Population pharmacokinetic/pharmacodynamic modelling of the analgesic effects of tramadol in pediatrics

The efficacy of tramadol (T) in children is not clearly understood because it is still unknown the ability of that population to form the active metabolite O-demethyltramadol (M1) and, whether or not the parent compound has a contribution to the efficacy. The aim was to develop a population pharmacokinetic/pharmacodynamic model for T in pediatrics, identifying the main active components. One hundred four children, mean age (4.55 years) received intravenously 1 mg/kg dose of T over 2.5 min at the end of surgery. If pain relief was inadequate, then an additional 0.33 mg/kg dose was given at 15, 30 and/or 45 min. Plasma samples and analgesic responses such as crying and movement were measured during a 6-h period. The estimates of the apparent volumes of distribution of the central compartment and at steady state and total plasma clearance of T were 8 l, 46.2 l, and 15.2 l/h, respectively. M1 formation clearance represented only a minor elimination pathway of T. Effect site concentrations of T and M1 were found to be the best predictors of the movement and crying responses, respectively. Steady-state plasma concentration levels of T and M1 of 100 and 15 ng/ml were associated with a 95% probability of adequate pain relief. Children have the ability to produce enough M1 to achieve proper pain relief. The response variables investigated give further evidence that not only the opioid effects of the metabolite are relevant, also the non-opiod effects of tramadol seem to give a significant contribution in its clinical use.