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Placebo and Outcome Measurement Damien Finniss Clinical Senior Lecturer, Pain Medicine, Sydney Medical School University of Sydney Pain Management Research Institute Royal North Shore Hospital Placebo: a substance or procedure that is inert and designed to please rather than to exert a specific effect (Brody 2000). e.g. sugar pill, saline injection, sham procedure. Placebo: a substance or procedure that is inert and designed to please rather than to exert a specific effect (Brody 2000). e.g. sugar pill, saline injection, sham procedure. However, if placebos are inert they can’t cause an effect ! What is ‘Placebo’ ? Placebo: a substance or procedure designed to simulate an active therapy in a particular psychosocial context (Price, Finniss & Benedetti 2008) What is ‘Placebo’ ? Placebo: a substance or procedure designed to simulate an active therapy in a particular psychosocial context (Price, Finniss & Benedetti 2008) Placebo Effect: The “group effect” seen following administration of a placebo What is ‘Placebo’ ? Placebo: a substance or procedure designed to simulate an active therapy in a particular psychosocial context (Price, Finniss & Benedetti 2008) Placebo Effect: The “group effect” seen following administration of a placebo Placebo Response: A particular individuals response following administration of a placebo What is ‘Placebo’ ? Placebo: a substance or procedure designed to simulate an active therapy in a particular psychosocial context (Price, Finniss & Benedetti 2008) Placebo Effect: The “group effect” seen following administration of a placebo Placebo Response: A particular individuals response following administration of a placebo Placebo effects and responses are used interchangeably (Colloca, Finniss & Benedetti 2008) Meaning response, context effects etc…… Contributions of the psychosocial context surrounding the patient (or placebo component of a given therapy) to the overall response Psychosocial context surrounding the patient Response Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “DoctorPatient Relationship” (such as communication, empathy, reassurance, bedside manner, enthusiasm), and factors comprising the treatment environment (location, type and nature of treatment e.g. route of drug administration, use of technological devices, therapeutic ritual etc) Administration of a specific treatment e.g. an active drug Response due to both the specific treatment and the psychosocial context in which it was delivered. + + Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” Response due to the psychosocial context surrounding the patient. The administration of a “placebo” only serves to mimic the psychosocial context. The placebo is “inert” but the psychosocial context is not. Finniss, Kaptchuk et al, Lancet 2010 Contributions of the psychosocial context surrounding the patient (or placebo component of a given therapy) to the overall response Psychosocial context surrounding the patient Response Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “DoctorPatient Relationship” (such as communication, empathy, reassurance, bedside manner, enthusiasm), and factors comprising the treatment environment (location, type and nature of treatment e.g. route of drug administration, use of technological devices, therapeutic ritual etc) Administration of a specific treatment e.g. an active drug Response due to both the specific treatment and the psychosocial Specific treatment + context in which it was psychosocial context delivered. + + Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” Response due to the psychosocial context surrounding the patient. The administration of a “placebo” only serves to mimic the psychosocial context. The placebo is “inert” but the psychosocial context is not. Contributions of the psychosocial context surrounding the patient (or placebo component of a given therapy) to the overall response Psychosocial context surrounding the patient Response Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “DoctorPatient Relationship” (such as communication, empathy, reassurance, bedside manner, enthusiasm), and factors comprising the treatment environment (location, type and nature of treatment e.g. route of drug administration, use of technological devices, therapeutic ritual etc) Administration of a specific treatment e.g. an active drug Response due to both the specific treatment and the psychosocial Specific treatment + context in which it was psychosocial context delivered. + + Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” Response due to the psychosocial context surrounding the patient. The administration of a “placebo” Psychosocial context only serves to mimic the psychosocial context. The placebo is “inert” but the psychosocial context is not. only Contributions of the psychosocial context surrounding the patient (or placebo component of a given therapy) to the overall response Psychosocial context surrounding the patient Response Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “DoctorPatient Relationship” (such as communication, empathy, reassurance, bedside manner, enthusiasm), and factors comprising the treatment environment (location, type and nature of treatment e.g. route of drug administration, use of technological devices, therapeutic ritual etc) Administration of a specific treatment Routine Care e.g. an active drug Response due to both the specific treatment and the psychosocial Specific treatment + context in which it was psychosocial context delivered. + + Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” Response due to the psychosocial context surrounding the patient. The administration of a “placebo” Psychosocial context only serves to mimic the psychosocial context. The placebo is “inert” but the psychosocial context is not. only Contributions of the psychosocial context surrounding the patient (or placebo component of a given therapy) to the overall response Psychosocial context surrounding the patient Response Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “DoctorPatient Relationship” (such as communication, empathy, reassurance, bedside manner, enthusiasm), and factors comprising the treatment environment (location, type and nature of treatment e.g. route of drug administration, use of technological devices, therapeutic ritual etc) Administration of a specific treatment Routine Care e.g. an active drug Response due to both the specific treatment and the psychosocial Specific treatment + context in which it was psychosocial context delivered. + + Administration of a “placebo” e.g. Research on Placebo Sham procedure, sugar pill which isTrial a or Clinical Treatment “simulation” Response due to the psychosocial context surrounding the patient. The administration of a “placebo” Psychosocial context only serves to mimic the psychosocial context. The placebo is “inert” but the psychosocial context is not. only Contributions of the psychosocial context surrounding the patient (or placebo component of a given therapy) to the overall response Psychosocial context surrounding the patient Response Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. INTERACTING WITH Administration of a specific treatment Routine Care e.g. an active drug Response due to both the specific treatment and the psychosocial Specific treatment + context in which it was psychosocial context delivered. + Placebo Mechanisms Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “DoctorPatient Relationship” (such as communication, empathy, reassurance, bedside manner, enthusiasm), and factors comprising the treatment environment (location, type and nature of treatment e.g. route of drug administration, use of technological devices, therapeutic ritual etc) + Administration of a “placebo” e.g. Research on Placebo Sham procedure, sugar pill which isTrial a or Clinical Treatment “simulation” Response due to the psychosocial context surrounding the patient. The administration of a “placebo” Psychosocial context only serves to mimic the psychosocial context. The placebo is “inert” but the psychosocial context is not. only The model “Specific” component to therapy “Placebo” component to therapy 2+2=4? Assess the difference between the two by giving placebo to some patients and the “real” drug to others in RCT’s. But is it this simple ? How do placebo’s work? NOT ONE PLACEBO EFFECT, THERE ARE MANY PAIN Some mediated by opioids (e.g. Benedetti, 1999) Others are clearly NOT related to opioids (Finniss, Kaptchuk et al 2010) Expectation of benefit is associated with placebo effects, but only in certain cases and not others (Price, Finniss & Benedetti 2008) Conditioning mechanisms play a role and work synergistically with expectancy (Amanzio et al 1999) Change in anxiety and desire for symptom relief account for significant variance in placebo effects, but moreso in laboratory experiments than the clinical setting (Price et al, 2005) How do placebo’s work? Placebo effects are different based on prior experience (conditioning) How do placebo’s work? Placebo effects are different based on prior experience (conditioning) Condition with an opioid analgesic and then give placebo = opioid mediated placebo effect How do placebo’s work? Placebo effects are different based on prior drug experience (conditioning) Condition with an opioid analgesic and then give placebo = opioid mediated placebo effect Conditioning with a non-opioid analgesic then give placebo = non-opioid medicated effect (CB1 cannabanoid receptor) (Benedetti 2011) Other considerations Placebo effects are stronger when the focus of study is placebo and not the active drug (Vase 2002) (Experimental Placebo > RCT Placebo). Different placebos work better for different people (de Craen 1999) High tech placebos work better than low tech (Kaptchuk 1998) More expensive placebos work better than less expensive ones (Waber 2008) Two placebo tablets are better than one (Moerman 2001) Placebo effects operated in a graded manner (Kaptchuk 2008) There is no such thing as a placebo responder and non-responder . It is context and situation specific. The effects can go the other way - Nocebo Nocebo effects The negative counterpart of placebo, representing a worsening in symptoms/signs based in the psychosocial context of a given therapy. Several different mechanisms. Alterations in verbal instructions change the nocebo component of certain therapies (Benedetti 1997, Colloca & Finniss 2012). Not limited to verbal instructions, includes informed consent (Kaptchuk 2006) The model “Specific” component to therapy “Placebo” component to therapy (clearly complex and variable) Consideration of a potential nocebo component 2+2=4? The open-hidden paradigm A drug is administered in two ways Open: Given in full view of the patient Hidden: Given to the patient when they do not know it is being given The open-hidden paradigm A drug is administered in two ways Open: Given in full view of the patient Drug plus psychosocial context Hidden: Given to the patient when they do not know it is being given The open-hidden paradigm A drug is administered in two ways Open: Given in full view of the patient Drug plus psychosocial context Hidden: Given to the patient when they do not know it is being given Drug only Morphine Open Hidden Buprenorphine Open Hidden Tramadol Open Hidden Ketorolac Open Metamizol Hidden Open Hidden 0 -1 -2 -3 Finniss & Benedetti 2007 Interactions between placebo mechanisms and active drugs Benedetti 1995 Randomised, double blinded placebo controlled trial of 93 post-operative patients. Compared the cholecystokinin antagonist (proglumide) to placebo. Involved using an “open” and “hidden” administration. Compared to a no treatment, natural history group. Benedetti F, Amanzio M et al, 1995 Benedetti F, Amanzio M et al, 1995 0.5 No Treatment Placebo CCK antagonist (Open Administration) CCK antagonist (Hidden Administration) 0 Pain Reduction -0.5 -1 -1.5 -2 -2.5 -3 -3.5 Finniss & Benedetti 2006 Conclusions 2 + 2 doesn’t equal 4. Giving a placebo in a clinical trial assesses responsiveness in the context of a clinical trial, not “real practice”. It is likely that placebo mechanisms interact with the index therapy We can measure placebo effects in almost any setting but need to understand what it tells us From the research perspective, alternatives such as open-hidden paradigm may represent different options for assessing synergistic actions between placebo mechanisms on drug mechanism. Very exciting area – the focus should be on better understanding components of placebo effects and figuring out how to enhance them. Acknowledgements Prof Michael Cousins Prof Don Price Prof Michael Nicholas Prof Dan Moerman Dr Charles Brooker Prof Ted Kaptchuk Prof Fabrizio Benedetti Dr Frank Miller Dr Luana Colloca Dr Ron Kupers