1. Clinical and Applied Physiology Program
at the
Department of Neuroscience
University of Turin Medical School
Turin, Italy
/ fabrizio.benedetti

2. Symbols
molecules
RECEPTORS
Drugs
Therapeutic
effects
Negative
effects

3. evolution

4. Pre-operative phase 1st post-operative day 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

5. Consultation Two weeks later Thomas (1987) Br Med J 294: 1200 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
Consultation
Two weeks later
This treatment will certainly
make you better
% who got better 64
I am not sure that this treatment
will have an effect
% who got better 39

6. Placebo administration
1st model:
Placebo administration
2nd model:
Open-hidden paradigm
This treatment will certainly
make you better

7. Words Sight Touch Smell Dummy treatment Medical treatment
Placebo effect = Context effect
Words
Sight
Touch
Dummy treatment
Medical treatment
Smell

8. Effect PSYCHOSOCIAL CONTEXT Conscious Unconscious COGNITION
Conditioned
response
COGNITION
Expectation
Belief
Trust
Hope
Conditioned
stimulus
Effect
Unconditioned
stimulus
(e.g. drug)

9. 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

10. Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552

11. 30
Pain
tolerance
(minutes) 25 20 15
DAY1 DAY2 DAY3 DAY4 DAY5
Zubieta et al. (2005) J. Neurosci. 25: 7754 –7762
MOR
MOR
PLA
NAL
Amanzio & Benedetti (1999) J. Neurosci. 19:

12. Remifentanil Placebo ACC PAG Pons Medulla
Petrovic et al. (2002) Science 295:

13. Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552

14. 3
Pain
intensity
(NRS) 2 1
Control
Nocebo-
induced
anxiety
PROGLUMIDE
CCK-A (CCK-1)
CCK-B (CCK-2)
receptor
antagonist
Benedetti et al. (1997) Pain 71:

15. Placebo
suggestions
Nocebo
suggestions
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6:

17. Nocebo
suggestions
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6:

18. 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

19. Parkinson’s disease Decrease of raclopride binding
de la Fuente-Fernandez et al. ( 2001) Science 293:

21. P r e – p l a c e b o
P o s t – p l a c e b o

22. Firing rate (spikes/s)
Benedetti et al. (2004) Nature Neurosci, 7:

23. Placebo administration
1st model:
Placebo administration
2nd model:
Open-hidden paradigm
This treatment will certainly
make you better

24. Benedetti et al. (1995) Lancet 346: 1231

25. hidden drug
Benedetti et al. (1995) Lancet 346: 1231

26. Open injection Hidden injection BUPRENORPHINE TRAMADOL KETOROLAC
computer
Open injection
Hidden injection
BUPRENORPHINE
TRAMADOL
KETOROLAC
METAMIZOL
open
hidden
open
hidden
open
hidden
open
hidden
Pharmacodynamic
effect -1
Pain reduction
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:

27. 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

28. Cognitive impairment
Benedetti et al (2006) Pain 121:

29. P l a c e b o
buprenorphine
1.2
1.15 mg/patient
1.0
0.8
-33.8%
buprenorphine
request
0.76 mg/patient
0.6
Buprenorphine intake/patient (mg)
Comparison between natural history, double blind administration and deceptive administration. Note the reduction of narcotic intake with the deceptive paradigm
0.4
0.2 10 20 30 40 50 60 70
Pollo et al. (2001) Pain 93: 77-84
Hours from surgery

30. Symbols Drugs Is mind as real as matter? Therapeutic Negative effects
molecules
RECEPTORS
Drugs
Therapeutic
effects
Negative
effects

31. Clinical and Applied Physiology Program
at the
Department of Neuroscience
University of Turin Medical School
Turin, Italy
/ fabrizio.benedetti
NEUROLOGY
Bruno Bergamasco
Leonardo Lopiano
Innocenzo Rainero
Giovanni Asteggiano
Luisella Tarenzi
Elena Torre
NEUROPHYSIOLOGY
Luana Colloca
Antonella Pollo
Sergio Vighetti
SURGERY
Giuliano Maggi
Caterina Casadio
Anna Arslanian
PSYCHOLOGY
Martina Amanzio
Claudia Arduino
Sara Costa
RESPIRATORY
PATHOPHYSIOLOGY
Sergio Baldi
NEUROSURGERY
Michele Lanotte
Antonio Melcarne