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Dipartimento di Neuroscienze, Università degli Studi di Torinoe
Istituto Nazionale di Neuroscienze (INN)
www.personalweb.unito.it / fabrizio.benedettiwww.ist-nazionale-neuroscienze.unito.it
Placebo
Improvement
Biases
Detectionambiguity
Unidentifiedco-interventions
Psychosocial-psychobiologicalfactors
Pavlovianconditioning
Expectation
Rewardmechanisms
Anxietymechanisms
Spontaneousremission
Regression tothe mean
Placeboresponse
Antidepressants
Drug effect25%
Spontaneousremission
25%
Patients’expectations
50%
Kirsch and Sapirstein (1998) Prevention & Treatment
Placebo effect = Context effect
Medical treatmentDummy treatment
Conscious Unconscious
Conditionedstimulus
Unconditionedstimulus
(e.g. drug)
Conditionedresponse
EffectEffectCOGNITION• Expectation• Belief• Trust• Hope
DISEASE/SYSTEM TREATMENT MECHANISM________________________________________________________________________________________________Pain Placebo administration Expectation-induced activation of
Nocebo administration endogenous opioids and cholecystokininVerbal suggestions as well as of several brain regionsOpen vs hidden administration
________________________________________________________________________________________________Parkinson’s Placebo administration Expectation-induced release of dopamineDisease Nocebo administration in the striatum and changes of firing
Verbal suggestions pattern of subthalamic nucleus neuronsOpen vs hidden administration
________________________________________________________________________________________________Depression Placebo administration Changes of metabolic responses in different
brain regions (inhibition of 5-HT re-uptake?)________________________________________________________________________________________________Anxiety Placebo administration Change of activity of some brain regions
Open vs hidden diazepam________________________________________________________________________________________________Addiction Expected vs unexpected Changes of metabolic activity in
methylphenidate different brain regions________________________________________________________________________________________________Autonomicresponses to DBS Open vs hidden DBS Change of neuronal excitability in limbic areas________________________________________________________________________________________________Cardiovascular Placebo administration Reduction of β-adrenergic activity of heart________________________________________________________________________________________________Respiratory Pharmacological pre-conditioning Conditioning of opioid receptors in
with buprenorphine the respiratory centers________________________________________________________________________________________________Immune Pharmacological pre-conditioning Conditioning of some immune mediatorssystem with immunosuppressive drugs (e.g., IL-2, IFN-g, lymphocytes)________________________________________________________________________________________________Endocrine Pharmacological pre-conditioning Conditioning of some hormonessystem with 5-HT1B-1D receptor agonists (e.g., growth hormone, cortisol)
Benedetti (2008) Ann Rev Pharmacol Toxicol 48: 33-60
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552
Paintolerance(minutes)
15
20
25
30
Experimental ischemic arm pain
DAY1 DAY2 DAY3 DAY4 DAY5
MOR MOR PLA
NAL10mg
Amanzio & Benedetti (1999) J. Neurosci. 19: 484-94
Carfentanilµ-opioid receptor radiotracer
Zubieta et al. (2005) J. Neurosci. 25: 7754 –7762
Remifentanilµ-opioid receptor agonist
ACCACCPAGPAG
MedullaMedulla
PonsPons
Placebo
Petrovic et al. (2002) Science 295: 1737-40
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552
cortisol
ACTH
Pain
0 5 10
10
9
8
7
6
5
4
3
2
1
0
Pain
inte
nsity
(NR
S)
100
90
80
70
60
50
40
30
20
10
0
Pla
sma
AC
TH (p
g/m
l)
5 100
Pla
sma
corti
sol(
ug/l)
100
90
80
110
120
130
140
150
160
170
180
5 100
minutes
minutes
NOCEBO
Benedetti et al (2006) J Neurosci 26: 12014-12022minutes
cortisol
ACTH
Pain
0 5 10
10
9
8
7
6
5
4
3
2
1
0
Pain
inte
nsity
(NR
S)
100
90
80
70
60
50
40
30
20
10
0
Pla
sma
AC
TH (p
g/m
l)
5 100
Pla
sma
corti
sol(
ug/l)
100
90
80
110
120
130
140
150
160
170
180
5 100
minutes
minutes
Diazepam0.28 mg/kg
NOCEBO
Benedetti et al (2006) J Neurosci 26: 12014-12022minutes
cortisol
ACTH
Pain
0 5 10
10
9
8
7
6
5
4
3
2
1
0
Pain
inte
nsity
(NR
S)
100
90
80
70
60
50
40
30
20
10
0
Pla
sma
AC
TH (p
g/m
l)
5 100
Pla
sma
corti
sol(
ug/l)
100
90
80
110
120
130
140
150
160
170
180
5 100
minutes
minutes
NOCEBO CCK-A/B blockade
Proglumide1.5 mg/kg
Benedetti et al (2006) J Neurosci 26: 12014-12022minutes
cortisol
ACTH
Pain
NOCEBO
AnxietyCCK-A (CCK-1)IC50 = 6.3X10-3 M
CCK
CCK-B (CCK-2)IC50 = 11X10-3 M
Benedetti et al (2007) Neuroscience 147: 260-271
Nocebosuggestions
Placebosuggestions
µ-opioidreceptors
CCK A/Breceptors
Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552
DISEASE/SYSTEM TREATMENT MECHANISM________________________________________________________________________________________________Pain Placebo administration Expectation-induced activation of
Nocebo administration endogenous opioids and cholecystokininVerbal suggestions as well as of several brain regionsOpen vs hidden administration
________________________________________________________________________________________________Parkinson’s Placebo administration Expectation-induced release of dopamineDisease Nocebo administration in the striatum and changes of firing
Verbal suggestions pattern of subthalamic nucleus neuronsOpen vs hidden administration
________________________________________________________________________________________________Depression Placebo administration Changes of metabolic responses in different
brain regions (inhibition of 5-HT re-uptake?)________________________________________________________________________________________________Anxiety Placebo administration Change of activity of some brain regions
Open vs hidden diazepam________________________________________________________________________________________________Addiction Expected vs unexpected Changes of metabolic activity in
methylphenidate different brain regions________________________________________________________________________________________________Autonomicresponses to DBS Open vs hidden DBS Change of neuronal excitability in limbic areas________________________________________________________________________________________________Cardiovascular Placebo administration Reduction of β-adrenergic activity of heart________________________________________________________________________________________________Respiratory Pharmacological pre-conditioning Conditioning of opioid receptors in
with buprenorphine the respiratory centers________________________________________________________________________________________________Immune Pharmacological pre-conditioning Conditioning of some immune mediatorssystem with immunosuppressive drugs (e.g., IL-2, IFN-g, lymphocytes)________________________________________________________________________________________________Endocrine Pharmacological pre-conditioning Conditioning of some hormonessystem with 5-HT1B-1D receptor agonists (e.g., growth hormone, cortisol)
Benedetti (2008) Ann Rev Pharmacol Toxicol 48: 33-60
Video by Pollo and Benedettifrom the DATABASE of Nature Med 2005
table.mpg.2005
Parkinson’s disease
Decrease ofraclopride binding
de la Fuente-Fernandez et al. ( 2001) Science 293: 1164-6
D2 D3
dopamine
D2 D3
dopamine
SNrSNc
STN
GPe GPi
Thalamus
GABA
GABA
GABA
GABA-opioids
Glutamate
D1D2
Dorsal striatum(n. caudatus + putamen)
+
+Ventral striatum(n. accumbens)
raclopride
+Clinicalbenefit
Expectationof benefit
Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60
Benedetti et al. (2004) Nature Neurosci, 7: 587-588
Therapeuticeffects
Negativeeffects
D2-D3 CCK-A/B mu
dopamine CCK opioid
anti CCK-8 narcoticsparkinsonian
Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60
Benedetti et al. (1995) Lancet 346: 1231
hidde
n drug
Benedetti et al. (1995) Lancet 346: 1231
computer
Open injection Hidden injection
BUPRENORPHINE TRAMADOL KETOROLAC METAMIZOL
open hidden open hidden open hidden open hidden
0Pharmacodynamic
effect
Psychologicaleffect
Pain
redu
ctio
n
-1
-2
Benedetti et al (1995) Lancet 346: 1231Amanzio et al. (2001) Pain 90:205-15Colloca et al (2004) Lancet Neurol. 3: 679-684
-3
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
Pai
nin
tens
ity(N
RS
)
0 1 2 3 4 5 60
2
4
6
8
10
0
2
4
6
8
10
Open injection of metamizol
Hidden injection of metamizol
Pai
nin
tens
ity(N
RS
)
hours
IFN-γ, IL-2 5-HT1B-1D 5-HT re-uptake D2-D3 CCK-A/B µ-opioid β-adrenergic
immuno sumatriptan anti anti CCK narcotic β-blockersuppressive depressant parkinsonian antagonist
Psychosocial context
D r u g s
e x p e c t a t i o na n d / o r c o n d i t i o n i n g
Analgesia andcardiovascularsystem
Hyperalgesia
Parkinson
DepressionHormonalresponsesImmune
responses
Analgesia andrespiratorycenters
??
Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60
Dipartimento di Neuroscienze, Università degli Studi di Torinoe
Istituto Nazionale di Neuroscienze (INN)
www.personalweb.unito.it / fabrizio.benedettiwww.ist-nazionale-neuroscienze.unito.it
NEUROFISIOLOGIA
Antonella PolloLuana CollocaSergio Vighetti
PSICOLOGIA
Martina AmanzioClaudia ArduinoElisa Carlino
NEUROLOGIA
Leonardo LopianoInnocenzo RaineroGiovanni Asteggiano
CHIRURGIA
Giuliano MaggiCaterina CasadioAnna Arslanian
NEUROCHIRURGIA
Michele LanotteAntonio Melcarne