The distinct properties of tapentadol and tramadol generate different CNS functional activities, making each drug the prototype of different classes of opioid/nonopioid analgesics. Tramadol's analgesia derives from relatively weak µ-opioid receptor (MOR) agonism, plus norepinephrine and serotonin reuptake inhibition, provided collectively by the enantiomers of the parent drug and a metabolite that is a stronger MOR agonist, but has lower CNS penetration. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effect. Accordingly, tramadol is well-suited for pain conditions for which a strong opioid component is not needed-and it has the benefit of a low abuse potential; whereas tapentadol, a schedule-II controlled substance, is well-suited for pain conditions requiring a strong opioid component-and it has the benefit of greater gastrointestinal tolerability compared to classical strong opioids. Both drugs offer distinct and complementary clinical options.

The novel centrally acting analgesic tapentadol [(Ϫ)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, -opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the ␣ 2 -adrenoceptor antagonist yohimbine. Two different pain models were used: 1) low-intensity tail-flick and 2) spinal nerve ligation. In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, NRI, and unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dose-dependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both isobolographic analysis of occupationeffect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2-to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action.

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We have studied the pharmacokinetics of a single bolus dose of tramadol 2 mg kg-1 injected either i.v. or into the caudal epidural space in 14 healthy children, aged 1-12 yr, undergoing elective limb, urogenital or thoracic surgery. Serum concentrations of tramadol and its metabolite O-demethyl tramadol (MI) were measured in venous blood samples at various intervals up to 20 h by non-stereoselective gas chromatography with nitrogen-selective detection. All pharmacokinetic variables were evaluated using a non-compartmental model. After a single i.v. injection (n = 9), the mean elimination half-life of tramadol was 6.4 (SD 2.7) h, with a volume of distribution of 3.1 (1.1) litre kg-1 and total plasma clearance of 6.1 (2.5) ml kg-1 min-1. All of these pharmacokinetic variables were similar to those reported previously in adults. After caudal epidural administration (n = 5), mean elimination half-life was 3.7 (0.9) h, volume of distribution was 2.0 (0.4) litre kg-1 and total clearance was 6.6 (1.9) ml kg-1 min-1. The caudal/i.v. quotient of the AUC was 0.83, which confirms that there is extensive systemic absorption of tramadol after caudal administration. Serum concentrations of MI showed a time course typical of a metabolite after both modes of administration. Serum concentrations of MI after caudal administration were lower than those after i.v. injection.

Tapentadol is a novel, centrally acting oral analgesic with a dual mode of action that has demonstrated efficacy in preclinical and clinical models of pain relief. The present study investigated and characterized the absorption, metabolism, and excretion of tapentadol in humans. Four healthy male subjects received a single 100-mg oral dose of 3-[14C]-labeled tapentadol HCl for evaluation of the pharmacokinetics of the drug and the excretion balance of radiocarbon. The concentration-time profiles of radiocarbon in whole blood and serum and radiocarbon excretion in the urine and feces, and the expired CO2 were determined. The serum pharmacokinetics and excretion kinetics of tapentadol and its conjugates were assessed, as was its tolerability. Absorption was rapid (with a mean maximum serum concentration [Cmax], 2.45 microg-eq/ml; a time to Cmax, 1.25-1.5 h), and the drug was present primarily in the form of conjugated metabolites (conjugated:unconjugated metabolites = 24:1). Excretion of radiocarbon was rapid and complete (>95% within 24 h; 99.9% within 5 days) and almost exclusively renal (99%: 69% conjugates; 27% other metabolites; 3% in unchanged form). No severe adverse events or clinically relevant changes in vital signs, laboratory measurements, electrocardiogram recording, or physical examination findings were reported. In our study group, it was found that a single oral dose of tapentadol was rapidly absorbed, then excreted into the urine, primarily in the form of conjugated metabolites, and was well tolerated.