Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, Other opioids
ATC code: N02A X02

Tramadol is a centrally acting analgesic. It is a pure non-selective μ, delta and k morphine receptor agonist with a higher affinity for μ receptors. Other mechanisms responsible for the product’s analgesic effects include the inhibition of the neuronal re-uptake of noradrenalin and an increase in serotonin release.

Tramadol has an antitussive effect. Unlike morphine, broad ranges of analgesic tramadol doses do not have any respiratory depressant effect. Nor is there any effect on gastro- intestinal motility. The effects on the cardiovascular system tend to be slight. Tramadol has 1/10 to 1/6 the potency of morphine.

Paediatric population
Effects of enteral and parenteral administration of tramadol have been investigated in clinical trials involving more than 2000 paediatric patients ranging in age from neonate to 17 years of age. The indications for pain treatment studied in those trials included pain after surgery (mainly abdominal), after surgical tooth extractions, due to fractures, burns and traumas as well as other painful conditions likely to require analgesic treatment for at least 7 days.

At single doses of up to 2 mg/kg or multiple doses of up to 8 mg/kg per day (to a maximum of 400 mg per day) efficacy of tramadol was found to be superior to placebo, and superior or equal to paracetamol, nalbuphine, pethidine or low dose morphine. The conducted trials confirmed the efficacy of tramadol. The safety profile of tramadol was similar in adult and paediatric patients older than 1 year (see section 4.2).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Following oral administration of a single dose, Tramadex OD is almost completely absorbed (>90%).

The absolute bioavailability is approximately 70%, independent of food intake. The difference between the tramadol absorbed and the non-metabolised available tramadol is probably due to a weak first-pass effect. The first-pass effect following oral administration is a maximum of 30%.

Tramadol has a high tissue affinity (volume of distribution = 203 ± 40 litres). Approximately 20% is bound to plasma proteins.

Following single-dose administration of one 200 mg Tramadex OD prolonged- release tablet, in a fasted state, a mean maximum plasma concentration (Cmax) of 241 ± 62 ng/ml is reached after a median time (tmax) of 6.0 hours.

Tramadol crosses the blood-brain barrier and the placenta. Very small quantities of the active substance and its O-demethylated derivative have been found in breast milk (0.1% and 0.02% of the administered dose respectively).

The elimination half-life is approximately 6 hours, regardless of route of administration. The half life can be prolonged by a factor of approximately 1.4 in patients over 75 years of age.

In man, tramadol is extensively metabolised by N- and O-demethylation and by conjugation of the O-demethylation products with glucuronic acid. Only the O-desmethyltramadol metabolite is pharmacologically active. Considerable quantitative inter-individual differences have been observed between the other metabolites: 11 different metabolites have been identified to date in urine. Tests on animals showed that O-desmethyltramadol is more potent than the parent molecule by a factor of 2 to 4. Its half life (6 healthy volunteers) is 7.9 hours (range 5.4 to 9.6 hours), similar to that of tramadol.

The inhibition of cytochrome CYP3A4 and/or CYP2D6, the isozymes responsible for biotransformation of tramadol could modify the plasma concentration of tramadol or its active metabolite. Tramadol and its metabolites are almost wholly excreted in urine.
Cumulative urinary excretion accounts for 90% of the total radioactivity of the administered dose. The half-life may be slightly longer in the case of hepatic or renal impairment.
In patients with liver cirrhosis, an elimination half-life of 13.3 ± 4.9 hours (tramadol) and 18.5 ± 9.4 hours (O-desmethyltramadol) has been observed, with one extreme case of elimination half-lives of 22.3 and 36 hours respectively. In renal insufficiency (creatinine clearance < 5 ml/min), elimination half-lives of 11 ± 3.2 and 16.9 ± 3 hours respectively have been observed, with one extreme case of 19.5 and 43.2 hours respectively. Tramadex OD presents a linear pharmacokinetic profile within the recommended therapeutic dosing regimen.

The relationship between serum concentration and analgesic effect is dose-dependent but varies considerably between individuals. A serum concentration of 100 ng/ml to 300 ng/ml is usually effective.

Paediatric population
The pharmacokinetics of tramadol and O-desmethyltramadol after single-dose and multiple- dose oral administration to subjects aged 1 year to 16 years were found to be generally similar to those in adults when adjusting for dose by body weight, but with a higher between-subject variability in children aged 8 years and below.
In children below 1 year of age, the pharmacokinetics of tramadol and O-desmethyltramadol have been investigated, but have not been fully characterized.
Information from studies including this age group indicates that the formation rate of O-desmethyltramadol via CYP2D6 increases continuously in neonates, and adult levels of CYP2D6 activity are assumed to be reached at about 1 year of age. In addition, immature glucuronidation systems and immature renal function may result in slow elimination and accumulation of O-desmethyltramadol in children under 1 year of age.