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Placebo and Outcome Measurement
Damien Finniss
Clinical Senior Lecturer, Pain Medicine, Sydney Medical School
University of Sydney Pain Management Research Institute
Royal North Shore Hospital

Placebo: a substance or procedure that
is inert and designed to please rather
than to exert a specific effect (Brody
2000). e.g. sugar pill, saline injection,
sham procedure.

Placebo: a substance or procedure that
is inert and designed to please rather
than to exert a specific effect (Brody
2000). e.g. sugar pill, saline injection,
sham procedure.

However, if placebos are inert they can’t
cause an effect !
What is ‘Placebo’ ?

Placebo: a substance or procedure designed to simulate an active therapy
in a particular psychosocial context (Price, Finniss & Benedetti 2008)
What is ‘Placebo’ ?

Placebo: a substance or procedure designed to simulate an active therapy
in a particular psychosocial context (Price, Finniss & Benedetti 2008)

Placebo Effect: The “group effect” seen following administration of a
placebo
What is ‘Placebo’ ?

Placebo: a substance or procedure designed to simulate an active therapy
in a particular psychosocial context (Price, Finniss & Benedetti 2008)

Placebo Effect: The “group effect” seen following administration of a
placebo

Placebo Response: A particular individuals response following
administration of a placebo
What is ‘Placebo’ ?

Placebo: a substance or procedure designed to simulate an active therapy
in a particular psychosocial context (Price, Finniss & Benedetti 2008)

Placebo Effect: The “group effect” seen following administration of a
placebo

Placebo Response: A particular individuals response following
administration of a placebo

Placebo effects and responses are used interchangeably (Colloca, Finniss
& Benedetti 2008)

Meaning response, context effects etc……
Contributions of the psychosocial context surrounding the patient (or placebo component of a given
therapy) to the overall response
Psychosocial context
surrounding the patient
Response
Individual Patient and
Clinician Factors
e.g. Patient’s and clinicians
beliefs, expectations, desire
for symptom change, past
experiences.
INTERACTING WITH
Interaction between the Patient,
Clinician and Treatment Environment.
e.g. factors comprising the “DoctorPatient Relationship” (such as
communication, empathy, reassurance,
bedside manner, enthusiasm), and
factors comprising the treatment
environment (location, type and nature
of treatment e.g. route of drug
administration, use of technological
devices, therapeutic ritual etc)
Administration of a
specific treatment
e.g. an active drug
Response due to both
the specific treatment
and the psychosocial
context in which it was
delivered.
+
+
Administration of a
“placebo” e.g.
Sham procedure,
sugar pill which is a
Treatment “simulation”
Response due to the
psychosocial context
surrounding the patient. The
administration of a “placebo”
only serves to mimic the
psychosocial context. The
placebo is “inert” but the
psychosocial context is not.
Finniss, Kaptchuk et al, Lancet 2010
Contributions of the psychosocial context surrounding the patient (or placebo component of a given
therapy) to the overall response
Psychosocial context
surrounding the patient
Response
Individual Patient and
Clinician Factors
e.g. Patient’s and clinicians
beliefs, expectations, desire
for symptom change, past
experiences.
INTERACTING WITH
Interaction between the Patient,
Clinician and Treatment Environment.
e.g. factors comprising the “DoctorPatient Relationship” (such as
communication, empathy, reassurance,
bedside manner, enthusiasm), and
factors comprising the treatment
environment (location, type and nature
of treatment e.g. route of drug
administration, use of technological
devices, therapeutic ritual etc)
Administration of a
specific treatment
e.g. an active drug
Response due to both
the specific treatment
and the psychosocial
Specific treatment +
context in which it was
psychosocial context
delivered.
+
+
Administration of a
“placebo” e.g.
Sham procedure,
sugar pill which is a
Treatment “simulation”
Response due to the
psychosocial context
surrounding the patient. The
administration of a “placebo”
only serves to mimic the
psychosocial context. The
placebo is “inert” but the
psychosocial context is not.
Contributions of the psychosocial context surrounding the patient (or placebo component of a given
therapy) to the overall response
Psychosocial context
surrounding the patient
Response
Individual Patient and
Clinician Factors
e.g. Patient’s and clinicians
beliefs, expectations, desire
for symptom change, past
experiences.
INTERACTING WITH
Interaction between the Patient,
Clinician and Treatment Environment.
e.g. factors comprising the “DoctorPatient Relationship” (such as
communication, empathy, reassurance,
bedside manner, enthusiasm), and
factors comprising the treatment
environment (location, type and nature
of treatment e.g. route of drug
administration, use of technological
devices, therapeutic ritual etc)
Administration of a
specific treatment
e.g. an active drug
Response due to both
the specific treatment
and the psychosocial
Specific treatment +
context in which it was
psychosocial context
delivered.
+
+
Administration of a
“placebo” e.g.
Sham procedure,
sugar pill which is a
Treatment “simulation”
Response due to the
psychosocial context
surrounding the patient. The
administration of a “placebo”
Psychosocial
context
only serves to mimic the
psychosocial context. The
placebo is “inert” but the
psychosocial context is not.
only
Contributions of the psychosocial context surrounding the patient (or placebo component of a given
therapy) to the overall response
Psychosocial context
surrounding the patient
Response
Individual Patient and
Clinician Factors
e.g. Patient’s and clinicians
beliefs, expectations, desire
for symptom change, past
experiences.
INTERACTING WITH
Interaction between the Patient,
Clinician and Treatment Environment.
e.g. factors comprising the “DoctorPatient Relationship” (such as
communication, empathy, reassurance,
bedside manner, enthusiasm), and
factors comprising the treatment
environment (location, type and nature
of treatment e.g. route of drug
administration, use of technological
devices, therapeutic ritual etc)
Administration of a
specific
treatment
Routine
Care
e.g. an active drug
Response due to both
the specific treatment
and the psychosocial
Specific treatment +
context in which it was
psychosocial context
delivered.
+
+
Administration of a
“placebo” e.g.
Sham procedure,
sugar pill which is a
Treatment “simulation”
Response due to the
psychosocial context
surrounding the patient. The
administration of a “placebo”
Psychosocial
context
only serves to mimic the
psychosocial context. The
placebo is “inert” but the
psychosocial context is not.
only
Contributions of the psychosocial context surrounding the patient (or placebo component of a given
therapy) to the overall response
Psychosocial context
surrounding the patient
Response
Individual Patient and
Clinician Factors
e.g. Patient’s and clinicians
beliefs, expectations, desire
for symptom change, past
experiences.
INTERACTING WITH
Interaction between the Patient,
Clinician and Treatment Environment.
e.g. factors comprising the “DoctorPatient Relationship” (such as
communication, empathy, reassurance,
bedside manner, enthusiasm), and
factors comprising the treatment
environment (location, type and nature
of treatment e.g. route of drug
administration, use of technological
devices, therapeutic ritual etc)
Administration of a
specific
treatment
Routine
Care
e.g. an active drug
Response due to both
the specific treatment
and the psychosocial
Specific treatment +
context in which it was
psychosocial context
delivered.
+
+
Administration of a
“placebo” e.g.
Research
on Placebo
Sham procedure,
sugar
pill which isTrial
a
or Clinical
Treatment “simulation”
Response due to the
psychosocial context
surrounding the patient. The
administration of a “placebo”
Psychosocial
context
only serves to mimic the
psychosocial context. The
placebo is “inert” but the
psychosocial context is not.
only
Contributions of the psychosocial context surrounding the patient (or placebo component of a given
therapy) to the overall response
Psychosocial context
surrounding the patient
Response
Individual Patient and
Clinician Factors
e.g. Patient’s and clinicians
beliefs, expectations, desire
for symptom change, past
experiences.
INTERACTING WITH
Administration of a
specific
treatment
Routine
Care
e.g. an active drug
Response due to both
the specific treatment
and the psychosocial
Specific treatment +
context in which it was
psychosocial context
delivered.
+
Placebo Mechanisms
Interaction between the Patient,
Clinician and Treatment Environment.
e.g. factors comprising the “DoctorPatient Relationship” (such as
communication, empathy, reassurance,
bedside manner, enthusiasm), and
factors comprising the treatment
environment (location, type and nature
of treatment e.g. route of drug
administration, use of technological
devices, therapeutic ritual etc)
+
Administration of a
“placebo” e.g.
Research
on Placebo
Sham procedure,
sugar
pill which isTrial
a
or Clinical
Treatment “simulation”
Response due to the
psychosocial context
surrounding the patient. The
administration of a “placebo”
Psychosocial
context
only serves to mimic the
psychosocial context. The
placebo is “inert” but the
psychosocial context is not.
only
The model

“Specific” component to therapy

“Placebo” component to therapy

2+2=4?

Assess the difference between the two by giving placebo to some patients
and the “real” drug to others in RCT’s.

But is it this simple ?
How do placebo’s work?

NOT ONE PLACEBO EFFECT, THERE ARE MANY

PAIN

Some mediated by opioids (e.g. Benedetti, 1999)

Others are clearly NOT related to opioids (Finniss, Kaptchuk et al 2010)

Expectation of benefit is associated with placebo effects, but only in certain
cases and not others (Price, Finniss & Benedetti 2008)

Conditioning mechanisms play a role and work synergistically with expectancy
(Amanzio et al 1999)

Change in anxiety and desire for symptom relief account for significant variance
in placebo effects, but moreso in laboratory experiments than the clinical setting
(Price et al, 2005)
How do placebo’s work?

Placebo effects are different based on prior experience (conditioning)
How do placebo’s work?

Placebo effects are different based on prior experience (conditioning)

Condition with an opioid analgesic and then give placebo
= opioid mediated placebo effect
How do placebo’s work?

Placebo effects are different based on prior drug experience (conditioning)

Condition with an opioid analgesic and then give placebo
= opioid mediated placebo effect

Conditioning with a non-opioid analgesic then give placebo
= non-opioid medicated effect (CB1 cannabanoid receptor) (Benedetti 2011)
Other considerations

Placebo effects are stronger when the focus of study is placebo and not the
active drug (Vase 2002) (Experimental Placebo > RCT Placebo).

Different placebos work better for different people (de Craen 1999)

High tech placebos work better than low tech (Kaptchuk 1998)

More expensive placebos work better than less expensive ones (Waber
2008)

Two placebo tablets are better than one (Moerman 2001)

Placebo effects operated in a graded manner (Kaptchuk 2008)

There is no such thing as a placebo responder and non-responder . It is
context and situation specific.
The effects can go the other way - Nocebo
Nocebo effects

The negative counterpart of placebo, representing a worsening in
symptoms/signs based in the psychosocial context of a given therapy.

Several different mechanisms.

Alterations in verbal instructions change the nocebo component of certain
therapies (Benedetti 1997, Colloca & Finniss 2012).

Not limited to verbal instructions, includes informed consent (Kaptchuk
2006)
The model

“Specific” component to therapy

“Placebo” component to therapy (clearly complex and variable)

Consideration of a potential nocebo component

2+2=4?
The open-hidden paradigm

A drug is administered in two ways

Open: Given in full view of the patient

Hidden: Given to the patient when they do not know it is being given
The open-hidden paradigm

A drug is administered in two ways

Open: Given in full view of the patient
Drug plus psychosocial context

Hidden: Given to the patient when they do not know it is being given
The open-hidden paradigm

A drug is administered in two ways

Open: Given in full view of the patient
Drug plus psychosocial context

Hidden: Given to the patient when they do not know it is being given
Drug only
Morphine
Open
Hidden
Buprenorphine
Open
Hidden
Tramadol
Open
Hidden
Ketorolac
Open
Metamizol
Hidden
Open
Hidden
0
-1
-2
-3
Finniss & Benedetti 2007
Interactions between placebo mechanisms and active drugs

Benedetti 1995

Randomised, double blinded placebo controlled trial of 93 post-operative
patients.

Compared the cholecystokinin antagonist (proglumide) to placebo.

Involved using an “open” and “hidden” administration.

Compared to a no treatment, natural history group.
Benedetti F, Amanzio M et al, 1995
Benedetti F, Amanzio M et al, 1995
0.5
No Treatment
Placebo
CCK antagonist (Open
Administration)
CCK antagonist (Hidden
Administration)
0
Pain Reduction
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
Finniss & Benedetti 2006
Conclusions

2 + 2 doesn’t equal 4.

Giving a placebo in a clinical trial assesses responsiveness in the context
of a clinical trial, not “real practice”.

It is likely that placebo mechanisms interact with the index therapy

We can measure placebo effects in almost any setting but need to
understand what it tells us

From the research perspective, alternatives such as open-hidden paradigm
may represent different options for assessing synergistic actions between
placebo mechanisms on drug mechanism.

Very exciting area – the focus should be on better understanding
components of placebo effects and figuring out how to enhance them.
Acknowledgements

Prof Michael Cousins

Prof Don Price

Prof Michael Nicholas

Prof Dan Moerman

Dr Charles Brooker

Prof Ted Kaptchuk

Prof Fabrizio Benedetti

Dr Frank Miller

Dr Luana Colloca

Dr Ron Kupers