Placebo: Are They Really Inert?

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Placebo response has always been an enigma in the field of medicine. This slide shall take you through the journey of placebo response through the years...

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Placebo: Are They Really Inert?

  1. 1. PLACEBOAre they Really Inert? Dr. Zarrin Ansari Mumbai
  2. 2. What do We understand By Placebo and Placebo effect?Dummy pill Sugar Pill Fake Drug Sham Surgery
  3. 3. Placebo EffectSwallow a dummy pill that contains nothing but starch:yet your migraine vanishesA saltwater injection eases your asthma the sameamount that puffing on a bronchial inhaler doesA surgeon cuts the skin over your knee instead ofperforming arthroscopic surgery, but your knee painstill goes awaySwallow a dummy pill, without knowing it is a dummypill and depression, anxiety and mood problems getlifeted
  4. 4. What Placebos cannot do?Placebos CANNOT shrink a tumor, reduce viral or bacterial load in the body or cure HIV Placebo response has been observed only in diseases where the reactive component of the patient matters a lot Migraine Pain Insomnia Asthma Anxiety Depression IBD Stomach ulcers
  5. 5. Defining Placebo Pharmacologically Inert Substances1960, Shapiro ―Any therapeutic procedure which has aneffect on a patient, symptom, syndrome or disease, but which is objectively without specific activity for the condition being treated‖ Brody ―An intervention designed to simulate medical therapy, that at the time of use is believed not to be aspecific therapy for the condition for which it is offered‖Hornung ―an empty preparation or intervention imitatingan effective preparation or intervention where one must decide on the emptiness of the preparation in each particular situation J Royal Soc Med 1999: 92: 511-
  6. 6. Let’s Go Back inHistory of Placebo
  7. 7. Placebo in Latin means ―I shall please‖ 14th Century, Mourners at Funeral ―Placebo Domino in regione vivorum‖―I shall please the Lord in the land of the living‖ 1811, the revised Quincy‘s Lexicon-Medicum defines placebo as ―an epithet given to any medicine adapted more to please than to benefit the patient‖ J Royal Soc Med 1999: 92: 511-
  8. 8. Placebo in Clinical Practice Pious Fraud ―One of the most Placebo was a fraud successful physicians I have ever know has and deception that assured me that he used had ―moral effect of a more bread pills, drops of remedy given colored water, and specially for the powders of hickory disease, but placebos ashes, than all other did not affect the medicines put together‖ natural course of Placebo were therapeutic disease; they were a duds to manage priori excluded from patients, or, a camouflage having such an impact behind take which to watch nature take itsJ Royal Soc Med 1999: 92: 511- course
  9. 9. In 1863, Austin Flint tried to understand whether drugs given for articular rheumatism changed the natural history of disease. Flint placed 13 patients ―on the use of a placebo which consisted, in nearly all the cases, of the tincture of quassia, very largely diluted. This wasgiven regularly, became well known as the placeboic remedy for rheumatism.Flint, in accord to the understanding at his time, hasno idea of concurrent control, but concluded that ―the disease does end from self limitation‖ and that inert treatment worked. Royal Soc Med 1999: 92: 511- J
  10. 10. In 1938, the word placebo was first applied in reference to the treatment given to concurrent controls in a trial of vaccines for preventing coldThe trial gave negative results, although the results in the vaccine-treated groups were comparable with those in previously reported experiments. It was the substantial improvement in the placebo group that made the findings negative The PLACEBO EFFECT was born J Royal Soc Med 1999: 92: 511-
  11. 11. 1955, Henry K. Beecher, M. D. BostonHenry Knowles Beecher (February 4, 1904– July 25, 1976) was an important figure in the history of anesthesiology and medicine, Seminal Article Quantifying the Placebo effect almost for the First Time JAMA 1955; 159: 1602-06
  12. 12. Condition Study Agent Route Patients % Relieved by No. PlaceboSevere post- Keats 1950 Saline I. V 118 21operativewound pain Beecher 1951 Saline S. C. 29 31 Keats 1951 Saline I. V 34 26 Beechers 1953 Lactose P.O 52 40 36 26 44 34 33 40 32 Lasagna 1954 Saline S. C 14 50 20 37 15 53 21 40 39 15 40 15 15Cough Gravenstein 1954 Lactose P. O 22 40Experimental Hills 1952 Isotonic S. C 1 37cough NaClHeadache Jellinek 1946 Lactose P. O 199 52
  13. 13. Condition Study Agent Route Patients % Relieved by No. PlaceboDrug-induced Lasagna 1955 Isotonic S. C. 20 30mood changes NaCl (normal) 30 30 (PA)Pain from angina Evans 1933 NaCl P. O. 66 38pectoris Travell 1949 NaCl P. O 19 26 Greiner 1950 Lactose P. O 27 38Sea-sickness Gay & Carliner Lactose P. O 33 58 1949Common cold Diehl 1933 Lactose P.O Acute 110 35 Subacute/ 35 chronic 48 Total Patients: Average 1082 relieved: 35.2 ± 2.2% In 15 studies, involving 1082 patients, placebos are found to have an average significant effectiveness of 35.2±2.2%. JAMA 1955; 159: 1602-06
  14. 14. Objective ResponsesAbbot, Mack and Wolf found in 13 experiments with placebo on subjects with Gastric fistula. The gastric acid levels apparently fell about twice as often when a placebo was given as when no agent agents were given JAMA 1955; 159: 1602-06
  15. 15. Nocebo effect Subjective side-effects of Placebo Dry mouth 7/77 9% Nausea 9/92 10%Sensation of 14/77 18% heaviness Headache 23/92 25% Difficulty 14/92 15%concentration Drowsiness 36/72 50% Warm glow 6/77 8% Fatigue 10/57 18% JAMA 1955; 159: 1602-06
  16. 16. The great power of placebos provides one of thestrongest supports for the view that drugs that are capable of altering subjective responses and symptoms and do so to an important degreethrough their effect on the reaction component of suffering.This paper had a great impact on the concept of placebos No more a Humble HumbugIt evoked a response as well showed side-effects JAMA 1955; 159: 1602-06
  17. 17. For Beecher, the Placebo was indeed “Powerful” It was Beecher‘s double-blind, placebo- controlled, randomized clinical trial or RCT was enshrined as the gold standard of the emerging pharmaceutical industry. Today, to win FDA approval, a newmedication must beat placebo in at least two authenticated trials.
  18. 18. 1997, Gunver S. Kienle and Helmut KienePointed out the limitations of Beecher’s Analysis J Clin Epidemiol. 1997; 50: 1311-
  19. 19. The Analysis was based on two questions The existence of the placebo effect demonstrated in those 15 trials that Beecher had surveyed in the ―The Powerful Placebo‖ If not, what are the factors that can create a false impression of a placebo effect? J Clin Epidemiol. 1997; 50: 1311-
  20. 20. “Placebo Effect” is an oxymoronSomething which is “inert” cannot produce “effects” “Placebo Response” J Clin Epidemiol. 1997; 50: 1311-
  21. 21. Though these studies were placebo controlled study, they were not carried out to investigate the effect of placebo They were retrospectively analyzed Beecher completely neglected all obviousreasons for the outcome in the placebo groups, simply calling the reported results “real therapeutic effects” Beecher misinterpreted the results J Clin Epidemiol. 1997; 50: 1311-
  22. 22. Factors thatcan cause the falseimpression of a placebo effect J Clin Epidemiol. 1997; 50: 1311-
  23. 23. Natural course of the disease Spontaneous Remission: Common cold, post-operative pain Fluctuation of symptoms: Chronic illness like ulcers, migraine, muscle tension or headache have anxiety and other mood symptomsRegression to mean: Tendency of extreme values to move closer to the average on repeated measurements. McDonald et all, ―how much of placebo effect is really statisticalregression? Most improvements attributed to the placebo effects are actually instances of regression to mean‖ J Clin Epidemiol. 1997; 50: 1311-
  24. 24. Additional TreatmentSo-called placebo effects often occur under additional treatment. In the cold trials, patients were allowed to take hot baths, gargles diets, rest etc. Irritable colon treatment, all patients were given special dietsIn some alcoholism studies, patients were given specialized psychological support J Clin Epidemiol. 1997; 50: 1311-
  25. 25. Conditional switching Some trials selected by Beecher amplifiedthe ―placebo effect‖ by selecting the patients in the following manner When the patients felt well, they received placebo and when they felt worse they received medication or excluded from trial (angina)
  26. 26. Answers of Politeness & Experimental SubordinationAnswer of Politeness: Placebo means to please, it applies both ways. When the patient is grateful for clinician‘s time and effort in trying to help them, this gratitude (plus simple good manners) often is reflected in an exaggeration ofbenefits of the latest prescription when they are asked ―Did that medicine help you?‖ Experimental subordination: in an experiment patientstend to say what they are expected to say and not what they J Clin Epidemiol. 1997; 50: 1311-
  27. 27. Neurotic or Psychotic Misjudgment The reliability of a patient’s report is often particularly difficult to assess in neurotic or psychotic disturbances. One of the common feature in psychosis or neurosis is disturbed interpretation of reality Therefore one has to clearly differentiate betweenpsychosis or neurotic judgment on one hand and a correct observation of a therapeutic effect on the other hand. J Clin Epidemiol. 1997; 50: 1311-
  28. 28. Irrelevant or Questionable Response VariableIn some patients of Multiple sclerosis, for the assessmentof subjective variables, parameters like euphoria, strength and agility were recorded. Euphoria itself can be a symptom of multiple sclerosis.Thus, a question like this is not relevant to assess placebo response in these patients. Uncritical Reporting of Anecdotes J Clin Epidemiol. 1997; 50: 1311-
  29. 29. According to Kiene and KienleThere is no doubt that the extent and frequency of placebo effects as published in most of the literature are gross exaggerationsShapiro et al. ―In our opinion, the belief that placebos and psychological factors have a specific and clinicallymeaningful effect on physical illness is not supported by a critical, data-oriented review of the literature‖ Robert et al, ―The so-called placebo response is a mythborn out of misconception, misunderstanding, mystery and hope‖ J Clin Epidemiol. 1997; 50: 1311-
  30. 30. Finally, these factors that can create false impressionsof placebo effects might seem to be compelling reasons for randomization and blindingHowever, analysis indicates that these factors evoking aplacebo response are not necessarily distributed equally in drug and control groups, thus challenging the validity of randomized double-blind trials J Clin Epidemiol. 1997; 50: 1311-
  31. 31. For Kiene and Kienle“The Powerful Placebo Turned out to be a Fiction” J Clin Epidemiol. 1997; 50: 1311-
  32. 32. Let us hear Another Placebo Story
  33. 33. Awaiting its block buster Substance P antagonist MK 869 as an antidepressant
  34. 34. Merck noted that the Phase II study, which tested two doses of MK-869 and a selective serotonin reuptake inhibitor versus placebo in several hundred patients, was a failure because the SSRI was unable to outperform placebo. Despite the fact that one dose of MK-869 was better than control, the overall trial was compromised owing to the high response rate for the placebo group.
  35. 35. Trials between January 1981 and December 2000 in which outpatients with MDD wererandomly assigned to receive medication or placebo. Seventy-five trials were included JAMA 2002; 287: 1840-47
  36. 36. The mean proportion of patients in theplacebo group who responded was 29.7% and in the active treatment group was 50% JAMA 2002; 287: 1840-47
  37. 37. Both the proportion of patients responding toplacebo as well as to the treatment medicationwere significantly positively correlated with the year of publicationIn the last 2 decades, the proportion of patientsresponding to placebo has clearly increased at the rate of ~ 7% However, the association between year ofpublication and response rate were statistically robust for placebo than medication JAMA 2002; 287: 1840-47
  38. 38. Trials between January 1980 and December 2005 in which 9566 patients with depressionwere randomly assigned to receive medication or placebo. Ninety-six trials were included J Affective Dis. 2009; 118: 1-8
  39. 39. ResultsThe overall effect size of the placebo effect was 1.69as compared to d=2.5 in the drug groupThe ratio of the effect sizes suggests that 67.6% ofthe improvements in the drug groups wereattributable to placeboThere was a high correlation between the effect sizesin the placebo and drug groups (P<0.001) indicatingthat reported improvements in placebo and druggroups were strongly interdependent Eur Neuropsychopharmacol. 1999; 9: 271-276
  40. 40. Publication Year Effect Placebo GroupDrug Group
  41. 41. Publication Year Effect PlaceboThe mean effect sizes in the Placebo groups of Groupstudies published around 2005 were more than twice as great as though published before 1985. In the drug group, the same tendency was found, although due to more variance this effect was less clear and failed to reach Drug Group significance
  42. 42. So according to these meta-analysis, “Placebo was growing stronger”
  43. 43. Eur Neuropsychopharmacol. 1999; 9: 271-276
  44. 44. Objective of the Meeting Eur Neuropsychopharmacol. 1999; 9: 271-276
  45. 45. Discussion at the meet
  46. 46. Differences in the diagnostic modality The diagnostic modality used in earlier studies were far more stringent than today Placebo responses are more evident in milder than severe casesShorter minimum duration of illnesses criteria for diagnosis means the patients have afluctuating and intermittent nature of illness. This could be responsible for the inflated placebo response Eur Neuropsychopharmacol. 1999; 9: 271-276
  47. 47. Recruitment methodsIn developing nations, the recruitment patternsmay not be restricted to the protocols and such errors may be responsible for higher placebo responsePressure to recruit rapidly in order to finish the study in a timely fashion, might mean the inclusion criteria less accurately applied Eur Neuropsychopharmacol. 1999; 9: 271-276
  48. 48. Geographical criteriaPlacebo response is very subjective to cultural differenceCultural influences might be expected due to the relatively subjective nature of the instruments used for diagnosis and severity measurement. This might not be confined to psychiatry Eur Neuropsychopharmacol. 1999; 9: 271-276
  49. 49. Higher drop out ratesThe drug placebo difference substantially reduces if a large number of patients are withdrawn because of lack of efficacy or side- effects, particularly if they drop out early in the study Withdrawal because of lack of efficacy are encouraged as ethical solution in studies with placebo controls However, if drop-outs occur before the drug has had time to be effective the result will be to Eur Neuropsychopharmacol. 1999; 9: 271-276
  50. 50. Severity of the diseaseAntidepressants like Venlafaxine might require a diagnosis of Major Depression rather a mild depression to show its efficacy. Thus, if patients with less severe illness arerecruited, the drug effect might not be seen very differently from the placebo effect. Eur Neuropsychopharmacol. 1999; 9: 271-276
  51. 51. Trial design Trial settingsPlacebo-run-in phase Analytical issues
  52. 52. ConclusionNeed for investigation of failure of these studiesCompanies should share their database of allstudies including the negative studies rather thanhoarding it backThe reason for failure may well differ betweencenters that have followed the same protocolAnalysis of different working methods, differentsources of patients, different support therapy orcovert additional therapy, addition of co-medication
  53. 53. Harvard ‗s Ted Kaptchunk, director of ―Program in Placebo studies and Therapeutic EncounterHe calls placebos "surrogate markers" that measure the effect of just caring-the words, gestures, eye contact, attitude, the medical symbols of white coats, diplomas, prescriptions pads, and medical trappings. They are embedded in an elaborate context of ritual procedures that are part of every encounter: waiting, talking, attentive listening, disrobing, the laying on of hands and being examined, and then being treated with pills, talk, or surgery. Ultimately they have to do with the power of imagination, trust, and hope in both parties. In this view, the placebo doesnt do anything. Being in a healing relationshipdoes. Dummy pills, saline injections, and even sham operationsbring forward what has previously been hidden in the elaborate context of caring, rituals, and symbols that constitute every doctor-patient relationship.
  54. 54. Yellow pillsmake the most effective antidepressants, like little doses of pharmaceutical sunshine. The color of a tablet can boost the effectiveness even of genuine meds—or help convince a patient that a placebo is a potent remedy.—Steve Silberman Yellow pills: make the most effective antidepressants, like little doses of pharmaceutical sunshine. Red pills: can give you a more stimulating kick. Wake up, Neo. The color green reduces anxiety, adding more chill to the pill
  55. 55. White tablets—particularly thoseWhite tablets—particularly those labeled "antacid"—are superior for soothing ulcers, even when they contain nothing but lactose. labeled "antacid"—are superior for soothing ulcers, even when they contain nothing but lactose Branding matters: Placebos stamped or packaged with widely recognized trademarks are more effective than "generic" placebos.
  56. 56. Implications and several questionsFor Researchers: Designing a trial to minimizingthe bias, selection of the apt diagnostic modality, correct inclusion criteriaShould there be a switch from placebo trials to comparison trials? For Regulators: to have a deeper insight in not only the results but should be deep-diving within For Clinicians: Could the placebo be a CURE?
  57. 57. PLACEBOAre They Really Inert? The enigma continues……………..

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