep outcomes were sustained; rebound
insomnia and withdrawal effects were not reported. During the extension study,176 3.8% of
patients discontinued due to adverse events. The most common treatment-related adverse events
were unpleasant taste (6.8%), headache (4.7%), somnolence (3.8%), abnormal dreams (3.0%),
and dizziness (2.5%).
Abuse and Dependence
Cases of abuse and dependence have been associated with zolpidem and zopiclone. 120,
121, 123, 132, 134, 139, 140, 142, 144-146, 149, 156-158, 162, 163, 168 A review of case reports and epidemiological
data of zolpidem abuse and dependence potential found most patients had a history of drug or
alcohol abuse or other psychiatric conditions.177
A 2003 survey of 297 patients admitted to addiction treatment sites in the United
Kingdom109 found that while zopiclone was used by many more subjects than zolpidem (53.7%
vs 5.8%), both drugs were similar in their use to induce sleep (88% vs 82%) or to get high
(22.9% vs 23.5%).
Eszopiclone, zaleplon, zolpidem extended release, and ramelteon have been in use for a
shorter period of time than zolpidem and zaleplon, so there is less information about their effects
over the long term. All of the newer insomnia drugs, with the exception of ramelteon, are
classified by the US Drug Enforcement Administration as controlled substances. Because of its
different mechanism of action, ramelteon is not considered to have the potential for abuse and
dependence that the newer sedative hypnotics have.
Key Question 3. Are there subgroups of patients based on demographics (age,
racial groups, gender), other medications, or co-morbidities for which one newer
insomnia drug is more effective or associated with fewer adverse events?
Summary of the Evidence
• Older adults (age >65 years)
- In a 2-week head-to-head trial of zolpidem vs zaleplon in older adults, efficacy was
similar to that in younger adults.
- Somnolence was more common (p<0.05) with zolpidem 5 mg (10%) than with
placebo (2%) or zaleplon 5 mg (4%), but there was no difference in overall adverse
events or in withdrawals due to adverse effects.
- A case-control study of the relationship of the use of zolpidem to hip fracture in
6,110 older women found an increased risk in patients using zolpidem (adjusted
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odds ratio vs nonuse 1.95; 95% CI 1.09-3.51). The risk was higher than for
benzodiazepines (adjusted odds ratio vs nonuse 1.46; 1.21-1.76)
• We found no evidence that one newer insomnia drug is safer or more effective in any
subgroup based on gender or race.
• Pregnancy
- In a prospective cohort study in 40 women with exposure to zopiclone in the first
trimester of pregnancy, zopiclone use was associated with lower mean birth weight
(3249 + 676 grams vs 3624 + 536 grams; p=0.01) and gestational age (38.3 + 2.7
weeks vs 40.0 + 1.6 weeks; p=0.002), but there were no differences in other
pregnancy outcomes.
- A prescription event monitoring study in the UK found no congenital anomalies
among 18 births in women who had taken either zolpidem or zopiclone during the
first trimester of pregnancy.
- No evidence is available about use in pregnancy for other newer insomnia drugs.
• Comorbid conditions
- There is evidence from active control trials that zopiclone is similar to
benzodiazepines for sleep outcomes and adverse effects in patients withdrawing
from alcohol, patients with generalized anxiety disorder, and inpatients with stroke.
- Zolpidem 5 mg, but not 10 mg, was more effective than triazolam 0.25 mg for some
sleep outcomes in patients with COPD.
Detailed Assessment
Older adults
One head-to-head trial,8 one placebo-controlled trial96 (discussed under Key Questions 1
and 2), six active-control trials (Evidence Tables 7-9),22, 26, 35, 36, 46, 55 and three observational
studies (Evidence Table 17)101, 111, 116 were conducted in older adults.
In a 2-week trial in older adults,8 somnolence was significantly more common (p<0.05)
with zolpidem 5 mg (10%) than with placebo (2%) or zaleplon 5 mg (4%). There was no
difference in overall adverse events or in withdrawals due to adverse events (see Table 6). A
one-year, open-label extension of this trial was conducted to assess the longer-term safety of
zaleplon in older patients.101 Adverse events were mild (see long-term safety section for more
details of this extension study).
A case-control study of the relationship of the use of zolpidem or other medications to
hip fracture in 6,110 older women found an increased risk in patients using zolpidem (adjusted
Odds Ratio 1.95; 95% CI 1.09-3.51).116 The risk was higher than for benzodiazepines (adjusted
Odds Ratio 1.46; 1.21-1.76). This study did not include other newer insomnia drugs, so it does
not provide information about the comparative risk of zolpidem versus other newer drugs for
insomnia.
An observational study used data from a representative survey of Medicare beneficiaries
to determine if the increased risk of hip fracture observed with sedative hypnotic use might be
due to confounding factors that are not available from claims data.117 These potential
confounders were BMI, current smoking status, activities of daily living (ADL) score, cognitive
impairment, and Rosow-Breslau physical impairment scale. The authors found that ADL score
was the strongest confounder, causing an overestimation of 10% when comparing zolpidem
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users with benzodiazepine users. They conclude, however, that the magnitude of the effect of
unmeasured confounders is unlikely to explain completely the elevations in hip fracture observed
in older sedative hypnotic users.
A good-quality systematic review and meta-analysis of pharmacological treatments for
insomnia in older people (at least 60 years) was recently published.99 The review included
studies of newer sedative hypnotics, along with benzodiazepines and over-the-counter
medications such as antihistamines. Only subjective sleep measures were included. Results are
combined for all sleep agents for most outcomes, so it is not possible to use this review to make
conclusions about the comparative efficacy and safety of newer sedative hypnotics to each other
or about newer sedative hypnotics to other sleep agents. Studies of zaleplon, zopiclone, and
zolpidem (combined) versus benzodiazepines found no significant difference in cognitive
adverse events (odds ratio 1.12; 95% CI 0.16 to 7.76), or psychomotor-type adverse events (odds
ratio 1.48; 95% CI 0.75 to 2.93).99 For all sedative hypnotics (newer and older), the number
needed to harm for all adverse events compared with placebo was 6 (95% CI 4.7 to 7.1), and the
number needed to treat compared with placebo for improved sleep quality was 13 (95% CI 6.7 to
62.9). On the basis of these results, the authors concluded that in older people, the benefit of
sleep agents may not outweigh their risks.
Gender and Racial Groups
We found no evidence that one newer insomnia drug is safer or more effective in
subgroups based on gender or race.
Use in Pregnancy
A prospective cohort study in Canada evaluated pregnancy outcomes following firsttrimester exposure to zopiclone in 40 women.106 The sample consisted of women who had
initiated contact with a program that provides counseling for pregnant women, so it is not
representative of the total population of women who were exposed to zopiclone in pregnancy.
Newborns in the zopiclone group had a significantly lower mean birth weight (3249 +
676 grams vs 3624 + 536 grams; p=0.01) and lower gestational age (38.3 + 2.7 weeks vs 40.0 +
1.6 weeks; p=0.002). Once birth weight was adjusted for gestational age, the differences were
no longer significant. There were no differences in outcome of pregnancy, delivery method,
assisted deliveries, fetal distress, and presence of meconium at birth, preterm deliveries, or
neonatal intensive care admissions between study and control groups.
A 1998 report of prescription-event monitoring studies of newly marketed drugs,
conducted in general practices in the UK, includes information on pregnancy outcomes in 23
women exposed to zolpidem and 18 exposed to zopiclone during pregnancy.178 In women who
had taken zolpidem, there were 2 spontaneous and 6 legal abortions; in those who had taken
zopiclone, there were 3 spontaneous and 3 legal abortions, and in one the outcome is unknown.
There were no congenital anomalies among the 18 births in women exposed to either drug.
Patients with Comorbid Conditions
There is evidence from active control trials that zopiclone is similar to benzodiazepines
for sleep outcomes and adverse effects in patients withdrawing from alcohol,19 patients with
generalized anxiety disorder,30 and inpatients with stroke.37
Zolpidem 5 mg, but not 10 mg, was more effective than triazolam 0.25 mg for some sleep
outcomes in a trial in patients with chronic obstructive pulmonary disease.51
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Placebo-controlled trials of zolpidem have been conducted in patients with depression64
and other psychiatric conditions,88 in peri- and postmenopausal women,68 and in patients with
fibromyalgia.79 Zaleplon has been studied in placebo-controlled trials in patients undergoing
kidney dialysis.85 Zopiclone has been compared to placebo in trials of patients with upper
airway resistance syndrome,78 rheumatoid arthritis,70 fibromyalgia,69, 72 and in shiftworkers.81
Eszopiclone was more effective than placebo for insomnia in patients with rheumatoid
arthritis,179 in patients with depression who were also taking fluoxetine,180 and in peri- and
postmenopausal women.181 While these studies provide evidence that these drugs are effective
for some sleep outcomes in certain patients with co-morbid conditions, they do not provide
evidence about the comparative efficacy of newer insomnia drugs in these subgroups.
Overall Summary
Table 12 summarizes the quality of the overall body of evidence for each key question.
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Table 12. Summary of the evidence by key question
Key Questions 1 and 2:
Benefits and Harms
Quality of Evidence Conclusion
Short-term efficacy and
safety: Pediatrics
Poor No evidence
Short-term efficacy and
safety: Adults
Good for zolpidem vs
zaleplon
Fair for zolpidem vs
zopiclone
Fair for zolpidem vs
eszopiclone
Poor for zolpidem
extended release vs
other newer drugs for
insomnia
Poor for zaleplon vs
zopiclone and
eszopiclone
Poor for ramelteon vs
newer sedative
hypnotics
There is evidence from four fair-quality head-to-head trials that
zaleplon is more effective than zolpidem for sleep latency, but
zolpidem is more effective than zaleplon for sleep duration and
sleep quality. The drugs were similar for number of awakenings
and daytime alertness. Zolpidem caused more rebound
insomnia than zaleplon on the first night after discontinuation.
Short-term adverse events and withdrawals due to adverse
events were similar.
One fair-quality head-to-head trial found that zolpidem and
zopiclone were similar in efficacy on patient-rated sleep
outcomes and investigator’s global assessment of improvement.
Zopiclone caused more rebound sleep latency insomnia than
zolpidem. Overall adverse events and effects of withdrawal were
similar in another study designed to measure withdrawal effects.
There is limited indirect evidence that zopiclone was more
effective for sleep latency at one week.
In one fair-quality head-to-head trial, zolpidem and eszopiclone
had similar objective sleep latency and Wake Time After Sleep
Onset. There was no difference between zolpidem and
eszopiclone on subjective measures of next-day effects.
Limited indirect comparisons provide evidence that the drugs
were similar for sleep latency and number of awakenings, but
eszopiclone was more effective for increasing sleep duration.
There are no head-to-head trials, and no active-control trials.
Two placebo-controlled trials, one in adults and one in older
adults, found zolpidem extended release superior to placebo on
objective and subjective sleep outcomes. These trials have not
been fully published, and method of reporting limits indirect
comparisons.
There are no head-to-head trials. Limited indirect comparisons
suggest the drugs are similar for sleep latency at one week.
Indirect comparisons for other sleep outcomes were not
possible.
There are no trials of ramelteon compared to newer sedative
hypnotics, benzodiazepines, or trazodone in patients with
insomnia.
One placebo-controlled crossover trial of 2 nights of treatment in
adults has been fully published. This trial provides indirect
evidence that ramelteon is similar to zolpidem and eszopiclone
for objective sleep latency. There was no difference between
ramelteon and placebo on any subjective measure, with the
exception of sleep latency at the 16 mg dose. There were no
significant next-day effects on alertness or ability to concentrate
associated with ramelteon
A 5-week placebo-controlled trial in older adults found ramelteon
4 mg and 8 mg more effective than placebo for subjective sleep
latency and total sleep time at some time points, but no different
from placebo on other subjective sleep outcomes. There was no
rebound insomnia.
Abstracts of additional placebo-controlled trials of ramelteon do
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Fair to poor for newer
insomnia drugs vs
benzodiazepines
Poor for newer
insomnia drugs vs
trazodone
not provide sufficient information to assess internal validity and
are not included.
There are no trials of eszopiclone versus benzodiazepines. Most
comparisons found the newer sedative hypnotics to be similar to
benzodiazepines in efficacy and short-term adverse events.
Some studies found less rebound insomnia with newer sedative
hypnotics.
We identified one fair-quality, short-term trial of zolpidem versus
trazodone. Sleep latency was shorter with zolpidem after 1 week
of treatment, but the difference was not significant at week 2.
Sleep duration, number of awakenings, sleep quality, and
patients’ global impressions of treatment were similar for the
drugs at weeks 1 and 2. More patients reported somnolence
with trazodone. Withdrawals due to adverse events and overall
adverse events were similar between the drugs.
A trial of zaleplon versus trazodone was rated poor quality.
Long-term efficacy and
safety
Fair for eszopiclone,
poor for others
Evidence about long-term efficacy and safety is limited; there is
no comparative evidence.
Two longer-term placebo-controlled trials (one available only as
a poster) provide evidence that eszopiclone 3 mg is efficacious
for up to 6 months, but do not add any information about the
comparative efficacy and safety of eszopiclone versus other
sedative drugs for insomnia. No withdrawal effects were
observed. There was no rebound insomnia in one trial; rebound
insomnia was not assessed in the other. In a 6-month openlabel extension of one trial, improvements in sleep outcomes
were sustained; 3.8% of patients discontinued due to adverse
events. Withdrawal effects and rebound insomnia were not
assessed.
A one-year open-label extension study of zaleplon in older adults
found most adverse events were mild. Sleep outcomes
worsened after discontinuation, but did not approach baseline
levels.
There are case reports of dependence with both zolpidem and
zopiclone.
Key Question 3:
Subgroups
Quality of Evidence Conclusion
Older adults (age > 65
years)
Fair
In a 2-week head-to-head trial of zolpidem vs zaleplon in older
adults, efficacy was similar to that in younger adults.
Somnolence was more common with zolpidem 5 mg (10%) than
with placebo (2%) or zaleplon 5 mg (4%), but there was no
difference in overall adverse events or in withdrawals due to
adverse effects.
In a placebo-controlled trial in older adults, zolpidem extended
release was superior to placebo for objective and subjective
sleep outcomes.
A case-control study of the relationship of the use of zolpidem to
hip fracture in 6,110 older women found an increased risk in
patients using zolpidem (adjusted odds ratio vs nonuse 1.95;
95% CI 1.09-3.51).
Gender and race Poor We found no evidence that one newer drug for insomnia is safer
or more effective in any subgroup based on gender or race.
Pregnancy Fair for zopiclone,
poor for others
In a prospective cohort study in 40 women with exposure to
zopiclone in the first trimester of pregnancy, zopiclone use was
associated with lower mean birth weight and gestational age, but
there were no differences in other pregnancy outcomes. A
prescription event monitoring study in the UK found no
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congenital anomalies among 18 births in women who had taken
either zolpidem or zopiclone during the first trimester of
pregnancy.
No evidence is available about use in pregnancy for other newer
drugs for insomnia.
Patients with comorbid
conditions.
Poor There is no comparative evidence in patients with comorbid
conditions. There is evidence from active control trials that
zopiclone is similar to benzodiazepines for sleep outcomes and
adverse effects in patients withdrawing from alcohol, patients
with generalized anxiety disorder, and inpatients with stroke.
Zolpidem 5 mg, but not 10 mg, was more effective than triazolam
0.25 mg for some sleep outcomes in patients with COPD.
Placebo-controlled trials do not provide additional comparative
evidence.
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164. Toner LC, Tsambiras BM, Catalano G, Catalano MC, Cooper DS. Central nervous
system side effects associated with zolpidem treatment. Clin. Neuropharmacol.
2000;23(1):54-58.
165. Tripodianakis J, Potagas C, Papageorgiou P, Lazaridou M, Matikas N. Zolpidem-related
epileptic seizures: A case report. European Psychiatry. May 2003;18(3):140-141.
166. Tsai M-J, Huang Y-B, Wu P-C. A Novel Clinical Pattern of Visual Hallucination after
Zolpidem Use. Journal of Toxicology - Clinical Toxicology. 2003;41(6):869-872.
167. Van Puijenbroek EP, Egberts ACG, Krom HJ. Visual hallucinations and amnesia
associated with the use of zolpidem Int. J. Clin. Pharmacol. Ther. 1996;34:318%N 317.
168. Vartzopoulos D, Bozikas V, Phocas C, Karavatos A, Kaprinis G. Dependence on
zolpidem in high dose. Int. Clin. Psychopharmacol. 2000;15(3):181-182.
169. Vogel SD, Bayliff CD, George CFP. Zopiclone-associated respiratory depression.
Canadian Journal of Hospital Pharmacy. 1998;51(2):58-60.
170. Yang W, Dollear M, Muthukrishnan SR. One rare side effect of zolpidem--sleepwalking:
a case report. Archives of Physical Medicine & Rehabilitation. Jun 2005;86(6):12651266.
171. FDA. Statistical review of ramelteon.
http://www.fda.gov/cder/foi/nda/2005/021782s000_Rozerem_statr.pdf.
172. Roth T, Seiden D, Sainati S, Wang-Weignad S, Zhang J, Zee P. Effects of ramelteon on
patient-reported sleep latency in older adults with chronic insomnia. Sleep Medicine.
2006:Article in Press.
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173. Griffiths RR, Suess P, Johnson M. Ramelteon and triazolam in humans: behavior effects
and abuse potential. Sleep. 2005;28(Supplement):A4.
174. Roth T, Seiden S, Weigand S, Zhang J, Rieckhoff H, Sainati S. Phase III study to
determine the efficacy of ramelteon in elderly patients with chronic insomnia.
Proceedings of New Clinical Drug Evaluation Unit. 2005(303).
175. Krystal A, Walsh J, Roth T, Rubens R, Wessel TC. Evaluation of the efficacy and safety
of eszopiclone over six-months of treatment in patients with insomnia [poster].
176. Roth T, Walsh JK, Krystal A, Wessel T, Roehrs TA. An evaluation of the efficacy and
safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep
Medicine. 2005;6(6):487-495.
177. Hajak G, Muller WE, Wittchen HU, Pittrow D, Kirch W. Abuse and dependence
potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: A review of case
reports and epidemiological data. Addiction. 2003;98(10):1371-1378.
178. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy
in women exposed to newly marketed drugs in general practice in England. Br. J. Obstet.
Gynaecol. 1998;105(8):882-889.
179. Schnitzer T, Rubens R, Price J, Wessel TC. The effect of eszopiclone 3 mg compared
with placebo in patients with rheumatoid arthritis and co-existing insomnia [poster].
180. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in
patients with insomnia coexisting with major depressive disorder. Biol. Psychiatry. 2006
in press.
181. Soares C, Rubens R, Amato D, et al. Evaluation of eszopiclone in insomnia associated
with menopausal transition [poster].
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Appendix A. Literature search strategies
Newer Drugs for Insomnia included interventions:
1. zaleplon (Sonata/Starnoc in Canada)
2. zolpidem (Ambien)**
3. zolpidem tartrate (Ambien CR)**
4. zopiclone (Imovane)*
5. eszopiclone (Lunesta)**
6. ramelteon (Rozerem)**
* available in Canada
** available in the US but not in Canada
Database: Medline 1966 -- November Week 3 2005
Embase 1985 -- 2005 (March)
Cochrane -- 4th Quarter 2005
PsycINFO --1985 to December Week 4 2005
Search Strategy:
--------------------------------------------------------------------------------
1 (zaleplon or zolpidem or zopiclone or eszopiclone).mp. [mp=title, original title, abstract,
name of substance word, subject heading word]
2 limit 1 to yr="2004 - 2006"
3 (sonata or ambien or Imovane or lunesta or estorra or stilnoct or zimovane or zileze).mp.
[mp=title, original title, abstract, name of substance word, subject heading word]
4 limit 3 to yr="2004 - 2006"
5 2 or 4
6 (zolpidem tartrate or ramelteon).mp. [mp=title, original title, abstract, name of substance
word, subject heading word]
7 (Starnoc or "Ambien CR" or Rozerem).mp. [mp=title, original title, abstract, name of
substance word, subject heading word]
8 5 or 6
10 from 8 keep 1-222
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Appendix B. Quality assessment methods for drug class reviews for the Drug
Effectiveness Review Project
The purpose of this document is to outline the methods used by the Oregon Evidence-based
Practice Center (EPC), based at Oregon Health & Science University, and any subcontracting
EPCs, in producing drug class reviews for the Drug Effectiveness Review Project.
The methods outlined in this document ensure that the products created in this process are
methodologically sound, scientifically defensible, reproducible, and well-documented. This
document has been adapted from the Procedure Manual developed by the Methods Work Group
of the United States Preventive Services Task Force (version 1.9, September 2001), with
additional material from the NHS Centre for Reviews and Dissemination (CRD) report on
Undertaking Systematic Reviews of Research on Effectiveness: CRD’s Guidance for Carrying
Out or Commissioning Reviews (2nd edition, 2001) and “The Database of Abstracts of Reviews
of Effects (DARE)” in Effectiveness Matters, vol. 6, issue 2, December 2002, published by the
CRD.
All studies or systematic reviews that are included are assessed for quality, and assigned a rating
of “good”, “fair” or “poor”. Studies that have a fatal flaw in one or more criteria are rated poor
quality; studies which meet all criteria, are rated good quality; the remainder are rated fair
quality. As the “fair quality” category is broad, studies with this rating vary in their strengths
and weaknesses: the results of some fair quality studies are likely to be valid, while others are
only probably valid. A “poor quality” trial is not valid—the results are at least as likely to
reflect flaws in the study design as the true difference between the compared drugs.
For Controlled Trials:
Assessment of Internal Validity
1. Was the assignment to the treatment groups really random?
Adequate approaches to sequence generation:
Computer-generated random numbers
Random numbers tables
Inferior approaches to sequence generation:
Use of alternation, case record numbers, birth dates or week days
Not reported
2. Was the treatment allocation concealed?
Adequate approaches to concealment of randomization:
Centralized or pharmacy-controlled randomization
Serially-numbered identical containers
On-site computer based system with a randomization sequence that is not
readable until allocation
Other approaches sequence to clinicians and patients
Inferior approaches to concealment of randomization:
Use of alternation, case record numbers, birth dates or week days
Open random numbers lists
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Serially numbered envelopes (even sealed opaque envelopes can be subject to
manipulation)
Not reported
3. Were the groups similar at baseline in terms of prognostic factors?
4. Were the eligibility criteria specified?
5. Were outcome assessors blinded to the treatment allocation?
6. Was the care provider blinded?
7. Was the patient kept unaware of the treatment received?
8. Did the article include an intention-to-treat analysis, or provide the data needed to calculate it
(i.e., number assigned to each group, number of subjects who finished in each group, and their
results)?
9. Did the study maintain comparable groups?
10. Did the article report attrition, crossovers, adherence, and contamination?
11. Is there important differential loss to followup or overall high loss to followup? (give
numbers in each group)
Assessment of External Validity (Generalizability)
1. How similar is the population to the population to whom the intervention would be applied?
2. How many patients were recruited?
3. What were the exclusion criteria for recruitment? (Give numbers excluded at each step)
4. What was the funding source and role of funder in the study?
5. Did the control group receive the standard of care?
6. What was the length of followup? (Give numbers at each stage of attrition.)
For Studies Reporting Complications/Adverse Effects
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Assessment of Internal Validity
1. Was the selection of patients for inclusion non-biased (Was any group of patients
systematically excluded)?
2. Is there important differential loss to followup or overall high loss to followup? (Give numbers
in each group.)
3. Were the events investigated specified and defined?
4. Was there a clear description of the techniques used to identify the events?
5. Was there non-biased and accurate ascertainment of events (independent ascertainer;
validation of ascertainment technique)?
6. Were potential confounding variables and risk factors identified and examined using
acceptable statistical techniques?
7. Did the duration of followup correlate to reasonable timing for investigated events? (Does it
meet the stated threshold?)
Assessment of External Validity
1. Was the description of the population adequate?
2. How similar is the population to the population to whom the intervention would be applied?
3. How many patients were recruited?
4. What were the exclusion criteria for recruitment? (Give numbers excluded at each step)
5. What was the funding source and role of funder in the study?
Systematic Reviews:
1. Is there a clear review question and inclusion/exclusion criteria reported relating to the
primary studies?
A good quality review should focus on a well-defined question or set of questions, which
ideally will refer to the inclusion/exclusion criteria by which decisions are made on whether
to include or exclude primary studies. The criteria should relate to the four components of
study design, indications (patient populations), interventions (drugs), and outcomes of
interest. In addition, details should be reported relating to the process of decision-making,
i.e., how many reviewers were involved, whether the studies were examined independently,
and how disagreements between reviewers were resolved.
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2. Is there evidence of a substantial effort to search for all relevant research?
This is usually the case if details of electronic database searches and other identification
strategies are given. Ideally, details of the search terms used, date and language restrictions
should be presented. In addition, descriptions of hand-searching, attempts to identify
unpublished material, and any contact with authors, industry, and research institutes should
be provided. The appropriateness of the database(s) searched by the authors should also be
considered, e.g. if MEDLINE is searched for a review looking at health education, then it is
unlikely that all relevant studies will have been located.
3. Is the validity of included studies adequately assessed?
A systematic assessment of the quality of primary studies should include an explanation of
the criteria used (e.g., method of randomization, whether outcome assessment was blinded,
whether analysis was on an intention-to-treat basis). Authors may use either a published
checklist or scale, or one that they have designed specifically for their review. Again, the
process relating to the assessment should be explained (i.e. how many reviewers involved,
whether the assessment was independent, and how discrepancies between reviewers were
resolved).
4. Is sufficient detail of the individual studies presented?
The review should demonstrate that the studies included are suitable to answer the question
posed and that a judgement on the appropriateness of the authors' conclusions can be made.
If a paper includes a table giving information on the design and results of the individual
studies, or includes a narrative description of the studies within the text, this criterion is
usually fulfilled. If relevant, the tables or text should include information on study design,
sample size in each study group, patient characteristics, description of interventions, settings,
outcome measures, follow-up, drop-out rate (withdrawals), effectiveness results and adverse
events.
5. Are the primary studies summarized appropriately?
The authors should attempt to synthesize the results from individual studies. In all cases,
there should be a narrative summary of results, which may or may not be accompanied by a
quantitative summary (meta-analysis).
For reviews that use a meta-analysis, heterogeneity between studies should be assessed using
statistical techniques. If heterogeneity is present, the possible reasons (including chance)
should be investigated. In addition, the individual evaluations should be weighted in some
way (e.g., according to sample size, or inverse of the variance) so that studies that are
considered to provide the most reliable data have greater impact on the summary statistic.
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Appendix C. Excluded Trials
307 trials were excluded with the exclusion code shown below (new trials from Update 1
are highlighted in gray-scale)
Codes:
1 = Foreign language
2 = Wrong outcome
3 = Wrong drug (including combination therapy)
4 = Wrong population
5 = Wrong publication type (letter, editorial, nonsystematic review, etc.)
6 = Wrong design (including dose-ranging study,
pharmacokinetics, single-dose study, drug
interaction)
7 = cannot find the study
8 = duplicated study
AO = abstract only
Poster= Poster only
Trials Code
Abe K, Hikita T, Sakoda S. A hypnotic drug for sleep disturbances in
patients with Parkinson's disease. No to Shinkei - Brain & Nerve. Apr
2005;57(4):301-305.
1
Allain H, Bentue-Ferrer D, Tarral A, Gandon JM. Effects on postural
oscillation and memory functions of a single dose of zolpidem 5 mg,
zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A
randomized, cross-over, double-blind study versus placebo. European
Journal of Clinical Pharmacology. 2003;59(3):179-188.
4
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.
(AO)
Allain H, Patat A, Lieury A, et al. Comparative study of the effects of
zopiclone (7.5 mg), zolpidem, flunitrazepam and a placebo on nocturnal
cognitive performance in healthy subjects, in relation to pharmacokinetics.
European Psychiatry. 1995;10(Suppl 3):129S-135S.
4
Allen D, Curran HV, Lader M. The effects of single doses of CL284,846,
lorazepam, and placebo and psychomotor and memory function in normal
male volunteers. European Journal of Clinical Pharmacology.
1993;45(4):313-320.
4
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Trials Code
Amsterdam JD, Brunswick DJ, Hundert M. A single-site, double-blind,
placebo-controlled, dose-ranging study of YKP10A - A putative, new
antidepressant. Progress in Neuro-Psychopharmacology and Biological
Psychiatry. 2002;26(7-8):1333-1338.
3
Amsterdam JD. A double-blind, placebo-controlled trial of the safety and
efficacy of selegiline transdermal system without dietary restrictions in
patients with major depressive disorder. Journal of Clinical Psychiatry.
2003;64(2):208-214.
3
Ansseau M, Pitchot W, Hansenne M, Gonzalez Moreno A. Psychotic
reactions to zolpidem. Lancet. 1992;339:809; 8796.
4
Aranko K, Luurila H, Backman JT, Neuvonen PJ, Olkkola KT. The effect
of erythromycin on the pharmacokinetics and pharmacodynamics of
zopiclone. British Journal of Clinical Pharmacology. 1994;38(4):363-367.
4
Arbus L, Lavoisy J, Belin J, Soubrane C. Efficacy and safety of zolpidem
10 mg administered pro re nata (P.R.N) during 4 weeks in patients with
chronic insomnia. Journal of the European College of
Neuropsychopharmacology. 1999;9(Suppl 5):S309.
(AO)
Balkin TJ, O'Donnell VM, Wesensten N, McCann U, Belenky G.
Comparison of the daytime sleep and performance effects of zolpidem
versus triazolam. Psychopharmacology. 1992;107(1):83-88.
4
Beaumont G, Holland RL. A multi-centre open study in general practice to
evaluate the efficacy and acceptability of zopiclone 7.5 mg nocte in patients
requiring the prescription of an hypnotic. International Clinical
Psychopharmacology. 1990;5 Suppl 2:11-20.
6
Beaumont M, Batejat D, Coste O, et al. Effects of zolpidem and zaleplon on
sleep, respiratory patterns and performance at a simulated altitude of 4,000
m. Neuropsychobiology. 2004;49(3):154-162.
6
Beaumont M, Goldenberg F, Lejeune D, Marotte H, Harf A, Lofaso F.
Effect of zolpidem on sleep and ventilatory patterns at simulated altitude of
4,000 meters. American Journal of Respiratory & Critical Care Medicine.
1996;153(6 Pt 1):1864-1869.
4
Beaupre A, Soucy R, Phillips R, Bourgouin J. Respiratory center output
following zopiclone or diazepam administration in patients with pulmonary
disease. Respiration. 1988;54(4):235-240.
2
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Trials Code
Bech P, Tanghoj P, Cialdella P, Andersen HF, Pedersen AG. Escitalopram
dose-response revisited: an alternative psychometric approach to evaluate
clinical effects of escitalopram compared to citalopram and placebo in
patients with major depression. International Journal of
Neuropsychopharmacology. Sep 2004;7(3):283-290.
3
Bechelli LP, Navas F, Pierangelo SA. Comparison of the reinforcing
properties of zopiclone and triazolam in former alcoholics. International
Pharmacopsychiatry. 1982;17 Suppl 2:235-241.
4
Beer B, Ieni JR, Wu W-H, et al. A placebo-controlled evaluation of single,
escalating doses of CL 284,846, a non-benzodiazepine hypnotic. Journal of
Clinical Pharmacology. 1994;34(4):335-344.
4
Benoit O, Bouard G, Payan C, Borderies P, Prado J. Effect of a single dose
(10 mg) of zolpidem on visual and spectral analysis of sleep in young poor
sleepers. Psychopharmacology. 1994;116(3):297-303.
2
Bensimon G, Foret J, Warot D, Lacomblez L, Thiercelin JF, Simon P.
Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg,
flunitrazepam 2 mg and placebo. British Journal of Clinical Pharmacology.
1990;30(3):463-469.
4
Bergener M, Kranzhoff EU, Schwalb B, Fischer W. Sleep disorders in the
elderly - Results of a multicenter study with zopiclone.
Pharmacopsychiatry. 1995;28(165).
6
Berlin I, Warot D, Hergueta T, Molinier P, Bagot C, Puech AJ. Comparison
of the effects of zolpidem and triazolam on memory functions, psychomotor
performances, and postural sway in healthy subjects. Journal of Clinical
Psychopharmacology. 1993;13(2):100-106.
4
Berthelon C, Bocca ML, Denise P, Pottier A. Do zopiclone, zolpidem and
flunitrazepam have residual effects on simulated task of collision
anticipation? Journal of Psychopharmacology. 2003;17(3):324-331.
2
Bertschy G, Ragama-Pardos E, Muscionico M, et al. Trazodone addition for
insomnia in venlafaxine-treated, depressed inpatients: A semi-naturalistic
study. Pharmacological Research. 2005;51(1):79-84.
3
Besset A, Tafti M, Villemin E, Borderies P, Billiard M. Effects of zolpidem
on the architecture and cyclical structure of sleep in poor sleepers. Drugs
under Experimental and Clinical Research. 1995;21(4):161-169.
6
Billiard M, Besset A, de Lustrac C, Brissaud L. Dose-response effects of
zopiclone on night sleep and on nighttime and daytime functioning. Sleep.
1987;10(1):27-34.
4
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Trials Code
Biondi F, Casadei GL. Results of a multicenter trial with the hypnotic
zolpidem in 1152 insomniac patients. Current Therapeutic Research Clinical and Experimental. 1994;55(3):262-274.
6
Blin O, Micallef-Rolle J, Legangneux E, Zobouyan I. Zolpidem modifiedrelease 12.5 mg has no residual effects on psychomotor performance and
cognitive function in health adult subjects. Sleep. 2005;28(Suppl):A246.
(Poster)
Bliwise DL, Freeman A, Ingram CD, Rye DB, Chakravorty S, Watts RL.
Randomized, double-blind, placebo-controlled, short-term trial of ropinirole
in restless legs syndrome. Sleep Medicine. 2005;6(2):141-147.
3
Blois R, Gaillard JM, Attali P, Coquelin JP. Effect of zolpidem on sleep in
healthy subjects: a placebo-controlled trial with polysomnographic
recordings. Clinical Therapeutics. 1993;15(5):797-809.
4
Bocca ML, Le Doze F, Etard O, Pottier M, L'Hoste J, Denise P. Residual
effect of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg
and placebo on driving performance and ocular saccades.
Psychopharmacology. 1999;143(4):373-379.
4
Boissl K, Dreyfus JF, Delmotte M. Studies on the dependence-inducing
potential of zopiclone and triazolam. International Pharmacopsychiatry.
1982;17(2):242-247.
4
Bond A, Lader M. Correlations among measures of response to
benzodiazepines in man. Pharmacology, Biochemistry & Behavior. Feb
1983;18(2):295-298.
6
Boniface PJ, Martin IC, Nolan SL, Tan ST. Development of a method for
the determination of zopiclone in whole blood. Journal of Chromatography
- Biomedical Applications. 1992;584(2):199-206.
2
Borgen L. Trial effects of oral Xyrem and Zolpidem on sleep-disordered
breathing in obstructive sleep apnea patients. clinicaltrials.gov. 2004.
2
Boulanger-Rostowsky L, Fayet H, Benmoussa N, Ferrandi J. Dependence
on zolpidem: a report of two cases. Encephale. Mar-Apr 2004;30(2):153155.
1
Brunelle E, Rotily M, Lancon C, et al. Letter to the Editor: Zolpidem:
Intravenous misuse in drug abusers. Addiction. Sep 2005;100(9):1377-1378.
4
Burton JH, Lyon L, Dorfman T, Tomassoni AJ. Continuous flumazenil
infusion in the treatment of zolpidem (Ambien(registered trademark)) and
ethanol coingestion [1]. Journal of Toxicology - Clinical Toxicology.
1998;36(7):743-746.
2
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Trials Code
Busto UE, Sproule BA, Knight K, Herrmann N. Use of prescription and
nonprescription hypnotics in a Canadian elderly population. Canadian
Journal of Clinical Pharmacology. 2001;8(4):213-221.
6
Caldwell J, Caldwell JL. Comparison of the effects of zolpidem-induced
prophylactic naps to placebo naps and forced rest periods in prolonged work
schedules. Sleep. 1998;21(1):79-90.
4
Cashman JN, Power SJ, Jones RM. Assessment of a new hypnotic imidazopyridine (zolpidem) as oral premedication. British Journal of Clinical
Pharmacology. 1987;24(1):85-92.
4
Cashman JN, Power SJ. An evaluation of tests of psychomotor function in
assessing recovery following a brief anaesthetic. Acta Anaesthesiologica
Scandinavica. 1989;33(8):693-697.
2
Caville P. Homeopathy in dementia and agitation. Homeopathy.
2002;91(2):109-112.
5
Chang M-Y, Lin J-L. Irreversible Ischemic Hand Following Intraarterial
Injection of Zolpidem Powder. Journal of Toxicology - Clinical Toxicology.
2003;41(7):1025-1028.
2
Channer KS, Dent M, Roberts CJC. The effect of posture at the time of
administration on the central depressant effects on the new hypnotic
zopiclone. British Journal of Clinical Pharmacology. 1984;18(6):879-886.
2
Cialdella P, Boissel JP, Belon P. Homeopathic specialities as a substitute for
benzodiazepines: A double-blind vs. placebo study. Therapie. 2001;4:397402.
3
Cipriani A, Brambilla P, Furukawa T, et al. Fluoxetine versus other types of
pharmacotherapy for depression [Systematic Review]. Cochrane Database
of Systematic Reviews. 2005;4:4.
2
Clauss RP, Guldenpfennig WM, Nel HW, Sathekge MM, Venkannagari
RR. Extraordinary arousal from semi-comatose state on zolpidem. South
African Medical Journal. 2000;90(1):68-72.
2
Cluydts R, De Roeck J, Cosyns P, Lacante P. Antagonizing the effects of
experimentally induced sleep disturbance in healthy volunteers by
lormetazepam and zolpidem. Journal of Clinical Psychopharmacology.
1995;15(2):132-137.
4
Cluydts R, Heyde K, De Volder I. Polysomnographic findings during noncontinuous administration of zolpidem. Sleep Medicine Reviews.
2002;6(SUPPL. 1):S13-S19.
6
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Trials Code
Cluydts R, Peeters K, De Bouyalsky I, Lavoisy J. A pilot, randomized,
double-blind study of zolpidem 10 mg comparing intermittent versus
continuous administration. Sixth World Congress of Biological Psychiatry,
Nice, France. June. 1997.
6
Cluydts R, Peeters K, de Bouyalsky I, Lavoisy J. Comparison of continuous
versus intermittent administration of zolpidem in chronic insomniacs: a
double-blind, randomized pilot study. Journal of International Medical
Research. 1998;26(1):13-24.
6
Cluydts RJ, De Roeck JM, Jolie AM. A three week multicentre general
practitioner study of zoldipem in 651 patients with insomnia. Acta
Therapeutica. 1993;19(1):73-91.
6
Cohn MA. Effects of zolpidem, codeine phosphate and placebo on
respiration. A double-blind, crossover study in volunteers. Drug Safety.
1993;9(4):312-319.
4
Coleman DE, Ota K. Hallucinations with zolpidem and fluoxetine in an
impaired driver. Journal of Forensic Sciences. Mar 2004;49(2):392-393.
4
Colle M, Rosenzweig P, Bianchetti G, et al. Nocturnal profile of growth
hormone secretion during sleep induced by zolpidem: a double-blind study
in young adults and children. Hormone Research. 1991;35(1):30-34.
2
Colle M, Rosenzweig P, Bianchetti G, et al. Nocturnal profile of growth
hormone secretion during sleep induced by zolpidem: a double-blind study
in young adults and children. Hormone Research. 1991;35(1):30-34.
2
Conway DH, Turner SJ, Eddleston J, Guthrie E. Sedation on intensive care:
A pathway into dependence. Care of the Critically Ill. 2001;17(5):170-171.
6
Corrigan MH, Gallen CC, Bonura ML, Merchant KM. Effectiveness of the
selective D4 antagonist sonepiprazole in schizophrenia: A placebocontrolled trial. Biological Psychiatry. 2004;55(5):445-451.
3
Coskunol H, Gokden O, Ercan ES, Bayraktar E, Tuglular I, Saygili R.
Long-term efficacy of sertraline in the prevention of alcoholic relapses in
alcohol-dependent patients: A single-center, double-blind, randomized,
placebo-controlled, parallel-group study. Current Therapeutic Research Clinical and Experimental. 2002;63(11):759-771.
3
Danjou P, Paty I, Fruncillo R, et al. A comparison of the residual effects of
zaleplon and zolpidem following administration 5 to 2 h before awakening.
British Journal of Clinical Pharmacology. 1999;48(3):367-374.
4
Darko W, Guharoy R, Rose F, Lehman D, Pappas V. Myoclonus secondary
to the concurrent use of trazodone and fluoxetine. Veterinary and Human
Toxicology. 2001;43(4):214-215.
3
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Trials Code
Darwish M, Parker V, Harper D, Leister C, Raible D, Fruncillo R. The lack
of drug interactions between zaleplon and venlafaxine extended release.
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Appendix D. Summary of results of trials of newer insomnia drugs versus benzodiazepines
Comparators KQ outcome Hypnotic Benzodiazepine
(No. of Studies)
Citations
Zaleplon vs Triazolam
Effectiveness outcomes Zaleplon 5, 10mg =,= Triazolam 0.25mg (2) 1, 2
Effectiveness outcomes Zaleplon 20mg < Triazolam 0.25mg (1) 2
Effectiveness outcomes Zaleplon 40-60mg Mixed Triazolam 0.25mg (1) 2
Safety outcomes Zaleplon 5, 10mg = Triazolam 0.25mg (1) 1
Nausea Zaleplon 5mg > Triazolam 0.25mg (1) 1
Zolpidem vs Flurazepam
Effectiveness outcomes Zolpidem 10, 20mg > Flurazepam 30mg (1) 3
Safety outcomes Zolpidem 10mg = Flurazepam 30mg (1) 3
Safety outcomes Zolpidem 20mg < Flurazepam 30mg (1) 3
Zolpidem vs Temazepam
Effectiveness outcomes Zolpidem 5mg = Temazepam 15mg (1) 4
Effectiveness outcomes Zolpidem 10mg = Temazepam 20mg (1) 5
Less rebound Zolpidem 10mg = Temazepam 20mg (1) 5
Zolpidem vs Trazodone
Effectiveness outcomes Zolpidem 10mg = Trazodone 50mg (1) 6
Zolpidem vs Triazolam
Effectiveness outcomes Zolpidem 5mg > Triazolam 0.125mg (1) 4
Effectiveness outcomes Zolpidem 10mg =,= Triazolam 0.25mg (2) 7, 8
Effectiveness outcomes Zolpidem 10mg > Triazolam 0.5mg (1) 9
Less rebound Zolpidem 5mg > Triazolam 0.25mg (1) 7
Less rebound Zolpidem 10mg >,> Triazolam 0.25mg (2) 7, 8
Less rebound Zolpidem 10mg > Triazolam 0.5mg (1) 9
Zopiclone vs Flurazepam
Effectiveness outcomes Zopiclone 3.75mg = Flurazepam 30mg (1) 10
Effectiveness outcomes Zopiclone 7.5mg =,>,= Flurazepam 30mg (3) 10-12
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Comparators KQ outcome Hypnotic Benzodiazepine
(No. of Studies)
Citations
Effectiveness outcomes Zopiclone 11.5mg =,> Flurazepam 30mg (2) 10, 11
Effectiveness outcomes Zopiclone 15mg = Flurazepam 30mg (1) 10
Safety outcomes Zopiclone 7.5mg =,= Flurazepam 30mg (1) 13, 14
Less rebound Zopiclone 7.5mg < Flurazepam 30mg (1) 12
Zopiclone vs Nitrazepam
Effectiveness outcomes Zopiclone 7.5mg =,= Nitrazepam 5mg (2) 15, 16
Daytime alertness Zopiclone 7.5mg >,> Nitrazepam 5mg (2) 15, 16
Safety outcomes Zopiclone 7.5mg = Nitrazepam 5mg (1) 15
Zopiclone vs Temazepam
Effectiveness outcomes Zopiclone 7.5mg =,=,= Temazepam 20, 30mg (3) 17-19
Safety outcomes Zopiclone 7.5mg = Temazepam 20mg (1) 17
Zopiclone vs Triazolam
Effectiveness outcomes Zopiclone 7.5mg =,=,= Triazolam 0.25mg (3) 20-22
Safety outcomes Zopiclone 7.5mg = Triazolam 0.25mg (1) 20
Less rebound Zopiclone 7.5mg >,< Triazolam 0.25mg (2) 21, 23
*Efficacy outcomes: Sleep Duration, total sleep time, length of sleep, total sleep time; Sleep Quality, sleep efficiency, No. of awakenings, Night awakenings, wake time after sleep
onset, Daytime alertness, status of work, drowsiness, quality of morning awakening, morning state, feelings on awakenings, daytime well-being, Mental alertness on rising,
morning sleepiness, morning alertness, Sleep latency, rapidity of sleep onset, sleep induction, sleep onset duration, Delay in falling sleep, latency to persistent sleep,
Safety outcomes: Overall adverse events, side effects, safety,
Rebound insomnia: Rebound, withdrawal effects
**Explanation of symbols for individual studies:
“≥” some outcomes showed a preference for the newer sedative hypnotic and others were equivalent;
“≤” some outcomes showed a preference for the benzodiazepine and others were equivalent;
“>” all outcomes (or the majority of outcomes) showed a preference for the newer sedative hypnotic;
“<” all outcomes (or the majority of outcomes) showed a preference for the benzodiazepine;
“=” all outcomes (or the majority of outcomes) showed no difference;
“mixed” some outcomes showed a preference for the newer sedative hypnotic and others showed a preference for the benzodiazepine.
(See Evidence Tables 4 through 9 for details of the population, interventions, and outcomes of these studies).
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