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Study Title and Description

A translational, caffeine-induced model of onset insomnia in rats and 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 A translational, caffeine-induced model of onset insomnia in rats and healthy volunteers.
Author LM Paterson,SJ Wilson,DJ Nutt,PH Hutson,M Ivarsson,
Country
Year 2007
Numbers

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Extraction Form: Behavior - Design Details - INCLUDED Studies
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 17225163
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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)? The purpose of this study was to develop a translational, caffeine-induced model of insomnia in rats and healthy volunteers. We used sleep onset latency (SOL) as a comparable sleep measure between the two species.
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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) Human volunteer study Study design This was a double-blind, randomised, placebo- controlled volunteer study with a four-way crossover design. Ambulatory polysomnography recordings were obtained from volunteers in their own homes. This method has previously been validated and shown to reduce the disturbance caused by sleeping in unfamiliar surroundings (Iber et al. 2004). Treatments were given as a combination of three capsules at different times before bed to produce the following four drug treatment groups: (1) placebo, (2) caffeine, (3) caffeine-plus-zolpidem, and (4) caffeine-plustrazodone. Sleep measurements took place on four separate occasions at the subject’s home, with every subject receiving each of the four drug combinations in a randomised order with at least a 7-day washout period between them. Subjects Twelve healthy male volunteers, age range 21– 34 years (mean 24.9), were recruited from our volunteer panel and via advertisement within the University of Bristol and Bristol Royal Infirmary. All subjects were screened with medical history, physical examination, electrocardiogram, routine blood haematology and biochemistry and a urine screen for drugs of abuse. Subjects’ sleep and EEG were also assessed by overnight home polysomnography. Exclusion criteria included smokers, the presence of any pathological condition, self-reported psychotropic medication within the last 8 weeks, abnormal findings of clinical significance on medical or psychiatric history and sleep or EEG abnormalities. All subjects reported low to moderate alcohol consumption (0–25 U per week) and reported having regular sleep/wake routines of 7 to 9 h per night (bedtime 2230 to 0000, wake time 0630 to 0900 hours). Individual sensitivity to the effects of caffeine is very variable, and some people will often abstain from caffeine intake during the evening to avoid sleep disturbance, where others appear able to sleep normally despite regular evening caffeine intake. Healthy subjects with moderate caffeine intake were recruited (average weekly intake 50–3,000 mg), who were likely to be sensitive to its effects on sleep, but who were unlikely to suffer from withdrawal over the course of the experiment. Those with a daily caffeine intake of over 600 mg were therefore excluded. Written informed consent was obtained from all subjects before screening, and the study was approved by the local Research Ethics Committee and carried out in accordance with Good Clinical Practice Guidelines and the principles outlined in the Declaration of Helsinki (1989). Volunteers received payment for the completion of the study. Drugs All treatments were prepared and randomized by the Pharmacy Department at Bristol Royal Infirmary and presented as matching red capsules. Capsules contained either placebo, caffeine (150 mg), zolpidem (10 mg) or trazodone (100 mg). The caffeine dose was chosen based on previous literature, where significant changes in SOL have been reported (Okuma et al. 1982; Karacan et al. 1976). Clinically effective doses of zolpidem and trazodone were used (Brunner et al. 1991; Yamadera et al. 1998). Procedures Throughout the duration of the study, volunteers were asked to maintain a regular sleep pattern and were issued with a sleep diary and actiwatch (Cambridge Neurotechnology, UK) to monitor compliance and encourage good sleep hygiene. Before the test nights, they were asked to refrain from alcohol consumption for 24 h and from caffeine intake from 3 p.m. on the day of testing. Breathalyser tests were performed, and salivary samples were taken on each study night to monitor compliance. On each test night, subjects were visited in their own home and were issued with medication in randomised order according to Table 1. Polysomnography recordings were obtained with an ambulatory digital sleep recorder (Embla, Flaga, Reykjavik, Iceland), with EEG, EOG and EMG electrodes attached according to the standard methodology (Rechtschaffen and Kales 1968). When the setup was complete and all medications were issued, volunteers were left to go to sleep at their usual time. They were asked to maintain their usual bed and rise times and to keep these times the same for each of the four test nights. The next morning, subjects returned the recording equipment and completed the Leeds Sleep Evaluation Questionnaire (LSEQ) to assess subjective sleep effects (Parrott and Hindmarch 1978). Sleep scoring Sleep was scored blind to treatment using automatic scoring available in Somnologica software (version 2.0, Flaga, Reykjavik, Iceland) for each 30 s epoch and then visually checked according to standard R&K criteria (Rechtschaffen and Kales 1968). Scoring was started when subjects closed their eyes to try to fall asleep (as seen on EOG channel), and SOL was measured as the time taken to reach at least 120 s of any sleep stage other than W or S1 (Wilson et al. 2000). Statistical analysis In crossover studies, variables which were normally distributed were analysed using repeated measures ANOVA or Student’s paired t test, including those that were not normally distributed using the Friedman’s repeated measures ANOVA for ranked data. Where appropriate, the Student– Newman–Keuls post hoc test was used for between-group comparisons of placebo, caffeine and caffeine-plus-drug treatment. The significance level was P<0.05.
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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 focus on sleep onset latency
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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? NCT
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What were the diagnostics or methods used to measure the outcome? Both
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Optional: Name of Method or short description sleep diary and actiwatch and polysomnograph
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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 (no caffeine) vs 150 mg caffeine
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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) N/A
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Provide a general description of results (as reported by the authors). Objective effects Figure 1 shows the results from the human volunteer study. A 150 mg dose of caffeine resulted in a significant prolongation of SOL, with values increased to 155% of placebo. Subjective effects Table 3 shows the subjective effects of caffeine and caffeine in combination with hypnotic medication as measured by the LSEQ. In the caffeine-alone group, subjects reported a significant increase in the ‘getting to sleep’ factor.
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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? In healthy volunteers, 150 mg caffeine resulted in a 155% mean increase in SOL compared with placebo, a similar magnitude to previously reported values (Karacan et al. 1976). In summary, these two studies have shown that caffeine can prolong objective sleep onset in both rats and in humans, where volunteers also reported a subjective increase in sleep onset. This suggests that caffeine administration is a simple and effective model of one of the common symptoms of insomnia, difficulty in initiating sleep.
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What were the sources of funding? This study was funded by an unrestricted educational grant from Merck Sharp and Dohme
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What conflicts of interest were reported? N/A
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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/day (increasing the sleep onset latency)
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. caffeine was administered 1 hour prior to bedtime; effects occur below levels in Nawrot. et al.
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What is the importance of the study with respect to the adverseness of the outcome? Important
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