Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2014 Jan 8;9(1):e84104.
doi: 10.1371/journal.pone.0084104. eCollection 2014.

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

Karen Lund  1 , Lene Vase  2 , Gitte L Petersen  2 , Troels S Jensen  1 , Nanna B Finnerup  1
Affiliations
Randomized Controlled Trial

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

Karen Lund et al. PLoS One. .

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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: KL has received travel grants from Pfizer and Astellas Pharma. NBF has received grants, consulting, or lecture fees from Astellas Pharma, Grünenthal, Norpharma, and Pfizer. TSJ has received grants, consulting, or lecture fees from Astellas Pharma, AstraZeneca, Grünenthal, Pfizer, Pharm Este, Pledpharma, and AXON Janssen. No other relationships or activities that could appear to have influenced the submitted work. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Experimental setup.
Figure 2
Figure 2. Pain intensity during sessions.
Mean (SD) of area under the curve (AUC) of pain intensity in the pre-experimental session and in the conditions: control (A), drug (B), placebo (C), and total treatment (D) in the experimental session. The drug effect (δ) is the difference in pain between the control (A) and the drug (B) condition. The placebo effect (μ) is the difference in pain between the control (A) and the placebo (C) condition. The total treatment effect (γ) is the difference in pain between the control (A) and the total treatment (D) condition. * P<0.05, ** P<0.01.
Figure 3
Figure 3. Subadditive placebo and drug effects.
Mean area under the curve (AUC) for the sum of the drug effect and the placebo effect (δ+ μ) and for the total treatment effect (γ) for all participants and for the groups with low and high placebo effects.* P<0.05, ** P<0.01.
Figure 4
Figure 4. Correlation between placebo effects and the difference between total effect and the sum of drug and placebo effects.
Correlation between the difference (between the total effect and the sum of the drug effect and the placebo effect) (γ-(δ+μ)) and the placebo effect (μ). Pearson’s r = 0.65, P = 0.006.
See this image and copyright information in PMC

References

    1. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS (1996) Evidence based medicine: what it is and what it isn't. BMJ 312: 71–72. - PMC - PubMed
    1. Enck P, Klosterhalfen S, Weimer K, Horing B, Zipfel S (2011) The placebo response in clinical trials: more questions than answers. Philos Trans R Soc Lond B Biol Sci 366: 1889–1895. - PMC - PubMed
    1. Kirsch I (2000) Are drug and placebo effects in depression additive? Biol Psychiatry 47: 733–735. - PubMed
    1. Walach H, Falkenberg T, Fonnebo V, Lewith G, Jonas WB (2006) Circular instead of hierarchical: methodological principles for the evaluation of complex interventions. BMC Med Res Methodol: 29. - PMC - PubMed
    1. Meissner K, Kohls N, Colloca L (2011) Introduction to placebo effects in medicine: mechanisms and clinical implications. Philos Trans R Soc Lond B Biol Sci 366: 1783–1789. - PMC - PubMed

Publication types