Placebo analgesia

Predrag Petrovic, MD, PhDKarolinska Institute, Stockholm, Sweden

Wellcome Institute of congnitive Neuroscience, London, UK

Cognition and pain

Ret

SBlSTTaSTT

Amy

PAG

PBn

dlPT / LC

RVM

mObfc

vmPfc

rACC

cACC

lObfc

Ant Ins

Post Ins

MDvcILVMp/bVMP VPL VPI

S2 / iPC

S1Hyp

vlPFC

Basal gangliaBasal ganglia

Main effect of pain

Petrovic et al Science 295 (1737-1740) 2003

Jackson et al Neuroimage 771-779 2005

Can we feel pain wihout noxious input

Jackson et al Neuroimage 771-779 2005

Can we feel pain wihout noxious input

Anticipation of pain

Jensen et al Neuron 40 1251-1257 2003

Empathy for pain

Singer et al Science 1157-1152 2004

vs.

Saarelet al Cerebral Cortex 2006

Empathy for pain

Petrovic et al Pain 85 (1-2) 2000

Distraction and pain

?

Cognitive modulation of pain

Placebo analgesia

Bottlenecks in Placebo analgesia

Expectation Opioid system

Pain presentation

Treatment expectation and Placebo analgesia

Expectation manipulationand learning

Placebo manipulation

Rating: 75 Rating: 25 Rating: 50

Voundouris et al J Per Soc Psychol 48 (47-53) 1985Voundouris et al pain 38 (109-116) 1989Voundouris et al pain 43 (121-128) 1990Montgomery and Kirsch Pain 72 (107-113) 1997

Placebo cream Placebo cream

Opioid analgesia Placebo analgesia

Naloxone

- -

The Opioid system and Placebo analgesia

pop wop

ppl wpl

wp

HeatPain

Non-painfulWarrm stim

Opioids (remifentanil)

Placebo (saline)

No treatment

Placebo and opioid analgesia

Petrovic et al Science 295 (1737-1740) 2003

Pain network

Petrovic et al Science 295 (1737-1740) 2003

Opioid effects and Placebo analgesia

(PPL – P)(POP+WOP)-(P+W)

Petrovic et al Science 295 (1737-1740) 2003

Orbitofrontal cortex

(PPL – P)

Petrovic et al Science 295 (1737-1740) 2003

Kong et al. J Neurosci. 2006 Jan 11;26(2):381-8.

Placebo and expectation modulation

Bingel et al. Pain. 2006 Jan;120(1-2):8-15

Placebo and expectation modulation

Wager et al. Science. 2004 Feb 20;303(5661):1162-7.

Placebo and expectation modulation

Wager et al. Science. 2004 Feb 20;303(5661):1162-7.

Placebo and expectation modulation

Lieberman et al. Neuroimage. 2004 May;22(1):447-55.

Placebo in chronic pain patients

Placebo analgesia effect- activation of cognitive modulatory network

ACC and Placebo

Opioid effects and Placebo analgesia

Petrovic et al Science 295 (1737-1740) 2003

The Cortical Opioid System

Rostral ACC

Willoch et al 1999

High Placebo responders Low Placebo responders

Opioid analgesia

(POP-P)(POP-P)

Petrovic et al Science 295 (1737-1740) 2003

Opioid receptor imaging

Zubieta et al 2005

Filelds et al Nature NeuroscienceReviews 2004

POP PPL P

Regression analysis

Petrovic et al Science 295 (1737-1740) 2003

Emotional Counting Stroop

Counting Stroop

ThreeThreeThreeThree

MurderMurderMurderMurder

Bush et a. Trends in Cognitive Sciences 4 (6) 2000

ACC and Cognition - Conflict monitoring or conflict resolution ?

• Anterior Cingulate Cortex: – Interaction with cognitive attentional systems

that regulate conflicting processes.– Modulation of pain processing through opioid

system.

Obfc / vlPFC and Placebo

Placebo. Petrovic et al 2002

Petrovic et al Science 295 (1737-1740) 2003

Opioid effects:

Placebo effects:

Opioid effects:

Placebo effects:

Relation between rACC and vlPFC in Placebo 1

Orbitofrontal cortex- goals and expectations

Orbitofrontal cortex- goals and expectations

Orbitofrontal cortex- goals and expectations

Aversive temporal difference prediction error

Seymour et al Nature Neuroscience 8 (1234-1240) 2005

• 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.

Emotional Placebo

Emotional Placebo

International Affective Picture System (IAPS)

Pain presentation

Manipulation of treatment expectation

Expectation manipulationand learning

Placebo manipulation

Rating: 75 Rating: 25 Rating: 50

Voundouris et al J Per Soc Psychol 48 (47-53) 1985Voundouris et al pain 38 (109-116) 1989Voundouris et al pain 43 (121-128) 1990Montgomery and Kirsch Pain 72 (107-113) 1997

Placebo cream Placebo cream

Lanexate i.v.

Bezodiazepines i.v.

5129

61

IAPS IAPS IAPS

Day 1 – Induction of expectation

Rating of unpleasantness

Day 2 - fMRI of the placebo effect

IAPS IAPSx3

Rating of unpleasantness

36

Information:Bezodiazepines(Anxiety reducing drug)

51

Information:Lanexate(No anxiety reduction)

Placebo och unpleasantness- activation of cognitive modulatory network

Petrovic et al Neuron - In Press

Placebo och unpleasantness- correlation with the expectation effect

Petrovic et al Neuron - In Press

Relation between rACC and vlPFC in Placebo

PET-study fMRI-study

Prof Martin IngvarProf Per HanssonProf Eija Kalso

Katrina CarlssonKarl Magnus Petersson

Per Hamid GhatanPeter Fransson

Jesper Andersson