Treatment effects and placebo effects

Answers

Statements a, b, and c are all true.

The aim of the trial was to establish the effectiveness of iron supplementation in reducing fatigue in non-anaemic women with unexplained fatigue. A randomised controlled trial was performed. The control group received a placebo, which had no therapeutic ingredients but resembled the intervention (oral ferrous sulphate, 80 mg daily) in appearance and taste. The use of a placebo permitted double blinding and therefore minimised ascertainment bias, sometimes referred to as detection bias.2 Ascertainment bias is the systematic distortion of the assessment of outcome measures by investigators or trial participants, possibly as a result of having been aware of treatment allocation. Ascertainment bias is more likely in the measurement of subjective outcomes, as in the above trial of self reported fatigue. The use of the placebo, together with the random allocation of trial participants to treatment group, facilitated the inference of causality—that is, any differences between the treatment groups in outcomes at the end of the trial would have been the result of differences in treatment and not confounding or other biases.3

The change in the primary outcome that occurred in the intervention group—a mean decrease in fatigue of 1.82 points after four weeks of iron supplementation, is referred to as the treatment response (a is true). The difference between the treatment group and placebo group in the mean change in the primary outcome is referred to as the treatment effect (b is true). It is the part of the treatment response that is caused by the chemical composition or therapeutic components of the intervention. The treatment effect was a mean reduction in fatigue of 0.97 units, which was reported as significant (95% confidence interval 0.32 to 1.62 units; P=0.004).

As described above, the change in fatigue for the intervention group that occurred after iron supplementation is referred to as the treatment response. It therefore seems appropriate to refer to the mean change in the primary outcome for the placebo group—that is, the mean decrease in fatigue of 0.85 units after four weeks, as the placebo response. The placebo had no known therapeutic ingredients, so the placebo response was a result of non-specific treatment effects—that is, the effects were not a result of any therapeutic treatment. These non-specific treatment effects will have included the natural variation in fatigue for non-anaemic women with unexplained fatigue, regression towards the mean, and the placebo effect. In this instance, the phenomenon of regression towards the mean would be characterised by high reported measures of fatigue naturally being followed by measurements that were lower on average. Regression towards the mean will be described in further detail in a future question. Although a distinction between the placebo response and the placebo effect is proposed, not all authors consider such definitions useful, and some use the terms interchangeably.

The placebo effect has been described as a psychological phenomenon in response to the anticipation and expectation of clinical improvement. It represents the patient’s response to investigation, including the response to a therapeutic ritual, subsequent response to observation and assessment, and response to the patient-doctor interaction. There is probably a complex association between these components. The placebo effect is probably more aptly referred to as placebo effects because it consists of different components. The placebo effects in the above trial would have included changes in behaviour as a result of the women being aware that they were part of a scientific investigation and being observed. Such a non-specific treatment effect is typically referred to as the Hawthorne effect.4

The non-specific treatment effects of the placebo response, including the placebo effects, would also have been part of the treatment response (c is true). The magnitude of such effects would no doubt have been difficult to quantify in the above trial. Furthermore, the magnitude of such non-specific treatment effects may not have been equal in the treatment and placebo groups. Presumably they would have depended, in part, on the success of blinding. It is not uncommon for trial participants and researchers to predict treatment allocation in a double blind trial. Patients who had a preference for iron supplementation but predicted that they were allocated to placebo might have been disappointed and experienced “resentful demoralisation.” As a result, this might have had an effect on the perceived benefit of their treatment allocation.

A placebo may be pharmacological, physical, or psychological. In general, the term “placebo” is typically used in pharmacological studies, whereas “sham treatment” is used for non-pharmacological studies, including those of devices and of psychological and physical treatments.5

Placebo effects are not found only in scientific investigations. There is evidence that any medical consultation might result in placebo effects as well as the benefits of any specific therapeutic regimen used. However, there is considerable debate about, and understanding of, the mechanisms involved in placebo effects.