Placebos from St Jerome to functional MRI


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Placebos from St Jerome to functional MRI

  1. 1. Placebos from St Jerome to functional MRI or c an we double our gas mileage if we wished for it hard enough? W Wallis Middlemore Medical Society Millbrook 2011
  2. 2. Placebo Definitions <ul><li>A placebo (L. “ I shall please”) is an inert substance or sham medical intervention, which by definition cannot have therapeutic effect , but it can </li></ul><ul><li>When it does it is termed the placebo effect </li></ul><ul><li>Pure placebos are sugar or talc pill </li></ul><ul><li>Impure placebos are vitamins, antibiotics, physiotherapy, manipulations, acupuncture,etc when ritualistically prescribed by a doctor without expectation of benefit. That is to please patient (and doctor) </li></ul><ul><li>A nocebo ( L.”to harm’) is the unwanted side effect of a placebo </li></ul>
  3. 3. How placebos are Used <ul><li>In medical research , placebos are given as control treatments and depend upon deception. These are employed in randomised controlled medical trials (RCT) , where a presumably effective treatment is compared against a placebo. That is to see if studied treatment works better than no treatment. </li></ul><ul><li>Commonly employed research placebos are inert tablets and injections , and sham forms of: surgery, acupuncture, electrical stimulation, spinal manipulation , and other procedures based on false information. </li></ul><ul><li>Outside of research trials, doctors (unless they are pathologists) like using placebos . </li></ul><ul><li>. </li></ul>
  4. 4. Doctors like using placebos
  5. 5. Doctors like using placebos <ul><li>In one survey 86% of GPs and 54% of specialists knowingly prescribed placebos, usually impure ones, such as physiotherapy, antibiotics, antidepressants, vitamins and so on, not because they expect them to work but rather to avoid conflict and give patients what doctors thinks they want. </li></ul>
  6. 6. Placebos Have been with us since prehistoric times
  7. 7. Placebo : Historical Aspects St Jerome (c347-420) introduced the term placebo to Christianity when translating the Hebrew Bile to vulgate but “lost in translation” Medieval placebo mourners Chaucer 1386 Squire Placebo the sycophant
  8. 8. Many other well-publicized exorcisms with exposures to sham religious objects are recorded. For example, in 1565, King Charles IX arranged to meet a notorious demoniac who testified to Protestant ungodliness. This demoniac had been tested with ordinary wine deceptively mixed with holy water. Her violent reactions to the concealed holy water confirmed to observers that her possession was genuine. Later, however, when other more sceptical investigators repeated the experiment, she could not distinguish genuine from fake exposures. Placebo Controlled Trials are not New Used by the early Church To expose fake possession by the devil (as depicted by Goya)
  9. 9. <ul><li>The first relatively modern use of placebo was by Benjamin Franklin in Paris, in 1784, to discredit the quack and high society hypnotist Mesmer. Mesmer would transform inanimate objects with “animal magnetism” that had extraordinary effects upon his customers. Franklin showed that such people had the same reaction to similar objects not bestowed with these properties </li></ul>“ Well done is better than well said.”
  10. 10. <ul><li>Placebos entered mainstream medicine in the 18 th and 19th centuries and were intentionally used to deceive patients into feeling better. </li></ul>
  11. 11. There have always been doubters <ul><li>The great sceptic, HL Menken, on his visit to the shrine of Lourdes, after contemplating piles of wheelchairs, crutches, and walking sticks - observed: “The one thing I did not see were glass eyes, wooden legs, and wigs.” </li></ul><ul><li>. </li></ul>
  12. 12. Wall Street uses placebos
  13. 13. Politicians use of Placebos The Republicans’ view of Obama’s economic stimulus package
  14. 14. Placebos in Modern Medicine <ul><li>After the Second World War, the placebo gained wide recognition because of randomised controlled trials (RCT ). </li></ul>RCTs are a way of testing a therapy in which, in addition to a group of subjects that receive the treatment to be evaluated, a separate control group receives a &quot; placebo &quot; treatment which is specifically designed to have no real effect. Placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment.
  15. 15. Placebos in Modern Medicine <ul><li>Design of single-blind or double-blind randomised placebo-controlled trials </li></ul>Treatment arm ˅ Placebo arm ˅ Placebo ˂ and nocebo effects Treatment Effects and ˃ side effects
  16. 16. People with post dental surgery pain > Randomly assigned to either morphine or placebo. Both patient and doctor > unaware (both “blind”) of which was used. Outcome judged by observers unaware of which treatment used > effects and side effects of: morphine ˄ vs. ˄ placebo Note that both the morphine and the placebo effects are reversed by a morphine antidote (naloxone) Example of double-blind controlled trial of a drug vs. a placebo
  17. 17. People with low back pain > Randomly assigned to either traditional Chinese Acupuncture (L) or “sham” > Acupuncture (R) . Patients unaware of which was used. Single-blind because only patient is unaware, not the acupuncturist. Outcome judged by observers unaware of which treatment used > effects and side effects of “real” ^ acupuncture vs. “sham” ^ acupuncture Example of single-blind controlled trial of a procedure vs. a sham procedure
  18. 18. Not all Placebo controlled Trials are with “inert” substances Sham surgery for Parkinson’s and Comparing leeches to Voltaren
  19. 19. What is the “true” placebo effect? First we need to remove confounding factors <ul><li>natural course of the disease </li></ul><ul><li>fluctuations in symptoms </li></ul><ul><li>regression towards the mean </li></ul><ul><li>The effect of other medications. </li></ul><ul><li>Reporting bias by doctor or patient </li></ul><ul><li>The placebo effect minus confounding factors = “true” placebo effect </li></ul><ul><li>The confounding factors do not explain all the phenomenology </li></ul><ul><li>of the placebo effect. </li></ul><ul><li>They do not take into account the psychobiological effect of therapeutic milieu (doctor-patient relationship) and the placebo’s capacity to produce genuine physiological changes. A placebo may be inert but the surrounding psychosocial circumstances are not </li></ul>
  20. 20. How does placebo effect work ? The psychobiological effects and how to remove them
  21. 21. Expectation and conditioning drive the “true” placebo effect <ul><li>Expectation means what the patient is expecting. An analgesic cream, described as the most powerful available, is more effective than an ordinary one, when in fact both are placebos. Colour helps. </li></ul><ul><li>Expectation is increased by ritual . That is, the placebo becomes more effective if the ritual surrounding the procedure (such as elaborate sham acupuncture) and supportive-practitioner relationships intensify. </li></ul><ul><li>Expectation can be incrementally added in a manner resembling a graded drug dose escalation </li></ul>
  22. 22. Doctors’ appearance and behaviour enhance both the placebo and nocebo effects expectation good BAD
  23. 23. Pavlovian Conditioning (dog, ring bell, feed, salivate and so on) amplifies the placebo effect <ul><li>When placebos are alternated with effective medications </li></ul><ul><li>both the placebos and the medications work better. </li></ul><ul><li>i.e. morphine – placebo – morphine – placebo - morphine </li></ul><ul><li>Conditioning works in both mice and men. </li></ul>
  24. 24. Conditioning put to good use treatment of psoriasis with steroid cream full daily dose, alternate placebo-steroid, and gradually reducing steroid dose vs. relapse rate
  25. 25. Objective placebo effects on brain imaging <ul><li>Placebos have powerful objective effects on brain function as seen on brain imaging. </li></ul><ul><li>Placebos analgesia has the same effect on sophisticated brain imaging as opioid drugs . </li></ul><ul><li>Placebo analgesia is reversed by the opioid antidote naloxone. </li></ul>
  26. 26. Objective placebo effects on brain imaging Placebo analgesic produces identical response to opioid. Reversed by naloxone ˂ Placebo produces identical response In Parkinson's disease To levodopa ˂
  27. 27. Placebos “work” even when patients in RCTs are told that they are receiving them Welcome to the home of the original Obecalp® The first consumer placebo utilizing pharmaceutical grade ingredients available for sale at retail locations around the country.
  28. 28. How does one tell if placebos work ? ˂ 4. Covert use of placebo First remove expectation conditioning, and confounding factors . How does one remove expectation ? By 4 strategies : 2. Using cross over trial design 3. Using an untreated control to compare to the placebo 1. Use objective outcomes
  29. 29. Example of good trial design meeting criteria 1-3 objective outcome (FEV 1 ), cross-over design, and untreated control <ul><li>Double-blind, crossover pilot study, 46 patients with asthma assigned to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, and no treatment. Objective outcome was FEV1 . Subjective outcome is what patients reported . </li></ul>Wechsler,M Albuterol or Placebo, Sham Acupuncture, or No Intervention in Asthma Michael E. N Engl J Med 2011;365:119-26
  30. 30. How well would this chap respond to a placebo when he wakes up ? Thoracotomy
  31. 31. Covert Placebo <ul><li>Post thoracotomy patients given basal iv saline infusion (placebo) for 3 days. </li></ul><ul><li>1/3 told iv was a “powerful pain reliever’ ( placebo ) </li></ul><ul><li>1/3 told it might be a” placebo or a powerful pain reliever” ( double-blind group ) </li></ul><ul><li>1/3 told nothing ( covert placebo ) </li></ul><ul><li>That is all received the same placebo but 2 were given expectation, 1 told nothing </li></ul><ul><li>All patients given access to buprenorphine as requested (prn) </li></ul><ul><li>Record of total mg of buprenorphine used in each of 3 groups recorded </li></ul><ul><li>mg buprenorphine </li></ul><ul><li>“ powerful pain reliever’ ( placebo ) 7.5 mg </li></ul><ul><li>might be a” placebo ( double-blind group) 9.15 mg </li></ul><ul><li>Told nothing ( covert placebo ) 11.55 mg </li></ul><ul><li>Covert administration of placebo eliminates it the placebo effect </li></ul>Pollo A ,et al Response expectancies in placebo analgesia and their clinical relevance. Pain. 2001:9377-84. Ju
  32. 32. Summary Do placebos work? Well, yes and no . <ul><li>Yes , if there is conditioning , expectation , and the outcome is subjective . </li></ul><ul><li>No, if one removes conditioning, expectation, and uses objective outcomes; particularly, when a placebo is compared to an untreated cohort </li></ul><ul><li>So you cannot double your gas mileage if you wish for it hard enough or find glass eyes, artificial legs, and wigs in Lourdes. </li></ul>