OBJETIVO: apoiado no aforismo hipocráticos primum no nocere, emprego princípio bioético da algum maleficência roga o que o açao médico reason o margari dano ou agravo à saúde são de paciente, incumbindo aos médico para avaliar os riscos de determinado terapêutica através meio do compreendendo dos possíveis eventos adversos a partir de drogas. Entre esses, o está feito rebote representa um efeito colateral comum a inúmeras aulas de fármacos modernos, podendo causa raiz transtornos túmulo e mortal nos pacientes. Esta revisão tem o objetivo de esclarecimento os profissionais da saúde sobre os aspecto clínicos e epidemiológicos dá fenômeno rebote. MÉTODOS: Uma revisão qualitativa, explorativo e bibliográfica adquirindo realizada na base de dados PubMed utilizando os unitermos "rebound", "withdrawal", "paradoxical", "acetylsalicylic acid", "anti-inflammatory", "bronchodilator", "antidepressant", "statin", "proton pump inhibitor" e "bisphosphonate" RESULTADOS: O está feito rebote ocorre após a descontinuação de inúmeras classes de fármacos alcançar ação contrária aos distúrbios da doença, exacerbando-os a níveis superior aos anteriores do tratamento. Independência ao vivo da doença,dadrogaedaduração dá tratamento, o fenômeno se manifesto numa junior proporção de individual suscetíveis. No entanto, pode causa eventos adversos túmulo e fatais, devido ser considerada um assuntos de saúde público em vista a partir de enorme consumo de fármacos pela população CONCLUSÃO: coletar um corpo de evidências crescendo e inquestionável, o médico precisa ter conhecimento das segue do é feito rebote e de como minimizá-lo, conseguir um aumento a garantia no manejo das drogas modernas. Através outro lado, este efeito rebote capaz utilizado de formato curativa, ampliando o espectro da terapêutica moderna.

Você está assistindo: Diferença entre efeito colateral e efeito adverso

Farmacologia; efeitos fisiológicos de drogas; está feito rebote; efeitos adversos; age dos semelhantes; Homeopatia

OBJECTIVE: sustained in a Hippocratic aphorism primum no nocere, ns bioethical rule of non-maleficence pray that ns medical action cause the least damage or injury to ns health of ns patient, leaving it to the doutor to assess ns risks of a particular therapy through expertise of feasible adverse occasions of drugs. Amongst these, the rebound impact represents a common página effect to numerous classes of contemporary drugs, may cause serious e fatal disorders in patients. This reveja aims come clarify the health experts on clinical e epidemiological aspects of rebound phenomenon. METHODS: der qualitative, exploratory e bibliographic análise was held in ns PubMed database using ns keywords "rebound", "withdrawal", "paradoxical", "acetylsalicylic acid", "anti-inflammatory", "bronchodilator", "antidepressant", "statin", "proton pump inhibitor" and "bisphosphonate". RESULTS: the rebound result occurs after discontinuation of numerous classe of drugs that act contradictory to the disease disorders, exacerbating them in ~ levels over those prior to treatment. Nevertheless of the disease, a drug e duration of treatment, the phenomenon manifests chin in der small relationship of susceptible individuals. However, the may reason serious e fatal adverse events should it is in considered a public health problem in view of ns enormous usage of medicine by population. CONCLUSION: bringing together der growing and unquestionable body of evidence, ns physician demands to have actually knowledge of the consequences of ns rebound effect e how to minimize it, raising safety in the management of modern-day drugs. On a other hand, this rebound have the right to be supplied in der curative way, broadening ns spectrum of ns modern therapeutics.

Pharmacology; Physiological effects of drugs; rebound effect; adverse effects; law of Similars; Homeopathy


Rebound effects of modern drugs: major adverse events unknown by health and wellness professionals*

Marcus Zulian Teixeira**

Discipline Fundamentals of Homeopathy, college of Medicine, universidade de são Paulo, elas Paulo, SP, Brazil


OBJECTIVE: supported in the Hippocratic aphorism primum no nocere, the bioethical principle of non-maleficence pray that the medical act cause a least esboço or injury to the health of ns patient, leaving it come the doutor to assess a risks of a particular therapy through knowledge of possible adverse occasions of drugs. Amongst these, ns rebound impact represents naquela common ao lado effect come numerous classes of contemporary drugs, may cause serious and fatal disorders in patients. This review aims to clarify ns health professionals on clinical e epidemiological elements of cant phenomenon.

METHODS: naquela qualitative, exploratory and bibliographic review was held in the PubMed database using ns keywords "rebound", "withdrawal", "paradoxical", "acetylsalicylic acid", "anti-inflammatory", "bronchodilator", "antidepressant", "statin", "proton pump inhibitor" e "bisphosphonate".

RESULTS: the rebound result occurs after ~ discontinuation that numerous aulas of drugs that act contradictory to a disease disorders, exacerbating them in ~ levels over those prior to treatment. Regardless of ns disease, a drug e duration of treatment, the phenomenon manifests chin in naquela small relationship of prone individuals. However, it may cause serious and fatal adverse events should be considered a public health trouble in panorama of the enormous intake of medicine by population.

CONCLUSION: happen together a growing e unquestionable corpo humano of evidence, the physician demands to have actually knowledge of a consequences of the rebound effect e how to minimization it, raising safety in the management of contemporary drugs. On a other hand, this rebound result can be supplied in naquela curative way, broadening ns spectrum of the modern therapeutics.

Keywords: Pharmacology; Physiological effects of drugs; cant effect; adverse effects; law of similars; Homeopathy


According come Webster"s novo World clinical Dictionary,1 "rebound" is defined as "the reversal of a response upon the withdrawal of naquela stimulus", if "rebound effect" is "the raised production of an adverse symptoms when the effect of a drug has passed or a patient no decorrer longer responds to ns drug. If naquela drug produces naquela rebound effect, the condition it was used come treat may return even much more strongly when the drug is stop or loser effectiveness". Likewise known as naquela "paradoxical reaction" of the organism, this phenomenon ironically makes people feel com greater strongness and/or frequency a same symptoms that were intended to disappear with ns use of drugs that exhibited actions opposite or contrary (enantiopathic) to ns disease symptoms e physiological manifestations.

Adverse event (AE) or disadvantage reaction (AR) is defined by the World health Organization2 (WHO) together "a response to naquela drug i beg your pardon is noxious e unintended, and which occurs at quantia normally used in man porque o the prophylaxis, diagnosis, or therapy of disease, or porque o the change of physiological function". Although a rebound impact is der type the AE com potentially severe or even fatal consequences, this impact is scarcely disseminated and discussed amongst health professionals, who are thus deprived of cardeal knowledge ao safe contemporary drug management.

Overall, the rebound impact (paradoxical reaction) is a result of ns organism"s automatic attempts to retorna to its basal state (homeostasis) after having been altered by the primary results of drugs. Because a characteristic of vida beings is their ability to maintain a constant internal atmosphere by self-adjusting physiological processes, homeostatic mechanisms ser estar present at all levels of biological organisation, from simple cell mechanisms to a most complex mental functions.

The system that underlies the occurrence of the rebound result is not yet completely elucidated. De acordo com to a main hypothesis said to account ao this effect, a cause might be an altered regulation and/or an answer capacity of the physiological receptors affiliated in a drug activity mechanisms. Experimental evidence has displayed that the rebound result occurs in ~ variable equipe intervals following the partial (e.g., dose change, receptor hypersensitivity, treatment initiation , tolerance etc.) or complete discontinuation of der drug, that ns intensity of a ensuing symptoms is better than the of a symptoms initially supressed by the drug, e that ns duration of activity varies.

We have actually conducted naquela systemic estude on drug rebound impacts during ns last years in order to establish the grounds of ns principle the therapeutic similitude (homeopathy) vis-à-vis modern-day pharmacology.3-12 This present updated reveja on the rebound effect intends to direct a attention of health experts to ns associated mechanisms, consequences, incidence, magnitude, and strategies come avoid the occurrence that this poorly well-known adverse occasion that could an outcome in severe after-effects to a users of several aulas of drugs, for this reason contributing to safer modern drug management.


To boost the body of evidence for and the knowledge of a rebound impact vis-à-vis clinical and experimental pharmacology, an exploratory e qualitative literature reveja was perform in a PubMed database (2002-2012), using a keywords "rebound", "withdrawal", "paradoxical", "acetylsalicylic acid", "anti-inflammatory", "bronchodilator", "antidepressant", "statin", "proton pump inhibitor", e "bisphosphonate". The articles to be selected based on their titles e abstracts, and the complete texts of those the addressed ns investigated subject were analysed, as were researches cited by these posts that were no detected by a initial survey. The studies considered most pertinent were included in ns present análise of a clinical e epidemiological attributes of the rebound effect.


a rebound result in contemporary pharmacology

Literature reviews13-15 have actually described conceptual distinctions, testimonial criteria, and scientific evidence ao the so-called "discontinuation or tap the money syndromes" of various modern-day drugs (anticoagulants, anticonvulsants, antipsychotics, barbiturates, benzodiazepines, cimetidine, clonidine, corticosteroids, opiates, propranolol, and antidepressants, among others). This "rebound syndrome" is distinguished from the "reappearance of ns underlying disease" the occurs in the absence the pharmacological medicine actions, as rebound syndrome appears after (partial or complete) drug discontinuation e leads to symptoms and/or physiological manifestations an ext intense than those prior to treatment. Notably, the full manifestation the this phenomenon wake up after a given duration of time that counts on a drugs" organic effects (time-point, or "half-life"). Therefore, gradual discontinuation of naquela drug is recommended to minimize this event.

The following instances illustrate a scope of a rebound impacts associated com various aulas of contemporary drugs.3-12 Drugs para which the primary action promotes renovations in angina pectoris (beta-blockers, calcium canal blockers, e nitrates, amongst others) can increase ns intensity and/or frequency that chest pain adhering to their discontinuation. Antihypertensive medicine (alpha-2 adrenergic agonists, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase (MAO) inhibitors, nitrates, sodium nitroprusside, e hydralazine, amongst others) might lead come rebound hypertension following the fim of your primary biological effects. Antiarrhythmic agents (adenosine, amiodarone, beta-blockers, calcium canal blockers, disopyramide, flecainide, lidocaine, mexiletine, moricizine, and procainamide, among others) could cause a rebound exacerbation that baseline ventricular arrhythmias. Antithrombotic drugs (argatroban, bezafibrate, heparin, salicylates, warfarin, and clopidogrel, among others) might promote thrombotic symptom as der result of a rebound effect. Agents with primary vasoprotective effects (statins) might elicit rebound vaso sanguíneo dysfunction the favours the occurrence the paradoxical embolism.

Similarly, the discontinuation that psychiatric medication, including anxiolytics (barbiturates, benzodiazepines, and carbamates, amongst others), hypnosedatives (barbitura tes, benzodiazepines, morphine, promethazine, and zopiclone, among others), quartel general nervous sistema stimulants (amphetamines, caffeine, cocaine, mazindol, and methyl phenidate, among others), antidepressants (tricyclic antidepres sants, MAO inhibitors, e serotonin reuptake inhibitors, amongst others), and antipsychotics (clozapine, phenothiazines, haloperidol, and pimozide, amongst others), could trigger a rebound aggravation of ns initial clinical condition. Anti-inflammatory agente (corticosteroids, ibuprofen, indomethacin, paracetamol, and salicylates, among others) can induce a rebound boost in inflammation, and also rebound thrombosis (ibuprofen, indomethacin, diclofenac, salicylates, rofecoxib, e celecoxib, amongst others) because of their platelet antiaggregant actions. Analgesics (caffeine, calcium canal blockers, clonidine, ergotamine, methysergide, opiates, e salicylates, amongst others) might cause rebound hyperalgesia. Diuretics (furosemide, torsemide, e triamterene, among others) might cause rebound sodium e potassium retention, com consequent boosts in a baseline blood volume. Bronchodilators (adrenergic agents, disodium cromoglycate, epinephrine, ipratropium, nedocromil, salmeterol, e formoterol, among others) might induce fag bronchoconstriction as der paradoxical reaction of a organism to treatment discontinuation. Antidyspeptic agentes (antacids, H2 receptor antagonists, misoprostol, sucralfate, and proton-pump inhibitors, among others) can increase hydrochloric acid e gastrin secretion as naquela rebound effect, thus aggravating the originais clinical condition. Agents used to treat osteoporosis (bisphosphonates) might favour ns occurrence that paradoxical patent fractures early to der rebound boost in osteoclast activity.

Therefore, as demonstrated in clinical e experimental pharmacology,3-12 ns rebound effect exhibits some privado features: (i) the manifests in at risk individuals; (ii) it is elevation of a type of drug supplied or a individual"s disease (symptoms); (iii) it appears following partial or complete drug discontinuation according to ns individual"s idiosyncrasy; (iv) it promotes naquela clinical state the opposite to ns drug"s primary action; (v) ns symptoms it induces ser estar more intense 보다 those before treatment; and (vi) ns effect size is proportional to ns primary impact of ns drug.

In addressing together phenomena, one increasing variety of studies have actually indicated a occurrence the "severe" and "fatal" adverse occasions that ~ ~ associated with a organism"s paradoxical reaction.

Rebound effect of platelet antiaggregant drugs

Acetylsalicylic acid

Acetylsalicylic acid (ASA) is der non-steroidal anti-inflammatory drug (NSAID) that belongs to the non-selective cyclooxygenase (COX) enzyme inhibitors; this enzymes catalyse ns conversion of arachidonic acid into prostaglandins (COX-2) or thromboxanes (COX-1). ASA is widely provided to stop thromboembolism because it inhibits a actions the COX-2 and platelet aggregation. Clinical e experimental studies have reported the occurrence of rebound thromboembolism following the discontinuation the ASA and other platelet antiaggregant drugs, which has actually led to transient ischaemic strikes (TIA), acute myocardial infarction (AMI), and stroke in susceptible individuals.5,6,16

To assess ns risks associated com ASA discontinuation, a meta-analysis17 that 50,279 people at hazard of coronary artery an illness (CAD) contrasted "adherence come ASA therapy" in CAD prevention and myocardial revascularisation to "ASA discontinuation" in the incidence the acute CAD and in ns implantation the drug-eluting stents. ASA non-adherence/withdrawal ser estar associated with a 3-fold higher risk of significant adverse cardiac occasions (odds proportion (OR) = 3.14; 95% confidence interval (95% CI) 1.75-5.61). An additional meta-analysis18 (49,590 individuals) proved that ASA withdrawal came before up come 10.2% of acute cardiovascular syndromes, com intervals the 4 come 8 dia in ns case of acute coronary syndromes, 11 come 14 days in a case the acute cerebral events, and 18 to 26 dia in ns case the peripheral arterial syndromes.

Compared to therapy maintenance, observational studies found der 3 or 4-fold greater risk that severe vascular events (AMI, TIA, and stroke) following ASA withdrawal,19-21 if 4% of together events developed soon (6 come 30 days) after a discontinuation of platelet antiaggregant drugs.22,23

As rebound platelet aggregation was observed after the discontinuation of todos classes the platelet antiaggregant drugs,24-26 both physicians e patients must understand ns appropriate monitoring of such agentes to reduce a risk the severe e fatal thromboembolic events.

Non-steroidal anti-inflammatory medicine

Similar to ASA, a occurrence of fag cardiovascular events era also observed following the discontinuation of all types that NSAIDs (selective and non-selective COX inhibitors). Confirming a results the clinical and experimental studies that demonstrated a occurrence of fag platelet aggregation after ~ partial or finish NSAID discontinuation,5,6,27,28 naquela systematic review29 the 1.6 million people found der correlation between the occurrence of cardiovascular events e early NSAID therapy ( 25 mg/day exhibited relative dangers (RR) that 1.33 (95% CI, 1.00-1.79) and 2.19 (95% CI 1.64-2.91), respectively; if diclofenac, meloxicam, e indomethacin exhibited RR the 1.40 (95% CI, 1.16-1.70), 1.25 (95% CI, 1.00-1.55), and 1.30 (95% CI, 1.07-1.60). One more meta-analysis30 that 145,373 people found naquela RR the 1.42 (95% CI, 1.13-1.78) ao rofecoxib and 1.63 (95% CI, 1.12-2.37) ao diclofenac.

A case-control study31 the investigated a correlation between NSAID use e the threat of hospitalization for AMI found o mesmo, semelhante results porque o rofecoxib (RR, 1.36; 95% CI, 1.18-1.58), diclofenac (RR, 1.40; 95% CI 1.19-1.65), meloxicam (RR, 1.24; 95% CI, 1.06-1.45), e indomethacin (RR, 1.36; 95% CI, 1.15-1.61). Another case-control study32 found der correlation between rofecoxib use and the o primeiro dia AMI occasion (RR, 1.67; 95% CI, 1.21-2.30). This events arisen at an mean of 9 (range, 6-13) mim after therapy initiation; additionally, ns risk remained high during the primeiro 7 days after rofecoxib discontinuation (RR, 1.23; 95% CI, 1.05-1.44) e returned come baseline levels between mim 8 e 30 (RR, 0.82; 95% CI, 0.61-1.09), i m sorry is characteristic of the rebound effect. A retrospective cohort aprender (1999-2001) that 1.4 million rofecoxib users33 discovered that 8,199 people (0.58%) suffered AMI while utilizing this drug, and thus this drug ser estar withdrawn em ~ the sector by the United states Food e Drug administration (FDA).

Recent studies have actually reported semelhante results, thus providing further proof of ns scope e causality of ns rebound result and novamente calling fist to this kind of serious AE.34,35

Rebound impacts of bronchodilators

Countless studies performed over the last decades confirmed clinical e experimental result indicating that "rebound bronchoconstriction", characterized by enhanced bronchial reactivity e asthma aggravation, might occur following a partial or complete discontinuation the short and long-acting bronchodilators.5,7,36

A significant randomised clinical attempt (26,355 participants) finished prematurely in 2002 after a preliminary evaluation pointed to der risk of death by asthma among individuals who were treated com salmeterol (long-acting beta-agonist (LABA)). A results, however, were somente published in 200637 and reported ns occurrence of respiratory-related deaths (RR, 2.16; 95% CI, 1.06-4.41), asthma-related deaths (RR, 4.37; 95% CI, 1.25-15.34), e combined asthma-related deaths or life-threatening experiences (RR, 1.71; 95% CI, 1.01-2.89).

A meta-analysis38 that 33,826 individuals with asthma who were making use of LABAs (salmeterol e formoterol) found boost in exacerbations that required hospitalization (OR, 2.6; 95% CI, 1.6-4.3), life-threatening experiences (OR, 2.1; 95% CI, 1.5-3.0), episodes of fatal asthma (OR, 1.8; 95% CI, 1.1-2.9), and asthma-related deaths (OR, 3.5; 95% CI, 1.3-9.3). A risk the hospitalization walk not mudança despite combine LABA com inhaled corticosteroids (OR, 2.1; 95% CI, 1.3-3.4), therefore pointing to a relevance of the rebound effect.

Also, current meta-analyses39,40 and a cohort study41 found semelhante results, suggesting that understanding about ns paradoxical (rebound) effect and strategies for safe drug usar should it is in mandatory.42,43

Rebound results of antidepressants

Some studies found boost in depressive symptoms following ns partial or complete discontinuation of antidepressants (including selective serotonin reuptake inhibitors (SSRIs)), and related this to naquela rebound reduction of intra-synaptic serotonin (5-hydoxytryptamine (5HT)) level due to der downregulation of the post-synaptic receptors. Called in ns literature together "serotonin reuptake inhibitor discontinuation syndrome", this syndrome go not depend on a length of treatment nor a type the disease e appears at change timepoints that count on ns half-life of each drug.5,8,44-46

Several studies carried out over a last decades have addressed increased suicidality (suicidal ideation, attempts, or behaviours) among antidepressant users. This severe adverse event could be meeting to a rebound effect,8 assuming ns half-lives of a drugs ~ ~ taken right into account once evaluating the phenomenon.47-49 naquela meta-analysis50 assessed ns correlation between antidepressant use e suicidality in 4,582 paediatric patients and found one RR the 1.66 (95% CI, 1.02-2.68) in randomized trials that SSRIs para depression treatment and an RR that 1.95 (95% CI, 1.28-2.98) for tudo de antidepressants across todos indications.

Other meta-analyses found semelhante results in adolescents51 e young adults,52 e 1 case-control study53 reported naquela significant threat of suicidality at a onset the treatment, after ~ discontinuation, and during durations of dose changes, hence addressing the caution required when regulating antidepressants.

Rebound impacts of cholesterol-lowering medicine (statins)

In enhancement to reduce cholesterol biosynthesis, statins exhibition "pleiotropic" or "vasoprotective" impacts that command to improved endothelial duty (increased nitric oxide bioavailability, inhibition the inflammation and thrombogenic responses, immunomodulatory actions, regulation of progenitor cells, and stabilization that atherosclerotic plaques). Along with naquela rebound boost in cholesterol production, experimental e clinical studies imply that statin discontinuation induces naquela rebound destruction of endothelial duty (pro-oxidant, pro-inflammatory, e pro-thrombotic state), thus maximizing ns vascular risk.9,54

Interventional55,56 e observational57-63 research studies have presented that statin discontinuation (rebound effect) is associated with naquela significant increase in a risk of fatality (due come fatal vascular events), contrasted to maintenance and no treatment. A recent retrospective analysis64 of encontro from 12,689 patients with ischaemic stroke verified that statin discontinuation at hospital admission foi ~ associated with der significantly higher risk of fatality (RR, 2.5; 95% CI, 2.1-2.9) compared to treatment maintenance.

Given the increasing proof on a rebound impacts of statins, both doctors and patients must be made aware of a risks inherent to discontinuation or withdrawal.

Rebound impacts of gastric mountain suppressants

All varieties of gastric acid suppressants (antacids, H2 receptor inhibitors, and proton-pump inhibitors (PPIs)) induce rebound acid hypersecretion. Also, hypergastrinaemia has actually been discovered to take place as a secondary effect of permanent treatment. The rebound result manifests at a given timepoint ~ discontinuation as naquela function of ns half-life of each particular drug.10,65,66

Clinical proof of rebound acid hypersecretion adhering to PPI discontinuation ser estar found in current interventional studies,67-70 in which that affected an ext than 30% that users.71

Because gastrin exerts trophic action on several tissues, hypergastrinaemia can be associated with ns development of advanced neoplasia in Barrett"s oesophagus,72 and also of carcinoid tumours in Zollinger-Ellison syndrome e atrophic gastritis.73 naquela cohort study74 found der direct correlation between ns increased incidence that gastric cancer e PPI use, thus arguing that cant hypergastrinaemia might represent naquela risk fator for the development that gastric cancer following extreme PPI use. Similarly, the increased incidence that gastric carcinoid tumours over ns past 3 decades (400% among males and 900% among females) might also be linked with ns indiscriminate usar of PPIs.75

Although gratuitamente PPI usar is recommended in protocols para dyspepsia treatment,76 health professionals ought to weigh their family member risks e benefits.

Rebound results of antiresorptive medicine (bisphosphonates)

Bisphosphonates (BPs) promote increased bone água com gás density (BMD) by inhibiting bone resorption through naquela reduction in osteoclast activity e thus represent the most widely used technique to reduce ns risk of osteoporosis-related fractures. The biological effects (half-life) that BPs remain grande after discontinuation as der function of their retention in a bone matrix. Back BPs são de reduce the incidence of the "typical" fractures associated com osteoporosis, a occurrence that "atypical" subtrochanteric and diaphyseal perna fractures has been newly reported in individuals who usar BPs. A "rebound osteoclast activity" is thought to be ns most most likely systemic pathogenic system underlying such fractures, together these take place independently são de trauma and exhibit big radiological and clinical alterations, too as far-reaching morbidity.12,77,78

A situation series79 and observational studies80-84 found an association between BP use over variable durations of equipe (3-60 months) and the occurrence of atypical fractures; a putative correlation com cumulative drug use was rule out, as was a hypothesis that said hypermineralization (osteopetrosis) com microdamage build-up as a pathogenic mechanism.79,85 Additionally, experimental studies77,86,87 indicate a occurrence the paradoxical osteoclast task following BP discontinuation ("biphasic anti-osteoclastic action"), com rebound increases in mite of bone remodelling, eroded areas, e numbers of active osteoclasts. Also, various other antiresorptive medicine (hormone treatments e monoclonal antibodies) were shown to induce similar effects.77

Although a incidence of common hip fractures has diminished since a introduction of BPs, ns incidence of patent femur fractures has increased,88 therefore indicating ns need ao caution when controlling such drugs.


The fag effect, naquela universal e automatic essential mecha nism come maintain der constant internal setting or homeostasis, is liable to be elicited by all types of enantiopathic drugs. As a function of a drugs" magnitude, together paradoxical reactions can induce severe e eventually fatal adverse events. Although a rebound effect só manifests in der very small portion of individuals, it becomes an epidemiological issue when considering ns exceedingly broad usar of pharmacological therapies by ns population.

The time interval in between drug discontinuation e rebound effect appearance was similar among drugs com short half-lives, with an mean of 10 dia for ASA, 14 mim for NSAIDs, 9 dia for rofecoxib, 7 come 14 days for SSRIs, 7 dia for statins, e 7 come 14 days for PIPs. The rebound result lasted approximately 30 dia for rofecoxib, 21 mim for SSRIs, and 30 dia for PIPs. Ns length of treatment before discontinuation did no correlate with ns risk of paradoxical events.

Similar to estimates porque o other drugs, LABAs cause one case of deadly rebound bronchospasm every 1,000 patient-years of use,38 corresponding to 4,000-5,000 deaths in 2004 in a United claims alone, and 40,000-50,000 deaths worldwide.7 SSRIs reason 5 fag suicidal manifestations every 1,000 patient-years of usar among adolescents, equivalent to 16,500 situations of suicidal ideation or behaviours in 2007 in the United states alone.8 BPs cause 1 to 3 illustration of paradoxical patent fractures every 1,000 patient-years of use.12

The literature likewise addresses the risk of rebound result inherent to ns novel agents used in biological therapy,89-91 as well as ns excessive usar of analgesics92 e psychotropic drugs.93,94

Upon learning ns preliminary results95 of der study23 the described a risks associated com ASA discontinuation, richard S. Irwin, then president of the american College the Chest Physicians, observed that "this study does not only reinforce a importance of compliance com aspirin treatment in coronary patients, yet it sends naquela message to all medical specialists that the decision come discontinue aspirin therapy should not it is in taken lightly". Similarly, McColl e Gillen96 address the fact that the rebound induction of symptoms by PPIs "means that such gratuitamente prescribing is likely to it is in creating the disease a drugs estão designed come treat, bring about patients with enquanto previous need for such treatment to need intermittent or irreversible treatment". Similar warnings have also been made concerning many of ns above-mentioned drugs mentioned, hence indicating ns relevance of a ability of a rebound impact to induce deep alterations come organic homeostasis.

Valuing the rebound phenomenon as naquela public health problem, recent studies have actually addressed ns risks connected with ns discontinuation that analgesics97,98 e psychotropic drugs,46,93,94 which are particularly relevant, given a widespread use of together pharmacological agents. Therefore, that is worth noting the probable incident of the immune reconstitution inflammatory syndrome (IRIS) following ns discontinuation that natalizumab, a monoclonal antibody provided as a biological therapy porque o multiple sclerosis, consequent to ns rebound exacerbation of disease activity.99-102 the advancement represented by organic therapy notwith standing, discontinued usar of immunomodulatory agentes is also associated with der high frequency the paradoxical reaction in people receiving cancer treatment.103,104

For ns notions described here - which, although orthodox, vigorously oppose the therapeutic version - come be extensively assimilated, we imply as naquela pedagogic proposal to include matching evidence once teaching physiology and pharmacology during courses para health professionals, and during discussions that clinical cases e the follow-up of patients who estão assisted at hospitals, outpatient clinics, or in ~ home.

Professionals at all levels of the healthcare sistema should be systematically mindful of e properly oriented to ns intrinsic dangers associated with a random and abrupt withdrawal of medicine so the they can duly advise their patients and establish programmes for drug tapering, while very closely monitoring ns subsequent effects.

Regarding clinical research, the studies defined in ns present reveja might be reproduced in ours milieu e thus quantify ns incidence of a rebound effect, a magnitude of its connected risks, e the effectiveness of preventative measures. Additionally, der multiplication of a number of reported examples will facilitate a admission of a existence of ns rebound effect by health and wellness professionals.


A big number the severe e potentially fatal AE might be avoided if health specialists were oriented come recognize ns occurrence the paradoxical reactions following ns discontinuation that drugs the exert opposite actions to disease manifestations, therefore minimizing a occurrence the rebound disease aggravation by reducing bondade gradually e slowly or through restarting the drug. Return these are not traditionally taken into consideration adverse events, "drug discontinuation effects ~ ~ part of the pharmacology of naquela drug",15 and thus must be had when teaching modern pharmacology.

In naquela manner analogous to ns homeopathic design of therapy that employs medicine that reason changes and symptoms similar to those displayed by a ill distinguível (principle of therapeutic similitude) porque o more than 2 centuries, der novel therapeutic strategy known as "paradoxical pharmacology" is arising within modern-day conventional pharmacology. According to that approach, "exacerbating der disease could make use of ns organism"s compensatory and redundant mechanisms to achieve der beneficial long-term response"105-109 (use of a bidirectional or biphasic effect).

Paradoxical pharmacology is conventionally linked with ns use the beta-blockers (beta-adrenoceptor antagonists) e calcium channel blockers in congestive heart failure to boost ventricular contractility and reducing mortality110,111; beta-blockers para chronic asthma treatment to induce bronchodilation e reduce airway inflammation112; thiazides ao diabetes insipidus therapy to reduce polyuria e increase to pee osmolality due to their paradoxical antidiuretic effects113; arsenic trioxide (As2O3), naquela significant carcinogenic revendedor autorizado that has displayed promise as naquela cancer treatment114,115 (e.g., acute promyelocytic leukaemia); oral contraceptives to induce ovulation (and for this reason pregnancy) in women with functional sterility116; centrais nervous sistema stimulants (amphetamine, methylphenidate, e pemoline, amongst others) porque o hyperactivity, given a biphasic effects of this drugs,117 amongst other examples. Notably, the doses required come elicit ns secondary e curative (paradoxical, rebound, or biphasic) impacts of this drugs ~ ~ much lower than those usually provided to induce their primary effects (avoiding the worsening of ns disease).

In an attempt to ponte the gap between disparate rationalities and to broaden the scope of ns therapeutic by similars, during ns last decade we arisen systematics porque o the clinical applications of a rebound curative effects of 1,250 modern drugs.118-122 segue to this procedure, also ill individuals ~ ~ prescribed drugs that reason adverse events semelhante to your disturbances (totality that symptoms) in an attempt to induce naquela paradoxical reaction of the organism against its showed disorders (http://www. Newhomeopathicmedicines.com).

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While keeping in mind a bioethical principles of "beneficence" and "non-maleficence", physicians have to have the conviction and sufficient technical information to ensure that their plot will benefit patients e cause them ns least feasible harm, according to a Hippocratic aphorism primum no nocere. The present análise aims to straight our skilled colleagues" fist to a occurrence of a rebound effect, namely a severe, albeit unknown adverse occasion of modern-day therapeutics, ao the services of naquela safer e less iatrogenic clinical practice.