EVIDENCE OF DRUG EFFICACY

EBM PLACEBO HOMEOPATHYProf. M. Kršiak

Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague

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

syllabus : http://vyuka.lf3.cuni.cz

subjectiveAssessment

objective

ASSESSMENT OF EFFICACY AND SAFETY OF DRUGS:

SYSTEM OF EVALUATION OF EFFICACY AND SAFETY IN NEW DRUGS

PRECLINICAL DEVELOPMENT

CLINICAL TRIALS

REGISTRATION

POSTMARKETING

SURVEILLANCE

SAFETY -PHARMACOVIGILANCE

CLINICAL TRIALS

GCP (Good Clinical Practice)

selection of probands, randomization, control group, double-blind experiment, randomized controlled trials (RCT), placebo, bias, informed consent, Declaration of Helsinski, ethical committees …

RCT (Randomized Controlled Trial)

randomizedcontrolled: placebo effect, bias double-blind arrangement

RCT is a basis of „Good Clinical Practice“ (GCP)

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

RCT is a basis of EBM (Evidence Based Medicine)

Strengths of EBMEBM 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 …

Beecher HK (1955) The Powerful Placebo. JAMA159: 1602-1606

Kienle GS, Kiene H (1997)

PLACEBO: according meta-analyses, RCTs is

both EFFECTIVE and INEFFECTIVE:

EFFECTIVE :

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

PLACEBO: according meta-analyses, RCTs is

both EFFECTIVE and INEFFECTIVE:

INEFFECTIVE :

0 10 20 30 40 50 60 70 80 90 100

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

%

Percentage of pacients with at least 50% relief of acute pain

Oxfordská liga analgetik

When analysis is focused on a particular

disorder: PLACEBO IS EFFECTIVE, even by meta-analses, RCTs - e.g.

IN ACUTE PAIN:

Oxford League of Analgesics

Kirsch I. a spol. PLoS Medicine 5 (2): 260-268,2008 www.plosmedicine.org

Effects of antidepressants differ from those of placebo only in more severe depressions

When analysis is focused on a particular disorder: PLACEBO IS EFFECTIVE, even by meta-analses, RCTs - e.g.

IN DEPRESSION:

Naloxon blocks analgesia produced by placebo [Levine a spol. Lancet 1978]

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]

PLACEBO: when analysis is focused on a particular individual

IS EFFECTIVE

Evidence of placebo effects in the brain in humans by PET, fMRI

When analysis is focused on a particular individual

PLACEBO IS EFFECTIVE

Published by AAAS

PET:

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)

P. Petrovic et al., Science 295, 1737 -1740 (2002)

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 effectPlacebo 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?

Limits of EBM:

EBM can ascertain only effects (phenomena) which can be evoked experimentally,

not effects (phenomena) which cannot be evoked experimentally

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?

“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):

homeopathy acupuncture, TCHM traditional Chinese medicine herbal medicine chiropractice

Homeopathy

Founder: Dr. S. Hahnemann (1755-1843) German physician

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.

Principles of homeopathy I:

DILUTION

decimal 1:10 1:10 … D6 =10-6

centesimal 1:1001:100 … 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 …

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

Principles of homeopathy II:

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

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 HEALER‘S PRACTICES) STILL SO POPULAR ?

(even in well educated populations, developed countries )

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)

WHY IS HOMEOPATHY (AND HEALERS PRACTICES) STILL SO POPULAR ?

DOSTOEVSKY:

"Man needs the mysterious and the infinite just as much as he does the small planet which he inhabits ".

Humans seem to be able to feel a mystery. They even seem to need a mystery.

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.

4. Homeopaths and healers create a good personal therapeutic relationship with the patient

WHY IS HOMEOPATHY (AND HEALER‘S PRACTICES) STILL SO POPULAR ?

(even in well educated populations, developed countries )

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

5. Homeopathy (and some healer‘s practices) is a big bussiness, an excellent source of money

WHY IS HOMEOPATHY (AND HEALER‘S PRACTICES) STILL SO POPULAR ?

(even in well educated populations, developed countries )

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)