A placebo is defined as an inert medication or procedure, one that is selected specifically because it cannot affect the underlying process of the disorder: a saline injection, a sugar pill. When a patient given placebo appears to respond, such a response is often mistakenly labeled a placebo effect. However, since this response cannot be attributed to the placebo, the more appropriate label is placebo response. As noted above, the placebo response is experienced both by those receiving T and those receiving C, but it is experienced in its pure form only by those in a placebo control group (see "Each Patient as His or Her Own Control [Pre-Post Study Design]").
Because of the artifacts associated with pre-post study designs (regression to the mean, expectation effects, secular trends in the clinical condition of the patient or in the measurement process, etc.), it is very common for patients randomly assigned to placebo treatment to appear to respond favorably. In fact, it is reasonable to expect that given a large enough sample size, one will always find a statistically significant placebo response.
There has long been discussion of how one might 1) understand the placebo response and 2) reduce the placebo response in RCTs to make it easier to detect the efficacy or effectiveness of treatment versus placebo. That portion of placebo response related to artifacts, however, is already well understood. They are controlled in well-designed RCTs to the extent that is possible, by use of reliable measures and consistent application of measurement protocols over the course of the RCT.
Clinically, the most interesting aspect of placebo response is the expectation effect in both patients and assessors of response. Why would we want to reduce such expectation effects? Such expectations have a great deal to do with compliance and cooperation of patients during RCTs, as well as with their potential response to treatment. It would certainly be worthwhile to understand on whom one might expect strong expectation effects, how and why they exist, and exactly how they influence clinical response to treatment. But the goal would be to consider how to increase expectation effects to maximize the efficacy or effectiveness of any treatment, rather than to reduce them.
Like the waiting list control group, the placebo control group amounts to a withholding of treatment for the duration of the study. However, having a placebo control group repairs many, though not all, of the technical problems associated with a waiting list control group. One clear advantage is that use of a placebo control group facilitates blinding of outcome measurement. Thus, the problem of measurement bias expected in waiting list-controlled RCTs can be obviated in a placebo-controlled trial.
In the past, many patients did not actually understand what a placebo was, and when U.S. drug studies are conducted in Third World countries, this problem is still of concern. With the growing sophistication of medical consumers and medical advocates, however, and with the increasing scrutiny of how the placebo group is described in informed consent forms, this is less of a problem today. As is the case for use of waiting list control groups, patients with the greatest impairment from their disorder—who are most anxious to get relief, most in need of effective treatment, and most likely to cooperate and comply with treatment—are less likely to be willing to agree to randomization in a placebo-controlled trial. Moreover, their primary care physicians often have the same reaction and are reluctant to recommend participation in an RCT for those most in need of treatment. Thus, placebo-controlled trials run a strong risk of having a nonrepresentative sample from the relevant clinical population. Accordingly, the CONSORT guidelines for reporting the results of an RCT (Altman et al. 2001) ask that researchers provide a patient flowchart that includes how many patients were eligible for the RCT and how many refused participation. This information sheds light on the possible sample bias in any RCT but particularly in a placebo-controlled one.
Moreover, the problems that waiting list-controlled RCTs have with dropouts can be exacerbated (Kemmler et al. 2005) by substituting a placebo control group. Now patients in both the active treatment and placebo control groups are equally aware that they might be receiving a placebo. Patients in either group who do not experience the relief from their disorder that they hope for are likely to suspect that they are in the placebo control group, and thus are likely to drop out of the RCT. Again, their physicians, observing no amelioration of symptoms, may add to the problem by recommending dropping out and initiation of what they would consider effective treatment. Once again, such concerns are reflected in the CONSORT guidelines (Altman et al. 2001) with the requirement that researchers report the number of patients randomly assigned to each group (the intention-to-treat samples) and the number that drop out in each group, with reasons for such dropouts. This information is intended to help assess the possible biases that might result from such dropouts.
The RCT requirement that all randomly assigned patients be considered in assessing the treatment effect (an intention-to-treat analysis) in the face of any appreciable dropout is difficult to comply with. Although imputation methods, both simple and complex, are often used, there is no imputation procedure that completely corrects for the impact of dropouts or missing data on an RCT that are directly related to the experiences of patients with the treatment that they were assigned to receive. The fact that a placebo control often increases the risk for dropouts and missing data is thus an important consideration.
Although missing data and dropouts remain major issues in considering the use of placebo control groups, the major source of contention arises not from the theory of RCTs, or from the implementation problems of RCTs, but rather from the ethics of proposing a placebo-controlled RCT in the first place and from the clinical value of the results of a placebo-controlled RCT. To understand these arguments, let us consider a few specific contexts in which placebo control groups might be considered.
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