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Study Title and Description

Does the presence of a pharmacological substance alter the placebo effect?--results of two experimental studies using the placebo-caffeine paradigm.



Key Questions Addressed
1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on cardiovascular outcomes?
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Primary Publication Information
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TitleData
Title Does the presence of a pharmacological substance alter the placebo effect?--results of two experimental studies using the placebo-caffeine paradigm.
Author H Walach,R Schneider,
Country
Year 2009
Numbers

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


Extraction Form: Cardiovascular Design
Design Details
Question... Follow Up Answer Follow-up Answer
What outcome is being evaluated in this paper? Cardiovascular
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What is the objective of the study (as reported by the authors)? We employed the placebo-caffeine paradigm to test whether the presence or absence of a substance (caffeine) influences the placebo effect.
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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) Study design: We conducted two experiments sequentially. For theoretical reasons these experiments were organizationally independent, participants were not randomized to experiments, but only to conditions within experiments, and experimenters were under the impression that the second experiment was a replication of the first. In the first experiment only placebo was used, and we randomized participants into four groups (n=15 in each group): one group received no beverage and was only measured as a control condition for random fluctuation, one group received a placebo with the information that caffeine was being administered and two groups received placebo under double-blind conditions (double blind X and Y). In the second experiment, we administered caffeine in the double blind condition Y, mimicking a clinical trial, and we added a group that received caffeine and was told so (open caffeine; n =15). All procedures and participant contacts were handled by the same two female experimenters, who were blind to the actual purpose of the study and the substances administered. Experiment 1 – Procedures: Participants responded to newspaper advertisements announcing a study investigating the effects of caffeine on well being, arousal, and cognitive performance. Participants were deemed eligible for the study if they had no medical impairment and agreed to abstain from caffeine consumption for 24 h and to fast for 4 h prior to participation. To test for compliance, random saliva specimens (five per condition totaling 20) were taken and screened for etofyllin. Samples were stored at _808C and analyzed using an enzyme immunoassay (EIA) method developed in the Department of Forensic Medicine of the University Hospital Freiburg. Samples were considered satisfactory if the saliva concentration was below 500 ng/ml caffeine. The study was carried out at the Institute for Environmental Medicine and Hospital Epidemiology Freiburg, Germany. Ethical approval for the experimental procedures was obtained from the Hospital’s Ethics Committee. Randomization to the experimental groups was done with the software RITA (Pahlke et al., 2004). We used a quinine hydrochloride solution (0.1%) as placebo to match the bitter taste of pure caffeine in a concentration of 1 ml/10 kg body weight, sampled with a syringe and mixed with 100 ml orange juice, following effective published procedures (Flaten and Blumenthal, 1999). In the ‘‘double-blind condition,’’ participants were given the information that the liquid contained caffeine with a 50% probability. In the placebo condition, participants were told they would receive caffeine. Sessions were scheduled in the morning (8:00– 12:00). At the beginning of the sessions, participants were given written information about the alleged purpose of the study and the physiological, mood, and performance enhancing effects of caffeine. They then gave their written informed consent. Each session consisted of a baseline assessment of well being, cardiovascular measures, and cognitive performance followed by experimental intervention and posttreatment assessments. Physiological measures were taken three times with 2 min rest intervals and averaged. Then, baseline values for well being were taken. Finally, baseline measures for reaction time (RT) were taken after participants achieved an accuracy rate of 80% in a familiarization test. Following the baseline measurements, the experimenter opened a sealed and numbered envelope containing the random assignment to the experimental group. Participants were asked to rate how they expected the beverage would affect their well being, physiology, and cognitive performance. They were then weighed and given the appropriate amount of ‘‘caffeine’’ in juice. This had to be consumed within 1 min. This was followed by a waiting period of 30 min ‘‘to allow the caffeine to take effect,’’ during which participants rested and read magazines. After the waiting period, they were asked to rate how the beverage affected them and how certain they were that they had consumed caffeine. Then, post-treatment measures were taken in the same order as previously. Experiment 1 – Participants: Sixty participants, 14 males and 46 females with an average age of 32.3 (SD.11.9; range.20–64 years) took part in experiment 1. All were normotensive, not taking any prescription medication and were not suffering from any medical condition, not receiving treatment for problems with alcohol and/or drug use, and not breast-feeding. They reported to consume on a daily basis on average 1.6 cups of regular coffee and 1.3 cups of tea. Experiment 1 - Measures: Blood pressure. Blood pressure (systolic and diastolic) and heart rate were measured with a calibrated digital oscillometric sphygmomanometer, the OMRON M5 Professional (Omron Inc, Germany) which automatically inflates the arm cuff and shows and stores the values on a LCD display. Participants sat on a chair relaxing with their extended left arm lying on a cushion. The cuff was wrapped around the upper arm, with the lower edge placed 1–2 cm above the inner side of the elbow joint. The level of the cuff was placed at the same level as the heart during measurement. Experiment 2 – Study design and procedure: All aspects of experiment 2 were the same as in experiment 1. In contrast to experiment 1, however, two major design alterations were implemented. In the double blind condition Y, participants received 3 mg caffeine/kg per body weight but were told that the probability to be given caffeine was 50%. In an additional experimental condition, participants were administered a dose of 3mg caffeine/ kg body weight and informed about this (open caffeine condition). The caffeine solution (3%) was given in amounts of 1 ml/10 kg body weight, sampled with a syringe, and mixed in 100 ml orange juice. The two female experimenters, who were identical to experiment 1, were told that this additional condition investigated the effects of caffeine in a different carrier solution (note that in the double blind condition of experiment 1 experimenters believed to administer caffeine). Post study assessment of the plausibility of this experimental condition showed that the cover story did not arouse suspicion and that the blinding of the experimenters was uncompromised. Experiment 2 – Participants: Seventy-five participants, 25 males and 50 females with an average age of 29.9 (SD.10.3; range.19–60 years) participated in experiment 2. Inclusion and exclusion criteria were the same as in experiment 1. Participants reported to consume on a daily basis on average 1.3 cups of regular coffee and 1.2 cups of tea. Experiment 2 – Measures: The same measures were applied as in experiment 1.
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How many outcome-specific endpoints are evaluated? 2
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What is the (or one of the) endpoint(s) evaluated? (Each endpoint listed separately) Blood pressure
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List additional health endpoints (separately). 2 Heart rate
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List additional health endpoints (separately).3
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List additional health endpoints (separately).4
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List additional health endpoints (separately).5
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List additional health endpoints (separately).6
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Clinical, physiological, other Physiological
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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?
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Optional: Name of Method or short description Blood pressure. Blood pressure (systolic and diastolic) and heart rate were measured with a calibrated digital oscillometric sphygmomanometer, the OMRON M5 Professional (Omron Inc, Germany) which automatically inflates the arm cuff and shows and stores the values on a LCD display.
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Caffeine (general) Caffeine (general)
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Coffee, Chocolate, energy drink, gum, medicine/supplement, soda, tea, other?
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Measured or self reported? Measured
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Children, adolescents, adults, or pregnant included? Adults
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Placebo and a control group.
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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) To determine treatment effects, ANCOVAs were carried out with the baseline measures as covariates. Simple contrasts were applied where appropriate. Effect sizes were calculated according to Cohen (1988). In experiment 1, for all dependent variables, significant differences between the placebo group and the control group (placebo effect) and the double-blind groups X and Y (placebo response) were expected. In experiment 2, a significant difference between the placebo group and the control group was expected (placebo effect). Furthermore, significant differences were also expected between the double blind group Y and the control group (pharmacological effect) and the caffeine group and the control group (pharmacological effect/expectancy). To see whether the presence of a substance in double-blind arms makes a difference, a randomly selected group of the double-blind arm of experiment 1 (i.e., double-blind placebo) was tested against the double-blind placebo group of experiment 2 (non-classical placebo effect). Expectancy measures were correlated with difference scores of appropriate outcome variables using the Spearman rank correlation coefficient. To test for significance, p-levels were adjusted according to Holm (1979). Specifically, for the physiological parameters systolic and diastolic blood pressure, and heart rate, the significance level was set at p</=0.017 (0.05/3). Accordingly, for psychomotor performance the number of correct reactions and mean reaction time the significant level was set at p</=0.025 (0.05/2). Finally, for the well-being measures mood, calmness, and alertness the significance level was set at p</=0.017 (0.05/3). For none of the measures it was specified which one would have to be significant. This was in line with our reasoning that placebo effects may show in varied, to some extent unpredictable ways.
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What conflicts of interest were reported? The authors have no conflicts of interest.
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Refid 19697301
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What were the sources of funding? The study was supported by a grant from the Samueli Institute (www.siib.org), Alexandria VA. We are grateful to Katrin Hassenpflug and Lena Stopatschinskaja for conducting the experiments.
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Results & Comparisons

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