Psychopharmacology (2011) 215:537–548 Other interactions were followed up by Tukey HSD post hoc test for unplanned comparisons. In the balanced placebo design, there are two sources of information about the placebo response: the difference between the placebo condition and the control condition, and the difference between the drug administered with information and without information (Benedetti et al. 1995; Ross et al. 1962). Both of these comparisons measure the effect of information. Accordingly, the placebo response was com- puted in two ways: by subtracting the difference score (posttest–pretest) in the control condition from the differ- ence score in the placebo condition (inert placebo response), and by subtracting the difference score in the caffeine condition from the difference score in the active placebo condition (active placebo response). Correlations between these scores and the primary outcome variables were performed using Pearson’s r (two-tailed). The level of significance was p < 0.05. Results Manipulation check As a manipulation check, all subjects were asked at the end of each test day whether they had expected a reduction in pain in the posttest. It was hypothesised that subjects in the control and caffeine conditions who were told that they received no drug would expect no reduction in pain, while subjects in the placebo and active placebo conditions who were told that they received a painkiller should expect a reduction in pain. Six of 20 subjects in the control condition, 11 of 20 subjects in the placebo condition, three of 20 in the caffeine condition, and 12 of 20 in the active placebo condition expected a reduction in pain. It was also predicted that expectancies of pain relief in the active placebo condition should be larger compared to the placebo condition. However, subjects were not significantly more certain that the drug would relieve pain in the active placebo condition (M=34.4%, SD=31.3) compared to the placebo condition (M = 22.5%, SD = 18.0, t(19) = −1.65, p=.11). Subjective arousal Table 1 present the pre- and posttest ratings on subjective arousal. There was a significant main effect of drug, F(1, 18)= 9.77, p= .006, with a decrease in arousal after 0 mg/kg caffeine and no change after 4 mg/kg caffeine (Fig. 1). The effect of information was not significant, F(1, 18) =0.04, p =.86, nor was the interaction between drug and information F(1, 18)= 2.78, p= .11. There was no main effect or interactions including gender. 541 Table 1 Pre-, post- and difference scores on arousal in all conditions (n=20, mean±SEM) Pre Post Difference Control 5.1±0.4 4.1±0.5 −1.0±0.3 Placebo 4.8±0.4 4.1±0.4 −0.7±0.2 Caffeine Active placebo 4.6±0.4 4.8±0.4 0.2±0.2 4.5±0.4 4.5±0.4 0.0±0.2 Subjective stress Pain intensity The pre- and posttest ratings are presented in Table 2. There were no significant main effects or interaction in the ANOVA. The pain intensity data are displayed in Fig. 2a and Table 3. The ANOVA showed a main effect of drug, F(1, 18)= 7.54, p =.01, with a reduction in pain after 4 mg/kg caffeine compared to 0 mg/kg. There was no main effect of information (F(1, 18)= 0.96, p= .34) nor any interaction between drug and information (F(1, 18)= 0.31, p= .58). There was no main effect or interactions including gender. In order to assess whether there were any changes over time in placebo responding, the 20 pre- and posttest stimuli were collapsed into four blocks of five stimuli in each test. The four blocks in the pretest was subtracted from the four blocks in the posttest, yielding four difference scores for all conditions. A two drug × two information × four block- Fig 1 Arousal. Mean subjective arousal (± SEM) in all four conditions before and after administration of the drink