1. Eyal Shahar, MD, MPH Professor (credit to Doron Shahar, BS) December 5, 2013

2. Outline Principles of causal diagrams What is “placebo”? What is the “placebo effect”? The expectation effect rather than the placebo effect Previous study designs Suggested study design

3. Principles of causal diagrams Name the variables T OFFERED T TAKEN D … Draw postulated arrows (from cause to effect) Depict theories of confounding bias Depict theories of effect modification

4. Example D Q R q r T OFFERED T TAKEN C Confounder Modifier

5. Example: an elaborated diagram* T OFFERED D E R B b t ( TAKEN ) t ( OFFERED ) b T TAKEN e Blinding status Expectation All possible causes of the offered treatment *Note theories of effect modification

6. A successful double-blinded randomized trial T OFFERED D E R B t ( TAKEN ) t ( OFFERED ) B =blinded: null effect T TAKEN e = blinded

7. Outline Principles of causal diagrams What is “placebo”? What is the “placebo effect”? The expectation effect rather than the placebo effect Previous study designs Suggested study design

8. What is “placebo”? Too many definitions to cover All allude to “effect” or “lack of effect” Yet, most cannot be encoded in a causal diagram A VERY BAD SIGN!

9. What is “placebo”? “A treatment that does not objectively affect the outcome” A meaningless adverb No such thing as “objectively affect” No such thing as “subjectively affect” Can’t depict in a diagram Not rigorous enough for science

10. What is “placebo”? “An inert/inactive/ineffective treatment” Really? How do you know, in advance, that something doesn’t have an effect? And what about the “placebo effect”? Can’t depict in a diagram Not rigorous enough for science

11. What is “placebo”? “A treatment that on its own has no beneficial effect” What exactly is “on its own”? Can’t depict in a diagram Not rigorous enough for science

12. Placebo: a possible definition “A treatment is called placebo if the effect of that treatment (versus no treatment) is null when the patient has no particular expectation about the outcome.”

13. t 0 below (a value of T TAKEN ) is “placebo” T OFFERED T TAKEN D=d E t E=indifference: null effect t 0 vs. nothing

14. So, what is the desired definition of placebo? Who cares? Definitions are much less important than we tend to think We don’t really need the term to acquire knowledge

15. Outline Principles of causal diagrams What is “placebo”? What is the “placebo effect”? The expectation effect rather than the placebo effect Previous study designs Suggested study design

16. The placebo effect At least 6 definitions All are clear (for a change…) Can be depicted in a causal diagram Some refer to placebo Which requires a clear definition of placebo… Some do not refer to placebo at all! Can be organized in two groups

17. Group 1: Some effect of a treatment variable on some value of the outcome variable T TAKEN D=d E placebo vs. nothing T TAKEN D=d E = e placebo vs. nothing D=d placebo vs. nothing T OFFERED t TAKEN

18. Group 2: Some effect of the expectation variable on some value of the outcome variable E D=d E T TAKEN T TAKEN = placebo E D=d T TAKEN = t T TAKEN

19. Outline Principles of causal diagrams What is “placebo”? What is the “placebo effect”? The expectation effect rather than the placebo effect Previous study designs Suggested study design

20. The expectation effect T OFFERED D E R B t ( TAKEN ) t ( OFFERED ) B =blinded: null effect T TAKEN e = blinded

21. The expectation effect No need to mention the word “placebo” E D=d T TAKEN = t T TAKEN e The effect of expectation might vary according to the treatment taken The effect of the treatment taken might vary according to the level of expectation

22. Expectation: two kinds of questions Causes of expectation Effects of expectation E A B C D E W X Y Z And don’t forget the possibility of effect modification for each arrow

23. Outline Principles of causal diagrams What is “placebo”? What is the “placebo effect”? The expectation effect rather than the placebo effect Previous study designs Suggested study design

24. Previous study designs Claim to estimate the “placebo effect” Don’t estimate the same effect Don’t estimate well the expectation effect

25. Previous study designs Drug or placebo Neither drug nor placebo Drug Nothing Drug Placebo DrugPlacebo Drug Treatment Patient told Treatment Patient told Placebo Nothing Three arms Concealed treatment Balanced placebo design

26. What’s the problem? “TELLING” and “EXPECTING” are different variables Telling the patient something affects expectation, but does not fully determine expectation There are other causes of expectation: Trust Prior beliefs Education None of these designs estimates well the expectation effect

27. Outline Principles of causal diagrams What is “placebo”? What is the “placebo effect”? The expectation effect rather than the placebo effect Previous study designs Suggested study design

28. Measure expectation! T OFFERED D E R B t ( TAKEN ) t ( OFFERED ) B =blinded: null effect T TAKEN e = blinded E*E*

29. What is “expectation”? A single variable or multiple variables? Don’t know Have psychologists figured it out? Maybe (or maybe not) How do we measure the variable(s)? I am no expert in psychology and mental state variables

30. Conclusions (1) “Placebo” and “placebo effect” are vague terms Stop using them; they are poorly defined Stop using them; neither is needed to advance knowledge The “placebo” pill is made up of something. Call it by its name (its chemical composition)

31. Conclusions (2) Measure expectation! Study the causes and effects of expectation!! Use an observational cohort within a blinded randomized trial!!! Deal with confounding bias and explore effect- modification

32. Thank you Causal diagrams, the placebo effect, and the expectation effect. Shahar E, Shahar DJ. Int J Gen Med. 2013 Sep 27;6:821-8 PMID: 24101881 [PubMed] Free PMC ArticleFree PMC Article