Dipartimento di Neuroscienze, Università degli Studi di Torino e Istituto Nazionale di Neuroscienze (INN)

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1 Dipartimento di Neuroscienze, Università degli Studi di Torino e Istituto Nazionale di Neuroscienze (INN) / fabrizio.benedetti

2 Placebo Improvement Spontaneous remission Regression to the mean Biases Detection ambiguity Unidentified co-interventions Psychosocialpsychobiological factors Expectation Reward mechanisms Placebo response Anxiety mechanisms Pavlovian conditioning

3 Antidepressants Spontaneous remission 25% Drug effect 25% Patients expectations 50% Kirsch and Sapirstein (1998) Prevention & Treatment

4 Placebo effect = Context effect Dummy Medical treatment

5 Conscious Unconscious COGNITION Expectation Belief Trust Hope Effect Conditioned response Conditioned stimulus Unconditioned stimulus (e.g. drug)

6 DISEASE/SYSTEM TREATMENT MECHANISM Pain Placebo administration Expectation-induced activation of Nocebo administration endogenous opioids and cholecystokinin Verbal suggestions as well as of several brain regions Open vs hidden administration Parkinson s Placebo administration Expectation-induced release of dopamine Disease Nocebo administration in the striatum and changes of firing Verbal suggestions pattern of subthalamic nucleus neurons Open vs hidden administration Depression Placebo administration Changes of metabolic responses in different brain regions (inhibition of 5-HT re-uptake?) Anxiety Placebo administration Change of activity of some brain regions Open vs hidden diazepam Addiction Expected vs unexpected Changes of metabolic activity in methylphenidate different brain regions Autonomic responses to DBS Open vs hidden DBS Change of neuronal excitability in limbic areas Cardiovascular Placebo administration Reduction of β-adrenergic activity of heart Respiratory Pharmacological pre-conditioning Conditioning of opioid receptors in with buprenorphine the respiratory centers Immune Pharmacological pre-conditioning Conditioning of some immune mediators system with immunosuppressive drugs (e.g., IL-2, IFN-g, lymphocytes) Endocrine Pharmacological pre-conditioning Conditioning of some hormones system with 5-HT1B-1D receptor agonists (e.g., growth hormone, cortisol) Benedetti (2008) Ann Rev Pharmacol Toxicol 48: 33-60

7 Colloca and Benedetti (2005) Nature Rev. Neurosci. 6:

8 Pain tolerance (minutes) Experimental ischemic arm pain 15 DAY1 DAY2 DAY3 DAY4 DAY5 MOR MOR PLA NAL 10mg Amanzio & Benedetti (1999) J. Neurosci. 19:

9 Zubieta et al. (2005) J. Neurosci. 25: Carfentanil µ-opioid receptor radiotracer

10 Remifentanil µ-opioid receptor agonist Placebo PAG ACC Pons Medulla Petrovic et al. (2002) Science 295:

11 Colloca and Benedetti (2005) Nature Rev. Neurosci. 6:

12 10 NOCEBO Pain ACTH cortisol Pain intensity (NRS) minutes Plasma cortisol (ug/l) Plasma ACTH (pg/ml) minutes 90 Benedetti et al (2006) J Neurosci 26: minutes

13 NOCEBO Pain ACTH minutes cortisol Pain intensity (NRS) Benedetti et al (2006) J Neurosci 26: Plasma cortisol (ug/l) Diazepam 0.28 mg/kg Plasma ACTH (pg/ml) minutes minutes

14 NOCEBO Pain ACTH minutes cortisol Pain intensity (NRS) Benedetti et al (2006) J Neurosci 26: Plasma cortisol (ug/l) CCK-A/B blockade Proglumide 1.5 mg/kg Plasma ACTH (pg/ml) minutes minutes

15 NOCEBO CCK-A (CCK-1) IC 50 = 6.3X10-3 M CCK Pain Anxiety CCK-B (CCK-2) IC 50 = 11X10-3 M ACTH cortisol Benedetti et al (2007) Neuroscience 147:

16 CCK A/B receptors µ-opioid receptors Nocebo suggestions Placebo suggestions Colloca and Benedetti (2005) Nature Rev. Neurosci. 6:

17 DISEASE/SYSTEM TREATMENT MECHANISM Pain Placebo administration Expectation-induced activation of Nocebo administration endogenous opioids and cholecystokinin Verbal suggestions as well as of several brain regions Open vs hidden administration Parkinson s Placebo administration Expectation-induced release of dopamine Disease Nocebo administration in the striatum and changes of firing Verbal suggestions pattern of subthalamic nucleus neurons Open vs hidden administration Depression Placebo administration Changes of metabolic responses in different brain regions (inhibition of 5-HT re-uptake?) Anxiety Placebo administration Change of activity of some brain regions Open vs hidden diazepam Addiction Expected vs unexpected Changes of metabolic activity in methylphenidate different brain regions Autonomic responses to DBS Open vs hidden DBS Change of neuronal excitability in limbic areas Cardiovascular Placebo administration Reduction of β-adrenergic activity of heart Respiratory Pharmacological pre-conditioning Conditioning of opioid receptors in with buprenorphine the respiratory centers Immune Pharmacological pre-conditioning Conditioning of some immune mediators system with immunosuppressive drugs (e.g., IL-2, IFN-g, lymphocytes) Endocrine Pharmacological pre-conditioning Conditioning of some hormones system with 5-HT1B-1D receptor agonists (e.g., growth hormone, cortisol) Benedetti (2008) Ann Rev Pharmacol Toxicol 48: 33-60

18 Video by Pollo and Benedetti from the DATABASE of Nature Med 2005 table.mpg.2005

19 Parkinson s disease Decrease of raclopride binding de la Fuente-Fernandez et al. ( 2001) Science 293:

20 Clinical benefit Expectation of benefit Dorsal striatum (n. caudatus + putamen) Ventral striatum (n. accumbens) raclopride dopamine D2 D3 dopamine D2 D3 + GABAopioids D1 GPe D2 GPi GABA + Glutamate GABA STN + SNr SNc Thalamus GABA Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60

21

22 Benedetti et al. (2004) Nature Neurosci, 7:

23 dopamine CCK opioid D2-D3 CCK-A/B mu anti CCK-8 narcotics parkinsonian Therapeutic effects Negative effects Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60

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

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

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

27 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

28 10 8 Open injection of metamizol Pain intensity (NRS) Hidden injection of metamizol Pain intensity (NRS) hours

29 Psychosocial context e x p e c t a t i o n a n d / o r c o n d i t i o n i n g Immune responses Hormonal responses?? Depression Parkinson Analgesia and respiratory centers Hyperalgesia Analgesia and cardiovascular system IFN-γ, IL-2 5-HT 1B-1D 5-HT re-uptake D2-D3 CCK-A/B µ-opioid β-adrenergic immuno sumatriptan anti anti CCK narcotic β-blocker suppressive depressant parkinsonian antagonist D r u g s Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60

30 Dipartimento di Neuroscienze, Università degli Studi di Torino e Istituto Nazionale di Neuroscienze (INN) NEUROFISIOLOGIA Antonella Pollo Luana Colloca Sergio Vighetti PSICOLOGIA Martina Amanzio Claudia Arduino Elisa Carlino NEUROLOGIA Leonardo Lopiano Innocenzo Rainero Giovanni Asteggiano / fabrizio.benedetti CHIRURGIA Giuliano Maggi Caterina Casadio Anna Arslanian NEUROCHIRURGIA Michele Lanotte Antonio Melcarne

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