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Canadian Journal of Cardiology 33 (2017) 1535e1542

The Placebo Effect in Cardiology: Understanding and
Using It
Robert Sheldon, MD, PhD,a and Morwenna Opie-Moran, MA, PhDb
Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada
King’s College Hospital NHS Foundation Trust, London, United Kingdom

The placebo effect is the clinical benefit caused by interaction with a Par effet placebo, on entend le bienfait clinique de coulant de l’inter-
caregiver and health care system in the absence of a biologically active action avec un professionnel de la sante  et le système de soins de
intervention and has been used successfully for millennia. The placebo sante en l’absence d’une intervention biologiquement active, phe no-
response results from the interaction of psychosocial mechanisms, hu- mène ayant e  te
 avec succès depuis des mille naires. La re
man relationships, and preconceptions functioning in specific neuroan- placebo re sulte de l’interaction de me canismes psychosociaux, de
atomic locations with known genes and neurotransmitters. It occurs with relations humaines et de pre conceptions fonctionnant dans des zones
or without the administration of an inactive substance to deliberately neuro-anatomiques pre cises sur la base de gènes et de neuro-
deceive patients. Our purpose is to review the history, benefits, and transmetteurs connus. Elle survient avec ou sans l’administration
mechanisms of the placebo effect. The placebo response results from d’une substance inactive visant à de libe
ment tromper le patient.
classic conditioning and positive expectations about outcome expressed Notre objectif est de revoir l’histoire, les bienfaits et les me canismes
by the caregiver. The outcomes are usually symptoms such as pain de l’effet placebo. La re ponse placebo re sulte d’un conditionnement
rather than biological outcomes such as death, and the powerful pla- classique et d’une attente positive quant aux re sultats exprimes par le
cebo may account for more than half the effect of treatment in many fournisseur de soins. Les re sultats touchent habituellement des
situations. The placebo effect results from activation of opioid, canna- symptômes, comme la douleur, plutôt que des issues biologiques,
binoid, and dopaminergic pathways involved in reward, expectancy, comme la mort, et la puissance du placebo peut compter pour plus de
conditioning, and pain modulation. Eleven specific anatomic features in la moitie de l’effet du traitement dans de nombreuses situations.
the brain identified by positron emission tomography and magnetic L’effet placebo re sulte de l’activation de voies opioïdes, cannabinoïdes

The time has come to re-evaluate the role of placebo in car- It has been used for millennia (Table 1), but the term “pla-
diovascular medicine. It is now clear that the placebo effect is cebo” is less than a thousand years old.2 In medieval Europe,
a complex interaction of psychosocial mechanisms, human funerals included chanting prayers for the dead. One of these,
relationships, and preconceptions, operating through specific “placebo domino in regione vivorum” meant “I will please the
neuroanatomic locations, neurotransmitters, and alleles of Lord in the land of the living.” After the funeral, the
specific genes. Most efforts in clinical trials have focused on mourning family gave gifts to the chanting mourners. Later, as
minimizing the impact on study power of this mix of patients, plagues swept through Europe, the land of the living became
practitioners, practices, beliefs, treatment characteristics, and less populated, and professional mourners arose. They sang
interactional styles. However, these factors may be central to the chant for gifts, without actually mourning, and became
patient improvement, and the placebo can be used for clinical known as placebosd“falsely pleasing.”
benefit. In the 16th century, priests exorcised illness with holy
water and by wielding fragments of the ostensible true cross.2
Many individuals with a variety of neurologic diseases, and
The Provenance of Placebo probably some with conversion syndromes, were apparently
The placebo effect may be defined as a clinical benefit cured. The difficulty was to explain nonresponders. This
elicited by interaction with a caregiver or health care system in caused political problems for Henry IV of France, who struck
the presence or absence of a biologically inactive intervention. a commission to resolve the issue.2 Single-blind studies
compared false fragments and false holy water to true icons
and holy water. Some responded to the false interventions,
Received for publication September 20, 2017. Accepted September 28, 2017.
and these were deemed to be placebo responders. Michel de
Corresponding author: Dr Robert Sheldon, University of Calgary, 3280 Montaigne in 1580 suggested that at times physicians pro-
Hospital Dr NW, Calgary, Alberta T2N 4Z6, Canada. Tel.: þ1-403-220-
8191; fax: þ1-403-210-9350.
vided “false promises. and their fraudulent concoctions,”
E-mail: sheldon@ucalgary.ca and that medicine’s efficacy might in part arise in the patient’s
See page 1541 for disclosure information. imagination.3

0828-282X/Ó 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
1536 Canadian Journal of Cardiology
Volume 33 2017

resonance imaging are involved. Polymorphisms in the structural et dopaminergiques implique es dans la re
compense, l’expectative, le
genes for catecholamine O-methyltransferase and fatty acid amide conditionnement et la modulation de la douleur. La tomographie par
oxidase significantly influence the placebo response. The placebo ef- mission de positrons et l’imagerie par re
e sonance magne tique ont
fect may be important in symptom suppression in angina, paroxysmal permis de de celer la participation de onze composantes anatomiques
atrial fibrillation, and congestive heart failure. In the absence of cises de l’ence
pre phale à ce phe nomène. Des polymorphismes
deliberate deception, there are no ethical issues and given its potency, observes dans les gènes de structure codant pour la cate cholamine-O-
the time has come to consider how best to use the placebo in clinical methyltransferase et l’oxydase de l’acide amine  influent de façon
practice. importante sur la re ponse placebo. L’effet placebo peut jouer un rôle
important dans la suppression des symptômes de l’angine, de la
fibrillation auriculaire paroxystique et de l’insuffisance cardiaque
congestive. En l’absence de tromperie de libe
ree, il n’y a aucun pro-
blème e thique et, en raison de son pouvoir, le temps est venu d’e tudier
comment tirer le meilleur du placebo dans la pratique clinique.

In the 1780s, Mesmer proposed that an invisible substance Improvement in vasovagal syncope
in objects could permit them to both cause and cure disease.
Studies of vasovagal syncope have a wide range of blinding,
In 1784, Louis XVI commissioned the liberal polymath
controls, and populations, which permit us to explore these
Benjamin Franklin and the father of chemistry Antoine Lav-
variables. In these studies, at least 99% of patients fainted in
oisier to prove or disprove whether the force existed.4 They
the 1-2 years before study entry.6 Examples include the first
used a single-blind, two-step, cross-over design and could find
International Study of Syncope of Uncertain Etiology (ISSUE
no evidence for the existence of the substance. By the
1), which was a prospective observational study in which
beginning of the 19th century, the concept of the role of the
participants received an implantable loop recorder, and a few
placebo was acknowledged, the need for blinding with placebo
received a specific intervention.7 Most participants did not
controls accepted, and the structure of crossover studies
faint in up to 15 months of follow-up. Improvement occurred
without deception or offer of clinical gain, but all patients had
The placebo now is largely understood as an inactive
been seen by specialists. Similar results were reported in the
substance deliberately administered with deception to a pa-
Physical Counterpressure Manoeuvres Trial (PC-Trial) of
tient with the intent of inducing a beneficial response, usually
physical manoeuvres.8 These reduced the likelihood of a
in controlled trials. However there are 3 important questions.
syncope recurrence compared with no specific treatment. The
Does the placebo response necessarily involve a biomedical
control arm consisted of lifestyle and dietary suggestions of
intervention? What are the effective components of how the
dubious biomedical value, yet it also showed reduced syncope
placebo is administered? What are the human components
recurrences. General advice by specialists about marginally
that permit or foster a successful placebo response?
useful lifestyle changes appears to reduce syncope recurrence.
We will examine the nature of the placebo, its compo-
Open-label, randomized, pacemaker studies report similar
nents, and its role in cardiovascular research and care. It can
effects. In the Vasovagal Syncope International Study (VASIS)
be a potent tool in treating pain and mental health disorders as
study,9 all patients in the control arm had fainted in the
well as inflammatory and stress-associated lifestyle illnesses. It
preceding year, with a median frequency of 3 faints per year,
is time to revisit the placebo as treatment armed in the light of
yet over an extended follow-up, only 61% had a recurrence of
new mechanistic insights.
syncope. In a meta-analysis of observational and randomized
studies, we found that all studies reported large reductions in
the probability of syncope in the control arms compared with
Effects and Settings of Placebo Use the period before enrollment.6 There were no significant
The definition of a placebo as an inactive substance differences based on the degree of blinding whether the
administered with deliberate deception distracts from its studies were observational cohorts or randomized controlled
mechanisms (Table 2) and potential for clinical benefit. We studies, whether the data were collected prospectively or
prefer to define the placebo response as a clinical benefit retrospectively, and whether the active interventions were
caused by interaction with a caregiver or health care system in devices, drugs, or lifestyle aspects. In short, all populations had
the presence or absence of a biologically inactive intervention. large proportions of patients who improved. The common
The placebo effect mainly involves how individuals subjec- factor was interaction of the patient with a specialist physician.
tively perceive, register, and appraise symptoms.3 This in-
cludes subjective interpretation of the significance of disease
Invasive vs noninvasive placebo
and symptoms. Reducing these negative interpretations may
relieve anxiety, depression, and subjective symptoms. One syncope trial inadvertently addressed whether an
Conversely, there is no evidence that a placebo reduces invasive placebo was more efficacious than a medication.
mortality or alters the pathophysiological mechanisms of the Ammirati et al.10 performed a prospective open-label
disease. For example, placebo improves asthma symptoms controlled trial that randomized patients to medical
with no measureable changes in airway reactivity,5 and (b-blocker) or invasive (permanent cardiac pacing) in-
placebos reduce cancer symptoms and symptomatic side ef- terventions. Both were later shown elsewhere to have little or
fects of treatments but do not inhibit tumor growth. no true benefit. Both groups improved, and the patients with
Sheldon and Opie-Moran 1537
Placebo: Mechanisms and Use

Table 1. Recent western history of the placebo ascertainment bias, involuntary communications to the pa-
Dateline Paradigms and changes tient, or the expectancy effect.
Bronze age Europe, Middle East, Numerous descriptions of rites and Active engagement by care provider
Asia potions unlikely to be biologically
ineffective Taken together, these findings suggest a powerful benefi-
Middle ages, Europe Emergence of professional mourners
known as placebos, from Placebo
cial force embedded in the physician-patient relationship in-
Dominae (I will please the Lord) dependent of whether a biomedical placebo of any sort is
Renaissance, France Controlled trials of holy water and administered.17,18 Is there a gradation within this effect?
fragments of the p in exorcisms Kelley et al.19 reported an ingenious dose-ranging study of the
Enlightenment, France Franklin-Lavoisier placebo-controlled impact of involvement of health care providers on the placebo
trials of mesmerism
1931 Randomized placebo-controlled trial of effect. Patients with irritable bowel syndrome were enrolled in
sanocrysin in tuberculosis1 a parent study of an acute placebo-controlled infusion of a
1931-present Dominance of the paradigm of the medication to reduce symptoms. The parent study of the
placebo effect as deliberate deception biological infusion produced negative results. However in the
with an inactive substance or
placebo study, patients were allocated to 1 of 3 groups: to a
21st century Re-emergence of the paradigm of the waitlist, to receive educational material in a sparse and neutral
placebo effect as a neurobiological infusion room, or to a 45-minute scripted encounter with an
response to human interactions investigator designed to mimic a sympathetic and engaged
physician. Both written information and engagement were
significantly better than waiting, and human interactions were
pacemakers had significantly fewer outcomes than the patients markedly more effective than simple written information.
who received b-blockers. In retrospect, this was a randomized Similar results were reported with gastroesophageal reflux
trial of invasive vs noninvasive placebos, and patients with the disease.20 The placebo effect is real, is independent of inten-
invasive placebo had a better outcome. These observations tional deception, is a potent tool for symptom suppression,
have driven our interests reflected in this reviewdthat in and is embedded in human interaction.
treating vasovagal syncope, the placebo effect may be the
signal and not the noise.
Statistical Considerations
Biomedical components Syndromes with recurring events commonly have pro-
longed asymptomatic periods, and these are often ascribed to
Placebo research in orthopaedics speaks to the importance regression to the mean, a statistical term. Recurring events can
of the perceived potency of intervention. Arthroscopic partial be described with models that assume a random series of
meniscectomy is frequently used to reduce symptoms from a events: either a 1-time event such as death or a random
meniscal tear. Sihvonen et al.11 performed a randomized recurrence of events in each patient over time. These occur
controlled study of arthroscopic meniscectomy compared with randomly in time and some events occur sooner and some
sham surgery. After 1 year, no significant difference in later, leading to the appearance of long and short asymp-
symptoms existed between the 2 groups, suggesting that much tomatic intervals and periods of more and less frequent
of symptom suppression was caused by nonbiomedical factors. symptoms. The apparent improvement in symptom frequency
A clinical trial of back surgery for osteoporotic fractures found might simply be regression from higher-frequency periods to
similar results.12 In patients with hypertrophic obstructive the mean frequency.
cardiomyopathy, permanent cardiac pacing initially appeared Testing whether the asymptomatic intervals are part of a
to reduce symptoms, but in a double-blind randomized trial, random process can be performed with a simple Poisson
there was no difference in symptoms between active and distribution,21 also known as a monoexponential decay curve.
inactive pacing.13 Jonas et al.14 concluded from a systematic These fit many classic medical survival curves. The Poisson
review of randomized sham controlled trials that the
nonspecific effects of surgery composed about 66% of the
beneficial effect, and often the benefits of true surgery are not Table 2. Key issues in placebo research and practice
significant. Similar effects are seen with tablets. The size of the Issue Key point
placebo effect depends on size, colour, and labelling. In 1
The placebo: a thing or a process? Conventionally, the placebo is defined
study, sham migraine tablets labeled as active were as effective as an inactive biomedical
as active tablets that were labeled as sham.15 intervention. How accurate is this?
Magnitude of the placebo response How much of symptomatic relief
Effect of observer blinding results from the placebo and not the
active intervention?
In a meta-analysis by Sud et al.,16 the likelihood of a Regression to the mean Is the placebo response simply a
syncopal recurrence was reduced in patients with active pacing statistical artifact?
Pills or procedures Is the biomedical placebo a substance
vs patients with no implanted pacemaker, and this reduction or an invasive procedure, or both?
was not seen in double-blinded randomized trials. Strikingly, Blinding Who needs to be blinded? Patients?
in single-blinded studies in which the patients, but not the Investigators? Both?
physicians, were blinded, there was still a large reduction in The human touch Does the placebo response depend on
the likelihood of syncope, ie, physicians knowing the treat- the human touch, or will
information alone suffice?
ment allocations in some way altered outcome, perhaps by
1538 Canadian Journal of Cardiology
Volume 33 2017

Table 3. Psychology: maximizing the placebo benefit potent medications you responded well to yesterday” by a
Psychological effect Mechanism Practice kindly and sympathetic senior consultant in a comfortable
Conditioning Links present clues to Stress how new
private room with framed degrees. He feels rapid relief. This
past benefits treatment builds on scenario includes several potent psychological placebo pro-
previous similar cesses. These include expectancy,29 (calming cognition
successes anticipating and contributing to pain reduction), condition-
Expectancy Anticipates positive Express clear optimistic ing,26 (rapid unconscious pre-emptive biochemical changes
outcomes warm hope
Treatment variables Improves conditioning Reassuring expert associated with previous benefit), treatment variables
and expectancy environment; be (including the reassuring room and impressive pills), and
aware that physician behaviour.27,28,30 Key to the latter seems to be a
invasiveness may warm, friendly, reassuring, and competent style.19
heighten placebo
Physician behaviour Human touch Be warm, engaged, Expectancy
improves expectancy curious about
patient story, Expectation anticipates an event to better cope with it and
empathetic, can include hope, anticipation of a positive outcome, relief,
optimistic; plan a and anxiety reduction.32 Clear positive messages cause positive
follow-up and expectations, and these lead to analgesia. Kirsch first hy-
pothesized that placebo effects are produced by a self-fulfilling
effect called “expectancy.”29 If a person believes that he or she
distribution is often used to test the randomness of events will feel different, they actually will feel different. Brain im-
with low recurrence rates. It was used to determine whether aging and in situ single nerve recordings demonstrate that
the number of false convictions in early 19th century France similar brain regions are activated by real or imagined change
truly did cluster,22 whether the likelihood of getting kicked by (see further on). Patients who expect to feel better have subject
a horse in the Prussian army was clustered,23 and whether response expectancy, whereas subjects whose physicians expect
World War II flying bombs were targeting specific areas in them to feel better have observer response expectancy. Both
London.24 All were shown to be randomly occurring events. are independently important, and placebo effects are seen
The use of Poisson modelling shows promise for estimating when a patient does not anticipate benefit but the clinician
patient-specific changes in time if they are random events. They does.
permit calculation of patient-specific rates and address a critical
issue in clinical trials of paroxysmal events. The Poisson distri- Conditioning
bution permits the calculation of a mean frequency in data sets Pavlovian preconditioning, such as with a beneficial
bounded on either side by an event for patients who withdraw response to a biologically effective medication, can enhance
prematurely and does not require a full observation period.25 The the subsequent placebo response.31 These controlled placebo
Poisson distribution enables the prediction of the likelihood of effects, observable in biochemical changes as well as in self-
recurrences and also the statistical significance of periods without reporting, occur in a wide range of settings, including anal-
events. This directly tests whether asymptomatic periods are truly gesia, Parkinson disease, response to chemotherapy, and sports
simply regression to the mean. medicine.31 Similar effects on physiology are elicited by
The casual invocation of “regression to the mean” can experienced meditators as well as when social isolation is
deflect the investigator from what is truly happening. If events reduced for improved health.33,34 The patient brings factors to
or states do not fluctuate randomly, this cannot be ascribed to the interaction, including optimism, pessimism, depression,
regression to the mean and must reflect a response to a sto- anxiety, and anticipatory anxiety. These psychological states
chastic influence. Indeed the placebo response is a combina- can be altered by caregiver interaction and by symptoms
tion of factors interacting in the patient’s psyche. causing anxiety and depression that in turn worsen symptoms.
These findings underline the importance of properly con-
ducted randomized clinical trials in assessing biomedical in-
Psychology and Expectancy terventions and also illuminate the powerful potential of
The placebo effect is complex and highlights the inadequacy understanding the mechanism of the beneficial effect of a
of the conceptual duality that separates mind and body.26-29 A placebo.
seminal review in 2001 concluded that the placebo effect did not
exist,30 but it included only studies in which biologically inactive
control substances were administered. This neglected the potent Neurobiology of the Placebo Effect
psychologically mediated mechanisms in the patient-doctor The neurobiology of the placebo effect has been mapped in
relationship. The placebo effect most likely results from psy- some detail.31 Most studies have addressed pain and pain
chological interactions (Table 3) between pre-existing experiences relief. Although many of the neurotransmitters and brain
and behaviours, the health care setting, and the interaction be- centres have clear relevance to pain, some are more tangential.
tween patient and physician.31 These can include conditioning,26 To date, 3 neurotransmitter systems have been identified:
expectancy,29 and physician behaviour.27,28,30 opioids, dopamine, and cannabinoids. The opioid and
Consider this example. A distressed patient, just moments cannabinoid pathways are active in expectancy and condi-
after being administered multiple brightly colored analgesic tioning; the dopamine pathways are active in expectancy,
tablets is told that they are a “higher dose of those highly motivation and reward; and all 3 pathways are active in pain
Sheldon and Opie-Moran 1539
Placebo: Mechanisms and Use

Table 4. Key genetic examples

Pathway Gene symbol Protein Function Allelic activity Placebo effect
Dopamine COMT Catechol-O-methyltransferase Degrades dopamine Met/met least active Met/met most effective
Endocannabinoid FAAH43 Fatty acid amide hydrolase Degrades fatty acids Pro-pro least active Pro-pro most effective
Opioids OPRM141 Mu opioid receptor Binds opioids Asn/asn most active Asn/asn most effective
Examples of 3 genes with corresponding biological activities and placebo effectiveness. More complete summaries are in the Genetics of the Placebo Effect
section. Other alleles and genes with evidence of matching activities and effectiveness exist and are not covered here.41

modulation. Other neurotransmitters, such as cholecysto- polymorphism might also predict the nocebo response.42
kinin, serotonin, nitric oxide, and oxytocin, might also be Patients were given cyclosporine or placebo and warned
involved. about the side effects of cyclosporine. Participants receiving
Placebo analgesia releases endogenous opioids and can be placebo who were homozygous for val/val had severalfold
blocked by naloxone.35 A second nonopioid analgesic more side effects than did those with val/met or met/met.
component can be blocked by rimonabant, the cannabinoid These allele-specific effects are seen in a number of other
CB1 receptor antagonist.36 Dopamine is involved in reward, diseases and in inactivation of certain drugs.41 These findings
motivation, and expectation of reward. Pain relief may itself may have practical implications if we become able to target
be a reward, and a placebo promises the reward of pain re- treatment to patients depending on their COMT
lief,31 Expectancy triggers the dopamine pathway, which then polymorphism.
activates the downstream analgesic response. Interestingly Several other genes are implicated. Fatty acid amide hy-
much of the understanding of the involvement of dopamine drolase (FAAH) polymorphisms may modulate the placebo
in the placebo effect comes not from pain studies but from response to pain. FAAH inactivates cannabinoids, which bind
studies on Parkinson disease. Some of these included single to the CB1 receptor to suppress pain. Patients with homo-
neuron recordings in conscious patients using deep brain zygous Pro129/Pro129 are more likely to respond to placebo
stimulators. than are those with Thre129 alleles, but whether this is
The neuroanatomy of the placebo effect has been studied involved in a placebo pathway or pain pathway is unclear.43
with blood oxygen leveledependent magnetic resonance im- Statistically significant associations between the placebo ef-
aging and positron emission tomography.31,37 A number of fect and genes involved in serotonin signalling and opioid
distinct areas of the brain are involved, and these have func- signalling have also been reported.41 The neurobiology of
tions that are plausibly involved. For example, the opioid placebo establishes its biological legitimacy, and the magni-
pathway involves, among others, the dorsolateral prefrontal tude of the effect may have clinical implications.
cortex, which modulates brain attentiveness to constant pain.
Similarly the anterior insula is involved in pain transmission
and modulation of internal emotional states, the peri- Placebo in Cardiovascular Medicine
aqueductal grey area modulates the experience of pain, and the The perils and promise of placebo are well known in car-
rostral anterior cingulate cortex integrates cognition and diology. Myocardial laser revascularization showed a prom-
emotions. The dopamine pathways are active in areas such as ising ability to reduce angina in open-label studies, but
the nucleus accumbens and the dorsal striatum. subsequent sham-controlled studies produced negative re-
sults.44 Similarly open-label studies of pacing for vasovagal
syncope were encouraging, but sham-controlled randomized
Genetics of the Placebo Effect trials produced negative results.6 More recently, renal artery
The role of neurotransmitters on the placebo response denervation, after much initial promise, failed to be effective
suggest that there may be genetic influences as well in a properly controlled study.45
(Table 4).38,39 Not everyone is susceptible to the placebo ef- These and similar studies suggest that a placebo might
fect,40 raising the possibility of a genetic basis. The placebo reduce subjective symptoms and possibly autonomic re-
response in patients with social anxiety is linked to attenuated sponses. Hypertension, congestive heart failure, and parox-
amygdala excitability,38 which itself is associated with specific ysmal atrial fibrillation all cause considerable symptom
alleles encoding tyrosine hydroxylase and the serotonin re- burden. Patel et al.46 in a meta-analysis of blood pressure
uptake transporter. The persuasive evidence for genetic cor- changes in the placebo arms of hypertension clinical trials
relates of the placebo effect led Hall et al.41 to coin the term noted that systolic blood pressure fell a highly significant mean
“placebome” in an elegant and accessible review. of 5.9-8.8 mm Hg. The causes are conjectural, but placebo
Several model systems provide insights into the neurobi- effects are possible. Paroxysmal atrial fibrillation is treated
ological mechanisms of the placebo response. Hall et al.39 increasingly with intracardiac ablation techniques. However,
reported the associations of specific alleles of catecholamine there is more reduction in symptoms than in documented
O-methyltransferase on symptoms in patients with irritable atrial fibrillation,47 most recurrences are asymptomatic,47 there
bowel syndrome in their landmark placebo dosing experi- is similar impact on quality of life in biologically successful vs
ment. Catecholamine O-methyltransferase (COMT) in- unsuccessful ablations,48 and there is no evidence that the
activates catecholamines, including dopamine. The met/met procedures prevent stroke or reduce mortality. This might
variant is severalfold less active, leading to higher dopamine result in part from damage to autonomic ganglia or possibly
levels. The placebo response is higher in individuals with met/ to a placebo effect. Given the numerous factors associated
met than in those with val/met and val/val variants. The with the development of atrial myopathy,49 an alternative
1540 Canadian Journal of Cardiology
Volume 33 2017

investment in research might target lifestyle modification and intervention. Margo recently suggested that the physician is a
development of effective placebo interventions. placebo,28 and Lichtenberg et al.55 argued that the “placebo is
Heart failure syndromes are attractive arenas for placebo deception only for those who would reduce treatment to a
research. Sohaib et al.50 systematically reviewed symptom purely biomedical pursuit.” Physicians intervene in caring for
improvement in controlled randomized clinical trials of car- their patients in many nonbiomedical ways, including au-
diac resynchronization therapy (CRT). The mean responder thority and insight, encouragement, reassurance, optimism,
rate was 51% with CRT and 35% in the control arms, offers of help, and resolving uncertainty.
indicating that about 70% of the apparent benefit did not
result from the biological intervention. Roughly similar re-
Harnessing the placebo in practice
sponses in control arms were reported for b-blockers,
angiotensin-converting enzyme inhibitors, and aldosterone Patients do not need to be deceived intentionally for the
antagonists.50 placebo effect; indeed, deliberate deception is probably irrel-
Yue et al.51 reported a provocative meta-analysis of the evant. Bishop et al.56 recently redefined the placebo effect as
effects of compliance with taking a placebo on mortality in 8 “the physiological and/or psychological changes that result
randomized clinical trials of cardiovascular drugs. Patients from the meaning derived by a person in a health care
with good compliance with taking a placebo had significantly setting.” An earlier systematic review by Di Blasi et al.32
lower mortality than did those with poor compliance, as well concluded that physicians “who adopt a warm, friendly, and
as lower mortality than patients with poor compliance with reassuring manner are more effective than those who keep
taking true medications. There are several explanations, but at consultations formal and do not offer reassurance.” Subse-
the least it illustrates the difficulty of interpreting randomized quently Bishop et al.56 reviewed 169 publications dealing with
clinical trial results. pain relief, developed a taxonomy of types of presumed
Finally, vasovagal syncope has a large and documented effective placebos, and validated the taxonomy with experts in
placebo effect and occurs in many patients in clusters,25 and the field. They identified 30 interventions thought likely to be
placebo research appears promising.6 The role of placebo in effective and grouped them into 5 themes. These included
relieving anxiety, and the responses of the autonomic nervous patient characteristics and beliefs, practitioner characteristics
system to anxiety and stress, hint at the promise of placebo in and beliefs, the health care setting, treatment characteristics,
cardiovascular care. and patient-practitioner interactions.

Components of effective placebos

The Practice of Using Placebo
The placebo has 2 faces. The placebo effect is usually Patient characteristics include selecting patients who have
viewed as a difficulty to be overcome with randomized not yet failed to respond to the general type of intervention,
controlled trials, and if anything, the negative results of the creating positive expectancy with a positive message, and
sham-controlled SYMPLICITY trial of renal denervation tailoring the intervention to the patient’s sociocultural
strengthen the arguments for tightly crafted studies.45,52 context. Positive practitioner characteristics include their own
However these studies usually focus on whether a biological positive expectations and physician status manifested by ti-
intervention causes a true biological effect and not whether a tles, reputation, and displayed certificates. The health care
treatment strategy improves outcomes compared with base- setting refers to characteristics such as planned follow-up,
line. Pragmatic clinical trials are 1 way of testing strategies.53 having patients participate in research, and having patients
The converse might also be true: Are we missing an self-monitor their symptoms with practitioner reassessment.
important therapeutic tool, 1 that despite our unstructured Effective treatment characteristics include withdrawing inef-
approach is already quite effective? Understandably, most fective interventions, highlighting side effects as evidence that
clinicians are unwilling to use placebos that require active the treatment is effective, and maximizing treatment char-
concealment or deception. Clinicians respect patient auton- acteristics such as high doses, invasiveness, specific colours,
omy and informed consent and believe that harnessing the pill size, and office rituals. Finally, effective interactions with
power of placebo may require deliberate deception. the patient include paying focused attention, obtaining a
Counterarguments to placebo are important.54 First, pre- detailed history, performing tests, and eliciting patient
scribing a deceptive placebo prevents true informed consent. preferences.
Second, for placebos to be ethical they should be effective; this Virtually nothing is taught in medical schools or post-
would incorporate placebo effects into evidence-based medi- graduate training about placebo responses and the effect of
cine. A meta-analysis of 114 randomized trials that compared physician attitudes and behaviours, yet this seems critical for
biomedical placebo to no treatment suggests that these in- effective therapy. Once we deconstruct the true meaning of
terventions may not be effective.30 However, this may over- placebo from the deceptive use of inactive biological in-
look aspects of nominal “no treatment,” including expert terventions, its true potential becomes evident, and at the
opinion, reassurance and so ondthe conditions for positive centre of this is physician style. Patients respond better when
expectancy. Third, deliberately deceptive placebo administra- physicians are optimistic and positive about recommenda-
tion runs the risk or rupturing physician-patient trust, con- tions. The glass should always be half full and not half empty.
travenes the idea of patient dignity, and may lead to patient The “physician as healer” brings something that “doctor by
unhappiness. internet” cannot. We ourselves can be forces for good in
All these counterarguments become irrelevant if human addition to whatever biomedical treatments and benefits are
interactions and expectancy, and not deception, are the true available.
Sheldon and Opie-Moran 1541
Placebo: Mechanisms and Use

Disclosures 19. Kelley JM, Lembo AJ, Ablon JS, et al. Patient and practitioner influences
The authors have no conflicts of interest to disclose. on the placebo effect in irritable bowel syndrome. Psychosom Med

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