1. Placebo analgesia Predrag Petrovic, MD, PhD
Karolinska Institute, Stockholm, Sweden
Wellcome Institute of congnitive Neuroscience, London, UK

2. Cognition and pain

3. 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

4. Main effect of pain
Petrovic et al Science 295 ( ) 2003

10. Can we feel pain wihout noxious input
Jackson et al Neuroimage

11. Can we feel pain wihout noxious input
Jackson et al Neuroimage

12. Anticipation of pain
Jensen et al Neuron

13. Empathy for pain
Singer et al Science

14. Empathy for pain
vs.
Saarelet al Cerebral Cortex 2006

15. 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

16. ?

17. Cognitive modulation of pain

18. Placebo analgesia

19. Bottlenecks in Placebo analgesia
Expectation
Opioid system

20. 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

21. The Opioid system and Placebo analgesia - - Opioid analgesia
Naloxone

22. 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

23. Pain network
Petrovic et al Science 295 ( ) 2003

24. Opioid effects and Placebo analgesia
(POP+WOP)-(P+W)
(PPL – P)
Petrovic et al Science 295 ( ) 2003

25. Orbitofrontal cortex (PPL – P)
Petrovic et al Science 295 ( ) 2003

26. Placebo and expectation modulation
Kong et al. J Neurosci Jan 11;26(2):381-8.

27. Placebo and expectation modulation
Bingel et al. Pain Jan;120(1-2):8-15

28. Placebo and expectation modulation
Wager et al. Science Feb 20;303(5661):

29. Placebo and expectation modulation
Wager et al. Science Feb 20;303(5661):

30. Placebo in chronic pain patients
Lieberman et al. Neuroimage May;22(1):

31. Placebo analgesia effect - activation of cognitive modulatory network

32. ACC and Placebo

33. Opioid effects and Placebo analgesia
Petrovic et al Science 295 ( ) 2003

34. The Cortical Opioid System
Rostral ACC
Willoch et al 1999

35. Opioid analgesia High Placebo responders Low Placebo responders
(POP-P)
(POP-P)
Petrovic et al Science 295 ( ) 2003

36. Opioid receptor imaging
Zubieta et al 2005

37. Filelds et al Nature NeuroscienceReviews 2004

38. POP PPL P Regression analysis
Petrovic et al Science 295 ( ) 2003

39. 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

40. Anterior Cingulate Cortex:
Interaction with cognitive attentional systems that regulate conflicting processes.
Modulation of pain processing through opioid system.

41. Obfc / vlPFC and Placebo

42. Placebo. Petrovic et al 2002
Petrovic et al Science 295 ( ) 2003

43. Opioid effects:
Placebo effects:

44. Opioid effects:
Placebo effects:

45. Relation between rACC and vlPFC in Placebo 1

46. - goals and expectations
Orbitofrontal cortex
- goals and expectations

47. - goals and expectations
Orbitofrontal cortex
- goals and expectations

48. - goals and expectations
Orbitofrontal cortex
- goals and expectations

49. Aversive temporal difference prediction error
Seymour et al Nature Neuroscience 8 ( ) 2005

50. 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.

51. Emotional Placebo

52. Emotional Placebo

53. International Affective Picture System (IAPS)

54. 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

55. Day 1 – Induction of expectation
Bezodiazepines i.v.
Lanexate i.v.
IAPS
IAPS
IAPS 61 51 29
Rating of unpleasantness

56. 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

57. Placebo och unpleasantness
- activation of cognitive modulatory network
Petrovic et al Neuron - In Press

58. Placebo och unpleasantness - correlation with the expectation effect
Petrovic et al Neuron - In Press

59. Relation between rACC and vlPFC in Placebo
PET-study
fMRI-study

61. Prof Martin Ingvar
Prof Per Hansson
Prof Eija Kalso
Katrina Carlsson
Karl Magnus Petersson
Per Hamid Ghatan
Peter Fransson
Jesper Andersson