Placebo

understanding what is placebo. " I shall please". "Humble humbug".

1. PLACEBO Presenter : Dr Nazuk sharma

2. Introduction Definition History Incidence Types Mechanism of action Factors influencing placebo response Application Ethics Human research protection guidelines Problems with placebo

3. Definition D ummy medicine containing no active substance Latin : 'I shall please‘ Psychodynamic > Pharmacodynamic Patients who respond to placebo are termed as “ Placebo responders ”

4. 1811 : Quincy's Lexicon- Medicum defines placebo as 'an epithet given to any medicine adapted more to please than to benefit the patient 1960s :{ Shapiro} Any therapeutic procedure which has an effect on a patient, symptom, syndrome or disease, but which is objectively without specific activity for the condition being treated.

5. H istory Dates back to 116 th psalm in Hebrew bible ( 19 th verse of psalm “et ha lech ” meaning I shall walk which in latin is “ placera ” “I shall please” ) 14th century: hired mourners at funerals. Earlier known as “ Humble Humbug ” In 1801, John Haygarth reported the results of what may have been the first placebo controlled trial

6. 1785 : M otherby’s new medical dictionary as a “ comman -place method or medicine” 1795: calculated to amuse for a time , rather than for any other purpose 1930: . Evans and Hoyle and Gold and colleagues actually used the word placebo for the inert treatment given to controls in an experimental situation.

7. 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, the tincture of quassia , very largely diluted. Became well known placeboic remedy for rheumatism )

8. Incidence 15 studies , carried out by Beecher (1955 ) involving 1082 patients, the average placebo response rate determined was 35.2% . When patients do not know they are receiving placebos , high as 70-82 % A ngina pectoris: the use of vitamin E,ligation of the internal mammary artery, were about 80 % effective

9. B ack surgery : suggested by Spangfort’s review of long-term outcomes of 2504 “ diskectomies ” for lumbar disk disease. Complete relief of back pain was noted in 43% of patients who had sham surgery done

10. Placebo effect Result obtained by use of placebo. Shapiro ( 1959):” the psychological, physiological or psycho-physiological effect of any medication or procedure and which operates through a psychological mechanism “ a change in a patients illness attributable to the symbolic import of a treatment rather than a specific pharmacologic or physiologic property

11. Types Positive Negative Improvement in symptoms Symptoms Getting worse

12. H awthorne effect 1930s Phenomenon whereby a subject’s performance changes simply because he or she is being studied.

13. Nocebo latin : nocero (inflicting harm) Opposite of placebo Negative psychodynamic effect evoked by the pessimistic attitude of the patient, or loss of faith in medication/physician To induce a nocebo effect, an inert substance is administered along with negative verbal suggestions of clinical worsening Mediated by receptors like CCK1 & NK1.

14. Colloca et al (2008) used a nocebo procedure, in which verbal suggestions of painful stimulation were given to healthy volunteers before administration of either tactile or low-intensity painful electrical stimuli . This study showed that these anxiogenic verbal suggestions were capable of turning tactile stimuli into pain , as well as low-intensity painful stimuli into high-intensity pain.

15. Types of placebo Inert or Pure placebos : substances that could have no conceivable pharmacologic effect on the patient . Examples : Dummy pills or capsules containing lactose or chalk

16. Active or Impure placebo : Have potential pharmacological effects, though not necessarily any specific activity for the condition under treatment. Examples :vitamin B 12 or iron in the absence of anemia , Antibiotics in viral infections

17. Inert substances used Inert pills, drugs, or injections Sham surgeries Inactive medical devices Injections of distilled water

18. MECHANISM OF ACTION

19. MECHANISM OF ACTION Conditioning reflex model Opioid model Expectancy model

20. Conditioning reflex model Involuntary conditioned reflex of the patient’s body A rachnoiditis pain , were relieved after they received intrathecal injections of novocaine. But actually injected with saline rather than novocaine

21. Conditions like Physician physical examination prescription Procedure Places I nformation obtained by reading and remarks of other people Previous experience

22. Expectancy model Aimed at preparing the body to anticipate an event to better cope with it For example, resuming a normal daily schedule, and negative expectations leading to its inhibition ( bootzin , 1985;bandura, 1997). Effects of expectations modulated by Decrease in self-defeating thoughts. Motivation

23. Expectation of Reward E xpectations of future events modulate not only anxiety , but they may also induce physiological changes through reward mechanisms . These mechanisms are mediated by specific neuronal circuits linking cognitive, emotional , and motor responses. studied in the context of the pursuit of natural ( eg , food) Monetary

24. Opioid model Release of endogenous opiate : endorphins & enkephalins Field et all (1997) shown that placebo induced analgesia can be reversed by naloxone

25. Interference between placebo/expectation effects and drug action.

26. FACTORS INFLENCING PLACEBO RESPONSE Patient characteristics Provider characteristics Appearance of treatment procedures Environment relationship

27. M esolimbic dopaminergic system may be activated in some circumstances when a subject expects clinical improvement after placebo administration . In 2001, de la Fuente –Fernandez et al (2001) assessed the release of endogenous dopamine using positron emission tomography (PET) with raclopride ,( a radiotracer that binds to dopamine D2 and D3 Receptors), competing with endogenous dopamine. In this study , Parkinsonian patients were aware that they would be receiving an injection of either active drug ( apomorphine , a dopamine receptor agonist) or placebo, according to classical clinical trial methodology. After placebo administration, it was found that dopamine was released in the striatum , corresponding to a change of >200 % in extracellular dopamine concentration and comparable to the response to amphetamine in subjects with an intact dopamine system.

28. Applications Regression to mean Natural history of disease Specific effects of treatment Nonspecific effects of treatment- placebo effects Efficacy of treatment

29. Application in clinical trials Researcher compares the results of experimental treatment versus placebo . The placebo-controlled trial the gold standard for testing the efficacy of new treatments .” B est evidence for new treatment come from randomized placebo-controlled (RCT) double-blind studies .

30. placebo is used in clinical drug trials for the following reasons : Compare effects with those of the active drug Comparison of active drugs validated by a placebo Blind administration of two drugs that cannot be made indistinguishable (Double Dummy technique )

31. Wihdrawal period Toxicity Placebo responders to be excluded Identify treatment non- compliers

32. Ethics Topic of debate Ethical : use of placebos is essential to protect the society from the harm that could result from the widespread use of ineffective medical treatments . Unethical: Alternative study designs would produce similar results with less risk to individual research participants .

33. Declaration of Helsinki : “In any medical study, every patient including those of control group, if any should be assured of the best proven diagnostic and therapeutic methods and no patient should suffer from unnecessary pain .”

34. CONTROVERSY O bserved response to placebo in RCT may reflect the natural course of the disease fluctuations in symptoms regression to the mean response bias with respect to the patient's reporting of subjective symptoms and other concurrent treatments

35. Clinical equipoise in placebo-controlled trials state where clinicians are unsure whether the new treatment or intervention is as good as the standard treatment . ? Violation of the therapeutic obligation of physicians to offer optimal medical care. right of the patient to receive the best care possible is compromised .

36. H uman research protection guidelines The Office for Human Research Protection (OHRP) published guidelines in 2008 for the use of placebo “Placebos may be used in clinical trials where there is no known or available (i.e., FDA-approved) alternative therapy that can be tolerated by subjects.”

37. The use of placebos in controlled clinical trials must be justified by a positive risk-benefit analysis The subjects must be fully informed of the risks involved in the assignment to the placebo group. Continued assignment of subjects to placebo is unethical , once there is good evidence to support the efficacy of the trial therapy

38. Subjects with an increased risk of harm from non-response may be excluded . Increased monitoring for deterioration of subjects and the use of rescue medications may be included in the protocol . ‘ Early escape ’ mechanisms and explicit withdrawal criteria may be built in so that subjects will not undergo prolonged placebo treatment if they are not doing well . The size of the population placed on placebo may be kept smaller than the number in the active treatment arms.

39. Some drug trials involve a period during which all participants receive only a placebo prior to the initiation of the study. This period is called a ‘ placebo washout’. The purposes of a washout period include : Terminating the effects of any drug the subject may have been taking before entering the clinical trial, so that the effects of the trial drug may be observed.

40. 2. Understanding whether the subjects co-operate with instructions to take drugs . 3. Understanding which subjects are ‘placebo responders’, in that they experience a high degree of placebo effect. 4. In some protocols, the investigators plan to exclude those subjects they find either poorly compliant or highly responsive to the placebo

41. T he informed consent information : The subjects must be informed that they may be given a placebo. A clear lay definition of the term ‘placebo ’ must be given to the subjects. The rationale for using a placebo must be explained to the subjects. .

42. If applicable, the subjects must be informed of any viable medical alternatives to being placed on placebo. The duration of time that a subject will be on a placebo, degree of discomfort, and potential effects of not receiving medication must all be explained. Any consequences of delayed active treatment must be explained to the subjects

43. A statement in the risk section of the consent that the condition of the subject may worsen while on placebo should be included. A discussion in the benefits section that subjects who receive placebo will not receive the same benefit as those who receive active treatment if that treatment is effective should also be included.

44. Problems assosciated with placebo Imperfect likeness Impure placebos Selecting placebo nonreactors Overestimation of placebo effects

45. Refrences Roy v. Roy T.Placebos : current status. Indian journal of pharmacology 2001; 33: 396-409 EDUCATIONAL FORUM Lichtenberg P, Heresco-Levy U,Nitzan U . The ethics of the placebo in clinical practice.J Med Ethics 2004;30:551–554 . Gupta   U.and Verma M. Placebo in clinical trials.Perspect clin res.2013 Jan;4(1): 49-52 Anton J M, Kaptchuk O, Jan G P, Tijssen P.Placebos and placebo effects in medicine: historical overview; JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 92 October 1999 Benedetti F,Carlino E,Pollo A. How Placebos Change the Patient’s Brain; Neuropsychopharmacology REVIEWS (2011) 36, 339–354