ORIGINAL ARTICLEEstimation of infant dose and exposure to pethidine and norpethidine via breast milk following patient-controlled epidural pethidine for analgesia post caesarean delivery
Introduction
Pethidine is a μ-opioid receptor agonist with potent spinal and supraspinal effects.1 Its moderate lipophilicity makes it attractive for epidural administration, after which it provides rapid onset of analgesia and a very low risk of respiratory depression. In adults, pethidine has a short elimination half-life (mean 3.2 h).2 It is metabolised in the liver to pharmacologically active norpethidine, with a much longer half-life (15–40 h), which is then excreted via the kidneys.3 Norpethidine may accumulate after prolonged or high-dose pethidine administration or in renal failure and cause adverse central nervous system effects such as agitation, tremulousness, hallucinations and convulsions.3, 4, 5 Metabolism of pethidine is impaired in neonates and infants,6 and in two separate studies, its half-life was longer than in adults, with mean values of 10.7 h and 22.7 h.7, 8
Pethidine continues to be widely used in birth suites in Australasia and the United Kingdom for labour analgesia via the intramuscular (i.m.) route. The potentially harmful effects of parenteral pethidine in neonates were demonstrated approximately three decades ago.9, 10, 11, 12, 13, 14, 15 Breastfed infants of mothers who receive repeated post-caesarean doses of intravenous (i.v.) pethidine show diminished alertness on day 3–4 of life.16, 17 Pethidine excretion in breast milk following i.m. or i.v. administration postpartum has been investigated previously,18, 19, 20 and infant exposure to pethidine (relative infant dose) ranged from 0.6 to 6% of the weight-adjusted maternal dose. Only one study measured norpethidine in milk, with the metabolite contributing an additional estimated infant dose of 6%.20
Administration of pethidine early after caesarean delivery using patient-controlled epidural analgesia (PCEA) is efficacious, but significant maternal plasma concentrations of pethidine and norpethidine can be measured at the time therapy is ceased.21 Given that lactation commences around the same time, the primary aim of our study was to estimate the transfer of pethidine and norpethidine via breast milk following PCEA administration of pethidine to women post-caesarean delivery. We also measured pethidine and norpethidine in the exposed infant’s plasma (expressed as a percentage of the corresponding concentrations in the mother’s plasma), as a novel additional measure of drug exposure via milk.
Section snippets
Methods
This prospective observational study was approved by the Human Research and Ethics Committee of King Edward Memorial Hospital for Women and registered with the Australian and New Zealand Clinical Trials Registry. Twenty healthy women undergoing elective caesarean section were recruited at antenatal clinics and gave written informed consent to their own and their infants’ participation. The sample size was chosen based on our previous experience of sparse-sampling study design for drug studies
Results
The first woman in the study was transferred to another hospital for ongoing care and therefore only contributed the first samples of plasma and milk and neonatal plasma. Maternal and infant demographics are shown in Table 1. There were 9 male and 11 female neonates. Characteristics of the maternal pethidine dose, its relation to infant blood sampling and NACS administration, as well as NACS, are shown in Table 2. The median [IQR] pethidine dose of 670 [346–818] mg was delivered at a mean (95%
Discussion
The combined pethidine plus norpethidine milk RID estimates of 1.4% and 0.9% at our two separate sampling times compare favourably with the notional 10% cut-off value of acceptability that has been applied to a wide range of drugs,26 provided the drug effects on the infant are also acceptable.29 Our RID values are similar to the 1.3% that can be calculated using the highest pethidine concentration occurring after a 50-mg i.v. dose18 and lower than the 1.2–3.5% after 25–75-mg single i.v.
Acknowledgements
This study was funded by a grant from the Women and Infants Research Foundation of Western Australia. The corresponding author of this article has no affiliation with the funding body. The design and implementation of this original work were completely independent of the funding source.
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