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: 16.3). 12/2012; 345:e8343. DOI: 10.1136/bmj.e8343
Source: PubMed


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.

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Available from: Markos Klonizakis, Oct 05, 2015
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    • "This is contrary to current evidence derived from meta-analyses of randomized trials. The improvements in sleep latency were found to be small when compared with placebo and the non-specific placebo response is a major contributor to the effectiveness of hypnotics [14], [15]. Another interesting finding is that the overall ratio of benefits and harms of Z-drugs in elder patients was comparable to their younger counterparts or even rated more positive. "
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    ABSTRACT: Objective: Newer non-benzodiazepines zolpidem and zopiclone (“Z-drugs”) are often prescribed instead of benzodiazepine hypnotics, although there is no evidence of differences in effectiveness and safety. Aim was to compare perceptions on benefits and harms of benzodiazepines and Z-drugs between general practitioners (GPs) and community pharmacists (CPs). Methods: A questionnaire was mailed to a random sample of 1,350 GPs and 600 CPs in 2012. They were asked to rate perceptions on a five-point Likert scale used for both benzodiazepines and Z-drugs. Wilcoxon signed rank test was performed for the comparison of perceptions between GPs and CPs. Due to multiple testing, only p-values ≤0.01 were considered statistically significant. Results: 458 GPs and 202 CPs returned questionnaires (response 33.9% and 33.7%). Mean age of GPs was 53.3 years (40.6% female) and 48.8 years for CPs (59.2% females). Perceptions on benefits of benzodiazepines (and Z-drugs) between GPs and CPs were not different for 3 (and 2) of 5 items. Concerning side effects of benzodiazepines, there were no statistically significant differences for 3 of 5 comparisons. CPs perceived that 4 of 5 studied side effects of Z-drugs occur significantly more often than GPs (p=0.003 or less). For instance, whereas 45.2% of CPs answered that withdrawal effects on stopping happen often or very often/always on Z-drugs, these were only 28.3% of the GPs. Conclusions: Although it is difficult to draw unambiguous conclusions from these findings, pharmacists might have a somewhat more critical view on Z-drugs, especially concerning side effects.
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    ABSTRACT: Sind die Nicht-Benzodiazepine Eszopiclon, Zaleplon und Zolpidem (Z-Substanzen) wirksamer als Placebo, wenn bei einer Metaanalyse auch Daten aus Studien hinzugezogen werden, die nicht publiziert wurden?
    MMW Fortschritte der Medizin 06/2013; 155(12):30-30. DOI:10.1007/s15006-013-1005-y
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