Clinical Pharmacology of Tramadol

Abstract

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.

Use of tramadol in early pregnancy and congenital malformation risk

“…It was registered in Sweden in 1995 but is has been on the European market since the 1970s [8] and it is used for moderate to severe pain. Despite the widely use of the drug little is known about its possible teratogenicity.…”

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

“…In most countries, tramadol is the only clinically available non -scheduled opioid. The marketed tramadol is a racemic mixture containing 50% of (+) tramadol and 50% of (-) tramadol, and is mainly metabolized to O-desmethyltramadol (M1) and N-desmethyltramadol (M2) by the cytochromes P450 CYP2B6/CYP3A4 and CYP2D6, respectively [1,2]. The pharmacokinetic and pharmacodynamic properties of tramadol are known to be both enantioselective and influenced by the CYP2D6 phenotype [1,[3][4][5][6].…”

“…The marketed tramadol is a racemic mixture containing 50% of (+) tramadol and 50% of (-) tramadol, and is mainly metabolized to O-desmethyltramadol (M1) and N-desmethyltramadol (M2) by the cytochromes P450 CYP2B6/CYP3A4 and CYP2D6, respectively [1,2]. The pharmacokinetic and pharmacodynamic properties of tramadol are known to be both enantioselective and influenced by the CYP2D6 phenotype [1,[3][4][5][6]. The analgesic effect of tramadol is mainly due to morphinomimetic effects, the main metabolite of the CYP2D6 pathway, (+)-M1, showing the highest affinity for opioid receptors [1,7].…”

“…The pharmacokinetic and pharmacodynamic properties of tramadol are known to be both enantioselective and influenced by the CYP2D6 phenotype [1,[3][4][5][6]. The analgesic effect of tramadol is mainly due to morphinomimetic effects, the main metabolite of the CYP2D6 pathway, (+)-M1, showing the highest affinity for opioid receptors [1,7]. Accordingly, CYP2D6 ultrarapid metabolizers (UM) have been shown to produce high levels of M1 and to display a more efficient anti-nociceptive response, as well as more adverse effects, with tramadol [5,6].…”

Safety and efficacy of tramadol hydrochloride on treatment of premature ejaculation

“…48 As a result of its short half-life, tramadol can be used in an on-demand dosing protocol. 58 The inability to control and defer ejaculation until the female partner is sexually satisfied in at least 50% of intercourse attempts was proposed as a definition of PE by Masters and Johnson. 3 An inherent problem exists in defining a man as dysfunctional based on the sexual response of his partner, as only 30% of women achieve orgasm during sexual intercourse, regardless of the extent of their partner's ejaculatory control and latency.…”