Dipartimento di Neuroscienze, Università degli Studi di Torino e Istituto Nazionale di Neuroscienze (INN), Torino www.personalweb.unito.it / fabrizio.benedetti www.ist-nazionale-neuroscienze.unito.it

IMPROVEMENT IN THE PLACEBO GROUP Spontaneous remission Unidentified co-interventions Biases Psychosocial- psychobiological factors Regression to the mean Detection ambiguity IMPROVEMENT IN THE PLACEBO GROUP PLACEBO RESPONSE Expectation Pavlovian conditioning Reward mechanisms Anxiety mechanisms

Words Sight Touch Smell Dummy treatment Medical treatment Placebo effect = Context effect Words Sight Touch Dummy treatment Medical treatment Smell

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

Social stimuli Drugs Therapeutic Negative effects effects molecules RECEPTORS Drugs Therapeutic effects Negative effects Benedetti (2008) Ann Rev Pharmacol Toxicol 48: 33-60

Psychosocial context D r u g s 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 Analgesia and respiratory centers Parkinson Analgesia and cardiovascular system Hormonal responses Immune responses Depression ? ? Hyperalgesia IFN-g, IL-2 5-HT1B-1D 5-HT re-uptake D2-D3 CCK-A/B m-opioid b-adrenergic immuno sumatriptan anti anti CCK narcotic b-blocker suppressive depressant parkinsonian antagonist D r u g s Benedetti (2008) Annu Rev Pharmacol Toxicol 48: 33-60

Benedetti et al. (1995) Lancet 346: 1231

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

Open injection Hidden injection BUPRENORPHINE TRAMADOL KETOROLAC computer Open injection Hidden injection BUPRENORPHINE TRAMADOL KETOROLAC METAMIZOL open hidden open hidden open hidden open hidden Pharmacodynamic effect -1 Pain reduction Psychological effect -2 Benedetti et al (1995) Lancet 346: 1231 Amanzio et al. (2001) Pain 90:205-15 Colloca et al (2004) Lancet Neurol. 3: 679-684 -3

TRIAL Met#2 Is metamizol (300 mg) effective in post-thymectomy pain? (Colloca and Benedetti, Nature Rev Neurosci 6: 545-552, 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

Open injection of metamizol 10 Open injection of metamizol 8 6 Pain intensity (NRS) 4 2 10 Hidden injection of metamizol 8 6 Pain intensity (NRS) 4 2 1 2 3 4 5 6 hours

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