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Study Title and Description

Effects on sleep stages and microarchitecture of caffeine and its combination with zolpidem or trazodone in healthy volunteers.



Key Questions Addressed
1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on behavior*?
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Primary Publication Information
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TitleData
Title Effects on sleep stages and microarchitecture of caffeine and its combination with zolpidem or trazodone in healthy volunteers.
Author LM Paterson,DJ Nutt,M Ivarsson,PH Hutson,SJ Wilson,
Country
Year 2009
Numbers

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Behavior - Design Details - INCLUDED Studies
Arms
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 19351801
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What outcome is being evaluated in this paper? Behavior
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What is the objective of the study (as reported by the authors)? This study assessed the effects of caffeine on sleep architecture and electroencephalography (EEG) spectrum alone and in combination with two different sleep-promoting medications.
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Provide a general description of the methods as reported by the authors. Information should be extracted based on relevance to the SR (i.e., caffeine related methods) Subjects were 12 young healthy males (age range 21–34 years, mean 24.9 years) who had regular bedtime routines with a nighttime sleep period of 7–9 h lying between 22.30 p.m. and 9 a.m. and who did not report sleep disturbance. Subjects completed a detailed caffeine consumption questionnaire to determine average weekly intake (Heatherley, et al., 2006). Subjects were prepared for overnight digital polysomnography (Embla, Broomfield, Colorado, US). Trazodone (100 mg) or matching placebo was administered 2 h before bedtime, caffeine (150 mg) or matching placebo was given 1 h before bedtime and zolpidem (10 mg) or matching placebo was given 15 min before bedtime. Subjects then slept at home as usual and in the morning removed the electrodes and visited the study centre for handover of equipment and a health check. Each of the four study days were separated by at least 1 week.
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How many outcome-specific endpoints are evaluated? 1
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What is the (or one of the) endpoint(s) evaluated? (Each endpoint listed separately) Sleep
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes Sleep architecture included a large number of measured parameters such as sleep-onset latency, REM-onset latency, total time in bed, etc.
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Clinical
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Physiological Physiological
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Other
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What is the study design? Controlled Trial
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Randomized or Non-Randomized? RCT
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What were the diagnostics or methods used to measure the outcome? Objective
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Optional: Name of Method or short description Sleep architecture was measured using overnight digital polysomnography.
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Caffeine (general) Caffeine (general)
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Coffee
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Chocolate
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Energy drinks
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Gum
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Medicine/Supplement
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Soda
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Tea
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Measured Measured
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Self-report
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Children
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Adolescents
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Adults Adults
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Pregnant Women
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Placebo control group vs 150 mg
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What were the listed confounders or modifying factors as stated by the authors? (e.g. multi-variable components of models.  Copy from methods) No confounders listed
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Provide a general description of results (as reported by the authors). [Sleep-onset latency] was significantly increased and [total sleep time], [sleep efficiency] and stage 2 sleep were significantly decreased by caffeine compared with placebo. Wake after sleep onset (WASO) and the number of awakenings were not significantly altered by caffeine, although a trend to an increase in both was observed. No significant effects on REM sleep were observed in any treatment group. Evolution of SWA activity showed the expected decline over the night with placebo, with each successive sleep cycle displaying progressively less delta power (Figures 2 and 3i). A different pattern was observed with caffeine, with less SWA in the first cycle and more in the second cycle of sleep compared with placebo; the delta sleep ratio is shown in Table 1 (P = 0.09, Figure 3). A similar pattern was observed with theta activity: theta power decreased with each successive sleep cycle in the placebo condition (Figure 3ii) and increased in the second cycle relative to the first in the caffeine condition (theta sleep ratio, Figure 3ii).
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Did the authors perform a dose-response analysis (or trend/related analysis)? No
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What were the authors's observations re: trend analysis?
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What were the author's conclusions? As expected from the literature caffeine delayed sleep onset, shortened TST, decreased SE and decreased S2 sleep (Okuma, et al., 1982; Landolt, et al., 1995a; Drapeau, et al., 2006). Interestingly, the negative correlation between SOL in response to caffeine and self-reported caffeine intake appears to indicate that higher caffeine users may be less sensitive to its effects on sleep onset, a finding which could be consistent with tolerance to the effects of caffeine (for review, see Fredholm, et al., 1999), genetic mechanisms, for example, the presence of an A2A receptor polymorphism (Retey, et al., 2007), or differences in its metabolism, which is known to vary considerably between individuals, even when smokers and women taking the oral contraceptive pill (factors known to alter caffeine elimination) are excluded (Tiffin, et al., 1995). The absence of an effect of caffeine on REM sleep is consistent with previous reports (Karacan, et al., 1976; Landolt, et al., 1995a). Only minor effects of caffeine on sleep continuity were observed: there were no significant increases in the number of awakenings or WASO. The high level of variability in the spectral data make it difficult to draw firm conclusions, but there was a tendency for delta and theta activities to be decreased in the first cycle in response to caffeine and to increase in the second relative to the first sleep cycle.
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What were the sources of funding? Merck, Sharp and Dohme
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What conflicts of interest were reported? None reported
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Does the exposure (dose) need to be standardized to the SR? No
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Provide calculations/conversions for the exposure based on the decision tree in the guide (for all endpoints/exposure levels of interest).
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List all the endpoint(s) followed by the dose (mg) which will be used in comparison to Nawrot.  Characterize value as LOAEL/NOAEL, etc. if possible.  Sleep LOAEL = 150 mg/d
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. Measures where a significant effect was seen include sleep-onset latency, sleep efficiency, total sleep time, and time in S2. This study only included one exposure level for caffeine.
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What is the importance of the study with respect to the adverseness of the outcome? Low
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