Transcript Placebo effect

Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General Pharmacology
Lecture: 2nd November2011
8:00-9:30 Burian Hall, Ruská 87, Prague
EVIDENCE OF DRUG EFFICACY
EBM PLACEBO HOMEOPATHY
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine, Charles University
in Prague
syllabus :
http://vyuka.lf3.cuni.cz
ASSESSMENT OF EFFICACY AND SAFETY OF DRUGS:
subjective
Assessment
objective
SYSTEM OF EVALUATION OF EFFICACY AND SAFETY
IN NEW DRUGS
PRECLINICAL
DEVELOPMENT
CLINICAL
TRIALS
POSTMARKETING
REGISTRATION
SURVEILLANCE
SAFETY PHARMACOVIGILANCE
CLINICAL TRIALS
GCP (Good Clinical Practice)
selection of probands, randomization, control group, doubleblind experiment, randomized controlled trials (RCT), placebo,
bias, informed consent, Declaration of Helsinski, ethical
committees …
RCT is a basis of „Good Clinical Practice“ (GCP)
RCT (Randomized Controlled Trial)
randomized
controlled: placebo effect, bias
double-blind arrangement
RCT is a basis of EBM (Evidence Based Medicine)
Levels of EBM:
A
Meta-analyses of numerous RCT
B
RCTs less numerous
C
Case studies
with comparable case studies, preferably prospective
D
Expert opinion
Strengths of EBM
EBM separates the chaff from the wheat
Weakness of current EBM
● current EBM mixes pears with apples
● current EBM is focused on average, not on the
individuum
example: problems in detecting placebo effect …
PLACEBO: according meta-analyses, RCTs is
both EFFECTIVE and INEFFECTIVE:
EFFECTIVE :
Beecher HK (1955) The Powerful Placebo. JAMA159: 1602-1606
INEFFECTIVE :
Kienle GS, Kiene H (1997)
PLACEBO: according meta-analyses, RCTs is
both EFFECTIVE and INEFFECTIVE:
INEFFECTIVE :
Hróbjartsson A, Gøtzsche PC (2001) Is the placebo powerless? An
analysis of clinical trials comparing placebo with no treatment.
New England Journal of Medicine 344: 1594-1602
EFFECTIVE:
Wampold BE,et al. (2005) The placebo is powerful
They re-analyzed a part of material from the Hróbjartsson‘s and Gøtzsche‘s study
and come to the conclusion that effect of placeba is robust
When analysis is focused on a particular
disorder: PLACEBO IS EFFECTIVE,
even by meta-analses, RCTs - e.g.
Oxfordská liga analgetik
IN ACUTE PAIN:
Percentage of pacients with at least 50% relief of acute pain
0
10
20
30
40
50
60
70
METAMIZOL 500
DIKLOFENAK 50
IBUPROFEN 400
MORFIN 10 i.m.
PARACETAMOL 650 + TRAMADOL 75
PARACETAMOL 600 + KODEIN 60
PARACETAMOL 600/650
TRAMADOL 75
PLACEBO
KODEIN 60
Oxford League of Analgesics
80
90
100
%
When analysis is focused on a particular
disorder: PLACEBO IS EFFECTIVE,
even by meta-analses, RCTs - e.g.
IN DEPRESSION:
Effects of antidepressants differ from those of placebo only in more severe
depressions
Kirsch I. a spol. PLoS Medicine 5 (2): 260-268,2008 www.plosmedicine.org
PLACEBO: when analysis is focused on a particular
individual
IS EFFECTIVE
Placebo increases levels of endorphines in CSF in patients
with chronic pain
but only in placebo-reactors,
not in those, who do not respond to placebo [Lipman et al.
Psychopharmacology 1990]
Naloxon blocks analgesia produced by placebo
[Levine a spol. Lancet 1978]
When analysis is focused on a particular individual
PLACEBO IS EFFECTIVE
Evidence of placebo effects in the brain in humans by PET, fMRI
Placebo responders (A) showed more pronounced rostral anterior cingulate regional blood flow by
the systemic administration of mu-opioid receptor agonist remifentanil or placebo with expectation
of analgesia than non-responders (B)
PET:
P. Petrovic et al., Science 295, 1737 -1740 (2002)
Published by AAAS
Placebo acts, but
• only in some patients
• only in some disorders
• only in some context
Placebo effect
• is transitory
• can be conditioned (as a cond. reflerx)
Distinguish:
Placebo – imitation of drug (or of treatment) for seprating
proper biological effect of the drug (treatment) from a
psychological effect
Placebo is used practically only in research, should not be
used in clinical practice
Placebo effect – psychological effect resulting from positive
expectations, trust, good faith in a drug, treatment, doctor,
healer, hospital ….
Placebo effect should be utilized in clinical practice
„Your faith has healed you.” – is it only a placebo (=psychological) effect?
The problem is that there are phenomena which cannot be
evoked experimentally, which occur spontaneously and which may
have a great importance subjectively , which can be adequately
known only personally, which defy objective testing, knowledge
from outside …
phenomena in the self (e. g. ideas, meaning of one‘s own life,
romantic love, knowledge of one‘s own beeing) …. spiritual
phenomena?
Limits of EBM:
EBM can ascertain only effects (phenomena) which
can be evoked experimentally,
not effects (phenomena) which cannot be evoked
experimentally
“ALTERNATIVE” MEDICINE
(or rather “COMPLEMENTARY” MEDICINE
because it does not substitute a standard medicine
[e.g. an astrologist is not an alternative astronomist]
[dr. O. Vinař]
some dare to say a „fringe medicine“
or „healer‘s medicine“
Complementary & Alternative Medicine - CAM
Some examples of CAM
(Complementary and Alternative Medicine):
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homeopathy
acupuncture,
TCHM traditional Chinese medicine
herbal medicine
chiropractice
Homeopathy
Founder: Dr. S. Hahnemann (1755-1843)
German physician
Principles of homeopathy I:
1/ The 'Principle of Similars', 'like cures like' ‚
„Similia similibus curantur”)
Hahnemann noticed, that quinine produces symptoms of malaria at
high doses, while it produces the opposite at low doses
let likes cure likes…
Homeopathy holds the premise of treating the sick with extremely
diluted agents that, in undiluted doses, produce similar symptoms in the
healthy.
DILUTION
decimal 1:10  1:10 …
D6 =10-6
centesimal 1:1001:100 … CH10 = 10-20
(CH centesimal according to Hahnemann) …
Hahnemann advocated CH30 dilutions for most
purposes
This „thirtieth potency“ (1 in 1060) provides solution
which practically contains no molecule of the initial
drug (a Mother Tincture)
Mainstream medicine in Hahneman‘s days:
bloodletting , purging …
Principles of homeopathy II:
2/ The principle of „dynamization“
Vigorous shaking of solutions during their
successive dilutions increases the potency of the
preparation
The higher the number of dilutions, the higher the
potency
What do homeopathic preparations contain?
Classical homeopathics: mostly contain no effective drug
Initial components:
- Mineral (e.g. mercury, sulphur, lava, coral)
- Herbal
- Animal (e.g. ants, whale ambergris, corpora lutea
[nosoda – not in Cz.R.])
Major problem of homeopathy:
It lacks the rigorous evidence of efficacy
required by modern standards (scientific,
objective evidence, e.g. EBM)
E Ernst. A systematic review of systematic reviews of homeopathy.
British Journal of Clinical Pharmacology 2002 54: 577-582.
WB Jonas et al. A critical overview of homeopathy. Annals of
Internal Medicine 2003 138: 393-399
Bandolier 116
Current errors of present homeopaths:
- They believe effects of homeopathics can
be proven by current meta-analyses
- They strive after scientific explanation of
effects of homeopathics
Current errors of opponents of homeopathy:
- they require scientific/objective evidence
of efficacy of homeopathics (by current meta-analyses)
- they ascribe effects of homeopathics only
to the effect of placebo
WHY IS HOMEOPATHY (AND HEALER‘S
PRACTICES) STILL SO POPULAR ?
(even in well educated populations, developed
countries )
1. People are not only rational machines,
computers (as some economists
presume), but also emotional [and
moral] beeings. Their decissions are
influenced also by emotional (and
moral) aspects. If an emotional (or moral)
value of something (e.g. health or life of
their own or of their dearest) prevails, they
disregard the rational or material value
WHY IS HOMEOPATHY (AND HEALER‘S
PRACTICES) STILL SO POPULAR ?
(even in well educated populations, developed
countries )
2. People need hope.
Homeopaths (and healers) fill up a niche
of a huge demand for hope
hope-sellers
WHY IS HOMEOPATHY (AND HEALERS
PRACTICES) STILL SO POPULAR ?
3. Homeopaths and healers (in contrast to modern science)
do not stonewall [deny] mystery, spiritual influences.
In the contrary, they build on them (more or less
appropriately)
Humans seem to be able to feel a mystery.
They even seem to need a mystery.
DOSTOEVSKY:
"Man needs the mysterious and the infinite
just as much as he does the small planet
which he inhabits ".
If the need for mystery is not satisfied
properly, their hunger for mystery is
satisfied e.g. by astrology, horoscopes,
occultism and false healing practices.
WHY IS HOMEOPATHY (AND HEALER‘S
PRACTICES) STILL SO POPULAR ?
(even in well educated populations, developed
countries )
4. Homeopaths and healers create a good
personal therapeutic relationship with the
patient
Which is so much neglected in the present
technological medicine.
Development of individual (personal)
therapeutic relationship is essential for a
sucessful treatment in many disorders/
patients
WHY IS HOMEOPATHY (AND HEALER‘S
PRACTICES) STILL SO POPULAR ?
(even in well educated populations, developed
countries )
5. Homeopathy (and some healer‘s
practices) is a big bussiness, an
excellent source of money
Risks of homeopathy I:
Risks knowable by a reason (a common sense):
• hindering of early diagnosis
 hindering of effective treatment
 regression to a magic thinking
 waisting human talent and faculties (knowledge,
initiative)
So, when to use homeopathy (or CAM)?
Only as a treatment of last choice if modern medicine
fails –
as „ultimum refugium“ (last resort)