Garrido María J, Habre Walid, Rombout Ferdinand, Trocóniz Iñaki F
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Apartado 177, Pamplona, Spain.
Pharm Res. 2006 Sep;23(9):2014-23. doi: 10.1007/s11095-006-9049-7. Epub 2006 Aug 9.
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.
曲马多（T）在儿童中的疗效尚不清楚，因为该人群形成活性代谢物O-去甲基曲马多（M1）的能力以及母体化合物是否对疗效有贡献仍不明确。目的是建立儿童T的群体药代动力学/药效学模型，确定主要活性成分。
104名平均年龄为4.55岁的儿童在手术结束时于2.5分钟内静脉注射1mg/kg剂量的T。如果疼痛缓解不充分，则在15、30和/或45分钟时额外给予0.33mg/kg剂量。在6小时内测量血浆样本和镇痛反应，如哭闹和活动情况。
T的中央室表观分布容积、稳态表观分布容积和总血浆清除率估计值分别为8L、46.2L和15.2L/h。M1形成清除率仅代表T的次要消除途径。发现T和M1的效应部位浓度分别是活动和哭闹反应的最佳预测指标。T和M1的稳态血浆浓度水平分别为100和15ng/ml时，疼痛充分缓解的概率为95%。
儿童有能力产生足够的M1以实现适当的疼痛缓解。所研究的反应变量进一步证明，不仅代谢物的阿片样作用相关，曲马多的非阿片样作用在其临床应用中似乎也有显著贡献。
