Allocation concealment and blinding: when ignorance is bliss

To the Editor: In their article on controlled trials, Forder et al1 described the trial by Karlowski et al on vitamin C and the common cold2 as an example of how patients’ or investigators’ preconceptions about the value of the treatment may affect a trial’s results. However, their presentation of this trial is misleading in two respects.

Firstly, the Karlowski et al trial was reanalysed and the “placebo-effect explanation” of the original authors was shown to be erroneous.3 For example, their subgroup analysis of “blinded” and “non-blinded” participants excluded 42% of all episodes of colds, even though the subgroups were presented as complementary; numerous further problems are detailed elsewhere.3 Thus, the trial by Karlowski and colleagues cannot be seen as an example of the placebo effect in action. The concept of large and omnipresent placebo effects can be traced back to an early article by Beecher, who chose “15 illustrative studies” covering such conditions as, “severe postoperative wound pain, cough, headache, seasickness, etc.”4 Beecher calculated that the “average placebo-effect” was 35.2% (SE, ± 2.2%). However, these studies did not use a control group. The comparison was “before–after”, which is affected by the regression to the mean phenomenon as most of these conditions are self-limiting. Thus, Beecher’s studies did not measure the “effect” of placebo. A recent meta-analysis of 114 trials comparing a placebo group with a no-treatment group found no evidence of placebo effect on binary outcomes, and only a rather small effect on pain, thus disproving Beecher’s notion of great and universal placebo-effects.5 This empirical evidence was disregarded by Forder and colleagues. Although there are reasons to use placebo whenever practicable, the bias caused by the absence of a placebo control should not be exaggerated, and the “placebo effect” should also not be misused to support investigators’ own preconceptions.3

Secondly, the trial by Karlowski et al was focused on the effect of vitamin C on the common cold,2 and thus the “placebo effect explanation” in this particularly influential trial is crucial to the biological question. A recent meta-analysis of 55 placebo-controlled trials found that regular vitamin C supplementation had no effect on the incidence of colds in the general population (relative risk [RR], 0.98; 95% CI, 0.95–1.00), but reduced the incidence of colds in people exposed to substantial physical or cold stress (RR, 0.50; 95% CI, 0.38–0.66).6 Also, regular vitamin C intake reduced the duration of colds in adults by 8% (95% CI, 3%–13%) and in children by 13.5% (95% CI, 5%–21%). Although further studies are needed to evaluate the practical significance of these findings, it is evident that the interpretation by Karlowski and colleagues that the effect of vitamin C on the common cold may be explained by the break in the double blind2 is false and should not be reiterated.