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PubMed2004

Pharmacokinetic assessment of a fast-release orodispersible tramadol tablet compared to a conventional tramadol capsule.

The purpose of this clinical trial was to compare the pharmacokinetics of a recently developed fast-release orodispersible tramadol tablet (CAS 27203-92-5, Zamadol Melt) to that of a conventional tramadol capsule. This new formulation, once placed into the mouth, disintegrates rapidly in contact with the saliva. Therefore, when the saliva is swallowed, the drug reaches the gastrointestinal tract. In an open, randomised, two-period, crossover study performed in 20 healthy volunteers, the orodispersible tramadol tablet and a conventional tramadol capsule were administered. Even although the galenics of both products are far different, statistical analysis of pharmacokinetic parameters allows concluding bioequivalence, not only for the parent molecule (tramadol), but also for its active metabolite O-desmethyl tramadol. This orally dispersible formulation, being bioequivalent to the standard capsules so far used, has the practical advantage that it can be taken without liquids. This facilitates an early treatment of emergent pain, irrespective of the place or situation where it may arise.

Adolescent↗
PubMed2002

A comparison of once-daily tramadol with normal release tramadol in the treatment of pain in osteoarthritis.

OBJECTIVE: To compare the efficacy and tolerability of once daily (OD) tramadol tablets with normal release tramadol capsules (50 mg) taken 3 or 4 times daily in a multicenter, double blind, double dummy parallel study. METHODS: Patients with moderate to severe pain due to osteoarthritis (OA) were recruited from general practice. Following a titration period of a week, patients were assessed over one month for the analgesic efficacy and tolerability of the test medications. RESULTS: Both treatments were shown to be effective. There was no difference between treatments and both produced good pain control as shown by clinically relevant decreases from baseline pain scores, low escape medication use, and sleep disturbance. The efficacy of the OD tramadol over the 24 h dosing interval was confirmed by the low sleep disturbance, absence of "end of dose" effects in morning pain scores, and low escape medication use. Of the 279 patients recruited, 140 withdrew, mostly because of adverse events. The adverse event profiles were typical of opioids and were similar for both treatments. CONCLUSION: Tramadol OD was at least as effective and well tolerated as normal release tramadol in the management of OA pain. However, OD tramadol offers the advantage of a reduced dosing regimen, which is especially valuable in the elderly population.

Analgesics, Opioid↗
PubMed1996

Assessment of analgesia in man: tramadol controlled release formula vs. tramadol standard formulation.

OBJECTIVE: The present study tested analgesia produced by a new controlled release formulation of tramadol. The investigation employed an experimental pain model based on chemo-somatosensory event-related potentials (CSSERP) in response to painful chemical stimuli applied to the nasal mucosa. STUDY: Twenty healthy volunteers participated in the experiments, which followed a controlled, randomised, double-blind, 3-way cross-over design. Each of the three medications (tramadol 100 mg [T100], tramadol controlled release 100 mg [TCR100] and tramadol controlled release 150 mg [TCR150]) was administered orally to fasting subjects. There was at least a 6 day washout period between tests. Each experiment was divided into five sessions, which took place before and 2, 4, 6, and 12 h after drug administration. In addition to the assessment of CSSERP, subjects rated the intensity of both the tonic and phasic painful stimuli. Nonspecific drug effects were also monitored by means of frequency analysis of the spontaneous EEG, ratings of adverse effects, and the subjects' performance in a tracking task. RESULTS: The significant reduction of amplitude N1 at central recording positions indicated that TCR 150 was the most effective analgesic 12 h after administration. Both 6 and 12 h after administration TCR 100 was more effective in terms of analgesia compared to T100. In addition, TCR100 appeared to produce fewer adverse effects than the standard formulation of tramadol. CONCLUSIONS: The controlled release formulation can be expected to become a valuable tool in peroral therapeutic regimens for chronic pain.

Adult↗
PubMed2004

Postoperative patient-controlled analgesia with intravenous tramadol, intravenous fentanyl, epidural tramadol and epidural ropivacaine+fentanyl combination.

PURPOSE: The aim of this study was to compare the effects of IV tramadol, IV fentanyl, epidural tramadol, and an epidural ropivacaine+fentanyl combination in patient-controlled analgesia (PCA) after lower abdominal surgery. METHODS: Eighty adult patients undergoing lower abdominal surgery were randomly allocated to one of four groups to receive analgesics with PCA pumps. Patients in group I received IV tramadol, group II patients IV fentanyl, group III patients epidural tramadol, and group IV patients an epidural infusion of 0.125% ropivacaine + 2 microg ml(-1) fentanyl combination. Analgesic effectiveness and side-effects were assessed at 1, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours after surgery. RESULTS: Adequate analgesia was achieved in all groups. The analgesia was highest in group IV (p < 0.05), and lowest in group III patients (p < 0.05). Eleven patients (55%) in group I and eight patients (40%) in group II suffered from nausea/vomiting. CONCLUSION: Although adequate pain relief was achieved with all regimens that were used in the study, intravenous tramadol and intravenous fentanyl are associated with a high incidence of nausea and vomiting.

Abdomen↗
PubMedDate not supplied

Patient-controlled analgesia with tramadol versus tramadol plus ketorolac.

AIM: In this double-blinded, randomized controlled trial, we compared the clinical advantages and disadvantages of patient-controlled-analgesia (PCA) with continuous infusion (CI) with tramadol alone versus a combination of tramadol plus ketorolac in the management of postoperative pain after major abdominal surgery. METHODS: Sixty adult patients were randomly assigned to 2 groups. Group T, was given 10 mg/mL tramadol and Group TK was given 1.50 mg/mL ketorolac plus 5 mg/mL tramadol. After an i.v. loading dose of 0.07 mL/kg, the demand bolus injection was set at 0.2 mL, with a lockout interval of 30 min, and a continuous background i.v. infusion was set at 1.5 mL/h. Data of PCA demand, dose delivered and total analgesic consumption were retrieved from the computer memory bank of PCA device. Visual analogue scale at rest, sedation score and the occurrence of adverse effects were assessed every 3 h for 18 h. RESULTS: No significant differences were found with regard to pain scores and side effects. Patients in Group TK were significantly more alert. CONCLUSIONS: We concluded that the combination of ketorolac plus tramadol in the same PCA device was an effective and safe treatment for postoperative analgesia in abdominal surgery.

Abdomen↗
PubMed2006

Which has the least immunity depression during postoperative analgesia--morphine, tramadol, or tramadol with lornoxicam?

BACKGROUND: Analgesics are commonly used to provide pain relief after surgery. These drugs produce some extended depression of immunity. A prospective randomized controlled trial was designed to observe expressions of T-lymphocyte subsets (CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+)), natural-killer cells (CD3(-)CD16(+)CD56(+)), and activated T-lymphocytes (CD3(+)CD25(+)) of patients undergoing gastric cancer surgeries and receiving patient-controlled intravenous analgesia (PCIA). METHODS: Forty-five patients undergoing elective gastric cancer surgeries under general anesthesia were randomly allocated into 3 groups. Group I received PCIA using morphine after surgery, group II using tramadol, and group III using tramadol with lornoxicam. The analgesic efficacy was evaluated by visual analog scale (VAS) and Bruggrmann comfort scale (BCS). Expressions of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) were measured as percentages of total lymphocytes by flow cytometer at 5 time points. RESULTS: There was no significant difference in analgesic efficacy and the baselines of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) in all groups. Compared with the baseline, CD3(+)CD8(+) had no changes in all groups at any time point. Ninety minutes after incision, CD3(+), CD3(+)CD4(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) were lower in all groups (P<0.05). 24 h after surgery, CD3(+), CD3(+)CD4(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) were lower in group I and group II (P<0.05); meanwhile CD3(+), CD3(+)CD4(+), and CD3(+)CD25(+) returned to the baseline but CD3(-)CD16(+)CD56(+) was still low (P<0.05) in group III. 48 h after surgery, CD3(+), CD3(+)CD4(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) returned to the baseline in group II and group III, but not in group I (P<0.05). 72 h after surgery, CD3(+), CD3(+)CD4(+), CD3(+)CD4(+)/CD3(+)CD8(+) returned to the baseline, but CD3(+)CD25(+) and CD3(-)CD16(+)CD56(+) were still low in group I (P<0.05). CONCLUSION: PCIA using lornoxicam with tramadol has the same good analgesic efficacy and less immunity depression than PCIA using morphine or tramadol.

Adult↗
PubMed2003

A comparison of the pharmacokinetics, clinical efficacy, and tolerability of once-daily tramadol tablets with normal release tramadol capsules.

This report describes a pharmacokinetic study and a clinical study of three different formulations of oral tramadol: once-daily tramadol tablets 150 and 200 mg, and normal release tramadol capsules 50 mg 8-hourly. The randomized, open-label, crossover pharmacokinetic study included 22 subjects. The three treatments showed equivalent mean systemic availability of tramadol. The mean relative systemic availabilities (90% confidence intervals) for the once-daily tablets 150 mg and the once-daily tablets 200 mg versus the normal release capsules were 89.6 (83.3-95.8)% and 90.5 (84.6-96.8)%, respectively. The values for the once-daily tablet 150 mg versus the once-daily tablet 200 mg were 99.0 (92.6-105.9)%. The randomized, double-blind, double-dummy, crossover clinical study included 134 patients with moderate osteoarthritic pain. The three treatments showed similar efficacy; they all reduced patients' pain scores from baseline and there were no significant treatment differences in pain scores during treatment. The three treatments were also well tolerated.

Adult↗
PubMed1993

Achiral and chiral high-performance liquid chromatographic determination of tramadol and its major metabolites in urine after oral administration of racemic tramadol.

A reversed-phase high-performance liquid chromatographic method for the simultaneous determination of tramadol and its major metabolites O-demethyltramadol and N-demethyltramadol in urine has been developed. The determination of the enantiomeric ratios of the three compounds was achieved using a Chiralpak AD column and a Chiralcel OD column, respectively. After oral administration of racemic tramadol to five healthy volunteers, inter-individual differences of the excreted amounts and the enantiomeric ratios of the compounds were observed.

Administration, Oral↗
PubMed2004

Migration behaviour and separation of tramadol metabolites and diastereomeric separation of tramadol glucuronides by capillary electrophoresis.

Capillary electrophoresis with UV detection was used to separate tramadol (TR), a centrally acting analgesic, and its five phase I (M1, M2, M3, M4, M5) and three phase II metabolites (glucuronides of M1, M4 and M5). Several factors were evaluated in optimisation of the separation: pH and composition of the background electrolyte and the influence of a micellar modifier, sodium dodecyl sulfate. Baseline separation of TR and all the analytes was obtained with use of 65 mM tetraborate electrolyte solution at pH 10.65. The lowest concentrations of the analytes that could be detected were below 1 microM for the O-methylated, below 2 microM for the phenolic and ca. 7 microM for the glucuronide metabolites. The suitability of the method for screening of real samples was tested with an authentic urine sample collected after a single oral dose (50 mg) of TR. After purification and five-fold concentration of the sample (solid-phase extraction with Oasis MCX cartridges), the parent drug TR and its metabolites M1, M1G, M5 and M5G were easily detected, in comparison with standards, in an interference-free area of the electropherogram. Diastereomeric separation of TR glucuronides in in vitro samples was achieved with 10 mM ammonium acetate-100 mM formic acid electrolyte solution at pH 2.75 and with basic micellar 25 mM tetraborate-70 mM SDS electrolyte solution at pH 10.45. Both separations showed that glucuronidation in vitro produces glucuronide diastereomers in different amounts. The authentic TR urine sample was also analysed by micellar method, but unambiguous identification of the glucuronide diastereomers was not achieved owing to many interferences.

Analgesics, Opioid↗
PubMed2006

Enantiomeric determination of tramadol and O-desmethyltramadol by liquid chromatography- mass spectrometry and application to postoperative patients receiving tramadol.

A liquid chromatographic-mass spectrometric assay with atmospheric pressure chemical ionization is presented for quantification (selected-ion mode) of tramadol (T) and O-desmethyltramadol (ODT) in blood plasma after liquid-liquid extraction. The enantiomeric separation was achieved on a Chiralpak AD column containing amylose tris-(3,5-dimethylphenylcarbamate) as chiral selector. The validation data were within acceptable limits. The assay was successfully applied to authentic plasma samples allowing confirmation of diagnosis of overdose or intoxication as well as monitoring of patients' compliance. In postoperative patients receiving T, mean therapeutic plasma concentrations were determined as follows: 422.8 and 440.8 ng/mL for (+)-T and (-)-T, respectively, and 23.7 and 40.7 ng/mL for (+)-ODT and (-)-ODT, respectively. Quantitative results demonstrated a great interindividual variability in postoperative plasma analgesic drug concentrations and, therefore, a wide therapeutic concentration range. The 7.7% of the samples that revealed negative results for ODT are likely explained by genetic polymorphisms resulting in absent enzyme activity of CYP2D6.

Analgesics, Opioid↗
PubMed2004

Clinical pharmacology of tramadol.

Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.

Acute Disease↗
PubMed1997

[Tramadol in acute pain].

Tramadol has been in clinical use in Germany since the late 1970s and has proven effective in both experimental and clinical pain without causing serious cardiovascular or respiratory side effects. Moreover, the negligible abuse potential of tramadol has meant that it has never been a restricted drug, and it therefore very quickly became the most popular analgesic of its class in Germany. Although tramadol has been used in myocardial emergencies, in trauma and obstetric pain, or to supplement balanced anaesthesia, most studies have investigated postoperative patients. The focus of this article is to review clinical experience with tramadol in the treatment of acute postoperative pain. Tramadol, a synthetic opioid of the aminocyclohexanol group, is a centrally acting analgesic with weak opioid agonist properties, and effects on noradrenergic and serotonergic neurotransmission. In addition, these opioid and nonopioid modes of action appear to act synergistically. Tramadol has been shown to provide effective analgesia after both intramuscular and intravenous administration for the treatment of postoperative pain. The drug is available in formulations suitable for oral, rectal and parenteral administration. Clinically effective analgesic doses of tramadol were comparable to those of pethidine (meperidine) and about 10 times higher than those of morphine. While it is not recommended as a supplement to general anaesthesia because of its insufficient sedative activity, tramadol has been successful in the treatment of postoperative pain. A randomised double-blind study reported acceptable analgesia with postoperative intravenous tramadol 50mg, repeated once if required after 30 minutes. It produced an effect similar to that of morphine 5mg or the alpha 2 agonist, clonidine 150 micrograms. In another study, it was shown that the 50mg dose of tramadol fulfilled the requirements of an analgesic for the treatment of moderate postoperative pain, whereas for severe pain a higher dose was recommended. Tramadol is generally well tolerated, the most common adverse events being nausea and vomiting. In contrast to agents such as morphine and pethidine, clinically relevant respiratory depression is rarely observed during tramadol administration at equipotent doses and consequently it can be recommended for first-line management of postoperative pain instead of morphine. It is also associated with a low incidence of cardiac depression and significantly less dizziness and drowsiness than morphine. Finally, the dependence and abuse potential with tramadol is negligible. Comparative studies have generally shown that tramadol is more effective than NSAIDs for controlling post operative pain. Use of a combination of tramadol and NSAIDs allows the tramadol dose to be reduced and results in a lower incidence of adverse effects. Patient controlled analgesia (PCA) with tramadol has been frequently used and is well accepted by patients. Wide individual variations exist with regard to analgesic requirements and, nowadays, it is generally accepted that adequate pain management implies systematic individualisation of the therapy, i.e. titration of the analgesic effect to individual needs. Demand and loading doses play a decisive role in the success of PCA. Analgesic failures requiring rescue medication are rare, but it should be stressed that these can always occur with weak opioids. In conclusion, tramadol can be recommended as a basic analgesic for the treatment of moderate to severe pain. In the event of analgesic failure with tramadol, there is no reason not to switch to more potent opioids. Although no studies are available regarding its use in the management of postoperative pain after day case surgery, tramadol is frequently administered with good results in such patients. The most important side effects of tramadol are nausea and emesis, which can often be prevented by slow injection and administration of a prophylactic antiemetic such as metoclopramid

Acute Disease↗
PubMed1997

[Pharmacology of tramadol].

(+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.

Administration, Oral↗
PubMed1993

Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones.

1. Tramadol is a centrally acting analgesic with low opioid receptor affinity and, therefore, presumably additional mechanisms of analgesic action. Tramadol and its main metabolite O-desmethyltramadol were tested on rat central noradrenergic neurones of the nucleus locus coeruleus (LC), which are involved in the modulation of nociceptive afferent stimuli. 2. In pontine slices of the rat brain the spontaneous discharge of action potentials of LC cells was recorded extracellularly. (-)-Tramadol (0.1-100 microM), (+)-tramadol (0.1-100 microM), (-)-O-desmethyl-tramadol (0.1-100 microM) and (+)-O-desmethyltramadol (0.01-1 microM) inhibited the firing rate in a concentration-dependent manner. (+)-O-desmethyltramadol had the highest potency, while all other agonists were active at a similar range of concentrations. 3. (-)-Tramadol (10, 100 microM) was less inhibitory in brain slices of rats pretreated with reserpine (5 mg kg-1, 5 h before decapitation) than in controls. 4. The effect of (-)-tramadol (10 microM) was abolished in the presence of the alpha 2-adrenoceptor antagonist, rauwolscine (1 microM), whilst that of (+)-O-desmethyltramadol (0.3 microM) virtually disappeared in the presence of the opioid antagonist, naloxone (0.1 microM). (+)-Tramadol (30 microM) and (-)-O-desmethyl-tramadol (10 microM) became inactive only in the combined presence of naloxone (0.1 microM) and rauwolscine (1 microM). 5. In another series of experiments, the membrane potential of LC neurones was determined with intracellular microelectrodes. (-)-Tramadol (100 microM) inhibited the spontaneous firing and hyper-polarized the cells; this effect was abolished by rauwolscine (1 microM). (+)-O-desmethyltramadol (10 microM)had a similar but somewhat larger effect on the membrane potential than (-)-tramadol. The (+)-O-desmethyltramadol-(10 microM) induced hyperpolarization was abolished by naloxone (0.1 microM).6. The hyperpolarizing effect of noradrenaline (30 microM) was potentiated in the presence of (-)-tramadol(100 microM), but not in the presence of (+)-O-desmethyltramadol (10 microM). There was no potentiation of the noradrenaline (30 microM) effect, when the cells were hyperpolarized by current injection to an extent similar to that produced by (-)-tramadol (100 microM).7. Both noradrenaline (100 microM) and (- )-tramadol (100 microM) decreased the input resistance.8. The results confirm that the analgesic action of tramadol involves both opioid and non-opioid components. It appears that (-)-tramadol inhibits the uptake of noradrenaline and via a subsequent increase in the concentration of endogenous noradrenaline indirectly stimulates alpha2-adrenoceptors. (+)-0-desmethyltramadol seems to stimulate directly opioid micro-receptors. The effects of (+)-tramadol and(-)-O-desmethyltramadol consist of combined micro-opioid and alpha2-adrenergic components.

Action Potentials↗
PubMed2001

Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes.

The metabolism of cis-tramadol has been studied in human liver microsomes and in cDNA-expressed human cytochrome P-450 (CYP) isoforms. Human liver microsomes catalyzed the NADPH-dependent metabolism of tramadol to the two primary tramadol metabolites, namely, O-desmethyl-tramadol (metabolite M1) and N-desmethyl-tramadol (metabolite M2). In addition, tramadol was also metabolized to two minor secondary metabolites (each comprising < or =3.0% of total tramadol metabolism), namely, N,N-didesmethyl-tramadol (metabolite M3) and N,O-didesmethyl-tramadol (metabolite M5). Kinetic analysis revealed that multiple CYP enzymes were involved in the metabolism of tramadol to both M1 and M2. For the high-affinity enzymes involved in M1 and M2 formation, K(m) values were 116 and 1021 microM, respectively. Subsequent reaction phenotyping studies were performed with a tramadol substrate concentration of 250 microM. In studies with characterized human liver microsomal preparations, good correlations were observed between tramadol metabolism to M1 and M2 and enzymatic markers of CYP2D6 and CYP2B6, respectively. Tramadol was metabolized to M1 by cDNA-expressed CYP2D6 and to M2 by CYP2B6 and CYP3A4. Tramadol metabolism in human liver microsomes to M1 and M2 was markedly inhibited by the CYP2D6 inhibitor quinidine and the CYP3A4 inhibitor troleandomycin, respectively. In summary, this study demonstrates that cis-tramadol can be metabolized to tramadol metabolites M1, M2, M3, and M5 in human liver microsomal preparations. By kinetic analysis and the results of the reaction phenotyping studies, tramadol metabolism in human liver is catalyzed by multiple CYP isoforms. Hepatic CYP2D6 appears to be primarily responsible for M1 formation, whereas M2 formation is catalyzed by CYP2B6 and CYP3A4.

Analgesics, Opioid↗
PubMed2006

Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers.

OBJECTIVE: To describe in detail the intravenous, single oral and multiple oral dose enantioselective pharmacokinetics of tramadol in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). METHODS: Eight EMs and eight PMs conducted three phases as an open-label cross-over trial with different formulations; 150 mg single oral tramadol hydrochloride, 50 mg single oral tramadol hydrochloride every 8 h for 48 h (steady state), 100 mg intravenous tramadol hydrochloride. Urine and plasma concentrations of (+/-)-tramadol and (+/-)-M1 were determined for 48 h after administration. RESULTS: In all three phases, there were significant differences between EMs and PMs in AUC and t(1/2) of (+)-tramadol (P< or =0.0015), (-)-tramadol (P< or =0.0062), (+)-M1 (P< or =0.0198) and (-)-M1 (P< or =0.0370), and significant differences in C(max) of (+)-M1 (P<0.0001) and (-)-M1 (P< or =0.0010). In Phase A and C, significant differences in t(max) were seen for (+)-M1 (P< or =0.0200). There were no statistical differences between the absolute bioavailability of tramadol in EMs and PMs. The urinary recoveries of (+)-tramadol, (-)-tramadol, (+)-M1 and (-)-M1 were statistically significantly different in EMs and PMs (P<0.05). Median antimodes of the urinary metabolic ratios of (+)-tramadol / (+)-M1 and (-)-M1 were 5.0 and 1.5, respectively, hereby clearly separating EMs and PMs in all three phases. CONCLUSION: The impact of CYP2D6 phenotype on tramadol pharmacokinetics was similar after single oral, multiple oral and intravenous administration displaying significant pharmacokinetic differences between EMs and PMs of (+)-tramadol, (-)-tramadol, -(+)-M1 and (-)-M1. The O-demethylation of tramadol was catalysed stereospecific by CYP2D6 in the way that very little (+)-M1 was produced in PMs.

Adult↗
PubMed1997

Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes.

1. Tramadol hydrochloride is a centrally acting opioid analgesic, the efficacy and potency of which is only five to ten times lower than that of morphine. Opioid, as well as non-opioid mechanisms, may participate in the analgesic activity of tramadol. 2. [3H]-5-hydroxytryptamine (5-HT) uptake in rat isolated cortical synaptosomes was studied in the presence of tramadol, desipramine, fluoxetine, methadone and morphine. Methadone and tramadol inhibited synaptosomal [3H]-5-HT uptake with apparent Kis of 0.27 +/- 0.04 and 0.76 +/- 0.04 microM, respectively. Morphine essentially failed to inhibit [3H]-5-HT uptake (Ki 0.50 +/- 0.30 M). 3. Methadone, morphine and tramadol were active in the hot plate test with ED50s of 3.5, 4.3 and 31 mg kg-1, respectively. At the highest tested dose (80 mg kg-1) tramadol produced only 77 +/- 5.3% of the maximal possible effect. 4. When [3H]-5-HT uptake was examined in synaptosomes prepared from rats 30 min after a single dose of morphine, methadone or tramadol, only tramadol (31 mg kg-1, s.c., equal to the ED50 in the hot plate test) and methadone (35 mg kg-1, s.c., equal to the ED90 in the hot plate test) decreased uptake. 5. Animals were chronically treated for 15 days with increasing doses of tramadol or methadone (5 to 40 mg kg-1 and 15 to 120 mg kg-1, s.c., respectively). Twenty-four hours after the last drug injection, a challenge dose of methadone (35 mg kg-1, s.c.) or tramadol (31 mg kg-1, s.c.) was administered. [3H]-5-HT uptake was not affected in synaptosomes prepared from rats chronically-treated with methadone, whereas chronic tramadol was still able to reduce this parameter by 42%. 6. Rats chronically-treated with methadone showed a significant increase in [3H]-5-HT uptake (190%) 72 h after drug withdrawal. In contrast, [3H]-5-HT uptake in rats chronically-treated with tramadol (110%) did not differ significantly from control animals. 7. These results further support the hypothesis that [3H]-5-HT uptake inhibition may contribute to the antinociceptive effects of tramadol. The lack of tolerance development of [3H]-5-HT uptake, together with the absence of behavioural alterations after chronic tramadol treatment, suggest that tramadol has an advantage over classical opioids in the treatment of pain disorders.

Analgesics, Opioid↗
PubMed2006

Tramadol for osteoarthritis.

BACKGROUND: Tramadol is increasingly used for the treatment of osteoarthritis because, in contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol does not produce gastrointestinal bleeding or renal problems, and does not affect articular cartilage. OBJECTIVES: We sought to determine the analgesic effectiveness, the effect on physical function, the duration of benefit and the safety of oral tramadol in people with osteoarthritis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS databases up to August 2005. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the effect of tramadol or tramadol plus paracetamol on pain levels and/or physical function in people with osteoarthritis. No language restriction was applied. DATA COLLECTION AND ANALYSIS: We analyzed separately placebo-controlled and active-controlled studies. We used fixed-effect models for the meta-analyses as the results across studies were similar. MAIN RESULTS: We included eleven RCTs with a total of 1019 participants who received tramadol or tramadol/paracetamol and 920 participants who received placebo or active-control. The placebo-controlled studies indicated that participants who received tramadol had less pain (-8.5 units on a 0 to 100 scale; 95% confidence interval (CI) -12.0 to -5.0) than patients who received placebo. This represents a 12% relative decrease in pain intensity from baseline. Participants who received tramadol had a 37% increase (95% CI 1.2 to 1.5) in the likelihood of reporting moderate improvement (number needed to treat to benefit = 6; 95% CI 4 to 9). Participants who received tramadol had 2.27 times the risk of developing minor adverse events and 2.6 times the risk of developing major adverse events, compared to participants who received placebo. Of every eight people who receive tramadol or tramadol/paracetamol, one will stop taking the medication because of adverse events, number needed to treat to harm (NNTH)= 8 (95% CI 7 to 12) for major adverse events. No conclusion could be drawn on how tramadol or tramadol/paracetamol compared with available pharmacological treatments because of the limited number of studies that evaluated such therapies. AUTHORS' CONCLUSIONS: Tramadol or tramadol/paracetamol decreases pain intensity, produces symptom relief and improves function, but these benefits are small. Adverse events, although reversible and not life threatening, often cause participants to stop taking the medication and could limit tramadol or tramadol plus paracetamol usefulness.

Acetaminophen↗