Placebos, placebo effect, and the response to the healing situation: the evolution of a concept
Epilepsia, 42(12):1614–1625, 2001 Blackwell Science, Inc. International League Against Epilepsy
Placebos, Placebo Effect, and the Response to the Healing
*Yiannis G. Papakostas and †Michael D. Daras
*Department of Psychiatry, Athens University Medical School, Athens, Greece; and the †Neurological Institute,Columbia-Presbyterian Medical Center, New York, New York, U.S.A.Summary: In spite of its impressive progress, medicine has
been established as the gold standard for the assessment of any
been strongly criticized for relying on its modern biomedical
new treatment. Recently a new trend regarding placebos seems
tradition to the neglect of the psychosocial aspects of health.
to have emerged. The placebo and other nonspecific effects
This neglect may account for patients’ dissatisfaction and even-
elicited by the “healing situation” have been independently
tual use of alternative health approaches. The concept of pla-
subjected to scientific study. Progress in this area may promote
cebo has sustained dramatic “protean” metamorphoses through
useful clinical applications, enabling physicians to broaden
the ages. For centuries, placebos have been regarded as pow-
their perspectives on the healing process. We present the his-
erful deceptive therapies. From the middle of the twentieth
torical changes of the concept of placebo and the ethical issues
century, however, conventional medicine has used placebos as
raised by their use. Key Words: Placebo—Nocebo—
methodologic tools to distinguish the specific from the nonspe-
Randomized controlled trials—Equivalence trials—Ethics—
cific ingredients in treatments. In modern medical research, the
double-blind, placebo-controlled, randomized clinical trial has
Socrates: “good doctors . . . (it) is not possible for them to
response to the healing situation, as well as to discuss
attempt to treat the head by itself, apart from the
certain ethical issues raised from their use. body . . . or the body without the soul . . . . and the treat-ment of the soul by means of certain charms, and thesecharms are words of the right sort . . . ” Plato, Charmides (1)
STAGE I: PLACEBOS
The history of placebo follows the same pattern as other
phenomena in science recognized as “artifacts” (2,3). For
In a group of untreated patients with depression, it is
centuries, healers, including physicians, have used inac-
expected that a certain percentage will improve after a
tive placebos or “dummy pills” worldwide, although the
few weeks. With the administration of an inactive pill,
official medical community ignored them (4–6). Next,
the percentage may be higher, and even higher if an
the nonspecific placebo effect was studied, isolated, and
antidepressant is used. This example illustrates at least
eliminated in the randomized controlled trials as a nui-
three hypotheses that may explain patients’ improvement
sance factor, in contrast to the “specific” pharmacologic
after a certain therapy (12–16). First, a whole spectrum
effect (7,8). Finally, the placebo effect or “the response
of “nonspecific” factors such as the natural course of the
to the healing situation” has recently become a subject of
disease, the regression toward the mean, and other overt
study in its own right, along with the exploration of its
or covert influences may contribute to this healing
through the time course of an untreated illness (17). Sec-
The purpose of this article is to present the historical
ond, in the case of the active drug, the patients improved
transition from placebos, to the placebo effect, and to the
because of the “specific” or “characteristic” effects of thetreatment that can be scientifically studied, isolated, and
predicted through specifically designed studies, the ran-
Address corresponding and reprint requests to Dr. M. D. Daras
domized controlled trials (RCTs) (7,8). Finally, in the
at Columbia-Presbyterian Medical Center, The Neurological Institute,
case of the “inert” therapy, it is obvious that the inactive
710 West 168th Street, New York, NY 10032, U.S.A. E-mail:[email protected]
pill, because it lacked a specific pharmacologic effect,
acted therapeutically through its “symbolic power” and
includes objective end points (such as blood pressure,
its impact on the patient’s imagination, beliefs, expecta-
EEG, serum hormone concentration), whereas the im-
tions, and emotions (7,12). Patients were under the im-
provement can be long lasting (10,30,31). Double-blind
pression that they were taking an active or specific drug
RCTs have shown that placebos can have healing effects
with known efficacy for their condition. This therapy
in diverse conditions as angina pectoris (32), epilepsy
with the inert sugar pill lacking specific activity repre-
sents a typical example of what is called placebo
The notion, however, of a powerful placebo has not
therapy, and the “dummy” pill is called a placebo (from
been unchallenged. By reanalyzing the classic Beecher’s
the Latin: “I shall please”) (4). Besides the administra-
review (25), Kienle and Kiene (35) pointed to Ն19 pos-
tion of a drug, this nonspecific “therapy” can take the
sible reasons for the changes in the placebo-treated
form of a physical (i.e., manipulation), psychological
groups. They argued that the significance of the placebo
(i.e., conversation), or any other form of therapy.
effect has been grossly overestimated and that the re-
The elicited and measurable response after the admin-
ported placebo effect may not be a distinctive one but
istration of a placebo, the ingestion of the inert pill, is
may be part of a spectrum of care and treatment (35).
called a placebo response. It may not necessarily be elic-
They further consider these reports as misleading, per-
ited by the symbolic characteristics of the inert therapy
petuating widespread misconceptions about the magni-
but may constitute a “time effect,” such as spontaneous
tude of the placebo effect. Indeed, the placebo response
improvement (18). Placebo effect is the nonspecific psy-
rates quoted from clinical trials may indiscriminately in-
chophysiologic effect produced by placebos through the
clude both the spontaneous and natural recovery from
symbolic significance of the administered therapy (5).
disease and the “true” placebo effect (15,17,35). Review
The “true” placebo effect may be estimated as the dif-
of clinical trials with patients randomly assigned to either
ference between the magnitude of the placebo response
a placebo or no treatment showed small differences in
(“perceived placebo effect”) minus the magnitude of the
clinical outcome, leading to the conclusion that there is
“time effect” on untreated patients (“other nonspecific
little evidence to support the assertion that placebos have
effect”) (17). In practice, however, distinguishing the
powerful clinical effects (36). Therefore, far from being
“true” placebo effect from the “perceived placebo effect”
resolved, the question of the existence and magnitude of
is not easy (13,19,20). Actually, because these terms are
a true placebo effect is valid and should be addressed by
hard to define precisely (13,21), it was suggested that
Nocebo (from the Latin: I shall harm) and nocebo
The ethics of giving placebos
effects are terms less familiar to physicians, used in cases
There are at least two distinct uses for placebos: in
when patients attach negative meanings and emotions to
research as tools for reducing bias in clinical trials and
a treatment perceived as harmful. In contrast, the defini-
in clinical practice for therapeutic purposes. In both
tion of a treatment as “placebo” depends on the degree of
cases, major ethical issues may arise whenever two key
patients’ positive (beneficent) meanings and emotions to-
considerations or requirements, beneficence and au-
ward it (22). The most common adverse effects of systemic
tonomy, are violated. (37). Beneficence refers to the phy-
placebos are headache and drowsiness (23). Placebos used
sician’s fundamental duty to respond according to the
in healthy volunteers usually cause negative effects because
best interests of an individual patient by providing the
healthy persons anticipate no medical benefit (24).
best available treatment and optimal care to this patient
In dealing with placebos, at least two important ques-
(37,38). This old principle dates back to the Hippocratic
tions arise: first, does a clinically significant “true” placebo
code urging physicians to provide benefits to the patient
effect exist, and second, because their use, either in clinical
and balancing them against risks: “As to diseases, make
practice or in research, almost invariably implies some
a habit of two things, to help, or at least to do not harm”
form of deception, what are the ethical issues involved?
(␣ı´ ı´ ␣ ´␣␣ ␦´, ´ ´
␤a´) (39). Conflicts may arise whenever the phy-
Does a clinically significant “true” placebo
sician has the additional role of a researcher whose pri-
mary concern is to produce valid, generalized knowledge
It is generally accepted that placebos are associated
that may benefit future patients (40–42). Hence, research
with powerful nonspecific effects (3,25–29). According
differs from optimized individual clinical treatment as it
to Oh (27), placebo is “the most effective medication
typically contains an element of increased risk. Admin-
known to science, subjected to more clinical trials than
istration of placebo instead of standard treatment, as it
any other medication, yet generally always does better
usually occurs in research, may be considered unethical
than anticipated. The range of susceptible conditions ap-
because it places some people at risk for the good of
pears to be limitless.” The response is not limited to
others, future patients, and society (43). According to the
subjective (such as pain or anxiety) end points but also
Hippocratic code and the Declaration of Helsinki, the
physician’s role as a healer must take precedence over
the brain associated with the perception of a stimulus as
his role as a researcher. The advancement of scientific
“meaningful” in a healing-related sense, thus producing
knowledge, therefore, must always be secondary to the
end-organ changes (57). Various “mind–body” healing
concern for the individual, whose well-being is the phy-
pathways of the brain such as the endogenous opioid
sician’s highest priority. Nevertheless, physicians also
(58), the neuroendocrine (59), and the psychoneuroim-
have an ethical obligation to find better treatments for
mune pathways (60) have been implicated. Mental and
diseases (44); thus one duty may be at times in discord
emotional stimuli related to the placebo phenomena can
reach the immune system through the autonomic nervous
Autonomy refers to the patient’s right to be informed
system and the neuroendocrine outflow via the pituitary,
about treatment options, the pros and cons of each, and to
linking the brain to the immune system (60,61).
decide about health matters without coercion (37,38).
Although nothing is expected to be absorbed, distributed,
For centuries, beneficence, in the form of benevolent
and metabolized by the ingestion of an “inert” substance,
paternalism, not truthfulness, was the modus operandi of
placebos nevertheless display certain “pharmacologic,”
physicians (7,45). During the second half of the twenti-
behavioral, or physiologic characteristics noted in active
eth century, however, autonomy became a major issue,
drugs (62). “Peak effects,” “cumulative effects,” “ carry-
and the new medical ethics replaced “beneficence” with
over effects,” “tolerance,” and “dependence” are some of
“informed consent” (7). Violation of autonomy (decep-
the subjective or behavioral characteristics of placebo
tion) may occur whenever placebos are used without
administration (63,64). Similarly, placebo-generated per-
adequate patient information and consent. Because some
ceptions can result in the production or release of active
form of deception is believed to be necessary for place-
materials, or may influence the enterohepatic circulation
bos to exert their effect, the patient’s autonomy is threat-
or the local blood flow and the rate of the agonist turn-
ened by a (benevolent) paternalistic attitude that may
over, thus leading to physiologic alterations (62).
influence physicians to administer placebos against thepatient’s knowledge and consent (45). Deception can be
STAGE TWO: PLACEBO EFFECT
detected by evaluating the patient’s understanding and
For centuries, placebos were the most physicians
voluntary participation, the two main components of the
could to offer their patients and through them maintain
modern informed-consent process (46). The issue of au-
their reputation (5,26). In that regard, the history of
tonomy becomes even more pressing in individuals with
medicine was the history of placebos (5). After World
questionable capacity to consent (47).
War II, as medicine adopted biologic principles, the “art”of healing was replaced by the “science” of therapeutics
Mechanism of the placebo action
(65,66), and the traditional beneficence paternalism
As an example of the mind–body relations and com-
yielded to informed consent (67). As a result, the use of
patible with a the holistic view (27), the placebo effect
placebos for therapeutic purposes started to decline.
offers unique opportunities to study the interplay of en-
Treatments with “specific” action replaced “nonspecific
vironmental, mental, and brain processes (48). Because
therapies,” and the principle of autonomy overrode the
the placebo effect seems to exist across all medical dis-
principle of benevolence. Therapeutic or even diagnostic
ciplines, a single universal theory that can explain all
use of placebo in noninformed patients, with rare excep-
placebo effects is unlikely (4). Hence, several psycho-
tions in well-defined cases, is considered ethically unac-
logical and biologic explanations have been proposed
ceptable and may have detrimental effects on the
(2,50). Currently two psychological theories, the classic
patient–therapist relationship (20,41,68–70). Nonethe-
conditioning theory and the expectation theory, have
less, even today there are instances in which clinicians
been used to account for the placebo effect.
prescribe placebos, intentionally or unintentionally, in a
According to the classic conditioning theory, a variety
covert (deceptive) form and frequently in the least-
of inert substances, procedures, persons, or places, if
appropriate cases (71). This practice illustrates ignorance
associated with effective treatments (e.g., penicillin, in-
and prejudice (41) and can be considered nothing more
sulin, morphine) come to function as conditioning
than “a face-saving disguise for medical impotence”
stimuli eliciting similar responses to the unconditioning
(72). For example, controlled studies have shown that
stimuli (51–53). Conversely, the expectation theory pro-
vitamin C for cold prevention is ineffective, as are small
poses that a special type of cognition called expectations
doses of antidepressants, tricyclics in particular, for de-
or expectancies triggers the placebo response (54,55).
pression; yet both are common clinical practices (73,74),
It has been suggested that specific expectations, which
occasionally leading to serious side effects (75). It should
reflect knowledge about the therapeutic agent, the circum-
be emphasized, however, that even if placebos were
stances under which it is administered, and the condition to
given in a direct, nondeceptive way (i.e., patients were
be treated, are directly linked to the placebo effect (56).
informed about the inertness of the given substance), a
The biologic approach aims at identifying pathways in
placebo effect might still be obtained (76,77). This raises
the possibility that in appropriate clinical circumstances,
(93). The first outcome suggests a specific pharmaco-
a placebo could be among the therapeutic choices if of-
logic effect exhibited by the new drug, whereas the op-
fered to patients in a nondeceptive way (3,28). The clini-
posite suggests lack of such an effect and/or even
cal applications, however, of the nondeceptive use of pla-
adverse effects. A demonstration of a difference can
cebo, although theoretically intriguing, is open to question.
serve as compelling evidence, defined as evidence that
Before World War II, a medical therapy was legiti-
“on its own, without the need for any supplementary
mate if it had a positive outcome. But because both inert
sanguine assumption based on assertions about condi-
and active therapies were observed to produce results
tions external to an experiment, leads to one and only
beyond their predicted physiologic properties, the need
logical conclusion about the meaning of the evidence
to study and control them was formally acknowledged
adduced in the RCT. . . ” (93). The absence of difference
and pursued. Subsequently a new trend developed in
is not so informative, because the new drug may lack
medicine. The long-standing tradition of clinical use of
efficacy, but not necessarily so, for various reasons (93).
placebos to promote the healing process was replaced by
The main disadvantage of an inert placebo use in
the investigators’ attempt to disentangle, isolate, and re-
RCTs is the risk and consequences of a nonspecific treat-
move the placebo and other nonspecific effects from the
ment in the placebo-arm patients. Apparently, “the ethi-
“specific” action (10,78). Beginning with the streptomy-
cality of a placebo arm in a trial is inversely related to the
cin trial (79), a new standard was established, and a
availability of an excellent standard treatment, the seri-
medical intervention was scientifically acceptable only
ousness of the condition under study, and the probability
if it successfully passed the powerful screening proce-
of irreversible harm resulting from the denial of thera-
dure of RCT (7,8). In spite of their limitations (80–82),
peutic benefit from conventional therapy” (94). Two ad-
RCTs are widely acknowledged as the most secure
ditional issues not unique to placebo-controlled trials
source for valid interpretation of the treatment effect
apply to any RCTs not involving placebos. First, the
(83,84) and the first step in improving the efficacy of
blind RCTs include an element of deception, as patients
medical care (85). The random assignment of individuals
do not know the type of treatment they receive. This,
involved in RCTs, the sole defining characteristic of
however, may be compensated for by the fact that opti-
these trials (86), is the best way to achieve a balance
mally consenting patients are considered “partners” in
between groups for known and unknown factors that
the deception (95). The rationale of the placebo-arm use
influence outcome, so that any difference can be ex-
in double-blind RCTs is to maintain blinding and mini-
plained only by the treatment (87). It permits a compari-
mize bias (96). Similarly, concerns about whether the
son of the effects of two or more treatments “ceteris
consent to participate was obtained under the optimal
paribus” (all other facts being equal) (88).
conditions of understanding and voluntary participation
Randomized controlled trials
in a placebo-arm RCT are legitimate, but also apply to
The RCT technology offers two distinct ways to show
the effectiveness of a new treatment: comparing it witheither a placebo or an active therapy. Each approach has
Active control “equivalence” trials
These trials are used to show that the new therapy is
equivalent to or not worse than a known effective treat-
These trials aim to show that the experimental treat-
ment, either as an alternative or as having advantages in
ment is superior to the “nonspecific” elements solidified
safety, convenience, or cost (97,98). Because “equiva-
and assessed through the use of a placebo arm. They
lence” or “noninferiority” is the most probable expecta-
intend to prove if the experimental drug has any specific
tion (superiority is seldom asked), these trials have been
or pharmacologic effect (89). The nonspecific elements
called “active controlled equivalence studies” (99).
in RCTs often include many influences, such as support,
Unfortunately, a study that successfully shows
attention, education about the treatment or the illness,
“equivalence” is uninformative, as it does not by itself
and so on (49,90). Hence, in placebo-controlled RCTs,
demonstrate that both treatments were effective. It also
the experimental drug is compared with the “nonspecific
can mean that both were ineffective in the study
treatment” and not with “nothing” (16,42,91). It is pos-
(93,97,100–103). The conclusion that the new treatment
sible that the placebo effect elicited under these circum-
is effective on the basis of its similarity to the active
stances may be even more powerful than that of
control requires the critical assumption that the active
treatment had an effect in that particular study. Only in
Assuming that a placebo-arm study was designed and
trials in which “sensitivity” is proven (that is the standard
performed in a scientifically reasonable manner, a statis-
treatment is superior to placebo) can correct conclusions
tically significant difference favoring either the experi-
of equivalence be made. But such an assumption cannot
mental drug over placebo or vice versa is informative
be maintained, however, as it is known that one third to
one half of RCTs are negative, even when the standard
make sacrifices for the good of others (violation of the
therapy is known to be clinically effective (104). Clearly,
beneficence principle). These volunteer patients are ex-
a third group taking placebo is needed. Conversely, even
posed to the risks of harm from lack of treatment during
if the experimental therapy is less effective than the
their participation in the clinical trial. To support their
active one, the possibility exists that it may still have
arguments, these critics usually cite the following sen-
clinical use for a subpopulation or because of a better
tence from the Declaration of Helsinki in 1997: “In any
side-effect profile. These advantages cannot be known
medical study, every patient including those of a control
group should by assured of the best proven diagnostic
Active control equivalence trials can be informative in
and therapeutic method” (117). Furthermore, the recent
many areas such as treatment of cancer, infectious, and
fifth revision of the Declaration of Helsinki in 2000
cardiovascular diseases, provided that assay sensitivity is
(118), that medical researchers and ethicists have agreed
not in doubt (97). Temple and Ellenberg (97) claimed
on, emphasizes in much clearer terms than ever before
that “the larger the effect size, the less study-to-study
the already restricted conditions allowing the use of pla-
variability in outcomes, and the fewer the instances of
cebo in RCT. Researchers, drug companies, and journal
unexplained failure of the control agent to show superi-
editors may be profoundly affected, as the new principles
ority to placebo in well-controlled studies, the more per-
are expected to tighten the rules for clinical research and
suasive is the case for using this design.” The active
use of placebos, putting new limitations on the risks to
control “equivalence” studies differ from “superiority”
which patients may be exposed (119–122). Ethicists also
studies (i.e., studies designed to detect differences such
raise objections to the use of placebo-controlled RCTs on
as the placebo RCTs), in several important ways. The
methodologic grounds. Several researchers (89,90,93,94,
design and analysis of the former, as compared with the
97,100–102,123,124), however, have firmly disputed
latter, are more complex and less precise scientifically
their assertion that placebo-controlled studies are not sci-
(98,105). Among their disadvantages, the approval of
drugs that are ineffective or have serious adverse effectsremains the main concern (75,93,106). In addition, more
The future of placebos in research
patients are exposed to a possibly ineffective and dan-
The World Medical Association (WMA) decision is at
gerous drug as compared with placebo-controlled RCTs.
odds, and clashes with the opinion of those who consider
They also may incur significant cost increase and delay
these recommendations impractical, interconflicted, and
in the process of drug development (44). These draw-
unattainable (90,94,97,124–127). A literal interpretation
backs raise ethical concerns, as it is obviously unethical
of the Declaration means that if an effective treatment
to engage human subjects in research lacking scientific
exists for any condition, however benign it may be, the
validity and unable to suggest interpretable conclusions.
use of placebo control is unethical. Several problems
The most obvious advantage of the active control RCTs
arise with such a strict interpretation: first, the use of
is that they pose no ethical dilemmas, if there is a “genu-
placebo control will be permissible in only a few cases
ine uncertainty” about which of the two, or more, treat-
(116,128). The main bulk of research will be instead
ments tested is preferable [a condition known as
conducted through active control equivalence trials with
all the aforementioned problems, including the approvalof ineffective therapies. As Khan and Brown (90) stated,
Placebo-controlled trials disputed
“The elimination of placebo controls in favor of non-
Researchers and U.S. Food and Drug Administration
inferiority trials is not only bad science, it is bad for the
regulators (106) prefer and/or require placebo-controlled
public’s health.” Second, a strict interpretation of the
RCTs at least during the initial phase of establishing the
declaration would exclude not only the use of placebo,
efficacy and safety of a new drug and its superiority
but also active-control trials, because patients taking the
against placebo. The use of randomized placebo-controlled,
investigational drug instead of the established therapy
double-blind clinical trial is considered the gold standard
would not receive the “best” proven, current treatment
in research designs, as it is believed to provide the most
(94,97). Any nontherapeutic or nonmedically indicated
definite test of efficacy (93,98). This doctrine, however,
investigational procedure, such as magnetic resonance
has recently been disputed (108,109), and the RCT trials
imaging (MRI) or positron emission tomography (PET),
using placebo arms have come under increasing attack
might also be restricted in clinical research if the same
on ethical and, perhaps less convincingly, methodologic
standard of individualized beneficence applied as in
grounds (110–116). Critics of the placebo-controlled
clinical medicine (42). Finally, a strict interpretation
RCTs consider it unethical to give patients placebos
seems to preclude the free will of patients who, for their
when an approved therapy exists, even if the required
own reasons, choose to participate, such as self-interest,
informed consent has been obtained, because patients are
altruism, or the desire to “be treated as special patients”
asked to participate in a medical trial with the intent to
(129–131). This may appear as another form of revived
beneficent “paternalism” conflicting with and overpow-
the RCT, when randomization is inappropriate, impos-
ering the “autonomy” principle (100).
sible, or unacceptable. Thus in spite of their limitations,
The confusion over the use of placebo forced the
well-designed observational studies can provide valuable
WMA recently to establish a task force to investigate the
information, because their results may not overestimate
issue and refine changes to the Declaration of Helsinki
the magnitude of the therapeutic effect, as previously
(132). Meanwhile, the International Conference for Har-
monization (ICH) released a statement that considers
It seems but erroneous that the use of placebos in
ethical the use of placebo-arm RCT, even if an effective
RCT, the principal research tool or the gold standard,
treatment is available for the condition under study, pro-
through which medicine in the twentieth century had
vided that no serious harm is expected from withholding
made all its great therapeutic discoveries, is seriously
available treatment, and patients are fully informed about
challenged (7). Some expect that the use of placebos in
existing therapies and consequences of delayed treatment
research will progressively change or decrease as medi-
(133). This report is in agreement with the appraisal of
cal knowledge accumulates (105,114), whereas others
Temple and Ellenberg (97) from the FDA on the ethical
believed that the continued use of a placebo control
and scientific issues of placebo-controlled trials.
It seems that a universal agreement exists that place-
bos can certainly be used, when no effective treatment
STAGE III: RESPONSE TO THE
exists, and should not to be used in life-threatening situ-
ations, when standard treatment exists (37,97,116,128). The task, therefore, of the research community is to
In spite of its impressive progress, medicine has been
evaluate specific cases that fall in between, balancing
strongly criticized that by relying on its modern biomedi-
ethical and scientific considerations. Examples of the
cal tradition has neglected the psychosocial aspects of
types of data that the research community may need,
health (142). The price is significant, leading among oth-
come from the work of Al-Khatib et al. (134) and Khan
ers to patients’ dissatisfaction and use of alternative
et al. (135). They evaluated through meta-analysis the
health approaches associated with allegedly powerful
risks of using placebo controls as opposed to the active
nonspecific effects (67,143,144). The last approaches are
drug condition in short–term treatment of mild to mod-
often described with such desirable characteristics as
erate hypertension and acute treatment of depression,
Hippocratic, integrative, preventive, and holistic, whereas
correspondingly. They both found no additional risks
conventional medicine suffers by being considered ga-
from the use of the placebo as compared with those of the
lenic, analytic, curative, and specific (145).
The accumulated knowledge on placebo and the other
Furthermore, researchers should consider reducing the
nonspecific effects of medical care may offer medicine a
number of patients exposed to placebos. For example,
unique opportunity scientifically to explore and expand
because measurement errors are compensated by increas-
the therapeutic processes within a broader biopsychoso-
ing the number of studied subjects (136), improvement
cial framework and, therefore, a more integrative, yet
of raters’ reliability through systematic training or use of
scientific, approach. Physicians may learn how to use
multiple raters will reduce placebo requirements. Next,
these effects in a nondeceptive and ethically acceptable
adaptive allocation designs aiming at reducing the num-
manner. This can be possible because the administration
ber of patients receiving either ineffective and/or poten-
of a placebo is neither a necessary nor a sufficient con-
tially dangerous treatments may be considered (137). In
dition for the initiation of a placebo effect (3,146). Not
the “play the winner” design, the probability of ending
only placebos but also any feature of the nonspecific
up in one arm of the trial or the other depends on how
elements (concomitants) of the physician–patient en-
well previous subjects responded to the treatment (138).
counter may recruit the healing response. Hence, it is
In such a paradigm, the better the experimental treatment,
probably more appropriate to speak of the “response to
the greater the odds that the subsequent patient will be
the healing situation” than of the “placebo response” (3).
assigned to this study arm, and, therefore, the smaller the
Instead of, therefore, being conceptualized as the product
number of patients taking placebos. These types of adaptive
of placebo administration (5), the placebo effect can be
allocation designs, however, are at their very beginning, are
redefined as any effect attributable to the symbolic im-
logistically complex, and lack supportive evidence (137).
portance of a treatment, treatment setting, or treatment
Other strategies, common in cancer, heart failure, and
process (11). This reconceptualization bypasses the con-
epilepsy trials that seem to pose no ethical dilemmas, are
troversial issue of the existence or the magnitude of the
the “add-on” designs in which the patient’s baseline
placebo effect as it encompasses all the nonspecific in-
medication is maintained and then either a placebo or the
fluences. In addition, because the elicited effect is not
new investigational drug is added (97). Finally, clinically
solely dependent on placebo administration, it has the
significant evidence may come from sources other than
potential of being ethically immune.
It seems that a new era in the life of an artifact has
priate emotional involvement appears to be a basic,
come of age, and the growing debate on ethics (87,108)
nonspecific, healing-promoting component, yet neglected
as well as the changing face of medical curricula (147)
during the modern era. Instead, “seeing” became the pri-
may be instrumental in this transition. The phenomena of
mary tool in knowing and understanding during the heal-
placebo and the other nonspecific effects have become
ing endeavors (151). It has been estimated that the mean
objects of scientific scrutiny on their own right.
length of time that elapses before doctors interrupt thepatient’s first response is 18 s (152). As Sir Theodore
Harnessing the placebo effect
Fox wrote, “Lack of time made us all bad doctors” (153).
By recognizing the importance of the response to the
The recent rise of medical interest in the lost tradition of
healing environment, the clinician should be interested in
narrative may force physicians to listen more construc-
developing strategies to optimize this effect in clinical
tively to their patients (154–157). Both patients’ verbal
practice (3,9–11,148). The new “healing art,” however,
and nonverbal communication should be taken into ac-
is in its infancy, lacking a conceptually elaborated and
count, with encouragement to voice their agenda con-
empirically tested body of knowledge. As opposed to a
cerning covert fears and hopes (158).
placebo-elicited effect that has been systematically stud-
Because doctors and patients talk to each other with
ied, there are only few studies of the “response to the
different “voices,” it is the doctors’ duty to smooth com-
healing situation” (3). It is still unknown which of the
munication by explaining in clear and comprehensible
nonspecific factors and to what extent each of them con-
language the diagnostic, prognostic, and therapeutic as-
tributes to the healing effect. Future research should ad-
pects of the illness. Additionally, physicians must be
dress these questions in studies comparing two situations
sensitive to cultural differences and understand how pa-
differing in only one nonspecific factor (14,49). The
tients’ models of health and disease affect their beliefs
need for a multidisciplinary approach to formulate the
and behaviors (159–161). Patients vary in their desire
most important questions pertinent to the nonspecific
for involvement in decision making, so the degree of
factors in the healing process is mandatory (2,50,92,
their participation cannot be predetermined, being in
need of constant revision throughout the therapeutic en-
At the moment, various attempts and suggestions are
deavor and monitored according to individual needs
based on physicians’ clinical experience and some prin-
ciples drawn from psychological, conditioning, or expec-tation theories (3,9,11). It is possible that in the future,
The patient and his or her illness
this healing potential may be deliberately mobilized onan evidence-based manner or invoked in other ways,
such as biochemical. Psychosocially or biochemically
At one time it was thought that only a specific type of
enhanced, the response to the healing situation can be
individual responded to placebo, a consistent placebo
incorporated into standard pharmacologic and surgical
reactor (165,166), but such an individual has not been
treatments to act synergistically with them, thus pro-
identified, and no type of personality is prone to a con-
viding the medical healing art with a strong integrative
sistent placebo-elicited effect (167). Hence, physicians
and holistic trend. At least theoretically, the placebo ef-
must try to elicit the “placebogenic” and/or “nocebo-
fect depends on the patient, the dispensing physician,
genic” aspects of each individual patient with a particular
and prominent between them, the quality of their rela-
disease, positive and negative nonspecific effects in the
patient’s previous beliefs and experiences with treat-ments (background placebo variables), as well as atti-
tudes toward the present illness, and faith in or distrust of
The value of a sound patient–physician relationship
a particular physician or form of treatment (situational
has been historically recognized and is considered the
placebo variables) (9,168). This type of history will pro-
cornerstone for achieving, maintaining, and improving
vide the physician with valuable information to deter-
health (149). We do not know the key elements of such
mine the conditions favoring a placebo effect.
an ideal relationship and whether they influence the pla-cebo effect.
During the past three decades, the patient–physician
Although the establishment of predictable placebo re-
relationship has changed more than during the preceding
sponse patterns to particular disorders has been proven
25 centuries. It cannot any longer be seen as a kind of
difficult, the physician should be aware of the limits and
parent–child relationship, but rather as one between two
potentials of placebo use in each illness. The most thor-
morally autonomous adults (150). And although the de-
oughly studied placebo-responsive disorders are chronic
sirable characteristics change over time, the respect for
pain and psychiatric illnesses (23). Generally, the pres-
the patient’s autonomy is the core of such an ideal rela-
ence of anxiety and pain, the involvement of the auto-
tionship (149). Empathic “listening” that requires appro-
nomic nervous system, and the immunobiochemical
processes are believed to respond favorably to placebo,
(172), or cholesterol for ischemic heart disease (173),
whereas hyperacute illnesses (i.e., heart attack), chronic
seems to be relevant to the issue of referral.
degenerative diseases, or hereditary diseases are ex-pected to resist (27). Conversely, different diseases
invoke different meanings for each individual. An en-
Practitioners tend to prescribe more medications than
counter with a physician is most likely to produce a
patients expect, possibly because they fail to consider the
placebo effect when it changes the meaning of the illness
patients’ reason for coming (174). From a placebo per-
experience for that individual in a positive direction. This
spective, a prescription, if needed, should preferably
is most likely to occur when the patient is listened to and
combine the specific ingredients with nonspecific,
receives an explanation for the illness that makes sense;
placebo-promoting concomitants revealed during the
the patient feels care and concern by the physician and
placebo history-taking procedure (9). The prescription
others in the environment, and experiences an enhanced
should be offered with realistic optimism because the
sense of mastery or control over the illness or its symp-
placebo effect depends on the confidence of the therapist
toms (11). The physician, however, must be cautious
(175). Based on the placebo-promoting effect of predic-
not to raise false hopes that may produce further disap-
tive accuracy, the physician should inform the patient
about the time course of the effect and possible adverseeffects of the treatment (9). A patient who responded
The physician and the treatment setting
well to a particular treatment in the past should be con-
The presence of a physician is the most common fac-
sidered to receive the same in case of a recurrence, es-
tor able to induce a placebo effect, the most frequently
pecially if the disorder is relatively minor, definite
used “drug” in general practice (57). Furthermore, a
treatment does not exist, the prior treatment was not dan-
well-informed physician, without misconceptions,
gerous, or the patient is convinced that the treatment
(31,169) may intentionally use placebo knowledge to
optimize the placebo effect in various ways (3,9–11,51). Perceptual characteristics of the treatmentPredictive accuracy as a placebo-elicited tool
The potentially important effect of these characteris-
According to learning theory, there are at least two
tics is recognized in RCTs, in which various measures
reasons for the physician’s strong “placebogenic power”
are taken to isolate them. From the plethora of these
(51). First, the physician possesses treatments with “spe-
factors and guided by information obtained during the
cific” effects tested by RCTs therapeutic ingredients. The
placebo history, physicians may choose treatments
more effective a treatment, the bigger the placebo effect
whose perceptive characteristics are possibly associated
and the placebogenic power of the physician. Second, the
with strong placebo effects. For example, a new treat-
physician has exceptional diagnostic and prognostic
ment, irrespective of the specific effect, appears more
abilities that represent another source of placebogenesis
effective than an old one (5), or capsules more potent
for the patient, who may confuse them with the physi-
than tablets in anxiety states (176); generally, the more
cian’s healing potential. Accurate diagnosis and progno-
invasive a treatment or the more actively it involves the
sis are, therefore, important tools at the physician’s
patient, the larger the placebo effect (177). The color of
disposition, because, if properly handled, they bear sig-
the pill seems to influence its effectiveness (178), but
nificant possibilities for eliciting a placebo effect (3,9).
consistent trends are not universally apparent (148).
The name of the drug is generally considered to pos-
Appropriate referrals for testing–reassurance
sess tremendous symbolic and practical significance.
While certain referrals and diagnostic tests are neces-
Creating a generic name is a scientific task, but finding a
sary and self-reassuring, oftentimes ordering laboratory
brand name seems to be more an art (179). The FDA
tests, primarily for reassurance purposes, may not be the
forbids use of words that make promises and raise ex-
best strategy and definitely is not without problems
pectations and hopes about cure or safety, but drugs with
(170). The diagnostic tests may leave a patient more
allusive names implying actions far beyond the known
anxious than before unless the true fears are addressed
pharmacologic actions of a given product are not uncom-
(171). Thus a false-positive test result will not allow
reassurance; an inconclusive result may leave doubt andanxiety, and reassurance may not be entirely successful
Conceptual characteristics of the treatment
despite a normal test result (170). Obtaining a test should
Besides its perceptual aspects, a treatment also has
be avoided if an expert clinical opinion suffices because
particular meanings for each patient. Physicians, how-
of the risk of residual anxiety and the epidemiologic
ever, who focus their efforts primarily on properties of
hazard of a false-positive or inconclusive test result
drugs and their effects often ignore the psychological and
(170). The current skepticism about the benefit/risk ratio
behavioral aspects of taking a medication (181). Thus on
of procedures like mammography for breast cancer
a personal level, the patient might hold a beneficent or
harmful view on the treatment offered. On an interper-
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10 km REGIONAL WATER PLAN Rio de Chama Acequias Association Rio Arriba County REGIONAL WATER PLAN Published by the Rio de Chama Acequias Association and Rio Arriba CountyResearched and edited by La Calandria Associates, Inc. Cover photo by Brother Bernard Cranor, OSBGeological cross sections by Andrea KronIn July of 1995, the New Mexico Interstate Stream Commission arranged with R
DEBAT SUR L’EDUCATION - TAIN - LE 29.01.04 - COMPTE-RENDU - QUELLE ECOLE POUR CONCILIER LES ATTENTES DES FAMILLES, DES ENTREPRISES, DES ENSEIGNANTS ? A l’initiative des sections cantonales du PS de Tain-Tournon, ce débat sur l’éducation a permis à une vingtaine de participants d’échanger et de confronter leurs points de vue pendant deux heures. L’objectif affiché était de favoriser