Placebo and nocebo

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PLACEBO And NOCEBO
Dr. Ashishkumar Baheti
MD Pharmacology

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

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• 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) States that 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.
History

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• In 1801, John Haygarth reported the results
of what may have been the first placebo
controlled trial
• 1930: . Evans and Hoyle with colleagues
actually used the word placebo for the inert
treatment given to controls in an
experimental situation.

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• 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

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Incidence
• 15 studies, carried out by Beecher (1955)
involving 1082 patients, the average
placebo response rate determined was
35.2%.
•When the patients do not know they are
receiving placebos, rate high as 70-82%

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

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Placebo effect
• 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.

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Types
Positive Negative
Improvement
in symptoms
Symptoms
Getting
worse

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Hawthorne effect
• 1930s -Phenomenon whereby a subject’s
performance changes simply because he or
she is being studied.

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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
• T
o induce a nocebo effect, an inert substance is
administered along with negative verbal
suggestions of clinical worsening.
• Mediated by receptors like CCK1 & NK1.

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• 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.

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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

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Active or Impure placebo :
 Have potential pharmacological effects, though
not necessarily any specific activity for the
condition under treatment.
Examples : vitamin B12 or iron in the absence
of anemia,Antibiotics in viral infections

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

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MECHANISM OF ACTION
Conditioning
reflex model
Opioid
model
Expectancy
model

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Conditioning reflex model
• Involuntary conditioned reflex of the patient’s
body
• Arachnoiditis pain ,were relieved after
they received intrathecal injections of
procain.
. But actually injected with saline rather
than procaine

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Other Conditions Are
• Presence Of Physician
• physical examination
• prescription
• Procedure

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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
 Effects of expectations modulated by
-Decrease in self-defeating thoughts.
-Motivation

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Expectation of Reward
Expectations 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.

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

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FACTORS
INFLUENCING
PLACEBO
RESPONSE
Patient characteristics
Provider
characteristics
Appearance of
treatment
procedures
Environment
relationship

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

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

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4. Wihdrawal period
5. Toxicity

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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.

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

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CONTROVERSY
• Observed response to placebo in RCT may
reflect the
1. natural course of the disease
2. fluctuations in symptoms
3. regression to the mean
4 . response bias with respect to the
patient's reporting of subjective
symptoms and other concurrent
treatments

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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 .

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Human 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.”

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 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.

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 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.

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• 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:
1. 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.

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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

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• The informed consent information:
1. The subjects must be informed that they
may be given a placebo.
2. A clear lay definition of the term ‘placebo’
must be given to the subjects.
3. The rationale for using a placebo
must be explained to the subjects.
.

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

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7. A statement in the risk section of
the consent that, the condition of
the subject may worsen while on
placebo should be included.
8. 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.

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Problems assosciated with placebo
1. Imperfect likeness
2. Impure placebos
3. Selecting placebo non-reactors
4. Overestimation of placebo effects

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THANK YOU…….

Placebo and nocebo

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