Tramadol Concentrations Research Articles

Tramadol inhibits the contractility of isolated human myometrium

This study was conducted to determine whether the atypical opioid analgesic tramadol inhibits the contractility of isolated non-pregnant human myometrium. Ten strips of non-pregnant human myometrium stimulated with 55mm potassium chloride (KCl) were treated with three concentrations (30, 100 and 300μm) of tramadol to test for any inhibitory effect of tramadol. The effects of concurrent administration of the ß adrenoceptor antagonist propranolol (1μm), the guanylyl cyclase and nitric oxide synthase inhibitor methylene blue (20μm) and the opioid receptor antagonist naloxone (100μm) with tramadol were also studied. Tramadol caused a concentration-dependent inhibition of KCl-induced myometrial contractility, which was statistically significant at all three concentrations of tramadol used. Propranolol significantly reversed the inhibitory effect of 100μm tramadol on KCl-induced myometrial contractility but not that of 300μm tramadol. Neither methylene blue nor naloxone reversed the inhibitory effect of tramadol on KCl-induced myometrial contractility. These results suggest that tramadol inhibits KCl-induced contractility of isolated human myometrium. They also suggest that tramadol relaxes the myometrium due to stimulation of ß1 adrenoceptors. However, the concentrations of tramadol required to relax the myometrium were high and likely to be attained at toxic doses, rather than therapeutic doses, of tramadol.

Electrospun Nanofibers of Poly(methylmethacrylate)/Polystyrene Blend as a Microcolumn Extraction Sorbent Followed by Corona Discharge Ion Mobility Spectrometry for Analysis of Tramadol in Biological Fluids

Electrospun nanofibers from poly(methylmethacrylate) (PMMA) and polystyrene (PS) blend were used as a sorbent to extract tramadol from urine and plasma samples. Then, the tramadol concentration was determined by corona discharge ion mobility spectrometry. The hydrophilic (PMMA) and hydrophobic (PS) properties of the blend polymer improved extraction efficiency of the analyte. The scanning electron microscopy images of the PMMA/PS nanofibers showed a diameter range of 130–600 nm with a smooth morphology. Parameters affecting extraction efficiency were optimized and under the optimized conditions, the dynamic ranges and detection limit of tramadol were found to be 30–500 and 10–200 ng mL−1, and 9.4 and 1.6 ng mL−1 in plasma and urine samples, respectively.

Effects of a Single Bolus Intravenous Dose of Tramadol on Minimum Alveolar Concentration (MAC) of Sevoflurane in Dogs

Tramadol is an atypical opioid analgesic widely used in small animal practice. This study was designed to determine the effect of a single intravenous (IV) dose of tramadol on the minimum alveolar concentration (MAC) of sevoflurane in dogs. Six beagle dogs were anesthetized twice to determine the sevoflurane MAC with or without an administration of tramadol (4 mg/kg, IV) at 7 days interval. The sevoflurane MAC was determined using a tail clamp method in each dog ventilated with positive pressure ventilation. The tramadol administration produced a significant reduction in the sevoflurane MAC by 22.3 ± 12.2% (1.44 ± 0.28% with tramadol versus 1.86 ± 0.30% without tramadol, P=0.010). This MAC reduction had been determined from 122 ± 19 to 180 ± 41 min following the tramadol administration. During this period, the plasma concentrations of tramadol and its metabolite, O-desmethyltramadol (M1), decreased from 429 ± 64 to 332 ± 55 ng/ml and from 136 ± 24 to 114 ± 68 ng/ml, respectively, but these changes were not statistically significant. There was no significant difference in heart rate, mean arterial blood pressure and SpO2 between the control and tramadol treatment. The dogs that received tramadol treatment sometimes breathed spontaneously. Therefore, their respiratory rates significantly increased, and PETCO2 decreased during the MAC determination. In conclusion, the single IV dose of tramadol produced a significant reduction in the sevoflurane MAC in dogs.

Rifampicin markedly decreases the exposure to oral and intravenous tramadol

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. 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. 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. 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.

Pharmacokinetics and selected pharmacodynamic effects of tramadol following intravenous administration to the horse

Both the potential analgesic effect and the conflicting reports describing tramadol disposition in the horse warrant further study of the pharmacokinetics of tramadol in this species. To describe the pharmacokinetics of tramadol and its metabolites, O-desmethyltramadol and N-desmethyltramadol, following i.v. administration of 3 doses to the horse. Nine adult horses received a single i.v. dose of 0.5, 1.5 and 3 mg/kg bwt tramadol. Blood samples were collected prior to and at various times up to 72 h post administration. Plasma samples were analysed using liquid chromatography-mass spectrometry and data analysed using noncompartmental analysis. Chin-to-ground distance, heart rate and rhythm, step count and gastrointestinal activity were also assessed. Maximal measured plasma tramadol concentrations were 454 ± 101.6, 1086.7 ± 330.7 and 1697.9 ± 406.1 ng/ml for 0.5, 1.5 and 3 mg/kg bwt, respectively. Depending on the dose administered, the tramadol clearance, volume of distribution and half-life ranged from 24.6 to 25.0 ml/min/kg, 2.66 to 3.33 l/kg and 2.17 to 3.05 h, respectively. Following administration of 0.5, 1.5 and 3 mg/kg bwt tramadol, the maximal measured plasma concentrations of the active metabolite, O-desmethyltramadol, were 3.9 ± 1.9, 9.6 ± 4.8 and 12.9 ± 5.2 ng/ml, respectively. Muscle fasiculations and tremors were seen following administration of the 2 high doses. No significant changes in chin-to-ground distance, heart rate and rhythm, step count and gastrointestinal activity were observed. This study confirms and extends previous studies describing the pharmacokinetics of tramadol following i.v. administration to the horse. Plasma tramadol concentrations exceeded those necessary for analgesia in human patients; however, further studies are necessary to determine plasma concentrations of tramadol necessary for analgesic efficacy in the horse. These results support further investigation of the analgesic efficacy of tramadol in the horse.

Metabolite to parent drug concentration ratios in hair for the differentiation of tramadol intake from external contamination and passive exposure

Tramadol was found in a man's hair sample during an abstinence test necessary to regain his driving license. The suspect denied having taken tramadol claiming external contamination as the reason for the positive result, as he was working in a tramadol production company. Nevertheless, low concentrations of both major metabolites, N-desmethyltramadol (NDMT) and O-desmethyltramadol (ODMT), were found in hair (180 and 6pg/mg hair, respectively). To assess this case, tramadol concentrations and metabolite to parent drug concentration ratios were determined in hair samples of 75 patients taking tramadol and of eight employees working in the production and laboratory site of the same company. Additionally, wash water used for decontaminating hair was analyzed for both groups, patients and employees. Analysis of hair sample extracts was performed by LC–MS/MS using multiple reaction monitoring (MRM), information dependent acquisition (IDA) and enhanced product ion scan (EPI). High variations of metabolite to parent drug concentration ratios in hair samples of patients were observed. Differences in NDMT and ODMT to tramadol concentration ratios were found when comparing the cohort of patients to employees. The suspect could be included in the cohort of employees considering the ODMT to tramadol concentration ratio in hair and tramadol concentration ratio in wash water versus hair. Metabolite to parent drug concentration ratios of hair samples may represent a helpful tool for the differentiation of tramadol intake versus external contamination. Ratios of tramadol concentrations in wash water versus the subjects’ hair may provide additional information for case assessments.

Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction

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. 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. 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. 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.

ADP-induced platelet aggregation after addition of tramadol in vitro in fed and fasted horses plasma

Adenosine diphosphate (ADP)-induced platelet aggregation in fed and fasted horses after addition of tramadol hydrochloride was evaluated in vitro. On 10 horses citrated blood samples were collected 2h after feeding (fed animals) and 21h after feeding (fasted animals). Final concentrations of ADP 1 and 0.5μM, and tramadol hydrochloride (1, 15, 30, 45 and 60min after the addition of tramadol) were used to determine the maximum degree and initial velocity of platelet aggregation. Repeated measures multifactor analysis of variance (MANOVA) was used to evaluate the effect of feeding/fasting condition, ADP concentration and addition of tramadol. Findings showed statistical differences (P⩽0.05) on studied parameters after addition of tramadol to different ADP concentrations in fed and fasted horses. The clinical relevance of these results is that tramadol provides many advantages as a therapeutic option; in fact, it is an inexpensive and a relatively new analgesic in equine veterinary medicine. Further investigations would be appropriate to compare the effects of different opioids but also using different concentrations of tramadol associated with other drugs in order to have substances which can regulate the functional activity of the platelets and to extend the knowledges on equine platelet aggregation.

Development and Validation of a New GC-MS Method for the Detection of Tramadol, O-Desmethyltramadol, 6-Acetylmorphine and Morphine in Blood, Brain, Liver and Kidney of Wistar Rats Treated with the Combination of Heroin and Tramadol

Heroin is one of the most dangerous abused drugs in the world. Tramadol is an additive recently found at high concentration levels in street heroin seizures in Egypt. This substance could affect the usual analytical method for the detection of heroin and metabolites, as well as the pharmacokinetic and disposition of single analytes. One shortfall regarding this issue is present in the literature. This study describes a validated, simple, sensitive and selective method to determine tramadol, O-desmethyltramadol, 6-acetylmorphine and free morphine in the blood, brain, liver and kidney of Wistar rats, intraperitoneally treated with a combination of heroin and tramadol (10 and 70 mg/kg, respectively) using liquid-liquid extraction and gas chromatography-mass spectrometry detection. The calibration curves of tramadol, O-desmethyltramadol and 6-acetylmorphine in blood were linear in the concentration range from 25-5,000 ng/mL and morphine was found in the concentration range 50-5,000 ng/mL. The analytes were detected in all tested matrices, except 6-acetylmorphine, which was not detected in liver. The highest concentrations of tramadol and O-desmethyltramadol were observed in kidney (22,9381 and 28,498 ng/g), while 6-acetylmorphine and morphine were found at the highest levels in brain (3,280 and 3,899 ng/g, respectively). The present method is simple, rapid and sensitive and can be used to study the pharmacokinetics, disposition and interaction of these drugs in several animal models.

Comparison of fatal poisonings by prescription opioids

There is a rising trend of fatal poisonings due to medicinal opioids in several countries. The present study evaluates the drug and alcohol findings as well as the cause and manner of death in opioid-related post-mortem cases in Finland from 2000 to 2008. During this period, fatal poisonings by prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone, oxycodone, tramadol) increased as a share of all drug poisonings from 9.5% to 32.4%, being 22.3% over the whole period. A detailed study including the most prevalent opioids was carried out for the age group of 14–44 years, which is the most susceptible age for drug abuse in Finland. Poisonings by the weak opioids, codeine and tramadol, were found to be associated with large, often suicidal overdoses resulting in high drug concentrations in blood. Methadone poisonings were associated with accidental overdoses with the drug concentration in blood remaining within a therapeutic range. The manner of death was accidental in 43%, 55% and 94% of cases in codeine, tramadol and methadone poisonings, respectively. The median concentration of codeine and the median codeine/morphine concentration ratio were higher in codeine poisonings (1.4 and 22.5mg/l, respectively) than in other causes of death (0.09 and 5.9mg/l, respectively). The median concentrations of tramadol and O-desmethyltramadol were higher in tramadol poisonings (5.3 and 0.8mg/l, respectively) than in other causes of death (0.6 and 0.2mg/l, respectively). In methadone poisonings, the median concentration of methadone (0.35mg/l) was not different from that in other causes of death (0.30mg/l). Sedative drugs and/or alcohol were very frequently found in fatal poisonings involving these prescription opioids.

Pharmacokinetics after oral and intravenous administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis)

To determine pharmacokinetics after IV and oral administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). 9 healthy adult Hispaniolan Amazon parrots (3 males, 5 females, and 1 of unknown sex). Tramadol (5 mg/kg, IV) was administered to the parrots. Blood samples were collected from -5 to 720 minutes after administration. After a 3-week washout period, tramadol (10 and 30 mg/kg) was orally administered to parrots. Blood samples were collected from -5 to 1,440 minutes after administration. Three formulations of oral suspension (crushed tablets in a commercially available suspension agent, crushed tablets in sterile water, and chemical-grade powder in sterile water) were evaluated. Plasma concentrations of tramadol and its major metabolites were measured via high-performance liquid chromatography. Mean plasma tramadol concentrations were > 100 ng/mL for approximately 2 to 4 hours after IV administration of tramadol. Plasma concentrations after oral administration of tramadol at a dose of 10 mg/kg were < 40 ng/mL for the entire time period, but oral administration at a dose of 30 mg/kg resulted in mean plasma concentrations > 100 ng/mL for approximately 6 hours after administration. Oral administration of the suspension consisting of the chemical-grade powder resulted in higher plasma tramadol concentrations than concentrations obtained after oral administration of the other 2 formulations; however, concentrations differed significantly only at 120 and 240 minutes after administration. Oral administration of tramadol at a dose of 30 mg/kg resulted in plasma concentrations (> 100 ng/mL) that have been associated with analgesia in Hispaniolan Amazon parrots.

Tramadol inhibits the contractility of isolated caprine detrusor muscle

The atypical opioid analgesic tramadol has been shown to provide beneficial clinical and urodynamic effects in patients with detrusor overactivity. The effect of tramadol on isolated detrusor muscle has not been studied. This study investigated the ability of tramadol to inhibit acetylcholine (ACh)-induced contractility of the isolated caprine (goat) detrusor muscle. The effect of three concentrations (30, 100 and 300 μm) of tramadol on 10 caprine detrusor strips contracted by the addition of 100, 200 or 400 μm ACh was studied. The sensitivity of tramadol-induced inhibition of ACh responses to treatment with the β-adrenoceptor antagonist propranolol (1 μm) and the opioid receptor antagonist naloxone (100 μm) was also studied. Tramadol caused a concentration-dependent inhibition of ACh-induced detrusor contraction that was reversed by raising the concentration of ACh. Propranolol, but not naloxone, reversed the tramadol-induced inhibition of contractions to ACh in the detrusor. These results suggest that tramadol inhibits ACh-induced contractility of the isolated detrusor. They also suggest that tramadol does so by an indirect anticholinergic mechanism involving the stimulation of β-adrenoceptors. Tramadol may be useful in managing clinical conditions requiring relaxation of the detrusor muscle. Although the concentrations of tramadol needed to relax the detrusor were relatively high, these could be clinically attained via intravesical administration.

Effect of opioids on the phagocytosis of neutrophils and monocytes: a systematic in vitro analysis

BackgroundBacterial infection is a common complication in patients with advanced disease, including cancer. Ingestion (phagocytosis) and subsequent killing of bacteria by neutrophils and monocytes are critical in the control of...

Using tramadol to monitor hepatic drug metabolism in the critically ill

Previously, we have demonstrated significant inhibition of hepatic drug metabolism by the enzymes cytochrome P450 (CYP) 3A4 and 3A5 in acute kidney injury (AKI) using midazolam as a probe drug [1,2]. We are now developing the use of tramadol as a probe drug to test the hypothesis that CYP2D6 function is also inhibited by AKI in critical illness. In this study we sought to determine whether a single timepoint tramadol concentration could be identified as a reliable surrogate for measurement of a full area under the concentration time curve after intravenous administration in adults.

Enantioselective analysis of unbound tramadol, O-desmethyltramadol and N-desmethyltramadol in plasma by ultrafiltration and LC–MS/MS: Application to clinical pharmacokinetics

This study describes the enantioselective analysis of unbound and total concentrations of tramadol and its main metabolites O-desmethyltramadol (M1) and N-desmethyltramadol (M2) in human plasma. Sample preparation was preceded by an ultrafiltration step to separate the unbound drug. Both the ultrafiltrate and plasma samples were submitted to liquid/liquid extraction with methyl t-butyl ether. Separation was performed on a Chiralpak® AD column and tandem mass spectrometry consisting of an electrospray ionization source, positive ion mode and multiple reaction monitoring was used as the detection system. Linearity was observed in the following ranges: 0.2–600 and 0.5–250ng/mL for analysis of total and unbound concentrations of the tramadol enantiomers, respectively, and 0.1–300 and 0.25–125ng/mL for total and unbound concentrations of the M1 and M2 enantiomers, respectively. The lower limits of quantitation were 0.2 and 0.5ng/mL for analysis of total and unbound concentration of each tramadol enantiomer, respectively, and 0.1 and 0.25ng/mL for total and unbound concentrations of M1 and M2 enantiomers, respectively. Intra- and interassay reproducibility and inaccuracy did not exceed 15%. Clinical application of the method to patients with neuropathic pain showed plasma accumulation of (+)-tramadol and (+)-M2 after a single oral dose of racemic tramadol. Fractions unbound of tramadol, M1 or M2 were not enantioselective in the patients investigated.

In-vitro and in-vivo transdermal iontophoretic delivery of tramadol, a centrally acting analgesic

The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo. To examine the effect of species variation and current strength on skin permeability of tramadol, in-vitro skin permeation studies were performed using porcine ear skin, guinea-pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in-vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 µA/cm(2)) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included. The in-vitro steady-state skin permeation flux of tramadol current-dependently increased without significant differences among the three different skin types. In the in-vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in-vivo steady-state transdermal absorption rate was 499 µg/cm(2) per h as calculated by a constrained numeric deconvolution method. The present study reveals that anodal iontophoresis provides current-controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.

Tramadol Overdose: A Case Report

Tramadol, a commonly prescribed opioid analgesic, is considered to have a low abuse potential and devoid of side effects like drug dependence. Very few fatalities due to isolated tramadol overdose, either intentional or accidental, have been reported so far. We report a case of a 27-year-old female with isolated tramadol overdose, having a peripheral blood tramadol concentration of 4mg/L, which is exceeding the lethal blood concentration of 2mg/L. This is the first report of a patient in Singapore who survived tramadol overdose despite having a lethal blood concentration. Physicians should be aware that patients with tramadol overdose may only present with signs related to isolated Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) properties and not always associated with the features of classical opioid overdose. Some patients might exhibit a certain degree of tolerance to the drug after prolonged prior exposure to the medication, and this tolerance could extend beyond the therapeutic range. It also emphasises the need for physicians to be more cautious while prescribing tramadol to their patients.

Factors Related to Seizure in Tramadol Poisoning and Its Blood Concentration

This study examines the relation between seizure and plasma tramadol concentration in patients with tramadol poisoning, as a novel centrally acting analgesic used for the treatment of mild to severe pain. All patients admitted with a history of tramadol overdose accompanied by unconsciousness or seizures referred to Baharloo Hospital Poison Center, Tehran, Iran from March 2008 to March 2009 were included. Demographic information, clinical findings, and blood tramadol concentrations were studied. There were 401 patients with a history of tramadol overdose; 121 (30.2%) with a history of seizure and 14 (3.5%) with a history of unconsciousness were included. Most of overdoses involved men (83%). The mean age was 22.9 years (range, 14-50 years). Intentional overdose was the most common mode of poisoning (51.9%). The mean dose ingested was 1,511 mg (SD, 1,353; range, 200-7,000). Mean back-extrapolated tramadol blood concentrations were 3,843 ng/mL (3,715; 269-20,049). Back-extrapolated blood concentrations were correlated with dose (r = 0.313; P < 0.001) as well as blood concentration levels (r = 0.801; P < 0.001). Seizure was significantly correlated to higher reported dose (P < 0.001) and tramadol only to overdose (P < 0.001). However, it was neither related to higher tramadol blood concentrations, nor related to time elapsed, age, sex, history of addiction, and observed Glasgow Coma Scale of patients. Most patients experienced just one seizure (76%). The tramadol-induced seizure is dose dependent. Although higher doses of tramadol was related to higher blood concentration, blood tramadol concentrations was not associated with seizure.

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O-desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence. A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O-desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points. We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety.

Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol

We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. In contrast, O-desmethyltramadol showed low membrane permeability, and OCT1 overexpression increased O-desmethyltramadol uptake 2.4-fold. This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.