Background. Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available. Methods. A population pharmacokinetic analysis of tramadol and M1 time-concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time-concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity. Results. Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h-1 [70 kg]-1) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric '1/4 power' models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg]-1) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance. Conclusions. Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 μg litre-1 is achieved after a bolus of tramadol hydrochloride 1 mg kg-1 and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg-1 h-1 at 25 weeks PCA, 0.14 mg kg-1 h-1 at 30 weeks PCA, 0.17 mg kg-1 h-1 at 35 weeks PCA, 0.18 mg kg-1 h-1 at 40 weeks, 0.19 mg kg-1 h-1 at 50 weeks PCA to 1 yr, 0.18 mg kg-1 h-1 at 3 yr and 0.12 mg kg-1 h-1 in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.

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British Journal of Anaesthesia
Department of Pediatric Surgery

Allegaert, K.M, Anderson, B.J, Verbesselt, R, Debeer, A, de Hoon, J.N, Devlieger, H, … Tibboel, D. (2005). Tramadol disposition in the very young: An attempt to assess in vivo cytochrome P-450 2D6 activity. British Journal of Anaesthesia, 95(2 PAPER), 231–239. doi:10.1093/bja/aei170