Can basic and clinical research on placebo lead to evidence-based clinical trials? Fabrizio Benedetti University of Turin Medical School, Turin, Italy Plateau Rosà Labs, Plateau Rosà, Switzerland
Evidence from basic and clinical research OVERVIEW Patients ’ expectations are crucial for the therapeutic outcome Repeated exposure to drugs may lead to substantial placebo responses Communication across participants may affect the therapeutic outcome Placebo responders and nonresponders can be identified a priori
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 Benedetti (2014) Neuron
Benedetti et al (1995) Lancet Colloca et al (2004) Lancet Neurol Benedetti et al (2016) Lancet Neurol
No expectation Benedetti et al (1995) Lancet Colloca et al (2004) Lancet Neurol Benedetti et al (2016) Lancet Neurol
No expectation Open injection Hidden injection computer BUPRENORPHINE TRAMADOL KETOROLAC METAMIZOL open hidden open hidden open hidden open hidden 0 Pharmacodynamic Pain reduction effect -1 Psychological effect -2 -3 Benedetti et al (1995) Lancet Colloca et al (2004) Lancet Neurol Benedetti et al (2016) Lancet Neurol
TRIAL Met#2 (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
10 Open (expected) injection of metamizol 8 Pain intensity (NRS) 6 4 2 0 10 Hidden (unexpected) injection of metamizol 8 Pain intensity (NRS) 6 No expectation 4 2 0 0 1 2 3 4 5 6 hours
GET R e m i f e n t a n i l TOLD S a l i n e R e m i f e n t a n i l I n t e r r u p t i o n No Positive Negative expectation expectation expectation 0 Pain decrease -1 Hippocampus -2 -3 DLPFC Bingel et al (2011) Science Trans Med ACC
Evidence from basic and clinical research OVERVIEW Patients ’ expectations are crucial for the therapeutic outcome Repeated exposure to drugs may lead to substantial placebo responses Communication across participants may affect the therapeutic outcome Placebo responders and nonresponders can be identified a priori
Activation likehood estimation (ALE) meta-analysis Activation Inhibition Previous activation of Previous activation of opioid receptors CB1 cannabinoid receptors Memory Memory ON ON CB1 opioid cannabinoid receptor receptor Benedetti et al. (2011) Nature Med
Enriched Enrolment with Randomized Withdrawal Lack of efficacy withdrawal Active Titrate to Randomise Assessment Screen effect with active Increased Control placebo responses Adverse event withdrawal McQuay et al (2008) Pain
Evidence from basic and clinical research OVERVIEW Patients ’ expectations are crucial for the therapeutic outcome Repeated exposure to drugs may lead to substantial placebo responses Communication across participants may affect the therapeutic outcome Placebo responders and nonresponders can be identified a priori
1 day 2 days 3 days 4 days 5 days 6 days 7 days Benedetti et al (2014) Pain
52% 86% Socially infected Not informed (negative expectations) (no expectations) 200 200 % increase % increase 100 100 0 0 Benedetti et al (2014) Pain Benedetti (2014) Neuron Benedetti et al (2016) Lancet Neurol
52% 86% Not informed Socially infected (negative expectations) (no expectations) aspirin vs placebo aspirin vs placebo with a pre-existing nocebo effect Benedetti et al (2014) Pain Benedetti (2014) Neuron Benedetti et al (2016) Lancet Neurol
Evidence from basic and clinical research OVERVIEW Patients ’ expectations are crucial for the therapeutic outcome Repeated exposure to drugs may lead to substantial placebo responses Communication across participants may affect the therapeutic outcome Placebo responders and nonresponders can be identified a priori
Placebo non-responder Placebo responder Genetics
Placebo non-responder Placebo responder Personality Suggestibility Hypnotic susceptibility De Pascalis et al 2002 Derbyshire and Oakley 2013 Huber et al 2013 Optimism Pessimism Geers et al 2005, 2007, 2010 Dopamine-related personality traits (sensitivity to incentives and rewards) Schweinhardt et al 2009 Ego-resiliency Altruism Angry hostility Pecina et al 2013
Placebo non-responder Placebo responder Learning… …can create placebo responders and non responders in the lab Matching or mismatching what patients expect and what they get PLA Exp ANA Exp ANA PLA Exp ANA Exp ANA PLA Get ANA Get ANA Get No ef Get No ef Colloca & Benedetti (2006) Pain Benedetti & Frisaldi (2014) Pain Manag
Evidence from basic and clinical research CONCLUSIONS Patients ’ expectations should be assessed in all clinical trials Drug history should be assessed carefully to ascertain possible learning effects Communication across participants should be avoided Future research should be aimed at better identifying placebo (non)responders
Thanks to: NEUROPHYSIOLOGY PSYCHOLOGY Elisa Frisaldi Elisa Carlino Jennifer Durando Alessandro Piedimonte Sergio Vighetti Martina Amanzio Antonella Pollo Claudia Arduino Luana Colloca Rosalba Rosato Sara Palermo NEUROLOGY Diletta Barbiani University of Turin Medical School, Italy Eleonora Camerone Leonardo Lopiano Maurizio Zibetti Mario Rizzone NEUROIMAGING Innocenzo Rainero Carlo Porro Giovanni Asteggiano Fausta Lui Franco Cauda ENDOCRINOLOGY THORACIC SURGERY Catherine Blanchard Wilma Thoen Giuliano Maggi Sara Dogue Caterina Casadio NEUROSURGERY Michele Lanotte Plateau Rosa Laboratories, Switzerland
Recommend
More recommend
