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Phil. Trans. R. Soc. B (2011) 366, 1922–1930
doi:10.1098/rstb.2010.0399
Review
Harnessing the placebo effect: the need
for translational research
Luana Colloca1,2,* and Franklin G. Miller2
1
National Center for Complementary and Alternative Medicine (NCCAM), and
Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA
2
Laboratory research recently has greatly enhanced the understanding of placebo and nocebo effects by
identifying specific neuromodulators and brain areas associated with them. However, little progress
has been made in translating this knowledge into improved patient care. Here, we discuss the limitations in our knowledge about placebo (and nocebo) effects and the need for translational research
with the aim of guiding physicians in maximizing placebo effects and minimizing nocebo effects in
their routine clinical practice. We suggest some strategies for how, when and why interventions to
promote beneficial placebo responses might be administered in the clinical setting.
Keywords: clinical practice; patient– doctor relationship; placebo theory; ethics;
expectation; nocebo
1. INTRODUCTION
Laboratory research on the placebo and nocebo effects
has provided extensive evidence about the neurobiological nature of these phenomena, which can produce
health-related effects [1,2]. Beyond the scientific interest
in exploring the mechanisms underpinning these
fashionable mind–body interactions, the ultimate aim
of research on the placebo (and nocebo) effects is
to develop knowledge that can be translated into
improved patient care. To do this, it is necessary
to focus on translational placebo research emphasizing
the clinical significance of placebo and nocebo effects.
In biomedicine, translational research aims at applying basic in vitro and in vivo science to develop
knowledge that can be used to improve the diagnosis,
treatment or prevention of human diseases [3].
New treatments and research knowledge should reach
patients and clinicians for whom they were intended,
by promoting access, reorganization and coordination
of systems of care, encouraging clinicians and patients
to modify their behaviours, and improving the patient–
clinician relationship. In light of the general purposes
and objectives of translational research, we analyse
salient points of current scientific knowledge on placebo
and nocebo research and suggest strategies to promote
clinical benefits.
Translational placebo (and nocebo) research involves
a number of important issues such as (i) analysing
current theories of placebo and nocebo effects and
their relevance to clinical practice; (ii) integrating the
best evidence of clinically significant placebo and
nocebo effects with physician’s expertise and patient’s
attitudes; and (iii) bridging the gap between
* Author for correspondence ([email protected]).
One contribution of 17 to a Theme Issue ‘Placebo effects in
medicine: mechanisms and clinical implications’.
mechanistic research and clinical practice. Together
these points suggest the need for coordinating research
efforts among different disciplines and experts (basic
scientists, clinical researchers, trialists, anthropologists
and bioethicists) and for providing tentative indications
and recommendations for future patient-oriented
placebo (and nocebo) investigation.
In mapping translational placebo (and nocebo)
research, it is important to clarify some of the terminology that relates to these phenomena. The word
placebo has been often used to refer to inert substances
and simulation of interventions. Placebo research indicates the study of the impact of expectations on
brain – mind – body interactions. Inert substances and
simulation of interventions have been extensively
used as tools in placebo research. Substances and
interventions are considered placebos when they lack
the potential to produce benefit on the basis of
pharmacological properties or physical manipulations.
Some authors have distinguished between ‘pure’ and
‘impure’ placebos [4,5]. Examples of pure placebos
are talc, sugar and bread pills that physicians have
historically administered to placate patients and
comply with their wishes to receive medications.
(Most pharmacological placebos in clinical trials are
also pure placebos.) Impure placebos are treatment
interventions that typically have a specific active principle that is known to be effective in conditions other
than the condition being treated: e.g. use of a vitamin
to treat fatigue not related to vitamin deficiency.
Clinically speaking, what makes substances or interventions count as placebos is the lack of specific
efficacy in treating a specific patient’s condition
based on the inherent properties of the treatment.
Finally, the placebo effect refers to the multiple changes
occurring in the body that are produced by a placebo
administration or treatment simulation. However,
these effects do not depend necessarily on the
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This journal is q 2011 The Royal Society
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administration of ‘inert’ substances. The effects following the administration of a placebo can be due to
the general psychosocial context around the therapy.
As a positive psychosocial context may induce a placebo effect, a negative context, including information
about side effects, may lead to opposite expectations
and outcomes, called the nocebo effect.
2. PLACEBO AND NOCEBO THEORIES
Contemporary placebo and nocebo research has been
inspired by prior and current theories. Ideally, the
development and refinement of theoretical approaches
to understanding placebo and nocebo effects works in
tandem with translational research. Theoretical
perspectives inform hypotheses and the design of
experiments to test them. Patient-centred research
provides insights for evaluating and reframing theoretical perspectives. Placebo (and nocebo) phenomena
have been mainly attributed to expectation and
conditioning.
Kirsch [6] posited an expectancy theory whereby a
placebo produces an effect because the recipient
expects it. Because the placebo intervention does not
have physical properties with the potential of producing specific effects of interest, it is assumed that
these effects are due to the recipient’s expectations.
According to this view, Kirsch labelled the beliefs
that appear to mediate the placebo effects ‘response
expectancies’, defining them as ‘anticipation of the
occurrence of non-volitional responses’. Response
expectancies may also enhance effects of active treatments that do have specific efficacy based on their
pharmacological or physiological properties. Response
expectancies can be distinguished from ‘stimulus
expectancies’, which ‘are the anticipation of the occurrence of external consequences’, such as conditioned
experiences as well as from ‘anticipation of voluntary
response which have been labelled intention’ [6].
As noted above, placebo responses can also be
produced by conditioning. Although expectancyinduced placebo responses created by verbal
suggestions are conceptually distinct from conditioned
placebo responses, the two models clearly overlap to
some extent [7] and, expectations per se can be actively
built up through prior experience via conditioning.
Previous direct experience of benefit via pharmacological or biologically significant cue exposure can
powerfully change behaviour and clinical outcomes.
Originally demonstrated by Pavlov [8] with animals,
associative learning was considered essentially as a
pairing of two stimuli. One, initially neutral in that
by itself it elicits no response, is called the conditioned
stimulus (CS); the other that consistently elicits a
response is called the unconditioned stimulus (US).
The response elicited by the pairing of the CS
and the US is called conditioned response (CR). The
formation of the CRs may be due to repeated association of the CSs with active medication, the USs.
Pairing placebos with effective medication followed
by administering placebos without the medication
can produce a CR that is similar to the response to
medication [9,10]. Humans classical conditioning
probably often involves a cognitive process, which
Phil. Trans. R. Soc. B (2011)
1923
forms and/or changes expectations [11]. In his model
of expectation, Reiss stated that ‘ . . . what is learned
in Pavlovian conditioning is an expectation regarding
the occurrence or non occurrence of a US onset or a
change in the US magnitude or duration’ (p. 387).
However, while the CR may be modulated by cognition, a fundamental aspect of classical conditioning is
the automatic, non-cognitive aspect of the effect,
making it a widespread process across different
species.
In 1980, Brody [13] drew on an earlier anthropological analysis of doctor–patient relationship by Adler &
Hammett [12], arguing that the placebo response can
be explained by means of a meaning model. A placebo
response would occur when ‘the meaning of the illness
experience for the patient is altered in a positive direction,’ and the factors that contribute to that positive
change in the mind–body unit are essentially the
patient’s awareness of being listened to and attended
by the caregiver. Additionally, the empathetic communication between physician and patient (and the support
by other individuals) helps to create a sense of mastery
and control over the illness. Moerman & Jonas [14]
echoed Brody [15] in emphasizing that ‘meaningfulness . . . can make a huge difference for patients in the
objective and subjective dimensions of their illness’
and suggested to reframe the placebo response as
‘meaning response’.
The meaning model highlights the potential therapeutic effects of the psychosocial context of clinical
practice and the ritual of treatment. The context is
made up of words, attitudes, providers’ behaviour
and medical devices, or in other words the whole
atmosphere around the patient and the treatment.
The placebo response might derive from the processes
of tapping the body’s own powers of healing that are
not activated automatically but depend on intervention by a healer [16]. This view of placebo effects
finds confirmation in a series of studies showing a cognitive and emotional modulation of therapeutic
outcome following open versus hidden administration
of the same drug (for a review see [17]) and businesslike versus augmented clinician – patient interaction
[18]. By hiding the specific treatment from the
patient’s view and comparing the response to hidden
and open administration of medication, it becomes
possible to focus on all the factors in the clinical
encounter that are not attributed to the pharmacological properties of the treatment but may contribute to
clinically relevant patient outcomes. This paradigm
also directs attention away from the placebo as an
‘inert’ intervention, because in both the open and
hidden treatment conditions, the same dose of medication is provided to patients. Greater pain relief for
a given dose of open treatment, when compared with
hidden administration, demonstrates the therapeutic
effects of the context of the clinical encounter. What
is present in open treatment that is absent in hidden
treatment? Described globally, it is the presence of
the clinician—the way he or she relates to the patient
through sight, speech, body language and touch.
The open/hidden paradigm also illustrates the role
of clinician – patient interaction and communication
in the formation of nocebo effects. Patients openly
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L. Colloca & F. G. Miller Review. Translational placebo research
informed about the interruption of either anxiolytic or
analgesic treatment experienced a sudden increase of
anxiety and pain, while a hidden interruption
(controlled by a computer) did not induce any worsening. Anxiety seems to play a crucial role in nocebo
effects [2,19]. For example, anxiogenic verbal suggestions are also capable of activating cholecystokinin
pathways [20] and turning tactile stimuli into pain
[21]. Some have suggested that anxiety might take
part in placebo responses as well [22 – 24]. Highanxiety volunteers showed greater placebo and
nocebo responses [24] and patients with irritable
bowel syndrome experienced a reduction of anxiety
when they were given a placebo [25]. However, a
causal link between placebo effects and anxiety has
not been demonstrated.
A recent explanation of the formation of placebo
effects focuses on signs and conveying information
[26,27]. Placebo interventions and the context in
which they are administered consist of signs that are
detected and interpreted by patients. Miller & Colloca
[26] applied the semiotic theory developed by the
philosopher Charles Peirce to account for placebo
responses. Iconic, indexical or symbolic signs convey
information that is processed by a patient or a research
subject. In clinical encounters, these signs can be
vehicles of placebo responses. When placebo responses
occur, the interpreted sign is the therapeutic agent and
the response involves learning, by which the patient
processes and responds to the information the signs
convey [27]. Emotion and cognition shape the
interpretation of the signs, producing positive and
negative impacts on health and perception.
Overall, it is important to note that these theories
are not necessarily in opposition to each other;
rather, they emphasize different aspects of placebo
and nocebo phenomena. Further work is needed to
integrate conceptual and theoretical insights concerning placebo and nocebo effects, with the aim of
facilitating translation of scientific knowledge into
improved patient care.
3. BEST EVIDENCE, CLINICIAN BEHAVIOURS
AND PATIENT ATTITUDES TOWARDS PLACEBOS
The definition of circumstances and reasons for promoting healing processes based on placebo and
(undesirable) nocebo mechanisms in clinical practice
represents the core of translational research and the
endpoint of patient-centred placebo research. Translating knowledge about placebo and nocebo effects
for the benefit of patients requires a rigorous evaluation of potential benefits and harms associated,
respectively, with placebo and nocebo effects. Two
parallel underlying questions need to be addressed:
(i) Can placebo treatments produce clinically significant benefit? (ii) Can nocebo effects produce
clinically significant worsening?
(a) Evidence of placebo benefits
A recent series of meta-analyses have shed light on the
magnitude and clinical significance of placebo effects
in the randomized clinical trial (RCT ) and experimental settings. A systematic review of clinical trials was
Phil. Trans. R. Soc. B (2011)
conducted in which patients were randomly assigned
to either placebo or no treatment [28– 30]. The
authors’ goal was to study the clinical significance of
placebos by discerning whether patients randomized
to placebo under blind conditions have better outcomes than those randomized to no treatment.
Hróbjartsson and Gøtzsche considered the effect of
three types of placebos: pharmacological (e.g. a pill),
physical (e.g. a manipulation) and psychological (e.g.
conversation), and binary (e.g. the proportion of alcohol abusers and non-alcohol abusers) and continuous
outcomes (e.g. the amount of alcohol consumed).
No significant effects of placebo, when compared
with no treatment group, were detected on objective
outcomes. There was a statistically significant but
modest effect of placebo on subjective, continuous
outcomes, most notably in relief of pain. The authors
suggested that the observed significant effect of placebos on subjective outcomes may have been due to
biased reports of subjects: those receiving placebos
probably believed that they were receiving an active
treatment intervention, while those in the no-treatment
groups knew that they were not receiving a treatment
intervention.
By assessing the heterogeneity of included trials,
Hróbjartsson and Gøtzsche found a statistically significant effect for pain, nausea, asthma and phobia out of
60 medical conditions. The variations in the effect of
placebos were partially explained by trial designs and
whether patients were informed about the inclusion
of inert substances. For example, larger placebo effects
were present when patients were not informed that
they would receive a placebo intervention. Metaregression analyses showed a positive association
between magnitude of placebo effects and physical
placebo interventions (e.g. sham acupuncture) and
outcomes (larger effects in patient-reported outcomes
than in observer-reported outcomes) [30].
Most of the research supporting a placebo effect
powerful enough to influence body perception and clinical symptoms arises from laboratory investigation. Vase
et al. [31] conducted a meta-analysis aimed at comparing the placebo analgesic effects observed in laboratory
settings versus clinical trials. They included 23 clinical
trials from the meta-analysis by Hróbjartsson &
Gøetzche [28] and 14 studies that investigated placebo
analgesic mechanisms. The magnitudes of the placebo
analgesic effects were dramatically higher in studies
investigating placebo analgesic mechanisms compared
with clinical trials in which placebos served as a control.
In a follow-up meta-analysis with many more laboratory
studies (from 14 to 21 studies including control, placebo treatment, randomization and pain measures),
the authors found that the magnitude of placebo analgesia in laboratory settings was fivefold larger than
analgesia in placebo control studies [32].
Such a difference might be due to the context features of clinical trials versus experimental settings.
Participants’ expectations may vary based on receiving
different information about treatments and differing
perceptions of the interest of investigators. Trialists
typically avoid giving verbal suggestions of analgesia
in favour of neutral instructions, whereas investigators
looking at the placebo mechanisms tend to emphasize
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the analgesic properties of placebo treatments and procedures. Most of the experimental placebo analgesia
studies involved healthy volunteers with outcomes
monitored for a short time, thus raising doubts about
their clinical significance. However, acute pain has
major clinical implications in medicine, not only for
the acute episode, but also for memory effects
potentially influencing future pain management. To
elucidate the clinical significance of placebo responses,
more clinically oriented research with patient subjects
is needed.
(b) Evidence of clinical nocebo harms
Translational placebo research, aimed at improving
patient care, should consider the nocebo effects that
can negatively influence clinical outcome in addition
to placebo effects. Indeed, nocebo responses are
common in clinical trials and practice and can produce
discontinuation of trial participation, alteration of
treatment schedules and lack of adherence.
Communicating about potential side effects of drugs
may produce nocebo effects. For example, nocebo
effects (or placebo adverse effects) have been observed
in systematic reviews of randomized, double-blind,
placebo-controlled studies for migraine treatments
[33,34]. A systematic review of randomized placebocontrolled clinical trials including 56 trials for triptans,
nine trials for anticonvulsants and eight trials for nonsteroidal anti-inflammatory drugs (NSAIDs) revealed a
high rate of adverse events in the placebo arms of trials
matching those described for real drugs. For example,
anticonvulsant placebos produced anorexia, memory difficulties, paresthaesia and upper respiratory tract
infection—all adverse events reported in the side-effect
profile of this class of anti-migraine drugs [33].
Nocebo effects are high in sexual dysfunctions
[35,36]. Silvestri et al. [35] assessed the effect of the
beta-blocker atenolol on erectile dysfunction in
patients diagnosed with cardiovascular disease (40%
hypertension, 60% angina) and not suffering from
sexual dysfunctions. Patients were randomly assigned
to one of three groups. Group A was blind to the
drug administered; group B was informed about the
drug but not the side effects; group C was informed
about the drug and the side effects on erectile function. After three months of treatment, the incidence
of erectile dysfunction according to the International
Index of Erectile Dysfunction was 3.1 per cent in
group A, 15.6 per cent in group B and 31.2 per cent
in group C. Similar results came from a study by Mondaini et al. [36] who randomized patients active sexually
to receive 1 year finasteride (5 mg) for benign prostatic
hyperplasia (BPH) along with two different disclosures
(informed or not about probable occurrence of erectile
dysfunction, decreased libido, problems of ejaculation).
The six- and 12-month follow-up showed that finasteride treatment produced a substantially higher rate of
sexual dysfunction in those patients who were informed
about sexual adverse effects.
These and other nocebo studies demonstrate that
merely knowing about potential adverse effects may
lead to nocebo responses. In general, the clinical implications of nocebo effects illuminate the importance of
Phil. Trans. R. Soc. B (2011)
1925
cognitive appraisal in symptom worsening and the
power of words in the context of clinicians – patient
interaction. The findings from these studies raise the
clinically and ethically important issue of how physicians should frame information so that the truth
relating to risks of treatments is preserved and the
probability of producing harms is minimized. (A
detailed analysis of this point has been developed by
the authors elsewhere.)
(c) Clinician behaviours and patient attitudes
towards placebos
A recent systematic review of empirical studies from
12 different countries investigating the frequency of
placebos in clinical practice and motivations of healthcare professionals, students and patients for their use
indicated that their prevalence varies between 17 and
80 per cent among physicians and 51 and 100 per
cent among nurses, and that patients’ attitudes towards
placebos differ considerably among individuals [37].
Some recent surveys of clinicians report more details
about the widespread use of placebo therapy, physician
behaviours and motivations in prescribing placebos
[38–40]. For example, in Denmark, 503 physicians
were asked about the use of placebo described as ‘an
intervention not considered to have any ‘specific
effect’ on the condition treated, but with a possible
‘unspecific’ effect’. Eighty-six per cent of general practitioners, 54 per cent of hospital-based clinicians and
41 per cent of the private specialists had prescribed placebos at least once in the last year with a trend to reach
10 times for half of general practitioners. Commonly
they prescribed antibiotics (70% of general practitioners, 33% of hospital-based physicians and 18%
of private specialists), physiotherapy (59% of the general practitioners, 24% of hospital-based physicians
and 13% of private specialists), sedatives (45% of the
general practitioners, 24% of hospital-based physicians
and 10% of private specialists) and vitamins (48% of
the general practitioners, 10% of hospital-based physicians and 9% of private specialists). ‘Inert’ placebo
treatments (talc and sugar pills, saline solution and so
on) were prescribed rarely. The primary motivation
for prescribing placebos was ‘to follow the wish of the
patient and avoid conflict’ [38,39].
Another random sample of 1200 US internists and
rheumatologists was also surveyed. Physicians were
asked to indicate which of several placebo treatments
they had used in the past year, defined as ‘a treatment
whose benefits derive from positive patient expectations and not from the physiologic mechanism of
the treatment itself ’. Fifty-five per cent of the physicians reported having recommended at least one of
a list of interventions as a placebo treatment during
the past year: 41 per cent recommended use of overthe-counter analgesics, 38 per cent vitamins, 13 per
cent sedatives and 13 per cent antibiotics. Only 5 per
cent reported using pure placebos, such as sugar pills
and saline injections. When asked about their frequency of recommending a therapy ‘primarily to
enhance patient expectation’, 46 per cent reported
doing so at least two to three times per month. Of
those physicians who reported recommending one or
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L. Colloca & F. G. Miller Review. Translational placebo research
ethical and legal requirements
evidence of
immunosuppression
in healthy subjects [45]
evidence of
immunosuppression
in mice [44]
molecular
and animal research
immunosuppression
in patients with
lupus erythematosus [46]
or multiple sclerosis [47]
laboratory research
with healthy subjects
and patient subjects
clinical trial
in patients
with psoriasis [48]
clinical randomizedcontrolled trials
?
clinical practice
Figure 1. Translational placebo research. The scheme shows the way to move efficiently from animal and molecular findings to
clinical research with healthy and patient subjects. The scope is to apply scientific results into clinical research aimed at improving patient care. An evaluation of legal and ethical requirements is necessary to harness placebos in clinical routine practice. In
the field of the immune system, molecular and animal findings have been successfully transferred into clinical trials.
more placebo treatments in the past year, 68 per cent
described this recommendation to their patients as ‘a
medicine not typically used for your condition but
may benefit you’ [39].
In contrast, very little research has been conducted
on patient attitudes to placebo treatments in clinical
practice. A small survey of Swedish patients asking
for an evaluation of several case histories and general
statements about placebo treatments showed that
78 per cent of 83 patients believed that physicians
should follow the wishes of the patient to receive treatment ‘even if the treatment is tantamount to placebos
in the opinion of the physician’. Seventy six per cent of
them believed that a placebo would be acceptable in
terminally ill patients because ‘it preserves the patient’s
hope without making her final time unbearable’ [41].
4. BRIDGING THE GAP BETWEEN MECHANISTIC
RESEARCH AND CLINICAL PRACTICE
The core of translational science in medicine is to
identify the circumstance and requirements for the
transfer of knowledge from molecular and animal
models to clinical practice. However, two-third of
highly cited animal experiments fail to translate into
human research [42], while 44 per cent of human subject research translates successfully at the level of
randomized trials [43]. Interestingly, in the field of placebo and nocebo effects, most research has been
conducted in humans, thus facilitating dramatically
the potential for translation of scientific knowledge.
(a) Placebo-conditioned pharmacotherapeutic
model
An emblematic model of translatability of molecular
and animal findings into preclinical and clinical areas
is represented by the recent advances in applying classical conditioning involving placebo interventions to
the immune system. By using a conditioned strategy
of pharmacotherapeutic effects, it is possible to achieve
the goal of harnessing placebo effects in improving
patients’ care under conditions of chronic diseases.
Phil. Trans. R. Soc. B (2011)
Animal and human results in the immune system represent an elegant and a critical example of translational
placebo research, in which the evidence of immunosuppression via conditioning has been transferred
from laboratory to clinical practice (figure 1).
After the early observation by MacKenzie [49] that
some people who are allergic to flowers show an allergic
reaction when presented with something that superficially
looks like a flower, but contains no pollen (an artificial
flower), scientific studies have probed for immunological
placebo effects in animals and humans. Ader & Cohen
[44] provided experimental evidence that immunological
placebo responses can be obtained in mice by a sodium
saccharin solution administered after repetitively pairing
the solution (CS) with the immunosuppessive drug cyclophosphamide (US). At a molecular level, this model of
associative learning was able to induce a conditioned
enhancement of antibody production (immunization).
These results in animals have paved the way to human
experiments, which suggest promise for therapeutic conditioning. Interestingly, repeated associations between
cyclosporin A and a flavoured drink induced a suppression of the immune functions in healthy volunteers, as
assessed by means of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) mRNA expression, in vitro
release of IL-2 and IFN-gamma, as well as lymphocyte
proliferation [45]. Similar findings have been observed
in patients. A child with lupus erythematosus showed a
successful clinical outcome when half of 12 monthly chemotherapy sessions were replaced with taste and smell
stimuli alone following cyclophosphamide paired repetitively with the same taste and smell stimuli [46]. In
another study, multiple sclerosis patients received four
intravenous treatments with cyclophosphamide paired
with anise-flavoured syrup. Eight out of 10 patients displayed decreased peripheral leucocyte counts following
the syrup alone, an effect that mimics that of cyclophosphamide [47].
Overall, these findings have important implications for
clinically oriented research. According to conditioning
and associative learning, placebo responses can be strategically elicited on the basis of a planned sequence of drug
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Review. Translational placebo research L. Colloca & F. G. Miller
C\100
100\P25–50
C\25–50
full-dose
treatment (8 w)
partial
reinforced dose (8 w)
control
reduced dose (8 w)
22.2%
26.7%
61.5%
therapeutic
regime
100 100 100 100
frequency
of relapse
Figure 2. A model of conditioned pharmacotherapeutic effects.
The diagram shows an example of a conditioned pharmacotherapeutic trial in patients with severe psoriasis. The three-arm trial
included a full-dose treatment group (C\100); a partial
reinforced dose group (100\P25–50) and a control-reduced
dose group (C\25–50). The cumulative amount of active drug
in groups 100\P25–50 and C\25–50 was identical. However,
partial reinforcement patients received a full dose of corticosteroid medication 25–50% of the time and placebo medication
other times; patients in the control group received 25–50% of
the dose continuously. Similar outcomes (frequency of relapse)
were observed in the full-dose treatment and partial reinforcement group, suggesting that a regime of reinforcement can
gain significant clinical benefits. Data from Ader et al. [48].
and placebo administrations. Placebos given after an
active treatment may work to extend the effects of
drugs, with the potential to maintain therapeutic outcomes with reduced side effects. After repeated
associations of active drugs with different types of conditioned stimuli, the CS alone is capable of inducing
similar responses as those of the active drug. This suggests
that learned placebo responses following the exposure to
drugs can be successfully exploited in routine clinical
practice by integrating placebos in schedules of reinforcements so that conditioned stimuli can acquire properties
and characteristics of active treatments. These effects
can become part of the pharmacotherapeutic protocol
in order to produce beneficial effects. If this strategy
works clinically, side effects (and costs) of treatments
would be reduced while therapeutic benefits are
preserved. Ader et al. [48] recently provided proof-of-concept evidence that a partial schedule of pharmacological
reinforcement using lower cumulative amounts of corticosteroids was effective in suppressing symptoms of
psoriasis similarly to the full-dose treatment (figure 2).
Another example of conditioned pharmacotherapeutic effects, outside the realm of the immune
system, is provided by experiments conducted by
Sandler et al. [50] in a paediatric population with
attention deficit hyperactivity disorder (ADHD). Children were randomly assigned to one of three schedules
of eight week treatments: (i) reduction of amphetamine dose by pairing drug with placebo; (ii)
reduction of amphetamine without placebo substitution; or (iii) full dose of amphetamine treatment.
Children in arm 1 received an open placebo pill
paired with 50 per cent reduced dose of amphetamine.
The same reduction of treatment was performed in
arm 2 but without a controlled conditioned cue
(control group). Pairing a CS with amphetamines produced placebo CRs that allowed children with ADHD
to be treated effectively with a lower dose of stimulant
medication. The placebo treatment was described to
both parents and children transparently. They were
informed that placebos consisted of a pill with no
medication in it, thus overcoming the ethical problem
Phil. Trans. R. Soc. B (2011)
1927
of deception and consistent with requirements of
informed consent [51,52].
This line of research suggests that conditioned
placebo substitution may be understood as a specific
technology for promoting placebo responses, as
distinct from more informal expectation-related interventions in the context of the doctor – patient
relationship. More research will be needed to evaluate
the therapeutic potential and clinical feasibility of
placebo conditioning in a range of acute and chronic
pathological conditions, including investigation
aimed to analyse the optimal number of conditioning
trials, the best conditioned stimuli, and the role of
conditioning with respect to drug-related adverse events.
(b) Beneficial effects of the physician– patient
relationship
We have learned that nocebo adverse effects occur frequently in clinical trials and practice owing to the
impact of words and information. Verbal communication
can also produce beneficial effects. For example, suppose
that a patient experiences chest pain and become worried
about heart disease. He visits the doctor for a routine
physical examination, which indicates normal heart functioning. He complains about chest pain and the physician
suggests that this might be heart burn, which it would be
useful to treat with an antacid. As a result of this interaction he is no longer worried about heart disease and
feels much less distress when experiencing chest pain
relating to heart burn. Consistent with the meaning
model, this cognitive reappraisal produces symptomatic
relief. Elements of instructional learning are obviously
involved. He learned that he was mistaken about having
heart disease and he learned that the chest pain is no
more serious than heart burn that can be relieved by
over-the-counter medication. Verbal instructions can be
a potent mechanism for anxiety reduction, with general
significance insofar as anxiety exacerbates a wide range
of distressing symptoms.
Physicians can also teach patients to gain relief
without any placebos. An early study by Egbert et al.
[53] demonstrated that encouragement and
instructions reduced pain in patients following intraabdominal operation. The ‘active placebo action’
consisted of explaining to patients what to expect
during the post-operative period and teaching them
how to relax, breathe and move. Compared with a control group, patients who were encouraged and
informed by a physician required half the dosage of
narcotics to manage the post-operative pain.
Recently, Varelmann et al. [54] shed light on the crucial role of information during a painful procedure.
Women at term gestation requesting labour epidural
analgesia or non-labouring patients presenting for elective caesarean delivery under spinal anaesthesia were
randomized to either gentle and relief-oriented information (‘We are going to give you a local anaesthetic
that will numb the area and you will be comfortable
during the procedure’) or more conventional description
relating to anticipating pain (‘You are going to feel a big
bee sting; this is the worst part of the procedure’) during
the anaesthetic procedure. After the local anaesthetic
injection, a blinded observer came into the room to
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1928
L. Colloca & F. G. Miller Review. Translational placebo research
assess the patient’s pain (primary outcome). Women in
labour informed to expect pain comparable to a bee
sting during the local anaesthetic injection (nocebo
group) scored pain higher than those receiving the procedure along with gentle positive words.
These (and other comparable) studies indicate the
need for educating the medical profession in techniques of communication, ability to interact with
patients, as well as self-consciousness that the physician plays an important role in promoting placebo
effects and minimizing nocebo responses.
Consider a patient who comes to a physician complaining of chronic low back pain (CLBP), the second
most common complaint reported in primary care, and
who has tried different therapeutic strategies but is not
getting adequate relief. Because standard treatments
are often not accompanied by adequate improvement,
physicians might propose a series of interventions
oriented around promoting placebo responses, reducing
symptoms of illness, and improving the ability to cope.
After the diagnostic interview, exploring what is troubling the patient by inquiring about the illness
experience, the physician would explain to the patient
that efforts to take advantage of the placebo response
may provide beneficial symptomatic improvement.
For example, the physician might recommend acupuncture treatments [55], described as a treatment
that may work either by the physical stimulus of the
needling or by promoting a placebo response. Patients
would be explained that although clinical trials have
demonstrated that traditional acupuncture is not
clearly better than a fake acupuncture treatment,
both have been shown to be considerably better than
either no treatment or usual care. Finally, physicians
would recommend a series of follow-up visits to discuss the illness experience and success of the placebo
response treatment plan.
Such a plan for promoting placebo-based healing
processes represents a general and multiple approach
strategy consistent with ethical norms. However, it
should be tested for various conditions in ‘pragmatic’
randomized trials compared with ‘usual care’ and
active surveillance along with optimal clinical
attention. An open question is whether discrete interventions (e.g. action of taking pills and treatment
rituals) are necessary to optimally evoke clinical
benefit by virtue of placebo effects. Large-scale,
randomized trials are needed to obtain evidence
about what therapeutic strategies work best.
(c) Ethical– legal requirements of interventions
to promote placebo responses
Any attempts to harness placebo benefits and reduce
nocebo harms in clinical practice should be done consistently with professional norms and the ethical – legal
requirements of informed consent (figure 1). Although
the present paper does not discuss systematically the
complex issue of professional, legal and ethical
requirements in using placebos in clinical trials and
practices, we briefly list some key points because of
their importance for translating findings on placebo
(nocebo) research from laboratory to clinical trials,
and from trials to clinical practice.
Phil. Trans. R. Soc. B (2011)
There is controversy over whether it is ethical to recommend and prescribe placebo treatments in clinical
practice [56,57]. Miller & Colloca [57] argued that if
the placebo effect is a real phenomenon and there is
consistent evidence from randomized, controlled
trials that placebo treatments produce significantly
improved outcomes, then there may be a legitimate
place within contemporary medicine for using strategies and interventions to promote the placebo effect.
According to evidence-based medicine, superiority
to placebos is considered the minimal requirement
for validating active pharmacological and nonpharmacological procedure therapies. Similarly,
treatments that are likely to be effective solely or primarily by means of the placebo response should be
evaluated rigorously in randomized trials comparing
them with no-treatment or usual care groups. The
above-described dose-extender trials [48,50] represent
a good example of trials aimed to test and quantify the
effectiveness and the magnitude of placebo-induced
outcomes. Similarly, 3-arm trials comparing complementary and alternative treatment with usual care and
waiting list groups (e.g. traditional Chinese acupuncture,
sham acupuncture versus either no-treatment groups or
usual care group [58]) would be encouraged to understand if it is feasible and ethically justifiable to prescribe
treatments that work primarily, by virtue of placebo
effect [59].
Use of placebo treatments in clinical practice must
be consistent with the professional integrity of
clinicians [4,60]. They must offer a favourable riskbenefit ratio and their use must be compatible with
informed consent. The surveys of physician use of placebo treatments suggest that physicians are not only
less than transparent with patients about this practice,
but that they may not be clear themselves about what
they are trying to accomplish. It appears that physicians with some frequency engage in behaviours
conflicting with professional norms relating to medically indicated treatment by rationalizing the use of
placebos as a way to comply with the pressure of
patient demand. In particular, the prescription of antibiotics for probable viral infections is especially
problematic [38]. In addition to concerns about side
effects, there is an individual and societal risk of promoting bacterial pharmacological resistance, making this
type of intervention a poor candidate for placebogenic
treatment.
Second, the benevolent use of deception to invoke a
placebo response is contrary to the principle of respect
for patient autonomy. Very little research has been
conducted to understand whether placebo interventions can be prescribed overtly without deception
[61– 63]. Kaptchuk et al. [63] found that patients
with irritable bowel syndrome showed significant
improvement of symptom severity after receiving
open-label placebo when compared with a no-treatment control group with matched patient-provided
interactions. Some may argue that such a practice to
promote placebo effects might encourage medicalization and drug dependence; however, this concern
needs to be balanced against the potential for promoting clinically meaningful placebo responses without
adverse treatment effects.
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Review. Translational placebo research L. Colloca & F. G. Miller
5. CONCLUSIONS
Translational placebo research is still in its infancy, and
needs careful development both as a scientific discipline and in its applications in clinical trials. Recent
progress in laboratory investigation of the placebo
and nocebo effects has paved the way for fruitful
investment in clinically oriented placebo research
that can guide the promotion of therapeutically
valuable results.
The opinions expressed are the views of the authors and do
not necessarily reflect the policy of the National Institutes of
Health, the Public Health Service, or the U.S. Department
of Health and Human Services. This research
was supported by the Intramural Research Program of the
Clinical Center, NIH, the National Center for
Complementary and Alternative Medicine, International
Association for Study of Pain (Early Research Grant), and
EFIC-EGG Grant.
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