Clinical and Applied Physiology Program
at the
Department of Neuroscience
University of Turin Medical School
Turin, Italy
www.personalweb.unito.it / fabrizio.benedetti
Therapeutic
effects
Negative
effects
Egbert et al. (1964)
N Engl J Med 270: 825
Post-operative pain
Pre-operative phase
1st post-operative day
Pain intensity
1.187
Morphine intake
26 mg
Pain intensity
1.735
Morphine intake
38 mg
Thomas (1987)
Br Med J 294: 1200
Consultation
Cough
Sore throat
Cold
Abdominal pain
Back pain
Giddiness
Leg pain
Headache
Tiredness
Chest pain
Nasal congestion
Muscular pain
Earache
Painful arm
Breast pain
Neck pain
Two weeks later
This treatment will certainly
make you better
% who got better
64
% who got better
39
I am not sure that this treatment
will have an effect
1st model:
Placebo administration
This treatment will certainly
make you better
2nd model:
Open-hidden paradigm
Placebo effect = Context effect
Dummy
Medical treatment
treatment
Conscious
Unconscious
Conditioned
response
COGNITION
• Expectation
• Belief
• Trust
• Hope
Effect
Conditioned
stimulus
ICD-10 of the World Health Organization
Placebo-related effects
A00-B99 Certain infectious and parasitic diseases
C00-D48 Neoplasms
D50-D89 Diseases of the blood and blood-forming organs and
certain disorders involving the immune mechanism
Some immune mediators (IL-2, IFN-gamma, leukocytes.....)
(Giang et al 1996; Goebel et al 2002)
E00-E90 Endocrine, nutritional and metabolic diseases
Some hormones (growth hormone, cortisol.......) (Benedetti et al. 2003)
F00-F99 Mental and behavioural disorders
Major depression (Leuchter et al. 2002; Mayberg et al. 2002)
Anxiety (Benedetti et al 2003, Petrovic et al 2005)
DBS-induced emotions (Benedetti et al 2004)
G00-G99 Diseases of the nervous system
Pain (Levine et al 1978; Benedetti 1996; Amanzio & Benedetti 1999; Petrovic
et al 2002; Wager et al 2004; Lorenz et al 2005; Zubieta et al 2005)
Parkinson’s disease (de la Fuente-Fernandez et al 2001; Benedetti et al
2004)
H00-H59 Diseases of the eye and adnexa
H60-H95 Diseases of the ear and mastoid process
I00-I99 Diseases of the circulatory system
Autonomic control of heart (Pollo et al 2003; Lanotte et al 2005)
J00-J99 Diseases of the respiratory system
Drug-induced respiratory depression (Benedetti et al 1998, 1999)
K00-K93 Diseases of the digestive system
Irritable bowel syndrome (Lieberman et al 2004; Vase et al 2005)
L00-L99 Diseases of the skin and subcutaneous tissue
M00-M99 Diseases of the musculoskeletal system and
connective tissue
N00-N99 Diseases of the genitourinary system
O00-O99 Pregnancy, childbirth and the puerperium
P00-P96 Certain conditions originating in the perinatal period
Q00-Q99 Congenital malformations, deformations and
chromosomal abnormalities
R00-R99 Symptoms, signs and abnormal clinical and laboratory
findings, not elsewhere classified
S00-T98 Injury, poisoning and certain other consequences of
external causes
V01-Y98 External causes of morbidity and mortality
Z00-Z99 Factors influencing health status and contact with
health services
U00-U99 Codes for special purposes
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552
30
Pain
tolerance
(minutes)
25
20
15
DAY1
DAY2
DAY3
MOR
MOR
DAY4
DAY5
PLA
NAL
Amanzio & Benedetti (1999) J. Neurosci. 19: 484-94
Zubieta et al. (2005) J. Neurosci. 25: 7754 –7762
Remifentanil
Placebo
ACC
PAG
Pons
Medulla
Petrovic et al. (2002) Science 295: 1737-40
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552
3
Pain
intensity
(NRS)
2
1
0
Control
Benedetti et al. (1997) Pain 71: 135-140
Noceboinduced
anxiety
PROGLUMIDE
CCK-A (CCK-1)
CCK-B (CCK-2)
receptor
antagonist
Nocebo
suggestions
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552
Placebo
suggestions
Nocebo
suggestions
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552
ICD-10 of the World Health Organization
Placebo-related effects
A00-B99 Certain infectious and parasitic diseases
C00-D48 Neoplasms
D50-D89 Diseases of the blood and blood-forming organs and
certain disorders involving the immune mechanism
Some immune mediators (IL-2, IFN-gamma, leukocytes.....)
(Giang et al 1996; Goebel et al 2002)
E00-E90 Endocrine, nutritional and metabolic diseases
Some hormones (growth hormone, cortisol.......) (Benedetti et al. 2003)
F00-F99 Mental and behavioural disorders
Major depression (Leuchter et al. 2002; Mayberg et al. 2002)
Anxiety (Benedetti et al 2003, Petrovic et al 2005)
DBS-induced emotions (Benedetti et al 2004)
G00-G99 Diseases of the nervous system
Pain (Levine et al 1978; Benedetti 1996; Amanzio & Benedetti 1999; Petrovic
et al 2002; Wager et al 2004; Lorenz et al 2005; Zubieta et al 2005)
Parkinson’s disease (de la Fuente-Fernandez et al 2001; Benedetti et al
2004)
H00-H59 Diseases of the eye and adnexa
H60-H95 Diseases of the ear and mastoid process
I00-I99 Diseases of the circulatory system
Autonomic control of heart (Pollo et al 2003; Lanotte et al 2005)
J00-J99 Diseases of the respiratory system
Drug-induced respiratory depression (Benedetti et al 1998, 1999)
K00-K93 Diseases of the digestive system
Irritable bowel syndrome (Lieberman et al 2004; Vase et al 2005)
L00-L99 Diseases of the skin and subcutaneous tissue
M00-M99 Diseases of the musculoskeletal system and
connective tissue
N00-N99 Diseases of the genitourinary system
O00-O99 Pregnancy, childbirth and the puerperium
P00-P96 Certain conditions originating in the perinatal period
Q00-Q99 Congenital malformations, deformations and
chromosomal abnormalities
R00-R99 Symptoms, signs and abnormal clinical and laboratory
findings, not elsewhere classified
S00-T98 Injury, poisoning and certain other consequences of
external causes
V01-Y98 External causes of morbidity and mortality
Z00-Z99 Factors influencing health status and contact with
health services
U00-U99 Codes for special purposes
Parkinson’s disease
Decrease of
raclopride binding
de la Fuente-Fernandez et al. ( 2001) Science 293: 1164-6
Pre–placebo
Post–placebo
Firing rate (spikes/s)
Benedetti et al. (2004) Nature Neurosci, 7: 587-588
30 s
1st model:
Placebo administration
This treatment will certainly
make you better
2nd model:
Open-hidden paradigm
Benedetti et al. (1995) Lancet 346: 1231
Benedetti et al. (1995) Lancet 346: 1231
computer
Open injection
BUPRENORPHINE
open
hidden
Hidden injection
TRAMADOL
open
hidden
KETOROLAC
open
hidden
METAMIZOL
open
hidden
Pain reduction
0
-1
Pharmacodynamic
effect
Psychological
effect
-2
-3
Benedetti et al (1995) Lancet 346: 1231
Amanzio et al. (2001) Pain 90:205-15
Colloca et al (2004) Lancet Neurol. 3: 679-684
ICD-10 of the World Health Organization
Placebo-related effects
A00-B99 Certain infectious and parasitic diseases
C00-D48 Neoplasms
D50-D89 Diseases of the blood and blood-forming organs and
certain disorders involving the immune mechanism
Some immune mediators (IL-2, IFN-gamma, leukocytes.....)
(Giang et al 1996; Goebel et al 2002)
E00-E90 Endocrine, nutritional and metabolic diseases
Some hormones (growth hormone, cortisol.......) (Benedetti et al. 2003)
F00-F99 Mental and behavioural disorders
Major depression (Leuchter et al. 2002; Mayberg et al. 2002)
Anxiety (Benedetti et al 2003, Petrovic et al 2005)
DBS-induced emotions (Benedetti et al 2004)
G00-G99 Diseases of the nervous system
Pain (Levine et al 1978; Benedetti 1996; Amanzio & Benedetti 1999; Petrovic
et al 2002; Wager et al 2004; Lorenz et al 2005; Zubieta et al 2005)
Parkinson’s disease (de la Fuente-Fernandez et al 2001; Benedetti et al
2004)
H00-H59 Diseases of the eye and adnexa
H60-H95 Diseases of the ear and mastoid process
I00-I99 Diseases of the circulatory system
Autonomic control of heart (Pollo et al 2003; Lanotte et al 2005)
J00-J99 Diseases of the respiratory system
Drug-induced respiratory depression (Benedetti et al 1998, 1999)
K00-K93 Diseases of the digestive system
Irritable bowel syndrome (Lieberman et al 2004; Vase et al 2005)
L00-L99 Diseases of the skin and subcutaneous tissue
M00-M99 Diseases of the musculoskeletal system and
connective tissue
N00-N99 Diseases of the genitourinary system
O00-O99 Pregnancy, childbirth and the puerperium
P00-P96 Certain conditions originating in the perinatal period
Q00-Q99 Congenital malformations, deformations and
chromosomal abnormalities
R00-R99 Symptoms, signs and abnormal clinical and laboratory
findings, not elsewhere classified
S00-T98 Injury, poisoning and certain other consequences of
external causes
V01-Y98 External causes of morbidity and mortality
Z00-Z99 Factors influencing health status and contact with
health services
U00-U99 Codes for special purposes
Cognitive impairment
Benedetti et al (2006) Pain 121: 133-144
Placebo
buprenorphine
request
Buprenorphine intake/patient (mg)
buprenorphine
1.2
1.15 mg/patient
1.0
0.8
-33.8%
0.76 mg/patient
0.6
0.4
0.2
0
0
Pollo et al. (2001) Pain 93: 77-84
10
20
30
40
50
Hours from surgery
60
70
Is mind as real as matter?
Therapeutic
effects
Negative
effects
Clinical and Applied Physiology Program
at the
Department of Neuroscience
University of Turin Medical School
Turin, Italy
www.personalweb.unito.it / fabrizio.benedetti
NEUROPHYSIOLOGY
NEUROLOGY
Luana Colloca
Antonella Pollo
Sergio Vighetti
Bruno Bergamasco
Leonardo Lopiano
Innocenzo Rainero
Giovanni Asteggiano
Luisella Tarenzi
Elena Torre
PSYCHOLOGY
Martina Amanzio
Claudia Arduino
Sara Costa
SURGERY
Giuliano Maggi
Caterina Casadio
Anna Arslanian
NEUROSURGERY
RESPIRATORY
PATHOPHYSIOLOGY
Michele Lanotte
Antonio Melcarne
Sergio Baldi