Placebos and Painkillers: Placebos and Painkillers: Is Mind as Real as Matter?Is Mind as Real as Matter?

Luana Colloca and Fabrizio BenedettiLuana Colloca and Fabrizio Benedetti2005 in Nature Reviews Neuroscience2005 in Nature Reviews Neuroscience

Jess BenjaminJess BenjaminSteele TaylorSteele TaylorCeleste ParotCeleste Parot

January 30, 2008January 30, 2008

http://www.annkullberg.com/Shows/2003/Hild.jpg

Pain OverviewPain Overview1) Nociceptive neuron stimulated

through compression, heat, or chemical irritation in periphery

2) Nociceptive neuron synapses on Nociceptive neuron synapses on projection neurons and interneuron projection neurons and interneuron networks in the dorsal horn networks in the dorsal horn

3) Myelinated neospinothalamic Myelinated neospinothalamic axons project fine information to axons project fine information to thalamic relay nucleusthalamic relay nucleus

1) Thalamus relays to primary and Thalamus relays to primary and associative somatonsensory associative somatonsensory corticescortices

2) Ultimately these regions project Ultimately these regions project back to brainstem, prefrontal, back to brainstem, prefrontal, limbic system, and thalamuslimbic system, and thalamus

4) Slow unmyelinated Slow unmyelinated paleospinothalamic axon paleospinothalamic axon collaterals project crude collaterals project crude information to multiple targets in information to multiple targets in brainstem and limbic systembrainstem and limbic system

1) Emotional and behavioral Emotional and behavioral responses to painful stimuliresponses to painful stimuli

2) Vaguely localized throbbing painVaguely localized throbbing pain

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http://www.laesieworks.com/spinal/pict/SpinalCord.jpg

Pain OverviewPain Overview1) Nociceptive neuron stimulated Nociceptive neuron stimulated

through compression, heat, or through compression, heat, or chemical irritation in peripherychemical irritation in periphery

2) Nociceptive neuron synapses on projection neurons and interneuron networks in the dorsal horn

3) Myelinated neospinothalamic Myelinated neospinothalamic axons project fine information to axons project fine information to thalamic relay nucleusthalamic relay nucleus

1) Thalamus relays to primary and Thalamus relays to primary and associative somatonsensory associative somatonsensory corticescortices

2) Ultimately these regions project Ultimately these regions project back to brainstem, prefrontal, back to brainstem, prefrontal, limbic system, and thalamuslimbic system, and thalamus

4) Slow unmyelinated Slow unmyelinated paleospinothalamic axon paleospinothalamic axon collaterals project crude collaterals project crude information to multiple targets in information to multiple targets in brainstem and limbic systembrainstem and limbic system

1) Emotional and behavioral Emotional and behavioral responses to painful stimuliresponses to painful stimuli

2) Vaguely localized throbbing painVaguely localized throbbing pain

www.nursece.com/onlinecourses/imagesPain/Fig2.gif

Pain OverviewPain Overview1) Nociceptive neuron stimulated Nociceptive neuron stimulated

through compression, heat, or through compression, heat, or chemical irritation in peripherychemical irritation in periphery

2) Nociceptive neuron synapses on Nociceptive neuron synapses on projection neurons and interneuron projection neurons and interneuron networks in the dorsal horn networks in the dorsal horn

3) Myelinated neospinothalamic axons project fine information to thalamic relay nucleus

1) Thalamus relays to primary and associative somatonsensory cortices

2) Ultimately these regions project back to brainstem, prefrontal, limbic system, and thalamus

4) Slow unmyelinated Slow unmyelinated paleospinothalamic axon paleospinothalamic axon collaterals project crude collaterals project crude information to multiple targets in information to multiple targets in brainstem and limbic systembrainstem and limbic system

1) Emotional and behavioral responses Emotional and behavioral responses to painful stimulito painful stimuli

2) Vaguely localized throbbing painVaguely localized throbbing pain

www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm

Pain OverviewPain Overview1) Nociceptive neuron stimulated Nociceptive neuron stimulated

through compression, heat, or through compression, heat, or chemical irritation in peripherychemical irritation in periphery

2) Nociceptive neuron synapses on Nociceptive neuron synapses on projection neurons and interneuron projection neurons and interneuron networks in the dorsal horn networks in the dorsal horn

3) Myelinated neospinothalamic Myelinated neospinothalamic axons project fine information to axons project fine information to thalamic relay nucleusthalamic relay nucleus

1) Thalamus relays to primary and Thalamus relays to primary and associative somatonsensory associative somatonsensory corticescortices

2) Ultimately these regions project Ultimately these regions project back to brainstem, prefrontal, back to brainstem, prefrontal, limbic system, and thalamuslimbic system, and thalamus

4) Slow unmyelinated paleospinothalamic axon collaterals project crude information to multiple targets in brainstem and limbic system

1) Emotional and behavioral responses to painful stimuli

2) Vaguely localized throbbing pain

www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm

Centrally Mediated Pain RegulationCentrally Mediated Pain Regulation

1)1) Appropriate activation of Appropriate activation of periaqueductal grey matter periaqueductal grey matter (PAG) in mesencephalon and (PAG) in mesencephalon and opioid networks in thalamusopioid networks in thalamus

Some Psychobiological Stimuli Associated With Internally

Generated Analgesia:

1) Conditioned Anticipation of Pain Relief

2) Pain in Other Areas

3) Emotional Well Being

4) Concentration/Meditation

5) Hypnosis

6) Gate-Mediated Mechanical Stimuli http://www.doctordeluca.com/Library/Pain/Graphics/CP1NewDis-F2.bmp

http://www.sciencemag.org/cgi/content/full/288/5472/1769

Centrally Mediated Pain RegulationCentrally Mediated Pain Regulation

1) Appropriate activation of Appropriate activation of periaqueductal grey periaqueductal grey matter (PAG) in matter (PAG) in mesencephalon occursmesencephalon occurs

2) PAG projects into nucleus raphe magnus (serotonergic) and locus ceruleus (noradrenergic) in rostral ventral medulla (RVM)

3) Serotonergic innervation of inhibitory opiodergic neurons

1) Dorsal Horn Interneurons2) Central Pain Processing

Regions

Opiod-Mediated Inhibition Occurs Via:1) K+ channel Activation

(Hyperpolarization)2) Ca2+ channel Deactivation

(Reduced NT Release)

3) Other Mechanisms

http://www.mona.uwi.edu/fpas/courses/physiology/neurophysiology/PainRapheFeedback.jpg

(notice the inhibition of retrograde substance p release into the periphery!)

Opioid Reinforcement Through Opioid Reinforcement Through Dopamine SignalingDopamine Signaling

1) Reinforcement/addiction may be associated with impact on dopamine signaling

1) Opiod mediated inhibition of GABAergic neurons tonically inhibiting DAergic neurons in ventral tegmental area (VTA) of mesencephalon

(off + off = on)1) DA release into nucleus

accumbens (reward center) and cognitive cortices

thebrain.mcgill.ca/.../i_03_cr_que_1a.jpg

Isolating the Placebo Analgesia Isolating the Placebo Analgesia Pathways:Pathways:

The Chemical PlayersThe Chemical Players• Remfentanil Remfentanil is an opioid is an opioid

agonistagonist

• Comparison of brain imaging Comparison of brain imaging during remfentanil exposure during remfentanil exposure and placebo-analgesia reveals and placebo-analgesia reveals similarities in the activated similarities in the activated pathwayspathways

• This supports the opioid This supports the opioid hypothesis of the placebo-hypothesis of the placebo-analgesic responseanalgesic response

www.ym.edu.tw/rcinn/images/cp1-fg3.png

Functional MRI

http://www.nida.nih.gov/NIDA_notes/NNVol16N2/Positron.jpg

Positron Emission Tomography

Isolating the Placebo Analgesia Isolating the Placebo Analgesia Pathways:Pathways:

The Chemical PlayersThe Chemical Players• ProglutamideProglutamide: a CCK antagonist : a CCK antagonist

that enhances placebo analgesia that enhances placebo analgesia due to the facilitation of due to the facilitation of expectation pathwaysexpectation pathways

• Based on double-blind paradigm Based on double-blind paradigm one can erroneously conclude one can erroneously conclude that Proglutamide has intrinsic that Proglutamide has intrinsic analgesic activityanalgesic activity

• PET imaging and open-hidden PET imaging and open-hidden paradigm provides more paradigm provides more accuracyaccuracy

• Therefore, Proglutamide IS the Therefore, Proglutamide IS the disturbance in double-blind disturbance in double-blind studiesstudies

http://www.nature.com/nrn/journal/v6/n7/fig_tab/nrn1705_F1.html

Isolating the Placebo Analgesia Isolating the Placebo Analgesia Pathways:Pathways:

The Chemical PlayersThe Chemical Players• NaloxoneNaloxone is the prototypical is the prototypical

opioid antagonist (and OD opioid antagonist (and OD antidote)antidote)

• Naloxone reliably blocks placebo Naloxone reliably blocks placebo induced analgesiainduced analgesia– But, But, only through conditioning only through conditioning

with previous opioid-analgesic with previous opioid-analgesic responsesresponses

– Non-opiod associated placebo Non-opiod associated placebo effects are naloxone insensitiveeffects are naloxone insensitive

• Sumatriptan (5-HT agonist)Sumatriptan (5-HT agonist)

• Therefore, naloxone also blocks Therefore, naloxone also blocks side-effects accompanying opioid-side-effects accompanying opioid-operating placebo responsesoperating placebo responses– Respiratory depressionRespiratory depression– Cardiac depressionCardiac depression

• Disturbance:Disturbance: In a double-blind In a double-blind study, naloxone appears to have a study, naloxone appears to have a hyperalgesic effect (but not in hyperalgesic effect (but not in open-hidden paradigms)open-hidden paradigms)