Transcript Document 7146895

Placebos and Painkillers:
Is Mind as Real as Matter?
Luana Colloca and Fabrizio Benedetti
2005 in Nature Reviews Neuroscience
http://www.annkullberg.com/Shows/2003/Hild.jpg
Jess Benjamin
John Steele Taylor
Celeste Parot
January 30, 2008
Background
Placebo
•A placebo is an inert substance that is administered in the identical manner
as the real, active drug.
•The placebo works on the power of suggestion alone and was once thought
of to have no biological effect on the body
•The placebo effect was therefore used as a mechanism to rule out any
cognitive belief or ‘power of positive thinking’ persuading the biological
therapeutic outcome of the drug.
Clinical Trials Today
Clinical trials test the validity of a certain drug by comparing the
side effects and therapeutic outcome with a placebo
Randomized Double-Blind Study: Neither the patient nor the
administrator of the drug know if he or she is administering the
placebo or the active drug
It has been previously assumed that the active drug is responsible
for the biological outcome
The psychobiological mechanisms
acting on the placebo effect
Expectation of Clinical Benefit – This mechanism indicates the ‘power of
positive thinking’ or the ‘power of suggestion’. This is a mechanism working
on the cognitive aspects of therapeutic outcome
Pavlovian Conditioning – This mechanism is more of the body’s response
to a therapeutic outcome.
•Conditioned Stimulus: How the patient is treated
•Unconditioned Stimulus: Response of the patient to the medication
Does there exist an actual biological mechanism responsible for
the effectiveness demonstrated by the placebo???
Yes….
Proglumide… (1995)
•An antagonist to cholecystokinin; an endogenous anti-opioid
peptide in the CNS
•Shown to be more effective in analgesia than the placebo
•Placebo shown to be more effective than no treatment
•Hidden injection of proglumide was completely ineffective
•Proglumide acts on placebo-activated opioid mechanisms
enhancing the placebo analgesic response
•Therefore; there is an actual, biological explanation of the
placebo effect
Top Down and Bottom Up Processing
Mechanisms typically involved in
attention
TOP DOWN: The brain is acting
in an intentional manner; in this
case the expectation pathway is
intentionally looking for and
controlling pain
BOTTOM UP: The brain is
responding from the pain; the
pain is felt first and as a result
higher regions of the brain
respond
http://www.nature.com/nrn/journal/v6/n7/fig_tab/nrn1705_F1.html
Is placebo clinical design able to
conclude a drug therapy is
effective?
The Heisenburg Uncertainty Principle applied to the placebo effect:
The dynamical disturbance will always cause uncertainty due to the activation
of expectation pathways
In order to test a drugs biological effectiveness (in the absence of
psychobiological influence) these expectation pathways need to be eliminated.
Bottom-up processing needs to occur, not top-down processing.
http://www.scripps.edu/cb/patapoutian/nocisensor.jpg
Pain Overview
1) Nociceptive neuron stimulated
through compression, heat, or
chemical irritation in periphery
2)
Nociceptive neuron synapses on
projection neurons and interneuron
networks in the dorsal horn
3)
Fast myelinated nociceptors synapse
on neospinothalamic neurons that
project fine information to thalamic
relay nucleus
1)
2)
4)
Thalamus relays to primary and
associative somatonsensory cortices
Ultimately these regions project back
to brainstem, prefrontal, limbic
system, and thalamus
Slow unmyelinated nociceptors
synapse on paleospinothalamic
neurons whose axon collaterals
project crude information to multiple
targets in brainstem and limbic
system
1)
2)
Emotional/behavioral responses
Vaguely localized throbbing pain
http://www.laesieworks.com/spinal/pict/SpinalCord.jpg
1)
Nociceptive neuron stimulated
through compression, heat, or
chemical irritation in periphery
Pain Overview
2) Nociceptive neuron synapses on
projection neurons and
interneuron networks in the
dorsal horn
3)
Fast myelinated nociceptors synapse
on neospinothalamic neurons that
project fine information to thalamic
relay nucleus
1)
2)
4)
Thalamus relays to primary and
associative somatonsensory cortices
Ultimately these regions project back
to brainstem, prefrontal, limbic
system, and thalamus
Slow unmyelinated nociceptors
synapse on paleospinothalamic
neurons whose axon collaterals
project crude information to multiple
targets in brainstem and limbic
system
1)
2)
Emotional/behavioral responses
Vaguely localized throbbing pain
www.nursece.com/onlinecourses/imagesPain/Fig2.gif
1)
Pain Overview
Nociceptive neuron stimulated through
compression, heat, or chemical irritation in
periphery
2)
Nociceptive neuron synapses on projection
neurons and interneuron networks in the
dorsal horn
3)
Fast myelinated nociceptors synapse
on neospinothalamic neurons that
project fine information to thalamic
relay nucleus
1)
2)
4)
Thalamus relays to primary and
associative somatonsensory cortices
Ultimately these regions project back
to brainstem, prefrontal, limbic
system, and thalamus
Slow unmyelinated nociceptors synapse on
paleospinothalamic neurons whose axon
www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm
collaterals project crude information to
multiple targets in brainstem and limbic
system
1)
2)
Emotional/behavioral responses
Vaguely localized throbbing pain
1)
Pain Overview
Nociceptive neuron stimulated through
compression, heat, or chemical irritation in
periphery
2)
Nociceptive neuron synapses on projection
neurons and interneuron networks in the
dorsal horn
3)
Fast myelinated nociceptors synapse on
neospinothalamic neurons that project fine
information to thalamic relay nucleus
1)
2)
4)
Thalamus relays to primary and associative
somatonsensory cortices
Ultimately these regions project back to
brainstem, prefrontal, limbic system, and
thalamus
Slow unmyelinated nociceptors
synapse on paleospinothalamic
neurons whose axon collaterals
project crude information to multiple
targets in brainstem and limbic
system
1)
2)
Emotional/behavioral responses
Vaguely localized throbbing pain
www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm
Centrally Mediated Pain Regulation
1) Appropriate activation of
periaqueductal grey matter
(PAG) in mesencephalon and
opioid networks in thalamus
http://www.sciencemag.org/cgi/content/full/288/5472/1769
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
Centrally Mediated Pain Regulation
1) Appropriate activation of
2)
(notice the inhibition of retrograde
substance p release into the periphery!)
http://www.mona.uwi.edu/fpas/courses/physiology/neurophysiology/P
ainRapheFeedback.jpg
Opiod-Mediated Inhibition Occurs Via:
1) K+ channel Activation
(Hyperpolarization)
2) Ca2+ channel Deactivation
(Reduced NT Release)
3) Other Mechanisms
3)
periaqueductal grey matter
(PAG) in mesencephalon
occurs
PAG projects into nucleus
raphe magnus
(serotonergic) and locus
ceruleus (noradrenergic) in
rostral ventral medulla
(RVM)
Serotonergic innervation of
inhibitory opiodergic
neurons
1)
2)
Dorsal Horn Interneurons
Central Pain Processing
Regions
1)
Opioid Reinforcement Through
Dopamine Signaling
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
http://thebrain.mcgill.ca/flash/i/i_03/i_03_cr/i_03_cr
_que/i_03_cr_que_1a.jpg
Isolating the Placebo Analgesia Pathways:
The Chemical Players
Functional MRI
• Remfentanil is an opioid agonist
• Comparison of brain imaging
during remfentanil exposure and
placebo-analgesia reveals
similarities in the activated
pathways
www.ym.edu.tw/rcinn/images/cp1-fg3.png
Positron Emission Tomography
• This supports the opioid
hypothesis of the placeboanalgesic response
• Areas Activated Include:
–
–
–
–
http://www.nida.nih.gov/NIDA_notes/NNVol16N2/Positron.jpg
Rostral anterior cingulate gyrus
Orbitofrontal cortex
Anterior insula
PAG-RVM
Isolating the Placebo Analgesia Pathways:
The Chemical Players
• Proglutamide: a CCK antagonist
that enhances placebo analgesia due
to the facilitation of expectation
pathways
• Based on double-blind paradigm one
can erroneously conclude that
Proglutamide has intrinsic analgesic
activity
• PET imaging and open-hidden
paradigm provides more accuracy
• Therefore, Proglutamide enhancement
http://www.nature.com/nrn/journal/v6/n7/fig_tab/nrn1705_
F1.html
of expectation pathways IS the
disturbance in double-blind studies
Isolating the Placebo Analgesia Pathways:
The Chemical Players
• Naloxone is the prototypical opioid
•
http://content.answers.com/main/content/wp
/en-commons/thumb/5/57/220px-Naloxone3D-balls.png
antagonist (and OD antidote)
Naloxone reliably blocks placebo
induced analgesia
– But, only through conditioning with
previous opioid-analgesic responses
– Non-opiod associated placebo effects
are naloxone insensitive
• Sumatriptan (5-HT agonist)
• Therefore, naloxone also blocks side-
effects accompanying opioid-operating
placebo responses
https://www.epocrates.com/pillimages/RBK13060.jpg
– Respiratory depression
– Cardiac depression
• Disturbance: In a double-blind study,
naloxone appears to have a
hyperalgesic effect (but not in openhidden paradigms)
http://www.everydayhealth.com/PublicSite/D
rugsAZ/Images/thumbnails/image_425.jpg
Placebos and opioid agonist have a related analgesia
mechanism, the same regions of the brain are affected
by both treatments
Hidden Treatment: the patient is not
aware of when a drug is administered
Results from many clinical studies have shown that a hidden
treatment was less effective than the open treatment
http://content.apa.org/journals/pre/6/1/1a.html
http://www.sanimedtec.com/images/infusion2.jpg
The placebo response is not only effective on pain
• Conditioning
• Reward
• Hidden Treatments
All help us better understand the placebo effect but
more research is still needed
The Uncertainty Principle
A painkiller acts on pain pathways, but it
can also, or only act on the expectation
pathways.
Almost any drug can act on the placeboactivated endogenous opioids.
The true effect of
medication can be tested
without any psychological
interference
The Open-Hidden Paradigm
Perceived assignment of treatment
What’s in the future for placebos and
clinical trials?
http://images.google.com/images?q=open+hidden+treatment&svnum=10&um=1&hl=en
&client=firefox-a&channel=s&rls=org.mozilla:en-US:official&start=20&sa=N&ndsp=20
Other examples of psychosocial activity that
influences physiological function
•Pseudocyesis
1 to 6 per every 22,000 births
•Multiple Personality Disorder or (DID)
Dissociative Identity Disorder
It is sometimes known as “disaggregate self
state” because it dissociates parts of the
mind influencing behavior
http://www.comic-book-collection-made-easy.com
http://www.womens-health.co.uk/false_pregnancy.html
http://www.medicinenet.com/script/main/art.asp?articlekey=38077
Is the sale and use of placebos effective or ethical?
Can placebos be guaranteed to generate safe and effective results?
What risks might be associated with the exploitation of the placebo
effect?
Did anybody feel warmer?
www.uvm.edu/~jstaylor/psyc223.ppt
(images removed)