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‘Paradoxical pharmacology’: therapeutic strategy used by the ‘homeopathic pharmacology’ for more than two centuries - Part 2

  • School of Medicine University of Sao Paulo


Using the empirical or phenomenological research method by observing the effects of drugs in the human physiology, Samuel Hahnemann proposed the homeopathic treatment. He synthesized modern pharmacodynamic in the ‘primary action’ of the drugs and in the consequent and opposite ‘secondary action’ or ‘vital reaction’ of the organism. Noting that drugs with ‘contrary’ primary action to the symptoms of the diseases caused worsening of the symptoms after its withdrawal, as a result of secondary action of the organism, Hahnemann proposed using this vital reaction (secondary action) in a curative way, administering to sick individuals the drugs that caused ‘similar’ symptoms in healthy individuals (therapeutic use of the similitude principle). According to the clinical and experimental pharmacology, this secondary action (vital reaction) of the organism is observed in the ‘rebound effect’ or ‘paradoxical reaction’ of several classes of drugs, which is the scientific basis of the ‘homeopathic pharmacology’. In the last decade, exponents of modern pharmacology have suggested the therapeutic use of the paradoxical reaction (‘paradoxical pharmacology’), proposing the use of drugs that cause an exacerbation of the disease in the short term to treat these same diseases in the long-term. In this review, we compare the various aspects between the ‘homeopathic pharmacology’ and the ‘paradoxical pharmacology’, reinforcing the validity of homeopathic assumptions and expanding the knowledge to optimize both proposals.
Vol:22 No:2
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According to Webster's New World
Medical Dictionary [16], 'rebound effect'
means “the production of increased
negative symptoms when the effect of a
drug has passed or the patient no longer
responds to the drug; if a drug produces
a rebound effect, the condition it was
used to treat may come back even
stronger when the drug is discontinued
or loses effectiveness”. Also named by
the term 'paradoxical reaction' of the
organism, one of the ironies of this
phenomenon is that it makes the
patients experience the very same
effects they had hoped to make
disappear by using palliative drugs, thus
deconstructing the main pillar of
modern pharmacological therapy, i.e.,
the treatment by principle of contraries.
Although its exact mechanism remains
unclear, the main hypothesis to explain
the rebound (paradoxical) effect is that it
mi g ht b e ca us e d b y i nc re a se d
responsiveness (up-regulation) of the
receptors of the involved drug.
In general terms, rebound effect is the
result of the attempts of the organism to
bring itself back into balance
(homeostasis) after a drug is taken in
order to ne u t ra l i ze the disease
symptoms. Descri bed in 1860 by
Sorbonne professor Claude Bernard as
“fixité du milieu intérieur”, the term
Marcus Zulian Teixeira
School of Medicine, University of São Paulo, São Paulo, Brazil
(Contd from previous issue)
Reprint Article,
Reproduced with permission from Editor, High Dilution.
Published at
Vol: 22 No: 2 Visit
salicylates, and others) can exhibit
significant hyperalgesia as a rebound
e f fe ct . D i ur et i cs ( fu r os em i d e,
torasemide, triamterene, and others)
enantiopathically used to diminish the
volume of plasma (edema, arterial
hypertension, congestive heart failure,
and others) may cause rebound
retention of sodium and potassium thus
increasing the basal volume of plasma.
Drugs primarily used as anti-dyspeptic
(antacids, H2 antagonists, misoprostol,
sucralfate, protons pump inhibitors, and
others) in the treatment of gastritis and
gastro-duodenal ulcers might promote,
after the primary decrease of acidity,
rebound increase of the production of
hydrochloric acid by the stomach
eventually causing p erforation of
chronic gastro-duodenal ulcers.
Bronchodilators (adrenergic drugs,
sodium chromoglycate, epinephrine,
ipratropium, nedocromil, formoterol,
salmeterol, and others) used in the
treatment of bronchial asthma can
worsen bronchial constriction as
paradoxical response of the organism to
the interruption or discontinuation of
treatment. Antiresorptive drugs
(bisphosphonates, denosumab, and
others), given to treat osteoporosis, can
cause paradoxical atypical fractures
after their biological effect (half-life), as
a result of rebound increased of the
o s t e o c l a s t i c a c t i v i t y .
Immunomodulatory drugs
(natalizumab, fingolimod, and others)
used in the treatment of multiple
sclerosis, can cause immune
reconstitution inflammatory syndrome
(IRIS) with rebound worsening of
disease, after treatment withdrawal,
among others [4-15].
Despite such phenomena appearing in a
minority of individuals in view of their
idiosyncratic nature, contemporary
scientific evidences point to the
occurrence of severe and fatal iatrogenic
events as a function of the rebound
effect or paradoxical reaction of the
organism following the discontinuance
of many classes of modern
enantiopathic drugs [6]. As a result of
primary anticoagulant action, all types of
non-steroidal anti-inflammatory drugs
awaken thrombo genic parad oxical
reactions after discontinuation, leading
to a significant increase to the incidence
of thrombosis and causing acute
my o cardial infa rction (AMI) an d
encephalic vascular accidents (EVA)
Analogously, long-acting β-agonist
bronchodilators after their primary
bronchodilator action can cause
signi f i c a n t irre v e rsible an d fata l
paradoxical bronchospasm [8,19,20].
Antidepressant agents, inhibiting the
recapture of serotonin (SSRIs), promote
a rebound exacerbation of suicidality
after an initial improvement of this same
symptom [9,21,22]. After a primary
increase of their pleiotropic effects
(vascular protective), statins cause
paradoxical and fatal vascular events
(AMI, EVA) [10,23,24]. Proton-pump
inhi b i t o rs ( P PIs) cause rebo u n d
h y p e r g a s t r i n e m i a a n d a c i d
hypersecretion after an initial decrease
of acidity, thus exacerbating gastritis and
ulcers, gastric cancer and carcinoid
tumor [11,25,26]. In addition to severe
paradoxical atypical fractures after
denosumab withdrawal [13,27] and
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'homeostasis' was minted in 1929 by
Harvard physiologist Walter Bradford
Cannon to name the tendency or ability
of living beings to keep their internal
environment constant through self-
adjustment of their physiological
processes. Such physiological processes
or homeostatic mechanisms are present
at all levels of the biological organization
from the simplest of cells to the most
comp l ex m ental an d e m oti o n al
Illustrating these assertions, drugs
classically used in the treatment of
angina pectoris (β-blockers, calcium
channel blockers, nitrates, and others)
with beneficial effects in their primary
effect (anti-angina), might awaken a
paradoxical increase of the frequency
and intensity of chest pain after
discontinuation or irregular use of
doses, which sometimes does not
respond to any therapeutic means.
Drugs used for the control of arterial
hypertension (α-2 agonists, β-blockers,
ACE inhibitors, MAO inhibitors, nitrates,
sodium nitroprusside, hydralazine, and
others) might produce rebound arterial
hypertension as a paradoxical reaction
of the organism to the primary stimulus;
an tiar r hyth mic drugs (adenosine,
amiodarone, β-blockers, calcium
channel blocke rs , di s o p y r a m i d e ,
fle c a inide, li d o caine, m exiletine,
moricizine, procainamide, quinidine,
digital, and others) may awaken a
rebound exacerbation of basal
ventricular arrhythmias, when the
treatment is interrupted. Hypolipidemic
d r u g s ( cl of ib r a te , c o le st ip ol ,
colestiramine, nicotinic acid, fluvastatin,
lovastatin, pravastatin, and others), used
in its primary action to treat
hyperlipidemia, promote increased
rebound of lipid after their interruption.
Antithrombotic drugs (argatroban,
heparin, salicylates, warfarin,
clopidogrel, and others), employed due
to their primary effect in the prophylaxis
of thrombosis, can promote thrombotic
complications as paradoxical reaction of
the organism.
In the use of psychiatric drugs such as
a n x i o l y t i c s ( b a r b i t u r a t e s ,
benzodiazepines, carbamates, and
others), sedative-hypnotics
(b a rb it u ra t e s, b en zod i az e pi n es ,
morphine, promethazine, zopiclone, and
others), stimulants of the central nervous
sy s tem (a m p h e tamines, c a ffeine,
cocaine, mazindol, methylphenidate,
and others), antidepressants (tricyclic,
MAO inhibitors, selective serotonin
reuptake inhibitors, and others) or
antipsychotics ( c l o z a p i n e ,
phenothiazines, haloperidol, pimozide,
and others) it can be observed a
paradoxical reaction of the organism,
whi c h see k ing to ke e p o rgan i c
homeostasis, promote the appearance
of symptoms contrary to the ones
expected from their primary therapeutic
use, consequently worsening the initial
clinical pic ture. D rugs wi th a nti-
inflammatory primary action
( c o r t i c o s t e r o i d s , i b u p r o f e n ,
indometacin, paracetamol, salicylates,
and others) might trigger paradoxical
reactions of the organism that increase
inflammation together with the serum
concentration of its mediators. Drugs
with analgesic primary action (caffeine,
calcium channels blockers, clonidine,
ergotamine, methysergide, opiates,
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severe relapses of multiple sclerosis
a f te r n at a l iz u m ab w it h dr a wa l
[14,28,29], recent studies warn of fatal
risks inherent to the rebound effect of
others drugs of modern biological
therapy [30,31].
According to this evidence of the
modern pharmacology, rebound effect
or paradoxical reaction of the organism
has an intensity higher than the one of
the symptoms originally suppressed: in
controlled studies, in relation to the
placebo, a risk of ischemic accidents was
3.4 times larger after salicylates
withdrawal, 1.52 times larger after non-
steroidal anti-i nflammato ry d rugs
withdrawal, 1.67 times larger after
rofecoxib withdrawal, and 1.69 times
larger after statins withdrawal; a risk of
suicidal behaviours 6 times larger after
SSRI antidepressants withdrawal, and a
risk of fatal paradoxical bronchospasm 4
times larger after long-acting beta
agonists withdrawal.
With similar estimates to the rebound
effect of other drugs, long-acting beta
agonists cause approximately 1 rebound
bronchospasm followed by death every
1,000 patients-year-use, corresponding
to 4,000-5,000 deaths/year in 2004 in
the USA alone (40,000-50,000
worldwide) [8,32]. SSRI antidepressants
cause approximately 5 rebound
suicidality events every 1,000 teenagers
patients-year-use, corresponding to
16,500 suicidal behavior or thoughts in
2007 only in USA [9]. Salicylates cause
approximately 4 r e b o und acute
myocardial infarction every 1,000
patients-year-use [33,34]. Studies
described the increased incidence of
gastric carcinoids in last decades (400%
in men and 900% in women) in view of
the growing consumption of the PPIs
[11]. Bisphosphonates cause 1-3 severe
paradoxical atypical fractures every
1,000 patients-year-use [13].
N a ta l i zu ma b a wa ke ns r eb oun d
worsening of multiple sclerosis around
10% of patients who discontinued
treatment [14].
The rebound effect appears some time
(hours to weeks) after the decrease or
discontinuation of the treatment
('withdrawal syndrome') according to
the pharmacokinetic properties of the
involved drug and the idiosyncratic
peculiarities of the individuals: average
of 10 days for salicylates, 14 days for the
non-steroidal anti-inflammatory drugs, 9
days for the rofecoxib, 7 days for the SSRI
antidepressants, 7 days for the statins,
and 7-14 days for the PPIs. The duration
of the rebound effect is also variable:
remaining for 30 days with rofecoxib, 21
days with SSRI antidepressants, and 30
days with PPIs. The duration of the
treatment did not show association with
the risk of awakening the paradoxical
Despite the fact that the drug withdrawal
('half-life' time) is a prerequisite for the
manifestation of the paradoxical
reaction of the organism or rebound
effect, because the primary effect of the
drug lasts as long as the receptors are
stimulated, studies show that the
rebound effect can occur even during
drug use, occurrence which can be
explained by the phenomenon of
'tolerance' (adaptation of the organism
to the drug with the loss of
pharmacological effect). On the other
hand, the slow and gradual decrease of
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the d o ses , a v oid i ng an a b r up t
discontinuation, is a procedure to
minimize the manifestation of the
rebound effect.
A s e v id e n ce d b y c l i ni c al a nd
experimental pharmacology [4-15], the
common properties of the rebound
effect or paradoxical reaction of the
organism are the same as the ones of the
homeopathic secondary action
described by Hahnemann (Organon of
medicine, paragraphs 59, 64, 69): (i) it
appears only in susceptible individuals,
who present in their constitution
symptoms similar to the pathogenetic
effects of the drug; (ii) it does not
de p e n d on t he dru g , repet i tion
(magnitude) of doses or type of
symptoms (disease); (iii) it appears after
the primary action of the drug
(discontinuation or decrease of the
doses), as an automatic manifestation of
the organism; (iv) it induces an organic
state (symptoms) opposite and greater
in intensity and/or frequency than the
primary action of the drug; (v) the
magnitude of its effect is proportional to
the intensity of the primary action of the
Use of modern drugs according to the
principle of similitude 'New
homeopathic medicines'
In order to learn the healing properties
of drugs to allow for the application of
the principle of therapeutic similitude,
homeopathy employs the 'proving of
medicinal substances on healthy
individuals' or 'homeopathic
pathogenetic trials' (HPTs) as its model
of pharmacological clinical research.
HPTs can be compared to the modern
'phase I studies' which takes into
account all types of primary or direct
actions, the so-called pathogenetic
effects or symptoms (mental, general or
physical), awakened by drugs on the
state of human health. These very same
pathogenetic effects are called by
modern pharmacology as therapeutic,
adverse or side effects of the drugs.
Although Hahnemann laid down the
ideal stipulations to carry out HPTs
(Organon of medicine, paragraphs 105-
145), the Homeopathic Materia Medica
(compendium which brings together the
primary or pathogenetic effects of
substances) is actually composed by a
compilation of the signs and symptoms
recorded along the testing of thousands
of drugs in both healthy and ill
individuals, in ponderable (substances in
raw state) and diluted (dynamized
medicines) doses. In this way, it
comprises the pictures of artificial states
of the disease needed to apply the
homeopathic therapeutic method.
To su b s tan t iate t h e val i dit y o f
pathogenetic trials with ponderable
doses and/o r o n ill individua l s ,
Hahnemann observed that the effects of
experiments described by previous
authors carried out with “large doses of
medicinal substances” on healthy
(po i s o n i n gs) and i l l (thera p eutic
overdoses) individuals were very similar
to his observations while testing the very
same substances on himself and other
healthy individuals (Organon of
medicine, paragraphs 110-112).
“I saw, moreover, that the morbid lesions
which previous authors had observed to
result from medicinal substances when
taken into the stomach of healthy
persons, either in large doses given by
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mistake or in order to produce death in
themselves or others, or under other
circumstances, accorded very much
with my own observations when
experimenting with the same
substances on myself and other healthy
individuals. These authors give details of
what occurred as histories of poisoning
and as proofs of the pernicious effects of
these powerful substances, chiefly in
order to warn others from their use;
partly also for the sake of exalting their
own skill, when, under the use of the
remedies they employed to combat
these dangerous accidents, health
gradually returned; but partly also,
when the persons so affected died
under their treatment, in order to seek
their own justification in the dangerous
character of these substances, which
they then termed poisons. None of
these observers ever dreamed that the
symptoms they recorded merely as
proofs of the noxious and poisonous
character of these substances were sure
revelations of the power of these drugs
to e x tingu i s h c u ra t i vely simil a r
symptoms occurring in natural disease,
th at t he se t he ir p at ho ge n et ic
phenomena were intimations of their
homoeopathic curative action, and that
the only possible way to ascertain their
medicinal powers is to observe those
changes of health medicines are capable
of producing in the healthy organism;
for the pure, peculiar powers of
medicines available for the cure of
disease are to be learned neither by any
ingenious a priori speculations, nor by
the smell, taste or appearance of the
drugs, nor by their chemical analysis,
nor yet by the employment of several of
th e m at one t ime i n a m i xture
(prescription) in diseases; it was never
suspected that these histories of
medicinal diseases would one day
furnish the first rudiments of the true,
pure materia medica, which from the
earliest times until now has consisted
solely of false conjectures and fictions of
the imagination - that is to say, did not
exist at all.” (Organon of medicine,
paragraph 110)
“The agreement of my observations on
the pure effects of medicines with these
older ones - although they were
recorded without reference to any
therapeutic object, - and the very
concordance of these accounts with
others of the same kind by different
authors must easily convince us that
medicinal substances act in the morbid
changes they produce in the healthy
human body according to fixed, eternal
laws of nature, and by virtue of these are
enabled to produce certain, reliable
disease symptoms each according to its
own peculiar character”. (Organon of
medicine, paragraph 111)
In this regard, it is worth observing that
the historical revisions carried out by
Robert Ellis Dudgeon [35] and Richard
Hughes [36] show that most of the
symptoms listed in the works of
homeopathic materia medica written by
Hahnemann (Fragmenta de Viribus
Medicamentorum Positivis, Materia
Medica Pura and The Chronic Diseases)
arise from the use of medicines in
ponderable (moderate-large) doses and
on ill individuals.
According to Hughes [36], in 1805,
Hahnemann published the pathogenetic
studies of 27 remedies in Fragmenta de
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Viribus Medicamentorum Positivis [37],
which thus represents the first
homeopathic materia medica that he
used in his clinical practice. The sources
of the pathogenetic symptoms listed
were his own observations (of
poisonings, therapeutic overdoses, self-
experimentation and tests on other
healthy individuals) as well as the ones
'by others' a nd repor ted in the
literature. In this context, 'observations
by others' (namely, reports of
poisonings in healthy individuals and
therapeuti c overdoses in the ill)
represent a large fraction of most
pathogenetic studies published in the six
volumes of Materia Medica Pura [38], in
which only 13 of the 61 remedies do not
present such kind of data. Still in Köthen,
Hahnemann published between 1828-
1830 the 4 volumes of the first edition of
The Chronic Diseases [39], which
introduced 17 new and 5 extended
pathogenetic studies of remedies
already published in Materia Medica
Pura. With the only exception of Kalium
carbonicum and Natrum muriaticum -
which were tested in potentiated doses
(30cH) and in (2 and 3, respectively)
healthy individuals - the remainder of
medicines were tested in diversified
potencies (e.g. 'small portions of a
grain', 2nd and 3rd trituration, 6th and
30th potency) and on individuals
suffering from chronic diseases. The
second edition of The Chronic Diseases,
published between 1830-1835, added
25 pathogenetic studies (13 new and 12
already published in Materia Medica
Pura and extended) to the 22 listed in
the first edition. In both editions, the
pathogenetic manifestations listed are
adverse and side effects of drugs
prescribed to patients suffering from
chronic diseases. Referring to the written
“Examination of the sources of the
common materia medica”, cited as
preamble to the second volume of the
Materia Medica Pura, Hughes stated
explicitly: “Hahnemann's own additions
to the second issue of his work must be
of the same character as his
contributions to the first, i.e., they must
be collateral effects of the drugs
observed on the patients to whom he
gave them” [36].
Analogously, homeopathic treatment
was also accomplished with ponderable
(moderate-large) doses on the grounds
of the pathogenetic manifestations
observed after the intake of ponderable
doses by healthy (poisonings) and ill
(therapeutic overdoses) individuals. In
work that inaugurates the homeopathy
[2], Hahnemann mentions the use of
drugs of his time in the homeopathic
treatment of numerous diseases and
epidemics (uterine colic with Matricaria
chamomilla; autumnal dysentery with
Arnica montana; painful indurations of
the lymph nodes with Conium
maculatum; paralytic and spasmodic
affections with Solanum dulcamara;
chronic hemorrhages, mania and
seizures with Hyosciamus niger; tremors,
fasciculations, cramps and intermittent
fevers with Ignatia amara; amaurosis,
cataracts and opacities of the cornea
with Anemona pratensis, etc.), applying
them according to the principle of
similitude ('adverse/side effects'
mentioned in literature) and substantial
doses. In The Lesser Writings [40],
Hahnemann describes similar
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applications in other epidemic diseases
(remittent and scarlet fevers, typhus,
cholera, etc). In 1799, during an
epidemic of scarlet fever [41]
Hahnemann used for the first time
diluted and agitated doses in order to
decrease the pathogenetic power of
doses and thus avoid aggravation [42].
In 1814, during the treatment of typhus
or hospital fever [43], Hahnemann
outlined the pharmacotechnique of
potentization (serial dilutions and
strong agitation). The “theory of
potentization” strictly speaking only
appeared in 1827 [44], when
Hahnemann incorporated the processes
of trituration and succussion in order to
devel op and exa lt the “dynami c
m e d i c i n al p ow e rs o f n a t ur al
In addition to the examples of classical
homeopathic medicines that were
derived in the past from conventional
drugs (Ammonium, Arsenic, Borax,
Camphora, Chamomilla, Digitalis,
Hydrastis, Mercurius, Nux vomica,
Opium, Sulphur, Valeriana, among
others), some modern studies have
used conventional drugs in accordance
with the curative rebound effect:
contraceptive drugs used as inducers of
rebound ovulation and consequent
pregnancy [45]; central nervous system
stimulants used with beneficial effect on
attention deficit hyperactivity disorder
(ADHD) [46]; among others.
Retracing classic homeopathy steps to
conclude this research [47-52], we
systemat ized the use of modern
conventional drugs according to the
principle of therapeutic similitude. This
proposal suggests stimulating the
curative rebound effect (paradoxical
reaction) by employing conventional
drugs that caused similar symptoms
(primary actions or pathogenetic effects)
in healthy or ill individuals.
To make this proposal operative a
Homeopathic Materia Medica of
Modern Drugs grouping together all
primary (therapeutic, adverse and side)
effects of drugs (described in The United
States Pharmacopeia Dispensing
Information [53]) according to the
traditional chapter scheme of the
homeopathic materia medica was
needed. To facilitate the effective
selection of an individualized medicine,
which is the basic premise for successful
homeopathic treatment, the second
stage involved the elaboration of a
Homeopathic Repertory of Modern
Drugs, where symptoms (primary or
direct effects) and their corresponding
remedies are arranged as in the classical
homeopathic repertories [49].
This research project is entitled “New
Homeopathic Medicines: use of modern
drugs according to the principle of
similitude” and can be found in free
o n l i n e v e r s i o n a t
Paradoxical pharmacology
Therapeutic approach suggested by
Richard A. Bond in 2001 [54,55], the
'paradoxical pharmacology' proposes a
strategy to treat chronic diseases using
the paradoxical drug reactions, where
the therapeutic effect is derived from
compensatory response, rather than the
primary or direct drug effect. These
pa radoxica l or bid irec t iona l dr ug
reactions produce an outcome that is
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opposite to the outcome that would be
expected from the drug's known effects.
Such bidirectional reactions arise in a
wide variety of drug classes, to a greater
or lesser frequency, in the same or
different individuals and not related to
the doses used. Although incompletely
understood, the clinical paradoxical
effect occurs when conflicts arise at
different levels in se lf-regulating
biological systems, as complexity
increases from subcellular components
(c h an n el s , e nz y me s , rec e pto r s ,
transporters, organelles, etc.) to cells,
tissues, organs, and the whole individual
As a possible general hypothesis to
expl a in the fu n cti o n in g o f t h e
paradoxical pharmacology is the
“difference between the chronic versus
the acute effect of drugs”. Reiterating
that the acute and chronic responses to
drugs often differ substantially and,
indeed, are often opposite in nature,
Bond [54] warns that most
contrain d i cation s for dru g s a r e
predicted on the basis of the false
assumption that the chronic effect will
be simply a more prolonged version of
the acute effect, in view of the fact that
experiments that analyze chronic effects
are not performed, in part, because we
cannot see how to get by the initial
contraindications. Certain drugs also
lose effectiveness with time (tolerance,
tachyphylaxis or desensitization) as is
the case of the analgesic effects of
opioids that wane with repeated
administration for weeks or months.
Occurring at any physiological system,
with various drug classes and without
changing doses, the mechanisms of such
paradoxical and bidirectional effects
include different actions at the same
receptor, owing to changes with time
and downstream effects (e.g., β-blockers
wit h i ntri n sic sy m p ath o mim e t ic
activity); stereochemical effects (e.g.,
salbutamol); multiple receptor targets
with or without associated temporal
effects (e.g., procainamide); antibody-
mediated reactions (e.g., heparin-
induced thromboembolism);
pharmacokinetic competing
compartment effects (e.g., bicarbonate);
disruption and non-linear effects in
oscillating systems (e.g., dopaminergic
agents), systemic overcompensation
(e.g., antiretroviral therapy and immune
reconstitution inflammatory syndrome),
and other hig h e r - l e vel feedback
mechanisms (e.g., digoxin) and feedback
response loops at multiple levels (e.g.,
isotretinoin-associated acne fulminans),
among others [60].
Some examples of paradoxical and
bidirectional drug effects are illustrated
in different pharmaceutical or systems
classes: immunomodulators (e.g.,
systemic glucocorticosteroids, TN
antagonists), antineoplastic agents and
ca rcinog ens (e . g ., ch e m othera py,
radiotherapy, arsenic), antidysrhythmic
drugs (e.g., procainamide, isoprenaline),
antihypertensive drugs (e.g.,
methyldopa, clonidine, guanabenz,
moxonidine, thiazides), vasodilators
(e.g., nitrates), drugs for congestive
heart failure (e.g., β-blockers, ACE
inhibitors, angiotensin II receptor
anta g o nist s , h y d ra laz i ne), l i p id-
mod i f yin g d r u gs (e. g . , fibrate s ,
ezetimibe), inotropes and chronotropes
(e.g., isoprenaline, epinephrine, β-
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blockers and calcium channel blockers),
vasoconstrictors (e.g., ergot alkaloids,
vasopressin), anaesthetics (e.g.,
sevof lurane, ketam ine, propofol),
antiepileptic drugs (e.g.,
b e n z o dia ze p ine s , b ar bit u r a te s,
hydantoins), hypnosedatives (e.g.,
antic h o l inergi c s , a nt ihistam i n es,
antispasmodics, barbiturates,
benzodiazepines, bromides, chloral
hydrate, ethanol, opioids), psychotropic
drugs (e.g., antidepressants,
antipsychotics), peripheral nervous
system drugs (e.g., acetylcholinesterase
inhibitors, capsaicin), antidyskinetic
drugs (e.g., dopaminergic agents), acid-
base agents (e.g., sodium lactate,
bicarbonate), bone metabolism agents
(e.g., parathyroid hormone,
bisphosphonates), electrolytes (e.g.,
hypertonic saline, magnaesium
hydroxide), glycaemic agents (e.g.,
insulin, antiglycaemics), steroid
hormones (e.g., dexamethasone
suppression), thyroid agents (e.g.,
iodine, lithium), antihyperuricaemics
(e.g., xanthine oxidase inhibitors, urate
oxidases), gastrointestinal agents (e.g.,
opioids, cholecystokinin or ceruletide),
h a e m a t o l o g i c a l a g e n t s ( e.g.,
erythropoietin, vitamin K antagonists,
plate l e t a den o s ine di p h osp h a t e
receptor antagonists), respiratory
agents (e.g., short- and long-acting β2-
agonists, oxygen), skin agents (e.g., high
intensity long-wave ultraviolet light and
8-methoxypsoralen, histamine1-
receptor antagonists), among others
In terms of 'doses', Smith et al [60], claim
that “clinical bidirectional and
paradoxical effects are not necessarily of
explicit dose responsiveness”, and “do
not necessarily occur at doses different
from those producing anticipated
effects”: “they may occur at entirely
appropriate doses or regardless of dose,
in intended or unintended target
systems”, and “they may arise in the
same patient at the same doses in
different circumstances (known or
unknown physiological or pathological
states in time)”. In view of these aspects
(no relationship with doses), the authors
ruled out the mechanism of hormesis
(biphasic dose-response curve, with
beneficial or stimulatory effects at low
doses and adverse or inhibitory effects at
high doses) [61] as an explanation for the
As in various physiological systems, in
which an external primary stress can
result in a secondary compensatory
benefit, a 'pharmacologic stress' can be
used therapeutically to gain long-term
benefit: “exacerbating a disease (acute
or short-term effect) can make use of the
body's compensatory and redundant
mechanisms to achieve a beneficial long-
term response (chronic effect)”. Like
other authors [56], Bond warns that
dosing will be a serious concern in this
strategy, proposing as a general rule
“start at a very low dose and increase the
dose over a period of weeks” [54].
Some examples of prescription of drugs
that cause similar effects to those which
are to be treated are cited in the
literature in which paradoxical and
bid i r e ctio n al re spo n s es may be
harnessed for benefit. Congestive heart
failure (CHF) is a disease of impaired
cardiac contractility usually as a result of
ischemic damage to the heart muscle,
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and the acute use of β-adrenoceptor
agonists, increasing cardiac contractility,
improved hemodynamic and decreased
symptoms of CHF.
However, their chronic use resulted in an
increase in mortality. On the contrary,
while the short-term use of β-
adrenoceptor antagonists (β-blockers:
carvedilol, metoprolol) exacerbate the
CHF (worsening of disease), the long-
term use results in an increase in cardiac
contractility and a decrease in mortality
[54,59,60,62]. The same is observed
with calcium channel blockers [63].
Analogously, β2-adrenoceptor agonists
are the most potent bronchodilators and
play a major role in every stage of
asthma management; however, as
previously mentioned, their chronic use
is associated with irreversible and fatal
paradoxical bronchospasm (asthma-
related deaths). On the other hand,
while the short-term use of β-
adrenoceptor antagonists (β-blockers)
produces bronchoconstriction and
worsening asthma, the long-term use
produces bronchodilation and a positive
outcome in asthmatics [54,59,64,65].
Additional examples include the use of
methyl phenidate (central nervous
system stimulant) in the treatment of
hyperactivity disorders, and the use of
serotonin 5-HT1A receptor agonist
(mediator of hyperalgesia) to produce
analgesia [59]. Thiazides have long
provid ed parad oxic al antidi uret ic
benefit in the treatment of diabetes
in s ipidus, reduc i ng po l yuria a n d
increasing urine osmolality [66].
Arsenic trioxide (As2O3), a major
carcinogenic agent that is employed by
ho meopat hy for m ore t han two
centuries to treat various types of cancer
(as initially described), have been used
paradoxically as a promising anticancer
agent (e.g., in acute promyelocytic
leukemia) [67,68], among others [60].
Non-p harmacological examples of
short-term detrimental behaviors
(exercising, dieting, saving money,
disciplining education, among others)
for a long-term benefit are also
described: exemplifying, exercises that
expose the heart to brief episodes of
ischemia protect the myocardium from
cell death produced by subsequent
prolonged ischemic episodes [54,59].
Despite the different terminologies
consequent to scientific knowledge of
different t imes , descri ptio ns a nd
properties of 'secondary action' or 'vital
reaction' of the homeopathic model
present similar aspects to the 'rebound
effect' or 'paradoxical reaction' of
modern pharmacology, indicating they
are the same phenomena.
Both phenomena are manifestations of
the secondary effects and opposite of
the organism to the primary effects of
the drugs, indicating a homeostatic
response of the organism to return to
initial balance modified by the inducing
agent. Demonstrating its universal
c h ar ac te r, t h e r e bo u nd e f fe ct
(paradoxical reaction) can occur with all
cla s ses o f d rug s w i th co n t rar y
(enantiopathic) action to the symptoms
of diseases and in different individuals,
although it manifests itself in a minority
of individuals in view of its idiosyncratic
By definition, the manifestation of the
rebound effect always reaches an
intensity and/or frequency greater than
the disturbance initially suppressed by
the drug, causing a worsening of the
natural disease. Described in detail in
studies about the rebound effect, the
'magnitude' of this paradoxical
phenomenon can cause serious and
fatal iatrogenic diseases on users of
various classes of modern drugs. In view
of this magnitude, the curative use of
the rebound ef fect (p a r a d oxical
re action) has great thera peutic
Despite not being valued in recent
studies of 'paradoxical pharmacology', it
is worth mentioning that this secondary
action of the organism occurs in the
absence of primary action of the drug. In
studies on the rebound effect, this
property is restricted to 'half life' time of
each drug, which varies around 7-14
days after discontinuation of drugs with
short-medium half-life; in drugs of
deposit (bisphosphonates, for example)
this time is longer. However, other
aspects of extreme importance must
also be ob s e rved : e v e n d u ring
treatment, some studies show the
manifestation of the rebound effect,
which can be justified by the gradual
decrease of dosage or temporary
discontinuation (therapeutic failure).
According to individual idiosyncrasy,
s m al l c h an g es i n d ru g s er um
concentration can trigger the
paradoxical phenomenon. Still on this
property, the phenomenon of
' t o l e ra nc e' ( t a c h yp hy l a x i s o r
desensitization) should also be valued:
as previously mentioned, even during
the treatment the adaptation of the
organism to the drug can occur with the
loss of primary pharmacological action,
allowing the manifestation of secondary
or paradoxical reaction of the organism.
A s d es c r i be d i n p a r a do xi c a l
pharmacology [60], the awakening of
paradoxical reaction of the organism is
independent of the doses of the drugs,
property also observed in the
homeopathic model and in the studies
on the rebound effect (unlike the
hormetic mechanisms) [61,69-74].
However, if drugs that cause similar
effects to those which are to be treated
are prescribed, their strong doses can
cause worsening of natural diseases,
with disastrous consequences. As well as
the homeopathic model uses ultrahigh-
diluted doses of medicines to arouse the
curative secondary action of the
o r ga ni sm s a fe l y ( av oi di n g t h e
'homeopathic aggravations'), Bond [54]
proposes as a general rule “start at a very
low dose and increase the dose over a
period of weeks”.
Unlike strong doses that awaken a
curative paradoxical reaction in a lot of
individuals (with the damages of the side
effects and the initial aggravation of the
diseases), ultrahigh-diluted or very low
doses (although they are safe for your
smaller pathogenetic power) arouse the
curative secondary action only in
i n di v i du al s w i th i di os yn c r at ic
characteristics of the drug (importance
of the 'individualized medicine' in
accordance with the totality of
characteristic symptoms). These are
aspects that should be taken into
consideration in the choice of the drug
and the dose.
On the other hand, studying and
Vol: 22 No: 2 Visit
describing the various physiological
m ec ha n i s m s i n v o l ve d i n t h e
manifestation of the rebound effect or
paradoxical reaction of the organism,
the 'paradoxical pharmacology' brings
important subsidies to elucidate the
modus operandi of the homeopathic
vital reaction, general term used to
describe the opposite and secondary
action of the organism (after cease the
primary action of the drug) in order to
maintain the internal homeostasis (“life-
pr eserving power”, a ccord i n g to
A great number of iatrogenic diseases
co u l d b e avoided i f the health
professionals were elucidated about the
homeostatic maintenance controlled
thro u g h the rebo u nd effect or
paradoxical reaction of the organism,
preventing the worsening of clinical
functions with the slow and gradual
discontinuation of the drugs used
according to the principle of the
contraries [12,15]. Although they are not
included in the conventional adverse
events for drugs, “drug discontinuation
effects are part of the pharmacology of a
drug” [65], and should be routinely
incorporated into the teaching of
modern pharmacology.
Describing the sad results of the
indiscriminate antipathic or palliative
employment of drugs (Organon of
m e d i ci n e , p a r ag r a ph s 5 9- 6 1 ),
Hahnemann alerts to the possible risks
produced by secondary action (rebound
effect) of the organism, validating the
principle of similitude through the
deductive logic “modus tollens” or
“indirect proof”:
“If these ill-effects are produced, as may
very naturally be expected from the
antipathic employment of medicines,
the ordinary physician imagines he can
get over the difficulty by giving, at each
renewed aggravation, a stronger dose of
the remedy, whereby an equally
transient suppression is effected; and as
there then is a still greater necessity for
giving ever - increasing quantities of the
palliative there ensues either another
more serious disease or frequently even
danger to life and death itself, but never a
cure of a disease of considerable or of
long standing”. (Organon of medicine,
paragraph 60)
Sin c e 1 997 , w e h ave grou n d ed
scientifically the 'old', 'classic' or
'traditional' similia principle, that was
founded by Hahnemann on 'symptom
similarity' (Organon, paragraphs 22-70),
confirming the principle of similitude as
'natural law' through the continuous
study of modern reports of increased
iatrogenic events after withdrawal of
enantiopathic drugs and demonstrating
the importance of the rebound
(paradoxical) symptoms in promoting
deep alterations in the organic balance,
although it was deemed 'unviable' and
'non-scientific' by other authors at the
“The old principle of similarity was
formulated as a general 'law' on the basis
of empirical evidence and analogical
reasoning, but this kind of formulation
does not allow any progress in the search
for the possible mechanism of the
alleged therapeutic effects. […] The last
question is whether these concepts can
be extended to the 'classic' similia
principle that was founded on 'symptom
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similarity'. This is the most controversial
point because the analysis of symptoms
does not appear to be as 'scientific' as
the objective measurement of some
physiological or biochemical parameter.
The use of symptoms as the basis for the
choice of remedy appears to be in
contradiction with modern scientific
medicine, which demands explanations
at the biochemical and molecular level”.
Using these rebound symptoms in a
curat i ve way, th e h o meo p a thi c
(paradoxical) pharmacology stimulates
the body to react against their own
As well as suggested by the spreaders of
the principle of therapeutic similitude
for more than two centuries [48], Bond
and Giles encourage the scientists and
researchers to examine the paradoxical
phenomenon systematically, changing
the dogma of current treatment and
incorporating new approaches to the
modern therapeutic arsenal:
“The identification of the phenomena of
temporal differences in the effects of
both agonists and antagonists in
numerous drug classes has, at first
obs e rvat i on, se e med ex t reme l y
paradoxical. However, as scientists, our
natural inclination is to ask the question
'why?'. Over the coming years the
mechanistic basis for such behavior will
undoubtedly be revealed, and the
pa r a do x w il l b e n o m or e . [ ]
Nevertheless for those of us who have
felt compelled to challenge dogma of
current treatment paradigms because
we observed paradoxical behavior, the
path has been long and challenging.
Seemingly 'simple' explanations of
mechanism of action of a particular drug
class become turned on their head, and
obtaining funding, and acceptance of
paradigm-shifting ideas by peers, takes
many years”.[59]
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Received: April 11th, 2014; Revised:
November 26th , 2014; Published:
December 20th, 2014.
Correspondence author: Marcus Zulian
w w w. f m . u s p . b r / h o m e o p a t i a ,
How to cite this article: Teixeira MZ.
'Paradoxical pharmacology': therapeutic
strategy used by the 'homeopathic
pharmacology' for more than two
centuries. Int J High Dilution Res [online].
2014 [cited YYYY Month dd]; 13(49):
207-226. Available from:
Vol: 22 No: 2 Visit
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