Clinical and Applied Physiology Program at the Department of Neuroscience University of Turin Medical School Turin, Italy www.personalweb.unito.it / fabrizio.benedetti

Symbols molecules RECEPTORS Drugs Therapeutic effects Negative effects

evolution

Pre-operative phase 1st post-operative day Egbert et al. (1964) N Engl J Med 270: 825 Post-operative pain Pre-operative phase 1st post-operative day Pain intensity 1.187 Morphine intake 26 mg Pain intensity 1.735 Morphine intake 38 mg

Consultation Two weeks later Thomas (1987) Br Med J 294: 1200 Cough Sore throat Cold Abdominal pain Back pain Giddiness Leg pain Headache Tiredness Chest pain Nasal congestion Muscular pain Earache Painful arm Breast pain Neck pain Consultation Two weeks later This treatment will certainly make you better % who got better 64 I am not sure that this treatment will have an effect % who got better 39

Placebo administration 1st model: Placebo administration 2nd model: Open-hidden paradigm This treatment will certainly make you better

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)

ICD-10 of the World Health Organization Placebo-related effects A00-B99 Certain infectious and parasitic diseases C00-D48 Neoplasms D50-D89 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism Some immune mediators (IL-2, IFN-gamma, leukocytes.....) (Giang et al 1996; Goebel et al 2002) E00-E90 Endocrine, nutritional and metabolic diseases Some hormones (growth hormone, cortisol.......) (Benedetti et al. 2003) F00-F99 Mental and behavioural disorders Major depression (Leuchter et al. 2002; Mayberg et al. 2002) Anxiety (Benedetti et al 2003, Petrovic et al 2005) DBS-induced emotions (Benedetti et al 2004) G00-G99 Diseases of the nervous system Pain (Levine et al 1978; Benedetti 1996; Amanzio & Benedetti 1999; Petrovic et al 2002; Wager et al 2004; Lorenz et al 2005; Zubieta et al 2005) Parkinson’s disease (de la Fuente-Fernandez et al 2001; Benedetti et al 2004) H00-H59 Diseases of the eye and adnexa H60-H95 Diseases of the ear and mastoid process I00-I99 Diseases of the circulatory system Autonomic control of heart (Pollo et al 2003; Lanotte et al 2005) J00-J99 Diseases of the respiratory system Drug-induced respiratory depression (Benedetti et al 1998, 1999) K00-K93 Diseases of the digestive system Irritable bowel syndrome (Lieberman et al 2004; Vase et al 2005) L00-L99 Diseases of the skin and subcutaneous tissue M00-M99 Diseases of the musculoskeletal system and connective tissue N00-N99 Diseases of the genitourinary system O00-O99 Pregnancy, childbirth and the puerperium P00-P96 Certain conditions originating in the perinatal period Q00-Q99 Congenital malformations, deformations and chromosomal abnormalities R00-R99 Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified S00-T98 Injury, poisoning and certain other consequences of external causes V01-Y98 External causes of morbidity and mortality Z00-Z99 Factors influencing health status and contact with health services U00-U99 Codes for special purposes

Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552

30 Pain tolerance (minutes) 25 20 15 DAY1 DAY2 DAY3 DAY4 DAY5 Zubieta et al. (2005) J. Neurosci. 25: 7754 –7762 MOR MOR PLA NAL Amanzio & Benedetti (1999) J. Neurosci. 19: 484-94

Remifentanil Placebo ACC PAG Pons Medulla Petrovic et al. (2002) Science 295: 1737-40

Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552

3 Pain intensity (NRS) 2 1 Control Nocebo- induced anxiety PROGLUMIDE CCK-A (CCK-1) CCK-B (CCK-2) receptor antagonist Benedetti et al. (1997) Pain 71: 135-140

Placebo suggestions Nocebo suggestions Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552

Nocebo suggestions Colloca and Benedetti (2005) Nature Rev. Neurosci. 6: 545-552

ICD-10 of the World Health Organization Placebo-related effects A00-B99 Certain infectious and parasitic diseases C00-D48 Neoplasms D50-D89 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism Some immune mediators (IL-2, IFN-gamma, leukocytes.....) (Giang et al 1996; Goebel et al 2002) E00-E90 Endocrine, nutritional and metabolic diseases Some hormones (growth hormone, cortisol.......) (Benedetti et al. 2003) F00-F99 Mental and behavioural disorders Major depression (Leuchter et al. 2002; Mayberg et al. 2002) Anxiety (Benedetti et al 2003, Petrovic et al 2005) DBS-induced emotions (Benedetti et al 2004) G00-G99 Diseases of the nervous system Pain (Levine et al 1978; Benedetti 1996; Amanzio & Benedetti 1999; Petrovic et al 2002; Wager et al 2004; Lorenz et al 2005; Zubieta et al 2005) Parkinson’s disease (de la Fuente-Fernandez et al 2001; Benedetti et al 2004) H00-H59 Diseases of the eye and adnexa H60-H95 Diseases of the ear and mastoid process I00-I99 Diseases of the circulatory system Autonomic control of heart (Pollo et al 2003; Lanotte et al 2005) J00-J99 Diseases of the respiratory system Drug-induced respiratory depression (Benedetti et al 1998, 1999) K00-K93 Diseases of the digestive system Irritable bowel syndrome (Lieberman et al 2004; Vase et al 2005) L00-L99 Diseases of the skin and subcutaneous tissue M00-M99 Diseases of the musculoskeletal system and connective tissue N00-N99 Diseases of the genitourinary system O00-O99 Pregnancy, childbirth and the puerperium P00-P96 Certain conditions originating in the perinatal period Q00-Q99 Congenital malformations, deformations and chromosomal abnormalities R00-R99 Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified S00-T98 Injury, poisoning and certain other consequences of external causes V01-Y98 External causes of morbidity and mortality Z00-Z99 Factors influencing health status and contact with health services U00-U99 Codes for special purposes

Parkinson’s disease Decrease of raclopride binding de la Fuente-Fernandez et al. ( 2001) Science 293: 1164-6

P r e – p l a c e b o P o s t – p l a c e b o

Firing rate (spikes/s) Benedetti et al. (2004) Nature Neurosci, 7: 587-588

Placebo administration 1st model: Placebo administration 2nd model: Open-hidden paradigm This treatment will certainly make you better

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 -3 Benedetti et al (1995) Lancet 346: 1231 Amanzio et al. (2001) Pain 90:205-15 Colloca et al (2004) Lancet Neurol. 3: 679-684

ICD-10 of the World Health Organization Placebo-related effects A00-B99 Certain infectious and parasitic diseases C00-D48 Neoplasms D50-D89 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism Some immune mediators (IL-2, IFN-gamma, leukocytes.....) (Giang et al 1996; Goebel et al 2002) E00-E90 Endocrine, nutritional and metabolic diseases Some hormones (growth hormone, cortisol.......) (Benedetti et al. 2003) F00-F99 Mental and behavioural disorders Major depression (Leuchter et al. 2002; Mayberg et al. 2002) Anxiety (Benedetti et al 2003, Petrovic et al 2005) DBS-induced emotions (Benedetti et al 2004) G00-G99 Diseases of the nervous system Pain (Levine et al 1978; Benedetti 1996; Amanzio & Benedetti 1999; Petrovic et al 2002; Wager et al 2004; Lorenz et al 2005; Zubieta et al 2005) Parkinson’s disease (de la Fuente-Fernandez et al 2001; Benedetti et al 2004) H00-H59 Diseases of the eye and adnexa H60-H95 Diseases of the ear and mastoid process I00-I99 Diseases of the circulatory system Autonomic control of heart (Pollo et al 2003; Lanotte et al 2005) J00-J99 Diseases of the respiratory system Drug-induced respiratory depression (Benedetti et al 1998, 1999) K00-K93 Diseases of the digestive system Irritable bowel syndrome (Lieberman et al 2004; Vase et al 2005) L00-L99 Diseases of the skin and subcutaneous tissue M00-M99 Diseases of the musculoskeletal system and connective tissue N00-N99 Diseases of the genitourinary system O00-O99 Pregnancy, childbirth and the puerperium P00-P96 Certain conditions originating in the perinatal period Q00-Q99 Congenital malformations, deformations and chromosomal abnormalities R00-R99 Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified S00-T98 Injury, poisoning and certain other consequences of external causes V01-Y98 External causes of morbidity and mortality Z00-Z99 Factors influencing health status and contact with health services U00-U99 Codes for special purposes

Cognitive impairment Benedetti et al (2006) Pain 121: 133-144

P l a c e b o buprenorphine 1.2 1.15 mg/patient 1.0 0.8 -33.8% buprenorphine request 0.76 mg/patient 0.6 Buprenorphine intake/patient (mg) Comparison between natural history, double blind administration and deceptive administration. Note the reduction of narcotic intake with the deceptive paradigm 0.4 0.2 10 20 30 40 50 60 70 Pollo et al. (2001) Pain 93: 77-84 Hours from surgery

Symbols Drugs Is mind as real as matter? Therapeutic Negative effects molecules RECEPTORS Drugs Therapeutic effects Negative effects

Clinical and Applied Physiology Program at the Department of Neuroscience University of Turin Medical School Turin, Italy www.personalweb.unito.it / fabrizio.benedetti NEUROLOGY Bruno Bergamasco Leonardo Lopiano Innocenzo Rainero Giovanni Asteggiano Luisella Tarenzi Elena Torre NEUROPHYSIOLOGY Luana Colloca Antonella Pollo Sergio Vighetti SURGERY Giuliano Maggi Caterina Casadio Anna Arslanian PSYCHOLOGY Martina Amanzio Claudia Arduino Sara Costa RESPIRATORY PATHOPHYSIOLOGY Sergio Baldi NEUROSURGERY Michele Lanotte Antonio Melcarne