Review

The placebo response in osteoarthritis and its implications for

clinical practice
M. Dohertyy* and P. Dieppez
y University of Nottingham, Nottingham, UK
z Peninsula Medical School, Plymouth, UK
Summary
Many observations support a major biological effect from the way in which people interpret the meaning of each component of their medical
experience and the context in which this occurs. A recent systematic review of randomised controlled trials in osteoarthritis has demonstrated
that the effect size of placebo is substantial and is usually greater than that obtained from the specic effect of an individual treatment. In the
context of a randomised controlled trial, such a large placebo or meaning response is considered a nuisance, but in the context of clinical
practice the optimisation of such meaning and contextual responses, through enhanced care, could greatly benet people who suffer from
osteoarthritis.
2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Key words: Placebo, Osteoarthritis, Clinical trials, Meaning response, Context effects.
Introduction
We recently published a systematic review and meta-anal-
ysis of placebo response in osteoarthritis (OA) randomised
controlled trials (RCTs)
1
. This conrmed the appreciable ef-
fect size (ES) of placebos on pain relief and identied
some of the factors that may determine the size of this ef-
fect in RCTs. These ndings clearly are of relevance to
the design of OA RCTs and to the interpretation of the
true ES of treatments. More importantly, however, these re-
sults have important implications for clinical practice. Here
we will: (1) briey review the history, nomenclature and
changing perspective of placebo; (2) summarise the nd-
ings of our meta-analysis; (3) present related key observa-
tions taken largely from the pain and mental health
literature; and nally (4) explain how this knowledge might
inuence our behaviour as clinicians and the care that we
offer patients with OA.
Historical changes in perspective concerning
placebo
Prior to the mid 20th century it was commonplace for doc-
tors to prescribe placebos with the assurance that they
would lead to health and coping benets
2
. This deliberate
prescription of inert products was described by Thomas Jef-
ferson in 1807 as the pious fraud
3
and in the Lancet in
1954 as humble humbug
4
. However, at a time when there
were few effective treatments such deception was
considered both ethical and benevolent
2,4,5
. Placebo
means I will please and up until the 1950s the prevailing
view was that products such as bread pills, coloured water,
or water injections, would do no harm and by a psychologi-
cal trick could comfort patients with incurable conditions, es-
pecially those low in intellect or inadequate and thus more
susceptible to suggestion
4,5
.
Inthesecondquarter of the20thcentury, however, twopar-
allel developments changed this perspective. Firstly, the ad-
vances in effective drug discovery, and secondly the
developments in medical statistics and epidemiology that
led to introduction of the RCT as the gold standard for clinical
trials. In a landmark publication in 1955 entitled The Power-
ful Placebo
6
Henry Beecher described the occurrence in
RCTs of real, not imagined, objective benets from placebo
in around 35% of patients. He reasoned that the total benet
from a treatment equals the real or specic effect of the
treatment plus the non-specic placebo effect, and impor-
tantly concluded that response to placebo was irrespective
of IQ. Subsequent research focused on how this effect may
arise, and amongst mechanisms suggested were the Haw-
thorne effect (behaviour change through being observed);
patient expectation of improvement; a meaning response;
classic conditioning; relief of anxiety; contextual healing; re-
sponse bias; and the patientepractitioner interaction
2,7,8
.
There has been much controversy over the meaning of
the word placebo and it is important to distinguish placebo
responses (sometimes called context effects) from pla-
cebo interventions
9
. Arguably the most useful denition of
placebo (and nocebo) effects is that provided by Grun-
baum in the 1980s
10,11
; he distinguishes the characteristic
effects of an intervention for the target condition, from all
the non-characteristic (or incidental) effects related to the
use of that intervention. Thus, for example, a sugar pill
might be used as a placebo tablet in a trial of an
*Address correspondence and reprint requests to: Michael
Doherty, Academic Rheumatology, Clinical Sciences Building,
City Hospital, Nottingham NG5 1PB, UK. Tel: 44-115-8231756;
Fax: 44-115-8231757; E-mail: michael.doherty@nottingham.ac.uk
Received 17 March 2009; revision accepted 22 March 2009.
Osteoarthritis and Cartilage (2009) 17, 1255e1262
2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.joca.2009.03.023
International
Cartilage
Repair
Society
1255
antidepressant drug since sugar is not thought to have any
specic (characteristic) effect on depression e but the
same could not be said for diabetes. And if a sugar pill pla-
cebo was used in a trial of antidepressant therapy, then its
effects will depend on a huge number of contextual factors
surrounding its administration, as outlined below. Paterson
and Dieppe have pointed out that in many complex inter-
ventions used for conditions such as OA these non-charac-
teristic (context) effects may interact with the characteristic
effects
9
. This not only makes it more difcult to interpret the
results of trials, it can invalidate the use of the classical
RCT as a way of assessing the value of such interventions
(Fig. 1).
At the turn of this century the existence of placebo re-
sponse was challenged. In a systematic review of RCTs
that randomised participants to either placebo or no treat-
ment (observation only), Hrobjartsson and Gotzsche found
no signicant benet from placebo for binary or objective
outcomes, but possible small benets for continuous sub-
jective outcomes and for the treatment of pain
12
. Although
there were many problems with this review and its
methodology was seriously challenged
13,14
, this publication
rekindled the debate about placebos. Alternative explana-
tions for apparent placebo benets in RCTs included un-
measured concomitant treatments and the patients
desire to please the doctor (the patients placebo), but
also impersonal statistical artefacts of measurement such
as natural uctuations in disease severity and regression
to the mean
12,15e17
. A key reason for such controversy
and confusion is that inclusion of a placebo in RCTs is
the accepted gold standard for the assessment of interven-
tion effects, and unless a no-treatment control is also in-
cluded (an approach often considered unethical) it is
impossible to ascertain what effect the placebo might
have e in effect the RCT is a way of deliberately ignoring
placebo responses
9
. It was because of such controversy
and confusion that we decided to examine whether there
was evidence for placebo response in OA RCTs, looking
specically for trials with no treatment control groups, and
to identify possible determinants of the size of any such
effects
1
.
Placebo effect in RCTs of OA
We identied by systematic review 198 trials that met our
inclusion criteria. These comprised 193 placebo groups
(16,364 patients) and 14 untreated control groups (1167 pa-
tients) and examined a range of non-pharmacological, phar-
macological and invasive treatments. There was clear
evidence to support positive benets from placebo. For
pain relief the overall ES (the standard mean difference be-
tween baseline and endpoint) was 0.51 [95% condence in-
terval (CI) 0.46e0.55] for placebo, but almost 0 for
untreated controls (ES 0.03, 95% CI 0.13 to 0.18). This
ES was even higher (0.77, 95% CI 0.65e0.89) in the three
trials that had head-to-head comparison between placebo
and no treatment. The ES for pain relief was also higher
(0.71, 95% CI 0.64e0.78) in the 15 trials that gave no res-
cue analgesia, perhaps reecting a greater expectation of
powerful effect if no rescue was offered. Placebo was
also effective for other subjective outcomes, for example
stiffness (ES 0.43, 95% CI 0.38e0.49), self-reported func-
tion (ES 0.49, 95% CI 0.44e0.54) and interestingly, physi-
cians global assessment (ES 0.66, 95% CI 0.53e0.78).
With respect to determinants of magnitude, the following
showed signicant independent effects for the primary out-
come of pain relief:
The ES of the treatment: the higher the treatment ES
the higher the placebo effect, perhaps explained by
higher expectation of benet by participants.
The baseline level of pain: the higher this was, the
greater the placebo ES.
treatment factors
intervention
group
control
group
effects in each group
measured
difference
actual
treatment effect
incidental
elements
(placebo response/
meaning effect)
unrelated to
treatment
characteristic
elements
characteristic
(specific) effect
incidental
(placebo) effect
Characteristic
and incidental
effects interact
Fig. 1. The effects of any treatment can be divided into characteristic effects (the specic effects of the intervention on the target disorder),
and incidental effects (also called non-characteristic effects, context effects, the meaning response or placebo effects), which are a complex
combination of all the other factors affecting the outcome (box on left of diagram). For problems such as pain and depression the size of the
incidental element is often larger than that of the characteristic element. In many complex interventions, such as physiotherapy, there is an
interaction between characteristic elements (e.g., muscle strengthening) and incidental elements (e.g., motivation by the physiotherapist). This
can lead to under-estimation of the effect of an intervention if a classical RCT is used to test it, as such trial designs only measure the differ-
ence between characteristic elements and non-characteristic elements.
1256 M. Doherty and P. Dieppe: Placebo response in OA e implications for clinical practice
The sample size: the larger the study numbers the
higher the placebo effect. This might be explained by
the power requirements to differentiate the relatively
small additional benet of treatments over placebo.
Similarly, the funnel plot of ES for pain relief showed
a skewed distribution, suggesting that trials with
smaller placebo effects are more likely to be published,
perhaps because it is easier to demonstrate superiority
of a treatment when this occurs.
The route of delivery: RCTs involving repeated nee-
dling (acupuncture, intra-articular injection of hyalur-
onan) had the highest placebo effects (Fig. 2).
Interestingly, the one steroid injection study that gave
serial injections had a higher placebo ES than studies
involving single injection. RCTs of topical NSAID also
had higher than average placebo ES.
Such determinants provide reassurance of the validity of
our main nding. Therefore, we found unequivocal evidence
of a large placebo response in OA, particularly for pain re-
lief. Notably the ES of placebo (0.5e0.7) is much larger
than that achieved with most of our conventional therapies,
such as analgesic and anti-inammatory drugs (0.2e0.3)
18
.
Recent publications showing similar results in depression
trials
19,20
attracted widespread publicity, leading one scien-
tic author to suggest that the effectiveness of antidepres-
sants was a myth
21
and some Press to wrongly conclude
that conventional therapy was of little or no value.
The determinants of placebo responses
Although hardly studied in OA, there is a large literature
on placebo and the non-specic effects of care in other
areas of medicine. Examples, especially from pain and
mental health studies, are worth examining here since
they are largely generic and therefore relevant to OA.
Many observations point to a major biological effect from
the way people interpret the meaning of each component
of their medical experience and the context in which it oc-
curs. The term meaning response encapsulates these ex-
planatory mechanisms, and placebo is just one example of
the responses that are integral to any clinical encounter or
treatment
8,22
. Although most examples relate to drugs, the
principles probably extend to any intervention.
COLOUR AND NUMBER
In a classic experiment medical students were given ei-
ther one or two blue or pink tablets and told that one was
a stimulant and the other a sedative, though in fact both
were inert. Overall, pink tablets caused stimulant effects
and blue tablets sedation, and two tablets had more effect
than one
23
. Clearly these effects are nothing to do with re-
gression to the mean or disease uctuation, but are ex-
plained by the meaning associated with the colour (pink
for hot, blue for cool) and the expectancy that a double is
more potent than a single dose. A systematic review in
1996 concluded that green and blue may have more seda-
tive, and red and orange more stimulant effects, and that
this difference is reected in the colour of marketed drugs,
perhaps boosting their efcacy
24
. In an Italian study of sed-
ative placebos, however, blue tablets had the usual seda-
tive effect in women but the opposite effect in men
25
,
perhaps because blue is the national soccer team colour
and associates in men with feelings of excitement. Thus it
is not the colour per se that inuences the outcome, but
the meaning attributed to it by an individual.
BRANDING AND COST
Having the condence that the treatment you are receiv-
ing is reputable and high class makes a difference to out-
come. In a placebo-controlled trial of aspirin for relief of
headache, patients were randomised to one of four treat-
ments: aspirin labelled with a well-known brand; plain un-
branded aspirin; placebo marked with the same brand; or
plain placebo. Aspirin worked better than placebo, but
branded tablets worked better than their unbranded coun-
terparts
26
. A recent US placebo analgesic study also
showed that patients who were told that their tablets were
obtained at full cost ($2.50) obtained better pain relief
than those who were told their tablets were discounted at
just 10 cents
27
.
METHOD OF DELIVERY AND FREQUENCY
In general, the larger the intervention the higher the pla-
cebo effect. As in our systematic review
1
, greater placebo ef-
fects have been reported with injections than with oral
medication in many conditions varying from pain relief in mi-
graine
28
tocontrol of hypertension
29
(Fig. 2). Also greater pla-
cebo benet from a higher frequency of administration has
been observed not just for sedation or stimulation
23
but for
other conditions including healing of peptic ulcer disease
30
.
Surgery, of course, is one of the ultimate treatments in
terms of magnitude. In OA, the report that invasive arthro-
scopic lavage, with or without debridement, is no better
than sham procedure
31
caused considerable controversy
32
since it implied that the benet to the patient resulted from
the expectancy and experience of the intervention rather
than to whatever was done inside the joint. Understandably,
for ethical reasons, there are very few placebo-controlled
studies of surgery. However, in 1959
33
and 1960
34
two
small controlled studies examined the efcacy of bilateral
internal mammary ligation (BIMAL) for treating angina.
This procedure was widely practiced at the time; the ratio-
nale being that ligation of these arteries would redirect
more blood through the coronary arteries. The combined re-
sults of the two studies showed that 73% of patients (24/33)
undergoing BIMAL had signicant improvement with re-
duced angina, better exercise tolerance, and reduced ni-
trate consumption. However, 83% of patients (10/12) who
received sham surgery (anaesthesia, chest incision, artery
exposed but not ligated) showed similar substantial im-
provement. Because of prevailing ethical considerations,
whether many currently performed technical procedures
give any benet above the experience of surgery itself will
remain open to question.
RESPONSE EXPECTANCY AND CONCEALMENT
The expectation of what a treatment will do is an impor-
tant determinant of the outcome. In a study of aerobic exer-
cise one group was told that their aerobic capacity should
increase after 10 weeks of the programme, and the other
group was told that their tness would improve but also their
wellbeing would be enhanced. Both groups equally im-
proved aerobic capacity but only the second group reported
feeling better
35
. In a study of the physiological effects of cof-
fee, one group was given either regular or decaffeinated
coffee in a double blind design, while a second group was
told they would all receive regular coffee, but in fact was
given decaffeinated. Increase in pulse rate, alertness and
blood pressure changes were greater in the second group
(who were all expecting such effects) than in those given
decaffeinated coffee in the rst group (who believed they
1257 Osteoarthritis and Cartilage Vol. 17, No. 10
had only a 50:50 chance of having active coffee)
36
. Such re-
sponse expectancy can even reverse the pharmacological
effect of a drug. For example, ipecachuana (a potent
emetic) can improve nausea if patients are told that they
are receiving an anti-emetic
37
.
Knowing that a treatment is being given is important. In
a post-operative analgesia study, patients who could see
morphine being administered into their line obtained rapid
and effective pain relief, whereas patients who received mor-
phine by concealed administration obtained much slower
benet, implying that the initial relief (fromour strongest anal-
gesic) is largely placebo effect. Equally, open discontinuation
of morphine led to rapid return of pain whereas covert discon-
tinuation did not
38
. Other studies of pain, anxiety and Parkin-
sons disease have similarly shown a decrease in treatment
efcacy when the patient is unaware that they are receiving
them
38
. This difference between open and covert administra-
tion is equivalent to the placebo component of the treat-
ment, and investigating this difference has been suggested
as an alternative strategy, at least for some treatments, to
a classic placebo RCT design.
BEHAVIOURAL CONDITIONING
In a study of the immunosuppressive effects of cyclospor-
ine A, the drug was given to healthy volunteers together
with a novel green liquid drink. The expected degree of
immunosuppression was observed. After conditioning
the subjects in four sessions over three consecutive days,
the experiment was repeated the following week with pla-
cebo tablets given with the same drink. The repeat
exposure, with dummy tablets, resulted in immunosupres-
sion
39
. The authors of this work point out that although
the mechanism of such responses remains to be eluci-
dated, it might be possible to enhance the effects of immu-
nomodulatory and other drugs by behavioural conditioning
interventions e an approach that could have widespread
implications in medicine.
HOW NEW THE INTERVENTION IS?
In studies of interventions for various conditions, includ-
ing depression and peptic ulcer healing, there are data to
suggest that drugs or other interventions that are new re-
sult in larger placebo responses than those which are es-
tablished
22,40
, suggesting that meaning is enhanced if
patients and practitioners believe that the intervention is
modern.
PROVIDER EFFECTS
Patients are inuenced by the expectation and behaviour
of the practitioner. In a double blind dental pain study pa-
tients were told that they would receive either fentanyl
Fig. 2. Treatments delivered by needling, such as acupuncture (shown above, with burning moxa) and intra-articular injection (shown below)
seem to associate with greater expectancy, higher placebo effects, and more magic.
1258 M. Doherty and P. Dieppe: Placebo response in OA e implications for clinical practice
(which might reduce pain), the opioid antagonist naloxone
(which might increase pain) or a placebo. However, early
in the study the investigators, but not the patients, were
told that due to administrative problems fentanyl was un-
available so patients would only be randomised to the nal-
oxone or placebo arms (i.e., only two negative
treatments). Later in the study investigators were informed
that fentanyl was now available and included in the adjusted
randomisation procedure. Patients receiving placebo in the
second phase of the study experienced signicant pain re-
lief but patients on placebo in the rst phase did not
41
. Thus
the clinicians optimism or pessimism concerning treatment
has a dynamic effect on the patients outcome.
A recent audit has shown that intentional prescribing of
placebo treatments, such as vitamins and over the counter
products regarded as inert, is commonplace amongst US in-
ternists and rheumatologists, and that usually these are de-
scribed to the patient as a potentially benecial treatment
not usually usedfor their condition
42
. Placebos areevencom-
mercially available in the US as obecalp (placebo spelt
backwards), cebocap (placebo capsules) and jujubes
(for parents to administer to their children). However, irre-
spective of the ethical issues of not being transparent with
a patient, it would appear that placebo is less likely to give
benet when it is knowingly administered.
BIOLOGICAL EFFECTS, ADHERENCE AND DEATH
There is growing evidence that context effects and mean-
ing responses can effect alterations in body systems (such
as immune function, mentioned above
39
) in addition to
changes in psyche and behaviour. For example, in some
pain studies placebo effects are abolished by naloxone, im-
plicating endogenous opioid release as one mechanism
that can convert expectancy to real analgesia
43e45
.
Neuroimaging studies have made major contributions to
the eld recently
46
. For example, positron-emission tomog-
raphy with [
11
C] carfentanil has been used to provide
graphic evidence that placebo analgesia causes endoge-
nous opioid activity in the m-opioid receptor rich regions
that play a central role in pain and affect
47
.
The ultimate reality of placebo and meaning response is
exemplied by studies of adherence and death. It is logical to
expect that people who adhere to a treatment usually do bet-
ter than non-adherers, but the same difference occurs with
placebo. In a study of antibiotic prophylaxis following chemo-
therapy
48
non-adherers to placebo had twice the infection
rate of adherers (64% vs 32%), and in a study of chlorprom-
azine for schizophrenia
49
non-adherers to placebo had twice
the relapse rate of adherers (80% vs 40%). This differential
outcome from adherence to placebo extends to mortality. In
a large RCT examining the effect of the cholesterol-lowering
agent clobrate on 5-year survival following myocardial in-
farction, participants who took >80% of study medications
did better than non-adherers, specically: 15% vs 25% mor-
tality for those on clobrate; and 15%vs 28%for those on pla-
cebo
50
. In addition to heart disease, reduced mortality in
adherers to placebo is reported in studies of diabetes, immu-
nosuppression following transplantation, and anti-retroviral
treatment for AIDS
51
. Therefore adherence to what you be-
lieve to be a benecial treatment may prevent development
of disease and even death.
ENVIRONMENT AND CONTEXT
The environment in which you receive treatment can
modify your outcome. Matched patients who had under-
gone gall bladder surgery were allocated to one of two
wards which were similar apart from their outlook e one
had a pleasant green-eld view and the other over-looked
a high wall and parking lot. The patients with the natural
Fig. 3. The importance of environment. A ward with a bleak view (left) elicits worse outcomes than a ward with a positive natural view (right).
1259 Osteoarthritis and Cartilage Vol. 17, No. 10
view had fewer post-operative complications, required less
analgesia, made fewer complaints and were discharged
earlier than those with the bleak view
52
(Fig. 3).
In an attempt to dissect out separate components of
placebo Kaptchuk et al. recently undertook a study of
sham acupuncture in patients with irritable bowel syn-
drome. Patients were randomised to one of three groups:
waiting list (assessment and observation); sham acupunc-
ture with only limited patientepractitioner interaction (the
therapeutic ritual); or sham acupuncture with more
usual patientepractitioner interaction augmented by
warmth, attention and condence. At 3 weeks the propor-
tions in each group with adequate pain relief were 28%
(observation), 44% (ritual) and 62% (augmented interac-
tion). A similar trend was observed for quality of life
(3.6, 4.1, 9.3) and all other measured outcomes
53
. Clearly
all three components contributed to benet but the most
robust was patientepractitioner interaction.
The importance of the patientepractitioner interaction
was also the focus of a study in general practice in which
200 patients with symptoms but no abnormal signs were
randomly assigned to either: (1) a positive consultation,
in which the patient was given a condent diagnosis and re-
assured that things would soon improve; or (2) a negative
consultation, where the doctor admitted I cannot be certain
of what is the matter with you. In both groups the doctor
could also prescribe thiamine tablets as placebo medica-
tion. Two weeks later, 64% of patients who had the positive
consult were better, compared to 39% of those who had the
negative encounter. Receiving a prescription made no dif-
ference. The overriding factor appeared to be the patient re-
sponse to the certainty of diagnosis and reassurance
concerning prognosis
54
. Other contextual aspects that are
suggested to encourage a benecial meaning response in-
clude: when the patient regards the practitioner as experi-
enced and competent
55,56
; when the clinician is optimistic
that the treatment will help
55,56
and when the practitioner
wishes to see the patient again to monitor progress
57
.
Implications for clinical practice
OA is a condition in which the pathology does not always
correlate with the symptoms
58
. Thus someone may have
severe joint damage but no pain, or severe pain but only
minor joint pathology. As outlined above, placebo re-
sponses can result in big effects on symptoms (the illness),
but we have not found evidence that they affect X-rays and
pathology (the disease). The fact that placebo responses
are best documented in other painful conditions and in
mental health disorders, suggests that the value of placebo
interventions is mainly for patient symptoms and distress.
These are the principal treatment targets in patients with
OA. We believe that we should be more aware of the
power of the placebo response to relieve pain and suffering
in people with OA, and that we should learn how to use it
better.
Fig. 4. The difference between a positive encounter (above) and a negative encounter (below) with a practitioner can inuence the outcome for
the patient. It is our professional responsibility to address such aspects.
1260 M. Doherty and P. Dieppe: Placebo response in OA e implications for clinical practice
From the above it is apparent that in the context of a clin-
ical encounter many facets of the patients experience de-
termine their outcome from any intervention. In audits of
care, including OA
59
, common patient complaints are:
that the doctor was too busy to listen,
that the doctor undertakes only a supercial examina-
tion, or no examination at all,
that the doctor didnt address key concerns,
that the doctor did not give a follow-up appointment.
Given these circumstances it is obvious that practitioners
should capitalise on the impact of context effects to en-
hance the benets to their patients, as a professional re-
sponsibility. Many of these aspects are nothing to do with
the ritual of a drug or physical treatment. When a practi-
tioner gives a patient their focused and unhurried attention
in a comfortable environment, listens to them, undertakes
a thorough examination, explains in understandable terms
what is happening, addresses concerns and provides
a way forward, the patient experiences a good deal.
This is in itself a treatment (Fig. 4). The patient often leaves
both looking and feeling better, long before they cash in any
(adjunctive) prescription they have just received. The con-
verse is also true. Recent studies of the nocebo effect
(expectation of a negative effect leading to worse outcome)
have shown, for example, that negative words that increase
anxiety can result in increased pain
60
.
The use of the term meaning response to cover what we
have here called non-characteristic or context effects
8,22
em-
phasises the importance of the meaningof aconsultation and
any suggested intervention to the patient. The meanings of
interventions are culturally determined and depend in part
on the health beliefs of the patient. Exorcismmay work better
thanaspirinif apatient rmly believes that their painis caused
by their possession by evil spirits
61
. Health beliefs can be eli-
cited in a clinical encounter, and measured for research pur-
poses
62
. Furthermore, in many cases practitioners can help
the patient towards a health belief that is more in tune with
the interventions that are available to help them.
Practitioners of complementary and alternative medicine
(CAM) often do this very well, and seem ahead of many
of us more traditional physicians. We often pride ourselves
on being over-worked and too busy to spend time on such
peripheral matters, and feel more useful and important
when we exercise our licence to prescribe potentially dan-
gerous drugs. We often label practitioners of CAM as char-
latans and explain their treatment success as just placebo
effect, apparently oblivious of the surprisingly large ES of
such non-treatment benets. But if we did learn from the
research literature, from practitioners of CAM, and from sim-
ple observation, and optimise these meaning responses
8,22
in our clinical practice, the benets of such contextual heal-
ing
7
to the population of people with OA would be huge.
Conict of interest
The authors have no conict of interest to declare.
References
1. Zhang W, Robertson J, Jones A, Dieppe PA, Doherty M. The placebo
response and its determinants in osteoarthritis e meta-analysis of
randomised controlled trials. Ann Rheum Dis 2008;67:1716e23.
2. Kaptchuk TJ. Powerful placebo: the dark side of the randomised con-
trolled trial. Lancet 1998;351:1722e5.
3. Jefferson T. In: Ford PL, Ed. The Writings of Thomas Jefferson. New
York: GP Putnams; 1898.
4. Anon. The humble humbug. Lancet 1954;ii:321.
5. Pepper OHP. A note on the placebo. Am J Pharm 1945;117:409e12.
6. Beecher HK. The powerful placebo. JAMA 1955;159:1602e6.
7. Miller FG, Kaptchuk TJ. The power of context: reconceptualising the pla-
cebo effect. J R Soc Med 2008;101:222e5.
8. Moerman D. Meaning, Medicine and the Placebo Effect. Cambridge,
UK: Cambridge University Press; 2002.
9. Paterson C, Dieppe P. Characteristic and incidental (placebo) effects in
complex interventions such as acupuncture. BMJ 2005;330:1202e5.
10. Gunbaum A. The placebo concept. Behav Res Ther 1981;19:157e67.
11. Gunbaum A. The placebo concept in medicine and psychiatry. Psychol
Med 1986;16:19e38.
12. Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of
clinical trials comparing placebo with no treatment. N Engl J Med
2001;344:1594e602.
13. Spiegel D, Kramer H, Carlson R. Is the placebo powerless? N Engl J
Med 2001;345:1276.
14. Miller FG, Rosenstein DL. The nature and power of the placebo effect. J
Clin Epidemiol 2006;59:331e5.
15. McDonald CJ, Mazucca SA, McCabe GP. How much of the placebo
effect is really statistical regression? Stat Med 1983;2:417e27.
16. Kienle GS, Kiene H. The powerful placebo: fact or ction? J Clin Epide-
miol 1997;50:1311e8.
17. Gotzsche PC. Is there logic to the placebo? Lancet 1994;344:
925e6.
18. Osteoarthritis e National Clinical Guideline for Care and Management in
Adults. NICE and Royal College of Physicians Guidelines on Osteoar-
thritis, <www.NICE.org>; 2008.
19. Turner EH, Mathews AM, Linardatos E, Tell RA, Rosenthal R. Selective
publication of antidepressant trials and its inuence on apparent ef-
cacy. N Engl J Med 2008;358:252e60.
20. Kirsch I, Deacon JB, Huedo-Medina TB, Scobaria A, Moore TJ,
Johnson BT. Initial severity and antidepressant benets: a meta-anal-
ysis of data submitted to the Food and Drug Administration. PLoS
Med 2008;5(2):e45.
21. Ionnidis J. Effectiveness of antidepressants: an evidence myth con-
structed from a thousand randomized trials? Philos Ethics Humanit
Med 2008;3:14.
22. Moerman DE, Jonas WB. Deconstructing the placebo effect and nding
the meaning response. Ann Intern Med 2002;136:471e6.
23. Blackwell B, Bloomeld SS, Buncher CR. Demonstration to medical stu-
dents of placebo responses and non-drug factors. Lancet 1972;
1(763):1279e82.
24. de Craen AJM, Roos PJ, de Vries LA, Kleijnen J. Effect of colour of
drugs: systematic review of perceived effect of drugs and of their ef-
fectiveness. BMJ 1996;313:1624e6.
25. Cattaneo AD, Lucchilli PE, Filippucci G. Sedative effects of placebo
treatment. Eur J Clin Pharmacol 1970;3:43e5.
26. Branthwaite A, Cooper P. Analgesic effects of branding in treatment of
headaches. BMJ 1981;282:1576e8.
27. Waber RL, Shiv B, Carmon Z, Ariely D. Commercial features of placebo
and therapeutic efcacy. JAMA 2008;299:101607.
28. de Craen AJM, Tijssen JG, de Gans J, Kleijsen J. Placebo effect in the
acute treatment of migraine: subcutaneous placebos are better than
oral placebos. J Neurol 2000;247:183e8.
29. Grenfell RF, Briggs AH, Holland WC. A double-blind study of the treat-
ment of hypertension. JAMA 1961;176:124e8.
30. de Craen AJ, Moerman DE, Heisterkamp SH, Tytgat GN, Tijssen JG,
Kleijnen J. Placebo effect in the treatment of duodenal ulcer. Br J
Clin Pharmacol 1999;48:853e60.
31. Moseley JB, OMalley K, Petersen NJ, Menke TJ, Brody BA,
Kuykenall DH, et al. A controlled trial of arthroscopic surgery for oste-
oarthritis of the knee. N Engl J Med 2002;347:81e8.
32. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N,
et al. OARSI recommendations for the management of hip and knee
osteoarthritis. Part II: OARSI evidence-based, expert consensus
guidelines. Osteoarthritis Cartilage 2008;16:137e62.
33. Cobb L, Thomas GI, Dillard GH, Merendino KA, Bruce RA. An eval-
uation of internal mammary artery ligation by double blind technic.
N Engl J Med 1959;260:1115e8.
34. Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammary li-
gation and sham operation for angina pectoris. Am J Cardiol 1960;5:
483e6.
35. Desharmais R, Jobin J, Cote C, Levesque L, Godin G. Aerobic exercise
and the placebo effect: a controlled study. Psychosom Med 1993;55:
149e54.
36. Kirsch I, Weixel LJ. Double-blind versus deceptive administration of
a placebo. Behav Neurosci 1988;102:319e23.
37. Wolf S. Effects of suggestion and conditioning on the action of chemical
agents in the human e the pharmacology of placebos. J Clin Invest
1950;29:703e9.
1261 Osteoarthritis and Cartilage Vol. 17, No. 10
38. Colloca L, Lopiano L, Lanotte M, Benedetti. Overt versus covert treat-
ment for pain, anxiety and Parkinsons disease. Lancet Neurol
2004;3:679e84.
39. Goebel M, Trebst A, Steiner J, Xie Y, Exton M, Frede S, et al. Behaviou-
ral conditioning of immunosuppression is possible in humans. FASEB
J 2002;16:1869e73.
40. Walsh B, Seidman S, Sysko R, Gould M. Placebo responses in studies
of major depression: variable, substantial and growing. JAMA 2002;
287:1840e7.
41. Gracely RH, Dubner R, Deeter WR, Wolskee PJ. Clinicians expecta-
tions inuence placebo analgesic. Lancet 1985;1:43.
42. Tilburt JC, Emanuel EJ, Kaptchuk TJ, Curlin FA, Miller FG. Prescribing
placebo treatments: results of national survey of US internists and
rheumatologists. BMJ 2008;337:a1938.
43. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo
analgesia: expectation-activated opioid systems versus conditioning-
activated specic subsystems. J Neurosci 1999;19:484e94.
44. Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to an-
algesics: a role for non-specic activation of endogenous opioids.
Pain 2001;90:205e15.
45. Gracely RJ, Dubner R, Wolskee PJ, Deeter WR. Placebo and naloxone
can alter post-surgical pain by separate mechanisms. Nature 1983;
306:264e5.
46. Lidstone SC, Stoessl AJ. Understanding the placebo effect: contribu-
tions from neuroimaging. Mol Imaging Biol 2007;9:176e85.
47. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid
activity during pain. Proc Natl Acad Sci USA 2007;104:11056e61.
48. Pizzo PA, Robichaud KJ, Edwards BK, Schumaker K, Kramer BS,
Johnson A. Oral antibiotic prophylaxis in patients with cancer: a dou-
ble-blind randomised placebo-controlled trial. J Paediatr 1983;102:
125e33.
49. Hogarty GE, Goldberg SC. Drug and sociotherapy in the aftercare of
schizophrenic patients. One year relapse rates. Arch Gen Psychiatry
1973;28:54e64.
50. Coronary Drug Project Research Group. Inuence of adherence to treat-
ment and response of cholesterol on mortality in the coronary drug
project. N Engl J Med 1980;303:1038e41.
51. Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT,
Varney J, et al. A meta-analysis of the association between adher-
ence to drug therapy and mortality. BMJ 2006;333:15e8.
52. Ulrich RS. View through a window may inuence recovery from surgery.
Science 1984;224:420e1.
53. Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE,
et al. Components of the placebo effect: randomised controlled trial in
patients with irritable bowel syndrome. BMJ 2008;336:999e1003.
54. Thomas KB. General practice consultations: is there any point in being
positive? BMJ 1987;294:1200e2.
55. Thomas KB. The placebo in general practice. Lancet 1994;344:1066e7.
56. Barford TS. Placebo therapy in dermatology. Clin Dermatol 1999;17:
69e76.
57. BernsteinCN. Placebos in medicine. SeminGastrointest Dis 1999;10:3e7.
58. Dieppe P, Lohmander S. Pathogenesis and management of pain in os-
teoarthritis. Lancet 2005;365:967e73.
59. OA Nation, <www.arthritiscare.org.uk.OANation>;; 2004.
60. Benedetti F, Lanotte M, Lopiano L, Collaco L. When words are painful:
unravelling mechanisms of the nocebo effect. Neuroscience 2007;
147:260e71.
61. Kleinman A. The Illness Narratives: Suffering, Healing and the Human
Condition. London, UK: Basic Books (Harper Collins); 1988.
62. Moss-Morris R, Weinman J, Petrie K, Horne R, Cameron L, Buick D. The
revised Illness Perception Questionnaire (IPQ-R). Psychol Health
2002;17:1e16.
1262 M. Doherty and P. Dieppe: Placebo response in OA e implications for clinical practice