October 19, 2010
Much of medicine is based on what is considered the strongest
possible evidence: The placebo-controlled trial.
A paper published
in the October 19 issue of Annals of Internal Medicine - entitled
"What's In Placebos: Who Knows?" calls into question this foundation
upon which much of medicine rests, by showing that there is no
standard behind the standard - no standard for the placebo.
The thinking behind relying on placebo-controlled trials is this: to
be sure a treatment itself is effective, one needs to compare people
whose only difference is whether or not they are taking the drug.
Both groups should equally think they are on the drug - to protect
against effects of factors like expectation.
So study participants
are allocated "randomly" to the drug or a "placebo"
- a pill that
might be mistaken for the active drug but is inert.
But, according to the paper's author, Beatrice Golomb, MD, PhD,
associate professor of medicine at the University of California, San
Diego School of Medicine, this standard has a fundamental problem,
"there isn't anything actually known to be physiologically inert. On
top of that, there are no regulations about what goes into placebos,
and what is in them is often determined by the makers of the drug
being studied, who have a vested interest in the outcome. And there
has been no expectation that placebos' composition be disclosed.
least then readers of the study might make up their own mind about
whether the ingredients in the placebo might affect the
interpretation of the study."
Golomb pointed out these limitations to the placebo in a pair of
letters to the journal Nature 15 years ago.
"A positive or negative effect of the placebo can lead to the
misleading appearance of a negative or positive effect of the drug,"
she said. "And an effect in the same direction as the drug can lead
a true effect of the drug to be lost. These concerns aren't just
Where the composition has been disclosed, the
ingredients of the placebo have in some instances had a likely
impact on the result of the study - in either direction (obscuring
a real effect, or creating a spurious one).
In the cases we know
about, this is not because of any willful manipulation, but because
it can in fact be difficult to come up with a placebo that does not
have some kind of problem."
Since 15 years have elapsed, the situation might have improved.
Therefore, Golomb and her colleagues analyzed just how often
randomized trials published in the past two years in each of the top
four general medical journals actually disclosed the makeup of
The answer is not reassuring, according to the researchers, who
found that the placebo ingredients for pills were disclosed in fewer
than 10 percent of cases.
(The nature of the "control" was
significantly more likely to be stated for other types of treatments
- like injections, acupuncture, or surgery - where people are more
likely to question what "placebo" actually means.)
"How often study results are affected by what's in the placebo is
hard to say - because, as this study showed, most of the time we
have no idea what the placebo is," Golomb concluded.