Tramadol withdrawal in a neonate: only one of the clinical presentations to be anticipated…

Abstract

Dear editor,We read the case report on tramadol withdrawal recentlypublished in this journal with great interest. The authorsdescribed a full-term neonate who developed clinical signsof opioid-related withdrawal on the second day of life afterbeing exposed to high dose (200 –400 mg/day) maternaltramadol intake throughout pregnancy. Symptom controlwith tinktura opii was achieved, and treatment was taperedover 2 weeks [ 1]. The authors hereby confirmed thattramadol, a moderately potent opioid, can also result inneonatal withdrawal, similar to observations after maternalcodeine intake. However, a single case observation does notrepresent the interindividual variability in clinical symp-toms. We therefore felt it appropriate to draw the attentionof the reader to recently reported observations on theinterindividual variability in the pharmacokinetics andpharmacodynamics of moderately potent opioids such astramadol and codeine in perinatal life [ 2–6].Firstly, interindividual metabolic elimation clearance oftramadol in neonates can only to a limited extent (54%) beexplained by the postmenstrual age alone [ 2]. Morerecently, it was documented that cytochrome P450 (CYP)2D6 polymorphisms explain the interindividual variabilityobserved in neonatal metabolic clearance [ 3]. This meansthat metabolic clearance capacity through O -demethyltramadol in part depends on age and on CYP2D6 poly-morphisms: a preterm neonate will display phenotypic lowCYP2D6 activity, while in term neonates and beyond,CYP2D6 activity score is also a relevant contributor ofphenotypic metabolic clearance. It is to be anticipated thatthis will have an impact on the extent and severity of cen-tral nervous system depression (decreased) or withdrawal(enhanced clearance) shortly after birth [ 2, 3].Secondly, as advocated by international organizationssuch as the World Health Organization, the majority ofneonates are breastfed. The mean contribution of postnatalexposure of the newborn to tramadol through mother ’smilk (3%) has been recently described based on observa-tions collected in 75 breastfeeding mothers treated withtramadol for post-caesarian analgesia [ 4]. In the specificsetting of 2 –3 days postnatal exposure of neonates whosemothers were not treated with tramadol before delivery, theexposed infants had similar characteristics, including Apgarscores at birth and neurologic and adaptive capacity scorescompared to controls. Once again, these observations aremean values and were collected in the specific setting ofpost-caesarean analgesia. Therefore, they may not representthe complete spectrum of interindividual variability. Fol-lowing a single case of fatal poisoning in a breastfednewborn after maternal codeine intake, the link between