Jess Benjamin John Steele Taylor Celeste Parot January 30, 2008

1. Placebos and Painkillers: Is Mind as Real as Matter?Luana Colloca and Fabrizio Benedetti2005 in Nature Reviews Neuroscience Jess Benjamin John Steele Taylor Celeste Parot January 30, 2008 http://www.annkullberg.com/Shows/2003/Hild.jpg

2. 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.

3. 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

4. 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???

5. 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

6. 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

7. 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.

8. Nociceptive neuron stimulated through compression, heat, or chemical irritation in periphery Nociceptive neuron synapses on projection neurons and interneuron networks in the dorsal horn Fast myelinated nociceptors synapse on neospinothalamic neurons that project fine information to thalamic relay nucleus 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 Emotional/behavioral responses Vaguely localized throbbing pain http://www.scripps.edu/cb/patapoutian/nocisensor.jpg Pain Overview http://www.laesieworks.com/spinal/pict/SpinalCord.jpg

9. Nociceptive neuron stimulated through compression, heat, or chemical irritation in periphery Nociceptive neuron synapses on projection neurons and interneuron networks in the dorsal horn Fast myelinated nociceptors synapse on neospinothalamic neurons that project fine information to thalamic relay nucleus 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 Emotional/behavioral responses Vaguely localized throbbing pain Pain Overview www.nursece.com/onlinecourses/imagesPain/Fig2.gif

10. Nociceptive neuron stimulated through compression, heat, or chemical irritation in periphery Nociceptive neuron synapses on projection neurons and interneuron networks in the dorsal horn Fast myelinated nociceptors synapse on neospinothalamic neurons that project fine information to thalamic relay nucleus 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 Emotional/behavioral responses Vaguely localized throbbing pain Pain Overview www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm

11. Nociceptive neuron stimulated through compression, heat, or chemical irritation in periphery Nociceptive neuron synapses on projection neurons and interneuron networks in the dorsal horn Fast myelinated nociceptors synapse on neospinothalamic neurons that project fine information to thalamic relay nucleus 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 Emotional/behavioral responses Vaguely localized throbbing pain Pain Overview www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm

12. Centrally Mediated Pain Regulation • 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: • Conditioned Anticipation of Pain Relief • Pain in Other Areas • Emotional Well Being • Concentration/Meditation • Hypnosis • Gate-Mediated Mechanical Stimuli http://www.doctordeluca.com/Library/Pain/Graphics/CP1NewDis-F2.bmp

13. Centrally Mediated Pain Regulation • Appropriate activation of 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 • Dorsal Horn Interneurons • Central Pain Processing Regions (notice the inhibition of retrograde substance p release into the periphery!) http://www.mona.uwi.edu/fpas/courses/physiology/neurophysiology/PainRapheFeedback.jpg • Opiod-Mediated Inhibition Occurs Via: • 1) K+ channel Activation • (Hyperpolarization) • 2) Ca2+ channel Deactivation • (Reduced NT Release) • 3) Other Mechanisms

14. Opioid Reinforcement Through Dopamine Signaling • Reinforcement/addiction may be associated with impact on dopamine signaling • Opiod mediated inhibition of GABAergic neurons tonically inhibiting DAergic neurons in ventral tegmental area (VTA) of mesencephalon (off + off = on) • 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

15. Remfentanil is an opioid agonist Comparison of brain imaging during remfentanil exposure and placebo-analgesia reveals similarities in the activated pathways This supports the opioid hypothesis of the placebo-analgesic response Areas Activated Include: Rostral anterior cingulate gyrus Orbitofrontal cortex Anterior insula PAG-RVM Isolating the Placebo Analgesia Pathways:The Chemical Players Functional MRI www.ym.edu.tw/rcinn/images/cp1-fg3.png Positron Emission Tomography http://www.nida.nih.gov/NIDA_notes/NNVol16N2/Positron.jpg

16. 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 of expectation pathways IS the disturbance in double-blind studies Isolating the Placebo Analgesia Pathways:The Chemical Players http://www.nature.com/nrn/journal/v6/n7/fig_tab/nrn1705_F1.html

17. Naloxone is the prototypical opioid 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 Respiratory depression Cardiac depression Disturbance: In a double-blind study, naloxone appears to have a hyperalgesic effect (but not in open-hidden paradigms) Isolating the Placebo Analgesia Pathways:The Chemical Players http://content.answers.com/main/content/wp/en-commons/thumb/5/57/220px-Naloxone-3D-balls.png https://www.epocrates.com/pillimages/RBK13060.jpg http://www.everydayhealth.com/PublicSite/DrugsAZ/Images/thumbnails/image_425.jpg

18. Hidden Treatments 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

19. BeyondPain • 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

20. Placebos in Clinical Trials 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 placebo-activated 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

21. Observed Phenomena • 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

22. Questions 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)