Psychopharmacology (2011) 215:537–548 DOI 10.1007/s00213-011-2233-4 ORIGINAL INVESTIGATION Interaction between expectancies and drug effects: an experimental investigation of placebo analgesia with caffeine as an active placebo Espen Bjørkedal & Magne Arve Flaten Received: 28 June 2010 / Accepted: 16 February 2011 / Published online: 8 March 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Rationale In a randomised placebo-controlled clinical trial it is assumed that psychosocial effects of the treatment, regression to the mean and spontaneous remission are identical in the drug and placebo group. Consequently, any difference between the groups can be ascribed to the pharmacological effects. Previous studies suggest that side effects of drugs can enhance expectancies of treatment effects in the drug group compared to the placebo group, and thereby increase placebo responses in the drug group compared to the placebo group. Objectives The hypothesis that side effects of drugs can enhance expectancies and placebo responses was tested. Method Painful laser stimuli were delivered to 20 healthy subjects before and after administration of a drink with 0 or 4 mg/kg caffeine. The drink was administered either with information that it contained a painkiller or that it was a placebo. Laser-evoked potentials and reports of pain, expec- tancy, arousal and stress were measured. Results Four milligrammes per kilogramme of caffeine reduced pain. Information that a painkiller was adminis- tered increased the analgesic effect of caffeine compared to caffeine administered with no drug information. This effect was mediated by expectancies. Information and expectan- cies had no effect on pain intensity when 0 mg/kg was administered. Conclusion The analgesic effect of caffeine was increased by information that a painkiller was administered. This was due to an interaction of the pharmacological action of the drug and E. Bjørkedal (*) : M. A. Flaten Department of Psychology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway e-mail: espen.bjorkedal@uit.no expectancies. Hence, psychosocial effects accompanying a treatment can differ when an active drug is administered compared to a placebo. Keywords Placebo analgesia . Pain . Expectancies Laser-evoked potentials . Active placebo . Caffeine . Arousal . Balanced placebo design Introduction A placebo is a treatment that mimics active treatment in all respects except that the placebo is inert. In randomised double-blind clinical drug trials a placebo group is used as a control in order to assess the pharmacological effect of a drug. The logic is that the observed effect in the group receiving the drug consists of the drug effect and effects due to psycholog- ical factors, spontaneous remission and regression to the mean. In the placebo group, the psychological factors, spontaneous remission and regression to the mean should be the same as in the drug group. Hence, any difference between the placebo group and the drug group can be ascribed to the pharmacological effects of the drug. Expectations of having received the drug can be modulated if the subjective effects of a drug inform the individual that active medication has been administered and increase expectations of drug effects. Consequently, the subjective effects of the drug in the active arm of a randomised double-blind clinical trial may enhance expectations and placebo responding compared to the placebo arm (Dinnerstein and Halm 1970; Flaten et al. 1999; Lyerly et al. 1964). To avoid this problem, active placebos may be used instead of, or in addition to, inert placebos. An active placebo is a drug that has no effect on the symptom under investigation, but that mimics the side effects of the active treatment.