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.

Trial registration: ClinicalTrials.gov identification number - NCT00426010.

Figure 1

Model of drug and placebo effects and their interaction. Total effect is inferred from the difference between received caffeine described as caffeine and received placebo described as placebo. Drug effect is inferred from the difference between received caffeine described as placebo and received placebo described as placebo. The model predicts two kinds of measured "placebo effect": a) PLACEBO-1 is inferred from the difference between received placebo described as caffeine and received placebo described as placebo, which contains the placebo effect only, and b) PLACEBO-2 is inferred from the difference between received caffeine described as caffeine and received caffeine described as placebo, which contains the placebo effect and the interaction effect. Note that PLACEBO-1 is depicted here larger than PLACEBO-2 and that the total effect is smaller than the combination of the drug and placebo effects (as measured by PLACEBO-1) to indicate that the drug and placebo effects are less than additive.

Figure 2

Flow diagram of study procedures. *Excluded because of failure to abstain from caffeine as reflected on baseline level.

Figure 3

Self-reported energy and sleepiness levels on continuous and binary scales over four hours after intervention. A and B: Time course of estimated unadjusted total effect (closed diamond), drug effect (closed squares), placebo effect (closed triangles), and interaction effect (closed circles with interrupted line) on VAS scores of energy and sleepiness level, respectively. C and D: Mean unadjusted VAS Scores for energy and sleepiness, respectively. E and F: Mean unadjusted percentage of time, lack of energy and sleepiness, respectively, were reported. T bars indicate standard errors. Squares indicate receiving 300 mg caffeine, described as caffeine (open square with continuous line) or as placebo (closed square with interrupted line) by 83 subjects in a balanced randomized cross-over design. Triangles indicate receiving placebo described as placebo (open triangle with continuous line) or as caffeine (closed triangle with interrupted line) by 85 subjects in a balanced randomized cross-over design. The difference between open squares and open triangles represents the total effect. The difference between closed squares and open triangles represents the drug effect. The difference between open triangles and closed triangles represents the placebo effect. The difference between open squares and closed squares represents the placebo+interaction effect.

Figure 4

Placebo effect on caffeine plasma levels and systolic blood pressure. A & B: Mean plasma caffeine levels over 14 hours after administration of caffeine to 22 participants in a balanced cross-over design before (A) and after natural logarithmic transformation (B). C: Systolic blood pressure over four hours following intervention. Squares indicate receiving 300 mg caffeine described as caffeine (open square with continuous line) or as placebo (closed square with interrupted line). Triangles indicate the administration of placebo described as placebo (open triangle with continuous line) or as caffeine (closed triangle with interrupted line). T bars indicate standard errors.