Tramadol

Tramadol has an oral absorption of 100%, with a mean bioavailability of 70% owing to a 20% to 30% first-pass metabolism after a single oral dose. After multiple oral dosing, the bioavailability may increase to 90% to 100%, which may be the result of a saturated first-pass hepatic metabolism. The bioavailability of tramadol after food intake, although increased, does not seem to be clinically relevant. The time to peak plasma concentration after an oral dose of the immediate-release tramadol is 1.6 to 1.9 hours. The time to peak plasma concentrations for the extended-release tramadol Ultram-ER is 12 hours.

Tramadol is rapidly distributed after oral intake with peak brain concentrations occurring at 10 minutes and at 20 to 60 minutes for its major active metabolite, O-desmethyl-tramadol (M1). The binding of tramadol to human plasma proteins is approximately 20%. After absorption and distribution, tramadol is extensively metabolized by the liver primarily via N– and O-demthylation and conjugation of O-demethylated compounds. The cytochrome P-450 (CYP450) system (CYP2D6 and CYP3A4 enzymes) appears to be much involved in the metabolism of tramadol, with alteration of tramadol pharmacokinetics seen in populations with varied amounts of CYP2D6 activity.

In total, 23 metabolites have been identified in humans (11 phase I metabolites and 12 conjugates). The major active metabolite is M1, which displays a μ-opioid receptor affinity 300 times greater than that of the parent drug, tramadol . The pharmacologic properties of many of the other metabolites have not been extensively studied but appear to have similar elimination half-lives and excretion via the kidneys. Elimination of tramadol and its metabolites occurs mostly through the kidneys (∼90%), with a negligible amount excreted in the bile and feces. The elimination half-life of tramadol is 5 to 6 hours, with that of M1 being slightly longer.

Elimination and metabolism, processes heavily dependent upon renal and hepatic mechanisms, are expected to be affected by changes in renal and/or hepatic function. The elimination half-life is not excessively prolonged, however, as long as one of the two excretion organs is virtually intact. In patients with severe cirrhosis of the liver, the elimination half-life of tramadol was extended to a mean of 13 hours and a maximum of 22 hours. The manufacturer (Ortho-McNeil) has recommended that its use be avoided in patients with liver failure.

In patients with renal failure (creatinine clearance <  5 ml/min), the mean elimination half-life was prolonged to about 11 hours, with a maximum of 19 hours. Dialysis does not have a significant effect on the plasma concentrations of tramadol. The total amount of tramadol and M1 removed after a 4-hour dialysis period (hemodialysis, intermittent or continuous hemofiltration, or peritoneal dialysis) was less than 7% of the administered dose.