Clinical and Applied Physiology Programat theDepartment of NeuroscienceUniversity of Turin Medical SchoolTurin, Italy

www.personalweb.unito.it / fabrizio.benedetti

Therapeutic effects

Negative effects

Egbert et al. (1964)N Engl J Med 270: 825

Post-operative painPre-operative phase 1st post-operative day

Pain intensity

Pain intensity

1.187

1.735

Morphine intake 26 mg

Morphine intake 38 mg

Thomas (1987)Br Med J 294: 1200

CoughSore throatColdAbdominal painBack painGiddinessLeg painHeadacheTirednessChest painNasal congestionMuscular painEarachePainful armBreast painNeck pain

I am not sure that this treatment will have an effect

This treatment will certainly make you better

Consultation Two weeks later

% who got better 64

% who got better 39

This treatment will certainly make you better

1st model:Placebo administration

2nd model:Open-hidden paradigm

Placebo effect = Context effect

Medical treatmentDummy treatment

COGNITION• Expectation• Belief• Trust• Hope

Conditioned stimulus

Unconditioned stimulus (e.g. drug)

Conditioned response

EffectEffect

UnconsciousConscious

ICD-10 of the World Health OrganizationA00-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

Placebo-related effects

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

DAY1 DAY2 DAY3 DAY4 DAY5

MOR MOR PLA

NAL

Amanzio & Benedetti (1999) J. Neurosci. 19: 484-94

Zubieta et al. (2005) J. Neurosci. 25: 7754 –7762

Paintolerance(minutes)

15

20

25

30

Remifentanil

ACCACC

PAGPAG

MedullaMedulla

PonsPons

Petrovic et al. (2002) Science 295: 1737-40

Placebo

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

0

1

2

3

Painintensity (NRS)

Control Nocebo-inducedanxiety

Benedetti et al. (1997) Pain 71: 135-140

PROGLUMIDECCK-A (CCK-1)CCK-B (CCK-2)receptorantagonist

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

Nocebosuggestions

Placebosuggestions

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

Nocebosuggestions

ICD-10 of the World Health OrganizationA00-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

Placebo-related effects

de la Fuente-Fernandez et al. ( 2001) Science 293: 1164-6

Parkinson’s disease

Decrease ofraclopride binding

P r e – p l a c e b o

P o s t – p l a c e b o

Firi

ng r

ate

(spi

kes/

s)

30 sBenedetti et al. (2004) Nature Neurosci, 7: 587-588

This treatment will certainly make you better

1st model:Placebo administration

2nd model:Open-hidden paradigm

Benedetti et al. (1995) Lancet 346: 1231

hidd

en d

rug

Benedetti et al. (1995) Lancet 346: 1231

0

Pain

reduct

ion

BUPRENORPHINE TRAMADOL KETOROLAC METAMIZOL

open openopen openhidden hiddenhidden hidden

-1

-2

-3

Open injection Hidden injection

computer

Pharmacodynamic effect

Psychological effect

Benedetti et al (1995) Lancet 346: 1231Amanzio et al. (2001) Pain 90:205-15Colloca et al (2004) Lancet Neurol. 3: 679-684

ICD-10 of the World Health OrganizationA00-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

Placebo-related effects

Cognitive impairment

Benedetti et al (2006) Pain 121: 133-144

0

1.2

0.6

0 10 70Hours from surgery

Bu

pre

norp

hin

e in

take/p

ati

en

t (m

g)

0.76 mg/patient

1.15 mg/patient

20 30 40 50 60

1.0

0.8

0.4

0.2

buprenorphine request

-33.8%

P l a c e b o

buprenorphine

Pollo et al. (2001) Pain 93: 77-84

Is mind as real as matter?

Therapeutic effects

Negative effects

Clinical and Applied Physiology Programat theDepartment of NeuroscienceUniversity of Turin Medical SchoolTurin, Italy

www.personalweb.unito.it / fabrizio.benedetti

NEUROPHYSIOLOGY

Luana CollocaAntonella PolloSergio Vighetti

PSYCHOLOGY

Martina AmanzioClaudia ArduinoSara Costa

NEUROLOGY

Bruno BergamascoLeonardo LopianoInnocenzo RaineroGiovanni AsteggianoLuisella TarenziElena Torre

SURGERY

Giuliano MaggiCaterina CasadioAnna Arslanian

RESPIRATORYPATHOPHYSIOLOGY

Sergio Baldi

NEUROSURGERY

Michele LanotteAntonio Melcarne