Mechanisms of the placebo response

Transcription

1 Mechanisms of the placebo response Fabrizio Benedetti Department of Neuroscience University of Turin Medical School and National Institute of Neuroscience Turin, Italy

2 OVERVIEW Definition Mechanisms in pain Mechanisms in Parkinson s disease Why are there responders and nonresponders? Clinical implications

3 Placebo effect = Context effect CB1 D2/D3 Dummy Medical treatment

4 DISEASE/SYSTEM MECHANISMS Pain Activation of endogenous opioids and dopamine (placebo). Activation of CCK and de-activation of dopamine (nocebo) Parkinson s Activation of dopamine in the striatum and changes in activity of neurons in disease basal ganglia and thalamus Depression Changes of electrical and metabolic activity in different brain regions, e.g. ventral striatum Anxiety Changes in activity of the anterior cingulate and orbitofrontal cortices. Genetic variants of serotonin transporter and tryptophane hydroxylase 2 Addiction Changes of metabolic activity in different brain regions Autonomic responses to DBS Change of neuronal excitability in limbic regions Cardiovascular Reduction of -adrenergic activity of heart Respiratory Conditioning of opioid receptors in the respiratory centres Immune Conditioning of some immune mediators (e.g., IL-2, IFN-, lymphocytes) system Endocrine Conditioning of some hormones (e.g., growth hormone, cortisol) system Physical Activation of endogenous opioids and increased muscle work performance Alzheimer s Prefrontal executive control and functional connectivity of prefrontal areas disease Finniss, Kaptchuk, Miller and Benedetti (2010) Lancet, 375:

5 OVERVIEW Definition Mechanisms in pain Mechanisms in Parkinson s disease Why are there responders and nonresponders? Clinical implications

6 Range of movement after thoracotomy Placebo Analgesia

7 Placebo - Expectation P a i n Activation Inhibition DLPFC racc I n h i b i t i o n PCC MCC PAG Caudate Thalamus Putamen Insula Amanzio, Benedetti, Porro, Palermo, Cauda (2013) Hum Brain Mapp 34:

8 Ritual of therapeutic act Psychosocial context Learning is crucial Expectation Benedetti et al. (2011) Nature Med, 17:

9 Experimental ischemic arm pain Pain tolerance (minutes) DAY1 DAY2 DAY3 DAY4 DAY5 MOR MOR PLA NALOXONE antagonist Amanzio & Benedetti (1999) J. Neurosci. 19:

10 Wager et al (2007) PNAS 104:

11 Ritual of therapeutic act Psychosocial context Expectation Benedetti et al. (2011) Nature Med, 17:

12 Experimental ischemic arm pain Pain tolerance (minutes) DAY1 DAY2 DAY3 DAY4 DAY5 KET KET PLA RIMONABANT CB1 antagonist Benedetti et al. (2011) Nature Med, 17:

13 CB1 cannabinoid receptors distribution with 11 C-JHU75528 radiotracer in the baboon Rimonabant SR Horti et al. (2006) J Nucl Med 47:

14 Ritual of therapeutic act Expectation Previous exposure to opioids Previous exposure to NSAIDs (CB1) opioid receptor Memory ON Memory ON CB1 cannabinoid receptor Benedetti et al. (2011) Nature Med, 17: Analgesia

15 Range of movement after thoracotomy Nocebo Hyperalgesia

16 VTA NAcc Suggestions of analgesiahyperalgesia CCK P A I N Decrease Increase nocebo placebo CCK activation -opioid deactivation D2-D3 deactivation Benedetti et al (2006) J Neurosci 26: Scott et al. (2008) Arch Gen Psychiatry 65:

17 OVERVIEW Definition Mechanisms in pain Mechanisms in Parkinson s disease Why are there responders and nonresponders? Clinical implications

18 Motor cortex Cortex Str GPe GPi VA VLa STN + SNr Suggestions of motor improvement

19 Parkinson s disease 200% increase in dopamine = One dose of amphetamine de la Fuente-Fernandez et al. ( 2001) Science 293:

20 Motor cortex Cortex Str GPe GPi VA VLa STN + SNr Suggestions of motor improvement

21 Placebo responder Placebo non-responder STN + + Th - - STN + + SNr decrease pre post pre Neuronal firing rate (Hz) increase Benedetti et al. (2004) Nature Neurosci, 7: Benedetti et al. (2009) J. Physiol. 587:

22 OVERVIEW Definition Mechanisms in pain Mechanisms in Parkinson s disease Why are there responders and nonresponders? Clinical implications

23 Learning Genetics Placebo responders Placebo non-responders

24 OVERVIEW Definition Mechanisms in pain Mechanisms in Parkinson s disease Why are there responders and nonresponders? Clinical implications

25 Ritual of therapeutic act Psychosocial context dopamine cannabinoids opioids D2-D3 CB1 mu anti-parkinson cannabis narcotics D r u g s Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60

26 Benedetti et al. (1995) Lancet 346: 1231

27 Benedetti et al. (1995) Lancet 346: 1231 hidden drug

28 Open injection Hidden injection computer BUPRENORPHINE TRAMADOL KETOROLAC METAMIZOL Pain reduction open hidden open hidden open hidden open hidden Pharmacodynamic effect Psychological effect -3 Amanzio et al (2001) Pain 90: Benedetti et al (1995) Lancet 346: 1231 Colloca et al (2004) Lancet Neurol. 3:

29 TRIAL Met#2 (Colloca and Benedetti, Nature Rev Neurosci 6: , 2005) Is metamizol (300 mg) effective in post-thymectomy pain? Open metamizol injection group (N=10) Hidden metamizol injection group (N=10) Informed consent You will receive metamizol but you don t know when Double blind

30 10 8 Open (expected) injection of metamizol Pain intensity (NRS) Hidden (unexpected) injection of metamizol Pain intensity (NRS) hours

31 Therapeutic rituals Immune responses Hormonal responses? Depression? Parkinson Analgesia and respiratory centers Hyperalgesia Analgesia and cardiovascular system IFN-, IL-2 5-HT 1B-1D 5-HT re-uptake D2-D3 CCK-A/B -opioid -adrenergic CB1 immuno sumatriptan anti anti CCK narcotic -blocker suppressive depressant parkinsonian antagonist D r u g s Benedetti et al Nat Med 2011 Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60

32 NEUROPHYSIOLOGY Antonella Pollo Luana Colloca Elisa Frisaldi Jennifer Durando Sergio Vighetti PSYCHOLOGY Martina Amanzio Elisa Carlino Claudia Arduino Rosalba Rosato Sara Palermo NEUROLOGY Leonardo Lopiano Innocenzo Rainero Giovanni Asteggiano NEUROIMAGING Carlo Porro Fausta Lui Franco Cauda ENDOCRINOLOGY Catherine Blanchard Wilma Thoen THORACIC SURGERY Giuliano Maggi Caterina Casadio NEUROSURGERY Michele Lanotte