Shapiro and colleagues raise important concerns about placebo-
controlled trials, particularly the challenge of effective blinding and
the limited efforts that have been made to address it.1 To circumvent
this problem, they contend that active treatments should be used as
controls instead of placebo. We would argue, however, that the authors are
avoiding one horn of a dilemma by impaling themselves with the other. The
problem with using an “established, effective therapy” as a control is
that many established therapies that seem to qualify turn out to be
ineffective when subjected to additional placebo-controlled studies or
meta-analyses.
Definitive proof of effectiveness is hard to achieve, and all too
often treatments have become widely accepted in medicine as a result of
conjecture, culture, uncontrolled or poorly controlled studies,
publication and other biases, and marketing. Some examples include:
internal mammary artery ligation2 and percutaneous myocardial laser
revascularization3 for coronary artery disease; use of certain
antiarrhythmic agents to prevent sudden cardiac death;4 and vertebroplasty
for painful osteoporotic spinal fractures.5-6 In each case, the apparent
effectiveness of the treatment was debunked as a result of placebo- or
sham-controlled studies. In psychiatry, concerns have been raised about
the ethics of using placebo in studies of antidepressants,7 which have
been considered “established, effective therapy” for depression. The
largest randomized antidepressant trial did not include placebo arms, and
it led to the conclusion that all antidepressants and antidepressant
combinations were equally effective8. Subsequent meta-analyses, however,
have challenged the effectiveness of antidepressants over placebo for all
but the most severely depressed patients.9,10
The authors have done an important service by highlighting that
blinding in placebo-controlled trials is often suspect. However, if we
eliminate placebo controls in favour of purportedly active comparators, we
risk consequences that are even more dangerous. In fact, problems with
blinding may also be present in comparisons of two active treatments.
Thus, rather than avoid placebos in trials, we believe one needs to be
well-aware of the important limitations raised by Shapiro and
colleagues, while attempts should be made to address these such as by
using active placebo comparators as well as implementation of the
relatively straightforward within-trial steps and systemic measures
suggested by the authors.
Elia Abi-Jaoude, MSc, MDa, b; Daniel A. Gorman, MDb, c
aUniversity Health Network, Toronto, Ontario; bUniversity of Toronto,
Toronto, Ontario; cThe Hospital for Sick Children, Toronto, Ontario
REFERENCES
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N Engl J Med 1959 May 28;260(22):1115-8.
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Placebo-controlled studies in depression: necessary, ethical and feasible.
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9. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ,
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10. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD,
Shelton RC, et al. Antidepressant drug effects and depression severity: a
patient-level meta-analysis. JAMA 2010 Jan 6;303(1):47-53.
Conflict of Interest:
None declared
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