Original ArticleTrial methodology and patient characteristics did not influence the size of placebo effects on pain
Introduction
In the 1950s, a review by Beecher was responsible for persuading the scientific community that placebo effects were powerful enough to produce satisfactory relief in a large proportion of patients with various medical conditions [1]. Recently, Hróbjartsson and Gøtzsche argued that Beecher had overestimated the size of the placebo effect because his estimates were based on within-group improvements reported in placebo groups [2], [3]. Within-group improvements reflect not only the placebo effect but also factors such as the natural course of the condition and regression to the mean. Hróbjartsson and Gøtzsche pointed out that the size of placebo effects is more accurately estimated by subtracting improvements seen in a no-treatment group from the improvement seen in a placebo group.
This reasoning underpinned Hróbjartsson and Gøtzsche's reviews of the effects of placebo [2], [3]. They systematically reviewed randomized trials that included both placebo and no-treatment conditions. Meta-analysis of this clinically heterogeneous set of trials revealed statistically significant effects on pain of approximately 6 points on a 100-point scale. We suspect, few clinicians would consider effects of this magnitude to be of clinical significance. Additionally, there was some indication that the effect may have been due to a small study effect, such as reporting bias [3].
Despite the striking evidence provided by the Hróbjartsson and Gøtzsche reviews that placebos have only modest effects, their findings have often been ignored in recent research [4], [5], [6], [7]. This may be in part due to criticisms directed at the methods used in the reviews, such as pooling studies on a heterogeneous group of medical conditions [6], [7], [8] and including trials in which co-interventions were allowed inthe no-treatment group [9]. In line with these criticisms, we were concerned that placebo effects were potentially masked by some aspect of the trial methodology or patient type. Our aim was to define some of these potentially confounding factors and test whether they influenced placebo effect size. For the purposes of this article, we have considered placebo effects to be those therapeutic effects resulting from the treatment ritual. We acknowledge that this definition does not take into account the totality of the effect of interactions between patients and providers [10].
Section snippets
Methods
We independently reanalyzed the studies identified by Hróbjartsson and Gøtzsche who reported on pain outcomes. Subsequently we conducted a series of meta-regressions to evaluate whether characteristics of trial methodology or patient type were predictive of placebo effect size.
Results
Point estimates of the effects of placebo from individual trials ranged from −12 to 18 points on a 100-point scale, and the distribution of effects was approximately normal (Fig. 1A). Visual inspection of funnel plots did not suggest small sample bias (Fig. 1B).
The pooled estimate was that placebo reduced pain, on average, by 3.2 points on a 100-point scale (95% confidence interval [CI] = 1.6–4.7).
There was evidence of moderate statistical heterogeneity (I2 = 39.3%; Q = 70.93, df = 43, P = 0.005). That
Discussion
Our analysis confirms the conclusions of Hróbjartsson and Gøtzsche that, at least in the context of clinical trials, placebo interventions appear to have little effect on pain. The results of the meta-regression analysis found that none of eight trial-level factors describing characteristics of the placebo, trial design, and trial participants predicted the size of placebo effects. Our results also suggest that some of the criticisms of Hróbjartsson and Gøtzsche's review are not valid. For
Conclusion
In the context of clinical trials and along with other researchers, we found that placebo interventions produce little more reduction in pain than no treatment. Importantly we found no evidence that placebo effects were masked by some aspect of the trial methodology, placebo, or patient type. At present, the evidence for large placebo analgesic effects in clinical trials is still lacking.
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