Center for Clinical Studies and Empirical Ethics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Trials. 2010 Nov 19;11:110. doi: 10.1186/1745-6215-11-110.
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.
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.
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] mmhr 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] mmhr 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).
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.
ClinicalTrials.gov identification number - NCT00426010.
药物的总效应是其药效、安慰剂效应（即反应）及其可能相互作用的总和。目前对临床试验结果的解释假设不存在相互作用。由于缺乏适当的研究设计，证明这种相互作用一直很困难。
180 名成年人被随机分配到咖啡因（300mg）或安慰剂组。每组按照研究者的描述接受分配的干预措施，即咖啡因或安慰剂，采用随机交叉设计。4 小时能量曲线下面积、嗜睡、恶心（100mm 视觉模拟量表）和收缩压水平以及咖啡因药代动力学（在 22 名嵌套在咖啡因组中的志愿者中）均已确定。通过比较接受描述为安慰剂的咖啡因和接受描述为安慰剂的咖啡因后得出的咖啡因药物、安慰剂、安慰剂加相互作用和总效应的结果，以及接受描述为咖啡因或安慰剂的咖啡因和接受描述为咖啡因或安慰剂的安慰剂，以及接受描述为咖啡因的咖啡因与接受描述为安慰剂的咖啡因相比，分别接受描述为安慰剂的咖啡因。
能量曲线下面积（平均差异）和嗜睡（几何均数比）的安慰剂效应大于安慰剂加相互作用效应（16.6[95%CI，4.1 至 29.0]与 8.4[-4.2 至 21.0]mmhr 和 0.58[0.39 至 0.86]与 0.69[0.49 至 0.97]），与药物效应（20.8[3.8 至 37.8]mmhr 和 0.49[0.30 至 0.91]）相似，且两者的组合大于总咖啡因效应（29.5[11.9 至 47.1]mm*hr 和 0.37[0.22 至 0.64]）。安慰剂加相互作用效应使咖啡因终末半衰期延长 0.40[0.12 至 0.68]hr（P=0.007）。
药物和安慰剂的药物作用可能小于加和，这会影响临床试验的解释。安慰剂效应可能会增加活性药物的终末半衰期，这是安慰剂作用的一种新机制。
ClinicalTrials.gov 标识符-NCT00426010。
