What does placebo mean?

Describe the opioids

Why are placebos a topic of research?

Placebo derives from latin: I

shall please
Modern definition: It is a
psycho-social biological
phenomenon activated when
the patient believes in an
effective therapy and so
expects a reduction of
symptoms. The placebo effect
is the outcome following a
dummy treatment or the
administration of an inert
medical treatment, which can
be pharmalogical or not
The component of opium
responsible for analgesia is
morphine
Opioid receptors are found in
brain tissue
They include mu-, delta- and
kappa
The first endogenous opioids to
be identified were metenkephalin and leu-enkephalin
Since then, several other
opiates have been discovered
These include the endorphins
and Dynorphins
Study of placebo effect means
finding the causal relationship
between any medical procedure
and the psychosocial context
surrounding the patient
The placebo effect, has been for
long considered a problematic
issue to deal with in clinical
trials (placebo groups in doubleblind trials were introduced in
the early 1900s)
Now it has become itself a
target of scientific enquiry
The psychosocial context tells
the patients brain to expect a
therapeutic effect
As a result, neurobiological
events occur in the brain via
unconscious and/or conscious
mechanism, bringing out the
release of effector molecules
These cause physiological

What are some placebo-related effects

What could the possible mechanisms

be causing the placebo effect?

changes in the brain and other

organs that can generate a
therapeutic effect
The placebo effect is greater in
experimental studies than in
clinical trials: different
instructions and suggestions
are given in the two settings
Very strong placebo effects
have been found in studies
involving pain treatment and
analgesia
Most placebo studies show a
link between expectancy and
pain
No placebo is given and effects
are attributed to the influence
of the context surrounding the
treatment on the patients brain
Verbal suggestions of
improvement or worsening can
be given alone, this inducing
expectations about the
outcome
Psychosocial context can act on
the patients brain:
o Consciously:
Cognition
Anticipation
Expectation
Belief
Trust
Hope
o Unconsciously:
Conditioned
stimulus =
conditioned
response
There is a cascade of
biochemical events in the brain
following placebo
administration

1. Expectation of clinical benefit:

a. Expectation has a role in
placebo-induced
analgesia
b. Expectation of reward
(less pain) results in
enhanced release of

Which areas of the brain are involved

in the placebo effect?

How can cognitive factors and

conditioning change the placebo
responses?

What are the non-opioid placebo

analgesia mechanisms?

dopamine in the nucleus

accumbens
c. Increased mu-opioid
receptor activity and
descending pain
inhibition by the PAG
d. Also causes anxiety
modulation (by the
orbitofrontal region): so
you expect less pain and
anxiety decrease
2. Classical conditioning
(unconscious mechanism)
a. After repeated
associations between a
conditioned stimulus
(CS), the environment
around the patient (e.g.
the colour of the pill) and
an unconditioned
stimulus (e.g. the active
drug morphine) the CS
alone is able to elicit a
conditioned response
similar to that induced by
the drug
b. Dorsolateral prefrontal
cortex might be involved
Dorsolateral pre-frontal cortex
Nucleus accumbens reward
Orbitofrontal cortex anxiety
response
Expectation triggers
endogenous opioids whereas
conditioning activates specific
subsystems
o If conditioning is
performed with opioids,
placebo analgesia is
mediated via opioid
receptors
o If conditioning is
performed with nonopioid drugs, other nonopioid mechanisms tend
to be involved
Non-opioid placebo analgesia
seems to be mediated by
cannabinoid receptors
Evidence for this is that the CB1
cannabinoid receptor

What are misconceptions regarding

placebos?

What are problems in identifying a

real placebo effect?

How are double-blind randomized

placebo-controlled studies designed?

What is hidden treatment?

Compared to morphine how potent is

antagonist rimonabant blocks

non-opioid placebo analgesia
When a placebo is given,
reduction of symptoms could be
due either to spontaneous
remission, regardless of
treatment or to regression to
the mean of the symptom
Spontaneous remission which
is why we compare the placebo
group with a no-treatment one
Regression to the mean pain
assessment is done when pain
is at its peak; 2nd is done at
lower levels
False positive errors a cointervention is responsible of
remission
Saying to the patient of the
50% chance of receiving a
placebo larger placebo effects
were found when it was told to
the patient that a powerful
analgesic drug will be given,
thus manipulating the degree of
expectancy
Spontaneous variation in pain
and illness taking a placebo
just before a period of less
intense pain might lead to
belief that this is due to the
placebo
One arm of trial: randomised
patient given active treatment
Second arm of trial: randomised
patients given an inert
treatment that mimic the active
one (placebo)
Double-blind: neither the doctor
nor the patient know what is
being given
The patients are told of the 50%
probability of receiving the
placebo or active drug
To conclude that the drug is
effective the outcome must be
better than that of the placebo
Telling a patient that a painkiller
is injected but only saline is, is
as potent as 6 8mg of

it?
What effect on pain management
does making expectation pathways
silent have?
What has brain imaging taught us
about the opioid hypothesis?

Does the placebo effect only work for

pain?

What is the latin etymology of

nocebo?
What can help make the expectation
process stronger?

MORPHINE!
Decreased effectiveness of
hidden therapy
Brain imaging supports the
opioid hypothesis
Same areas activated
administering a placebo and an
opioid drug (PET)
A descending rACC-PAG-ponsmedulla pain modulating circuit
involved in placebo analgesia
An fMRI study showed a
decrease in activity in pain
pathway areas after a placebo
treatment and a cognitiveevaluative network is activated
before the placebo response
Also cognitive functions affect
the placebo response because
Alzheimer patients have less of
a placebo response
No
Works for many conditions
The psychosocial context
around the treatment activates,
through expectation and/or
conditioning mechanisms, a
number of receptor pathways in
different diseases and
treatments
These receptors are the same
to which drugs bind, thus
indicating that cognitive and
affective factors are capable of
modulating the action of drugs
This interference has profound
implications for our
understanding of drug action
When a drug is given, the act of
administering (i.e. the
psychosocial context) may
perturb the system and change
the response to the drug
I shall harm
Integrate patients beliefs and
expectations into drug
treatment regimens alongside
traditional consideration in

order to optimize treatment

outcomes