Pharmacogenetics of Neonatal Opioid Toxicity Following Maternal Use of Codeine During Breastfeeding: A Case-Control Study (original) (raw)
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PLoS ONE, 2013
Background: Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety.
Establishing Causality of CNS Depression in Breastfed Infants Following Maternal Codeine Use
Pediatric Drugs, 2008
Background: We recently reported on a breastfed infant who succumbed to opioid toxicity following exposure Abstract to morphine, the active metabolite of codeine, which was prescribed to his mother who was a cytochrome P450 2D6 (CYP2D6) ultrarapid metabolizer. This report is believed to be the first case of neonatal fatality as a direct result of maternal drug excretion into breast milk and, therefore, it is critical to corroborate the causative relationship between maternal codeine use during breastfeeding and neonatal opioid toxicity with other existing evidence. Objective: To establish whether maternal use of codeine can be a cause of CNS depression in breastfed infants. Study design: A systematic review of the medical literature using several databases was conducted. The Naranjo Adverse Drug Reaction Probability Scale (NADRPS) was used to examine causality. Results: In addition to our case report, three abstracts and two full-length studies reported adverse drug reactions (ADRs) in infants exposed to codeine in breast milk. In total, 35 infants were identified. Specifically, ADRs were described as unexplained episodes of drowsiness, apnea, bradycardia, and cyanosis in suckling infants. Using the NADRPS, codeine was found to be a definite cause of CNS depression in breastfed infants. Conclusion: The use of codeine by breastfeeding mothers can cause adverse CNS events in breastfed infants. Physicians should recognize codeine use during breastfeeding as a cause of CNS depression in infants, and breastfeeding mothers should be educated on these adverse events before receiving codeine.
The pharmacogenetics of codeine pain relief in the postpartum period
The pharmacogenomics journal, 2015
The objective of this study was to examine interindividual variability in codeine requirements and pain management by examining select genetic polymorphisms in the codeine pharmacological pathway. The study included a nested cohort of 98 women who were prescribed codeine following cesarean section. Participants were genotyped for select polymorphisms of the COMT, ABCB1, CYP2D6, UGT2B7 and OPRM1 genes and instructed to describe their level of pain using the visual analog scale (mm) 1 h following each dose of codeine. Analysis revealed that reported pain increases with maternal age (P=0.041). Asians required more codeine than Caucasians (P=0.048). Significant differences in mean dose consumption were seen among the genotypic groups of the OPRM1 A118G (P=0.001) and UGT2B7 C802T (P=0.015) variants. These variants were found to predict codeine consumption in the cohort overall (P=0.000) and among Caucasians (P=0.001). These findings will assist in customizing therapy to effectively manag...
CYP2D6 Polymorphisms and Codeine Analgesia in Postpartum Pain Management: A Pilot Study
Therapeutic Drug Monitoring, 2011
Background: Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into morphine than normal individuals can. In contrast, poor metabolizers (PMs), individuals who have no active CYP2D6 genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine without attaining analgesia. Objective: The aim was to study the relationship between CYP2D6 genotype and codeine analgesia among women recovering from c-section. Methods: Forty-five mothers prescribed codeine provided a blood sample for CYP2D6 genotyping and recorded their pain level 4 times a day for 3 days immediately after a c-section. Codeine was used on an as-needed basis; doses and times were recorded. The relationship between CYP2D6 genotype, pain scores, need for codeine, and adverse events was studied. Theoretical morphine dose, based on CYP2D6 genotype, was estimated. Results: Women at the genotypic extremes reported codeine effects consistent with their genotype: the 2 PMs of codeine reported no analgesia as a result of taking codeine, whereas 2 of the 3 UMs reported immediate pain relief from codeine but stopped taking it due to dizziness and constipation. Much larger numbers are needed to study similar correlations among extensive and intermediate metabolizers. Conclusions: In this pilot study, the extreme CYP2D6 genotypes (PMs and UMs) seemed to predict pain response and adverse events. Larger sample sizes are needed to correlate the range of genotypes with pain response.
Effects of codeine on pregnancy outcome: results from a large population-based cohort study
European Journal of Clinical Pharmacology, 2011
Background Guidelines on codeine safety during pregnancy rely on small studies with inconsistent results, and associations between codeine use during pregnancy and increased risk of congenital malformations remain unsubstantiated. Objectives Our objective was to analyze the effect of codeine on pregnancy outcome. Methods Pregnancy outcomes of 2,666 women who used codeine during pregnancy were compared with 65,316 women who used no opioids during pregnancy. Information on maternal sociodemographic and medical characteristics, potential confounders, and pregnancy outcome was obtained from The Norwegian Mother and Child Cohort Study [den norske Mor & barn-undersøkelsen (MoBa)] data set and the Medical Birth Registry of Norway (MBRN) data set. The data sets were linked via the maternal personal identification number. Associations between codeine therapy and pregnancy outcomes were identified using logistic regression analyses. Results No significant differences were found in the survival rate [adjusted odds ratio (OR) 0.9, 95% confidence interval (CI) 0.6-1.5] or the congenital malformation rate (adjusted OR 0.9, 95% CI 0.8-1.1) between codeineexposed and unexposed infants. Codeine use anytime during pregnancy was associated with planned Cesarean delivery (adjusted OR 1.4, 95% CI 1.2-1.7; P<0.0001). Third-trimester use was associated with acute Cesarean delivery (adjusted OR 1.5, 95% CI 1.3-1.8; P<0.0001) and postpartum hemorrhage (adjusted OR 1.3, 95% CI 1.1-1.5; P<0.0001). No significant associations with other adverse pregnancy outcomes were found. Conclusions No effects of maternal codeine intake during pregnancy were observed on infant survival or congenital malformation rate. Our findings are reassuring; however, the association with acute Cesarean delivery and postpartum hemorrhage may justify a certain level of caution when administering codeine toward the end of pregnancy.
Pain, 1998
The analgesic effect and adverse events of the weak opioid codeine is assumed to be mediated by its metabolite morphine. The cytochrome P-450 enzyme CYP2D6 catalysing the formation of morphine exhibits a genetic polymorphism. Two distinct phenotypes, the extensive (EMs) and poor metabolisers (PMs), are present in the population. The prevalence of PMs in the Caucasian population is 7% to 10%. Since PMs do not express functional CYP2D6, they have a severely impaired capacity to metabolise drugs which are substrates of this enzyme. Provided the analgesic effect and the adverse events of codeine are mediated by its metabolite morphine, large phenotyperelated differences are to be expected and PMs, as they form only trace amounts of morphine, can serve as a model to test the hypothesis whether the analgesia and adverse events of codeine are mediated by the parent drug or its metabolite morphine. Therefore we have studied in a randomised placebo-controlled double-blind trial the analgesic effect of 170 mg codeine (p.o.) compared to 20 mg morphine (p.o.) and placebo in 9 EMs and 9 PMs using the cold pressor test. The duration and intensity of the side effects were assessed using visual analogue scales (VAS). Codeine and morphine concentrations were measured in serum and urine. Compared to placebo, 20 mg morphine caused a significant increase in pain tolerance in both phenotypes, EMs and PMs (16.2 ± 27.4 vs. −0.66 ± 27.4 s × h, n = 18). However, following administration of codeine, analgesia was only observed in EMs but not in PMs (EMs: 54.9 ± 42.2 vs. 1.7 ± 4.2 s × h, P Ͻ 0.01; PMs: 9.6 ± 10.9 vs. 3.3 ± 23.7 s × h, not significant). Adverse events were significantly more pronounced after morphine and codeine compared to placebo in both EMs and PMs. In contrast to the phenotype-related differences in the analgesic effect of codeine, however, no difference in adverse events between the phenotypes could be observed. In the pharmacokinetic studies, significant differences between the two phenotypes in the formation of morphine after codeine administration could be observed. Whereas morphine plasma concentrations were similar in PMs (C max : 44 ± 13 nmol/l; AUC: 199 ± 45 nmol × h/l) and EMs (C max : 48 ± 17 nmol/l); AUC: 210 ± 65 nmol × h/l) after morphine administration, following 170 mg codeine, morphine plasma concentrations comparable to those after morphine application were only observed in EMs (C max : 38 ± 16 nmol/l; AUC: 173 ± 90 nmol × h/l). In PMs only traces of morphine could be detected in plasma (C max : 2 ± 1 nmol/l; AUC: 10 ± 7 nmol × h/l). The percentage of the codeine dose converted to morphine and its metabolites was 3.9% in EMs and 0.17% in PMs. The interindividual variability in analgesia of codeine which is related to genetically determined differences in the formation of morphine clearly indicate that this metabolite is responsible for the analgesic effect of codeine. In contrast to the analgesic effect, frequency and intensity of the adverse events did not present significant differences between the two phenotypes. These findings have implications for the clinical use of codeine. Since side effects occurred in both EM and PM subjects, the use of codeine as an analgesic will expose 7% to 10% of patients who are PMs to the side effects of the drug without providing any beneficial analgesic effects. © 1998 International Association for the Study of Pain. Published by Elsevier Science B.V.
British Journal of Clinical Pharmacology, 1992
1 Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2 The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol 1-1 in the younger and 309, 251 and 169 nmol 1-1 in the older patients.
Sedative and Analgesic Cocktail During Parturition: Adverse Effects on Neonates?
Objective: To compare the neonatal outcome in women who received a sedative and analgesic medication during labor vs. women who did not. Methods: A consecutive sample of 5,196 nulliparous women not receiving medication and 411 nulliparous women receiving treatment with a combination of triazolam, codeine or morphine, terbutaline, and paracetamol (the medical cocktail) during prolonged latent phase of labor. Data on delivery, neonatal status, and transmission to neonatal intensive care unit (NICU) were extracted from patient files. Main outcome measures were Apgar scores, umbilical artery pH, mode of delivery, and transmissions to NICU. Results: Women who received the medical cocktail had a lower frequency of vaginal delivery (P = 0.01) and a higher risk of cesarean section due to birth complications (P < .001). Vaginally delivered neonates after cocktail had a lower five-minute Apgar score (P = .002). There were no significant differences in umbilical artery pH or transmissions t...
Detection of Codeine, Morphine, 6-Monoacetylmorphine, and Meconin in Human Umbilical Cord Tissue
Therapeutic Drug Monitoring, 2015
Background: Heroin abuse is a significant public health issue and is on the rise because of the unintended consequences of strengthening controls for nonmedical use of prescription pain killers. Included in this trend is an increase in opiate exposed newborns that are particularly vulnerable to a number of negative health outcomes. Methods: After presenting a fully validated liquid chromatography-tandem mass spectrometric method for codeine, morphine, 6-monoacetylmorphine, and meconin, a metabolite of the heroin contaminant noscapine, we compared the outcome of 46 authentic umbilical specimens with the results generated using a previous less sensitive method that did not include meconin. Additionally, we provided a summary of opiate finding from a year-long survey of specimens received into a commercial reference laboratory. Results: The limits of detection for all 4 compounds were 0.1 ng/g, the limit of quantitation was 0.2 ng/g, and the assay was linear from 0.2 to 10.0 ng/g. Of the 46 comparative specimens, this method improved the identification of heroin exposure from 2 to 5, and the year-long survey identified 86 heroin-exposed newborns with 11 of them identified by the sole identification of meconin. Conclusions: This study demonstrated that a more sensitive analytical platform and the inclusion of meconin in the opiates assay improved the ability to distinguish between in utero heroin exposure and maternal administration of codeine or morphine.