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EDITORIAL
T H E PE R P L E X I T Y
OF THE UNSEEN
Come, do not stop at the gate: Life and Death, the
two guardian angels, will transmute into the
Guardians of the Threshold, and let you in. There
lies Beauty, Truth, and Goodness, the attributes of Love,
and the primeval promoter of
g| IN THIS ISSUE
life who subtly affects the
whole being. I will be grateful
E D I T O R I A L | SAHLAN MOMO
if you could spread the good
The Perplexity of
news: “Come Death, I’m waitthe Unseen
2
ing for your call.” Realistic
FABRIZIO BENEDETTI
models should be integrated in
The Many Placebo Effects 5
the vision, they are needed as
EDZARD ERNST
long as we partake of this
The Ethical Implications of
Using Placebo in Clinical
dimension. What needs to be
Practice
9
reviewed after all? The inexplicCHRISTOPER J. BEEDIE
able that not even the finest
All in the Mind? Pain,
degree of angels could disclose
Placebo, and Ergogenic
to itself? Be my guest, I request
Effect of Caffeine in
you to step in: therein no abyss
Sport Performance
12
from where to surface, indeed
KURT GRAY ~
nothing is there, neither time
DANIEL M. WEGNER
nor space, nothing, Nothing at
The Sting of Potential
Pain
20
All. Still the dualistic vision is
creeping in this momentary
JOHN N. WILLIAMS
The Ethics of
dimension in which we all live.
Placebo-Controlled Trials
Placebo.
The body is a device to calculate the astronomy of the spirit.
Look through that astrolabe and become oceanic.
RUMI, Mathnawi.
D
O NOT BE SURPRISED BY
a pale aesthetical
glance, beauty is still
one of the best veils to
look throughout this world.
Beauty encompasses all, all and
everything, like Truth and
Goodness. Once freed from
time we wander to the accomplished deed immune to all illness. Having accomplished its
mortal function, the physical
body returns to its forming elementals whilst the soul progresses
to its further mansion, the house
of misericordiæ endowed with
prophethood. Indeed, there is
no ‘time’ if there is no ‘be’, and
surely there is no ‘die’ if there is
no Thee.
Taxi downtown to uncover
in Developing Countries to
what really matters: there are
Ut placet in mente dei? An
Prevent Mother-to-Child
more invisible things than visible
apophatic utterance uncovers
Transmission of HIV
23
ones. It is not what we see, that
the
world: get rid of all fears and
ABSTRACTS
29
is of importance, but what we do
statements of joy. No ground
not see that is the real substance.
around, no glamour, breathe
There is only one possible
deeply and plunge into the
equation valid for all planes of
Unknown: “Hallo, who are you?” You or me?!?
the being, where each particle is shaped by the
Definitely a day to celebrate and rejoice, hallelu-yah
sublime fashioner of the wor[l]d, an exquisite
– a dynamic shared field of awakened awareness in
sense of the phrase, a lace vaulting in a vacuum.
the higher collective consciousness is at play.
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Once the top-down stream of consciousness has
been granted, the U conversion of the energy occurs
and all blessings are gathered into the humane
dimension. A new chapter is being chiselled into the
soul: long seated marks are eradicated in a purification process to get rid of all rights – only the physical death will temporarily procrastinate freedom.
The human soul is bound to transit through the
realm of quantity to progress further; it needs to
experience its ‘physical’ body as an essential step to
reach up anew – only because we dwell on the relative realm of time and space this process is perceived
as bottom-up. A conversion of energies akin to the
one taking place at puberty or conversely at old age,
intention (imma), if there is no meaningful iatus or
temporal diastema between intention and execution, that action is effortlessly attuned with the
flow of the dharma, is one with it. In the occasion,
even the freewill vanishes, as it is one and the same
with the cosmic will. The intention is a focused
attitude toward a well defined goal, a pro-tension to
its realization by virtue of its own entelechy to
advance further and overcome all limits; in other
terms, the perennial drive of life pro-tensed towards
its fulfilment. The kernel is that the two energies
and their actions – anode and cathode, or ruh-illofi
and ruh al-kuds or whatever other combination of
opposites it may be – are really simultaneous, and
when the life energy inverts its polarity, changes
direction – the superabundance of a force inevitably
produces its opposite. On a different level, this parallels the principle of equilibrium in the natural
world in which any extreme is opposed by the system to restore balance. “Cold things warm, warm
things cool, wet things dry and parched things get
wet,” enantiodromia, an old acquaintance of mine
used to say. The ensuing plans of the being are
plainly passages from one stage to the next, at times
ignited by rites in the human endeavour. In consciousness (cit), it is a shift, a leap into a new state.
In Reality, in absence of time, the past, the present
and the future are condensed into the ‘now’, that
means that the shift already happened, is taking
place and will occur, altogether at the same time,
its awareness depending from which state of our
individual consciousness we are witnessing it.
Placebo. Here is not the unrestrained surge of the
unconsciousness into consciousness at work, as the
villain maintains, rather their simultaneously merging into oneness. To contemporarily perceive the
two fluxes is certainly vital, but being aware of the
action while displaying the ‘activity’ without interfering in the process is definitely a step ahead.
When the performance of an action is one with its
actually the same; if observed through the binary
manner to perceive the world of the thinking mind,
they appear to be two, for duality houses in time,
but in the dimensionless gathering place of the soul
they are one, just one.
In the midst of all this, by sightseeing randomly in
the groove of the path, we gladly report of a few
landmarks along its landscape, certainly not of the
inexplicable goal. We all are mixed blood, we are
all bastards, it depends from which stance we are
looking at ourselves. To the body, it may look like
health, to the spirit, as spiritual health, in between,
as a spiritual-material wealth. Placebo: something
pleases and soothes the wounds and recovers them to
their original state. The way in which the synapses
communicate in our brain counterparts our social
networking. This parallelism of planes may be
applied to the whole of the manifestation, as all
entities are connected through their dimensionless
centre by the axis mundi crossing in every possible
direction. Devoid of time and space, no direction
is at bay, everything happens contemporary in the
present, every and nowhere. The thinking mind is
unable to grasp this hierophany, this darshan,
unless it affords to be one with its own working
process and lifts its hold on it, only then intuition
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are now needed, at least in ourselves to start with.
Where has it gone that ability to keep together and
jointly strive for a clear direction? Where has Politics
vanished? Still busy with old credentials, with
models, concepts and visions of old, from ten to
one, and then bottom up. A thousand of existence
ago ‘ten’ was deprived of its wholeness and became
‘one’. If 1 is equal to 0, if uniqueness in wholeness
is attained, if one is the whole, then the tensorial
membrane between the two worlds within consciousness self-shapes itself according to its own
inborn input, and the world is informed by matter.
To transmute into its further stage, the soul links
spirit to matter into a whole.
The whole manifestation is nothing but how we
perceive our own projection on it, the projection of
our particular ‘self ’ in its reflexive mode. A paradox, a koan, no doubt, contrary to any opinion and
beyond any reasonable doubt. Indeed the paradox
has always been a powerful device to explore the
reality: by unveiling it, the opposites are reconciled:
inside and outside become paler and all boundaries
are loosened and lost. The ‘apparent’ movement
between the two polarities makes consciousness
spark and it gives rise to the whole. An itinerarium
animi in which an inclusive reform of the I, and of
the ability of the soul to manifest the reality is most
in demand. The middle world between spirit and
matter, the mundus imaginalis, links ta physica to ta
meta, in its ‘imaginal’ geography – not a phantasys –
the tensorial membrane – and the soul – receives
the ‘impressions’ of the spiritual world and reverberates
them into the world of matter as mundane outcome –
let us not forget that to show is not to perform.
Not a novel vision for sure, but one former to the dissection of spirit and matter in time, a compound
which still grants to placebo its effect, that, according
to the followers of the divided reality, shouldn’t
indeed be there. Spear me to detail further, we
could disperse a few. Enjoy the issue.
©
emerges as an insight in the heightened consciousness. Seen from the realm of quantity, intuition
looks faster and finer than thought: the manipulator
of matter. Placebo.
Harmony is a palintropos in a reflexive tension, like
the bow and the lyre. To be in a reflexive tension, to
be self-reflexive is to be re-flexed in oneself. The
entire matter lies on the capacity to be utterly empty,
aloof from the whole lot, yet gladly allow the energy
to flow by its own course, according to its own pace,
synchronic to the rhythm of the body: the inner and
outer are here focused in a spiritual-material alliance.
Certainly consciousness is not made up of matter, it
is much finer, deeper and higher than matter, is an
assembly of relations in a reflexive tension. Indeed,
what really matters in all human affairs are the quality
of the relations, not its su[o]bjects (persona), for, the
former – being immaterial – will last; while the latter
will perish. Yesterday I would have liked to give you
a rose, not solely a rose but a flowering rose in your
pose, in your improbable chest. But you were not
present, emptiness around, not even the bristle of a
leaf, or the cry of an angel, nor the glance of your eyes
I once thought blue. The whole universe couldn’t
compete with that hue: a triumph could not have
been better, certainly no better than you. How long
should I stand at your dazzling face before joining
with you? Placebo. Pinocchio identified himself with
his dream and became human. Who for God’s
‘shake’ (quiver, spanda) would prefer a placebo
instead of a real shot? “The spiritual life is knowledge in the time of trial”: a charming thought in
actual fact, which certainly needs a skilled cryptographer to endorse it as a whole. Nothing can exist
without movement, yet the ultimate movement
takes place in consciousness where time has no grip:
an endless cycle of expansion and contraction, of
internalization and externalization of consciousness
itself, relating to the most elevated plane (citananda)
of the manifestation.
At times it appears as the direction is nowhere to
be found: no longer faiths nor religions to cling to,
no more containers of a long lost content, just the
reality that inspires and sustains them is here. No
sound came out of their tongues but their hassle to
slaughter each other: fundamentalist to their roots,
who lost connection with the original life. Be
assured, everything passes and changes, they too
soon will be gone. Let’s swing the ladder to the
encounter of the two seas. Prospero or Papageno?
Even though these bastards deserve a diamond as
crown, for now I can only offer them a leaded
basin and a blade of red iron lore – transmute…
transmute… Thought and self-awareness are the
two parts of the same unfolding process of doing,
the non-discursive state of consciousness can hardly,
if ever, be conveyed into words. A good intention
is not enough; action must follow. Placebo.
Theory, poiesis, praxis… theà horào, yes, we all saw
the goddess, but global thought and local action
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ab
We live our lives, for ever taking leave.
RAINER MARIA RILKE ,
Duineser Elegien.
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THE MANY PLACEBO EFFECTS
F A B R I Z I O
B E N E D E T T I
to clinical practice and neuroethics. The terms
placebo effect and placebo response are often used
as synonymous, thus both terms will be used here.
E X P E C T A T I O N S
Most of the research on placebos
has focused on expectations as
the main factor involved in
g | OVERVIEW
Fabrizio Benedetti, MD is Professor of
placebo responsiveness. In genPhysiology and Neuroscience at the
eral, expectation is aimed at
University of Turin Medical School
preparing the body to anticipate
and at the National Institute of
an event in order to better cope
Neuroscience, Italy. He has been
The miserable
with it, and as such offers a clear
nominated member of The Academy
evolutionary advantage (Kirsch,
of Europe and of the European
have no other
1999). There are several mechaDana Alliance for the Brain. He has
written the books Placebo Effects
nisms through which expecta(Oxford 2008) and The Patient’s
tion of a future event may affect
medicine
Brain (Oxford 2010).
different physiological functions.
Email: [email protected].
For example, the expectation of
a negative outcome is aimed at
but only
anticipating a possible threat,
I N T R O D U C T I O N
thus increasing anxiety, whereas
hope.
the expectation of a forthcoming
PLACEBO EFFECT IS A
positive outcome may reduce
psychobiological pheanxiety and/or activate the neunomenon occurring in
WILLIAM SHAKESPEARE
ronal networks of reward mechthe patient’s brain folanisms (Price et al, 2008).
lowing the administration of an inert substance, or of
Indeed, anxiety has been found
a sham physical treatment such
to be reduced after placebo
as sham surgery, along with
administration in some studies. If one expects a
verbal suggestions (or any other cue) of clinical
distressing symptom to subside shortly, anxiety
benefit (Price et al, 2008). Therefore, the effect that
tends to decrease. In brain imaging studies reduced
follows the administration of a placebo cannot be
activation of anxiety-related areas during a placebo
attributable to the inert substance alone, for saline
response can be observed (Petrovic et al, 2005). The
solutions or sugar pills will never acquire therapeutic
best evidence that anxiety takes part in placebo
properties. Instead, the effect is due to the psychosoresponses is shown by the nocebo effect, which is
cial context that surrounds the inert substance and
opposite to the placebo effect (Benedetti et al,
the patient. We now know that there is not a single
2007). In order to induce a nocebo effect, an inert
placebo effect, but many, with different mechasubstance is administered along with negative vernisms and in different diseases, systems, and therabal suggestions of clinical worsening, e.g. pain
peutic interventions (Benedetti, 2008b; Enck et al,
increase. Overall, expectations of a negative out2008). In other words, different processes may be at
come, such as pain increase, may result in the
work in the patient’s brain in different conditions.
amplification of pain, and several brain regions,
Sometimes it is anxiety that is modulated, at some
like the anterior cingulate cortex, the prefrontal
other times reward mechanisms are involved, and
cortex, the insula, and the hippocampus have been
in some other circumstances different types of
found to be activated during the anticipation of
learning, or even genetic variants, may take place in
pain in a variety of studies. Nocebo hyperalgesia
placebo responsiveness. In this sense, the placebo
has been studied in some detail also from a pharmaeffect is a melting pot of neuroscientific concepts
cological perspective, in order to identify possible
and ideas, ranging from anxiety and reward mechaneurotransmitters that are involved in anxietynisms to Pavlovian conditioning and social learninduced pain increase. By using an anxiogenic nocebo
ing, and from neurogenetics and neurophysiology
procedure, it was shown that cholecystokinin (CCK)
“
”
A
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plays a crucial role. In fact, the pharmacological
blockade of CCK receptors prevents the occurrence
of nocebo responses.
Not only can expectations of future events modulate anxiety, but they may also induce physiological
changes through reward mechanisms. These mechanisms are mediated by specific neuronal circuits
linking cognitive, emotional, and motor responses,
and are traditionally studied in the context of the
pursuit of natural (e.g., food), monetary, and drug
rewards. There is compelling experimental evidence
that the mesolimbic dopaminergic system, the main
reward network, may be activated in some circumstances when a subject expects clinical improvement
L E A R N I N G
Learning is another mechanism that is central to
placebo responsiveness. Subjects who suffer from a
painful condition, such as headache, and who regularly consume aspirin, can associate the shape, color
and taste of the pill to pain decrease. After repeated
associations, if they are given a sugar pill resembling
aspirin, they will experience pain decrease. Not only
can shape, color and taste of pills be associated to
clinical improvement, but countless other stimuli as
well, such as hospitals, diagnostic and therapeutic
equipments, and medical personnel features. The
mechanism that underlies this effect is conditioning, whereby a conditioned (neutral) stimulus, e.g.
after placebo administration. This was observed in
Parkinson’s disease (de la Fuente-Fernandez et al
2001), depression (Mayberg et al 2002) and pain
(Scott et al 2007). In the case of the placebo response,
the reward can be conceptualized as the clinical
improvement.
the color and shape of a pill, can become effective in
inducing the reduction of a symptom if repeatedly
associated to an unconditioned stimulus, i.e. the
active principle contained in the pill.
Conditioned immune responses can be obtained
both in animals and in humans. For example,
Goebel et al (2002) showed that behavioral conditioning of immunosuppression is possible in humans.
Repeated associations between cyclosporine A and a
flavored drink induced conditioned immunosuppression in healthy male volunteers, in which the
flavored drink alone produced a suppression of the
immune functions. In the endocrine system, similar
effects can be found. The hypoglycemic effects of
insulin can be conditioned by pairing insulin with a
conditioned stimulus in animals and in humans,
and several other hormones, such as the growth
hormone and cortisol, can be conditioned as well
(Benedetti, 2008a, 2008b).
Several neuropharmacological and neuroimaging
studies investigated neither anxiety nor reward
mechanisms, making it impossible to state specifically whether the observed placebo responses were
attributable to a reduction in anxiety or to the activation of the reward circuitry. In all probability,
here too anxiety and/or reward mechanisms play a
role, depending on the experimental condition. In
any case, these studies have provided evidence that
a complex neural network is involved during the
placebo analgesic and the nocebo hyperalgesic
responses (for a detailed review, see Zubieta and
Stohler 2009; Tracey 2010).
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just when reduced connectivity of the prefrontal
lobes with the rest of the brain was present. The
loss of these placebo-related mechanisms reduced
the overall effectiveness of the treatment, and
indeed a dose increase was necessary to make up
for this loss in order to produce adequate analgesia.
According to this view, the impairment of prefrontal connectivity would reduce the communication between the prefrontal lobes and the rest of
the brain, so that no placebo and expectation
mechanisms would be triggered. In recent years
this notion has been supported by the deactivation
of the prefrontal cortex in the experimental setting.
On the basis of previous experiments on the blockade of placebo analgesia by the opioid antagonist
naloxone, Eippert et al (2009) conducted a study to
investigate the location of naloxone action in the
brain. By combining naloxone administration with
functional magnetic resonance imaging (fMRI),
these authors found that naloxone reduced placebo
effects as well as placebo-induced responses in the
dorsolateral prefrontal cortex and the rostral anterior
cingulate cortex. Therefore, as it occurs for prefrontal
degeneration in Alzheimer’s disease, placebo analgesic responses are disrupted by the pharmacological
blockade of prefrontal opioidergic functioning in the
experimental setting.
More complex forms of learning can be involved
in placebo responsiveness, whereby different cognitive factors play a crucial role. For example,
social learning is a form of learning, whereby individuals in a society learn from one another by
observation and imitation. Placebo effects may
involve social learning as well. In other words, the
mere observation of others responding to analgesics
may lead to robust placebo analgesic responses
(Colloca and Benedetti 2009).
G E N E T I C S
A central issue in placebo research is whether an
individual in whom a placebo works possesses one
or more specific characteristics, which can reliably
identify him a priori as a “placebo responder”,
with important implications for both clinical trials
design and personalized therapy optimization.
Results have so far been rather inconclusive, with
demographic, psychosocial, personality, and
behavioral variables all proposed to play a role, but
all inconsistently present across different trials.
Recently, however, some genetic variants have been
found that are particularly responsive to placebo
treatment. For example, there is some experimental
evidence that some genetic variants affect placebo
responses in psychiatric disorders, such as social anxiety (Furmark et al, 2008) and depression (Leuchter et
al, 2009). In social anxiety, it was found that the
reduced stress-related activity in the amygdala
which accompanied the placebo response could be
observed only in subjects who were homozygous
for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, but not in
carriers of short or T alleles. In depression, subjects with monoamine oxidase A G/T polymorphisms (rs 6323) coding for the highest activity
form of the enzyme (G or G/G) had a significantly
lower magnitude of placebo response than those
with other genotypes.
N O
P R E F R O N T A L
N O
P L A C E B O
C O N T R O L
Prefrontal degeneration in Alzheimer’s disease and
pharmacological blockade of prefrontal opioidergic
transmission are not the only conditions in which
placebo responses are disrupted. The inactivation of
the prefrontal cortex, particularly the dorsolateral
prefrontal cortex, by means of repetitive transcranial
magnetic stimulation (rTMS) has the same effect
(Krummenacher et al, 2010). Therefore, the inactivation of prefrontal regions by transcranial magnetic
stimulation has the same effects as those induced
by pharmacological blockade or prefrontal degeneration in Alzheimer’s disease. On the basis of all
these studies, a normal functioning of prefrontal
areas appears to be critical for placebo responsiveness. In the presence of a loss of prefrontal control,
we also witness a loss of placebo response.
,
R E S P O N S E
Benedetti et al (2006) studied Alzheimer patients at
the initial stage of the disease and after one year, in
order to see whether the placebo component of the
therapy (an ever-present part of the drug effect
which makes the overall outcome greater than that
produced purely by the intrinsic principle) was
affected by the disease. The placebo component of
the analgesic therapy was correlated with both cognitive status, as assessed by means of the Frontal
Assessment Battery (FAB) test, and functional connectivity among different brain regions, as assessed
by means of electroencephalographic connectivity
analysis. It was found that Alzheimer’s patients
with reduced FAB scores showed reduced placebo
component of an analgesic treatment. In addition,
the disruption of the placebo component occurred
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R E S E A R C H
D I R E C T I O N S
Despite the recent explosion of neurobiological
placebo research and the recent findings that help us
better understand both human biology and clinical
practice, several issues need further clarifications
and many questions still remain unanswered. First of
all we need to know where, when, and how placebos
work across different diseases and therapeutic interventions. Second, a better understanding of the contribution of different mechanisms, such as expectation, anxiety, reward, learning, genetics, in different
types of placebo responses is in order, and this
would surely help identify the social, psychological
and neurobiological determinants of the different
placebo effects. Third, we need to understand why
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FURMARK T., APPEL L., HENNINGSSON S., AHS F., FARIA
V., LINNMAN C., et al (2008). “A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety”,
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MS., FREDE S., et al (2002). “Behavioural conditioning of immunosuppression is possible in humans”,
in FASEB J 16: 1869-1873.
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AF.,
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some subjects respond to placebos, whereas other
subjects do not, a critical point that is likely to be
clarified by pursuing further research into both
learning and genetic mechanisms.
©
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293: 1164-1166.
EIPPERT F., BINGEL U., SCHOELL ED., YACUBIAN J.,
KLINGER R., LORENZ J., et al (2009). “Activation of
the opioidergic descending pain control system
underlies placebo analgesia” in Neuron 63: 533-43.
ENCK P., BENEDETTI F., SCHEDLOWSKI M. (2008). “New
insights into the placebo and nocebo responses”, in
Neuron 59: 195-206.
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8
THE ETHICAL IMPLICATIONS
OF
USING
PL ACEBO
IN
E D Z A R D
CLINICAL
PRACTICE
E R N S T
The subject of placebo is notoriously complex, and
discussions of this topic are often too abstract to
provide practical guidance. It might therefore be
helpful to focus on a concrete example: homeopathy.
The best evidence available to date strongly suggests that highly dilute homeopathic remedies are
pure placebos e.g.9,10. That is to
say, they are devoid of specific
A LT E R N AT I V E S
therapeutic effects. Yet it is undeniable that many physicians and
other healthcare professionals
regularly use homeopathy. Many
It takes
of them must be aware of the
evidence and employ it as a
a wise
“benign placebo” e.g.11. The question thus is whether this prevadoctor
lent behaviour can be ethically
justified.
to know
Edzard Ernst (1948, Wiesbaden, Gerg|
many) a British citizen since 1999, is
the first Professor of Complementary
Medicine in the world. He was born
and trained in Germany and began
his medical career at a homeopathic
hospital in Munich. In 1993, he left
his chair in Physical Medicine and
Rehabilitation (PMR) at the University
of Vienna to set up the department of
Complementary Medicine at the
University of Exeter & Plymouth,
UK. He became director of Complementary Medicine of the Peninsula
when
2 ~ A R G U M E N T S I N
Medical School (PMS) in 2002. He is
F A V O U R
the first occupant of the Laing chair
not to
in Complementary Medicine.
Physicians using placebos, such
Ernst is the editor-in-chief of two
as homeopathic medicines, in
prescribe.
medical journals, Perfusion and
clinical practice might claim do
Focus on Alternative and Compleso because they want to help
mentary Therapies. Ernst once conGRACIÁN
their patients via a beneficial
tributed a regular column to the
placebo effect4-6. Prescribing a
Guardian newspaper, frequently
highly
diluted homeopathic
reviewing news stories about complementary medicine from an evidenceremedy is, of course, unlikely to
based perspective.
have direct adverse effects. Many patients expect to
Since his research began on alternative modalities, Ernst
receive a prescription when consulting their doctor,
has become “the scourge of alternative medicine” for puband many believe in homeopathy, i.e. they are
lishing critical research that exposes methods that lack docuunaware of the evidence 9,10 and convinced that homementation of efficacy. Email: [email protected].
“
”
1
R
~
P R E V A L E N C E
O F
opathic remedies generate specific effects. Issuing a
prescription for a homeopathic remedy should
therefore be ethically commendable, particularly in
cases where no drug therapy is indicated 12.
U S E
E C E N T S U RV E Y D ATA F RO M S E V E R A L C O U N T R I E S
indicate that many clinicians use placebo
in their clinical practice 1,2,3,4,5,6,7,8, often on a
regular basis. Reasons for doing this
include:
~ to follow the wish of the patient;
~ to avoid conflict;
~ to calm the patient;
~ to comply with patients’ demand for receiving some sort of medications;
~ to prevent the patient complaining.
According to these data, prescribing placebos is
clearly considered to be ethically justifiable by a
large proportion of clinicians.
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~
A R G U M E N T S
A G A I N S T
At first glance this line of argument seems compelling.
However, several counter-arguments emerge, once
we scrutinize the issue in more depth.
3 . 1
~
M E R E
C O N V E N I E N C E
A critical analysis of the most frequent reasons for
placebo-use (see above) is revealing. The desire of
physicians to help their patients does not seem to be
a prominent factor. On the contrary, the reasons provided demonstrate that placebo-use is not altruistically
motivated but prompted mainly by convenience. It is
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9
the adherence to treatment and the clinical outcome14-17. Placebo-prescriptions cannot be used as
substitutes for acknowledging uncertainty, exploring
patients’ concerns, beliefs and preferences, considering non-pharmacological therapies and inviting
shared decision making18,19. These actions would be
consistent with the physician’s ethical responsibilities of non-maleficence, beneficence and respect for
patients without, at the same time, depending on
the deception of issuing a placebo.
quite simply easier for a doctor to write a prescription
for a placebo than to discuss with the patient that no
such prescription is required or no effective treatment
is available. The hope of avoiding conflict and the
desire to prevent a complaint are, of course, understandable motives, but they have little to do with the
physician’s duty to help patients. Physicians’ convenience, it would seem, is not a reason that is grounded in medical ethics.
3 . 2
~
D E C E I T
A N D
I N F O R M D
C O N S E N T
3 . 4
The prescription of placebos in clinical practice is
usually based on what might be called paternalistic
deception. Only a small proportion of clinicians
~
T H E R A P E U T I C
F O R
H A R M
Firstly, the placebo might be administered instead
of a treatment that has specific therapeutic effects.
Secondly, the placebo might not be free of adverse
effects. Homeopathic remedies, for instance are
unlikely to cause adverse effects, but other types of
placebos clearly do. For example, physicians often
use impure placebos, i.e. treatments that are
under-dosed or not indicated for a particular condition. A frequently prescribed impure placebo is an
antibiotic for a non-bacterial infection4,6. Such
impure placebos can cause serious, direct harm
through their pharmacological actions. Antibiotics
have a range of direct adverse effects and, can
harm the population at large through the development of bacterial resistance.
R E L A T I O N S H I P
3 . 5
Not telling the truth undermines trust which is an
essential ingredient of any therapeutic relationship.
A good therapeutic relationship can improve both
S P A N D A
P O T E N T I A L
Clinicians using placebos in routine practice should
consider at least two important risks of this approach.
would tell their patients the true nature of this
prescription 6. Without pretending that the homeopathic placebo is effective beyond placebo, doctors cannot expect their patients to experience a
clinically relevant placebo-effect. Truthfully telling
a patient that the prescribed remedy contains no
pharmacologically active ingredient would not
generate expectation of benefit. Thus little or no
placebo-response would result from telling the
truth. However, doctors would “violate the principle of respect for patient autonomy and contravene the legal and ethical requirement to obtain
informed consent”13, if they decided to deceive
patients, even if it were “for their own good”.
3 . 3
~
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M E D I C A L I Z A T I O N
Prescribing placebos for the types of self-limiting
complaint which placebos are most commonly
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10
5 NITZAN U., LICHTENBERG P. (2004). “Questionnaire
survey on use of placebo”, in BMJ 329: 944-946.
6 SHERMAN R, HICKNER J. (2008). “Academic physi-
prescribed for will almost inevitably result in the
medicalization of common states of reduced wellbeing. Such conditions are best treated by re-assurance and honesty. Prescribing a placebo in such
situations would simply reinforce the belief that
there is ‘a pill for every ill’. This would be neither
honest nor helpful. Braillon therefore stressed that
“a placebo is a dangerous tool” because it encourages “disease-mongering” 20.
3 . 6
~
P L A C E B O S
F O R
F O R
A R E
N O T
N E E D E D
G E N E R A T I N G
P L A C E B O
-
cians use placebos in clinical practice and believe in
the mind-body connection”, in J Gen Intern Med
23(1): 7-10.
7 TILBURT JC., EMANUEL EJ., KAPTCHUK TJ., CURLIN
FA., MILLER FG., (2008). “Prescribing ‘placebo treatments’: results of national survey of US internists and
rheumatologists”, in BMJ 337: a1938.
8 FÄSSLER M., GNÄDINGER M., ROSEMANN T., BILLERANDORNO N. (2009). “Use of placebo interventions
among Swiss primary care providers”, in BMC Health
Services Research 9: 144-152.
9 ERNST E. (2010). “Homeopathy: what does the ‘best’
evidence tell us?”, in MJA 192: 458-460.
10 SHANG A., HUWILER-MUNTENER K., NARTEY L., JUNI
P., DORIG S., STERNE JA. ET AL., (2005). “Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy”, in Lancet 366: 726-732.
11 DU Y., KNOPF H. (2009). “Paediatric homeopathy in
Germany: results of the German Health Interview
and Examination Survey for Children and Adolescents (KiGGS)”, in Pharmacoepidemiol and Drug
Safety 18: 370-379.
12 JÜTTE R., HOPPE J-D., SCIRBA P. (2010). “Stellungnahme des Wissenschaftlichen Beirats der Bundesärztekammer ‘Placebo in der Medizin’”, in
Deutsches Ärzteblatt 107(28-29): 1417-1421.
13 MILLER FG., COLLOCA L. (2009). “The legitimacy of
placebo treatments in clinical practice: evidence and
ethics”, in Am J Bioethics 9(12): 39-47.
14 STEWART MA. (1995). “Effective physician-patient
communication and health outcomes: A review”, in
CMAJ 152: 1423-1433.
15 ONG LM., DE HAES JC., HOOS AM. (1995). “Doctorpatient communication: a review of the literature”,
in Soc Sci Med 40: 903-918.
16 DIMATTEO MR. (2004). “‘Variations in patients’
adherence to medical recommendations: a quantitative review of 50 years of research”, in Med Care 42:
200-209.
17 HASKARD ZOLNIEREK KB., ROBIN DIMATTEO M.
(2009). “Physician communication and patient adherence to treatment. A meta-analysis”, in Med Care
47(8): 826-234.
18 SCHENKER Y., FERNANDEZ A., LO B. (2009). “Placebo prescriptions are missed opportunities for doctor-patient communication”, in Am J Bioethics 9(12):
48-54.
19 HROBJARTSSON A. (2008). “Clinical placebo interventions are unethical, unnecessary, and unprofessional”, in J Clin Ethics 19: 66-69.
20 BRAILLON A. (2009). “Placebo is far from benign: it is
disease-mongering”, in Am J Bioethics 9(12): 36-38.
21 CROW R., GAGE H., HAMPSON S., HART J., KIMBER
A., THOMAS H. (1999). “The role of expectancies in
the placebo effect and their use in the delivery of
health care: A systematic review”, in Health Technol
Assess 3(3): 1-97.
A
R E S P O N S E
In the vast majority of situations, effective treatments with proven effects beyond placebo are available – they may only be symptomatic rather than
curative but they are helpful nevertheless. If, in
such cases, we want to increase patient benefit
through maximising placebo-effects, we should
realize that the sympathetic and empathetic administration of any therapy would result in a placeboeffect, in addition to the specific effect of the prescribed therapy, particularly if expectancy is maximized 21. Thus prescribing a homeopathic remedy
to generate a placebo-effect is usually not only
unnecessary, it would also deprive the patient of
the specific effect of that treatment. This would
clearly not be ethical.
4
~
C O N C L U S I O N
The prescription of placebos in clinical practice
creates an ethical dilemma. On the one hand, clinicians might want to ease the suffering of their
patients. On the other hand, this approach violates
important ethical principles. The solution is to
analyse this behaviour (self ) critically. Once we do
this, we are likely to find that much of such placebo-prescribing serves the convenience of clinicians
rather than the welfare of the patient. Where possible, it should be avoided and replaced with more
ethical and professional behaviour.
©
R E F E R E N C E S
1 BERTHELOT JM., MAUGARS Y., ABGRALL M., PROST
A. (2001) . “Interindividual variations in beliefs
about the placebo effect: a study in 300 rheumatology inpatients and 100 nurses”, in Joint Bone Spine
68(1): 65-70.
2 NORHEIM AJ., FONNEBO V. (2002). “Attitudes to the
contribution of placebo in acupuncture - A survey”,
in Complementar Ther Med; 10(4): 202-209.
3 LIM EC., SEET RC. (2003). “Attitudes of medical students to placebo therapy”, in Intern Med J 37(3):
156-160.
4 HROBJARTSSON A., NORUP M. (2003). “The use of
placebo interventions in medical practice - a national questionnaire survey of Danish clinicians”, in
Evaluation & the Health Professions 26(2): 153-165.
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11
ALL IN THE MIND?
PAIN , PLACEBO EFFECT, AND ERGOGENIC EFFECT OF CAFFEINE IN SPORT PERFORMANCE
C H R I S T O P H E R
J
.
B E E D I E
experimental findings and the anecdotal reports of
athletes 5,11. Furthermore, caffeine-induced pain
reduction could explain, in part, both biologic and
placebo effects of caffeine on performance. Such a
pain hypothesis is supported by a number of factors. Firstly, caffeine has well documented hypoalgesic or pain-reducing properties12, secondly, pain is a limitSenior Lecturer/Programme Director,
ing factor on performance 13,
g| CHALLENGES
Canterbury Christ Church University,
thirdly, pain is highly placebo
Canterbury, UK. Email: christoresponsive 14 , and lastly, the
A man
[email protected]
sports in which ergogenic
effects of caffeine have been
who is
I N T R O D U C T I O N
observed tend to be those in
which athletes experience sub‘of
sound
mind’
H E E RG O G E N I C E F F E C T S O F
stantial levels of sustained pain
caffeine on sports perwithout the relief of regular
is
one
who
formance are well docdisruption of activity associated
1
umented . Although
with stop-go or interactive
keeps
the
these effects have been
sports. Given that pain is also
observed in a wide variety of
highly socially modifiable and
inner
madman
sports, they are generally more
context-dependent 14, a pain
evident in endurance and sushypothesis might explain the
under lock
tained high-intensity closed skill
interindividual variability in
sports than in interactive and
caffeine response observed in
and
key.
2
stop-go sports . The ergogenic
sport research 15. The present
effects of caffeine can be obtained
paper aims to examine the
at doses at or below the daily
PAUL VALÉRY
potential influence of psychoso3
intake of normal populations ,
cial factors in the ergogenic
and below levels representing
effect of caffeine in the context
health risks. Caffeine is not curof caffeine-induced pain reduction. The article will
rently proscribed by the World Anti-Doping Agency.
review selected findings demonstrating placebo
Several mechanisms for the ergogenic effects of cafeffects of caffeine on sports performance, hypoalfeine have been proposed, including enhanced fat
gesic effects of caffeine on sports performance, and
oxidation, sympathetic nervous system enhanceplacebo effects on pain in experimental and clinical
ment, reduction in central fatigue, attenuation of
medicine. It will also briefly discuss implications
neuromuscular conduction block, and potentiation
for research.
of muscular force output for given input4. These
mechanisms are not consistently supported by
P L A C E B O E F F E C T S O F C A F F E I N E O N
research evidence, eg, Graham et al concluded that
S P O R T P E R F O R M A N C E
there is very little evidence to support the fat oxida1
tion theory , whilst Tarnopolsky suggested there is
Placebo effects of caffeine on sports performance
no evidence for caffeine-induced changes in periphhave been reported in three recent experimental
eral nerve conduction or neuromuscular transmisstudies. Beedie et al examined the possibility of a
sion4. The lack of consistent support for any one
dose-response relationship to placebos presented as
physiologic mechanism, and the fact that an increas“zero”, “low”, and “high” dose caffeine among seven
ing number of studies in sport and elsewhere have
well-trained competitive cyclists5. Measures were
demonstrated significant and substantial placebo
power, heart rate, oxygen uptake, and blood lactate.
effects of caffeine5,10, suggests that psychologic factors
Following habituation and baseline trials, subjects
might play a significant role in caffeine effects.
were informed that, over three experimental trials,
they would receive a placebo, or 4.5 mg/kg or 9.0
Perhaps the obvious psychologic factor to consider
mg/kg
caffeine double-blind and randomly
is pain. The proposal that caffeine ingestion
assigned.
However, a biologically inert placebo was
reduces pain in performance is supported by both
“
T
”
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influence on performance in the absence of caffeine.
A possibly harmful negative placebo (nocebo) effect
relative to baseline was present when subjects were
correctly informed that they had ingested no caffeine (-1.9% ± 2.2%). No substantial changes relative
to baseline were observed in mean heart rate,
although clear and substantial increases in blood
lactate were evident following the receipt of caffeine. The within-subject CV for power in deceptive
conditions at 2.8% was 1.7 times larger than the CV
when subjects were truthfully informed that they
were receiving caffeine, indicating the possibility of
some disparity between internal sensations and
instructions amongst some subjects. The authors
suggested that their data supported the ergogenic
efficacy of caffeine, but noted that in the absence of
caffeine, the negative effect on performance of negative expectation was somewhat more substantial
than the positive effect of positive expectation (a
finding that could inflate effect sizes in placebo-controlled studies).
administered in all experimental conditions. Postexperimental baseline trials were also conducted. A
dose-response relationship was evident in experimental trials, with subjects producing 1.4% (range, -4.6%1.9%) less power than baseline when they believed
they had ingested a placebo, 1.3% (-1.4%-4.1%) more
power than at baseline when they believed they had
ingested 4.5 mg/kg caffeine, and 3.1% (0.4%-6.7%)
more power than at baseline when they believed
they had ingested 9.0 mg/kg caffeine. Of further
interest was the fact that no substantial differences
in any measured physiologic variables between baseline and experimental conditions were observed.
Follow-up interviews with each subject indicated
that five subjects believed that they had experienced
a placebo effect, proposing mechanisms such as pain
reduction, fatigue resistance, changes in strategy, and
reduced arousal.
Pollo et al investigated the effects of a caffeine
placebo on quadriceps muscle performance and
perceived fatigue6. Forty-four recreationally active
males were divided into four groups, ie, two control and two placebo (n=11 each). In the first experiment, a placebo was deceptively administered,
with the suggestion that it was a high dose of caffeine. This resulted in a significant increase in mean
muscle work (11.8%-16.1%, P< 0.01) but no perceived decrease in muscle fatigue (P> 0.05). In the
second experiment, placebo caffeine administration was accompanied by a conditioning procedure whereby the weight to be lifted was surreptitiously reduced.The load was then restored to the
original weight and placebo caffeine administered
again. Compared with the first experiment, the
placebo effect was larger, with a significant increase
in muscle work ( 22 . 1%-23 . 5% , P< 0 . 01 ) and a
decrease in perceived muscle fatigue (-7.8-10.1, P<
0.01). The authors suggested that their findings
indicated a central mechanism of topdown modulation of the global performance of muscles by
placebo and underscore the role of learning in the
placebo response.
Foad et al used the balanced placebo design with 14
well-trained competitive cyclists in a study examining the effects of caffeine and placebo on 40 km laboratory cycling performance7. Subjects performed
two 40 km time trials in each of four experimental
conditions (informed caffeine/received caffeine,
informed no-treatment/received caffeine, informed
caffeine/received placebo, and informed no-treatment/received no treatment). Measures were power,
oxygen uptake, blood lactate, and heart rate. The
authors reported a very likely beneficial main effect on
mean power of receiving caffeine (3.5% ± 2.0%), and a
possibly beneficial main effect of being informed of
caffeine (0.7% ± 1.4%). A substantial interaction
between belief and pharmacology (2.6% ± 3.3%)
indicated that caffeine exerted a greater effect on
performance when subjects were informed that they
had not ingested it, while belief exerted a greater
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Evidence for placebo effects associated with caffeine has also been provided elsewhere 8-10. It is evident from these findings that whilst caffeine ingestion often exerts an influence on behavior, so too
can beliefs about caffeine, and about whether or
not caffeine has been ingested. These findings beg
several questions as to the likely ergogenic mechanisms of caffeine and suggest a significant psychologic contribution.
H Y P O A L G E S I C
I N
E F F E C T S
S P O R T S
O F
C A F F E I N E
P E R F O R M A N C E
As suggested above, perhaps the most likely psychologic contribution would be pain reduction. There
is a large body of evidence attesting to the hypoalgesic properties of caffeine in both medicine16 and
physical activity5,12,17,18. Consistent with this are data
demonstrating that subjects’ ratings of perceived
exertion are lower when given caffeine19. Pain is a
highly complex biopsychologic phenomenon, and
even a brief overview of theories and potential
mechanisms is well beyond the scope of this paper.
It is reasonable to suggest that whilst pain is certainly
not a necessary condition of sports performance,
athletes in endurance and sustained short-duration
sports routinely experience pain in competition.
Many will experience pain with little respite for a
substantial part, if not for the entirety, of their event
(as stated above, it is in such sports that caffeine’s
ergogenic efficacy has been most widely demonstrated, lending further weight to the pain hypothesis).
Gliottoni et al state that there is an expanding body
of evidence that acute exercise is a natural stimulus
that might transiently, safely, and reliably produce
muscle pain12, whilst Cook et al suggest that not
only are descriptors used to describe pain during
exercise similar to those that have been used to
characterize clinical pain conditions20, but that pain
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13
ratings during exercise as measured by the short
form of the McGill Pain Questionnaire are nearly
one standard deviation above the mean scores associated with other laboratory methods of inducing
pain21. Research has suggested that ingestion of caffeine significantly reduces the pain response during
performance12,17,18,22,23. O’Connor et al reported that
caffeine ingestion has a dose-response effect on
reducing leg muscle pain during exercise22. Motl et al
reported that leg muscle pain ratings were significantly and moderately reduced after a high dose (10
mg/kg body weight) of caffeine18. Maridakis et al
reported that caffeine produced a large and statistically significant hypoalgesia effect during maximal
quadriceps contraction23. Gliottoni and Motl reported
that caffeine administration resulted in a large reduction in leg muscle pain intensity ratings17. Gliottoni
et al reported that caffeine ingestion is associated
with a moderate hypoalgesic effect during highintensity cycling12. Theoretically, any intervention
that reduces perceived exertion or pain should also
increase the perceived headroom for effort, and
therefore has the potential to enhance performance.
A hypoalgesic effect driven by caffeine could be
direct, ie, the action of caffeine attenuates the perception of pain. Indirectly, caffeine actions could
influence other biologic processes that attenuate the
pain response. The effect could also result from both
direct and indirect processes simultaneously.
Whichever way, and significantly for the present discussion, the large body of research in medicine and
psychology demonstrating substantial placebo effects
on pain could shed some light on the placebo effects
related to caffeine and sports performance.
P S Y C H O L O G I C A L
M O D U L A T I O N
O F
Montgomery and Kirsch exposed subjects to experimental pain at baseline, and in subsequent trials
surreptitiously reduced the pain stimulus whilst a
placebo analgesic cream was administered (the latter process designed to lead subjects to believe that
the cream had reduced the pain)24. Subjects were
then split into two groups, the first was correctly
informed about the deception, and the second was
not informed. On re-exposure to the pain at baseline level, subjects who had been correctly informed
of the deception experienced no pain relief when
the placebo analgesia cream was applied, whilst
those in the second group reported substantially
lower pain. The authors also assessed subjects’ expectation of analgesia, and reported that this accounted
for 49% of the observed effects. The authors concluded that an analgesic response can be conditioned, but that the conditioned response might be
either reversed or suppressed by correct information
or negative expectation respectively.
Levine et al administered active painkillers covertly
and placebo painkillers openly to two groups of
subjects following dental surgery25,26. They reported
that the overt injection of a saline placebo described
as morphine was as effective as a covert injection of
morphine. Similarly, Benedetti et al compared the
open administration of five different painkillers with
the hidden and automated administration of the
same drugs 27,29. The authors reported that in hidden
administration conditions the time taken for postoperative pain to diminish by 50% was greatly increased
for all drugs compared with open administration.
These findings suggest that anticipation of analgesia
is a factor in perceived analgesia.
Pollo et al treated postoperative patients with a
painkiller on request for three consecutive days, as
well as with a saline placebo (patients were given the
intravenous saline as a background infusion in addition to the routine analgesic treatment)30. Subjects
were divided into three groups, the first being told
nothing about the saline, the second that they had a
50:50 chance of receiving the painkiller or a placebo,
and the third that the saline solution was a potent
painkiller (these three conditions forming, respectively, natural history, double-blind, and deceptive
administration groups). The authors reported that,
compared with the natural history group, a 20%
decrease in requests for analgesia was observed in
the double-blind group, and a 34% decrease in
requests was observed in the deceptive administration group. The authors concluded that instructions
that induce a certain expectation of analgesia induce
greater placebo analgesia than those that induce
uncertain expectation, a finding subsequently supported in a meta-analysis of 14 similar studies31.
P A I N
Pain is highly susceptible to social and psychologic
modulation14, and perhaps because of this, over the
last few years, pain has become one of the most
fruitful areas of research into mind/body interaction. In short, evidence from such research demonstrates that expectation of pain relief can modify
the subsequent effectiveness of administered substances, be they active analgesics, such as morphine, or inactive placebos. These effects can be
both hypoalgesic and hyperalgesic. Several complex
designs have been used to elucidate this phenomenon, ranging from covert manipulation of experimental pain stimuli, to direct comparison of the
effects of the hidden/deceptive administration of
biologically active treatments with the overt administration of biologically inactive substances. Studies
using such designs are informative in demonstrating the degree to which pain can be modified by
psychosocial processes, such as conditioning and
expectation. On that basis, they are of interest to
those investigating or using interventions in which
pain reduction might be a factor in their efficacy.
Some illustrative examples of such studies are
briefly described below.
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In an interesting twist on their open-versus-hidden
administration design above, Benedetti et al used openversus-hidden interruption of morphine treatment in
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were replicated several times in both experimental
and clini-calsettings. At the University of Turin,
Benedetti et al further demonstrated that as well as
the opioids, cholecystokinin, a neurotransmitter
with an antiopioid action, plays a role in both
placebo analgesia35 and nocebo hyperalgesia32. Subsequent research has demonstrated, for example,
placebo-induced activation of brain areas involved
in the pain response36, placebo-induced deactivation of brain areas involved in pain processing37,
and correlations between the magnitude of placebo
analgesia and dopamine activity38.
postoperative patients2 8 , 2 9 . The authors reported that
patients who were aware that their treatment had been
discontinued were more likely to request further morphine than those who were unaware that their treatment had been interrupted. Similarly, Benedetti et al
demonstrated pain increases associated with the administration of a placebo expected to increase pain in both
clinical 32 and experimental patients33. The authors concluded that, in the same way that positive expectations
of pain relief might induce or enhance actual pain relief,
negative expectations might have the opposite effect.
E V I D E N C E
O F
F O R
P L A C E B O
B I O L O G I C A L
A N D
O N
N O C E B O
In a study of the placebo analgesia mechanism
related to sports performance, Benedetti et al investigated the placebo analgesic effects of morphine
on a pain endurance test39. Subjects had a tourniquet wrapped around their forearm and were
required to squeeze a hand spring exerciser repeatedly until they could no longer continue. During
precompetition training, two “teams”, A and B,
received no pharmacologic substance whilst teams
C and D were trained with morphine. During competition, team A received no treatment while teams
B and C were given placebo morphine one hour
before competition. Team D also received what they
believed was morphine, but they actually received
naloxone (which would be expected to antagonize
the opioid pathways). As hypothesized, the largest
placebo effect on pain tolerance was observed in
team C who received both the morphine preconditioning in the “training” trials and also believed
they had ingested morphine in the competition trials. In team D, who had received morphine in preconditioning trials, naloxone negated the morphine
M E C H A N I S M
E F F E C T S
P A I N
Whilst early research into the psychosocial modulation of pain tended to focus on demonstrating the
effect and speculating as to mechanisms, recent
research has gone beyond this to investigating
mechanisms in real time using technology such as
positron emission tomography and magnetic resonance imaging. A classic experimental model is the
administration of an agent known to antagonize
the pathway that an administered placebo analgesic
purports to mimic. For example, naloxone antagonizes the action of opiates such as morphine.
Therefore, naloxone would also be expected to
antagonize placebo analgesia if the same mechanisms as for morphine were responsible. In the first
study of its kind, Levine et al demonstrated that
naloxone did in fact disrupt placebo analgesia, concluding, logically, that the endogenous opioids are
involved in the placebo response34. These findings
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psychologic factors are rarely considered legitimate
variables in experimental research. This is despite the
growing experimental evidence for placebo effects on
sports performance. Whilst this literature is reviewed
elsewhere43, it suffices to state that placebo effects on
sports performance resulting from the belief that an
ergogenic substance had been ingested have been
reported in 12 well-controlled studies5-7,39-43-50. Most
of these effects were in the range of 1%-5%. In three
studies, nocebo (or negative placebo) effects were
observed as the result of subjects either being given
negative information about an intervention44, having previous negative experience with caffeine5, or
for reasons that were not entirely clear12. Many of the
positive effects were similar in magnitude to the
effects of the substance that the placebo mimicked.
In the few studies in which the biologically active
substance was administered alongside the placebo, as
is the case in the traditional placebo-controlled study,
results were arguably not as easily interpretable as
those in which placebos only were administered. This
suggests that the interaction of belief and biology in
real time, or that order effects in which subjects
were able to detect the presence or otherwise of the
active substance, might have created tension between
information (e.g. “Today you have been given a
placebo”) and perception (e.g. “I’m sure this feels
like I have been given caffeine”). This finding in
itself warrants further investigation. Whilst knowledge that placebos might be powerful in the absence
of the biologically active substance they mimic,
such an application is rare in the real world which
scientific research aims to inform.
preconditioning effects. These findings suggest
conditioned activation of endogenous opioids after
placebo administration, although a correlation
between morphine and placebo suggests the possible
contribution of nonopioid mechanisms. It is noteworthy that the placebo analgesic responses were
obtained after only two morphine administrations
separated by as much as a week. These long time
intervals suggest that pharmacologic conditioning
procedures have long-lasting effects (with implications for the use of proscribed drugs in training
and competition).
Collectively, the findings above and many others
suggest not only that placebo effects have biologic
mechanisms, but that these mechanisms may be
similar or identical to those of the drug the placebo
mimics. Given this, and given the reduced ratings
of perceived exertion/pain observed in both caffeine
and placebo caffeine research, it is reasonable to
speculate that pain reduction might be one mechanism by which both the biologic and placebo effects
of caffeine on sports performance operate.
I M P L I C A T I O N S
It is proposed above that pain might be a factor in
the observed ergogenic effect of both caffeine and
placebo caffeine on sports performance. This proposal was supported by a brief review of research
that has demonstrated the placebo effects of caffeine
on sports performance, the hypoalgesic effects of
caffeine in exercise, and the psychosocial modulation of pain responses. It is suggested that if pain
reduction is a key factor in the ergogenic effect of
caffeine, the findings of the latter body of research
will be instrumental in elucidating mechanisms and
explaining interindividual variability to response to
caffeine. Specifically, these findings suggest that: an
analgesic response can be conditioned and that the
conditioned response might be either reversed or
suppressed by correct information or negative
expectation, respectively; that expectation of analgesia is a factor in perceived analgesia; that instructions that induce a certain expectation of analgesia
induce greater analgesia than those that induce an
uncertain expectation; and that negative expectations of analgesia associated with an analgesic
intervention might offset some of the effectiveness
of that intervention. If pain is indeed a factor in
the ergogenic effect of caffeine, all of these findings are of interest to researchers investigating the
phenomenon.
M O D I F Y I N G
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T O
B E T T E R
Burke, in reviewing the caffeine and performance
literature, argued strongly for more ecologically
valid investigations of the phenomenon2. It is fair
to argue that, in order to understand any intervention fully, it is necessary to determine how it operates in the real world, outside of the laboratory.
However, there are many aspects of the ergogenic
effect of caffeine that can be examined in the laboratory, one of which is the contribution or otherwise of psychologic factors. The degree to which the
brain is capable of modulating the biologic effect of
an intervention, be that modulation trivial, as is
likely the case with a strong poison, or substantial,
as has been suggested is the case with several complementary medicine treatments, is still little
explored in sports performance. Biomedical research
is increasingly utilizing sophisticated and elegant
designs to investigate this area, and in doing so, is
providing a firm biologic basis for what were previously perceived as purely psychologic phenomena.
The differences between the laboratory and the field
and between research and competition are critical factors. Arguably as important, however, are differences
Beyond these findings, evidence from over fifty years
of scientific research indicates that when a person
receives any of a number of biomedical interventions, ranging from tablet to surgery, the brain
might play a role in modulating the effectiveness of
that intervention14,40-42. Whilst this fact is recognized
by sports scientists, and is accounted for in our use
of the placebo-controlled experimental design, such
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between the subjects’ certainty of having received an
intervention or of not having done so, or between
their lack of faith in an intervention or extreme
confidence in the same intervention. Burke also highlighted the interindividual variability in response to
caffeine ingestion in performance research2. Much of
this variability is likely the result of factors such as
habituation, diet, training status, and available
physiologic resources. The research described above
suggests that, if pain reduction is indeed a mechanism of the ergogenic effects of caffeine, several
psychosocial factors might also modulate the
ergogenic effects of caffeine. It has been suggested
that some athletes are nonresponsive to caffeine. It
even in the absence of caffeine. In this respect it is
also useful to evaluate whether a subject believes
they were given caffeine or placebo in any one trial.
Several recent studies have demonstrated that subjects who believed themselves to be in placebo control or no-treatment conditions performed below
baseline, suggesting a potentially powerful nocebo
effect. Such an effect is perhaps associated with the
hope/anticipation of a positive intervention being
replaced by the disappointment/anxiety of no intervention. It is important to distinguish between controlling for current use of, or habituation to, caffeine and for previous use. Whilst the physiologic
effects of caffeine might be extinct after a few days,
is, however, possible that if caffeine responses are
context-dependent, an athlete who would not
respond to caffeine in one context, for example, with
no explicit expectation of effect, might respond in
another context when given an explicit expectation
or when exposed to a conditioning stimulus with
false-positive performance outcome feedback. These
factors are largely related to the subject’s expectations, or conditioned responses, to the caffeine
intervention, and these themselves are dependent
on either previous experience or currently available
information. Therefore, to understand better the
effects of caffeine on performance, these psychosocial factors should be treated as variables of interest
in caffeine research. Previous experiences of caffeine
could be assessed, and in doing so, several aspects of
the caffeine experience, including whether the previous intervention had a positive or negative effect on
performance, or whether it was associated with any
side effects, such as nausea or insomnia, could be
factored in. It is also useful to evaluate the subjects’
expectations of caffeine. As was demonstrated by
Beedie et al 5, expectations of a negative effect can
result in a substantial nocebo effect on performance,
conditioned responses, expectations, or both, might
persist for several years or even indefinitely.
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The suggestion that caffeine’s mechanisms might
relate in part to psychologic factors is intuitively
appealing, especially when considering the multiple
feedback loops between brain and body during performance. However, to date, little research in sport
has examined, or even considered, such biologic and
psychologic interactions in this context. This is not
surprising, given the complex links between perception of effort and pain and the biologic reality at that
exact point in time. However, if sports scientists are
to understand fully the mechanisms of interventions,
such questions must, at the very least, be asked, if
not immediately or easily answered. A substantial
body of biomedical research has demonstrated that
brain and body interact in response to the administration of a substance about which the subject has
some expectation, be that expectation positive or
negative. This is of course the case when an athlete
uses caffeine, ie, the athlete has some expectation of
an effect. Given the failure to definitively support
several longstanding theories of caffeine’s ergogenic
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17 GLIOTTONI RC., MOTL RW. (2008). “Effect of caf-
effects described by Tarnopolsky above4, and the
increasing database of studies attesting to the potential psychologic contribution to the action of
ergogenic aids in sports performance42, it is perhaps
timely to investigate the pain hypothesis, and consider psychosocial variables that might modulate the
pain response, in future caffeine and performance
research.
©
18
19
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20
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39
40
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43
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ACE fitness matters”, available from http://www.acefitness.org/getfit/PlaceboStudy2006.pdf [Accessed
December 5, 2006].
ab
ab
Now, my tongue, the mistery telling
Of the glorious Body sing.
THOMAS AQUINAS ,
Pange Lingua Gloriosi.
ab
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THE STING
O F P O T E N T I A L PA I N
K U R T
G R A Y
~
D A N I E L
M
.
W E G N E R
reduction of pain without a change in physical
stimulation when context, expectations, or sugar
pills challenge the interpretation of a sensation as
painful (e.g., Fields, 2008). The nocebo effect, in turn,
is the experience of pain without any physical stimulation – as when participants report headaches when
told that a (nonexistent) electric
current is passing through their
P
R
O
P
O
S
A
L
heads (Schweiger & Parducci,
|
g
Kurt Gray is Assistant Professor at
1981). These variations in pain
Department of Psychology, University
experience seem to depend on
of Maryland, US. Email: kurtgraythe meaning of the stimulus: A
@umd.edu.
Old age
sugar pill is meant to decrease
Daniel M. Wegner is a social psycholpain, whereas electric current is
ogist, John Lindsley Professor in Memmeant to increase pain. In an
is the most
ory at William James Department of
interpersonal context, the meanPsychology, Harvard University, US,
ing of an action is derived from
and a fellow of the American Associaunexpected
the perceiver’s perceptions of
tion for the Advancement of Science.
He is known for his work on mental
the actor’s intention (Clark,
of all things
control (e.g., thought suppression)
1996), which means that intenand conscious will, and for originattional harms, unlike accidental
ing the study of transactive memory
harms, are meant to cause pain.
that happen
and action identification. His book,
The possibility that the maliThe Illusion of Conscious Will,
cious intent of other people
to man.
tackles the long-debated notion of free
could be translated into addiwill through the scope of experimenLEV TROTSKY
tional physical pain is suggested
tal psychology. Wegner's ideas have
by studies demonstrating that
sparked interest among psychologists,
similar areas of cortex respond
neuroscientists, theologians, and
to both physical pain and social
philosopher interested in the nature of
harms (Eisenberger, Lieberman,
consciousness and freedom of action.
& Williams, 2003). Social harms, which are presumably laden with intention, have also been shown
H E N S O M E O N E S T E P S O N YO U R TO E O N P U R P O S E ,
to be more painful to relive than simple physical
it seems to hurt more than when the perharms (Chen, Williams, Fitness, & Newton, 2008).
son does the same thing unintentionally.
So, although a broken toe (or electric shock) may
hurt, an intentionally broken toe (or electric shock)
The physical parameters of the harm may
should hurt more.
not differ – your toe is attened in both
cases – but the psychological experience of pain is
changed nonetheless. Intentional harms are preM E T H O D
meditated by another person and have the specific
purpose of causing pain. In a sense, intended
Forty-eight participants (68% female, 32% male)
harms are events initiated by one mind to commuparticipated in a lab study of ‘‘psychophysical pernicate meaning (malice) to another, and this could
ception in pairs.’’ Four participants were excluded
shape the recipient’s experience. This study examfor suspicion and one participant was excluded for
ined whether self-reported pain is indeed higher
failing to follow instructions, leaving a total of 43.
when the events producing the pain are underOn arrival, participants met their study partner – a
stood as intentionally (as opposed to unintentionconfederate – and were escorted to an individual
ally) caused by another person.
room. They were then introduced to the psychophysical tasks of color matching, number estimaAlthough pain was traditionally conceived to be
tion, pitch judgment, and discomfort assessment,
solely physical in nature (Aydede, 2005), its experieach of which they completed. Discomfort assessence varies substantially with psychological context.
ment involved being administered an electric shock
The placebo analgesia effect, for example, is the
“
”
W
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and evaluating it on a 7-point scale ranging from not
at all uncomfortable to extremely uncomfortable.
Shocks of 1-ms duration were delivered to the wrist
of the dominant hand through a stimulator (Biopac
Systems, Goleta, CA), with voltage precalibrated for
each participant to be ‘‘very uncomfortable.’’ Voltages ranged from 40 to 75V between subjects. Participants evaluated two blocks of computer-administered electric shocks initially in an individual practice session as a baseline pain measure.
On each experimental trial, participants saw a computer screen with two potential tasks before completing one of them. When discomfort assessment
electric shock and also reinforced the intentional or
unintentional nature of the shock. Pilot testing confirmed that shocks were perceived (on a 7-point
scale) as more intentional in the intentional conditional (M=5 5.64, SD=1.49) than in the unintentional
condition ( M=2 . 17 , SD=0 . 83 ), t( 24 )= 7 . 13 , p<. 01 ,
Prep=.99, and that the confederate was seen as more
blameworthy (on a 5-point scale) in the intentional
condition (M=2.43, SD=1.40) than in the unintentional condition (M=1.41, SD=0.67), t(24)=2.29, p<.03,
Prep=.91. In both conditions, participants completed
three blocks of experimental trials after the two
practice/baseline trials.
INTENTIONAL ELECTRIC SHOCK
UNITENTIONAL ELECTRIC SHOCK
EXPERIENCED PAIN
4
3
BLOCK 1
BLOCK 2
BLOCK 3
BASELINE/PRACTICE TRIALS
BLOCK 4
BLOCK 5
EXPERIMENTAL TRIALS
TIME
FIGURE
1 ~ Experienced pain as a function of whether electric shocks were perceived as intentional or unintentional.
was a potential task, the alternate task was evaluating the relative pitches of tones. On this and other
trials, participants were told that the participant in
the next room (the confederate) would select which
task the participant would complete.
In the intentional condition, the confederate chose
the discomfort-assessment task when it was an
option, and participants received an electric shock.
In the unintentional condition, the confederate
selected the pitch-judgment task when discomfort
assessment was an option. In this condition, however,
participants were told that the mapping between the
selection and administration of tasks was switched,
unbeknownst to the confederate, so they would
always receive the task opposite to the one selected
by the confederate. Thus, when pitch judgment was
selected for them, they completed discomfort assessment and received an electric shock.
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Mean pain ratings from shocks in each of the 5
blocks (see FIGURE 1) were submitted to a 2 (condition: intentional; unintentional) x 5 (time: block
number) between-within analysis of variance, which
revealed the predicted interaction, F(4, 164)=3.09,
p=.02, Prep=.93, π2=.07. A composite of the two practice blocks revealed no significant difference in
experienced pain between conditions (t<1); however,
an average of experienced pain in the three experimental blocks revealed that intended pain (M=3.62,
SD=0. 99) was experienced as more painful than
unintended pain ( M=3 . 00 , SD=0 . 78 ), t( 41 )= 2 . 21 ,
p=.03, Prep=.91.
Additionally, there was a significant decreasing linear trend of experienced pain in the unintentional
condition, F (1,17)=20.18, p=.001, Prep=.99, suggesting that participants in this condition exhibited the
standard pattern of habituation to repeated painful
stimulation (Greffrath, Baumgartner, & Treede,
2007). In contrast, there was no linear trend in the
On their computer screen, participants saw both
the confederate choice and the actual task to be
administered (in advance), which ensured that participants were not surprised when they received an
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FIELDS, H.S. (2008). Pain: Mechanisms and management
(2nd ed.) (New York: McGraw-Hill).
GREFFRATH, W., BAUMGARTNER, U., & TREEDE, R-D.
(2007). “Peripheral and central components of habituation to heat pain perception and evoked potentials
in humans”, in Pain 132,
301-311.
S CHWEIGER , A., & PAR DUCCI , A. (1981). “Nocebo: The psychologic induction of pain”, in Pavlovian
Journal of Biological Science
16, 140-143.
intentional condition, F=0.08, suggesting that participants in this condition continued to feel the fresh
pain of an intentional harm as time went on.
This study provides evidence that the experience
of pain changes depending upon the psychological context in which people are harmed. Specifically, the meaning of a
harm – whether it was
intended – influences the
amount of pain it causes.
Although people can
become accustomed to
the pain of an unintentional harm, the malice
behind an intentional
pain keeps it stinging. ©
ab
A C K N O W L E D G M E N T S
We thank assistant Tiffany
Niver, Jane Fang, Daniel
Liss, and Dan Scaduto. This
work was supported by the
Social Science and Humanities Research Council of
Canada, the Institute for
Humane Studies, and
National Institute of Mental
Helalth Grant MH 49127.
R E F E R E N C E S
AYDEDE , M. ( 2005 ) .
“Introduction: A Critical and Quasi-historical Essay on Theories
of Pain”, in M. Aydede
(ed.), Pain: New essays
on its nature and the
methodology of its study
(Cambridge, MA: MIT
Press): 1-58.
CHEN, Z., WILLIAMS, K.D.,
F ITNESS , J., & N EW TON, N. (2008). “When
hurt will not heal:
Exploring the capacity
to relive social and
physical pain”, in Psychological Science 19 ,
789-795.
CLARK, HH. (1996). Using
language (New York:
Cambridge UP).
N.I.,
E I S E NB E RG ER ,
LIEBERMAN, M.D., &
K.D.
W I LLI AMS ,
(2003). “Does rejection hurt? An MRI study of social
exclusion”. in Science 302: 290-292.
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THE ETHICS OF PL ACEBO - CONTROLLED
TRIALS IN DEVELOPING COUNTRIES TO PREVENT
MOTHER - TO - CHILD TRANSMISSION OF HIV *
JOHN NICHOLAS WILLIAMS
there are clear differences from country to country
which are morally relevant to the question above,
our answer to it should be the same whatever the
country in which such experiments are conducted.
Extracting a clear and consistent answer is not easy,
given the emotional horror that surrounds even a
suitably generalised question.
The consequences of the disg| REFLECTIONS
ease are horrible and threaten
John N. Williams is an Associate
Professor in Philosophy at the School
to multiply through successive
of Social Sciences, Singapore Mangenerations. The horror is
agement University. He received his
accentuated by the innocence
Apart
PhD from Hull University, UK. His
of the foetus as a recipient of
research interests include paradoxes,
of the
those consequences, an innotheory of knowledge, philosophy of
cence that remains regardless of
religion and applied ethics. His
known
the academic question of
research has been published in Acta
whether the foetus is a person
Analytica, American Philosophical
and the
or merely a potential person.
Quarterly, Analysis, Australasian
Add to this the perplexing
unknown,
Journal of Philosophy, Journal of
conundrum of placebo, with
Philosophical Research, Mind,
what
Philosophy East and West, Philoits levels of ignorance. Finally,
sophical Studies, Religious Studies,
we must contextualise the
else is
Synthese, and Theoria. He is a co-ediproblem against the backtor of Moore’s Paradox: New Essays
ground of the horrors built
there?
on Belief, Rationality and the First
into developing countries, such
Person, Oxford University Press 2007.
as unequal and inadequate
Email: [email protected]
HAROLD PINTER
resources, lack of education
and poverty.
Where is a doctor or a researcher
I N T R O D U C T I O N
to look for guidance in such a
L A C E B O - T R I A L S O N HIV- I N F E C T E D P R E G N A N T
case? ‘Conscience’, isn’t any substantive answer, since
women in developing countries like Thaidiffering consciences of doctors are just differing
land and Uganda1,2 have provoked recent
internalisations of some medical code. However,
controversy 3,4. Such experiments aim to
there is an authoritative code of medical practice,
find a treatment that will cut the rate of
which provides guidance, namely the Belmont
vertical transmission more efficiently than existing
Report 5.
‘gold standard’ treatments like zidovudine. Is such
The Belmont Report provides an excellent sharpenan experiment morally justified? I think that the
ing of the principles laid down in the unmodified
right question to ask is this: “Is it always, never or
Helsinki Declaration6. In essence, it urges three prinsometimes, morally justified to experiment on HIVciples: the Principle of Utility (there called Benefiinfected, pregnant women in developing countries
cence), the Principle of Autonomy (there called
(by means of placebo trials) in order to develop a
Respect for Persons) and the Principle of Justice.
new treatment X which will reduce the rate of
The Principle of Utility has a negative and a posimother-to-child HIV transmission more effectively
tive form. Its negative form states that
than the existing (‘gold standard’) treatment Y?”
~ PB neg) It is one’s duty to refrain from doing
harm while its positive states that
“
”
P
T H R E E
E T H I C A L
T H E Y
P R I N C I P L E S
A N D
~ PB pos) It is one’s duty to minimise harm and
maximise benefit, to society in general, including
that of future patients.
The Principle of Autonomy claims that individuals
should be treated as autonomous agents, and that
H O W
C O N F L I C T
Put like this, the issue acquires a level of generality.
For example, the specific country in which the
experiment is carried out is not the issue. Unless
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persons with diminished autonomy are entitled to
protection. In other words,
O N E
T H R E E
~ PA) It is one’s duty to respect autonomous
choices and to protect those with diminished
autonomy.
~ PJ) It is one’s duty to distribute benefits (of
research) fairly
or at least, not worsen the imbalance of benefits
and burdens of research among relevant groups.
These three voices of utility, autonomy and justice
cannot, in themselves, provide clear guidance in all
cases, since there are possible scenarios in which
they give conflicting rulings. It seems reasonable to
think that the negative voice of utility is not a total
prohibition of any form of harm, such as a slightly
painful injection. Rather it should be read as ‘Do
not cause more harm than benefit to a single individual’, but this may still conflict with the positive
voice of utility. Suppose that the general increase of
good over harm to society in general (by means of a
reduction of the number of children who will be
born with HIV) can be purchased only at the cost of
exposing the mothers in the experimental group to
a risk of substantial harm that is greater than the
chance of slight benefit. Since such exposure is itself
a type of harm, the voice of utility is confused.
Now consider the cost to the mothers in the control
group. Their babies are effectively condemned to
HIV infection, the incidence of which could have
been reduced by giving them the ‘gold standard’
standard treatment Y (for example, zidovudine) that
is known to be effective in cutting the rate of vertical HIV transmission. In the name of both babies
and their mothers, the negative voice of utility prohibits the experiment, while its positive voice
demands it. Suppose further that HIV-infected
mothers can only be recruited for the experiment by
coercing them to participate or by withholding
information about the risks involved (the absence of
any effective treatment in the case of the control
group and the risks-compared-to-benefits of treatment X in the case of the experimental group) relative to the benefits available to others (by means of
the existing treatment Y). Here the voice of utility
contradicts that of autonomy, since informed and
free choice to participate has been ruled out. Or
suppose that the treatment X, once available, will be
restricted to a minority of HIV-infected pregnant
women in countries wealthy enough to afford it,
excluding those in the developing country in which
they were originally developed. Even if we could be
sure that the rate of vertical transmission would
decrease worldwide, in line with the voice of utility,
we would still hear the cry of injustice.
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E T H I C A L
O F
T H E
P R I N C I P L E S
These examples show that the principle of utility
will contradict those of autonomy and justice in
cases that are at least possible. This means that we
must decide in advance which voice has authority
over which. As a matter of fact, most of us hear the
least authority in the voice of utility. In examples
such as those just considered, most will judge that
maximising utility at the cost of injustice or at the
cost of disrespecting the free choices of people (thus
treating them as means to the end of increased
health world-wide) is morally repugnant. Thus, one
way to achieve consistency among the three principles that will fit the moral intuitions of many is to
hold that the voice of utility must be obeyed, but only
after the voices of justice and autonomy have been
obeyed. Those who hear things that way will not be
swayed in the least by the tinkering with the original
wording of the Helsinki Declaration which was sent
to the World Medical Association’s member associations in advance of the World Medical Association
Council Session in Santiago, Chile on April 15, 1999.
Working from the background of the question
towards empirical specifics, the Principle of Justice
is the most effective choice of principles to apply
first. If the degree of poverty of most pregnant HIVinfected mothers in the developing country (such as
Uganda) will prevent them from buying the
improved cure, if found, for several generations of
HIV-infected offspring to come, while most of the
relatives of the researchers (such as Americans) will
be able to buy it as soon as it hits the market, then
surely this is injustice. As for other scenarios, surely
enlarging the relative size of burdened group versus
benefiting group proportionally worsens the injustice. Given that injustice will be done, there is something morally wrong with the experiment, quite
regardless of whatever else is ruled wrong by the
other principles. Taking the three principles as a
guide to procedure, we must at least postpone such
experiments until enough economic aid has been
given to these countries as makes the chances of benefit more fairly distributed. Otherwise the researchers
should experiment upon their own extended geopolitical-economic kin. Given the commercial hegemony of the rich drug companies involved, their
opposition to the production of cheaper ‘generic’
drugs and the huge disparity between levels of wealth
in developing countries and developed countries, the
chances of benefit to the burdened group were clearly
not fairly available to them.
Let us now suppose (hypothetically but implausibly)
that equality has been redressed or is not the issue.
What does the voice of autonomy tell us? There are
two groups for whom it could speak, the foetuses
and their mothers. Clearly the foetus is incapable of
making choices, informed or not, so whether or not
we say that they are potential persons or already persons, there can be no autonomous choices made by
The Principle of Justice states that ‘research should
not unduly involve persons from groups unlikely to
be among the beneficiaries of subsequent applications
of the research’. The spirit of this principle is that
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ending up in the control group, in which case her
foetus will certainly be born with HIV and a halfchance of ending up in the experimental group,
with possible risks and benefits to the foetus which
are uncertain. She must also understand that she faces
these two outcomes in the teeth of the knowledge that
treatment Y already exists, with its more certain risks
and benefits to the foetus.
them which are respected or disrespected. In this
respect, the voice of autonomy is neutral on the permissibility of the experiment. On the other hand,
the principle of autonomy also commands us to
‘protect those with diminished autonomy’, which
appears to include the foetus. If so, on balance, the
voice of autonomy prohibits the experiment in the
name of the foetus.
It might be objected that the class of those entitled
to protection excludes non-persons such as the
foetus. This objection clearly has little bite against
those who hold that the foetus is to some degree a
person at some stage in its development. Nor is it
persuasive against those, including the mothers,
who think that whether the foetus is an actual or
potential person, it is still something valuable,
which therefore needs protection.
It might be objected here that the lack of education
among such mothers renders them incapable of
understanding such information. If so, autonomy
demands that education be a more pressing priority
than medical research. The experiment must be postponed until the would-be participants are educated
to a level that enables them to understand what
choices are open to them. Since justice demands that
the benefits of education be fairly distributed
throughout the developing country in which the
experiment is to take place, this means that the
experiment must be postponed until any would-be
sub-group of participants has a level of education
that is representative of the whole population of
that country.
How does autonomy speak for the mothers? It
clearly prohibits the experiment unless the mother
has made an autonomous choice to participate.
Autonomous choices must be informed choices. In
the case of a non-placebo experiment in which the
new treatment X is to be tested, this means that the
mother must understand the risks and probable
benefits to herself and her foetus posed by the new
treatment X, as compared to risks and probable benefits conferred by the existing treatment Y. Since the
probability of risks and benefits of the new treatment may be precisely what the experiment is
designed to discover, it may not be possible to give
her precisely this information. In that case, the
mother must be informed of the degree of uncertainty
of the probability of possible harms and benefits of
the new treatment X, as compared to the degree of
certainty already established of the probabilities of
harms and benefits of the existing treatment Y.
Anything less would not be full information.
C O M P L I C A T I O N S
F R O M
P L A C E B O
This brings us back to the purpose of the placebo.
Suppose that an HIV-infected pregnant woman
believes that she is receiving a new miracle drug that
carries an ironclad guarantee of protecting her foetus from infection. In fact her belief is mistaken, for
the drug she has been given is just sugar. It seems
unlikely that her belief could have any positive psychological effect upon her foetus. In terms of the
mother, the placebo seems to serve no useful purpose. So far, there is no justification for the creation
of the control group, in which the foetuses are condemned to HIV infection. Thus the only other purpose that the placebo can serve is to separate the
causal powers of X in reducing vertical transmission
from the causal powers of the beliefs of the experimenters. A double-blind trial, in which the experimenters do not know which mother is receiving
sugar or receiving X, will ensure that they will not
bias the development of one group of foetuses over
the other, by giving different levels of care to the
two groups of mothers. The question to ask now is
whether the increased accuracy of the results of the
efficiency of X is worth the price of allowing the
mothers in the control group to go untreated. The
voice of autonomy tells us that the price need not
be paid. Since mothers in both groups are persons
equally deserving of care and respect, the experimenters have a duty to provide both groups with
the best possible level of care, regardless of their
beliefs about whose foetuses are most likely to be
protected from vertical transmission. Once this
duty is discharged, there is no possible justification
left for the inclusion of the placebo group.
Thus there appears to be no need for a placebo group
at all. Surely the ethical procedure would be to give
the control group treatment Y instead. After all, are we
A R I S I N G
C O N T R O L
In the case of a placebo experiment, things are more
complicated. Placebos aim to separate the causal
powers of X from the causal powers of the belief in
those causal powers. For example, they aim to filter
out cases in which a patient feels better simply
because that patient believes (correctly or incorrectly)
that the treatment will work. The belief in question
may be held by the mothers or the experimenters or
both. Clearly no such belief can be held by the foetus. Assume a simple single-blind placebo control in
which each mother has a fifty-fifty chance of being
selected for the control group to receive sugar as
opposed to the experimental group to receive the
new treatment X, such that no mother will know
which group she is in. Obviously, this design of
experiment rules out informing the mothers which
group they are in, but this does not mean they can be
given no information at all. Autonomy demands that
each mother understand that she has a half-chance of
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not trying to measure the difference in effectiveness
of the new treatment X as compared to the existing
treatment Y? If the participants in both groups were
fully informed of the experimental set-up, there
would be no room for objection on grounds of
autonomy, nor any room for objection on grounds of
utility to the treatment of the participants in the control group, since this group is assured of the best
known treatment available anyway.
Given my definition of a placebo as a control which
aims to separate the causal powers of a treatment
from the causal powers of belief (or faith) in that
treatment, there is, strictly speaking, a conceptual difference between a placebo group and a ‘no treatment’
those in the ‘no-treatment’ group were not fully
informed. Quinn et al 8 reported that 228 HIVinfected couples were left untreated for up to thirty
months, and the decision to inform the uninfected
persons that their partner was infected was left up
to the infected persons themselves, although the
experimenters regularly saw both. Surely this does
not count as discharging a duty to give all parties
concerned the full information. To so discharge it,
the experimenters should have told each couple
that one partner was infected as well as telling them
that the infection would go untreated.
In the same project, the investigators treated half of
the villagers for sexually transmitted diseases such
control group, which aims to help isolate possible
unwanted side-effects of the treatment. In experiments to develop new treatments that are more effective in reducing the vertical transmission of HIV, a ‘no
treatment group’ would help to isolate unwanted
sideeffects of the new treatment on the foetus. I now
turn to this issue.
as syphilis while leaving the other half untreated.
Their aim was to determine the effect of concurrent sexually transmitted diseases on the heterosexual transmission rate of HIV. Assume for the sake of
argument, that this information was obtained and
that it helped to develop more effective ways of
cutting the HIV transmission rate. In terms of maximising the utility to society in general, the investigators were morally justified. Moreover, anyone who
maintains consistently that the voice of utility always
overrides the voices of autonomy and justice can
defend the investigators, but that is not the moral
framework I have suggested. Given that utility is
subordinate to autonomy and justice, we need to ask
whether the investigators infringed the informed
choices of the villagers who were left untreated.
Deciding this is not easy. One way to look at it is to
say that the untreated villagers were simply left
alone by the investigators to carry on as before, so
no interference took place. On the other hand,
there is a clear sense in which the untreated villagers
were selected by the investigators to form one half of
the experiment. In this sense, they were intentionally included in the experiment by default. Therefore
‘
N O
-
T R A T M E N T
G R O U P S
C O N T R O L L E D
’
W I T H I N
S T U D I E S
Similar moral objections can be made to different
kinds of experiments such as the Rakai project in
Uganda7, in which the experimenters studied the
effect of other sexually transmitted diseases on the
rate of heterosexual transmission of HIV and the
natural risk factors that determine the heterosexual
transmission of HIV-1 over periods of unprotected
sex. Such experiments use a ‘no-treatment’ group
within a controlled study. Such an experiment is
ruled unethical on the grounds of autonomy, if
those who were left untreated were not fully
informed that this was precisely what would happen to them. By the experimenters’ own admission,
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women will know that they are in a kind of desperate
lottery that holds out a chance for the well-being of
their unborn. Since the chances of protection for
the foetuses in the experimental group are less than
certain, they should know that overall, the odds are
against them. Nonetheless, some basis for hope
exists, which may well be the very reason why they
have agreed to participate. Yet the experimenters
know in advance that for each mother in the placebo
group, all hope will be dashed. This burden of false
hope and its certain disappointment surely represents a significant cost to this group of mothers.
The no-loss argument gains its plausibility from
the claim that the personal utility of the volunteers
is not decreased. But it ignores the salient fact that
the volunteers start from a position of inequality.
Were justice done, the proven, if limited benefits
of the existing treatment Y would be distributed
fairly throughout the world to those in developing
countries who need them most. Given that the
inclusion of the placebo group is justified, the
autonomous choice of the mothers would then be
the more heroic one of taking a half-chance of no
protection for their unborn and a half-chance of
the uncertain degree of protection conferred by
treatment X, in preference to the guarantee of the
certain but limited degree of protection conferred
by the existing treatment Y. Given, as I suggested
above, that the inclusion of the placebo group is
not justified, the autonomous choice of the mothers would then be the less heroic but still courageous one of trading the certain but limited degree
of protection conferred by treatment Y for the possibly improved but uncertain degree of protection
conferred by treatment X.
In the original experiment, even those mothers
who end up in the experimental group are doubly
wronged. Firstly, they are wronged both in the
name of justice and in the name of autonomy by
being unfairly denied the choice of treatment Y.
Then the experimenters restrict their choices to
the options of no treatment (by refusing to participate) or the option of a half-chance of the uncertain benefits of treatment X (by consenting to participate). The restriction is genuine, since it is
always within the power of experimenters to offer
treatment Y as well. Since this is a perpetuation of
the original injustice and an erosion of autonomy,
this is a further wrong. In this respect, the wouldbe participant resembles a workman who has been
unfairly denied any payment. His employer offers to
toss a coin. If the coin comes down heads, the workman will receive half his wages; if tails, nothing. If
he refuses the bet, again he gets nothing. The
workman is first wronged by being deprived any
payment. When the bet is offered, he has nothing
further to lose. Yet surely the offer of the bet is a
second wrong since it perpetuates the original
deprivation of full payment, one that the employer
is in a position to put right.
the voice of autonomy demands that the experimenters give them an informed choice to continue
to participate, which in turn means telling them
that they would go untreated. Had the villagers
heroically agreed to forgo treatment for the sake of
future generations then there could be no objection
in the name of autonomy. Otherwise, continuing
to include them in the experiment would be morally wrong. Against this, it might be objected that
the investigators were not doing anything extraordinary, since the villagers would not have been
treated in the ordinary course of events anyway.
However, it is not so clear that this means the
investigators were not interfering. Given that the
investigators selected this particular group of villagers for the control arm of the experiment, and
then continued to withhold both treatment and
information when they could easily have supplied
both, were they not interfering? In selecting and
then ignoring them, surely the investigators were
actually doing something to them.
The scenario of the untreated villagers is no different
in principle from that in which a group of pregnant
HIV-infected mothers is left untreated as a control to
a second group who are given a new treatment X, in
order to help obtain information on (among other
things) whether X will have unwanted side-effects on
the foetus. Assume, for the sake of argument, that
the information is obtained and that it is instrumental in reducing harmful side-effects to babies who are
in general, less likely to be born with HIV (than
when their mothers were treated with the original
drug Y). Again, the voice of utility permits, even
demands, the inclusion of the ‘no-treatment group’,
but again, given that utility is subordinate to autonomy and justice, we need to ask whether the investigators infringed the informed choices of the mothers
who were left untreated. If the investigators first
selected them as a control arm and then withheld
treatment and information (including the information that they were infected and that treatment was
available), then the mothers’ autonomy was violated.
T H E
U T I L I T A R I A N
‘
N O
L O S S
’
D E F E N S E
9
Some commentators in the debate have argued
that most HIV-infected pregnant women in developing countries would not be able to afford any
sort of treatment against vertical transmission anyway. Thus the women in the original experiment
are in a no-loss situation. They have a half-chance
of ending up in the placebo group, in which case
they are no worse off than they would be anyway
and a half-chance of ending up in the experimental
group, in which case they have a secondary chance
(the degree of which is yet unknown) of protecting
their foetus.
This argument suffers from a number of flaws. Are
the women in the placebo group really no worse off
than they would have been had they never participated? If autonomy has been satisfied, then the
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E F F E C T S
O F
M O D I F Y I N G
D E C L A C A R A T I O N
O F
T H E
R E F E R E N C E S
H E L S I N K I
1 CONNOR E. M., SPERLING R. S., GELBER R., KISELEV
P., SCOTT G., O’SULLIVAN MJ. et al (1994). “Reduc-
Whereas the current Declaration assures research
participants of ‘the best proven diagnostic and therapeutic method,’ the corresponding section in the
modified Declaration adds the phrase ‘that would
otherwise be available to him or her.’ This appears
to vindicate the ‘no loss’ argument, since there is no
treatment available to the would-be participants in
the experiment should they not participate, given
that they are too poor to afford any treatment,
including treatment Y. But this vindication is an
illusion. For one thing, there is an ambiguity in the
phrase ‘available’. On one reading, treatment Y is
not available to the group in the sense that they
would not have been able to obtain it, had they
never come in contact with the experimenters. However,
in that sense, since the best treatment available otherwise is none, this amendment is just another way
of saying that the group in question is assured of no
treatment. We should therefore reject this amendment to the Declaration, in the name of both justice and utility as originally voiced by it. Utility
demands that the benefit to society be maximised
and justice demands that this benefit be fairly distributed. In other words, the group in question
must be given a fair chance of treatment Y. The
other, more sensible, reading of ‘available’ is that
treatment Y is not available to the group as would-be
participants who are now in contact with the experimenters. However, in this sense, treatment Y is available to them even if they now choose not to participate, since it is fully within the experimenters’
power to provide it. Thus even the modified declaration tells us that the experiment is morally wrong.
2
3
4
5
6
7
8
9
C O N C L U S I O N
tion of maternal-infant transmission of human
immunodeficiency virus type 1 with zidovudine
treatment”, in N Engl J Med 331: 1173-80.
S HAFFER N., C HUACHOOWONG R., M OCK P.A.,
BHADRAKOM C., SIRIWASIN W., YOUNG NL., et al
(1999). “Short-course zidovudine for perinatal HIV-1
transmission in Bangkok, Thailand: A Randomised
Controlled Trial”, in Lancet 353: 773-80.
LURIE P., WOLFE S. M. (1997). “Unethical trials of interventions to reduce perinatal transmission of the
human immunodeficiency virus in developing countries”, in N Engl J Med 337: 853-6.
ANGELL M. (1998). “The Ethics of Clinical Research
in the Third World”, in N Engl J Med 337: 847-9
[see also correspondence in N Engl J Med 1998; 338:
836-44].
N ATIONAL C OMMISSION FOR THE P ROTECTION OF
HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL
RESEARCH. The Belmont Report. April 18, 1979.
DECLARATION OF HELSINKI IV, 41st World Medical
Assembly, Hong Kong, September 1989. In: Annas
GJ., Grodin MA. (ed.) The Nazi Doctors and the
Nuremberg Code: Human Rights in Human Experimentation (New York: Oxford UP, 1992: 339-42.
WAWER MJ., S EWANKAMBO NK., S ERWADDA D.,
Q UINN TC., PAXTON LA., K IWANUKA N. et al
(1999). “Control of sexually transmitted diseases for
AIDS prevention in Uganda: a randomised community trial” in Lancet 353: 525-35.
QUINN TC., WAWER MJ., SEWANKAMBO N., SERWADDA D., L I C., WABWIRE-MANGEN F. et al (2000).
“Viral load and heterosexual transmission of human
immunodeficiency virus type 1”, in N Engl J Med
342: 921-9.
PHANUPHAK P. (1998). “Ethical issues in studies in
Thailand of the vertical transmission of HIV” in N
Engl J Med 338: 834-5.
ab
Given plausible assumptions about the level of
poverty and education in the developing country
targeted, the placebo-controlled trials of the type discussed are unethical violations of both justice and
autonomy. In any case, no moral justification can be
found for the inclusion of a placebo group. By contrast, the inclusion of a ‘no control’ group may be
justified, but only when the experimenters have not
interfered with the autonomy of its members. Experiments such as the Rakai project in Uganda are such
unethical violations of autonomy. The development
of third-world countries, in the form of economic
development and education, must be priorities that
come before such experiments.
©
ab
——————
The limits of my language
mean the limits of my world.
* This paper was first submitted when the author was a
Fellow in Philosophy in the Department of Philosophy,
National University of Singapore and subsequently revised
at the Singapore Management University).
S P A N D A
J O U R N A L
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LUDWIG WIT TGENSTEIN,
Tractactus Logico-Philosophicus.
ab
t h e
p l a c e b o
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28
THE
ETHICAL
E D Z A R D
E R N S T
IMPLICATIONS
IN
CLINICAL
OF
USING
PRACTICE
PLACEBO
K U R T
THE
By using the concrete example of homeopathy, this paper
considers whether placebo use can be ethically justified.
On one hand, clinicians may want to help patients
through a beneficial placebo effect, and highly diluted
homeopathic remedies are unlikely to have adverse
effects. Also, many patients expect to receive a prescription when visiting the doctor and believe in the effectiveness of homeopathy. However, the author presents several reasons the use of placebos may not be considered ethical. Recent survey data shows that the most frequent
reasons for prescribing placebos are mainly for the physicians’ convenience rather than for altruistic motives. To
obtain the placebo effect, physicians cannot tell the
patient they are receiving a placebo, which goes against
the ethical requirement for a doctor to obtain informed
consent from a patient. This deception can undermine
trust, which is necessary for good therapeutic relationships. Placebos, especially impure ones, also present the
risk of producing adverse effects and may cause people to
believe there is a medical cure for every state of reduced
well-being. This paper suggests that an effective treatment that treats a patient’s symptom(s) will be more useful than a homeopathic remedy because the patient will
get relief from his/her symptom(s) while also receiving
the placebo effect. The author recommends that clinicians analyse their own behaviour to determine whether
placebo use is in the best interest of the patient or for
their own convenience.
C H R I S T O P H E R
ALL
IN
EFFECT,
THE
CAFFEINE
AND
IN
MIND?
J
.
ERGOGENIC
SPORTSS
THE
TRIALS
I I
OF
, 1 /2 0 1 1
|
M
.
INTENTIONAL
W E G N E R
PAIN
W I L L I A M S
OF
PLACEBO-CONTROLLED
DEVELOPING
COUNTRIES
TRANSMISSION
TO
OF
PREVENT
HIV
Placebo-trials on HIV-infected pregnant women in developing countries like Thailand and Uganda have provoked controversy. Such experiments aim to find a treatment that will cut the rate of vertical transmission more
efficiently than existing treatments like zidovudine. This
scenario is first stated as generally as possible, before
three ethical principles found in the Belmont Report,
itself a sharpening of the Helsinki Declaration, are stated.
These three principles are the Principle of Utility, the
Principle of Autonomy and the Principle of Justice.
These are taken as voices of moral imperative. But
although each has intuitive appeal, it can be shown that
PERFORMANCE
J O U R N A L
ETHICS
IN
MOTHER-TOCHILD
The ergogenic effects of caffeine on performance are
well documented. These effects are more evident in
S P A N D A
OF
D A N I E L
N I C H O L A S
J O H N
PLACEBO
EFFECT
STING
~
This study tests whether the psychological context of
pain affects the amount of pain an individual feels,
namely whether intentional harm causes more perceived
pain than unintentional harm. The researchers used an
experiment in which the subjects were instructed to perform a series of tasks with a partner in a separate room,
who was actually an accomplice. One task, discomfort
assessment, involved the subject receiving an electric
shock and rating his/her level of discomfort. One group
was led to believe their partner intentionally chose for
them to receive the shock rather than choosing for them
to complete another task, while the other group was told
the partner unintentionally chose for them to get the
electric shock. The results show that intended pain was
experienced as more painful than unintended pain. In
addition, intended pain appeared to be felt fresh every
time, rather than lessening as the subject became habituated to repeated painful stimulation.
B E E D I E
PAIN,
G R A Y
t h e
p l a c e b o
e f f e c t
|
29
::
SUMMARIES
::
ABSTRACTS
Due to the involvement of many mechanisms, the study
of the placebo effect can be viewed as a melting pot of
concepts and ideas for neuroscience. Indeed, there exist
not a single placebo effect, but many, with different
mechanisms and in different medical conditions and
therapeutic interventions. In fact, expectation, anxiety
and reward are all involved, as well as a variety of learning phenomena. There is also some experimental evidence of different genetic variants in placebo responsiveness. Pain and Parkinson’s disease are today the most productive models to better understand the neurobiology of
the placebo effect, and the neural networks that are
involved have been identified, such as an opioidergiccholecystokinergic-dopaminergic modulatory network in
pain and part of the basal ganglia circuitry in Parkinson’s
disease. Important implications emerge from these recent
advances in placebo research, such as the impact of the
psychosocial context on the patient’s brain.
::
endurance and short-duration, sustained-effort events
than in interactive or stop-go sports. Experimentallyinduced placebo effects of caffeine on sports performance have also been observed in a number of recent
studies. In the present paper it is argued that, given the
nature of the sports in which caffeine effects are observed,
the well documented hypoalgesic effects of caffeine, and
the fact that pain is highly placebo-responsive, a reduction in perceived pain might be the common factor in
both the biologic and placebo ergogenic effects of caffeine on sports performance. This idea is supported by
evidence from medicine that suggests placebo effects are
often associated with mechanisms similar or identical to
those of the substance the subject believes they have
ingested. Research findings from both biomedicine and
sports medicine that attest to the interaction of biologic
and psychologic factors in caffeine and pain responses
are briefly reviewed. In conclusion, it is recommended
that researchers investigate the pain hypothesis. Furthermore, researchers should consider psychosocial factors
that might modulate the pain response as variables of
interest in future caffeine and performance research.
EFFECTS
SUMMARIES
B E N E D E T T I
PLACEBO
::
MANY
ABSTRACTS
THE
::
F A B R I Z I O
there are possible scenarios in which they give conflicting
prescriptions. To achieve consistency, one must be subordinate to the others. The voice of utility is taken as subordinate to those of justice and autonomy and it is
shown that given plausible assumptions about the level
of poverty and education in the developing country targeted, the experiment is ruled morally wrong in the
name of both justice and autonomy.
Moreover, it is argued that no justification can be found
for the inclusion of a placebo group, when strictly
defined. By contrast, a ‘notreatment’ control arm might
be justified, but only when the demands of autonomy
are satisfied, demands that are more stringent than they
might appear. A utilitarian defense of the experiment is
examined, namely that the would-be participants are in a
no-loss situation, and it is shown that this defense is seriously flawed. Finally, it is concluded that there is no justification for amending the Declaration of Helsinki. ©
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