Fabrizio Benedetti - ISCTMFabrizio Benedetti University of Turin Medical School, Turin, Italy...
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Fabrizio Benedetti University of Turin Medical School, Turin, Italy Plateau Rosà Labs, Plateau Rosà, Switzerland Can basic and clinical research on placebo lead to evidence-based clinical trials?
Transcript of Fabrizio Benedetti - ISCTMFabrizio Benedetti University of Turin Medical School, Turin, Italy...
Fabrizio Benedetti
University of Turin Medical School, Turin, Italy Plateau Rosà Labs, Plateau Rosà, Switzerland
Can basic and clinical research on placebo
lead to evidence-based clinical trials?
OVERVIEW
Patients’ expectations are crucial for the therapeutic outcome
Repeated exposure to drugs may lead to substantial placebo responses
Communication across participants may affect the therapeutic outcome
Placebo responders and nonresponders can be identified a priori
Evidence from basic and clinical research
Ritual of therapeutic act
Psychosocial context
D2-D3 CB1 mu
dopamine cannabinoids opioids
Benedetti (2008) Annu Rev Pharmacol Toxicol
Benedetti (2014) Neuron
anti-Parkinson cannabis narcotics
D r u g s
Benedetti et al (1995) Lancet
Colloca et al (2004) Lancet Neurol
Benedetti et al (2016) Lancet Neurol
No expectation
Benedetti et al (1995) Lancet
Colloca et al (2004) Lancet Neurol
Benedetti et al (2016) Lancet Neurol
0Pain
reduct
ion
BUPRENORPHINE TRAMADOL KETOROLAC METAMIZOL
open openopen openhidden hiddenhidden hidden
-1
-2
-3
Open injection Hidden injection
computer
Pharmacodynamic
effect
Psychological
effect
No expectation
Benedetti et al (1995) Lancet
Colloca et al (2004) Lancet Neurol
Benedetti et al (2016) Lancet Neurol
TRIAL Met#2(Colloca and Benedetti, Nature Rev Neurosci 6: 545-552, 2005)
Is metamizol (300 mg) effective in post-thymectomy pain?
Open metamizol injection group (N=10)
Hidden metamizol injection group (N=10)Informed consent “You will receive metamizol but you don’t know when”
Double blind
Pa
in in
ten
sity (
NR
S)
0 1 2 3 4 5 6
0
2
4
6
8
10
Pa
in in
ten
sity (
NR
S)
0
2
4
6
8
10
Open (expected) injection of metamizol
Hidden (unexpected) injection of metamizol
hours
No
expectation
R e m i f e n t a n i l
Positive
expectation
Negative
expectation
No
expectation
0P
ain
de
cre
ase
-1
-2
-3
GET
TOLD
S a l i n e R e m i f e n t a n i l I n t e r r u p t i o n
DLPFC
ACC
Hippocampus
Bingel et al (2011) Science Trans Med
OVERVIEW
Patients’ expectations are crucial for the therapeutic outcome
Repeated exposure to drugs may lead to substantial placebo responses
Communication across participants may affect the therapeutic outcome
Placebo responders and nonresponders can be identified a priori
Evidence from basic and clinical research
InhibitionActivation
CB1
cannabinoid
receptor
opioid
receptor
Memory
ON
Memory
ON
Previous activation of
opioid receptorsPrevious activation of
CB1 cannabinoid receptors
Benedetti et al. (2011) Nature Med
Activation likehood estimation (ALE) meta-analysis
Lack of
efficacy
withdrawal
Adverse
event
withdrawal
Screen Randomise
Active
Control
Assessment
McQuay et al (2008) Pain
Titrate
to
effect
with
active
Enriched Enrolment with Randomized Withdrawal
Increased
placebo
responses
OVERVIEW
Patients’ expectations are crucial for the therapeutic outcome
Repeated exposure to drugs may lead to substantial placebo responses
Communication across participants may affect the therapeutic outcome
Placebo responders and nonresponders can be identified a priori
Evidence from basic and clinical research
1 day
2 days
3 days
4 days
5 days
6 days
7 days
Benedetti et al (2014) Pain
% incre
ase
200
100
0
Socially infected(negative expectations)
Not informed(no expectations)
52% 86%
Benedetti et al (2014) Pain
Benedetti (2014) Neuron
Benedetti et al (2016) Lancet Neurol
% incre
ase
200
100
0
aspirin vs placeboaspirin vs placebo
with a pre-existing nocebo effect
Socially infected(negative expectations)
Not informed(no expectations)
52% 86%
Benedetti et al (2014) Pain
Benedetti (2014) Neuron
Benedetti et al (2016) Lancet Neurol
OVERVIEW
Patients’ expectations are crucial for the therapeutic outcome
Repeated exposure to drugs may lead to substantial placebo responses
Communication across participants may affect the therapeutic outcome
Placebo responders and nonresponders can be identified a priori
Evidence from basic and clinical research
Placebo non-responder Placebo responder
Genetics
Personality
Placebo non-responder Placebo responder
Suggestibility
Hypnotic susceptibilityDe Pascalis et al 2002
Derbyshire and Oakley 2013
Huber et al 2013
Optimism
PessimismGeers et al 2005, 2007, 2010
Dopamine-related
personality traits
(sensitivity to incentives
and rewards)Schweinhardt et al 2009
Ego-resiliency
Altruism
Angry hostilityPecina et al 2013
Learning……can create placebo responders
and non responders in the lab
Matching or mismatching what patients
expect and what they get
Placebo responderPlacebo non-responder
PLA Exp ANAGet ANA
Exp ANAGet ANA
PLA Exp ANAGet No ef
Exp ANAGet No ef
PLA
Colloca & Benedetti (2006) Pain
Benedetti & Frisaldi (2014) Pain Manag
CONCLUSIONS
Patients’ expectations should be assessed in all clinical trials
Drug history should be assessed carefully to ascertain possible learning effects
Communication across participants should be avoided
Future research should be aimed at better identifying placebo (non)responders
Evidence from basic and clinical research
NEUROPHYSIOLOGYElisa Frisaldi
Jennifer Durando
Sergio Vighetti
Antonella Pollo
Luana Colloca
PSYCHOLOGYElisa Carlino
Alessandro Piedimonte
Martina Amanzio
Claudia Arduino
Rosalba Rosato
Sara Palermo
Diletta Barbiani
Eleonora Camerone
NEUROLOGYLeonardo Lopiano
Maurizio Zibetti
Mario Rizzone
Innocenzo Rainero
Giovanni Asteggiano
THORACIC SURGERYGiuliano Maggi
Caterina Casadio
NEUROSURGERYMichele Lanotte
ENDOCRINOLOGYCatherine Blanchard
Wilma Thoen
Sara Dogue
NEUROIMAGINGCarlo Porro
Fausta Lui
Franco Cauda
University of Turin Medical School, Italy
Plateau Rosa Laboratories, Switzerland
Thanks to:
