Article

Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: Meta-analysis of data submitted to the Food and Drug Administration

Department of Allied Health Sciences, University of Connecticut, 358 Mansfield Road U-2101, Storrs, CT 06269-2101, USA.
BMJ: British medical journal (Impact Factor: 17.45). 12/2012; 345:e8343. DOI: 10.1136/bmj.e8343
Source: PubMed

ABSTRACT

To investigate the effectiveness of non-benzodiazepine hypnotics (Z drugs) and associated placebo responses in adults and to evaluate potential moderators of effectiveness in a dataset used to approve these drugs.
Systematic review and meta-analysis.
US Food and Drug Administration (FDA).
Randomised double blind parallel placebo controlled trials of currently approved Z drugs (eszopiclone, zaleplon, and zolpidem).
Change score from baseline to post-test for drug and placebo groups; drug efficacy analysed as the difference of both change scores. Weighted raw and standardised mean differences with their confidence intervals under random effects assumptions for polysomnographic and subjective sleep latency, as primary outcomes. Secondary outcomes included waking after sleep onset, number of awakenings, total sleep time, sleep efficiency, and subjective sleep quality. Weighted least square regression analysis was used to explain heterogeneity of drug effects.
13 studies containing 65 separate drug-placebo comparisons by type of outcome, type of drug, and dose were included. Studies included 4378 participants from different countries and varying drug doses, lengths of treatment, and study years. Z drugs showed significant, albeit small, improvements (reductions) in our primary outcomes: polysomnographic sleep latency (weighted standardised mean difference, 95% confidence interval -0.57 to -0.16) and subjective sleep latency (-0.33, -0.62 to -0.04) compared with placebo. Analyses of weighted mean raw differences showed that Z drugs decreased polysomnographic sleep latency by 22 minutes (-33 to -11 minutes) compared with placebo. Although no significant effects were found in secondary outcomes, there were insufficient studies reporting these outcomes to allow firm conclusions. Moderator analyses indicated that sleep latency was more likely to be reduced in studies published earlier, with larger drug doses, with longer duration of treatment, with a greater proportion of younger and/or female patients, and with zolpidem.
Compared with placebo, Z drugs produce slight improvements in subjective and polysomnographic sleep latency, especially with larger doses and regardless of type of drug. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produced to a reasonably large clinical response.

Full-text

Available from: Markos Klonizakis
Effectiveness of non-benzodiazepine hypnotics in
treatment of adult insomnia: meta-analysis of data
submitted to the Food and Drug Administration
OPEN ACCESS
Tania B Huedo-Medina assistant professor
1
, Irving Kirsch associate director of program in placebo
studies (PiPS), lecturer in medicine
2
professor of psychology
3
, Jo Middlemass research assistant
4
,
Markos Klonizakis research fellow
4
, A Niroshan Siriwardena professor of primary and prehospital
health care
4
1
Department of Allied Health Sciences, University of Connecticut, 358 Mansfield Road U-2101, Storrs, CT 06269-2101, USA;
2
Harvard Medical
School, Beth Israel Deaconess Medical Center, USA, ;
3
School of Psychology, Plymouth University, Plymouth, UK;
4
Community and Health Research
Unit, Lincoln School of Health and Social Care, University of Lincoln, Lincoln LN6 7TS, UK
Abstract
Objectives To investigate the effectiveness of non-benzodiazepine
hypnotics (Z drugs) and associated placebo responses in adults and to
evaluate potential moderators of effectiveness in a dataset used to
approve these drugs.
Design Systematic review and meta-analysis.
Data source US Food and Drug Administration (FDA).
Study selection Randomised double blind parallel placebo controlled
trials of currently approved Z drugs (eszopiclone, zaleplon, and
zolpidem).
Data extraction Change score from baseline to post-test for drug and
placebo groups; drug efficacy analysed as the difference of both change
scores. Weighted raw and standardised mean differences with their
confidence intervals under random effects assumptions for
polysomnographic and subjective sleep latency, as primary outcomes.
Secondary outcomes included waking after sleep onset, number of
awakenings, total sleep time, sleep efficiency, and subjective sleep
quality. Weighted least square regression analysis was used to explain
heterogeneity of drug effects.
Data synthesis 13 studies containing 65 separate drug-placebo
comparisons by type of outcome, type of drug, and dose were included.
Studies included 4378 participants from different countries and varying
drug doses, lengths of treatment, and study years. Z drugs showed
significant, albeit small, improvements (reductions) in our primary
outcomes: polysomnographic sleep latency (weighted standardised
mean difference, 95% confidence interval −0.57 to −0.16) and subjective
sleep latency (−0.33, −0.62 to −0.04) compared with placebo. Analyses
of weighted mean raw differences showed that Z drugs decreased
polysomnographic sleep latency by 22 minutes (−33 to −11 minutes)
compared with placebo. Although no significant effects were found in
secondary outcomes, there were insufficient studies reporting these
outcomes to allow firm conclusions. Moderator analyses indicated that
sleep latency was more likely to be reduced in studies published earlier,
with larger drug doses, with longer duration of treatment, with a greater
proportion of younger and/or female patients, and with zolpidem.
Conclusion Compared with placebo, Z drugs produce slight
improvements in subjective and polysomnographic sleep latency,
especially with larger doses and regardless of type of drug. Although
the drug effect and the placebo response were rather small and of
questionable clinical importance, the two together produced to a
reasonably large clinical response.
Introduction
Hypnotic drugs are often prescribed in primary care for
insomnia.
1
Despite a reduction in prescribing of benzodiazepine
hypnotics in the past decade, hypnotic use and costs remain
high because of the introduction and increase in use of Z drugs,
2
a group of non-benzodiazepine hypnotic drugs (including
eszopiclone, zaleplon, and zolpidem), which act on the GABA
aminobutyric acid) receptor and are used in the treatment of
insomnia. These are now the most commonly prescribed
hypnotic agents worldwide. Prescriptions exceed costs of $285m
(£178m, €221m) in the United States
3
and £25m (€31m, $40m)
Correspondence to: A N Siriwardena nsiriwardena@lincoln.ac.uk
Extra material supplied by the author (see http://www.bmj.com/content/345/bmj.e8343?tab=related#webextra)
Appendix 1: Details of how to obtain drug trial data from FDA
Appendix 2: Modified Jadad score
Appendix 3: Full details of studies included
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BMJ 2012;345:e8343 doi: 10.1136/bmj.e8343 (Published 17 December 2012) Page 1 of 13
Research
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in the UK.
4
Although widely prescribed, Z drugs are not without
risks. These include adverse cognitive effects (such as memory
loss), psychomotor effects (such as falls, fractures, road traffic
crashes), daytime fatigue, tolerance, addiction, and excess
mortality
5
with no significant difference from benzodiazepines.
6
These established risks need to be weighed against the benefits.
Previous meta-analyses
6-9
of clinical trials of Z drugs have been
prone to publication bias, such as unavailability of unpublished
trials, selective or duplicate publication, and selective reporting
of results in constituent studies.
10 11
An example of the distorting
effects of these publishing practices was shown in a study by
Mattila and colleagues.
12
This study compared European Public
Assessment Reports of three drugs for insomnia to identify
clinical trials that were performed between 1998 and 2007 for
the purpose of registration of these drugs in the European Union.
They found that the effect size of these drugs was 1.6 times
larger when it was based on published data compared with the
whole sample of studies, published and unpublished. They also
found “remarkable inconsistencies in the reporting of the
secondary end points, methods, results and, especially safety.”
Different characteristics of included studies have not been
examined as possible moderators of effects of Z drugs in
previous meta-analyses.
One way of reducing the problem of publication bias is to
analyse the effect of drugs that have been approved by
governmental agencies with data derived from regulatory
submissions.
13
Drug companies are required to provide
information on all sponsored trials, published or not, when
applying for new drug approvals.
14
Hence, the US Food and
Drug Administration (FDA) files contain a complete dataset of
published and unpublished trials up to the date of drug approval.
We therefore undertook a meta-analysis of randomised placebo
controlled parallel group studies of clinical effectiveness of Z
drug hypnotics for insomnia in adults using only data provided
to the FDA for drug approval.
Another concern with studies of hypnotics is the magnitude of
the placebo response. We have considered the distinction
between drug and placebo responses and drug and placebo
effects.
15 16
A drug response is the change that occurs after
administration of the drug. The effect of the drug is that portion
of the response that is due to the drug’s chemical composition;
it is the difference between the drug response and the response
to placebo. A similar distinction can be made between placebo
responses and placebo effects. The placebo response is the
change that occurs after administration of a placebo. It includes
such factors as improvement because of the natural course of
the condition and regression toward the mean, as well as the
placebo effect itself.
Previous studies have shown significant improvements in
placebo arms in placebo controlled trials of hypnotic drugs.
17 18
Assessment of the magnitude of the placebo effect is important
for understanding drug-placebo differences and their
implications for clinical practice. For example, a small
drug-placebo difference might lead to different treatment options
if the drug and placebo are both effective rather than if neither
are effective. Because change in the absence of placebo
administration is rarely assessed in randomised controlled trials
(and was not assessed in the trials contained in the FDA files),
we could not assess the placebo effect. Therefore, we assessed
changes in placebo groups, as well as those in drug groups, thus
allowing us to establish the magnitude and significance of
placebo responses, drug effects, and other variables that can
moderate these outcomes.
Methods
Data source
For this systematic review we adhered to PRISMA
guidelines.
19 20
We obtained data on all currently approved
(non-benzodiazepine) Z drugs: eszopiclone, zaleplon, and
zolpidem from the FDA website (see appendix 1).
Study selection
The criteria for inclusion were randomised double blind
controlled trials, recruitment of adults with primary insomnia
(transient or chronic), an intervention comparing a Z drug with
a placebo control, submission to the FDA before approval,
sponsored by the manufacturer, and studies from any country
or reported in any language (although we found only reports in
English). Studies were excluded if they were crossover designs,
included healthy patients with normal sleep, were single night
studies with induced insomnia, or did not report any inference
test or enough descriptive information (for instance, percentages
or means and a variability measure for both groups and/or both
time measures) as included studies were too heterogeneous and
not large enough to estimate the missing information to calculate
an effect size. We excluded crossover trials because of problems
associated with reactivity, learning, carry over effects, and
failure of blinding. Blinding failure is more likely with crossover
studies, leading to an enhanced placebo effect in the drug
treatment arm, thereby increasing the likelihood of a false
positive (type I) error. We did not include post-approval trials
in our analysis because it is not possible to obtain access to all
unpublished data for those trials.
Data extraction and quality assessment
Two independent trained raters extracted information related
to the study with high inter-rater reliability: mean Cohen’s κ
0.90, for categorical variables, and mean intraclass correlation
r=0.92 for continuous variables. Because of the nature of the
FDA data, extractors were blind to researchers and institutions.
Methodological quality was assessed with the Jadad scale
21 22
as adapted by Miller and colleagues
23
(see appendix 2). For each
study, we extracted statistical data for drug and placebo. We
also coded sample and study characteristics and included
dimensions such as study identifier, year of publication,
location/s of study (country and number of sites), and study
duration. Data were extracted for two primary outcomes and
eight secondary outcomes. The primary outcomes were
polysomnographic and subjective sleep latency. The secondary
outcomes were subjective and polysomnographic total sleep
time, subjective and polysomnographic number of awakenings,
subjective sleep quality, sleep efficiency, and subjective and
polysomnographic time awake after sleep onset. Measured
characteristics of participants included proportion of women,
age, and sample type (outpatients, elderly, etc). Design
characteristics included design type, recruitment method,
intervention drug(s), treatment duration, and statistics reported.
None of the trials reported race or ethnicity.
Data synthesis and analysis
For both measures of sleep latency (polysomnographic and
subjective) and the eight other sleep related outcomes, we
calculated effect sizes as the mean difference between pre-test
and post-test divided by the standard deviation (SD) of the
pre-test value
24
for each group separately (that is, repeated
measures effect sizes, correcting for sample size bias).
25
The
standardised mean change in the placebo group was subtracted
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from that of the intervention group to evaluate the drug effect
with respect to the placebo effect for each comparison (that is,
effect size between groups adjusted for baseline). We calculated
multiple effect sizes if the study reported more than one drug
group or multiple outcomes. The latter were analysed separately
to investigate main effects and moderators. For multiple dose
studies, with the same or different drug but with the same control
group, we controlled multi-treatment dependence by estimating
the covariance among them
26
to analyse the effect of different
drug and dose combinations. The sign of the effect size was set
so that negative values signified a decrease of waking after sleep
onset, sleep latency, and number of awakenings (all both
polysomnographic and subjective). The sign of the effect size
was positive for increases in polysomnographic and subjective
total sleep time, polysomnographic sleep efficiency, and sleep
quality.
We obtained repeated measures effects sizes for each group for
those comparisons reporting means and SDs and used medians
and interquartile ranges as the best approximation for those
studies missing mean and SDs for drug and placebo. Sensitivity
analysis was undertaken by comparing the main results, with
and without those comparisons where median and interquartile
range were used to obtain a standardised mean difference.
Transformations were conducted to obtain effect sizes between
groups for those cases where F test or P values were reported.
27
As 63% (41) of the comparisons did not report SDs of each
group and those provided were largely heterogeneous, we have
reported repeated measures results for only six studies (24
comparisons) with the most complete statistical data; two studies
were not included in the final analysis as they did not report
any inference test or variability measure either in their repeated
or two groups measures. We have reported effect sizes in their
raw metric for the same comparisons in parallel to facilitate
clinical interpretation.
We examined the effect sizes with random effects models
27 28
for weighted effect sizes and publication bias. Random effects
models are more robustly generalisable as they assume
variability not only within studies but also between studies, a
relevant assumption when studies from different populations
are integrated to account for sampling error and population
variance. Moderation patterns were examined under mixed and
fixed effects assumptions, but we have reported results only
under the latter assumptions because of the lack of power to
show any significant pattern under mixed effects models.
29
The
homogeneity statistic, Q, determined whether each set of
weighted mean effect sizes shared a common parametric effect
size: a significant Q indicates a lack of homogeneity. To assess
not only significance of the heterogeneity but also its size, we
calculated the I
2
index and its corresponding 95% confidence
intervals
30
to determine and compare across outcomes the extend
of the heterogeneity. I
2
varies between 0 (homogeneous) and
100% (non-homogeneous), and if the confidence interval around
I
2
includes zero, the set of effect sizes is considered
homogeneous.
31
We investigated possible asymmetries in the
distribution of the effect sizes, which could indicate reporting
bias, using the trim and fill technique,
32
Begg’s strategy,
33
and
Egger’s test.
34
We analysed the total Jadad score as well as
individual item scores to detect any possible bias effect on the
overall results. Finally, we conducted sensitivity analyses with
effect sizes with more than 2 SD from the average effect size.
Moderator analyses were conducted for the main outcomes,
polysomnographic and subjective sleep latency. To explain
possible moderation of the variability of the overall effect sizes,
we examined the relation between sample, methodological, or
condition characteristics and magnitude of effect using a
modified weighted least squares bivariate regression analyses
with weights equivalent to the inverse of the variance for each
effect size.
27 27 35
Because doses of different drugs are not
equivalent, we also tested the drug by dose interaction. We used
total score on the methodological quality scale as a moderator
to analyse possible interaction with the final weighted effect
sizes and have presented any significant pattern for either sleep
latency or its subjective measure.
Results
Description of studies
In the data obtained from the FDA website, we identified 13
clinical trials comprising 4378 participants that examined 65
separate drug-placebo comparisons by type of outcome, type
of drug, and dose and that met the inclusion criteria. Figure 1
shows the trial flow. Table 1 and appendix 3 provides
descriptive features of the studies. Methodological quality of
the studies ranged from 13 to 21 on the Jadad scale (mean 15.63,
SD 1.8). Publication year and quality score were not
significantly correlated (r=0.34, P=0.28).
Studies were conducted in North America (eight studies), North
America and Europe (one study), South America (one study),
or Australia (one study), with one study conducted entirely in
Europe, and another study without location information. The
mean duration of studies was 33.9 days (SD 33.3, range 14-180
days). Of the 4378 participants sampled, 61% were women,
61% were aged under 45, and the mean age was 49.6 (SD 13.3;
range 38-72) years.
All 13 studies included comparisons of at least one of our
primary outcomes. Ten studies (22 comparisons) assessed
polysomnographic sleep latency and seven (11 comparisons)
assessed subjective sleep latency. The eight remaining secondary
outcomes appeared in fewer studies: four studies (seven
comparisons) assessed subjective total sleep time, two (two
comparisons) assessed total polysomnographic sleep time, four
(six comparisons) assessed subjective number of awakenings,
three (four comparisons) assessed polysomnographic number
of awakenings, two (four comparisons) assessed subjective sleep
quality, three (five comparisons) assessed sleep efficiency, three
(three comparisons) assessed polysomnographic waking after
sleep onset, and one (one comparison) assessed subjective
waking after sleep onset.
Zolpidem was most commonly prescribed drug (eight studies);
eszopiclone and zaleplon were assessed in three studies each
(one study included both zolpidem and zaleplon). Zolpidem
was prescribed in eight studies (15 comparisons) measuring
polysomnographic sleep latency, zaleplon in three studies (six
comparisons), and eszopiclone in only one study (one
comparison). Only zolpidem and eszopiclone were used in
studies measuring subjective sleep latency, in five (eight
comparisons) and two (three comparisons) studies, respectively.
Quantitative analyses
For our primary outcomes, analyses of standardised effect sizes
showed significant but small to medium differences in
polysomnographic (weighted standardised mean difference
−0.36, 95% confidence interval −0.57 to −0.16) and subjective
sleep latency (−0.33, −0.62 to −0.04) for treatment versus
control. There were significant effect sizes for the primary
outcome (sleep latency) within groups separately for both
placebo (−0.39, −0.54 to −0.23 (for polysomnographic); −0.33,
−0.63 to −0.03 (for subjective)) and drug (−0.93, −1.32 to −0.54
(polysomnographic); −0.67, −1.30 to −0.03 (subjective)).
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Analyses of weighted mean raw differences indicated that drugs
decreased sleep latency by 22 minutes (−33 to −11 minutes).
Tables 2 and 3 show standardised and raw effect sizes,
respectively.⇓⇓ Figures 2 and 3 show forest plots for
polysomnographic and subjective sleep latency, respectively.⇓⇓
Analysis of secondary study outcomes showed no significant
drug effect. The lack of difference between groups for other
sleep measures coupled with the fact that few reports included
them meant there was insufficient evidence to show efficacy
on these measures.
There was no evidence of asymmetry of the distribution of the
effect sizes for sleep latency by the trim and fill technique,
Begg’s test
33
(P=0.88 (polysomnographic); P=0.22 (subjective)),
or Egger’s test
34
(P=0.34 (polysomnographic); P=0.77
(subjective)), which suggests that these results are not
significantly affected by publication bias. One study was an
outlier (eszopiclone study No 190-047, table 1 and appendix
3), with a large pooled effect size for sleep latency 0.46 (0.24
to 0.69) and >2 SD from the overall weighted effect size. When
we excluded this study, the pooled effect size for sleep latency
was −0.54 (−0.91 to −0.15). Sensitivity analysis showed no
significant differences in overall efficacy (the overall effect size
without the outlier was still significant, with a slightly lower
reduction of subjective sleep latency) and the same patterns for
the moderator results adjusted for the two outlier comparisons
provided by this study.
Every item was evaluated through bivariate weighted regression
analysis under fixed and random effects assumptions to critically
and robustly appraise any included study for risk of bias in
attributing outcomes to the intervention and their possible effect
on the overall efficacy, but none of the results was significant.
Therefore, there was no evidence of any interaction between
quality/risk of bias in the included studies and the final results.
Moderator effects on sleep latency
The main outcomes, polysomnographic and subjective sleep
latency, were the only measures with sufficient cases to permit
detailed models for moderator analyses (table 4). Sleep latency
was more likely to be reduced in studies published earlier, with
larger drug doses, longer treatment duration, and samples that
included a greater proportion of younger patients and/or female
patients (table 4). Polysomnographic and subjective sleep
latency were reduced when larger doses were used, regardless
of type of drug. The interaction of dose by type of drug was not
significant, and all drugs (zolpidem and zaleplon for
polysomnographic and subjective sleep latency and eszopiclone
and zolpidem for subjective sleep latency, the latter being
significantly more effective in this particular outcome) showed
a pattern of greater reductions in sleep latency with larger doses.
Subjective sleep latency was more likely to be reduced in studies
published earlier, or with greater numbers of younger patients
or women included in the sample, and with zolpidem. These
patterns were obtained under fixed effect meta-regression models
and these held under mixed effects assumptions.
Discussion
Main findings
In this meta-analysis of Z drugs using data published on the
FDA website, which are less likely to be affected by selection
or reporting bias, we found significant reductions in
polysomnographic and subjective sleep latency in both drug
and placebo groups. The difference between drug and placebo
was 22 minutes for polysomnographic sleep latency and seven
minutes for subjective sleep latency. Although these reductions
in sleep latency might have benefits, albeit short term, for quality
of life, the effect sizes corresponding to these differences were
−0.36 and −0.33, both of which are conventionally considered
to be small effects,
36
and well below the criterion for clinical
significance (0.50) suggested by the National Institute for Health
and Clinical Excellence (NICE) in their guidelines for the
treatment of depression.
37
There were insufficient data for other drug effect end points to
allow a valid analysis. The large heterogeneity in sleep latency
outcomes was mainly explained by larger doses needed to obtain
a greater drug than placebo effect. Z drugs were more likely to
be effective in reducing sleep latency in studies published earlier,
those including more younger and/or female patients, and those
using zolpidem. Significant placebo responses were present in
polysomnographic and subjective sleep latency. There have
been several previous meta-analyses of published data on Z
drugs, although none included moderator analyses and all
acknowledged publication bias.
4 6 8 9 38
Strengths and weaknesses
As in previous studies, we found that data submitted for
licensing enabled detailed investigation of drug efficacy.
13 39 40
We included sponsored studies submitted to the FDA but did
not assess whether they were subsequently published. Studies
submitted to the FDA are required to report all data so are less
likely to be affected by reporting bias.
Studies were subjected to the same methodological scrutiny and
analytical rigour as meta-analyses of published studies. As in
other meta-analyses, we did not include studies that did not
report enough statistical data to calculate an effect size. Because
of the small number of reports for some outcomes, and the
heterogeneity of statistical data reported, we could not compare
some studies directly or robustly impute missing data. There
was insufficient information about sample setting characteristics,
drug side effects, and other factors that might have explained
heterogeneity to fully account for these. The entry criteria for
studies varied, with some studies focusing just on sleep latency,
particularly for shorter acting drugs such as zalpelon. This could
have affected the capacity of some studies to identify effects
other than on sleep latency. All the drugs are licensed for
insomnia, and patients presenting for treatment have a range of
symptoms, not just sleep latency, for which these drugs are
commonly prescribed in general practice.
Another weakness in the present analysis is that all the trials
were industry sponsored. Industry sponsorship has been shown
to enhance the outcome of clinical trials.
41
Thus, although we
were able to include published and unpublished studies, at least
for the reports used to approve these drugs, we could not avoid
sponsorship bias, and our results might therefore overestimate
the drug effect. Unfortunately, eliminating both sources of bias
simultaneously is difficult, if not impossible. Although clinical
trials now need to be registered in advance to be published in
major medical journals,
42
there is no requirement that the results
be submitted for publication, and many failed clinical trials or
clinical trials with negative results go unpublished.
10
Furthermore, although many clinical trials are subject to
mandatory reporting of results to the FDA, most are not, and
for those that are, as many as 78% fail to comply with this
requirement.
42
Because sponsorship bias is in the direction of
greater effects for industry sponsored trials, our results might
overestimate the effects of Z drug hypnotics for treating adult
insomnia.
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We found evidence of a significant placebo response for sleep
latency. McCall and colleagues undertook a meta-analysis of
sleep changes associated with placebo in published hypnotic
clinical trials and found a clinically important and statistically
significant placebo response for subjective sleep latency and
total sleep time.
17
Belanger and colleagues undertook a
meta-analysis of sleep changes in control groups of 34 hypnotic
drug studies in which 23 used a pharmacological placebo, four
a psychological placebo, and seven a waiting list. They found
significant pre-post changes in the pharmacological placebo
group on several sleep outcomes, both objectively or
subjectively measured, suggesting that sleep measures might
change significantly in response to a pharmacological placebo.
18
The response to placebo is more than just the placebo effect.
Just as the effect of a drug is estimated by the difference between
the response to the drug and the response to a placebo, the
placebo effect would be the difference between the placebo
response and changes occurring without administration of a
placebo. Belanger and colleagues assessed the response to
placebo hypnotic drugs and compared it with sleep changes
among patients placed on a waiting list.
18
Compared with those
on a waiting list, there were significantly greater improvements
in subjective sleep onset latency (19.55 min v 2.43 min),
subjective total sleep time (31.13 min v 7.30 min), and objective
total sleep time (18.27 min v 10.34 min) in the placebo group.
18
These data were based on comparisons between studies rather
than comparisons within studies, and none of the trials in the
FDA database included waiting list controls. Nevertheless, the
results of Belanger and colleagues suggest that the placebo
response observed in our meta-analysis was largely caused by
a genuine placebo effect. Future clinical trials including both
placebo and untreated (natural course) controls would be useful,
as well as combining the results of studies using network
meta-analysis.
Meaning of the study
The response to a medical treatment consists of two components:
a true drug effect and a non-specific placebo response, which
includes the placebo effect, regression toward the mean, and
improvement because of the natural course of the condition.
For that reason, it is useful, both for current clinical practice
and for future treatment development, to know the effect sizes
for the placebo group as well as for the control group. For
example, finding that both placebos and drugs are effective but
that the drug is more effective than the placebo, suggests that
placebo characteristics can be used to amplify effectiveness of
a drug. Conversely, finding improvement only in drug arms
indicates that the placebo effect is not an important component
of treatment, whereas finding that both are equally effective,
compared with waiting list controls, suggests that non-specific
aspects of patient care might be having positive effects.
We found that both the drug effect and the placebo response
were small and of questionable clinical importance. The two
put together, however, lead to a reasonably large clinical
response. Although the drug-placebo difference in objectively
measured sleep latency was only 22 minutes, the response to
the Z drugs, including both drug effect and the placebo effect
components, was 42 minutes. Similarly, the effect size for the
drug response was −0.93 and that for the placebo response was
−0.39, accounting for about half of the drug response.
Insomnia is a symptom defined disorder characterised by distress
about perceived poor sleep or lack of sleep. Hence, subjective
sleep latency might be as important as objective sleep latency
in understanding the benefits of treatments for this condition.
The response to Z drugs was 25 minutes shorter for subjectively
perceived sleep latency, whereas the response to placebo was
an improvement of 19 minutes. Thus the benefit of Z drugs in
term of subjectively perceived sleep latency was only seven
minutes and was not significant. However, this was based on
only two comparisons. Effect sizes for subjective sleep latency
were calculable for a larger number of trials and the
drug-placebo difference (−0.33) was small but significant, with
the placebo response again accounting for about half of the drug
response.
Taken together, these data suggest that the placebo response is
a major contributor to the effectiveness of Z drugs. The
remaining effect needs to be balanced against the harms
associated with these drugs. The substantial proportion of the
drug response accounted for by the placebo response indicates
the importance of non-specific factors in the treatment of
insomnia. As the placebo effect is a psychological phenomenon,
these data suggest that increased attention should be directed at
psychological interventions for insomnia.
Unanswered questions and future research
FDA data could also provide further opportunities for studying
effects of adverse effects with Z drugs (particularly as larger
effect sizes were associated with higher drug doses), as well as
examining issues of publication and reporting delays and bias.
We did not look at adverse effects, which can pose significant
risks,
43
leading to concerns about the widespread and sometimes
inappropriate use of these drugs.
44 45
Conclusion
This study of FDA data shows that Z drugs improve objective
and subjective sleep latency compared with placebo, particularly
in younger and female patients. The size of this effect, however,
is small and needs to be balanced with concerns about adverse
effects, tolerance, and potential addiction. The placebo response
accounted for about half of the drug response. This suggests
that increased attention should be directed at psychological
interventions for insomnia.
Contributors: ANS and IK had the original idea for the study. All authors
were involved in the design of the review, developed the search strategy,
performed the study selection, interpreted and discussed results, and
contributed to the writing and review of the various drafts of the report.
JM, MK, and ANS extracted data from included studies. TBH-M, IK, and
ANS were involved in data analysis. ANS is guarantor.
Funding: This study was funded by the College of Social Science
Research Fund at the University of Lincoln. This research received no
specific grant from any funding agency in the public, commercial, or
not-for-profit sectors.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf (available on
request from the corresponding author) and declare: no support from
any organisation for the submitted work; no financial relationships with
any organisations that might have an interest in the submitted work in
the previous three years; no other relationships or activities that could
appear to have influenced the submitted work.
Ethical approval: Not required.
Data sharing: No additional data available.
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RESEARCH
Page 5
What is already known on this topic
Z drug hypnotics have short term benefits in the treatment of insomnia
Their effectiveness has been questioned because of publication bias reported in previous meta-analyses, and little is known about the
extent of the placebo response
What this study adds
Z drugs decreased subjective and polysomnographic sleep latency compared with placebo especially with larger doses and in younger
or female patients and regardless of type of drug
The drug effect and the placebo response were small and of questionable clinical importance, but the two together produced a reasonably
large clinical response
The FDA clinical trial data were free from publication bias but might have been subject to other forms of bias
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Accepted: 30 November 2012
Cite this as: BMJ 2012;345:e8343
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BMJ 2012;345:e8343 doi: 10.1136/bmj.e8343 (Published 17 December 2012) Page 6 of 13
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Tables
Table 1| Characteristics of studies included in review of Z drugs (a more detailed version of this table is in appendix 3)
Outcome
Patient
typeDesign
Baseline PSG
(subjective) sleep
latencyRecruitmentDrug
Mean
(SD)
age
(years)WomenNo
Study identifier,
year, country (No
of sites)
Wake after sleep onset
PSG, sleep latency
PSG, No of awakenings
PSG, No of awakenings
subjective, sleep
latency subjective, total
sleep time PSG
OutpatientsPhase II multicentre
randomised double
blind placebo
controlled parallel
group
Intervention: 41.7
(61.4); placebo: 43.8
(62.0)
CommunityZolpidem MR
12.5 mg
44 (13)58%212EFC4529, 2004,
US (29), Canada
(5), Australia (6)
Wake after sleep onset
PSG, sleep latency
PSG, No of awakenings
PSG, No of awakenings
subjective, sleep
latency subjective, total
sleep time PSG
OutpatientsRandomised
multicentre double
blind placebo
controlled
Intervention: 36.9
(56.0); placebo: 35.7
(62.9)
CommunityZolpidem MR
6.25 mg
70 (5)57%205EFC4530, 2004,
Argentina (5),
Canada (7),
France (4),
Germany (6),
Mexico (2), US
(16)
Sleep latency PSG,
Sleep efficiency PSG,
No of awakenings PSG,
sleep latency
subjective, total sleep
time subjective, No of
OutpatientsDouble blind parallel
group
Intervention: zolpidem
10 mg: 35.8 (38.4);
zolpidem 15 mg: 47.0
(61.0); placebo: 49.9
(70.4)
CommunityZolpidem MR
10 mg and 15
mg
3864%75LSH17, 1988, US
(4)
awakenings subjective,
sleep quality subjective.
Sleep latency
subjective, total sleep
time subjective, No
awakenings subjective,
sleep quality subjective
OutpatientsDouble blind parallel
group
Intervention: zolpidem
10 mg (65.1); zolpidem
15 mg (75.9); placebo:
(58.2)
CommunityZolpidem (10
mg and 15 mg)
4556%145LSH, 1992, US (6)
Sleep latency PSG,
sleep latency
subjective, Sleep
efficiency PSG
OutpatientsMulticentre double
blind randomised
placebo controlled
parallel group trial
Intervention: zolpidem
10 mg: 35.8 (57.0);
zolpidem 15 mg: 47.0
(61.0); placebo: 49.9
(70.4)
CommunityZolpidem 10
mg and 15 mg
NRNR75IV LSH, NR, NR
Sleep latency PSGOutpatientsPhase II, multicentre,
double blind
comparative parallel
group efficacy, safety,
tolerance, outpatient
and sleep laboratory
trial
Intervention: zaleplon
10 mg: 40.4; zaleplon
20 mg: 48.0; zolpidem
10 mg: 47.8; placebo:
48
CommunityZaleplon 10 mg
and 20 mg vs.
zolpidem 10 mg
NRNR130204-EU, 1997,
Spain (4), France
(3), Belgium (3),
Netherlands (1)
Sleep latency PSG.OutpatientsRandomised placebo
controlled parallel
group multicentre
double blind trial
Intervention: zaleplon 5
mg: 81.5; zaleplon 10
mg: 77.7; zaleplon 20
mg: 72.5; zolpidem 10
mg: 70.5; placebo: 80.4
CommunityZaleplon 5 mg,
10 mg and 20
mg; zolpidem
10 mg
41.858.4%586Trial 301, 1998,
US (27)
Sleep latency PSGOutpatientsRandomised placebo
controlled parallel
group multicentre
double blind trial
Intervention: zaleplon
10 mg/10 mg: 79.8;
zaleplon 10 mg/20 mg:
81.9; placebo: 77.93
CommunityZaleplon 10
mg/10 mg, 10
mg/20 mg
4360.6%637Trial 307, 1998,
US and Canada
(39)
Sleep latency PSGNRRandomised placebo
controlled parallel
group multicentre
double blind trial
Intervention: zaleplon 5
mg: 66.0; zaleplon 10
mg: 57.0; zaleplon 20
mg: 55.0; zolpidem 10
mg: 64.0; placebo: 58.0
CommunityZaleplon 5 mg,
10 mg, 20 mg,
zolpidem 10 mg
42.864.4%574Trial 303, 1998,
Europe and
Canada
Sleep latency PSGNRProspective
randomised double
blind placebo
controlled five arm
parallel group
multicentre trial
Intervention: zaleplon 5
mg: 62.1; zaleplon 10
mg: 70.7; placebo: 68.0
CommunityZaleplon 5 mg
and 10 mg
72.564.4%422Trial 306, 1998,
US
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Table 1 (continued)
Outcome
Patient
typeDesign
Baseline PSG
(subjective) sleep
latencyRecruitmentDrug
Mean
(SD)
age
(years)WomenNo
Study identifier,
year, country (No
of sites)
Sleep latency
subjective, total sleep
NRMulticentre
randomised trial
Intervention: NR;
control: NR
NREszopiclone 3
mg
44.163.2%791190-049, 2003,
US and Canada
(69) time subjective, wake
after sleep onset
subjective
Sleep latency PSG,
sleep efficiency PSG,
wake after sleep onset
PSG
NRMulticentre
randomised trial
Intervention: NR;
control: NR
NREszopiclone 2
mg
70.765.9%292190-047, 2003,
USA (48), Canada
(2)
Sleep latency
subjective, total sleep
time subjective
NRMulticentre
randomised trial
Intervention: NR;
control: NR
NREszopiclone 1
mg and 2 mg
72.357.7%234190-048, 2003,
US and Canada
(32)
NR=not reported; MR=modified release; PSG=polysomnographic.
*Trial 307-1998 had two intervention arms: (i) zaleplon 10 mg for 14 days with outcomes measured at 7 days and 14 days compared with placebo and (ii) zaleplon
10 mg for 7 days followed by 20 mg for 7 days with outcomes measured at 7 days and 14 days compared with placebo; in both studies we used last measurement
at 14 days and averaged dose at 15 mg as best approximation for study arm using 10 mg followed by 20 mg zaleplon.
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Table 2| Weighted standardised mean differences in effect of Z drugs (treatment) or placebo on insomnia
Homogeneity of effect sizes I
2
(95% CI)
Weighted mean effect size (95% CI)
Between groupsWithin groups
Treatment v
controlControlTreatmentTreatment v controlNo*ControlTreatmentNo*
Primary outcome-sleep latency
41 (1.18 to 64.30)0 (0 to 77.60)89 (83.58 to
92.47)
−0.36 (−0.57 to −0.16)22−0.39 (−0.54 to
−0.23)
−0.93 (−1.32 to
−0.54)
16PSG
83 (70.98 to
90.05)
0 (0 to 66.15)0 (0 to 49.26)−0.33 (−0.62 to −0.04)11−0.33 (−0.63 to
−0.03)
−0.67 (−1.30 to
−0.03)
4Subjective
Secondary outcomes
0 (0 to 93.84)50 (0 to 87.35)83 (29.36 to
95.94)
−0.24 (−0.72 to 0.24)3−0.29 (−0.67 to
−0.08)
−0.52 (−1.40 to
0.36)
2Wake after sleep
onset (PSG)
65 (0 to 88.10)0 (0 to 99.67)91 (70 to 97.57)−0.33 (−0.80 to 0.14)4−0.21 (−0.60 to
0.17)
−0.36 (−1.28 to
0.56)
2No of awakenings
(PSG)
85 (69 to 92.67)36 (0 to 79.25)87 (47.31 to
96.63)
−0.06 (−0.42 to 0.29)6−0.28 (−0.66 to
0.10)
−0.91 (−1.90 to
0.09)
2No of awakenings
(subjective)
042 (0 to 83.14)74 (0 to 94.19)0.41 (−0.51 to 1.32)20.65 (−0.67 to
1.98)
1.06 (−1.37 to
3.49)
2Total sleep time
(PSG)
0 (0 to 75.02)054 (0 to 88.82)0.59 (−0.12 to 1.29)50 (−0.59 to 0.59)0.52 (−1.23 to
2.28)
2Sleep efficiency
(PSG)
0 (0 to 71.12)0.45 (−0.08 to 0.98)70Total sleep time
(subjective)
0 (0 to 71.13)0.30 (−0.32 to 0.92)40Sleep quality
(subjective)
−0.16 (−0.60 to 0.28)10Wake after sleep
onset (subjective)
PSG=polysomnographic.
*No of comparisons.
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Table 3| Weighted mean raw differences in effect of Z drugs (treatment) or placebo on insomnia
Homogeneity of effect sizes I
2
(95% CI)
Weighted mean differences (95% CI)
Between groupsWithin groups
Treatment v
ControlControlTreatmentTreatment v controlNo*ControlTreatmentNo*
Primary outcome-sleep latency
94 (91.66 to
95.83)
41 (0 to 68.68)96 (94.75 to
97.15)
−22 (−33.00 to
−11.00)
14−20 (−28 to −11)−42 (−60 to −23)14PSG
27 (0 to 72.41)0 (0 to 100)0 (0 to 100)−6.90 (−26.00 to
12.37)
2−19.43 (−26.61 to
−12.25)
−24.99 (−30.06 to
−19.92)
2Subjective
Secondary outcomes
0 (0 to 99.98)63 (0 to 91.62)65 (0 to 91.96)−7.14 (−33.00 to
18.23)
2−13 (−34 to 7.89)−20 (−59 to 18)2Wake after sleep
onset (PSG)
0 (0 to 99.90)0 (0 to 99.98)94 (81.24 to
98.13)
−0.47 (−5.12 to 4.17)2−0.94 (−12 to 9.99)1.24 (−6.34 to
3.89)
2No of awakenings
(PSG)
0 (0 to 99.81)0 (0 to 99.95)0 (0 to 100)−1.77 (−4.61 to 1.07)2−1.05 (−4.86 to
2.76)
2.88 (−7.15 to
1.39)
2No awakenings
(subjective)
0 (0 to 99.68)61 (0 to 91.07)63 (0 to 91.45)14.05 (−31.00 to
58.72)
235.10 (−34 to 10)49.15 (−60 to 16)2Total sleep time
(PSG)
4.47 (2.08 to 6.86)10 (−2.52 to 2.52)4.27 (2.01 to 6.52)1Sleep efficiency
(PSG)
00Total sleep time
(subjective)
00Sleep quality
(subjective)
00Wake after sleep
onset (subjective)
PSG=polysomnographic.
*No of comparisons.
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Table 4| Moderator analysis for effect of Z drugs (treatment) or placebo on insomnia. Effect sizes are weighted standardised mean differences
β‡Effect size (95% CI)Moderator variable†
Polysomnographic sleep latency
Dose (22 comparisons):
−0.22*−0.24(−0.38 to −0.11)1 mg
−0.50 (−0.64 to −0.35)20 mg
Subjective sleep latency
Year of data collection (9 comparisons):
0.63***−0.88 (−1.19 to −0.58)1988
−0.03 (−0.16 to 0.10)2004
Age (9 comparisons) :
0.89***−0.65 (−0.82 to −0.48)38 years
0.31 (0.13 to 0.50)72 years
Percentage of women (9 comparisons):
−0.40**0.01 (−0.17 to 0.18)55.9 %
−0.67 (−0.99 to −0.34)67.5 %
Type of drug (11 comparisons):
−0.57**0.02 (−0.13 to 0.18)Eszopiclone (3 comparisons)
−0.47 (−0.61 to −0.33)Zolpidem (8 comparisons)
Dose (11 comparisons):
−0.70***0.13 (−037 to 0.30)1 mg
−1.01 (−1.31 to −0.70)20 mg
*P<0.05; **P<0.01; ***P<0 .001.
†Effect size of each outcome was entered as dependent variable into separate weighted least squares regressions under fixed effects assumptions for each
moderator variable independently; negative ds imply lower outcome at final available measures; estimates appear for observed extremes of continuous features.
‡Standardised regression coefficient.
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Figures
Fig 1 Identification of studies from FDA databases and inclusion in study
Fig 2 Forest plot for polysomnographic sleep latency under random effects assumptions
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Fig 3 Forest plot for subjective sleep latency under random effects assumptions
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  • Source
    • "Concerns about side effects and the lack of empirical support demonstrating efficacy for the treatment of pediatric insomnia with medication were cited as significant barriers to their use [9]. While some medications have proven modestly effective for the treatment of insomnia in children and adoles- cents [10], no medications are currently FDA approved for this indication (seeTable 1 ). As already noted, however , physicians are treating comorbid child and adolescent insomnia with a variety of medications for a vast spectrum of disorders and symptoms. "
    [Show abstract] [Hide abstract] ABSTRACT: Insomnia among children and adolescents is ubiquitous and takes a great toll on youth and their families, impacting academic achievement, mood, social functioning, and a variety of developmental outcomes. Unfortunately, however, pediatric insomnia most often remains unidentified and untreated. When treatment is provided, it is most often in the form of medications, which are not FDA approved for that indication in children and adolescents. A comprehensive literature review was employed to establish the recommendations in this report. This article provides a review of sleep physiology and both current and recommended approaches to assessing and treating pediatric insomnia. Comprehensive assessment, accurate diagnosis, and evidence-based treatment of insomnia is imperative to the healthy development of children and adolescents. While clinicians often prescribe a variety of medications to treat pediatric insomnia, there is insufficient data to demonstrate efficacy and endorse their routine use. At this time, behavioral techniques, such as cognitive behavior therapy for insomnia and sleep hygiene education, should remain the first line of treatment. As a second-line consideration, melatonin, a dietary supplement, may be effective. Pediatric insomnia has an enormous impact on children, adolescents, and their families that requires adequate attention from clinicians and parents alike.
    Full-text · Article · May 2016 · Current Psychiatry Reports
  • Source
    • "At the onset of this trial, in addition to determining the effects of MMFS-01 treatment on cognitive ability , we also sought to determine its effects on emotion and sleep. The large placebo effects observed in this study, typical in these types of trials [51] , is unfortunate because it prevented us from determining the true effects of MMFS-01 on emotion and sleep (Table 4). "
    [Show description] [Hide description] DESCRIPTION: Randomized double blind placebo controlled clinical trial.
    Full-text · Research · Mar 2016
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    • "Regarding the implications of our hypothesis for treatment of MA abusers, a central tenet is that one might begin by addressing the sleep disruptions themselves. There are several effective cognitive-behavioural and pharmacological sleep therapies (administered either singly, or in combination) that might be adapted for this population [42,120121122. For instance, sleep restriction therapies are an effective treatment for insomnia, at least in the short term, as they regulate the circadian clock and thereby restore normal sleep-wake rhythms [41]. "
    [Show abstract] [Hide abstract] ABSTRACT: Sleep is disrupted during active use of methamphetamine (MA), during withdrawal from the drug, and during abstinence from its use. However, relatively little is known about possible mediatory functions of disrupted sleep in the emergence, manifestation, and maintenance of cognitive and affective symptoms of MA abuse. We hypothesise that sleep functions as a mediator for stimulant drug effects. Specifically, we propose that objectively-measured sleep parameters can be used to explain some of the variability in the experience and presentation of memory deficits and emotion dysregulation in MA abusers. After describing how important healthy sleep is to unimpaired cognitive and affective functioning, we review literature describing how sleep is disrupted in MA abuse. Then, we provide a conceptual framework for our hypothesis by explaining the relationship between MA abuse, sleep disruption, memory deficits, emotion dysregulation, and changes in reward-related brain networks. We conclude by discussing implications of the hypothesis for research and treatment.
    Full-text · Article · Sep 2015 · Medical Hypotheses
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