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Pharmacology: (Summary of Pharmacodynamics and Pharmacokinetics): Tramadol is a centrally acting analgesic. Tramadol is a non-selective, pure agonist in the μ, and K opiate receptors, and it attaches itself most effectively to the μ-receptor. Other factors that contribute to its analgesic effects are inhibition of neuronal re-uptake of noradrenaline and enhancement of 5-HT release.
Tramadol has an antitussive effect. In opposition to morphine, analgesic doses of tramadol do not produce respiratory depression during a wide interval. Tramadol does not affect to gastrointestinal motility and its effects on the cardiovascular system are mild. The potency of tramadol is 1/10-1/6 of that of the morphine.
Antinociceptive efficacy of TRACIDOL has been shown with osteoarthritis patients.
Absorption: Tramadol is absorbed almost completely when administered orally, and the absolute efficiency is approximately 70%. Tramadol metabolises into O-desmethyl Tramadol, which has proven to have an analgesic effect in rodents. The half-life elimination of Tramadol is approximately 6 hours. The half-life increases, however, to 9 with the capsules of TRACIDOL due to the long absorption time.
When a single capsule of 200 mg of TRACIDOL was given to a fasting patient, the average maximum content concentration of the plasma (Cmax) achieved was 299.59 ng·ml-1 (in the interval 240-300 ng/ml). A median Tmax 9.59 hours (9-12 hours) was related to this. After the dosage had been adapted, the efficiency of Tramadol produced by a capsule of TRACIDOL of 200 mg was complete, in comparison with 50 mg of immediately liberated Tramadol. In the presence of food, the availability and controlled release properties of TRACIDOL capsules were maintained, with no evidence of dose dumping. In addition, a steady state study has shown that the capsule of 200 mg of TRACIDOL has a comprehensive systemic predisposition that corresponds to an immediately absorbed product, (immediate release capsule 50 mg). The scatter of the patients participating in the study was not superior to that of the reference group.
Distribution: Tramadol has a high tissue affinity with an apparent volume of distribution of 203 ± 40 litres after oral dosing in healthy volunteers. Protein binding is limited to 20%.
Biotransformation: In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by the factor 2-4. Its half-life t½β (6 healthy volunteers) is 7.9 h (range 5.4-9.6 h) and is approximately that of tramadol. The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. The clinical consequences of any such interactions are not known.
Elimination: Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36 h respectively have been determined. In patients with renal insufficiency (creatinine clearance <5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h, respectively.
Linearity/non-linearity: Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range. A single dose-proportionality study has confirmed a linear pharmacokinetic response (in relation to tramadol and O-desmethyltramadol) following administration of the 100 mg, 150 mg and 200 mg capsules.
The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100 - 300 ng/ml is usually effective.
