Horng-How ethical is the Placebo Surgery.pdf

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S O U N D I N G BO A R D
Sounding Board
I
S
P
LACEBO
S
URGERY
U
NETHICAL
?
S
URGICAL procedures are often introduced into
practice without rigorous evaluation. Moreover,
clinical trials of surgery have seldom included place-
bo surgery as a control, owing to ethical concerns.
In 1959, the
Journal
published the results of a pla-
cebo-controlled trial of ligation of the internal tho-
racic artery for the treatment of angina.
1
In this issue
of the
Journal,
Moseley et al. report on a placebo-
controlled trial of arthroscopic surgery for osteoarthri-
tis of the knee.
2
In both studies, the surgical interven-
tions were no more effective than placebo operations.
A major difference between the use of placebo surgery
43 years ago and its use now, however, is the degree of
attention to the ethical aspects of conducting clinical
research.
THE ETHICS OF CLINICAL RESEARCH
ical if they are not designed to answer valuable scien-
tific questions with the use of valid research methods.
In addition to having scientific merit, clinical trials
must present a favorable risk–benefit ratio: the risks
to participants must be minimized and justifiable by
the benefits to them, if any, and the potential value of
the scientific knowledge to be gained from the study.
Finally, investigators must obtain informed consent
from participants.
Use of an invasive procedure as a placebo control
poses risks to research subjects assigned to the control
group, without the prospect of a benefit from their
participation, and the burden of proof is therefore on
those who argue that placebo surgery is warranted as
a means of evaluating the efficacy of surgical proce-
dures. The use of placebo surgery in clinical trials raises
three key ethical questions. First, is placebo surgery
compatible with the ethical requirement to minimize
risks? Second, are the risks associated with placebo
surgery reasonable and justifiable in relation to the po-
tential value of the scientific knowledge to be gained
from its use? Third, can informed consent be obtained
for a trial that randomly assigns patients to undergo
genuine or placebo surgery?
PLACEBO SURGERY
Minimizing Risks
The idea of using placebo surgery is apt to elicit an
immediate negative judgment, because it appears to
violate the fundamental ethical principles of benefi-
cence and nonmaleficence.
3
Doctors should not ex-
pose patients to risks if there is no prospect of possible
benefits. With respect to surgery, this means that sur-
geons should not invade the body except for the pur-
pose of cure or amelioration. In a recent ethical cri-
tique of placebo surgery for Parkinson’s disease, Clark
asserted, “The researcher has an ethical responsibility
to act in the best interest of subjects.”
4
Although this statement reflects a commonly artic-
ulated moral stance with regard to clinical research,
it confounds the ethics of clinical research with the
ethics of clinical care. The randomized, controlled trial
is not a form of individualized medical therapy; it is a
scientific tool for evaluating treatments in groups of
research participants, with the aim of improving the
care of patients in the future. Clinical trials are not de-
signed to promote the medical best interests of en-
rolled patients and often expose them to risks that are
not outweighed by known potential medical benefits.
Accordingly, the use of placebo surgery must be eval-
uated in terms of the ethical principles appropriate to
clinical research, which are not identical to the ethical
principles of clinical practice.
5
Clinical research involves an inherent tension be-
tween the ethical values of pursuing rigorous science
and protecting participants from harm.
6
To avoid ex-
ploiting research subjects, clinical trials must satisfy
several ethical requirements.
5
Clinical trials are uneth-
Placebo-controlled trials of medical agents involve
the administration of inert substances disguised as ac-
tive medication. Trial participants do not incur risks by
taking the placebo pill, but they may be at risk for
clinical deterioration or lack of improvement because
they are not receiving an active therapeutic agent. In
contrast, participants in a placebo-controlled trial of
surgery are exposed to risks from the placebo proce-
dure itself.
Macklin argued that placebo surgery violates “an es-
sential standard for research: the requirement to min-
imize the risk of harm to subjects.”
7
The ethical re-
quirement to minimize risks in randomized, controlled
trials must be considered in the context of alternative
study designs for answering scientific questions about
the efficacy of treatment. Can a valid evaluation of a
given surgical intervention be conducted without the
use of a placebo control, thus minimizing risks with-
out compromising scientific rigor?
In the trial of arthroscopic knee surgery reported by
Moseley et al., the primary outcome measure was pain,
an inherently subjective phenomenon. It is doubtful
that valid data could be obtained from a randomized
clinical trial that compared a group of patients assigned
to undergo arthroscopic surgery with a control group
that received no treatment. Because patients enrolled
in such a trial would obviously know whether or not
they had undergone surgery, their reports of pain
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137
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
might be biased. In reporting the degree of knee pain
and function, patients might be influenced by their ex-
pectation of improvement after surgery and postoper-
ative care. Furthermore, assessment of the outcome
without knowledge of the treatment assignments
would require that patients not disclose the treatment
they had received — an unlikely prospect.
In addition to the possibility of biased evaluations of
outcomes, a trial that compares surgery with no treat-
ment or with standard medical treatment does not
control for the placebo effect of surgery.
8
Reduced
pain and improved function may result from the in-
vasiveness of the procedure and the belief that one is
undergoing surgery, rather than from any specific ef-
fects of surgery. A recent meta-analysis called into
question the power of the placebo effect,
9
but that
analysis did not include trials of surgery. Furthermore,
the outcome variable that was most suggestive of a
true placebo effect was pain. There is reason to believe
that the invasiveness of surgery may be associated with
a pronounced placebo effect.
10-13
These methodologic considerations lead to the con-
clusion that a placebo control is required for a rigor-
ous scientific evaluation of surgery when the primary
outcome is a subjective phenomenon such as pain or
the quality of life.
14
If a placebo control is necessary
for a valid test of the efficacy of a surgical procedure,
then use of placebo surgery does not contravene the
requirement of minimizing risks. In this case, there is
no alternative to a placebo control; no other sufficient-
ly rigorous study design poses less risk.
In addressing the issue of minimizing risks, one
must consider not only the question of whether pla-
cebo surgery is methodologically necessary but also
the question of whether the risks of placebo surgery
can be reduced. Moseley et al. reduced the risks of the
placebo surgery in their trial by using a short-acting
tranquilizer combined with an opioid for anesthesia,
which is less risky than general anesthesia with endo-
tracheal intubation, the standard form of anesthesia
used in patients undergoing arthroscopic surgery.
Justifying Risks
and well-being of research subjects only for the good
of future patients. In the trial of arthroscopic surgery
reported by Moseley et al., the risks for subjects who
were randomly assigned to the placebo group includ-
ed potential harm from three skin incisions and from
anesthesia. These risks are certainly greater than min-
imal, but they do not substantially exceed the risks of
other generally accepted research interventions, such
as muscle biopsy, bronchoscopy, and phase 1 testing
of experimental drugs in healthy volunteers, which do
not offer participants a prospect of direct benefits. The
trial of arthroscopic surgery posed considerably less
risk to participants in the placebo group than did the
controversial placebo-controlled trial of a cellular-based
treatment for Parkinson’s disease, which involved the
drilling of burr holes in the skull and the adminis-
tration of general anesthesia, intravenous antibiotics,
and low doses of cyclosporine.
16
Informed Consent
Even if the risks of a scientifically valuable and valid
clinical trial have been minimized, it does not follow
that they are justified. Critics of placebo surgery have
argued that it exceeds an acceptable threshold of risk
for subjects who are randomly assigned to undergo the
invasive intervention merely as a scientific control.
4,15
These subjects are exposed to substantial risks with-
out the prospect of possible benefits.
Can the potential value of the knowledge to be
gained from a well-controlled trial involving the use
of placebo surgery justify the risks to the participants?
It is clearly unethical to jeopardize severely the health
Why would subjects volunteer for a clinical trial if
they understood that they might undergo placebo sur-
gery? Empirical studies of informed consent in clinical
trials involving patients with psychiatric disorders and
those with cancer have shown evidence of a “therapeu-
tic misconception” about research.
17,18
Many research
participants appear to confuse treatment in the scien-
tific context of clinical trials with individualized med-
ical care. There is also evidence that they overestimate
the benefits of participation in a trial and underesti-
mate the risks.
18
These deficits in understanding make
it difficult to obtain meaningful informed consent.
Problems with informed consent are of particular con-
cern in studies involving interventions that depart sub-
stantially from standard clinical practice, especially if
the risks of these interventions, such as placebo sur-
gery, are substantial.
4,7
There is also concern about
the enrollment of “vulnerable” subjects — those who
may have an impaired capacity to give informed con-
sent or who may be susceptible to “undue induce-
ment” to participate in research.
19
We see no reason for special concern about in-
formed consent in the trial conducted by Moseley et
al. Osteoarthritis of the knee is a painful and potential-
ly debilitating condition, but it is not life-threatening.
Nor is it associated with impaired decision-making ca-
pacity. Moseley et al. report that enrolled patients were
required to write in their charts that they understood
that they might undergo an invasive placebo procedure
that would not involve potentially beneficial treatment
of their arthritis. The fact that 44 percent of the el-
igible patients declined participation indicates that the
enrolled subjects decided to participate in the trial
without undue inducement or coercion.
An additional ethical concern about obtaining in-
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·
N Engl J Med, Vol. 347, No. 2
·
July 11, 2002
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S O U N D I N G BO A R D
formed consent for participation in trials that involve
placebo surgery is the use of communication and ac-
tions designed to give the false impression that subjects
randomly assigned to placebo surgery have undergone
a real surgical procedure.
7
Because of the possibility
that some patients might remain conscious during the
placebo surgical procedure in the study by Moseley
et al., it was performed to resemble arthroscopic dé-
bridement. The report does not state whether the plan
to use a placebo intervention that mimicked arthro-
scopic débridement was disclosed to prospective sub-
jects as part of the informed-consent process. Such
a practice can be ethical if investigators inform pro-
spective participants that it will be used to maintain
the blinded condition and if they reveal the nature
of the deception at the end of the study.
20
CONCLUSIONS
the ethical requirements that are appropriate for clin-
ical research.
S
AM
H
ORNG
, B.A.
F
RANKLIN
G. M
ILLER
, P
H
.D.
National Institutes of Health
Bethesda, MD 20892-1156
The opinions expressed in this article are those of the authors
and do not necessarily reflect the views or policies of the National
Institutes of Health, the Public Health Service, or the Department
of Health and Human Services.
We are indebted to Ezekiel J. Emanuel, Donald L. Rosenstein,
and Lynn H. Gerber for helpful comments on drafts of this article.
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Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False
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Joffe S, Cook EF, Cleary PD, Clark JW, Weeks JC. Quality of in-
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Reasonable people are bound to differ over the eth-
ics of a controversial practice such as the use of placebo
surgery in clinical trials. Ethical objections — based
on the requirements to minimize risks, limit the level
of risks that are not offset by the potential benefits
to participants, and obtain informed consent — do not
support an absolute prohibition against the use of pla-
cebo surgery when its use is methodologically neces-
sary to answer clinically important questions. Indeed,
we suggest that the trial conducted by Moseley et al.
exemplifies the ethically justified use of placebo sur-
gery. Each proposed trial involving placebo surgery
must be evaluated carefully in the light of these ethical
considerations.
A full ethical assessment must include consideration
of the consequences of not conducting rigorous trials
of surgery. Arthroscopic surgery has become a com-
mon treatment for osteoarthritis of the knee in the
absence of rigorous scientific evaluation of its efficacy.
According to data cited by Moseley et al., the costs of
this intervention are approximately $3.25 billion per
year. Yet the results of this important study demon-
strate that two methods of arthroscopic surgery are
no more effective than a placebo operation. Thus,
patients have been exposed to risks and third-party
payers have incurred substantial costs for a treatment
that offers no benefit to the patient. Trials of surgical
procedures that include the use of placebo surgery
should be conducted before the procedures become
standard treatments, provided that these trials meet
Copyright © 2002 Massachusetts Medical Society.
N Engl J Med, Vol. 347, No. 2
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July 11, 2002
·
www.nejm.org
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139

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