title: Interaction between drug and placebo effects: a cross-over balanced placebo design trial.
abstract: BACKGROUND
  The total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design.
  
  
  METHODS
  180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively.
  
  
  RESULTS
  The placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P=0.007).
  
  
  CONCLUSIONS
  Drug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action.
  
  
  BACKGROUND
  ClinicalTrials.gov identification number - NCT00426010.
authors.affiliation: Center for Clinical Studies and Empirical Ethics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. muhammad@kfshrc.edu.sa
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Hammami
authors.forename: Eman A
authors.initials: EA
authors.lastname: Al-Gaai
authors.forename: Syed
authors.initials: S
authors.lastname: Alvi
authors.forename: Muhammad B
authors.initials: MB
authors.lastname: Hammami
mesh_terms: D000328:Adult; D002110:Caffeine / Q000494:pharmacology; D018592:Cross-Over Studies; D006801:Humans; D015990:Placebo Effect; D012107:Research Design
chemical_list: D002110:Caffeine