Placebo and Outcome Measurement

1. 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

3. 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.

4. 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 !

5. What is ‘Placebo’ ? • Placebo: a substance or procedure designed to simulate an active therapy in a particular psychosocial context (Price, Finniss & Benedetti 2008)

6. 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

7. 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

8. 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……

9. 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 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. Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. Administration of a specific treatment e.g. an active drug Response Response due to both the specific treatment and the psychosocial context in which it was delivered. + INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “Doctor- Patient 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. Sham procedure, sugar pill which is a Treatment “simulation” + Finniss, Kaptchuk et al, Lancet 2010

10. 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 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. Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. Administration of a specific treatment e.g. an active drug Response Specific treatment + psychosocial context Response due to both the specific treatment and the psychosocial context in which it was delivered. + INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “Doctor- Patient 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. Sham procedure, sugar pill which is a Treatment “simulation” +

11. 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 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. Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. Administration of a specific treatment e.g. an active drug Response Specific treatment + psychosocial context Response due to both the specific treatment and the psychosocial context in which it was delivered. + INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “Doctor- Patient 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) Psychosocial context only Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” +

12. 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 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. Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. Administration of a specific treatment e.g. an active drug Response Specific treatment + psychosocial context Response due to both the specific treatment and the psychosocial context in which it was delivered. Routine Care + INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “Doctor- Patient 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) Psychosocial context only Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” +

13. 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 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. Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. Administration of a specific treatment e.g. an active drug Response Specific treatment + psychosocial context Response due to both the specific treatment and the psychosocial context in which it was delivered. Routine Care + INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “Doctor- Patient 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) Psychosocial context only Research on Placebo or Clinical Trial Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” +

14. 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 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. Individual Patient and Clinician Factors e.g. Patient’s and clinicians beliefs, expectations, desire for symptom change, past experiences. Administration of a specific treatment e.g. an active drug Response Placebo Mechanisms Specific treatment + psychosocial context Response due to both the specific treatment and the psychosocial context in which it was delivered. Routine Care + INTERACTING WITH Interaction between the Patient, Clinician and Treatment Environment. e.g. factors comprising the “Doctor- Patient 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) Psychosocial context only Research on Placebo or Clinical Trial Administration of a “placebo” e.g. Sham procedure, sugar pill which is a Treatment “simulation” +

15. 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 ?

17. 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)

18. How do placebo’s work? • Placebo effects are different based on prior experience (conditioning)

19. 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

20. 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)

21. 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.

22. The effects can go the other way - Nocebo

23. 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)

24. The model • “Specific” component to therapy • “Placebo” component to therapy (clearly complex and variable) • Consideration of a potential nocebo component • 2 + 2 = 4 ?

25. 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

26. 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 Drug plus psychosocial context

27. 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 Drug plus psychosocial context Drug only

28. Morphine Buprenorphine Tramadol Ketorolac Metamizol Open Hidden Open Hidden Open Hidden Open Hidden Open Hidden 0 -1 -2 -3 Finniss & Benedetti 2007

29. 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.

30. Benedetti F, Amanzio M et al, 1995

31. Benedetti F, Amanzio M et al, 1995

32. Finniss & Benedetti 2006

34. 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.

35. Prof Michael Cousins Prof Michael Nicholas Dr Charles Brooker Prof Fabrizio Benedetti Dr Luana Colloca Prof Don Price Prof Dan Moerman Prof Ted Kaptchuk Dr Frank Miller Dr Ron Kupers Acknowledgements