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At least 19 recordsLinked to original sources
PubMed2006

Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis.

([3H]5-HT)-uptake and patch-clamp techniques were used to study the actions of (+) and (-) tramadol and the active metabolites of tramadol, (+) and (-) O-demethyl-tramadol on the human serotonin (5-HT) transporter and the human 5-HT3A receptor, stably expressed in HEK-293 cells. The (+) and (-) enantiomers of tramadol suppressed the human 5-HT transporter concentration-dependently (IC50=1.0 and 0.8 microM, respectively), resulting in 97% and 87% transport inhibition at their respective initial plasma concentrations (9.5 microM). The (+) and (-) enantiomers of the active tramadol metabolite were less potent than tramadol in inhibiting the human 5-HT transporter (IC50=15 and 44 microM, respectively), resulting in 19.2% and 4.8% transport inhibition at their highest plasma concentrations (2.5 microM). In contrast to their potent suppression of the 5-HT transporter, both, (+) and (-) tramadol inhibited 5-HT (30 microM)-induced currents only at substantially higher concentrations (IC50=199 and 251 microM, respectively), resulting in only 6% and 4% inhibition at the initial maximum plasma concentration. A similar low potent inhibition of human 5-HT(3A) receptors was found for (+) and (-) O-demethyl-tramadol (IC50=158 and 63 microM, respectively). In conclusion, at clinical plasma concentrations tramadol potently suppresses the human 5-HT transporter, whereas it has only a slight effect on the human 5-HT3A receptor. The results are compatible with a possible mechanism for tramadol-induced early emesis involving the serotonergic system.

Analgesics, Opioid↗
PubMed2002

A comparative study on the analgesic effect of tramadol, tramadol plus magnesium, and tramadol plus ketamine for postoperative pain management after major abdominal surgery.

BACKGROUND: We tested whether, after major abdominal surgery, the addition of magnesium or ketamine to tramadol for intravenous (IV) patient-controlled analgesia (PCA) improved analgesia and lowered pain scores, compared to a PCA containing only tramadol. METHODS: Sixty-six patients were allocated randomly to receive a PCA with tramadol alone (T), tramadol plus magnesium (TM) or tramadol plus ketamin (TK), in a double-blind randomized study. Postoperative analgesia was started when the verbal rating scale (VRS) score was 2 or more. Following a loading dose of the study solution (which contained 1 mg/kg tramadol), a background infusion of 0.4 mg/kg/h was started. Patients were allowed to use bolus doses of 0.2 mg/kg every 20 min without a time limit. Discomfort, sedation, pain scores, total and bolus PCA tramadol consumption, and side-effects, were recorded for up to 24 h after the start of PCA. RESULTS: Pain and discomfort scores were lower (P < 0.01) in groups TM and TK at 15, 30, 60 and 120 min than in group T. The addition of magnesium or ketamine significantly reduced the consumption of tramadol at 6, 12 and 24 h (P < 0.01). The incidence of nausea did not differ between the groups. CONCLUSION: Adding magnesium or ketamine to tramadol improved analgesia and patient comfort and decreased the amount of tramadol required for postoperative pain management after major abdominal surgery.

Abdomen↗
PubMed2006

The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes.

PURPOSE: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT(2C)R), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT(2C)R have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT(2C)R expressed in Xenopus oocytes. METHODS: We examined the effect of O-desmethyl tramadol on 5-HT(2C)R using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [(3)H]5-HT by 5-HT(2C)R. RESULTS: O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca(2+)-activated Cl(-) currents in oocytes that expressed 5-HT(2C)R. The inhibitory effect of O-desmethyl tramadol on 5-HT(2C)R was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [(3)H]5-HT by 5-HT(2C)R expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [(3)H]5-HT by 5-HT(2C)R without changing maximum binding, which indicated competitive inhibition. CONCLUSION: These results suggest that O-desmethyl tramadol inhibits 5-HT(2C)R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol.

Animals↗
PubMed2007

Stereoselective pharmacokinetic analysis of tramadol and its main phase I metabolites in healthy subjects after intravenous and oral administration of racemic tramadol.

The kinetics of tramadol enantiomers are stereoselective when doses of the racemic drug are given orally. To document whether the route of administration determines the stereoselective kinetics of tramadol enantiomers, healthy volunteers received 100 mg oral or intravenous doses of racemic tramadol, and serial blood samples were obtained to assay tramadol enantiomers and their main phase I metabolites, O-demethyltramadol and N-demethyltramadol. To assess accurately the involvement of their metabolites in the pharmacokinetics of tramadol, it is essential to determine the rate and extent of the formation of the enantiomers of these metabolites. A simultaneous pharmacokinetic model describing the plasma concentration-curves of the generated metabolites and the parent compounds after intravenous and oral drug administration is developed and presented. Tramadol and O-demethyltramadol were the major compounds detected in plasma after intravenous administration. Nevertheless, the N-demethylation of tramadol showed a significant increase when the oral route was used. After both oral and intravenous doses, the kinetics of the tramadol enantiomers were stereoselective. The AUC for (R )-(+)-tramadol was greater than the AUC for (S)-(-)-tramadol. The formation of N-demethyltramadol also was enantioselective after oral administration of racemic tramadol, with a greater AUC for (R)-(+)-N-demethyltramadol than for (S)-(-)-N-demethyltramadol. In the opposite form, (S)-(-)-O-demethyltramadol was formed faster than (R)-(+)-O-demethyltramadol. The metabolism of tramadol was also route-dependent with a different enantiomeric ratio for tramadol and its main phase I metabolites after intravenous and oral administration. The disposition of N-demethyltramadol was concentration-dependent.

Administration, Oral↗
PubMed2005

The effects of the tramadol metabolite O-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 or M3 receptors.

O-desmethyl tramadol is one of the main metabolites of tramadol. It has been widely used clinically and has analgesic activity. Muscarinic receptors are involved in neuronal functions in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets for analgesic drugs in the central nervous system. We have reported that tramadol inhibits the function of type-1 muscarinic (M(1)) receptors and type-3 muscarinic (M(3)) receptors, suggesting that muscarinic receptors are sites of action of tramadol. However, the effects of O-desmethyl tramadol on muscarinic receptor functions have not been studied in detail. In this study, we investigated the effects of O-desmethyl tramadol on M(1) and M(3) receptors, using the Xenopus oocyte expression system. O-desmethyl tramadol (0.1-100 microM) inhibited acetylcholine (ACh)-induced currents in oocytes expressing the M(1) receptors (half-maximal inhibitory concentration [IC(50)] = 2 +/- 0.6 microM), whereas it did not suppress ACh-induced currents in oocytes expressing the M(3) receptor. Although GF109203X, a protein kinase C inhibitor, increased the ACh-induced current, it had little effect on the inhibition of ACh-induced currents by O-desmethyl tramadol in oocytes expressing M(1) receptors. The inhibitory effect of O-desmethyl tramadol on M(1) receptor was overcome when the concentration of ACh was increased (K(D) with O-desmethyl tramadol = 0.3 microM). O-desmethyl tramadol inhibited the specific binding of [(3)H]quinuclidinyl benzilate ([(3)H]QNB) to the oocytes expressed M(1) receptors (IC(50) = 10.1 +/- 0.1 microM), whereas it did not suppress the specific binding of [(3)H]QNB to the oocytes expressed M(3) receptors. Based on these results, O-desmethyl tramadol inhibits functions of M(1) receptors but has little effect on those of M(3) receptors. This study demonstrates the molecular action of O-desmethyl tramadol on the receptors and may help to explain its neural function.

Acetylcholine↗
PubMed2002

Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally.

OBJECTIVE: To investigate a possible differential brain uptake of tramadol vs. its major metabolite (O-desmethyl tramadol; M1) in mice and rats. METHODS: An extraction and measurement technique (gas chromatograph equipped with a nitrogen phosphorus detector) was used to measure plasma and brain levels of tramadol and M1 at intervals 10-300 min after oral dosing of tramadol hydrochloride to mice and rats. RESULTS: For all doses of tramadol administered (5, 10, 20, or 40 mg/kg), tramadol and M1 plasma levels were greatest 10 min after dosing: in mice, peak tramadol plasma levels were 47.75-736.72 ng/mL and peak M1 levels were 75.30-1084.92 ng/mL; in rats, peak tramadol plasma levels were 185.03-455.81 ng/mL and peak M1 levels were 106.74-455.70 ng/mL. Tramadol brain levels were also greatest 10 min after dosing. In mice, peak tramadol brain levels were 226.42-1847.46 ng/g. Peak M1 levels (72.17-572.97 ng/g) occurred 20-60 min after dosing. In rats, peak tramadol brain levels were 258.50-1777.37 ng/g and peak M1 levels were 80.35-289.60 ng/g. In mice, the ratio of tramadol/M1 in plasma was 0.5-1.0 throughout the measurements, whereas the ratio in brain was about 10 at 10 min and about 2 from 20 to 50 min. In rats, the ratio of tramadol/M1 in plasma was 0.5-1.5, whereas the ratio in brain was about 15 at 10 min and about 4-7 thereafter. CONCLUSION: In mice and rats, there appears to be preferential brain vs. plasma distribution of tramadol over M1.

Administration, Oral↗
PubMed2006

Metabolism of two analgesic agents, tramadol-n-oxide and tramadol, in specific pathogen-free and axenic mice.

The in vivo metabolism of both tramadol-N-oxide (TNO) and tramadol was investigated in urine pools obtained from 0-24 h after a single 300 mg kg-1 oral dose administration of each compound to specific pathogen-free and axenic mice. Unchanged TNO (< or =42% of the initial drug sample), tramadol, and 23 metabolites from TNO-treated mice and unchanged tramadol (< or =15% of the sample) plus 20 metabolites from tramadol-treated mice were profiled, quantified and tentatively identified on the basis of atmospheric pressure ionization mass spectrometry (API-MS) and tandem mass spectrometry (MS/MS) data. Of the tramadol metabolites, five (M1-5) have been previously identified in mice. Of the tramadol and TNO metabolites, six (M18-23) are new metabolites. The tramadol and TNO metabolites were formed via the following seven metabolic pathways: N-oxide reduction (TNO), O/N-demethylation, cyclohexyloxidation, oxidative N-dealkylation, dehydration (TNO), N-oxidation (tramadol), and glucuronidation. Pathways 1-3 appear to be predominant steps forming four major O/N-desmethyl and hydroxycyclohexyl metabolites, and in conjunction with pathway 7, formed six minor glucuronides. Both tramadol-N-oxide and tramadol are extensively metabolized in mice, and no significant qualitative or quantitative differences in metabolism were observed between specific pathogen-free and axenic mice with the exception of a greater amount of unchanged TNO in axenic mice than in specific pathogen-free mice, more M2 in specific pathogen-free mice than in axenic mice in the TNO-dosed mice, and visa versa for M2 of tramadol-dosed mice.

Analgesics, Opioid↗
PubMed2001

Direct chiral assay of tramadol and detection of the phase II metabolite O-demethyl tramadol glucuronide in human urine using capillary electrophoresis with laser-induced native fluorescence detection.

A chiral separation using carboxymethyl-beta-cyclodextrin and methyl-beta-cyclodextrin for the direct assay of tramadol in human urine by capillary electrophoresis (CE) with laser-induced native fluorescence detection was developed. Furthermore, the phase II metabolite O-demethyl tramadol glucuronide was determined from the urine samples and the ratio of the diasteromers was determined. The chiral method was validated. Correlation coefficients were higher than 0.999. Within day variation showed accuracy in the range 96.1-105.8% with a RSD less than 6.00%. Day to day variation present an accuracy ranging from 100.2 to 103.5% with a RSD less than 5.4%. After oral administration of 150 mg tramadol hydrochloride to a healthy volunteer, the urinary excretion was monitored during 24 h. About 11.4% of the dose was excreted as 1S,2S-tramadol, 16.4% as 1R,2R-tramadol and 23.7% as O-demethyl tramadol glucuronide. The amount of 1S,2S O-demethyl tramadol glucuronide was more than three fold higher as IR,2R-O-demethyl tramadol glucuronide. The enantiomeric ratio of tramadol and the diastereomeric ratio of O-demethyl tramadol glucuronide was deviated from 1.0 showing that a stereoselective metabolism of tramadol occurs.

Analgesics, Opioid↗
PubMed2006

Tramadol, but not its major metabolite (mono-O-demethyl tramadol) depresses compound action potentials in frog sciatic nerves.

BACKGROUND AND PURPOSE: Although tramadol is known to exhibit a local anaesthetic effect, how tramadol exerts this effect is not understood fully. EXPERIMENTAL APPROACH: The effects of tramadol and its metabolite mono-O-demethyl-tramadol (M1) on compound action potentials (CAPs) were examined by applying the air-gap method to frog sciatic nerves, and the results were compared with those of other local anaesthetics, lidocaine and ropivacaine. KEY RESULTS: Tramadol reduced the peak amplitude of the CAP in a dose-dependent manner (IC50=2.3 mM). On the other hand, M1 (1-2 mM), which exhibits a higher affinity for mu-opioid receptors than tramadol, did not affect CAPs. These effects of tramadol were resistant to the non-selective opioid receptor antagonist naloxone and the mu-opioid receptor agonist, DAMGO, did not affect CAPs. This tramadol action was not affected by a combination of the noradrenaline uptake inhibitor, desipramine, and the 5-hydroxytryptamine uptake inhibitor, fluoxetine. Lidocaine and ropivacaine also concentration-dependently reduced CAP peak amplitudes with IC50 values of 0.74 and 0.34 mM, respectively. CONCLUSIONS AND IMPLICATIONS: These results indicate that tramadol reduces the peak amplitude of CAP in peripheral nerve fibres with a potency which is less than those of lidocaine and ropivacaine, whereas M1 has much less effect on CAPs. This action of tramadol was not produced by activation of mu-opioid receptors nor by inhibition of noradrenaline and 5-hydroxytryptamine uptake. It is suggested that the methyl group present in tramadol but not in M1 may play an important role in producing nerve conduction block.

Action Potentials↗
PubMed2005

Randomized double-blind, double-dummy crossover clinical trial of oral tramadol versus rectal tramadol administration in opioid-naive cancer patients with pain.

Tramadol is commonly used as second step drug of the analgesic ladder. In circumstances where the oral route is unavailable, rectal administration of opioids might be a simple alternative. The aim of this study was to compare the analgesic activity and tolerability of tramadol by oral and rectal administration in a double-blind, double-dummy crossover trial. The study included 60 cancer patients with cancer pain no longer responsive to non-opioid drugs. Each patient initially received oral tramadol 50 mg (drops), followed by tramadol sustained release 100 mg orally, and placebo rectally, or tramadol 100 mg rectally and placebo orally, twice a day, in a randomized sequence, on each of 3 days. Patients were allowed to take 50 mg of oral tramadol by drops as needed (four doses per day, to a maximum of 400 mg/day, including the basal dose given by the oral or rectal route). Pain intensity and relief and symptom scores were recorded every day and at the end of each phase of the crossover. The mean age of the patients was 66.1 years (SD 13.5 years); 36 were female, and 44 completed both periods. Patients dropped out due to adverse effects (15 patients) and refusal (1 patient). No differences in the use of rescue dose of oral tramadol were observed between the groups. No differences in pain intensity and relief scores, or in other symptoms between the two treatments were observed. No differences in treatment efficacy as judged by the clinician (P=0.73), in patient compliance (P=0.35), or in patient satisfaction regarding treatment (P<0.35) were found. No differences in adverse effects were found between the two treatments (25.5%, 13 patients, and 20.4%, 11 patients, with oral and rectal treatment, respectively). The proportion of preferences favored oral administration for both physicians (P=0.0002) and patients (P=0.002). Rectal administration of tramadol appears a reliable, noninvasive alternative method of pain control for patients no longer responsive to non-opioid analgesics, unable to take oral tramadol.

Administration, Oral↗
PubMed2006

Successful anticoagulation and continuation of tramadol therapy in the setting of a tramadol-warfarin interaction.

Tramadol is a commonly used synthetic opioid with the advantage of lowering the potential for dependence. Two reports of a tramadol-warfarin drug interaction have been published, and the current product insert states that increased international normalized ratios (INRs) with concomitant tramadol-warfarin use have been reported. We report a tramadol-warfarin drug interaction that caused a supratherapeutic INR in a 65-year-old man in previously stable condition who was being treated at our anticoagulation clinic. Within 6 days of starting tramadol 50 mg twice/day, the patient's INR rose from 2.5 to 6.14. He elected to continue therapy with the tramadol. A 30% dosage reduction from warfarin 60 to 42 mg/week was eventually needed. To our knowledge, this is the first case report of the successful continuation of tramadol after a tramadol-warfarin drug interaction. Based on our experience, we suggest an empiric dosage reduction of 25-30% in warfarin followed by repeat measurement of the INR within 1 week in patients who are starting tramadol therapy. As an alternative, maintaining the current dose of warfarin, followed by a repeat INR determination in 3 days, may be appropriate.

Aged↗
PubMedDate not supplied

Bioavailability of tramadol hydrochloride from tramadol--capsules 50 mg.

UNLABELLED: The aim of this study was to investigate the bioavailability of tramadol hydrochloride after oral administration of Tramadol--50 mg capsules, made in Synteza Pharmaceutical-Chemical Company in Poznań. As a reference preparation of Tramadol was used Tramal--50 mg capsules, (Grünenthal, Germany). The preparations were investigated in 20 healthy volunteers, according to a randomised two-way, cross-over design in the fasted state. Blood samples for determination of tramadol plasma concentrations were collected at pre-defined time points up to 24 h following drug administration. A washout period of one week separated both treatment periods. Tramadol plasma concentrations were determined by means of a validated HPLC method (fluorescence detector, verapamil as an internal standard). Values of 1,226.4 ng h/ml (Tramadol) and 1,397.01 ng x h/ml (Tramal) for the parameter AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum concentrations--Cmax (217.81 ng/ml and 246.0 ng/ml) and time to reach maximum plasma concentration--Tmax (2.14 and 2.31 h) achieved for Tramadol and reference preparation did not differ significantly. CONCLUSIONS: the bioavailability of tramadol hydrochloride after administration of Tramadol is the same as after administration of Tramal, whose clinical efficacy was tested before.

Adult↗
PubMed1998

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories.

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after rectal administration of tramadol suppositories (Tramal) were determined in a balanced crossover study in 10 female volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one rectally (1 suppository) and one intravenously (2 ml of a solution for injection). The formulations were administered in the morning, the washout period was one week. Serum concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability was calculated model-independently. The extent of the absolute bioavailability (F) of tramadol in the suppositories, based on AUC data, was 77.0% (point estimate; n = 10) with a 95% confidence interval of 70.8-83.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2933 +/- 304 h.ng/ml (rectal) and 3775 +/- 446 h.ng/ml (i.v.) [mean +/- SD; n = 10]. Optimal curve fitting of the serum concentration data after rectal administration presupposed the existence of two absorption sites with different absorption rates and lag times. Under this premise the absorption half-lives were t1/2,ka;1 = 1.7 h (median; range: 1.1-3.1 h) and t1/2,ka;2 = 0.98 h (0.35-1.9 h), and the corresponding lag times were t0;1 = 0 h (0-0.37 h) and t0;2 = 0.66 h (0.31-3.5 h). The relative portion of the more rapidly absorbed quantity of tramadol varied between 9.2 and 50% (median: 28%). The maxima of the serum concentration curves were reached 2-6 h after rectal administration; the means of the individual maxima were 294 +/- 50 ng/ml (Cmax) and 3.3 +/- 1.3 h (tmax). There were large differences in the distribution rate between the volunteers. The means of the half-life of the slower distribution (t1/2, alpha) were 1.38 +/- 0.47 h (rectal; n = 10) and 1.78 +/- 0.63 h (i.v.; n = 7). In the terminal phase the biological half-life (t1/2, beta) was 5.7 +/- 1.0 h (rectal) and 5.7 +/- 0.9 h (i.v.), respectively. The values determined after i.v. injection for the total distribution volume and the total clearance were 216 +/- 231 (Vd, beta) and 447 +/- 56 ml/min (Cltot). The results show that after rectal administration of the tramadol suppositories the absorption of the active ingredient is rapid enough for therapeutic purposes and that the extent of the absolute bioavailability is higher than after oral administration of tramadol-HCl, probably due to a reduced first-pass metabolisation after rectal administration.

Adult↗
PubMed2001

A comparison of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine administration for postoperative analgesia in children.

BACKGROUND: Our aim was to compare the effect of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine on the management of postoperative pain in children. METHODS: Sixty-three children in ASA groups I-II, between the ages of 1 and 5 were evaluated for postoperative pain randomly divided into three groups as follows: In group T, only tramadol was given caudally; in group TB, tramadol-bupivacaine was given caudally; in group B, bupivacaine was given alone. Pain was evaluated by using the paediatric objective pain scale (POPS). Sedation was evaluated with a 5-point test. There were no differences with age, weight, haemodynamic and respiratory parameters between groups. RESULTS: For 24 h postoperatively, the POPS value showed no statistically significant difference among groups (P > 0.05). Postoperative analgesia was maintained for 24 h. Nausea and vomiting was found to be higher in the tramadol group than in the bupivacaine group and tramadol-bupivacaine group (P < 0.001 and P < 0.01, respectively). CONCLUSION: Tramadol used caudally is as effective as bupivacaine in the management of postoperative pain in children and the addition of tramadol to bupivacaine, when both drugs were administered caudally, did not prolong the duration of action of bupivacaine and is a safe agent in children.

Analgesics, Opioid↗
PubMed2000

Patient-controlled analgesia with tramadol versus tramadol plus lysine acetyl salicylate.

UNLABELLED: By using a patient-controlled analgesia (PCA) delivery system, we compared the clinical advantages and disadvantages of PCA with tramadol and PCA with a mixture of tramadol plus lysine acetyl salicylate (a soluble aspirin). Fifty adult patients who had undergone major orthopedic surgeries were enrolled into a prospective, randomized, and double-blinded study. The general anesthesia was performed in a standard manner. At the beginning of wound closure, an equal volume dose of either tramadol 2.5 mg/kg (Group 1) or tramadol 1.25 mg/kg + lysine acetyl salicylate 12.5 mg/kg mixture (Group 2) was administered slowly IV. These solutions were continued postoperatively for IV PCA. Pain control, patient satisfaction, vital signs, and adverse effects were assessed for 48 h. Visual Analog Scale </=3 could be achieved with either group. Total tramadol consumption was significantly less in Group 2 than in Group 1 (614 +/- 259 mg vs 923 +/- 354 mg) (P: < 0.05). Patients in Group 2 were more alert (P: < 0.05). Blood loss from the surgical drain was similar, 865 +/- 275 mL (Group 1) vs 702 +/- 345 mL (Group 2). We conclude that aspirin can be used as an effective and safe adjuvant to tramadol for PCA after orthopedic surgery. IMPLICATIONS: Injectable aspirin can be used as an effective and safe adjuvant to tramadol for patient-controlled analgesia (PCA) in orthopedic patients. The tramadol requirement is therefore reduced. This combination supports the concept that drugs other than opioids can be used for PCA.

Aged↗
PubMed2000

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 4th communication: drops (without ethanol).

In a balanced two-period cross-over study with 12 (6 male, 6 female) healthy young subjects the pharmacokinetics and absolute bioavailability of tramadol (tramadol hydrochloride, CAS 36282-47-0) after oral administration of Tramal drops (without ethanol) were to be determined in comparison with a 30-min i.v. infusion. Each fasting volunteer received the two single doses of 50 mg tramadol-HCl each in the morning; the time interval between the administrations was one week. Serum and urine concentrations of tramadol were analysed by gas chromatography. The pharmacokinetic evaluation was carried out model-dependently after previous selection of the optimal model by means of the Akaike information criterion; solely the extent of bioavailability was calculated model-independently. The study population results were presented descriptively as geometric means with standard deviation [xg (SDg)] or as medians with range [x (min, max)]. Model-dependently and model-independently calculated areas under the serum concentration curves (AUC and AUC, resp.) differed only minimally. The extent of the absolute bioavailability (F) of tramadol in the drops, based on AUC data, was 70.6 (1.13)% with a 90% confidence interval of 65.9-75.6% (ANOVAlog). The p.o. serum concentration peaks were reached after tmax = 1.2 (0.74, 1.5) h and amounted to Cmax = 136 (1.33) ng/ml, the half-life of absorption was t1/2,ka = 0.23 (1.89) h and the lag time t0 = 0.23 (0.20, 0.49) h. The dose-normalised p.o. and i.v. results for all pharmacokinetic parameters agreed well with those of a previous study with ethanol-containing drops. In summary, it may be concluded that the active ingredient is rapidly absorbed after oral administration of the drops without ethanol. Rate and extent of the absolute bioavailability of tramadol in drops without ethanol were about the same as after administration of drops with ethanol. The results of this study gave no indication of a therapeutically relevant gender difference in the pharmacokinetics of tramadol.

Administration, Oral↗
PubMedDate not supplied

Influence of pre- or intraoperational use of tramadol (preemptive or preventive analgesia) on tramadol requirement in the early postoperative period.

The aim of this study was to assess the influence of iv tramadol on opioid requirement in the early postoperative period. The subjects were 90 patients scheduled for colon surgery (hemicolectomy) who received general anesthesia using the (N2O/O2) isoflurane technique. Thirty patients (group I) were administered 100 mg of tramadol iv before induction of general anesthesia (preemptive analgesia). Group II (30 patients) was administered 100 mg of tramadol iv immediately after peritoneal closure (preventive analgesia) and control group (30 patients) received 100 mg of tramadol iv immediately after operation. Following the operation, all patients were administered tramadol in the PCA-iv mode in order to treat postoperative pain. In the postoperative period, the following parameters were measured: pain intensity (using VAS), total consumption of tramadol, time until the first PCA activation, and frequency of side effects (drowsiness, nausea, vomiting). In patients of groups I and II who had received preemptive or preventive analgesia, a significantly lower total consumption of tramadol, as compared with control group, was observed in the early postoperative period. However, the time until the first PCA activation was significantly shorter in group I as compared to the other two groups. No significant differences between the groups were found regarding pain intensity and frequency of side effects.

Adult↗
PubMed1998

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol.

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.

Administration, Oral↗