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Placebo analgesia Predrag Petrovic, MD, PhD
Karolinska Institute, Stockholm, Sweden Wellcome Institute of congnitive Neuroscience, London, UK
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Cognition and pain
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vlPFC lObfc mObfc vmPfc Basal ganglia Basal ganglia rACC cACC Ant Ins Amy S1 Post Ins Hyp S2 / iPC PAG PBn Ret dlPT / LC VMP VPL VPI VMp/b IL MDvc RVM aSTT lSTT SB
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Main effect of pain Petrovic et al Science 295 ( ) 2003
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Can we feel pain wihout noxious input
Jackson et al Neuroimage
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Can we feel pain wihout noxious input
Jackson et al Neuroimage
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Anticipation of pain Jensen et al Neuron
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Empathy for pain Singer et al Science
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Empathy for pain vs. Saarelet al Cerebral Cortex 2006
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Distraction and pain • So which were the neural correlates for these behavioural findings? • When the pain-only condition was compared with the cold-only condition significant activations were observed in several sites, for example the primary somatosensory region for the stimulated hand and the secondary somatosensry areas bilaterally. • These activations were completely abolished when pain was subtracted with cold in the conditions where the subjects simultaneously solved the maze task and the pain was perceived as less unpleasant. Petrovic et al Pain 85 (1-2) 2000
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?
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Cognitive modulation of pain
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Placebo analgesia
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Bottlenecks in Placebo analgesia
Expectation Opioid system
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Expectation manipulation
Treatment expectation and Placebo analgesia Pain presentation Expectation manipulation and learning Placebo manipulation Placebo cream Placebo cream Rating: 75 Rating: 25 Rating: 50 Voundouris et al J Per Soc Psychol 48 (47-53) 1985 Voundouris et al pain 38 ( ) 1989 Voundouris et al pain 43 ( ) 1990 Montgomery and Kirsch Pain 72 ( ) 1997
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The Opioid system and Placebo analgesia - - Opioid analgesia
Naloxone
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Placebo and opioid analgesia Opioids (remifentanil)
Heat Pain Non-painful Warrm stim Opioids (remifentanil) pop wop Placebo (saline) ppl wpl No treatment p w Petrovic et al Science 295 ( ) 2003
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Pain network Petrovic et al Science 295 ( ) 2003
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Opioid effects and Placebo analgesia
(POP+WOP)-(P+W) (PPL – P) Petrovic et al Science 295 ( ) 2003
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Orbitofrontal cortex (PPL – P)
Petrovic et al Science 295 ( ) 2003
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Placebo and expectation modulation
Kong et al. J Neurosci Jan 11;26(2):381-8.
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Placebo and expectation modulation
Bingel et al. Pain Jan;120(1-2):8-15
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Placebo and expectation modulation
Wager et al. Science Feb 20;303(5661):
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Placebo and expectation modulation
Wager et al. Science Feb 20;303(5661):
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Placebo in chronic pain patients
Lieberman et al. Neuroimage May;22(1):
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Placebo analgesia effect - activation of cognitive modulatory network
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ACC and Placebo
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Opioid effects and Placebo analgesia
Petrovic et al Science 295 ( ) 2003
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The Cortical Opioid System
Rostral ACC Willoch et al 1999
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Opioid analgesia High Placebo responders Low Placebo responders
(POP-P) (POP-P) Petrovic et al Science 295 ( ) 2003
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Opioid receptor imaging
Zubieta et al 2005
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Filelds et al Nature NeuroscienceReviews 2004
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POP PPL P Regression analysis
Petrovic et al Science 295 ( ) 2003
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Conflict monitoring or conflict resolution ?
ACC and Cognition - Conflict monitoring or conflict resolution ? Emotional Counting Stroop Counting Stroop Murder Three Bush et a. Trends in Cognitive Sciences 4 (6) 2000
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Anterior Cingulate Cortex:
Interaction with cognitive attentional systems that regulate conflicting processes. Modulation of pain processing through opioid system.
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Obfc / vlPFC and Placebo
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Placebo. Petrovic et al 2002 Petrovic et al Science 295 ( ) 2003
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Opioid effects: Placebo effects:
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Opioid effects: Placebo effects:
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Relation between rACC and vlPFC in Placebo 1
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- goals and expectations
Orbitofrontal cortex - goals and expectations
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- goals and expectations
Orbitofrontal cortex - goals and expectations
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- goals and expectations
Orbitofrontal cortex - goals and expectations
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Aversive temporal difference prediction error
Seymour et al Nature Neuroscience 8 ( ) 2005
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Anterior Cingulate Cortex:
Interaction with cognitive attentional systems that regulate conflicting processes. Modulation of pain processing through opioid system. Orbitofrontal Cortex: Emotional and motivational goals and expectations. Computing errors between expected and real outcome.
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Emotional Placebo
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Emotional Placebo
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International Affective Picture System (IAPS)
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Expectation manipulation
of treatment expectation Pain presentation Expectation manipulation and learning Placebo manipulation Placebo cream Placebo cream Rating: 75 Rating: 25 Rating: 50 Voundouris et al J Per Soc Psychol 48 (47-53) 1985 Voundouris et al pain 38 ( ) 1989 Voundouris et al pain 43 ( ) 1990 Montgomery and Kirsch Pain 72 ( ) 1997
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Day 1 – Induction of expectation
Bezodiazepines i.v. Lanexate i.v. IAPS IAPS IAPS 61 51 29 Rating of unpleasantness
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Day 2 - fMRI of the placebo effect
Information: Lanexate (No anxiety reduction) Information: Bezodiazepines (Anxiety reducing drug) IAPS IAPS x3 51 36 Rating of unpleasantness
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Placebo och unpleasantness
- activation of cognitive modulatory network Petrovic et al Neuron - In Press
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Placebo och unpleasantness - correlation with the expectation effect
Petrovic et al Neuron - In Press
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Relation between rACC and vlPFC in Placebo
PET-study fMRI-study
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Prof Martin Ingvar Prof Per Hansson Prof Eija Kalso Katrina Carlsson Karl Magnus Petersson Per Hamid Ghatan Peter Fransson Jesper Andersson
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