Rebound effect of drugs: Fatal risk of conventional treatment and pharmacological basis of homeopathic treatment

Abstract

The homeopathic model applies the secondary action or vital reaction of the organism as a therapeutic method and thus prescribes treatment by similitude, which consists in administering to ill individuals substances that cause similar symptoms in healthy individuals. The vital, homeostatic or paradoxical reaction of the organism might be explained scientifically by means of the rebound effect of modern drugs, which might cause fatal iatrogenic events after discontinuation of antipathic (a term used in alternative medicine for palliative treatment, also known as enantiopathic) treatment. Although the rebound effect is studied by modern pharmacology, it is poorly communicated to and discussed among healthcare professionals, who are thus deprived of information needed for the safe management of modern drugs. This article presents an up-to-date review on the rebound effect of modern drugs that grounds the homeopathic principle of healing and calls the attention of doctors to this type of adverse effect that is usually unnoticed. The rebound effect of modern palliative drugs, which was pointed out by Hahnemann more than two centuries ago, might cause fatal adverse events and is illustrated by the examples of acetylsalicylic acid, anti-inflammatory agents, bronchodilators, antidepressants, statins, proton-pump inhibitors, etc. Although the rebound effect is expressed by a small fraction of (susceptible) individuals and might be avoided by gradual tapering of antipathic drugs, it exhibits epidemiologic importance as a function of the massive use of such palliative drugs and the lack of knowledge in its regard.

Full text

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Review article
Rebound effect of drugs: fatal risk of conventional
treatment and pharmacological basis of homeopathic
treatment
Marcus Zulian Teixeira
Faculty of Medicine, Universidade de São Paulo (FMUSP), São Paulo, Brazil
ABSTRACT
The homeopathic model applies the secondary action or vital reaction of the organism as a
therapeutic method and thus prescribes treatment by similitude, which consists in administering
to ill individuals substances that cause similar symptoms in healthy individuals. The vital,
homeostatic or paradoxical reaction of the organism might be explained scientifically by means of
the rebound effect of modern drugs, which might cause fatal iatrogenic events after
discontinuation of antipathic (a term used in alternative medicine for palliative treatment, also
known as enantiopathic) treatment. Although the rebound effect is studied by modern
pharmacology, it is poorly communicated to and discussed among healthcare professionals, who
are thus deprived of information needed for the safe management of modern drugs. This article
presents an up-to-date review on the rebound effect of modern drugs that grounds the
homeopathic principle of healing and calls the attention of doctors to this type of adverse effect
that is usually unnoticed. The rebound effect of modern palliative drugs, which was pointed out
by Hahnemann more than two centuries ago, might cause fatal adverse events and is illustrated
by the examples of acetylsalicylic acid, anti-inflammatory agents, bronchodilators,
antidepressants, statins, proton-pump inhibitors, etc. Although the rebound effect is expressed by
a small fraction of (susceptible) individuals and might be avoided by gradual tapering of
antipathic drugs, it exhibits epidemiologic importance as a function of the massive use of such
palliative drugs and the lack of knowledge in its regard.
Keywords: Homeopathy; Law of similarity; Pharmacodynamic action of homeopathic medicines;
Secondary effect; Rebound effect; Paradoxical reaction; Iatrogenic disease.
Introduction
The homeopathic method of treatment of diseases is based on four pillars: principle of cure by similitude,
proving of medicinal substances on healthy individuals, use of serially diluted and succussed (dynamized)
medicines, and prescription of individualized medicines. Although great importance was attributed to
‘dynamized medicines’ (ultra-high dilutions), which were introduced later to minimize the aggravation of
symptoms, the first two pillars are the proper foundation of homeopathic epistemological model remaining to
individualized medicine the essential condition for awakening the therapeutic response.
After his self-proving of Cinchona officinalis L., Samuel Hahnemann sought to confirm the ‘law of similarity’
by means of the scientific methods of ‘analogy’ and ‘enumeration’ and the study of clinical reports performed
by previous doctors. In those reports he was able to find countless references that eventually led him to raise
the principle of similitude to the level of a ‘natural law’ and that supported his use of inductive logic: for a
substance to heal definite symptoms in ill individuals, it must cause similar symptoms in healthy individuals.

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Inaugurating homeopathy in 1796 with the publication of the Essay on a new principle to ascertain the
curative power of drugs [1], Hahnemann described the direct primary actions of drugs and the consequent
indirect secondary action of the organism to them, systematizing these biphasic pharmacological effects in
dozens of palliative drugs used in his time. To illustrate with the example of Agaricus muscarius:
Direct primary action: furious and drunken-like mania (combined with revengeful and audacious
determination, disposition to make verses, prophecies, etc.), exaltation of strength, tremors and seizures;
direct action lasts between 12 and 16 hours. Indirect secondary action: successfully used in epilepsy (caused
by fear) combined with tremor; it heals mental affections and possession similar to those it causes.
In the introduction of the first edition of the Organon of medicine [2], Hahnemann described hundreds of
“examples of homeopathic cures verified involuntary by doctors of the old school”. Thus he was able to ground
his earlier observations in regard to the principle of therapeutic similitude on 247 bibliographic references
stemming from different authors. To continue with the example of Agaricus muscarius:
“The hurtful effects which some writers (Georgi, among others) ascribe to the use of the Agaricus muscarius,
by the inhabitants of Kamtschatka, and which consist of tremors, convulsions, and epilepsy, became a
salutary remedy in the hands of C. G. Whistling, who used this mushroom with success in cases of convulsions
accompanied with tremor; likewise in those of J. C. Bernhardt, who used it with success in a species of
epilepsy”.
In paragraphs 63 to 65 of the Organon [2], Hahnemann suggested a physiological explanation for this
“natural law of healing”, which based the principle of similitude on the primary action of the drug and the
corresponding and opposite secondary action or vital reaction of the organism:
“Every agent that acts upon the vitality, every medicine, deranges more or less the vital force, and causes a
certain alteration in the health of the individual for a longer or a shorter period. This is termed primary
action. [...]. To its action our vital force endeavors to oppose its own energy. This resistant action is a property,
is indeed an automatic action of our life-preserving power, which goes by the name of secondary action or
counteraction”. (Organon, paragraph 63)
Hahnemann exemplified this ‘universal’ mechanism of action of medicines (‘universal’ pharmacodynamics),
observed in the different changes of sensations and organic functions (signals and symptoms), in the biphasic
pharmacological effects of palliative (antipathic or enantiopathic) treatments used at that time:
“[...] A hand bathed in hot water is at first much warmer than the other hand that has not been so treated
(primary action); but when it is withdrawn from the hot water and again thoroughly dried, it becomes in a
short time cold, and at length much colder than the other (secondary action). A person heated by violent
exercise (primary action) is afterwards affected with chilliness and shivering (secondary action). To one who
was yesterday heated by drinking much wine (primary action), today every breath of air feels too cold
(counteraction of the organism, secondary action). An arm that has been kept long in very cold water is at first
much paler and colder (primary action) than the other; but removed from the cold water and dried, it
subsequently becomes not only warmer than the other, but even hot, red and inflamed (secondary action,
reaction of the vital force). Excessive vivacity follows the use of strong coffee (primary action), but
sluggishness and drowsiness remain for a long time afterwards (reaction, secondary action), if this be not
always again removed for a short time by imbibing fresh supplies of coffee (palliative). After the profound
stupefied sleep caused by opium (primary action), the following night will be all the more sleepless (reaction,
secondary action). After the constipation produced by opium (primary action), diarrhea ensues (secondary
action); and after purgation with medicines that irritate the bowels, constipation of several days’ duration
ensues (secondary action). And in like manner it always happens, after the primary action of a medicine that

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produces in large doses a great change in the health of a healthy person, that its exact opposite, when, as has
been observed, there is actually such a thing, is produced in the secondary action by our vital force”.
(Organon, paragraph 65)
The homeopathic method of treatment employs this secondary action or vital reaction of the organism for
therapeutic purposes by administering to ill individuals drugs that cause similar symptoms in healthy
individuals (principle of similitude) to awake a healing reaction of the organism against the disease.
By emphasizing that such secondary action of the organism (opposed in character to the primary action of the
drug) is observed “in each and every instance with no exceptions” with ponderable or infinitesimal doses in
both healthy and ill individuals, Hahnemann raised the principle of similitude to the level of a ‘natural law’
(Organon, paragraphs 58, 61, 110-112):
“In those older prescriptions of the often dangerous effects of medicines ingested in excessively large doses we
notice certain states that were produced, not at the commencement, but towards the termination of these sad
events, and which were of an exactly opposite nature to those that first appeared. These symptoms, the very
reverse of the primary action (§ 63) or proper action of the medicines on the vital force are the reaction of the
vital force of the organism, its secondary action (§ 62-67), of which, however, there is seldom or hardly ever
the least trace from experiments with moderate doses on healthy bodies, and from small doses none whatever.
In the homoeopathic curative operation the living organism reacts from these only so much as is requisite to
raise the health again to the normal healthy state”. (Organon, paragraph 112)
Upon alluding to the “sad results” of the indiscriminate palliative use of medicines (Organon, paragraphs 59-
61), Hahnemann warns against the risk represented by this undesirable secondary action of the organism
that may produce “more serious disease or frequently even danger to life or death itself”. Therefore, in
addition to denying the efficacy of conventional or palliative treatment (principle of contraries), Hahnemann
validates the homeopathic treatment (principle of similitude) through the Aristotelian syllogism or the modus
tollens of classic deductive logic (‘mode that affirms through negation’, ‘indirect proof’ or ‘null hypothesis’ of
modern biostatistics):
“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, paragraph 60)
In the terms of modern scientific reason and physio-pharmacological concepts, the primary action employed
by Hahnemann corresponds to the therapeutic, adverse and side effects of conventional drugs. The secondary
action or vital reaction, in turn, corresponds to the rebound effect or paradoxical reaction of the organism,
which was observed after the discontinuation of several classes of drugs that act contrarily to the symptoms of
diseases (conventional drugs, palliative, enantiopathic or antipathic). (Figure 1)
Following in the footsteps of Hahnemann, beginning 1996 we have been studying the rebound effect of
modern drugs with the intention to ground the homeopathic healing principle (principle of similitude or ‘like
cures like’) on notions of experimental and clinical pharmacology [3-10]. To call the attention of the medical
community to this type of adverse events that is frequently unnoticed, in the present updated review we
address the main features of the rebound effect and the care needed when discontinuing conventional drugs to
minimize these iatrogenic events, which might be fatal.

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Principle of Similitude
Therapeutic, adverse and Rebound effect or paradoxical
side effects of the drug reaction of the organism
(Pharmacology) (Pharmacology)
Figure 1. Universal mechanism of action of medicines: primary action of the drug
followed by secondary action of the organism (principle of similitude)
Material and methods
Aiming at broadening the understanding of the principle of similitude according to modern pharmacology, we
reviewed the literature cited in Pub Med database using search terms ‘rebound’, ‘withdrawal’, ‘acetylsalicylic
acid’, ‘anti-inflammatory’, ‘bronchodilator’, ‘antidepressant’, ‘statin’, and ‘proton pump inhibitor’. Adding other
references cited in the initial reviewed articles, the most relevant papers were selected to discuss the scientific
evidence available in association with the homeopathic postulates. Therefore, evidences that support the
principle of therapeutic similitude from Hahnemann’s to our times were gathered from classic homeopathic
sources mentioned in the introduction as well as by hundreds of scientific articles published in peer-reviewed
journals.
Rebound effect in modern pharmacology
An adverse event (AE) or reaction (AR) to a drug is defined by the World Health Organization (WHO) [11] as
“a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for
the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function”. Despite
‘rebound effect’ is an adverse event that might have serious consequences, it is little divulgated and discussed
by healthcare professionals, who are thus deprived of important knowledge needed for the management of
modern drugs.
According to Webster’s New World Medical Dictionary [12], the term ‘rebound’ is defined as “the reversal of
response upon withdrawal of a stimulus”, while ‘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 as 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.
In general terms, rebound effect is the result of the attempts by the organism to bring itself back into balance
(homeostasis) after a drug was taken in order to neutralize disease symptoms. Described in 1860 by Sorbonne
professor Claude Bernard as “fixité du milieu intérieur”, the term ‘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
Primary action of the drug
(Homeopathy)
Secondary action of the organism
(Homeopathy)

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processes or homeostatic mechanisms are present at all levels of the biological organization from the simplest
of cells to the most complex mental and emotional functions.
Although its exact mechanism remains unclear, the main hypothesis to explain the rebound effect is that it
might be caused by increased responsiveness (up-regulation) of the receptors of the involved drug. According
to pharmacological evidences, rebound effects exhibit greater intensity or frequency than the corresponding
original symptoms that were suppressed (which thus allows distinguishing a paradoxical reaction from the
natural reappearance of a disease after drug suspension), appear at variable intervals after the
discontinuation of drugs, and last also variable periods of time.
In a literature review, Hodding et al. [13] described conceptual distinctions, assessment criteria, and scientific
evidences in regard to the ‘withdrawal syndrome’ of several modern drugs (anticoagulants, anticonvulsants,
antipsychotics, barbiturates, benzodiazepines, cimetidine, clonidine, corticosteroids, opiates, propranolol,
tricyclic antidepressants, etc.). As in other reviews [14-16], also those authors considered the terms
‘withdrawal or discontinuation symptoms’ as synonym of ‘rebound symptoms’. They distinguished the rebound
or withdrawal syndrome from the natural evolution of disease: “symptoms resulting from discontinuation of a
medication may need to be distinguished from reappearance of disease symptoms or a ‘catching up’ of the
basic disease state, may emerge in the absence of the pharmacological action of the drug”. They also
mentioned that the appearance of symptoms is more severe than the baseline ones, and the gradual tapering
of the dose is recommended when therapy must be discontinued.
By definition [13-16], the more evident rebound effects occur with the withdrawal of palliative (enantiopathic
or antipathic) drugs after decrease or elimination of the drug serum concentration and the consequent partial
or total vacating of the receptors (absence of biological effect). This lack of biological effect of the drug allows
for the expression of the paradoxical reaction of the organism in the sense of returning to the initial
homeostasis altered by the pharmacological agent by producing symptoms with intensities superior to the
symptoms initially suppressed by the palliative drugs. As an intrinsic aspect of the phenomenon, the
minimum time (time-point) should be taken into account to observe the real magnitude of the rebound effect,
which is longer than the metabolism (half-life) of the drug and/or the normalization of the physiological
changes (absence of biological effect).
Studying carefully the rebound effect or paradoxical reaction of the organism after the interruption or partial
discontinuation of various classes of modern drugs, we found many descriptions of increase of the intensity
and/or frequency of symptoms compared to the state of the patients at the onset of treatment, which
corresponds to the secondary action or vital reaction of the organism (homeopathic model) to maintain its
internal balance after it was broken by the action of palliative drugs.
To illustrate this phenomenon, drugs classically used in the treatment of angina pectoris (beta-blockers,
calcium channel blockers, nitrates, and others) that induce beneficial effects during their primary effect (anti-
angina), might awaken paradoxical increase of the frequency and intensity of the 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 (alpha-2 agonists, beta-blockers, angiotensin converting enzyme
inhibitors, monoamine oxidase inhibitors, nitrates, sodium nitroprusside, hydralazine, and others) might
induce rebound arterial hypertension as paradoxical reaction of the organism to the primary stimulus;
antiarrhythmic drugs (adenosine, amiodarone, beta-blockers, calcium channel blockers, disopyramide,
flecainide, lidocaine, mexiletine, moricizine, procainamide, quinidine, digital, and others) may induce rebound
exacerbation of basal ventricular arrhythmias when treatment is interrupted. Hypolipidemic drugs
(clofibrate, colestipol, colestiramine, nicotinic acid, fluvastatin, lovastatin, pravastatin, and others) to treat
hyperlipidemia due to their primary action promote increased rebound of lipid levels after their interruption.
Antithrombotic drugs (argatroban, bezafibrate, heparin, salicylates, warfarin, clopidogrel, and others) used in

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the prophylaxis of thrombosis due to their primary effects may promote thrombotic complications as
paradoxical reaction of the organism. The use of psychiatric drugs such as anxiolytics (barbiturates,
benzodiazepines, carbamates, and others), sedative-hypnotics (barbiturates, benzodiazepines, morphine,
promethazine, zopiclone, and others), stimulants of the central nervous system (amphetamines, caffeine,
cocaine, mazindol, methylphenidate, and others), antidepressants (tricyclic, MAO inhibitors, selective
serotonin reuptake inhibitors, and others) or antipsychotics (clozapine, phenothiazines, haloperidol, pimozide,
and others) might be associated with a paradoxical reaction of the organism seeking to keep the organic
homeostasis, and thus induce the appearance of symptoms contrary to the ones expected from their primary
therapeutic use, consequently worsening the initial clinical state. Drugs with anti-inflammatory primary
action (corticoids, ibuprofen, 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, salicylates, and others) may exhibit significant hyperalgesia as rebound effect.
Diuretics (furosemide, 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 plasma volume. 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
hydrochloric acid production by the stomach, eventually causing perforation of chronic gastro-duodenal ulcers.
Bronchodilators (adrenergic drugs, sodium chromoglycate, epinephrine, ipratropium, nedocromil, formoterol,
salmeterol, and others) used in the treatment of bronchial asthma might worsen bronchoconstriction as
paradoxical response of the organism to the interruption or partial discontinuation of treatment, and others.
[3-10]
In addition to the need of a variable period of time or ‘time-point’ (hours to weeks) after the discontinuation of
treatment for the phenomenon to appear, the rebound effect or paradoxical reaction of the organism also lasts
a variable period of time (hours to weeks) depending on the properties of drugs and individual idiosyncrasy.
Evidenced by clinical and experimental pharmacology (5-10), some properties of the rebound effect or
paradoxical reaction of the organism are exhibited by all classes of drugs: (i) it appears only in susceptible
individuals (idiosyncrasy), who exhibit symptoms similar to the primary effects of the drug; (ii) it does not
depend on the drug, repetition of doses, nor the type of symptoms (disease); (iii) it follows the primary action
of the drug (discontinuation) as an automatic manifestation of the organism; (iv) it induces an organic state
(symptoms) opposite and greater in intensity and/or duration to the ones of the primary action of the drug; (v)
the magnitude of its effect is proportional to the intensity of the primary action of the drug.
Despite the idiosyncratic nature of rebound effect, which appears in a small fraction of individuals,
contemporary scientific evidences point to the occurrence of ‘severe and fatal iatrogenic events’ as a function
of the paradoxical reaction of the organism following the discontinuance of several classes of modern palliative
drugs.
Rebound effect of antiplatelet drugs [5,6]
Acetylsalicylic Acid (ASA)
Acetylsalicylic acid (ASA) is a non-steroidal anti-inflammatory drug (NSAID) belonging to the class of non-
selective inhibitors of enzyme cyclooxygenase (COX), which catalyzes the transformation of arachidonic acid
into prostaglandins (COX-2) and thromboxane (COX-1). Largely used to prevent thromboembolic events, in its
primary effect it is able to prevent the formation of clots by ASA inhibiting COX-1 [a mediator of activity of
blood platelets activity that stimulates the synthesis of thromboxane (TXA2)] and platelets aggregation.

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Experimental studies [17-24] showed that after the discontinuation of drugs used in the prophylaxis of
thromboembolism, the organism might react by means of a rebound effect or paradoxical reaction that
stimulates the production of COX-1 as well as the activity of platelets (TXA2) to levels much higher than the
initial ones, thus increasing the production of clots and the probability of stroke events [instable angina (IA),
acute myocardial infarction (AMI), cerebral vascular accident (CVA), and others] in susceptible individuals.
In a retrospective study [25], a total of 1,236 patients hospitalized for acute coronary syndrome (ACS) were
questioned to establish whether prophylactic ASA intake had been interrupted. The results showed that 51
cases of ACS had occurred within one month after aspirin withdrawal, i.e., 4.1% of all coronary events and
13.3% of relapses. Among the patients with relapse, the incidence of ACS with ST-segment elevation was
higher in those who had stopped ASA compared to 332 patients who had not stopped ASA (39% vs. 18%, P =
0.001). Mean delay between ASA withdrawal and the acute coronary event was 10 ± 1.9 days. Those results
support the hypothesis that ASA withdrawal in coronary patients may represent a real risk for the occurrence
of a new coronary event.
Investigating discontinuation of ASA therapy as risk factor for ischemic stroke (IS), Maulaz et al. [26]
conducted a case-control study with 309 patients with IS or transient ischemic attack (TIA) undergoing long-
term ASA treatment before their index event and 309 controls who had not had IS in the previous six months,
and compared the frequency of discontinuation of ASA therapy during 4 weeks before an ischemic cerebral
event in patients and the 4 weeks before interview in controls. Stopping ASA therapy was associated with an
odds ratio of 3.4 for IS or TIA (OR 3.4, 95% CI 1.08-10.63, P < 0.005), in other words, a risk 3.4 times larger of
developing ischemic accidents in patients who had interrupted treatment. These results emphasize the
importance of compliance with ASA therapy and give an estimate of the risk associated with the
discontinuation of ASA therapy in patients at risk for IS, particularly those with coronary heart disease.
A systematic review and meta-analysis [27] on the hazards of discontinuing or not adherence to ASA was
performed with 50,279 patients (six studies) at risk for coronary artery disease (CAD). One study (31,750
patients) focused on adherence to aspirin therapy in the secondary prevention of CAD, two studies (2,594
patients) on aspirin discontinuation in acute CAD, two studies (13,706 patients) on adherence to aspirin
therapy before or shortly after coronary artery bypass grafting, and another (2,229 patients) on aspirin
discontinuation among patients undergoing drug-eluting stenting. Overall, aspirin non-adherence/withdrawal
was associated with three-fold higher risk of major adverse cardiac events (OR = 3.14, 95% CI 1.75-5.61, P =
0.0001). This risk was higher in patients with intracoronary stents, as discontinuation of antiplatelet
treatment was associated with an even higher risk of adverse events (OR = 89.78, 95% CI 29.90-269.60).
To evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of
aspirin low dose in patients with a history of cardiovascular events, a recent case-control study was designed
in the United Kingdom with 39,513 individuals who received a first prescription of ASA (75-300 mg/day) for
secondary prevention of cardiovascular outcomes. Individuals were followed up for a mean of 3.2 years to
identify cases of non-fatal myocardial infarction or death from coronary heart disease, found 876 non-fatal
myocardial infarctions. Compared with current users, individuals who had recently stopped taking ASA had a
significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined
(RR 1.43, 95% CI 1.12-1.84) and non-fatal myocardial infarction alone (RR 1.63, 95% CI 1.23-2.14). There was
no significant association between recently stopping ASA low dose and risk of death from coronary heart
disease (RR 1.07, 95% CI 0.67-1.69). For every 1,000 patients, over a period of one year there were about four
more cases of non-fatal myocardial infarction among patients who discontinued treatment with ASA low dose
(recent discontinuers) compared with patients who continued treatment. [28,29]

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Studying the frequency of stroke occurring after discontinuation of antiplatelet drugs (APD), Sibon et al. [30]
found that only 4.49% of strokes were related to recent APD discontinuation, but all cases occurred between 6
and 10 days after drug discontinuation (P < 0.0001).
Confirmed by countless evidences as a natural and universal phenomenon, all classes of antiplatelet drugs
(aspirin, heparin, warfarin, clopidogrel, and others) induce rebound thromboembolism after suspension, and
may cause cardiovascular accidents. [31-37]
In view of the known importance of the use of aspirin to prevent thromboembolism, whose benefits might
surpass the risks, physicians and patients should be alerted to the danger of the abrupt suspension of ASA to
minimize serious iatrogenic thromboembolic events consequential to the rebound effect. [38-40]
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
The precise mechanisms by which NSAIDs including COX-2 inhibitors increase cardiovascular risk are not
clear: reduced prostacyclin production in the vascular endothelium, suppression of nitric oxide synthesis,
diminished neovascularization, abolition of adrenomedullin activity, and increased free-radical production
have all been implicated. Platelets play a pivotal role in the development of these cardiovascular events, and
all these mechanisms also affect platelet activity.
Similarly to ASA, other classes of NSAIDs non-selective COX inhibitors increase the risk of AMI after
interruption of treatment. Confirming the results of experimental studies in which NSAIDs stimulated
platelet adhesion and thrombin activity [41,42], a large case-control analysis conducted at the British General
Practice Research Database [43] with 8,688 cases and 33,923 controls studied the risk of AMI during NSAID
(diclofenac) exposure and after cessation of NSAID therapy. The results showed that the risk of AMI was 1.52
higher (95% CI 1.33-1.74) in the subjects who had stopped NSAIDs one to 29 days prior to the index event
compared to non-users. These results suggest that the risk of AMI is increased during several weeks after the
cessation of NSAID therapy. Withdrawal of ibuprofen provokes rebound platelet aggregation with increased
thrombus formation and cardiovascular events (AMI) [44]. The use of NSAIDs also appears to be
independently associated with increased cerebrovascular event risk in stable atherothrombosis patients [45].
To evaluate the cardiovascular risks of selective COX-2 inhibitors, a retrospective cohort study analyzed the
medical history of 1.4 million drug users (1999-2001) [46], showing that 8,199 patients (0.58%) suffered a
heart attack during the use of rofecoxib. Before that study, other researches demonstrated that the chronic
consumption of rofecoxib in high doses (> 50 mg/day) could elevate the risk of serious cardiovascular
problems, which was further confirmed by other studies [47-50].
Linking the rebound effect to platelet activity and considering that antiplatelet therapy with ASA is
associated with reduced vascular mortality, Serebruany et al. [51] sought to determine the effect of the use
and withdrawal of NSAIDs on platelet activity. Platelet characteristics from 34 aspirin-naive volunteers who
were receiving unselective NSAIDs or selective COX-2 inhibitors were compared to 138 drug-free controls.
Platelets were assessed twice at baseline (at least one month of treatment) and after 14-day washout. Platelet
activity during treatment was similar and unremarkable in both groups. However, there was a highly
significant increase of platelet activity after withdrawal of non-selective NSAIDs and selective COX-2
inhibitors. Those authors concluded that drug cessation, rather than continuous therapy with these drugs,
may be associated with rebound platelet activation, which may predispose to higher risk of vascular events. In
vitro experiments also demonstrated that the thrombogenic mechanism previously mentioned for others
NSAIDs also occur with rofecoxib [52].

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Confirming this hypothesis, previous observational studies found particularly high risk of AMI for new users
of rofecoxib [53,54], with events occurring short time after the suspension of low doses of the therapy, likely to
the dynamic of the rebound effect. Using data collected in a previous population-based cohort study [55], a
case-control study evaluated the temporal nature of the risk of a first AMI associated with the use of rofecoxib
and celecoxib, observing that the risk of AMI was higher following first-time use of rofecoxib (RR 1.67, 95% CI
1.21-2.30), with events occurring within a median of 9 (6-13) days after therapy was started. Treatment
duration was not associated with increasing risk, and the risk remained elevated for the first 7 days after
rofecoxib was discontinued (RR 1.23, 95% CI 1.05-1.44) but appeared to return to baseline between days 8 and
30 (RR 0.82, 95% CI 0.61-1.09), thus characterizing the rebound phenomenon [56].
In an important systematic review of the effects of NSAIDs (both selective and nonselective inhibitors of COX-
2) on cardiovascular events, 23 observational studies were analyzed (17 case-control and six cohort studies) in
a population of 1.6 million of patients [57]. A dose-related risk was evident with rofecoxib, relative risk (RR) of
1.33 (95% CI 1.00-1.79; 6 studies) with 25 mg/day or less, and 2.19 (95% CI 1.64-2.91; seven studies) with
more than 25 mg/day. Among the older, nonselective drugs, diclofenac had the highest risk with RR of 1.40
(95% CI 1.16-1.70; 9 studies), meloxicam RR 1.25 (95% CI 1.00-1.55; 3 studies) and indometacin RR 1.30 (95%
CI 1.07-1.60; 6 studies). These data indicate that risk increases early in treatment (first 30 days) and on first
cardiovascular events.
In a case-control study (33,309 cases; 138,949 controls) of the risk of hospitalization with myocardial
infarction and use of NSAIDs [58], the RR estimates were: rofecoxib, 1.36 (95% CI, 1.18-1.58; 12 studies);
diclofenac, 1.40 (95% CI 1.19-1.65; 10 studies); meloxicam, 1.24 (95% CI 1.06-1.45; 4 studies); indometacin,
1.36 (95% CI 1.15-1.61; 7 studies). In another meta-analysis, Kearney et al. [59] studied the effects of selective
and nonselective NSAIDs on the risk of serious vascular events for a period of at least 4-week duration
(145,373 participants), reviewing data from 138 randomized trials and estimated a RR for rofecoxib of 1.42
(95% CI 1.13-1.78) and for diclofenac of 1.63 (95% CI 1.12-2.37).
Enhancing the validity and the causality of the rebound phenomenon, recent studies showed similar results
[60-64]. Analogously to ASA, physicians and patients should be alerted to the danger of the abrupt suspension
of NSAIDs, to minimize fatal cardiovascular events [65-70].
Rebound effect of bronchodilator drugs [5,7]
Along the last decades, several studies confirmed the clinical and experimental observation that ‘rebound
bronchoconstriction’ occurs after partial interruption or discontinuation of bronchodilators, with ‘asthma
aggravation’ and increasing of the ‘bronchial reactivity’. [71-82]
At the request of the FDA (U.S. Food and Drug Administration), due to reports of serious paradoxical
bronchospasm associated with the use of long-acting beta-2 agonist (LABA) salmeterol and the previous
epidemics of asthma-related deaths in patients taking other long-acting beta agonists, laboratory
GlaxoSmithKline initiated in 1996 a randomized trial comparing salmeterol to placebo (Salmeterol
Multicenter Asthma Research Trial, SMART) that was prematurely halted in September 2002 after an
interim analysis suggested increased risk of asthma-related death in the patients who used the drug
compared to the placebo group.
Since 2005, the FDA Public Health Advisory informed about the danger of LABA (salmeterol, formoterol),
inclusively when combined with steroid fluticasone, “[they] have been associated with an increased risk of
serious asthma exacerbations and asthma-related death”, initially ordering the laboratory GlaxoSmithKline

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to put a ‘black box’ warning on the treatment’s packaging, alerting doctors to the fact that the medicine could
have potentially fatal side-effects [83].
After countless protests of the scientific community [84], since GlaxoSmithKline presented the partial data of
SMART at the 69ª Annual International Scientific Assembly of The American College of Chest Physicians
(CHEST 2003) claiming that “the interim analysis was inconclusive”, the results of the general analysis of
26,355 randomized subjects were published in 2006 [85]. Following the review of the interim analysis,
exploratory analyses of each outcome event within subpopulations were conducted, finding that there was
significant increase in respiratory-related deaths (RR 2.16, 95% CI 1.06-4.41) and asthma-related deaths (RR
4.37, 95% CI 1.25-15.34), and in combined asthma-related deaths or life-threatening experiences (RR 1.71,
95% CI 1.01-2.89) in subjects receiving salmeterol versus placebo. The imbalance occurred largely in the
African-American subpopulation (compared with Caucasian subjects): respiratory-related deaths or life-
threatening experiences (RR 4.10, 95% CI 1.54-10.90) and combined asthma-related deaths or life-threatening
experiences (RR 4.92, 95% CI 1.68-14.45) in subjects receiving salmeterol versus placebo.
In 2006, Salpeter et al. [86] published a meta-analysis of 19 placebo-controlled trials involving 33,826
participants with asthma followed for 16,848 patient-years (mean trial duration was 6 months).
Approximately 15% of the participants were African-American. The LABA used in the studies were
salmeterol, formoterol, and eformoterol. During the trials, concomitant inhaled corticosteroids were used in
approximately 53% of the participants in both groups. The aim of the study was to assess the effects of LABA
on severe asthma exacerbations requiring hospitalization, life-threatening asthma attacks, and asthma-
related deaths. Subgroup analyses were used to compare the results for salmeterol and formoterol and for
children and adults. The OR for hospitalization was 2.6 (95% CI 1.6-4.3) for long-acting beta-agonists
compared with placebo. Those authors did not include SMART in this analysis because the investigators had
not provided information on hospitalizations due to asthma, but only on life-threatening exacerbations. When
they included the SMART data on life-threatening exacerbations, the OR was 2.1 (95% CI 1.5-3.0). The risk
for hospitalization was increased with salmeterol (OR 1.7, 95% CI 1.1-2.7), formoterol (OR 3.2, 95% CI 1.7-
6.0), children (OR 3.9, 95% CI 1.7-8.8) and adults (OR 2.0, 95% CI 1.0-3.9). The OR for life-threatening
asthma attacks attributed to LABA was 1.8 (95% CI 1.1-2.9), which did not significantly differ between trials
of salmeterol and formoterol or between children and adults. The OR for asthma-related deaths was obtained
from SMART (OR 3.5, 95% CI 1.3-9.3, P = 0.013). As a whole, the risks of severe exacerbations and asthma-
related deaths increased by 2- to 4-fold. Despite the known protecting effect of inhaled corticosteroids, those
authors evaluated separately trials in which more than 75% of the participants were receiving concomitant
inhaled corticosteroids, and found that the risk of hospitalization was still increased 2-fold (OR 2.1, 95% CI
1.3-3.4), thus evidencing the importance of the rebound effect on the organic physiology.
In the physiologic explanation of the rebound phenomenon, authors correlated regular beta-agonist use
(associated or not with inhaled corticosteroids) with tolerance to the drug’s effects and worse control of disease
[87-92]. Tolerance results from a negative feedback mechanism of the beta-adrenergic system that is an
adaptive response to the stimulation of receptors causing uncoupling and internalization of receptors, which is
known as ‘desensitization’, followed by a decrease in receptor density and receptor gene expression, which is
known as ‘down regulation’ [93]. Regular use of beta-agonists has been shown to increase bronchial
hyperreactivity despite the maintenance of some degree of bronchodilation. These effects, along with a
reduction in the response to subsequent rescue beta-agonists may worsen asthma control without giving any
warning of increased symptoms [92,94]. As cited in previous studies [71-82], ‘bronchial hyperreactivity’ is the
same as ‘rebound hyperreactivity’ or ‘rebound bronchoconstriction’ [95].
A recent meta-analysis that included 17 randomized controlled trial (RCTs) (7,032 participants) compared the
efficacy and safety profile of adding either daily LABA or anti-leukotrienes (LTRA) in adults and children
with asthma who remain symptomatic on regular inhaled corticosteroids (ICS). The results showed that

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serious adverse events were more common with LABA than LTRA (RR 1.35, 95% CI 1.00 to 1.82), and that
the risk of withdrawal for any reason in adults was significantly lower with LABA and ICS compared to LTRA
and ICS (RR 0.84, 95% CI 0.74 to 0.96). [96]
In a recent retrospective cohort study, which studied the risk of serious asthma exacerbations associated with
LABA among 940,449 patients with asthma, LABA use was found to be positively associated with
hospitalizations and intubations compared to short-acting beta agonists. [97]
Other studies confirm severe rebound bronchoconstriction after suspension of LABAs, requiring a risk
evaluation and mitigation strategy to facilitate the safe use of the products that includes a medication guide
for patients and a plan to educate health care professionals about the appropriate use of these drugs [98-101].
Rebound effect of antidepressant drugs [5,8]
As other classes of palliative or antipathic drugs, also antidepressants exhibit rebound effect of the symptoms
of depression after withdrawal of treatment (discontinuation or alteration of doses, including even one single
dose missed in susceptible constitutions and/or with short half-life drugs), with evident changes in the
mediators involved (receptor sensitization and neurotransmitter levels).
In a review about this subject, Wolfe [12] states that antidepressants may cause a variety of withdrawal
reactions, “starting within a few days to a few weeks of ceasing to administer the drug and persisting for days
to weeks”. Both tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) cause similar
syndromes, most commonly characterized by gastrointestinal or somatic distress, sleep disorders, mood
fluctuations and movement disorders. Treatment involves restarting the antidepressant and tapering it more
slowly.
In a review, Lader [102] enhances the understanding of the antidepressant discontinuation syndrome
(rebound phenomenon) with further data and studies: “The phenomenon has been postulated to be associated
with rebound symptoms such as return of depression following abrupt discontinuation. Discontinuation
symptoms are now known to be associated with most classes of antidepressants, if medication is stopped
without appropriate down-tapering of dose and/or dose frequency. The phenomena associated with stopping
almost all antidepressants including the SSRIs are believed to result not from true dependence but from a
reduction in intra-synaptic serotonin (5-HT) levels following receptor down-regulation”.
This syndrome is characterized by the ‘time-locked emergence of new’ (time-point), clearly defined and
quantifiable signs and symptoms, which develop on cessation or reduction of an antidepressant that has been
taken for more than a few weeks [103]. Typically, patients describe transient symptoms that begin and peak
within one week of treatment interruption, are mild in severity and follow a finite time-course, usually lasting
between one day and three weeks [104]. In spite of the data from the published literature showing that the
incidence of these mild, self-limiting rebound symptoms is generally smaller than 5% [104,105], recent data
indicate that severe and disabling withdrawal syndromes occur in up to 5% of patients, requesting prompt
modification of the management strategy in these idiosyncratic individuals [106]. The literature reveals that
paroxetine is associated with significantly greater proportion of withdrawal reactions (around 5%) than the
other SSRIs (fluoxetine, for example), with deterioration in various aspects of health and functioning
[104,107-110]. The explanation for this difference most likely reflects the long half-life of the main metabolite
of fluoxetine, thus acting as a natural taper [111].
Like in other classes of drugs, the rebound reactions are not specific to the particular condition (disease) in
which the drug is used, whereas the antidepressant discontinuation syndromes are similar both in incidence,

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nature and extent throughout depression, panic disorder, generalized anxiety disorder, social anxiety
disorder, and obsessive-compulsive disorders. In a similar way, the duration of treatment does not influence
withdrawal reactions. [112]
In a revision of the neurobiological mechanisms of the antidepressant withdrawal syndrome, Harvey et al.
[113] suggested a preliminary molecular perspective and hypothesis on the neuronal implications of the
discontinuation of medication, and described the evidences that support association between antidepressant
rebound effect and disorders of the brain glutamate activity, nitric oxide synthesis, and gamma-amino butyric
acid: “Inappropriate discontinuation of drug treatment and noncompliance are a leading cause of long-term
morbidity during treatment of depression. Increasing evidence supports an association between depressive
illness and disturbances in brain glutamate activity, nitric oxide synthesis, and gamma-amino butyric acid.
Animal models also confirm that suppression of glutamate N-methyl-D-aspartate (NMDA) receptor activity or
inhibition of the nitric oxide-cyclic guanosine monophosphate pathway, as well as increasing brain levels of
gamma-amino butyric acid, may be key elements in antidepressant action. Imaging studies demonstrate, for
the most part, decreased hippocampal volume in patients with depression, which may worsen with recurrent
depressive episodes. Preclinical models link this potentially neurodegenerative pathology to continued stress-
evoked synaptic remodeling, driven primarily by the release of glucocorticoid, glutamate, and nitric oxide.
These stress-induced structural changes can be reversed by antidepressant treatment. In patients with
depression, antidepressant withdrawal after chronic administration is associated with a stress response as
well as functional and neurochemical changes. Preclinical data also show that antidepressant withdrawal
evokes a behavioral stress response that is associated with increased hippocampal NMDA receptor density,
with both responses dependent on NMDA receptor activation”.
The symptoms that follow the discontinuation of antidepressants include dizziness, nausea, gastrointestinal
distress, headache, gait instability, lethargy, paresthesia, anxiety, irritability, vivid dreams and lowered mood
among others. While cholinergic overdrive may explain certain symptoms after tricyclic antidepressants
withdrawal, many of these symptoms suggest increased excitability of serotonergic neurons. In the same way
that chronic antidepressant treatment results in desensitization of post and presynaptic serotonin (5-HT1A)
receptors, abrupt cessation of 5-HT reuptake inhibition will cause temporary deficit of available intra-
synaptic 5-HT (down-regulated receptors), resulting in a neurochemical and behavioral pattern caused by loss
of inhibitory 5-HT1A mediated synaptic control and an increase of circulating 5-HT. [113-115]
In severe and disabling withdrawal syndromes (around 5% of patients) [102], overtly raised synaptic 5-HT
levels may be detrimental to neuronal function and integrity by enhancing the efficacy of the brain glutamate
NMDA receptor. Reiterating the previously mentioned premises of the rebound effect, these severe rebound
phenomena are determined by various factors, such as the pharmacological profile of the antidepressant, the
time-point and duration of withdrawal, whether withdrawal or noncompliance is repeated and how often, and
the impact of associated contributors such as inherent genetic and environmental factors (idiosyncratic
constitution) [114].
In recent years, countless studies called the attention to the relationship between antidepressants and
suicidality. As initial hypothesis for this relationship, withdrawal of antidepressants provokes significant
worsening of the depressive symptoms initially suppressed (for example, suicidal ideation, attempts or
behavior) as consequence of the rebound effect. [8,116-120]
In the first meta-analysis that intended to investigate the relationship between antidepressant drugs and
suicidality in pediatric patients participating in placebo-controlled trials, Hammad et al. [121] included all
studies submitted to the FDA. The evaluated data was derived from 4,582 patients in 24 trials. Sixteen trials
studied patients with major depressive disorder (MDD), 4 trials studied patients with obsessive-compulsive
disorder (OCD), and 4 trials studied patients with non-obsessive-compulsive anxiety disorder. Only 20 trials

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were included in the risk ratio analysis of suicidality because 4 trials had no events in the drug or placebo
groups. The multicenter trial TADS [122] was the only individual trial to show a statistically significant risk
ratio (RR 4.62, 95% CI 1.02-20.92). The overall risk ratio for SSRIs in depression trials was 1.66 (95% CI 1.02-
2.68) and for all drugs throughout all indications was 1.95 (95% CI 1.28-2.98). The overall risk difference (RD)
for all drugs within all indications was 0.02 (95% CI 0.01-0.03). The FDA concluded that these medications
pose a 2-fold (4% verum vs. 2% placebo) increased risk for ‘suicidal behavior’ or ‘suicidal ideation’, a modestly
increased risk of suicidality.
It is worth to stress that the adverse events assessed by those meta-analyses were only the ones that occurred
during or immediately after the double-blind acute treatment period, and thus underestimated the rebound
effect of antidepressants with longer half-life. Some studies showed that abrupt interruption of continuous
SSRIs therapy for 3 to 8 days was associated with greater emergence of somatic and psychological rebound
symptoms (worsening of depression and increased suicidality, for example) in patients treated with short half-
life antidepressants (paroxetine, sertraline, venlafaxine, and others) than in those treated with fluoxetine
(longer half-life antidepressant). [116,117,120,123-125]
Other recent meta-analysis and prospective multicenter studies also evaluated the risk of suicidality in
youths and adults and found similar results, warning doctors and patients on the care required by suspension
of SSRIs. [126-132]
Rebound effect of antihypercholesterolemic drugs (statins) [9]
Statins are the most widely prescribed cholesterol-lowering drugs and are considered to be first-line
therapeutics for the prevention of coronary heart disease and atherosclerosis (the major cause of death in
developed countries). Statins act by inhibiting enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of
HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering the plasma total
cholesterol, low-density lipoprotein-cholesterol (LDL-C), and triglyceride levels in humans, and can therefore
be useful to treat atherosclerotic and dyslipidemic disorders.
However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing
cholesterol biosynthesis, inhibition of mevalonate by statins also leads to reduction in the synthesis of
important intermediates such as isoprenoids (farnesyl pyrophosphate, geranylgeranyl pyrophosphate,
coenzyme Q10, dolichol, isopentenyladenosine, and others). These intermediates are involved in the
posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular
processes including cellular signaling, differentiation, and proliferation. Given the central role of these
isoprenylated proteins in the endothelial function, atherosclerotic plaque stability, platelet activity,
coagulation, oxidation, and inflammatory and immunologic responses, it might be anticipated that these
compounds may exert multiple beneficial primary effects in a broad spectrum of disorders including
cardiovascular disease, osteoporosis, Alzheimer’s disease and related vascular dementia, viral and bacterial
infection, and others. These cholesterol-lowering-independent effects of statins are termed ‘pleiotropic effects’,
and involve vasculoprotective actions that include improvement of the endothelial function, increased nitric
oxide (NO) bioavailability, antioxidant properties, inhibition of inflammatory and thrombogenic responses,
immunomodulatory actions, regulation of progenitor cells, and stabilization of atherosclerotic plaques. [133-
135]
Regardless of the rebound increase in cholesterol biosynthesis, scientific evidence suggests that sudden
discontinuation of statin treatment leads to rebound impairing of the vascular function, and increased

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morbidity and mortality of patients with vascular diseases. Withdrawal of statin treatment leads to overshoot
activation of heterotrimeric G-proteins Rho and Rac, causing production of reactive oxygen species and
suppression of NO bioavailability. In humans, discontinuation of statin therapy leads to a prooxidant,
proinflammatory and prothrombotic state with impaired endothelial function. Epidemiological studies
indicated that cessation of statin medication in AMI and ischemic stroke patients confers a significantly
higher likelihood of early cardiologic and neurological deterioration, respectively, and poor outcome. In
summary, withdrawal of statin therapy results in a rapid return to endothelial dysfunction and amplification
of the oxidative and inflammatory processes, which may increase the cardiac and cerebrovascular risk. [136-
139]
Experimental studies described the physiological and molecular mechanisms involved in the statin
withdrawal syndrome, thus broadening the knowledge on the scope of action of the rebound effect: (i) increase
of markers of cholesterol biosynthesis [140-144]; (ii) worsening of the endothelial function [141,145-147]; (iii)
increase of inflammation and oxidative stress [148-151]; and (iv) stimulation of the thrombogenic response
[141-144].
Clinical studies found that discontinuation of statins (rebound phenomenon) particularly after acute events
(e.g. AMI or stroke) has a harmful effect on cardiovascular outcomes and all-cause mortality: patients who
discontinued their statin therapy had worse outcomes than those who were never prescribed statins.
Observational studies [152-157] showed that statins withdrawal resulted in increased risk of mortality
(secondary to fatal vascular events) compared to maintenance (2.3- to 7.5-fold) and absence (1.25 -to 1.69-fold)
of treatment. Interventional studies showed that suspension of statins led to significantly increased risk of
mortality compared to maintenance treatment (4.66-fold) [160], and significantly increased risk of fatal
vascular events compared to maintenance (2.27- to 8.67-fold) [158,160] and the absence of treatment (19.01-
fold) [160] as well as to placebo [158]. Statin therapy discontinuation was also considered an independent
predictor of all-cause one-year mortality [159].
Other recent studies on individuals without history of cardiovascular disease further broaden the scope of
evidence. Such studies showed that withdrawal of statins caused rebound impairment of the vascular
function, and thus predispose to coronary and cerebrovascular diseases. Consequently, practitioners ought to
become more aware of such effects and counsel their patients to adhere to their statin therapy. [161-172]
Rebound effect of gastric acid suppressing drugs [10]
According to the FDA [173], rebound acid hypersecretion is defined as an increase of the gastric acid secretion
(basal and/or stimulated) above pretreatment levels following discontinuation of antisecretory therapy.
Rebound was initially reported in studies following the use of histamine H2-receptor antagonists and was
thought to be due to increased serum gastrin and/or up-regulation of the H2-receptors. Elevated gastrin levels
or hypergastrinemia is a secondary effect that occurs during chronic inhibition of gastric acid secretion, such
as it happens with long-term antisecretory therapy. In humans, gastrin is the primary regulator of the gastric
acid secretion, which is mediated by histamine released by the enterochromaffin-like (ECL) cells. Increased
plasma gastrin stimulates and up-regulates ECL cells to produce and release more histamine to stimulate the
parietal cells. In addition, an increase of the parietal cell mass may occur together with the chronic use of
antisecretory agents, and this might be an additional mechanism explaining the increased acid secretion that
might occur after discontinuation of treatment. Another possible cause of rebound acid secretion is increased
sensitivity to histamine. [174]

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The neutralization of the gastric acidity by antacids (aluminum/magnesium hydroxide or calcium carbonate),
although it is not an antisecretory treatment might, also cause the rebound phenomenon after discontinuation
of treatment. Clinical trials confirmed this hypothesis after observing the occurrence of rebound effects in
healthy volunteers 1 hour after a standard dose of antacids. [175,176]
Similarly to other competitive antagonist drugs, the H2-receptor antagonists (cimetidine, famotidine,
nizatidine and ranitidine) cause rebound acid hypersecretion after drug withdrawal. Although the exact
mechanism remains unclear, the main hypotheses are that the rebound phenomenon may be caused by
increased responsiveness (up-regulation) of the H2-receptor to histamine stimulation after chronic competitive
inhibition, or that the inhibitory arm of acid secretion is impaired [177]. Studies with patients and healthy
individuals showed that rebound acid hypersecretion after discontinuance of H2-receptor antagonists occurred
within 2 or 3 days after 4 weeks of treatment and lasted 10 days [178-183].
Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole and pantoprazole) block the final step in the
secretion of acid, which results in severe and persistent gastric hypoacidity with concomitant increased
release of gastrin. This rebound hypergastrinemia results in continuous stimulation of the ECL cells and
consequent hyperhistaminemia that, however, does not lead to increased gastric acid secretion because the
proton pump is effectively blocked. In addition, the stimulation of ECL cells proliferation induces increase of
their mass, which remains longer than the effect of the proton-pump inhibitors (PPI) when the drug is
discontinued. As in any instance of rebound phenomenon, rebound acid hypersecretion is evident at a certain
time-point after treatment withdrawal as a function of the half-life of drugs (absence of biological effects).
Rebound acid hypersecretion after a sufficient period of PPI treatment occurs from the second week (PPI’s
half-life) until the normalization of the ECL cell mass (about 2 months), i.e., 2 or 3 months after stopping
treatment. This phenomenon is prolonged, lasts at least 2 months after a 2-month treatment course, with
persistence of significantly elevated submaximal and maximal acid hypersecretion. [184-190]
Gastrin has trophic effects on many tissues and stimulates a number of tumor cell lines in culture, including
colon cancer cells. Although according to some suggestions hypergastrinemia is associated with increased risk
of colon cancer, 2 population-based case-control studies conducted in United Kingdom (1987-2002) and
Denmark (1989-2005) found no evidence of such increase in patients using PPI [191,192]. In addition, there
are reasons to believe that patients with reflux disease are more affected during the period of rebound acid
hypersecretion after a course of PPI treatment than before. The increase of the gastroesophageal reflux
disease observed during the last decades might be due to low-threshold PPI overuse to treat reflux symptoms.
Due to the same reason, hypergastrinemia might have a possible effect on the progression of Barrett’s
esophagus to cancer, as a function of the marked rise in the incidence of adenocarcinoma at the
cardioesophageal junction over the past 2 decades, inasmuch as acid-suppressive therapy for
gastroesophageal reflux disease has greatly increased. [193-196]
A population-based cohort study conducted in Denmark (1990-2003) showed increased incidence of gastric
cancer among PPI users with the largest number of prescriptions or the longest follow-up compared with H2-
receptor antagonists’ users or non-users [197]. According to the authors, these data suggest that
hypergastrinemia might be a risk factor for the development of gastric cancer, in consequence of excessive use
of PPIs by the population.
Carcinoid tumors have long been recognized as consequence of hypergastrinemia in Zollinger-Ellison’s
syndrome and atrophic gastritis [198]. Analogous to the previous described suggestion, the increased
incidence of gastric carcinoids in the last 3 decades (400% in males and 900% in females) is also associated
with the widespread marketing of PPI [199-201]. According to McCarthy [196], the scientific basis to expect

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long-term PPI use to cause carcinoid tumors is quite strong and deserves serious consideration.
Hypergastrinemia may also stimulate the development of carcinoid tumors or their growth in other sites.
To evaluate the occurrence and clinical relevance of rebound acid hypersecretion after discontinuation of PPI,
Hunfeld et al. [202] performed a systematic review that included 8 studies (sample size 6-32). Five studies
(including 4 randomized trials) did not find any evidence for rebound acid hypersecretion after PPI
withdrawal. From the remaining 3 uncontrolled trials, 2 studies suggested that rebound acid hypersecretion
may occur in H. pylori-negative patients after 8 weeks of treatment with PPI. Those authors concluded that
there is no strong evidence for clinically relevant increased acid production after withdrawal of PPI therapy.
Upon criticizing the studies included in this systematic review, which did not take into account the need of a
duration of PPI therapy sufficient to allow for development of significant ECL cells hyperplasia and
subsequent acid rebound, Fossmark and Waldum [203] reiterated that it is impossible to evaluate rebound
acid hypersecretion after 1 single dose of PPI, nor after 25-day use, although the included studies had a
randomized design: “these 5 studies merely show that PPI must be used more than 1 to 25 days to induce
rebound acid hypersecretion”.
Clinical evidences for rebound acid hypersecretion after PPI withdrawal were found in recent interventional
studies [204-208]. Upon assessing indirectly whether rebound acid hypersecretion also occurs in patients
without gastroesophageal reflux disease, some studies described relapse of symptoms in approximately 70% of
long-term PPI users after discontinuation of therapy [204,207].
Proton-pump inhibitors are some of the most frequently used drugs worldwide and represent an important
financial onus for the healthcare system of many countries, because they are prescribed for a wide variety of
allegedly acid-induced upper gastrointestinal symptoms [209-213]. For instance, the total use of PPI increased
7 times between 1993 and 2007 in Denmark, and a substantially increased from 20 to 33 defined daily doses
per 1,000 individuals per day from 2003 to 2007. In 2006, approximately 7% of the Danish population was
treated with 1 PPI [214-216]. Whereas the use of H2-receptor antagonists declined 72% between 1995 and
2006 in Australia, the use of combined PPI increased by 1,318% [217].
Between 1999 and 2004, the use of PPI in the United States increased steadily, whereas the use of H2-
receptor antagonists decreased also steadily. In 2007, esomeprazole, lansoprazole, and pantoprazole were the
4th, 8th, and 14th leading brand-name prescription drugs sold in the United States, with 26.4, 20.4, and 16.1
million prescriptions, respectively. Comparatively, ranitidine and famotidine ranked 47th and 120th among the
generic drugs, with 13 and 3 million prescriptions dispensed, respectively. Neither cimetidine nor nizatidine
ranked among the top 200 drugs sold in 2007. [218]
Although this liberal use of PPI has been recently recommended by many guidelines for dyspepsia [219,220],
it is well documented that these drugs are often inappropriately prescribed for minor symptoms and without
clear indications, where the effects of acid-suppressive therapy is controversial [212,214,221-225]. As a result,
a large proportion of patients currently prescribed PPI do not have acid-related symptoms and thus, have no
true indication for such therapy. Some studies also showed that up to 33% of patients who initiate PPI
treatment redeem repeated prescriptions without any obvious indication for maintenance therapy [212,226].
This empirical behavior may complicate PPI discontinuation, due to the development of rebound acid
hypersecretion, leading to the relapse of the symptoms of the underlying acid-related disease (heartburn, acid
regurgitation and dyspepsia) that might result in resumption of therapy [204,205].
Other recent reviews that concluded for the existence of the rebound phenomenon after suspension of PPI
warn practitioners to ponder on the risks and benefits before starting them [227-232].

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Homeopathic use of conventional drugs: therapeutic application of the rebound effect [233-236]
Some instances of involuntary homeopathic cures with conventional drugs are reported in the scientific
literature. Biphasic contraceptives (anteovin) were used to promote rebound ovulation and consequent
pregnancy in women with functional sterility; stimulants of the central nervous system (methylphenidate)
were used to calm down and improve the attention in children with attention deficit hyperactivity disorder
(ADHD); stimulants of gonadotropin releasing hormone (leuprorelin) were used in the treatment of
testosterone-dependent prostate tumors; immunosuppressants (thiomorpholine analogous to prazosin)
induced rebound immunostimulation after primary immunosuppression, and so forth [3,4].
Retracing the steps of classical homeopathy to conclude an earlier stage of the present research [233-236], we
systematized the use of modern drugs according to the principle of therapeutic similitude. Consistently, we
suggest that the healing paradoxical reaction (vital reaction) of the organism might be stimulated by means of
drugs (in infinitesimal doses) that caused similar symptoms on human beings.
To make this proposal feasible, a Homeopathic Materia Medica of Modern Drugs was needed that grouped
together all the primary effects (therapeutic, adverse and side effects) of drugs as described in The United
States Pharmacopoeia Dispensing Information (USP DI, 2004) according to the traditional scheme of chapters
of works on homeopathic materia medica.
To facilitate the selection of an individualized medicine (similar to the totality of the patient’s symptoms) –
which is the essential premise for successful homeopathic treatment – the second stage involved the
elaboration of a Homeopathic Repertory of Modern Drugs, where symptoms and their corresponding medicines
are arranged as in the classic homeopathic repertories.
This research project is entitled New Homeopathic Medicines: use of modern drugs according to the principle
of similitude, and it is distributed across three volumes: Scientific Basis of the Principle of Similitude in
Modern Pharmacology; Homeopathic Materia Medica of Modern Drugs; and Homeopathic Repertory of Modern
Drugs. Aiming at divulgating this project among homeopaths worldwide as well as to allow for its
improvement, it is available online at www.newhomeopathicmedicines.com. [237]
Discussion
The notion of secondary action or vital reaction included in the homeopathic therapeutic model is supported
by studies on the rebound effect or paradoxical reaction of the organism associated with modern drugs used
according to the therapeutic principle of contraries (palliative, enantiopathic or antipathic effects).
Investigated by integrative physiology through the complex psycho-neuro-immune-endocrine-metabolic
system, homeostasis (“life-preserving power”) promotes organic reactions to restore the balance of the internal
environment altered by drugs, external stimuli or psychological factors.
Seeking to extend the paradoxical (homeostatic or vital) reaction of the organism to psychological factors
(namely, mental, emotional or behavioral features), some experimental studies showed that ‘thought
suppression’ (by cognitive therapy, for example) might have paradoxical effects resulting in the subsequent
increase of the suppressed ideas. Such effects might be implicated in the etiology or worsening of obsessions
(obsessive-compulsive disorder, etc.), phobias (social phobia, agoraphobia, etc.), addictions (smoking, binge
eating, etc.), or other psychopathological conditions [238-245]. These evidences based the therapeutic
application of the principle of similitude to the mental aspects of the individuality.
The severity of the paradoxical reactions mentioned above and eventually leading to serious or fatal iatrogenic
events agree with the pharmacological notion of the rebound effect, where the paradoxical reaction of the
organism sometimes is greater than the similar phenomenon initially suppressed. Although the rebound

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effect manifests in a small proportion of individuals as a function of their idiosyncratic nature, these serious
or fatal paradoxical events assume epidemiological importance when we consider the enormous current
consumption of enantiopathic or palliative drugs.
In the above mentioned placebo-controlled studies, the risk of ischemic accidents was 3.4 times greater after
ASA withdrawal, 1.52 times greater after NSAIDs withdrawal, 1.67 times greater after rofecoxib withdrawal,
and 1.69 times greater after statins withdrawal. The risk of suicidal behaviors was 6 times greater after SSRI
antidepressants withdrawal, whereas the risk of fatal paradoxical bronchospasm was 4 times greater after
LABA withdrawal.
The time for appearance of the paradoxical reaction does not exhibit remarkable variation after the
discontinuance of palliative drugs: it was average 10 days for ASA, 14 days for NSAIDs, 9 days for rofecoxib, 7
days for SSRI, 7 days for statins, and 7 to 14 days for PPI. The duration of the rebound effect was 30 days
with rofecoxib, 21 days with SSRI, and 30 days with PPI. The duration of treatment before the interruption of
drugs did not show association with the risk of inducing paradoxical events.
Similar to the fatal iatrogenic events of the above mentioned drugs, the asthma mortality rates increased
worldwide in the 1960s, when inhaled beta-agonists were introduced in the market [246-248], and further
rose in the last decade after LABA were introduced [249-251]. LABA cause about 1 case of rebound
bronchospasm followed by death per 1,000 patients-year-use [86], which corresponded to 4,000-5,000 deaths
in the USA in 2004 (40,000-50,000 worldwide) [7]. SSRI cause about 5 rebound suicidality events per 1,000
adolescents-year-use [252], which corresponded to 16,500 suicidal behaviors or ideas in the USA in 2007 [8].
ASA causes about 4 rebound acute myocardial infarctions per 1,000 patients-year-use [28,29]. Some studies
reported increased incidence of gastric carcinoids in the last decades (400% in men and 900% in women)
associated with the growing consumption of PPIs.
In addition to the above mentioned drugs, recent studies warn about the risks associated with the suspension
of analgesics [253-255] and psychiatric drugs [256-259] also associated with their huge and growing current
consumption.
Within this context, it is worth mentioning the risk of developing immune reconstitution inflammatory
syndrome (IRIS), which is confounded with progressive multifocal leukoencephalopathy (PML), after the
withdrawal of natalizumab (humanized monoclonal antibody) used in the treatment of multiple sclerosis, in
addition to the worsening of the activity of the disease [260-265].
Widely used in the treatment of osteoporosis and the prevention of fractures, bisphosphonates (alendronate,
etidronate, zoledronate, among others) increase the bone density, by hindering the dissolution of
hydroxyapatite crystals and inhibiting the activity of osteoclasts (bone cells that reabsorb those crystals).
Recently, several studies demonstrated rebound effect after discontinuation of bisphosphonates (and other
treatments such as estrogen and denosumab) with increase of the activity of osteoclasts and paradoxical
atypical subtrochanteric and diaphyseal femoral fractures. [266-277]
Conclusion
A large number of iatrogenic diseases might be avoided if doctors were advised to the maintenance of
homeostasis associated with the rebound effect or vital reaction of the organism, and thus prevent the
paradoxical aggravation of the clinical condition of patients by discontinuing slowly and gradually drugs used
according to the principle of contraries. Although they are not considered as conventional adverse events of
drugs, “drug discontinuation effects are part of the pharmacology of a drug” [16], and should be routinely
incorporated into the teaching of modern pharmacology.

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According to the observations by Hahnemann cited at the beginning of this article “on the sad results of the
use of antagonistic employment of medicines”, reputed researchers and doctors are increasingly pointing to
the risks associated with the rebound effect of modern palliative treatments. Thus they confirm the validity of
the application of the principle of similitude through Aristotelian deductive logic ‘modus tollens’ (‘mode that
affirms through negation’ or ‘indirect proof’):
“Had physicians been capable of reflecting on the sad results of the antagonistic employment of medicines,
they had long since discovered the grand truth, that the true radical healing art must be found in the exact
opposite of such an antipathic treatment of the symptoms of disease; they would have become convinced, that
as a medicinal action antagonistic to the symptoms of the disease (an antipathically employed medicine) is
followed by only transient relief, and after that is passed, by invariable aggravation, the converse of that
procedure, the homoeopathic employment of medicines according to similarity of symptoms, must effect a
permanent and perfect cure […]”. (Organon, paragraph 61)
After observing the iatrogenic effects of discontinuation of ASA in coronary patients [25], Emile Ferrari said
that “aspirin therapy cannot be safely stopped in any case, but especially in patients with a history of
coronary disease”, and emphasized that this evidence “serves as a reminder for all medical professionals who
treat coronary patients that aspirin withdrawal should not be advised, and that alternative recommendations
should be considered” [38]. In the same interview, Richard Irwin, president of The American College of Chest
Physicians, concluded that “this study not only reinforces the importance of compliance with aspirin therapy
in coronary patients, but it sends a message to all medical professionals that the decision to discontinue
aspirin therapy should not be taken lightly”. Analogously, McColl and Gillen [228] pointed to “evidence that
proton-pump inhibitor therapy induces the symptoms it is used to treat”, signaling that the fact that PPI
“induce symptoms means that such liberal prescribing is likely to be creating the disease the drugs are
designed to treat and causing patients with no previous need for such therapy to require intermittent or long-
term treatment”.
In addition to confirming the principle of similitude as a ‘natural law’, the continual contemporary reports of
increased iatrogenic events after withdrawal of modern palliative drugs demonstrate the importance of the
rebound phenomenon (homeopathic vital reaction) in promoting deep alterations of the organic balance.
Conversely, by using the rebound effect to achieve cures, homeopathy stimulates the organism to react
against disease.
Based on pure observation, Hahnemann went beyond the scientific thought of his time, and draw guidelines
for the treatment of diseases that remain effective even in the present time, although they are dismissed by
mainstream medicine:
“These incontrovertible truths, which spontaneously offer themselves to our notice in nature and experience,
explain to us the beneficial action that takes place under homeopathic treatment; whilst, on the other hand,
they demonstrate the perversity of the antipathetic and palliative treatment of diseases with antagonistically
acting medicines”. (Organon, paragraph 67)
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Efeito rebote das drogas: riscos fatais do tratamento convencional e bases
farmacológicas do tratamento homeopático
RESUMO
O modelo homeopático aplica a ação secundária ou reação vital do organismo como método
terapêutico. Assim, propõe o tratamento por semelhança, que consiste em administrar aos
doentes substâncias que produzem sintomas similares em pessoas sadias. A reação vital,
homeostática ou paradoxal do organismo pode ser explicada cientificamente com base no efeito
rebote das drogas modernas. Este pode produzir eventos iatrogênicos fatais depois da suspensão
do tratamento antipático (ou enantiopático, termo utilizado em medicina alternativa para se
referir ao tratamento paliativo). Embora o efeito rebote é abordado pela farmacologia moderna, é
pouco difundido e discutido pelos profissionais da saúde que, assim, são privados de informação
necessária para o manejo seguro das drogas modernas. Este artigo apresenta uma revisão
atualizada do efeito rebote das drogas modernas e que também embasa o princípio homeopático
da cura. Apontado por Hahnemann mais de dois séculos atrás, o efeito rebote das drogas
paliativas modernas pode causar efeitos adversos fatais, como ilustram os exemplos do ácido
salicílico, anti-inflamatórios, broncodilatadores, antidepressivos, estatinas, inibidores da bomba
de prótons, etc. Embora o efeito rebote seja expressado por uma pequena parte de indivíduos
(suscetíveis) e possa ser evitando através da retirada gradual das drogas antipáticas, atinge
importância epidemiológica devido ao uso maciço dessas drogas e do desconhecimento a seu
respeito.
Palavras-chave: Homeopatia; Lei de semelhança; Ação farmacodinâmica dos medicamentos
homeopáticos; Efeito secundário; Efeito rebote; Reação paradoxal; Doença iatrogênica.

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Efecto rebote de drogas: riesgos fatales del tratamiento convencional y bases
farmacológicas del tratamiento homeopático
RESUMEN
El modelo homeopático aplica la acción secundaria o vital del organismo como método terapéutico.
De este modo, propone el tratamiento por semejanza, que consiste en administrar al enfermo
sustancias que producen síntomas similares en personas sanas. La reacción vital, homeostática o
paradojal del organismo puede ser explicada científicamente sobre la base del efecto rebote de las
drogas modernas. Éste puede producir eventos iatrogénicos fatales después de la suspensión del
tratamiento antipático (o enantiopático, término utilizado en medicina alternativa para referirse
al tratamiento paliativo). Aunque el efecto rebote es abordado por la farmacología moderna está
poco difundido y es poco discutido por los profesionales en salud que, por lo tanto, carecen de
información necesaria para manejar drogas modernas con seguridad. Este artículo presenta una
revisión actualizada del efecto rebote de las drogas modernas, que también constituye la base del
principio homeopático de curación. Señalado por Hahnemann hace más de dos siglos, el efecto
rebote de las drogas paliativas modernas puede causar efectos adversos fatales, como ilustran los
ejemplos del ácido salicílico, anti-inflamatorios, broncodilatadores, antidepresivos, estatinas,
inhibidores da bomba de protones, etc. Aunque sólo una pequeña parte de las personas
(susceptibles) presenta efecto rebote y éste puede ser evitando retirando gradualmente las drogas
antipáticas, llega a tener importancia epidemiológica por causa del uso masivo de estas drogas y
del desconocimiento de este efecto.
Palabras clave: Homeopatía; Ley de semejanza; Acción farmacodinámica delos medicamentos
homeopáticos; Efecto secundario; Efecto rebote; Reacción paradojal; Enfermedad iatrogénica.
Licensed to GIRI
Support: authors declare that this study received no funding
Conflict of interest: authors declare there is no conflict of interest
Received: 03 May 2012; Revised: 23 June 2012; Published: 30 June 2012.
Correspondence author: Marcus Zulian Teixeira, www.homeozulian.med.br
How to cite this article: Teixeira MZ. Rebound effect of drugs: fatal risk of the conventional treatment and
pharmacological basis of the homeopathic treatment. Int J High Dilution Res [online]. 2012 [cited YYYY Month dd];
11(39): 69-106. Available from: http://www.feg.unesp.br/~ojs/index.php/ijhdr/article/view/552/561