Randomised controlled trials may underestimate drug effects: balanced placebo trial design

PLoS One. 2014 Jan 8;9(1):e84104. doi: 10.1371/journal.pone.0084104. eCollection 2014.

Abstract

Background: It is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment.

Objective: To test the assumption of additivity. The primary hypothesis was that the total treatment effect is smaller than the sum of the drug effect and the placebo effect. The secondary hypothesis was that non-additivity was most pronounced in participants with large placebo effects.

Methods: We used a within-subject randomised blinded balanced placebo design and included 48 healthy volunteers (50% males), mean (SD) age 23.4 (6.2) years. Experimental pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections with hypertonic saline along with lidocaine or matching placebo in randomised order: A: received hypertonic saline/told hypertonic saline; B: received hypertonic saline+lidocaine/told hypertonic saline; C: received hypertonic saline+placebo/told hypertonic saline+pain killer; D: received hypertonic saline+lidocaine/told hypertonic saline+pain killer. The primary outcome measure was the area under the curve (AUC, mm(2)) of pain intensity during injections.

Results: There was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm(2) (95% CI, 4936-7622)) and the total treatment effect (mean AUC 5455 mm(2) (95% CI, 4585-6324)) (P = 0.049). This difference was larger for participants with large versus small placebo effects (P = 0.015), and the difference correlated significantly with the size of the placebo effect (r = 0.65, P = 0.006).

Conclusion: Although this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, particularly in studies reporting large placebo responses. The implications for randomised controlled trials and systematic reviews need to be discussed.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Humans
  • Lidocaine / therapeutic use*
  • Male
  • Pain / drug therapy*
  • Placebos
  • Saline Solution, Hypertonic / administration & dosage
  • Young Adult

Substances

  • Placebos
  • Saline Solution, Hypertonic
  • Lidocaine

Grants and funding

The research leading to these results is part of the Europain Collaboration, which has received support from the Innovative Medicines Initiative Joint Undertaking, under grant agreement no 115007, the resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution www.imi.europa.eu. The funding source had the possibility to comment on the design and the reporting of the study, but had no role in the collection, analysis, and interpretation of the data and the decision to submit for publication.