PHARMACOKINETICS OF TRAMADOL AND O-DESMETHYLTRAMADOL IN GIANT TORTOISES (CHELONOIDIS VANDENBURGHI, CHELONOIDIS VICINA).

The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (1 mg/kg and 5 mg/kg) and its metabolite, O-desmethyltramadol (M1) in giant tortoises (Chelonoidis vandenburghi, Chelonoidis vicina). Eleven giant tortoises (C. vandenburghi, C. vicina) received two randomly assigned, oral doses of tramadol (either 1 mg/kg or 5 mg/kg), with a washout period of 3 wk between each dose. The half-life (t½) of orally administered tramadol at 1 mg/kg and 5 mg/kg was 11.9 ± 4.6 h and 13.2 ± 6.1 h, respectively. After oral administration of tramadol at 1 mg/kg and 5 mg/kg, the maximum concentration (Cmax) was 125 ± 69 ng/ml and 518 ± 411 ng/ml, respectively. There were not enough data points to determine pharmacokinetic (PK) parameters for the M1 metabolite from either dose. Tramadol administered orally to giant tortoises at both doses provided measurable plasma concentrations of tramadol for approximately 48 h with occasional transient sedation. Oral tramadol at 5 mg/kg, on average, achieves concentrations of >100 ng/ml, the reported human therapeutic threshold, for 24 h. Based on the low levels of M1 seen in this study, M1 may not be a major metabolite in this taxon.

Decreased Analgesic Effect of Tramadol in Japanese Patients with CYP2D6 Intermediate Metabolizers after Orthopedic Surgery.

Tramadol is metabolized by CYP2D6 to an active metabolite, which in turn acts as an analgesic. This study aimed to investigate the impact of CYP2D6 genotype on the analgesic effect of tramadol in clinical practice. A retrospective cohort study was performed in patients treated with tramadol for postoperative pain after arthroscopic surgery for rotator cuff injury during April 2017-March 2019. The impact of CYP2D6 genotypes on the analgesic effects was assessed by the numeric rating scale (NRS) pain scoring and analyzed by the Mann-Whitney U test. Stepwise multiple linear regression analysis was performed to identify predictive factors for the area under the time-NRS curve (NRS-AUC), which was calculated using the linear trapezoidal method. Among the 85 enrolled Japanese patients, the number of phenotypes with CYP2D6 normal metabolizer (NM) and intermediate metabolizer (IM) was n = 69 (81.1%) and n = 16 (18.9%), respectively. The NRS and NRS-AUC in the IM group were significantly higher than those in the NM group until Day 7 (p < 0.05). The multiple linear regression analysis indicated that the CYP2D6 polymorphism was a prediction factor of the high NRS-AUC levels in Days 0-7 (ß = 9.52, 95% CI 1.30-17.7). In IM patients, the analgesic effect of tramadol was significantly reduced one week after orthopedic surgery in clinical practice. Therefore, dose escalation of tramadol or the use of alternative analgesic medications can be recommended for IM patients.

A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children.

Tramadol is a bitter atypical opioid analgesic drug and is prescribed to treat postoperative pain in children. However, in many countries there is no licensed paediatric tramadol formulation available. We have formulated a novel chewable chocolate-based drug delivery system for the administration of tramadol to children. This pilot, single-centre, open-label, randomised clinical study assessed the taste tolerability and comparative population pharmacokinetics of the novel tramadol chewable tablet against a compounded tramadol hydrochloride oral liquid, at a dose of 1 mg.kg-1 . A 5-point facial hedonic scale was used by the children, parents and nurses to assess tolerability. One hundred and forty-one children aged 3-16 years were given tramadol 30 min before general anaesthesia. Blood samples were taken following the induction of anaesthesia and for up to 5 h following tramadol administration. Tramadol and its active metabolite O-desmethyltramadol were analysed using reversed-phase high-performance liquid chromatography. A population pharmacokinetic model was built using non-linear mixed effects modelling. The relative bioavailability for the tablet was 1.25 times higher (95%CI 1.16-1.35) than for tramadol hydrochloride oral liquid, while the absorption rate constant for the tablet was significantly lower (1.97 h-1 vs. 3.34 h-1 , p < 0.001). Larger inter-individual variability in absorption rates were observed with the liquid tramadol. The tramadol chewable tablet was more acceptable in taste to children when assessed by the children, parents and nurses (all p < 0.001). We conclude that the novel tramadol chewable tablet has favourable acceptability and more reliable relative bioavailability in children compared with tramadol hydrochloride oral liquid.

Physiologically Based Pharmacokinetic Modeling to Assess the Impact of CYP2D6-Mediated Drug-Drug Interactions on Tramadol and O-Desmethyltramadol Exposures via Allosteric and Competitive Inhibition.

Tramadol is an opioid medication used to treat moderately severe pain. Cytochrome P450 (CYP) 2D6 inhibition could be important for tramadol, as it decreases the formation of its pharmacologically active metabolite, O-desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol pharmacokinetics using quinidine and metoprolol as prototypical perpetrator drugs. A physiologically based pharmacokinetic model for tramadol and O-desmethyltramadol was developed and verified in PK-Sim version 8 and linked to respective models of quinidine and metoprolol to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol exposure. Our results show that there is a differentiated impact of CYP2D6 inhibitors on tramadol and O-desmethyltramadol based on their mechanisms of inhibition. Following allosteric inhibition by a single dose of quinidine, the exposure of both tramadol (51% increase) and O-desmethyltramadol (52% decrease) was predicted to be significantly altered after concomitant administration of a single dose of tramadol. Following multiple-dose administration of tramadol and a single-dose or multiple-dose administration of quinidine, the inhibitory effect of quinidine was predicted to be long (≈42 hours) and to alter exposure of tramadol and O-desmethyltramadol by up to 60%, suggesting that coadministration of quinidine and tramadol should be avoided clinically. In comparison, there is no predicted significant impact of metoprolol on tramadol and O-desmethyltramadol exposure. In fact, tramadol is predicted to act as a CYP2D6 perpetrator and increase metoprolol exposure, which may necessitate the need for dose separation.

In vitro release of new designs of modified-release tramadol hydrochloride included in a polymer matrix.

Tramadol reaches therapeutic plasma concentrations in a time interval of 0.5 to 1.7 hours, so it is necessary to dose 4 times/day, which reduces compliance with the dose and the effectiveness of the treatment. Design formulations of tramadol that allow the release time to be prolonged, surpassing those obtained with the commercial product and tramadol without excipients. Several formulations of 5% tramadol hydrochloride were designed in a matrix system based on poloxamer 407 at different concentrations (10%, 14%, 17%, and 20%). In vitro release studies were performed, using a spectrophotometer at a wavelength of 273.15 nm; were compared the results with tramadol without polymeric supplements and with the commercial formulation samples were taken in a period of time from 0.25 to 72 hours, and also compared the use or absence of dialysis membrane with a porosity of 50 kilodaltons was. With the use of the membrane, the designed formulations had a release of 98%, 50%, 23%, 16% at 72 hours, respectively, different from the commercial product and the tramadol formulation without excipients released the 24 hours. Without using dialysis membranes, a 90-100% release was achieved in the 10% and 14% formulation at 36 hours. The 17% and 20% formulation at 48 hours and the commercial formulation and tramadol without excipient were released within 2 hours. Modified release formulations were obtained, which retain and prolong the release of tramadol compared to the commercial product. Therefore, we propose to conduct further in vivo model experiments to confirm our conclusion.

Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

HPLC-UV assay of tramadol and O-desmethyltramadol in human plasma containing other drugs potentially co-administered to participants in a paediatric population pharmacokinetic study.

Multimodal analgesia is employed in paediatric pain management to maximise analgesia and minimise side effects. Tramadol is dosed at 1-1.5 mg/kg to treat severe pain in children but the assay for tramadol in plasma samples for pharmacokinetic and toxicology studies does not often consider concurrently administered medications. In this study we developed and validated an HPLC-UV method to quantify tramadol and its main metabolite (O-desmethyltramadol) in human plasma in the presence of seven potentially interfering drugs. Sample preparation method was developed by combining liquid-liquid extraction and protein precipitation. Chromatographic separation was achieved on a BDS-Hypersil-C18 column (5 µm, 250 × 4.6 mm) using a double gradient method. The limit of quantification was 6.7 ng/ml for both tramadol and ODT. The precision and accuracy were in compliance with ICH guidelines. This method was successfully employed to analyse the blood samples of 137 paediatric participants in a tramadol pharmacokinetic trial.

Toxicokinetics of U-47700, tramadol, and their main metabolites in pigs following intravenous administration: is a multiple species allometric scaling approach useful for the extrapolation of toxicokinetic parameters to humans?

New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100 µg/kg body weight (BW) of U-47700 or 1000 µg/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC-MS/MS. The concentration-time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L/kg for U-47700 and 1.25 L/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L/h/kg and 1.85 L/h/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration-time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data.

Multivariate Assessment for Bioequivalence Based on the Correlation of Random Effect.

BACKGROUND AND OBJECTIVE: Bioequivalence tests are fundamental step in assessing the equivalence in bioavailability between a test and reference product. In practice, two separate linear mixed models (LMMs) with random subject effects, which have an area under the concentration-time curve (AUC) and the peak concentration (Cmax) as the responses, have become the gold standard for evaluating bioequivalence. Recently, Lee et al developed a multivariate hierarchical generalized linear model (HGLM) for several responses that modeled correlations among multivariate responses via correlated random effects. The objective of this study was to apply this multivariate analysis to the bioequivalence test in practice and to compare the performance of multivariate HGLM and separate LMMs. METHODS: Three pharmacokinetic datasets, fixed-dose combination (naproxen and esomeprazole), tramadol and fimasartan data were analyzed. We compared the 90% confidence interval (CI) for the geometric mean ratio (GMR) of a test product to a reference product using the multivariate HGLM and two conventional separate LMMs. RESULTS: We found that the 90% CIs for the GMRs of both AUC and Cmax from the multivariate HGLM were narrower than those from the separate LMMs: (0.843, 1.152) vs (0.825, 1.177) for Cmax of esomeprazole in fixed-dose combination data; (0.805, 0.931) vs (0.797, 0.941) for Cmax in tramadol data; (0.801, 1.501) vs (0.762, 1.578) for Cmax and (1.163, 1.332) vs (1.009, 1.341) for AUC in fimasartan data, consistent with the random subject effects from two separate LMMs being highly correlated in the three datasets (correlation coefficient r = 0.883; r = 0.966; r = 0.832). CONCLUSION: This multivariate HGLM had good performance in the bioequivalence test with multiple endpoints. This method would provide a more reasonable option to reduce the 90% CI by adding correlation parameters and thus an advantage especially in evaluating the bioequivalence of highly variable drugs with broad 90% CIs.

Tapentadol Versus Tramadol: A Narrative and Comparative Review of Their Pharmacological, Efficacy and Safety Profiles in Adult Patients.

We conducted a narrative review of the literature to compare the pharmacological, efficacy and safety profiles of tapentadol and tramadol, and to assess the clinical interest of tapentadol in adult patients. Tapentadol and tramadol share a mixed mechanism of action, including both mu-agonist and monoaminergic properties. Tapentadol is approximately two to three times more potent than tramadol and two to three times less potent than morphine. It has no identified analgesically active metabolite and is not significantly metabolised by cytochrome P450 enzymes, thus overcoming some limitations of tramadol, including the potential for pharmacokinetic drug-drug interactions and interindividual variability due to genetic polymorphisms of cytochrome P450 enzymes. The toxicity profiles of tramadol and tapentadol are similar; however tapentadol is likely to result in less exposure to serotoninergic adverse effects (nausea, vomiting, hypoglycaemia) but cause more opioid adverse effects (constipation, respiratory depression, abuse) than tramadol. The safety of tapentadol in real-world conditions remains poorly documented, particularly in at-risk patient subgroups and also in the ability to assess the risk associated with its residual serotonergic activity (serotonin syndrome, seizures). Because of an earlier market introduction, more real-world safety data are available for tramadol, including data from at-risk patient subgroups. The level of evidence on the efficacy of both tramadol and tapentadol for the treatment of chronic pain is globally low. The trials published to date show overall that tapentadol does not provide a clinically significant analgesic improvement compared to existing treatments, for which the safety profile is much better known. In conclusion, tapentadol is not a first-line opioid but represents an additional analgesic in the therapeutic choices, which some patients may benefit from after careful examination of their clinical situation, co-morbidities and co-medications.

Pharmacokinetic profile of injectable tramadol in the koala (Phascolarctos cinereus) and prediction of its analgesic efficacy.

Tramadol is used as an analgesic in humans and some animal species. When tramadol is administered to most species it undergoes metabolism to its main metabolites M1 or O-desmethyltramadol, and M2 or N-desmethyltramadol, and many other metabolites. This study describes the pharmacokinetic profile of tramadol when a single subcutaneous bolus of 2 mg/kg was initially administered to two koalas. Based on the results of these two koalas, subsequently 4 mg/kg as a single subcutaneous injection, was administered to an additional four koalas. M1 is recognised as an active metabolite and has greater analgesic activity than tramadol, while M2 is considered inactive. A liquid chromatography assay to quantify tramadol, M1 and M2 in koala plasma was developed and validated. Liquid chromatography-mass spectrometry confirmed that M1 had been identified. Additionally, the metabolite didesmethyltramadol was identified in chromatograms of two of the male koalas. When 4 mg/kg tramadol was administered, the median half-life of tramadol and M1 were 2.89 h and 24.69 h, respectively. The M1 plasma concentration remained well above the minimally effective M1 plasma concentration in humans (approximately 36 ng/mL) over 12 hours. The M1 plasma concentration, when tramadol was administered at 2 mg/kg, did not exceed 36 ng/mL at any time-point. When tramadol was administered at 2 mg/kg and 4 mg/kg the area under the curve M1: tramadol ratios were 0.33 and 0.50, respectively. Tramadol and M1 binding to plasma protein were determined using thawed, frozen koala plasma and the mean binding was 20% and 75%, respectively. It is concluded that when tramadol is administered at 4 mg/kg as a subcutaneous injection to the koala, it is predicted to have some analgesic activity.

Acetaminophen and tramadol hydrochloride-loaded soft gelatin capsule: preparation, dissolution and pharmacokinetics in beagle dogs.

The objective of this study was to develop a novel acetaminophen and tramadol hydrochloride-loaded soft capsule (ATSC) with enhanced bioavailability of tramadol. The ATSC was manufactured in a pilot-scale batch size with the capsule contents composed of tramadol, acetaminophen, PEG 400 and Capmul MCM at a weight ratio of 37.5:325:177.5:30. Moreover, its dissolution, stability and pharmacokinetics in beagle dogs were carried out compared to commercial tablet. The dissolved amounts of acetaminophen from the ATSC and commercial tablet were not significantly different. However, compared to the latter, the former had significantly higher dissolution rate of tramadol at the initial times. In beagle dogs, the ATSC provided no significant difference in plasma concentrations and AUC of acetaminophen than did the commercial tablet; however, it significantly improved those of tramadol compared to the other, indicating the enhanced oral bioavailability of tramadol. Compared to the commercial tablet, the ATSC had a larger AUC value for tramadol (55.27 ± 11.06 vs. 92.62 ± 21.52 h·ng/ml). In the accelerated long-term stability, the ATSC offered higher than 96% drug content of acetaminophen and tramadol, suggesting that it was stable for at least six months. Therefore, this ATSC would be a recommendable candidate with enhanced oral bioavailability and excellent stability.

Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies.

BACKGROUND: Magnesium ions (Mg2+) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg2+ alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination. METHODS: Tramadol was administered to healthy Caucasian subjects with and without Mg2+ as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg2+ was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured. RESULTS: A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for Cmax and AUC0-t geometric mean ratios for tramadol were 91.95-102.40% and 93.22-102.76%. The 90% confidence intervals for Cmax,ss and AUC0-τ geometric mean ratios for tramadol were 93.85-103.31% and 99.04-105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg2+. CONCLUSIONS: The absence of Mg2+ interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.

Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug-drug interactions according to CYP2D6 phenotypes.

OBJECTIVES: The objective of this study was to establish physiologically based pharmacokinetic (PBPK) models of tramadol and its active metabolite O-desmethyltramadol (M1) and to explore the influence of CYP2D6 gene polymorphism on the pharmacokinetics of tramadol and M1. Furthermore, we used PBPK modeling to prospectively predict the extent of drug-drug interactions (DDIs) in the presence of genetic polymorphisms when tramadol was co-administered with the CYP2D6 inhibitors duloxetine and paroxetine. METHODS: Plasma concentrations of tramadol and M1 were used to adjust the turnover frequency (Kcat ) of CYP2D6 for phenotype populations with different CYP2D6 genotypes. PBPK models were developed to capture the pharmacokinetics between CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultra-rapid metabolizers (UMs). The validated models were then used to support dose adjustment in different CYP2D6 phenotypes and to predict the extent of CYP2D6-mediated DDIs when tramadol was co-administered with paroxetine or duloxetine. RESULTS: The PBPK models we built accurately describe tramadol and M1 exposure in the population with different CYP2D6 phenotypes. In our prediction, the area under the concentration-time curve (AUCinf-tDlast ) of M1 is 70% lower in PMs than in EMs, 27% lower in IMs, and 15% higher in UMs. Based on the models we built, we suggest that the oral dose of tramadol should be 50% higher for IMs and 25% lower for UMs to achieve an approximately equivalent plasma exposure of M1 as in EMs. When tramadol was co-administered with paroxetine or duloxetine, the magnitude of the inhibitor-substrate interaction was lowest in EMs (0.45), secondary in IMs (0.39), and highest in PMs (0.18) in terms of M1. CONCLUSION: The current example uses the PBPK model to guide dose adjustment of tramadol and to predict the effect of CYP2D6 genetic polymorphisms on DDIs for rational clinical use of tramadol in the future.

IV tramadol: A novel option for US patients with acute pain-A review of its pharmacokinetics, abuse potential and clinical safety record.

Tramadol is a centrally acting dual-mechanism (opioid and monoamine reuptake inhibition) analgesic that has been noted to have a lower risk of abuse compared to conventional opioids such as morphine. Oral tramadol has been ap-proved in the United States since 1995 and intravenous (IV) tramadol has been widely prescribed outside the United States (OUS); nevertheless, IV tramadol has not yet been approved for use in the United States. This paper provides a review of the pharmacokinetics (PK) of the IV tramadol dosing regimen being developed in the United States, its abuse potential as documented in the literature, and its safety record in clinical practice, and discusses how IV tramadol may become a useful option for patients in the United States with acute pain.

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.

Pharmacokinetics and analgesic efficacy of intranasal administration of tramadol in dogs after ovariohysterectomy.

OBJECTIVE: To assess analgesic efficacy and the pharmacokinetics of intranasal (IN) tramadol in dogs following ovariohysterectomy. STUDY DESIGN: Randomized, blinded clinical study. ANIMALS: A total of 30 bitches undergoing elective ovariohysterectomy. METHODS: Dogs were randomly assigned to one of three experimental groups (10 dogs per group): IN tramadol 4 mg kg-1 (group T-IN), intravenous (IV) tramadol 4 mg kg-1 (group T-IV) and IV methadone 0.2 mg kg-1 (group M). Drugs were administered at extubation. At established time points (before surgery and up to 8 hours after drug administration) analgesia was assessed using the Italian version of the Glasgow Composite Measure Pain Scale Short Form and physiological variables were recorded. To determine the pharmacokinetics of IN tramadol, blood samples were collected at predetermined time points. Shapiro-Wilk test was used to assess whether data were normally distributed and consequently parametric or non parametric tests were applied. A p value < 0.05 was considered significant. RESULTS: No significant intergroup differences were observed in the dogs that were administered rescue analgesia and time of its administration. Excluding dogs that were administered rescue analgesia, no significant intergroup differences emerged in pain scores and physiological variables, except for a lower rectal temperature in group M compared with the tramadol groups. After IN administration, tramadol was rapidly absorbed into the systemic circulation, reaching its maximum concentration (range 74.74-200.29 ng mL-1) within 30-60 minutes, it then decreased rapidly and was detectable in plasma for up to 2 hours after treatment in all dogs. CONCLUSIONS AND CLINICAL RELEVANCE: IN tramadol administration appears to be as effective as IV tramadol and methadone treatments in pain management of dogs after elective ovariohysterectomy. Given its low concentrations and short detection time in plasma after the IN route, systemic tramadol action appears unlikely.

Involvement of CYP2D6 and CYP2B6 on tramadol pharmacokinetics.

This study included 24 healthy volunteers who received a single 37.5 mg oral dose of tramadol. We analyzed 18 polymorphisms within CYP2D6, CYP2B6, CYP3A, COMT, ABCB1, SLC22A1 and OPRM1 genes by quantitative PCR, to study whether these polymorphisms affect its pharmacokinetics, pharmacodynamics and safety. CYP2D6 intermediate metabolizers (n = 6) showed higher tramadol plasma concentrations and lower clearance compared with normal and ultrarapid metabolizers. CYP2B6 G516T T/T (n = 2) genotype was also associated to higher tramadol plasma levels. No other polymorphism affected tramadol pharmacokinetics. Three volunteers experienced a prolonged QTc not associated with the genetic variants studied or altered phamacokinetic parameters. The correlation of CYP2B6 genotype with higher tramadol concentrations is remarkable since its influence on its elimination is also relevant and has been less studied to date. However, given our small sample size, it is important to interpret our results with caution.

ADME and toxicity considerations for tramadol: from basic research to clinical implications.

INTRODUCTION: Tramadol is widely being used in chronic pain management for improving patients' life quality and reducing trauma. Although it is listed in several medicinal guidelines, its use is controversial because of the conflicting results obtained in pharmacokinetic/pharmacodynamic studies. This multi-receptor drug acts as µ1 opioid receptor agonist, monoamine reuptake inhibitor, and inhibitor of ligand-gated ion channels and some special protein-coupled receptors. AREAS COVERED: This review provides a comprehensive view on the pharmacokinetic, pharmacodynamic, and toxicity of tramadol with a deep look on its side effects, biochemical and pathological changes, and possible drug interactions. In addition, the main ways of tramadol poisoning management describe according to in vivo and clinical trial studies. EXPERT OPINION: Given the broad spectrum of targets, increasing the cases of overdoses and toxicity, and probable drugs interaction, it is necessary to take another look at the pharmacology of tramadol. Regarding the adverse effects of tramadol on different tissues, especially the nervous system and liver tissue, more attentions to tramadol metabolites, their interaction with other drugs, and active agents seem critical. Seizure as the most cited effect of tramadol and its destructive effects on tissues would alleviate by co-administration with drugs with antioxidant properties.

Comparing the Pharmacokinetics of 2 Novel Intravenous Tramadol Dosing Regimens to Oral Tramadol: A Randomized 3-Arm Crossover Study.

Tramadol is a dual-mechanism (opiate and monoamine reuptake inhibition) analgesic. Intravenous (IV) tramadol has been widely prescribed outside the United States. However, there have not been studies comparing the pharmacokinetics (PK) of IV dosing regimens to that of oral tramadol. In this phase 1, open-label, single investigational center, 3-treatment, 3-period, multidose crossover study, we compared 2 novel IV dosing regimens (IV tramadol 75 mg and IV tramadol 50 mg) to oral tramadol 100 mg given every 6 hours (the highest approved oral dosage in the United States) Compared to the oral regimen, IV tramadol 50 mg administered at hours 0, 2, and 4 and every 4 hours thereafter reached initial tramadol peak serum concentration (Cmax ) more rapidly, while resulting in similar overall steady-state Cmax and area under the plasma concentration-time curve. IV tramadol 75 mg administered at hours 0, 3, and 6 and every 6 hours thereafter had higher Cmax and greater fluctuation in peak to trough tramadol concentration. The primary metabolite M1 (a potent µ agonist) had lower area under the plasma concentration-time curve and Cmax for both IV regimens than for the oral regimen. IV tramadol at both doses was well tolerated, with adverse event profiles consistent with the known pharmacological effects of tramadol. IV tramadol 50 mg is now in phase 3 development in patients with postsurgical pain.