Lecture 9:Placebo outline Dr.Anna

TOPICS FOR STUDY: Treatment Evaluation & Placebo Effect

TEXT: Provided articles and Lecture Powerpoint

1. What is meant by Treatment Evaluation?
- Definition: Impact of intervention on outcomes of interest
- How can treatments be evaluated? - Through experiments

2. What is meant by the placebo effect?
- Definition of placebo (Shapiro)
- How is the placebo effect different from other therapies that rely on direct physical
or chemical effects on disease processes?

3. Is the placebo effect psychologically or therapeutically inert?
- Which factors influence the placebo effect?
- Two proposed ideas to explain the effect: expectancy theory and classical
conditioning

4. General features of the placebo effect
- Long history and a wide range of interventions (herbs, procedures, preparations)
- Treats a wide variety of physical and psychological conditions (e.g. pain, depression)
- Not always pharmacologically inert
- Placebo effect is non-specific
- Can occur even with awareness of placebo procedure

5. How does the placebo effect work?
- Catalyzing self-healing mechanisms within the patient
- Body produces endorphins (endogenous opioids)

6. What is the Nocebo effect?
- Definition

7. How to control best for placebo effect in treatment evaluations?
- Randomized controlled trial (RCT)
- The importance of randomization
- Other Issues: Double-Blind Procedure, Informed Consent

DEPARTMENT OF MEDICAL HISTORY

Department of medical history

Powerful placebo: the dark side of the randomised controlled trial

Ted J Kaptchuk

The placebo went through a dramatic metamorphosis in
the years after World War II as the double-blinded
randomised controlled trial (RCT) developed. Until
1945 the placebo was a “morally” useful but innocuous
management tool without curative or symptomatic
consequences. By the time the double-blind randomised
controlled trial took form and began to establish itself,
around 1955, the placebo was imbued with powerful
therapeutic effects and its ethical clinical use was more
generally being questioned. In 10 years, the placebo
changed from what was called the “humble humbug” to
an entity with occult-like powers that could mimic potent
drugs. It may be that efforts to bring the precision of
science into the evaluation of efficacy with the RCT has
its own form of confusion and darkness.

Pre-RCT placebo
When pre-World War II paternalistic ethics prevailed,
informed consent was not a standard of care.1 Physicians
were generally comfortable with benevolent deception

Wellcome Institute Library, London
and a “polychromatic assortment of sugar pills” was
routinely swallowed by patients.2,3 In 1903, Richard
Cabot (1868–1939), the eminent professor at Harvard
Medical School, described the placebo’s persuasiveness.
He was “brought up, as I suppose every physician is, to
use placebo, bread pills, water subcutaneously, and other
devices . . . How frequently such methods are used varies
Richard Clarke Cabot
a great deal I suppose with individual practitioners, but I
doubt if there is a physician in this room who has not hypnosis, where the power of the imagination was
used them and used them pretty often . . . I used to give accepted.7 If there was a “medical” value for a placebo it
them by the bushels”.4 Cabot’s remarks are confirmed in was as an occasional diagnostic tool to separate imaginary
many other observations of medical practice. For “psychological” symptoms from real problems.8 In 1945,
example, in 1807, Thomas Jefferson (1743–1826) an influential article stated that the placebo was a
penned a description of what he called the “pious fraud” valuable device “to smooth [the patient’s] path”, which
and noted that, “one of the most successful physicians I “cannot harm and may comfort” patients, especially the
have ever known has assured me that he used more bread “ignorant . . . disappointed and displeased . . . hopeless,
pills, drops of coloured water, and powders of hickory [and] incurable case[s]”.9 A 1954 Lancet article, entitled
ashes, than of all other medicines put together”.5 “The Humble Humbug”, depicted the swan song on this
Peculiarly (at least in the current view), the bread pill old-fashioned understanding of the placebo; “a means of
was generally thought to have no consequences other reinforcing a patient’s confidence in his recovery, when
than giving patients (especially ignorant and complaining the diagnosis is undoubted and no more effective
ones) peace of mind. A medical dictionary published in treatment is possible; that for some unintelligent or
1785 described the placebo as “calculated to amuse for a inadequate patients life is made easier by a bottle of
time, rather than for any other purpose”; a dictionary medicine to comfort their ego; that to refuse a placebo to
from 1811 depicted it as “given more to please than to a dying incurable patient may be simply cruel; and that to
benefit the patient”; and until the 1950s medical decline to humour an elderly ‘chronic’ brought up on the
dictionaries echoed this definition of an inactive and bottle is hardly within the bounds of possibility”.10
innocent management contrivance.6 The main objections
to this prevailing view can be found in the few
RCT placebo effect
sympathetic discussions of such unorthodox practices as
In 1955, the modern biomedical concept of the placebo
Lancet 1998; 351: 1722–25 makes its first definitive appearance with the publication
Center for Alternative Medicine Research, Beth Israel Deaconess of Henry Beecher’s (1904–1976), “The Powerful
Medical Center, Harvard Medical School, Boston, Massachusetts Placebo” in the Journal of the American Medical Association
02215, USA (T J Kaptchuk OMD) (JAMA)11 Beecher, a distinguished medical researcher at

1722 THE LANCET • Vol 351 • June 6, 1998


Harvard Medical School, summarised and World War II the evaluation of new therapeutics was
mathematically presented a perspective that had been made by recognised leaders of the medical profession
developing in a few elite biomedical research centres whose judgments were based on clinical impressions, and
since 1946.12 Beecher used a proto-meta-analytic method on rare occasions, poorly controlled evidence.21 In an
to aggregate the percentage of patients satisfactorily effort to impose an objective and scientific discipline onto
relieved by a placebo across 15 clinical trials. Of 1082 the extraordinary postwar expansion of medical research,
patients, 35·2 (SD 2·2%) experienced therapeutic the components of the double-blind RCT were adopted
benefits. This number, which Beecher called “average and coalesced in the years after the war.22 The major
significant effectiveness” did not measure the exact features of these innovations included blind assessment
magnitude of improvement, (usually meaning a placebo
although that is how most control), random assignment to
people have subsequently comparable groups, and
interpreted his paper. Beecher inferential statistics as a
argued forcefully that placebos surrogate for determinism.23
alleviated beyond psychological The postwar placebo effect
problems by citing evidence resulted from an almost sleight-
that “these powerful placebo of-hand shift in the placebo’s
effects . . . can produce gross operational meaning in the new
physical change”, which RCT model. Instead of an inert
“include objective changes at sham given to individual
the end organ which may patients, the placebo became
exceed those attributable to the emblem for all the healing
potent pharmacological occurring in the disguised “no-
action”.11 In an important treatment” arm of an RCT. The
revision of old orthodoxy, “placebo effect” encompassed
Beecher considered this placebo all “nonspecific effects” that did
effect to operate regardless of not depend on the treatment in
the intelligence of a person. the active arm. The “powerful
Beecher explicitly assumed an A green placebo? placebo” became a hodge-podge
additive model of placebo of non-linear, difficult to
effects, “The placebo effect of active drugs is masked by quantify, remnants collected under the rubric of the
their active effects . . . The total ‘drug’ effect is equal to dummy control of an RCT. Anything that threatened the
its ‘active’ effect plus its placebo effect” (quotes in the fastidious detection of a predictable cause and effect
original).11 This premise took for granted that the active outcome was conveniently disposed of in a repository
drug response results partly from a placebo effect and labelled the “placebo effect”. This new concept of
that the placebo effect buried in the active arm is identical placebo was much larger both in meaning and power
to the placebo effect of the dummy treatment.13 The than its predecessor. It incorporated many contributors to
placebo was a single and stable “power” that behaved in a health outcomes such as natural history, routine medical
consistent manner. The new placebo effect, the and nursing care, and the “art” of medicine that had once
oxymoron-like enigma of an effect produced by been clearly distinct from the deception of an inert pill.
something that is inert came to haunt biomedicine. Still
to this day, extensive examination leaves scientists and Powerful placebo and acceptance of RCT
philosophers to conclude that “the placebo concept as Medical proponents of the RCT were under pressure to
presently used cannot be defined in a logically consistent convince their colleagues of the RCT’s value.23 Few
way and leads to contradictions”.14 Conflicting physicians wanted randomly to assign treatment to
explanations—expectation, faith, classic conditioning, patients, forgo the individualisation of therapy, and
anxiety relief, symbolic processes, patient-doctor withhold promising new therapies. Austin Bradford Hill
relationship, self-perceptions—vie for acceptance. The (1897–1991), the designer of the first randomised trial,
placebo effect has attributes of a neo-mesmeric energy. It many years later confessed that he “deliberately left out
is radically protean: placebo responders seem to react or the words ‘randomisation’ and ‘random sampling
not capriciously,15 and for the same disease the placebo numbers’ at the time because . . . I might have scared
effect can vary between 0% to 100%, when compared them [collaborating physicians] off”.24 Physicians resisted
with identical drugs.16,17 The theurgic placebo can even be treating patients as so “many bricks in a column” and the
more effective18,19 or, as noted by Beecher, completely “elimination of the responsibility of the doctor to get the
reverse the outcomes of known powerful pharmacological individual back to health”.25 In the same issue of JAMA
drugs.20 as Beecher’s paper, another research team concluded,
What happened in the 10 years between 1945 and “we seriously doubted whether the double blindfold
1955, when the placebo shifted from insipid decoy to a technique was a valid method of distinguishing between
mischievous genie that could trick the most discerning the effectiveness of analgesic agents”.26
clinician? For elite researchers, the moral imperative for scientific
method in therapeutic evaluation was critical. They
RCT and creation of the modern placebo realised that the imprecision of standard methods was a
World War II has been called the great divide in medical hazard for the health of nations. (The general public was
research and certainly, for the placebo, this is true. In mostly unaware of any problem until the much later
fact, the “powerful placebo” was born in the vortex of thalidomide tragedy). For these reformers, “the powerful
one of medicine’s most momentous transitions. Before placebo effect” became a major argument used to

THE LANCET • Vol 351 • June 6, 1998 1723


persuade the medical profession to accept the placebo- blind RCT became the instrument to prove its own self-
controlled RCT. The greater the placebo’s power the created value system. This shift from emphasising
more necessity there was for the masked RCT itself. outcomes to the purity of the means directly parallels
Because of this ominous threat, which could distort the developments in medical ethics where “informed
judgment of even the most unbiased and conscientious consent” replaced “beneficence” as the pinnacle of the
researcher, one needed to adopt the scientific device of value system.
placebo control which alone allowed a separation of real Presuppositions embedded in the new concept of
from false effects. An enhanced “placebo effect” came to placebo also helped implement new methods of using
serve a valuable scientific and rhetorical function of frequency statistics to make causal inferences. The critical
persuading colleagues of the necessity of the RCT. assumption here was that the placebo effect was a
A need to show the placebo’s power was monolithic effect which was present to the same degree
understandable. Understanding the phenomena itself was and same direction in both the treatment and dummy
of much less consequence. How the active treatment arms. (Anomalies such as placebo with a larger effect
worked was seen as important. The dummy side of a trial than the real drug or a placebo that could reverse
received inadequate attention, poor methodology, and a pharmacological activity, were conveniently overlooked as
priori assumptions. The archetypal example of this is was the possibility of verum and placebo being
Beecher’s original study with its many flaws, most of differentially effected by the context of the RCT or of
which have gone unnoticed until recently.27,28 For interacting.) For the emerging RCT model, the treatment
example, Beecher did not mention, although he and dummy arm of trials were assumed to receive equal
undoubtedly knew, that much of what was labelled a and independent amounts of this force; one could simply
powerful placebo effect was actually regression to the subtract the amount of placebo effect to determine the
mean, natural history, or concurrent interventions.27–29 presence (or absence) of specific drug effect. The
There had already been some well-designed experiments possibility that the placebo effect could act differentially
with two controls (a placebo arm and a “no-treatment in the two arms was discounted. This “assumption of
no-placebo” arm) which demonstrated no placebo additivity . . . enable[d] one to infer that the variabilities
effect.30 These were not included in the study. Beecher within the treatments should have a . . . [random]
retrospectively interpreted the two pre-World War II distribution.”35 Without the premise of a single placebo
trials used in his study as having a placebo effect when effect, commonly used statistical procedures would be
the original investigators have confidently reported the confounded.
results observed in the sham arm as being due to The placebo had value only as a comparison marker,
spontaneous recovery31 or spontaneous variations.32 Also, the magnitude of its absolute power has been an
in the calculation of the quantitative effect of the placebo, incidental question. Studies attempting mathematically to
Beecher deliberately did not include in his calculation the quantify across trials the magnitude of the placebo effect,
numbers of patients who got worse with placebo, like Beecher’s, can be counted almost on one hand.17,27,36–39
although this effect was reported in several trials Beecher When their results conflict, as they do, they have been
analysed.33 Inclusion of this group would have dissolved ignored or tolerated. Beecher’s vintage numbers are still
significant amounts of the placebo effect into equally routinely misquoted; they are preferable to any challenge
distributed normal variability.27 In fact, the entire point of of their written assumptions.
Beecher's exercise to establish the “powerful placebo”
was to demonstrate persuasively “that ‘clinical RCT and powerful placebo at 50 years
impression’ is hardly a dependable source of information The powerful placebo is a modern entity constructed in
without the essential safeguards of the double unknown the shadow of the RCT. In the current RCT era, a
technique, the use of placebos also as unknowns, legitimate therapy must demonstrate an effect greater
randomisation of administration . . . and mathematical than a decoy disguised as a real intervention. Yet, under
validation of any supposed differences”.11 Accurate the rhetorical label of powerful placebo lies many rich
portrayal of the placebo effect was of less importance than contributions to health care. These include: nature taking
invoking it as a threat to scientific evaluation, the its course; regression to the mean; routine medical and
elimination of which would be accomplished by the nursing care; regimens such as rest, diet, exercise, and
double-blind RCT. The “new” placebo became both the relaxation; easing of anxiety by diagnosis and treatment;
raison d’être for, and the sacrificial victim of, the masked the patient-doctor relationship; classic conditioning and
RCT. learnt behaviours; the expectation of relief and the
imagination; and the will and belief of both patient and
RCT and placebo: the light and dark of a practitioner.
partnership The placebo effect also includes another often-
Elite medical reformers created a symbiosis between the overlooked consequence of research activity. It is
RCT and the powerful placebo effect. A new gold modified by consequences due to the context of the RCT
standard was constructed to fit the new technical itself.40 Issues such as the method of recruiting patients,
procedures. Until the RCT, medical therapy became manner of giving informed consent, procedures for
legitimate because of beneficial outcomes; after the RCT, blinding, vehicle of delivery (colour of pills, pills vs
a medical intervention was only scientifically acceptable if injection), provider characteristics, provider verbal
it was superior to placebo.34 No longer was it sufficient for attitudes, and physical setting of the environment have
a therapy to work: it had to be better than placebo. For been insufficiently studied.
the first time in history (outside of religious healing But each of the components of the placebo effect has
scuffles), method became more important than consequences in healing and may have a differential
outcome.34 In a self-authenticating manner, the double- impact on each arm of an RCT. All the variables can

1724 THE LANCET • Vol 351 • June 6, 1998


create countless variations in outcomes that have 14 Gøtzsche PC. Is there logic in the placebo? Lancet 1994; 344:
925–26.
undoubtedly contributed to the haphazard trail that the
15 Liberman RP. The elusive placebo reactor. Neuropsychopharm 1967; 5:
placebo effect has traced. It is therefore essential, 557–66.
whenever ethically and financially feasible, that research 16 Joyce CRB. Placebos and other comparative treatments. Br J Clin
in medicine begins to disentangle the “non-specific” and Pharmacol 1982; 13: 313–18.
“art-of-medicine” aspects of healing and therapeutic 17 Moerman DE. General medical effectiveness and human biology:
placebo effects in the treatment of ulcer disease. Med Anthropol 1983;
evaluation. Besides comparing a real intervention and 14: 3, 13-16.
placebo, the inclusion of a third no-treatment no-placebo 18 Beecher HK, Keats AS, Mosteller F, Lasagna L. The effectiveness of
arm would be helpful to distinguish a perception of a placebo “reactors” and “non-reactors”. J Pharmacol Exp Ther 1953;
109: 393–400.
“placebo” effect from the ordinary natural history of a
19 Dinnerstein AJ, Lowenthal M, Blitz B. The interaction of drugs with
condition.41 Each “non-specific” effect needs to be placebos in the control of pain and anxiety. Perspect Biol Med 1996; 10:
disentangled, carefully varied, and systematically studied 103–117.
under controlled conditions.40 Preliminary evidence 20 Wolf S. Effects of suggestion and conditioning on the action of
chemical agents in human subjects—the pharmacology of placebos.
concerning the examination of non-specific effects and J Clin Invest 1950; 29: 100–09.
contextual effects of an RCT has been valuable, 21 Marks HM. The progress of experiment: science and therapeutic
provocative, and contributed to a more refined reform in the United State, 1900–1990. Cambridge: Cambridge
understanding of the internal and external validity of University Press, 1997.
22 Lilienfeld AM. Ceteris paribus: the evolution of the clinical trial.
trials.42 Bull Hist Med 1982; 56: 1–18.
Obviously, the double-blind RCT has meant a 23 Kaptchuk TJ. Intentional ignorance: a history of blind assessment in
tremendous improvement in research and subsequent medicine. Bull Hist Med 1998; in press.
medical care. In the beginning, the RCT needed a 24 Hill AB. Suspended judgment: memories of the British streptomycin
trial in tuberculosis. The first randomized clinical trial. Control Clin
simplistic neo-mesmeric placebo as a looming threat. It is Trials 1990; 11: 77–79.
undoubtedly time that the “powerful placebo” be 25 Hill AB. The clinical trial. N Eng J Med 1952; 274:4 113–19.
examined in all its myriad facets, otherwise medicine will 26 Batterman RC, Grossman AJ. J Am Med Assoc 1955; 159:17 1619–22.
always have a limited perception of healing. At age 50, 27 McDonald CJ, Mazzuca SA, McCabe GP. How much of the placebo
the RCT is ready to go through a mid-life crisis and face “effect” is really statistical regression? Stat Med 1983; 2: 417–27.
28 Kienle GS. Der sogenannte placeboeffectk: illusion, fakten realität.
its dark side. Stuttgart: Schattauer, 1995.
29 Kienle GS, Kiene H. Placebo effect and placebo concept: a critical
Acknowledgments methodological and conceptual analysis of reports on the magnitude of
Research for this paper was partly supported by grants from the John E the placebo effect. Altern Ther 1996; 2: 39–54.
Fetzer Institute, NIH grant U24 AR3441, and the Kenneth J 30 Tyler DB. The influence of a placebo, body position and medication
Germeshausen Foundation. The author also wishes to thank David of motion sickness. Am J Phys 1946; 146: 458–66.
Eisenberg, Howard Brody, Daniel Moerman, Adriane Fugh-Berman, 31 Diehl HS. Medicinal treatment of the common cold. J Am Med Assoc
Herman Engelbart, and David Stone for advice, discussion and feedback, 1993; 101: 2042–49.
and thank Marcia Rich and Janet Walzer for editorial assistance. 32 Gold H, Kwit NT, Otto H. The xanthines (theobromine and
aminophylline) in the treatment of cardiac pain. J Am Med Assoc 1937;
108 (26): 2173–79.
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6 Shapiro AK. Semantics of the placebo. Psych Quart 1968; 42: 653–95. 38 Porter DR, Capell HA. The ‘natural’ history of active rhematoid
7 Tuke DH. Illustrations of the influence of the mind upon the body in arthritis over 3–6 months: an analysis of patients enrolled into trials of
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8 Shideman DE, Beckman H. Comments on treatment. Wisconsin Med J 39 McQuay H, Carroll D, Moore A. Variations in the placebo effect in
1958; 57: 456. randomized controlled trials of analgesics: all is blind as it seems. Pain
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Rajagopal The placebo effect

special article
Psychiatric Bulletin (20 0 6), 30, 185^18 8

S U N D A R A R A J A N R A J A G O PA L

The placebo effect
The placebo effect is a fascinating phenomenon in clinical superficial procedures (e.g. skin incision, burr hole) are
practice. Studies have shown that there is a significant performed without the actual surgery.
placebo effect in a wide range of medical conditions Placebo equivalents are also employed in comple-
including psychiatric disorders. This article looks at the mentary medicine. For example, sham acupuncture
background of the placebo effect, defines the common consists of needles placed at non-acupuncture points. A
terms used, describes the various hypotheses that have recent study (Linde et al, 2005) showed that real
been put forward to explain this seemingly inexplicable acupuncture was no more effective than sham acupunc-
phenomenon and also covers the issue of using placebos ture in reducing migraine headaches, although both
in research trials, highlighting the important ethical interventions produced benefits compared with a waiting
dilemmas involved. Throughout, specific emphasis is given list control.
to psychiatry.

Why does the placebo effect occur?
Background
The term placebo is derived from the Latin verb ‘placare’,
Natural remission theory
‘to please’. The American anaesthetist Henry K. Beecher This states that the improvement that occurs with the
(1955) coined the term ‘placebo effect’. He reported that, administration of placebo is coincidental and would have
on average, about a third of patients with a range of occurred even without it. This theory explains the bene-
conditions improved when they were given placebos. This ficial effects of placebo in short-lived conditions like
subsequently led to the development of placebo- common cold, headache, etc, but does not satisfactorily
controlled trials, whereby a new drug is said to have explain why even patients with chronic conditions such as
significant benefit only if it shows superiority over hypertension or schizophrenia show improvement with
placebo. The placebo effect has also been a source of placebo.
recent interesting debate in psychiatry with some An allied hypothesis is the ‘regression to the mean’
claiming that a considerable proportion of benefit from theory. Regression to the mean is a statistical concept;
antidepressant medication derives from the placebo according to this, if an initial test result is extreme and
effect (Kirsch & Sapirstein, 1998), whereas others if the test is repeated, statistically there is a greater like-
(Leutcher et al, 2002) have stressed that response to lihood for the second result to be closer to the mean
placebo and to antidepressants involves distinct biological than for it to be more extreme than the first result.
mechanisms. Usually only patients who are significantly unwell (e.g.
depression score above a certain cut-off point) are
eligible to enter a trial. Hence, at follow-up they are more
Definitions likely to show an improvement (depression score being
In general, a placebo is an inert substance that has no closer to the mean than the first score) than a deteriora-
inherent pharmacological activity. It looks, smells and tion, owing to regression to the mean (McDonald et al,
tastes like the active drug with which it is compared. An 1983).
‘active placebo’ is one that has its own inherent effects
but none for the condition that it is being given for
(e.g. use of atropine as the control drug in trials of
Classical (Pavlovian) conditioning
tricyclic antidepressants). A placebo need not always be In the original experiment of Pavlov, the dog salivated at
pharmacological. It could be procedural, for example, the sound of the bell even without any food, as it had
sham electroconvulsive therapy (ECT), where the patient previously been conditioned to expect food by pairing
is anaesthetised but not given ECT. Surgical placebo is a the bell with food. Food is the unconditioned stimulus,
procedure where the patient is anaesthetised and salivation owing to food is the unconditioned response;

185


the bell is the conditioned stimulus and salivation owing particularly dopamine, in placebo effects on mood and
to the bell is the conditioned response. behaviour.
special In a similar manner, patients who have had past
article experience of getting better with active medication may
be conditioned to anticipate improvement by any subse- Pattern of placebo improvement
quent prescription, including placebo. Using the classical
Among psychiatric disorders, the placebo effect has been
conditioning analogy, the active medication is the
most extensively studied in depression. ‘Pattern analyses’
unconditioned stimulus, improvement owing to active
have shown that the improvement as a result of placebo
medication is the unconditioned response, the placebo is
in depression tends to be abrupt, occurs early in treat-
the conditioned stimulus, and improvement owing to
ment and is less likely to persist (Quitkin et al, 1991),
placebo is the conditioned response. whereas improvement in response to antidepressants
tends to be gradual, occurs later and is more likely to
Other psychological factors persist. Even among patients apparently responding to
the active drug, if the pattern of improvement is consis-
Patient expectations are important in determining the tent with a placebo response (i.e. abrupt and early), the
placebo effect. Treatments that are perceived as being improvement tends to be short-lived.
more powerful tend to have a stronger placebo effect Stewart et al (1998) investigated whether they could
than those that are perceived to be less so. Thus, placebo predict relapse of depression from the initial pattern of
injections have more effect than oral placebos, capsules response. Patients who had responded to treatment with
are perceived as being stronger than tablets, bright- fluoxetine for 12^14 weeks were then randomly allocated
coloured placebos are more effective than light-coloured to continuation/maintenance treatment for 50 weeks
ones larger placebos have more effect than smaller ones, with either placebo or fluoxetine. Those patients who had
and two placebos have more effect than one. Also, the shown a placebo pattern of improvement during the
status of the treating professional is directly related to initial fluoxetine phase relapsed in a similar manner
the placebo effect. The same compound has been found whether they continued on fluoxetine or were switched
to be more powerful if it is branded than when it is to placebo, but patients who had shown a true drug
unbranded (Branthwaite & Cooper, 1981). pattern of improvement relapsed more if they were
In a novel study, Benedetti et al (2003) examined the switched to placebo in the maintenance phase. This study
impact of the patient’s awareness that they are having a adds strength to the hypothesis that, even among drug
certain treatment administered/withdrawn on the responders, only a certain proportion will benefit from
outcome. They studied three treatments in three maintenance treatment.
groups of patients - intravenous morphine for post- Hrobjartsson & Gotzsche (2001) conducted a major
thoracotomy pain, intravenous diazepam for post- systematic review of placebo-controlled trials involving
thoracotomy anxiety and stimulation of the subthalamic 40 clinical conditions, including hypertension, asthma,
nucleus for idiopathic Parkinson’s disease. In each group, pain, depression, schizophrenia, anxiety and epilepsy.
some patients were informed of the fact that they were They concluded that placebos tended to have no signifi-
receiving the treatment (e.g. by a doctor administering cant effects on binary outcomes, and possibly had small
the injection) but others were not aware as they received beneficial effects on continuous subjective outcomes and
an infusion from an automatic pre-programmed machine. in the treatment of pain.
In all the groups, the efficacy of the respective inter-
ventions was greater when the patient was aware of the
procedure than when they were not. Similarly, being Use of placebos in clinical trials
aware that a treatment was being withdrawn worsened It is generally accepted that a double-blind randomised
the symptoms much more than when the treatment was controlled trial (RCT) is the best research method to
withdrawn without the patient’s knowledge. From a study the efficacy of clinical interventions.
psychiatric point of view, neither the hidden administra- However, the use of placebos for conditions for
tion nor hidden withdrawal of diazepam had any signifi- which effective treatments are already available raises an
cant positive or negative effect respectively but the open important ethical question. Should a new treatment be
administration of diazepam improved anxiety symptoms compared with an established treatment or should it only
and open withdrawal worsened them. have to demonstrate superiority over placebo in order to
be accepted as another effective treatment? Rothman &
Michels (1994) have criticised the use of placebo-
Role of endogenous opioids
controlled trials to test new drugs for conditions with
In a systematic review, ter Riet et al (1998) concluded potentially irreversible consequences, such as oncho-
that endogenous opioids (e.g. endorphins) play a cerciasis and rheumatoid arthritis, when established
significant role in mediating placebo-induced analgesia. treatments for these conditions already exist.
Previous studies had shown that placebo-induced Death by suicide is associated with major psychiatric
analgesia is partially reversed by administering the opioid disorders such as depression, and the use of placebo-
antagonist naloxone (Grevert et al, 1983). There is also controlled trials to test the efficacy of new drugs is
growing interest in the role of neurotransmitters, fraught with ethical issues.

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Another important question involves the masking of to the side-effects investigated during RCTs. Thus, side-
the double-blind trials. Margraf et al (1991) reported that effects reported by patients on placebo may be a reflec-
a majority of patients in a double-blind study of tion of pre-existing or spontaneously occurring symptoms special
alprazolam v. imipramine v. placebo could correctly guess rather than being placebo-induced. Similarly, RCTs may be article
whether they were on an active drug or placebo. In overestimating the side-effects (especially the non-
addition, the ‘masked’ assessors were even able to specific ones) of active drugs.
distinguish between the two active drugs. However, the nocebo effect is not purely psycholo-
Informed consent entails the patients being made gical. It has been shown that nocebo hyperalgesia (i.e. an
aware that they will be receiving either an active drug or increase in pain as a result of placebo) is mediated by
placebo. Therefore, it may not require more than just cholecystokinin and is abolished by the cholecystokinin
monitoring one’s side-effects closely to accurately deter- antagonist proglumide (Benedetti et al, 1997). In a
mine whether one is on active medication or placebo. systematic review of double-blind RCTs comparing fluox-
In addition to ethical issues, RCTs with a placebo etine and placebo, Casper et al (2001) found similar rates
control group have other limitations. RCTs only demon- of placebo response in men and women but slightly more
strate statistical significance. If the sample size is very nocebo effects in women.
large, even if the difference in clinical outcome between
the two groups is small and clinically insignificant, it may
be detected as being significant by the statistical test. Conclusions
In any RCT, the placebo is made by the manufacturer Despite half a century having passed since its inclusion in
of the active drug. Hence, placebos used in one study will modern medicine, the placebo effect is still poorly
be different in form (size, shape, tablet/capsule, etc.) understood. Beecher’s (1955) original study, which
from those used in another study, depending on the form showed an overall average placebo response of 35%, has
of the active drug. This may account for the wide varia- been strongly criticised for major methodological short-
tion in placebo response observed for the same condi- comings (Kienle & Kiene, 1997).
tion. All discussion regarding placebos is based on the
assumption that they are inert. But are they really so?
Placebos are generally referred to as ‘sugar pills’; sugar is
Side-effects of placebos not chemically inert. Similarly, the tablet coating or the
capsule covering are not inert. Hence, the possibility that
When a placebo produces prominent side-effects it is
the ‘inert’ chemical in the placebo may be relevant to the
known as a ‘nocebo’. The term ‘nocebo effect’ encom-
condition being studied should not be dismissed.
passes the negative consequences resulting from the
Whatever the reasons for the placebo effect, the
administration of a placebo. In placebo-controlled studies
most important message for clinicians is that just because
of psychotropic drugs, the placebos tend to cause a
someone responds to a placebo does not mean that the
similar range of side-effects as the active drugs but
initial ailment for which they sought help was false.
usually with a much lower incidence rate. Non-specific
side-effects, such as headache and nausea, tend to be
more common than more specific ones such as acute
dystonia or QT prolongation. ‘Placebo sag’ refers to the Declaration of interest
attenuation of the placebo effect with repeated use None.
(Peck & Coleman, 1991). There are historical reports of
placebo dependence (Vinar, 1969).
The nocebo effect clearly illustrates the role of References
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BENEDETTI, F., AMANZIO, M.,
tion in the past, as most major psychiatric disorders tend CASADIO, C., et al (1997) Blockade of GREVERT, P., ALBERT, L. H. &
to follow a chronic course. Hence, even if they are given nocebo hyperalgesia by the GOLDSTEIN, A. (1983) Partial
cholecystokinin antagonist proglumide. antagonism of placebo analgesia by
placebo this time, they may anticipate side-effects similar
Pain, 71,135-140. naloxone. Pain, 16,129-143.
to those that they experienced when they were receiving
treatment with the active drug. Also, patients may be BENEDETTI, F., MAGGI, G., LOPIANO, L.,
et al (2003) Open versus hidden medical HROBJARTSSON, A. & GOTZSCHE, P. C.
influenced by the list of side-effects experienced by their treatments: the patients’ knowledge (2001) Is the placebo powerless? An
friends or relatives who have received such treatment in about a therapy affects the therapy analysis of clinical trials comparing
outcome. Prevention & Treatment, 6. placebo with no treatment. New
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BRANTHWAITE, A. & COOPER, P. (1981) KIENLE, G. S. & KIENE, H. (1997) The
Just as doubts have been cast on the beneficial Analgesic effects of branding in powerful placebo effect: fact or
effects of the placebo, so have questions been raised treatment of headaches. BMJ, 282, fiction? Journal of Clinical
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not taking any medication have been shown to have a CASPER, R. C.,TOLLEFSON, G. D. & KIRSCH, I. & SAPIRSTEIN, G. (1998)
high prevalence of a range of symptoms which are similar NILSSON, M. E. (2001) No gender Listening to Prozac but hearing

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placebo: a meta-analysis of studies? Journal of Consulting and during placebo treatment. American with fluoxetine or placebo. Archives
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