Extension de temps QT
Effets indésirables des médicaments
Variantes ✨Pour l'évaluation intensive en calcul des variantes, veuillez choisir l'abonnement standard payant.
Explications pour les patients
Nous n'avons aucun avertissement supplémentaire pour l'association de tramadol et de cimétidine. Veuillez également consulter les informations spécialisées pertinentes.
|Tramadol||1.18 [0.69,3.86] 1,2||1.18|
Les changements d'exposition mentionnés sont liés aux changements de la courbe concentration plasmatique en fonction du temps [ASC]. L'exposition à la tramadol augmente à 118%, lorsqu'il est combiné avec la cimétidine (118%). L'ASC est comprise entre 69% et 386% selon le
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La tramadol a une biodisponibilité orale moyenne [ F ] de 66%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est assez courte à 4.5 heures et des taux plasmatiques constants [ Css ] sont atteints rapidement. La liaison aux protéines [ Pb ] est très faible à 20% et le volume de distribution [ Vd ] est très important à 238 litres. Étant donné que la substance a un faible taux d'extraction hépatique de 0,9, le déplacement de la liaison aux protéines [Pb] dans le contexte d'une interaction peut augmenter l'exposition. Environ 30.0% d'une dose administrée est excrétée inchangée par les reins et cette proportion est rarement modifiée par les interactions. Le métabolisme a lieu via le CYP2B6, CYP2D6 et le CYP3A4, entre autres et le transport actif se fait notamment via UGT1A1.
La cimétidine a une biodisponibilité orale moyenne [ F ] de 65%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est assez courte à 1.6333333 heures et des taux plasmatiques constants [ Css ] sont atteints rapidement. La liaison aux protéines [ Pb ] est très faible à 19% et le volume de distribution [ Vd ] est très important à 91 litres. Le métabolisme ne se fait pas via les cytochromes communs et le transport actif s'effectue en partie via BCRP et PGP.
|Les scores||∑ Points||tra||cim|
|Effets sérotoninergiques a||2||++||Ø|
Recommandation: Par mesure de précaution, les symptômes de surstimulation sérotoninergique doivent être pris en compte, notamment après augmentation de la dose et à des doses dans la plage thérapeutique supérieure.
Évaluation: La tramadol module le système sérotoninergique dans une mesure modérée. Le risque de syndrome sérotoninergique peut être classé comme faible avec ce médicament si la posologie se situe dans la plage habituelle. Selon nos connaissances, la cimétidine n'augmente pas l'activité sérotoninergique.
|Les scores||∑ Points||tra||cim|
|Kiesel & Durán b||2||+||+|
Recommandation: Par mesure de précaution, une attention particulière doit être portée aux symptômes anticholinergiques, en particulier après augmentation de la dose et à des doses dans l'intervalle thérapeutique supérieur.
Évaluation: La tramadol et la cimétidine n'ont qu'un effet léger sur le système anticholinergique. Le risque de syndrome anticholinergique avec ce médicament est plutôt faible si la posologie se situe dans la plage habituelle.
Extension de temps QT
|Les scores||∑ Points||tra||cim|
Évaluation: En association, la tramadol et la cimétidine peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||tra||cim|
|La nausée||26.5 %||26.5||n.a.|
|Sensation de chaleur et de bouffées vasomotrices||11.8 %||11.8||n.a.|
Gynécomastie (4%): cimétidine
Mal de crâne: tramadol
Crise d'épilepsie: tramadol
Pancréatite: cimétidine, tramadol
Réaction d'hypersensibilité: tramadol
Dépression respiratoire: tramadol
Sur la base de vos
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: (+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: No Abstract available
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.
Abstract: No Abstract available
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN: Prospective cohort study. SETTING: A Department of Veterans Affairs primary care clinic. PARTICIPANTS: Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS: The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS: Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION: Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
Abstract: WHAT IS ALREADY KNOWN: During recent years some opioids have been associated with prolonged QT and torsade de pointes (TdP). In vitro testing has shown that most opioids can block the cardiac potassium channels. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. WHAT THIS PAPER ADDS: This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293. Neither morphine nor tramadol doses are associated with the QT interval length. AIMS: During recent years some opioids have been associated with prolonged QT interval and torsade de pointes (TdP). In vitro patch clamp testing has shown that most opioids can block human ether-a-go-go related gene (hERG) channels that are known to underlie cardiac repolarizing I(Kr) current. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro. METHODS: One hundred chronic nonmalignant pain patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross-sectional study. The QTc was estimated from a 12-lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing hERG channels. RESULTS: There were no differences in gender distribution or age between the treatment groups. The known association between methadone dose and QTc was confirmed (R(2) = 0.09; P = 0.02). Higher oxycodone dose was also associated with longer QTc (R(2) = 0.21; P = 0.02). A 100 mg higher oxycodone dose was associated with a 10 ms(1/2) (95% CI 2-19) longer QTc. Neither morphine nor tramadol dose was associated with the QTc. Electrophysiological testing revealed low-affinity inhibition of the potassium current through hERG channels expressed in HEK293 cells (IC(50) = 171 microM oxycodone). CONCLUSIONS: Among patients treated with methadone or oxycodone, higher doses were associated with longer QTc. Oxycodone is capable of inhibiting hERG channels in vitro.
Abstract: No Abstract available
Abstract: PURPOSE: We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. METHODS: In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. RESULTS: Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-∞) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0-∞ of M1 to that of tramadol, but did not influence the AUC0-∞ of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. CONCLUSIONS: Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.
Abstract: PURPOSE: Tramadol is mainly metabolized by the cytochrome P450 (CYP) 2D6, CYP2B6 and CYP3A4 enzymes. The aim of this study was to evaluate the effect of enzyme induction with rifampicin on the pharmacokinetics and pharmacodynamics of oral and intravenous tramadol. METHODS: This was a randomized placebo-controlled crossover study design with 12 healthy subjects. After pretreatment for 5 days with rifampicin (600 mg once daily) or placebo, subjects were given tramadol either 50 mg intravenously or 100 mg orally. Plasma concentrations of tramadol and its active main metabolite O-desmethyltramadol (M1) were determined over 48 h. Analgesic and behavioral effects and whole blood 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured. RESULTS: Rifampicin reduced the mean area under the time-concentration curve (AUC0-∞) of intravenously administered tramadol by 43 % and that of M1 by 58 % (P < 0.001); it reduced the AUC0-∞ of oral tramadol by 59 % and that of M1 by 54 % (P < 0.001). Rifampicin increased the clearance of intravenous tramadol by 67 % (P < 0.001). Bioavailability of oral tramadol was reduced by rifampicin from 66 to 49 % (P = 0.002). The pharmacological effects of tramadol or whole blood serotonin concentrations were not influenced by pretreatment with rifampicin. CONCLUSIONS: Rifampicin markedly decreased the exposure to tramadol and M1 after both oral and intravenous administration. Therefore, rifampicin and other potent enzyme inducers may have a clinically important interaction with tramadol regardless of the route of its administration.
Abstract: BACKGROUND AND OBJECTIVE: Tramadol hydrochloride is used worldwide as an analgesic drug with a unique dual function. The metabolic enzymes cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6 and the various transporters [adenosine triphosphate-binding cassette B1/multidrug resistance 1/P-glycoprotein, organic cation transporter 1, serotonin transporter (SERT), norepinephrine transporter (NET)] and receptor genes (opioid receptor μ 1 gene) give possible genetic differences that might affect the pharmacokinetics and/or pharmacodynamics of tramadol. Therefore, the aim of this review is to present a systematic walkthrough of all possible genetic factors involved in the pharmacology of tramadol. METHOD: A systematic literature search was conducted in PubMed and EMBASE involving all metabolic enzymes, drug transporters and receptors, as well as SERT and NET that are involved in the pharmacokinetics and pharmacodynamics of tramadol. An additional search on population pharmacokinetics with genetic factors as covariates was performed separately. RESULTS: A total of 56 studies (45 cohort and case-control studies, three case reports, six in vitro studies, and two animal studies) were included. CONCLUSION: In this systematic review, the current knowledge on all possible genetic factors that might influence the metabolism or clinical efficacy of tramadol has been collected and summarized. Only the effect of CYP2D6 polymorphisms on the metabolism of tramadol and the consequent effect on pain relief has been thoroughly studied and sufficiently established as clinically relevant.
Abstract: UNLABELLED: In recent years, several cases of torsade de pointes have been associated with many opioids. However, to present no cases have been reported with tramadol. OBJECTIVE: To evaluate the effect of tramadol on QT-interval in the clinical setting. RESEARCH DESIGN AND METHODS: Medical history and comorbidities predisposing to QT interval prolongation were registered for patients requiring medical assistance that involved tramadol administration. Ionograms and ECGs were performed at baseline and intratreatment; QT interval was analyzed after correction with Bazzet, Fridericia, Framinghan and Hogdes formula. RESULTS: 115 patients were studied (50.4% males) All patients had received tramadol 150-400 mg/day during 3.0-5.0 days at the moment of intratreatment control. Plasma concentrations of tramadol were 201-1613 ng/mL. Intratreatment electrocardiographic control, as mean ± SD (range), showed QTcB 372±32 (305 to 433), QTcFri 356±37 (281 to 429), QTcFra 363±33 (299 to 429), QTcH 362±30 (304 to 427), ΔQTcB 26±40 (-73 to 110), ΔQTcFri 24±48 (-97 to 121), ΔQTcFra 22±42 (-81 to 109) and .QTcH 22±38 (-68 to 110) ms. QTc interval presents high correlation with plasma tramadol concentrations (for .QTc, R>0.77). Renal failure was associated with a relative risk for ΔQTc > 30 ms of 1.90 (IC95% 1.31-2.74) and for ΔQTc > 60 ms of 4.74 (IC95% 2.57-8.74). No patient had evidence of arrhythmia during the present study. CONCLUSION: Tramadol produces QTc interval prolongation in good correlation with plasma drug concentrations; renal failure is a risk factor for higher concentration and QT prolongation by tramadol.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18-55 years) in a randomized, phase I, double-blind, placebo- and positive-controlled, multiple-dose, 4-way crossover study. Participants were randomized to receive 1 of 4 treatments (A-D), 1 each in 4 treatment periods (1-4), separated by a washout period (7-15 days). Treatment A comprised tramadol 400 mg (therapeutic dose) on days 1 through 3, tramadol 100 mg and moxifloxacin-matched placebo on day 4, and placebo on all 4 days. Treatment B comprised tramadol 600 mg (supratherapeutic dose) on days 1 through 3, and tramadol 150 mg and moxifloxacin-matched placebo on day 4. Treatment C comprised placebo on days 1 through 4 and moxifloxacin-matched placebo on day 4. Treatment D comprised placebo on days 1 through 4 and moxifloxacin 400 mg on day 4. Of 68 participants enrolled, 57 (83.8%) completed the study. Both therapeutic and supratherapeutic doses of tramadol were shown to be noninferior to placebo regarding their effect on QTc prolongation. Sixty-one of 68 (89.7%) participants reported at least 1 treatment-emergent adverse event (mild); nausea was the most frequently reported treatment-emergent adverse event. Summarizing, tramadol at doses up to 600 mg/day did not cause clinically relevant QTc interval prolongation in healthy adults.
Abstract: In pediatric PBPK models, age-related changes in the body are known to occur. Given the sparsity of and the variability associated with relevant physiological parameters, different PBPK software providers may vary in their system's data. In this work, three commercially available PBPK software packages (PK-Sim®, Simcyp®, and Gastroplus®) were investigated regarding their differences in system-related information, possibly affecting clearance prediction. Three retrograde PBPK clearance models were set up to enable prediction of pediatric tramadol clearance. These models were qualified in terms of total, CYP2D6, and renal clearance in adults. Tramadol pediatric clearance predictions from PBPK were compared with a pooled popPK model covering clearance ranging from neonates to adults. Fold prediction errors were used to evaluate the results. Marked differences in liver clearance prediction between PBPK models were observed. In general, the prediction bias of total clearance was greatest at the youngest population and decreased with age. Regarding CYP2D6 and renal clearance, important differences exist between PBPK software tools. Interestingly, the PBPK model with the shortest CYP2D6 maturation half-life (PK-Sim) agreed best with the in vivo CYP2D6 maturation model. Marked differences in physiological data explain the observed differences in hepatic clearance prediction in early life between the various PBPK software providers tested. Consensus on the most suited pediatric data to use should harmonize and optimize pediatric clearance predictions. Moreover, the combination of bottom-up and top-down approaches, using a convenient probe substrate, has the potential to update system-related parameters in order to better represent pediatric physiology.
Abstract: OBJECTIVE: To determine the risk of prolonged opioid use in patients receiving tramadol compared with other short acting opioids. DESIGN: Observational study of administrative claims data. SETTING: United States commercial and Medicare Advantage insurance claims (OptumLabs Data Warehouse) January 1, 2009 through June 30, 2018. PARTICIPANTS: Opioid-naive patients undergoing elective surgery. MAIN OUTCOME MEASURE: Risk of persistent opioid use after discharge for patients treated with tramadol alone compared with other short acting opioids, using three commonly used definitions of prolonged opioid use from the literature: additional opioid use (defined as at least one opioid fill 90-180 days after surgery); persistent opioid use (any span of opioid use starting in the 180 days after surgery and lasting ≥90 days); and CONSORT definition (an opioid use episode starting in the 180 days after surgery that spans ≥90 days and includes either ≥10 opioid fills or ≥120 days' supply of opioids). RESULTS: Of 444 764 patients who met the inclusion criteria, 357 884 filled a discharge prescription for one or more opioids associated with one of 20 included operations. The most commonly prescribed post-surgery opioid was hydrocodone (53.0% of those filling a single opioid), followed by short acting oxycodone (37.5%) and tramadol (4.0%). The unadjusted risk of prolonged opioid use after surgery was 7.1% (n=31 431) with additional opioid use, 1.0% (n=4457) with persistent opioid use, and 0.5% (n=2027) meeting the CONSORT definition. Receipt of tramadol alone was associated with a 6% increase in the risk of additional opioid use relative to people receiving other short acting opioids (incidence rate ratio 95% confidence interval 1.00 to 1.13; risk difference 0.5 percentage points; P=0.049), 47% increase in the adjusted risk of persistent opioid use (1.25 to 1.69; 0.5 percentage points; P<0.001), and 41% increase in the adjusted risk of a CONSORT chronic opioid use episode (1.08 to 1.75; 0.2 percentage points; P=0.013). CONCLUSIONS: People receiving tramadol alone after surgery had similar to somewhat higher risks of prolonged opioid use compared with those receiving other short acting opioids. Federal governing bodies should consider reclassifying tramadol, and providers should use as much caution when prescribing tramadol in the setting of acute pain as for other short acting opioids.
Abstract: Genetic variants in the hepatic uptake transporter OCT1, observed in 9% of Europeans and white Americans, are known to affect pharmacokinetics and efficacy of tramadol, morphine, and codeine. Here, we report further opioids to be substrates and inhibitors of OCT1. Methylnaltrexone, hydromorphone, oxymorphone, and meptazinol were identified as OCT1 substrates. Methylnaltrexone is the strongest OCT1 substrate currently reported. It showed 86-fold higher accumulation in OCT1-overexpressing cells compared to control cells. We observed substantial differences in the inhibitory potency among structurally highly similar morphinan opioids (ICranged from 6.4 μM for dextrorphan to 2 mM for oxycodone). The ether linkage of C4-C5 in the morphinan ring leads to a strong reduction of inhibitory potency. In conclusion, although polyspecific, OCT1 possesses a strong selectivity for its ligands. In contrast to methylnaltrexone and hydromorphone, oxycodone and hydrocodone do not interact with OCT1 and may be safer for use in individuals with genetic OCT1 deficiency.