Lauren E. Kelly

More Codeine Fatalities After Tonsillectomy in North American Children

In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.

Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia.

OBJECTIVE To quantify the incidence of central nervous system (CNS) depression in neonates breastfed by mothers medicated with oxycodone as compared with neonates whose breastfeeding mothers used codeine or acetaminophen only. STUDY DESIGN We retrospectively compared 3 cohorts in 533 breastfeeding mother-infant pairs exposed to oxycodone (n = 139), codeine (n = 210), or acetaminophen only (n = 184). Standardized questionnaires were administered to mothers during the postpartum period to identify maternal and neonatal health outcomes temporally related to analgesia exposure. RESULTS Maternal exposure to oxycodone during breastfeeding was associated with a 20.1% rate of infant CNS depression (28/139) compared with 0.5% in the acetaminophen group (1/184; P < .0001; OR, 46.16; 95% CI, 6.2-344.2) and 16.7% in the codeine group (35/210; P > .05; OR, 0.79; 95% CI, 0.46-1.38). Mothers of neonates with symptoms in the oxycodone and codeine cohorts took significantly higher doses of medication compared with mothers of infants with no symptoms in the same cohorts (P = .0005 oxycodone; median, 0.4 mg/kg/day; range, 0.03-4.06 mg/kg/day versus median, 0.15 mg/kg/day; range, 0.02-2.25 mg/kg/day; codeine P < .001; median, 1.4 mg/kg/day; range, 0.7-10.5 mg/kg/day versus 0.9 mg/kg/day; range, 0.18-5.8 mg/kg/day). Mothers were significantly more likely to experience sedative adverse effects from oxycodone as compared with codeine (P < .0001; OR, 17.62; 95% CI, 9.95-31.21). CONCLUSION Oxycodone is not a safer alternative to codeine in breastfed infants.

Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial

BACKGROUND: Pediatric sleep disordered breathing is often caused by hypertrophy of the tonsils and is commonly managed by tonsillectomy. There is controversy regarding which postsurgical analgesic agents are safe and efficacious. METHODS: This prospective randomized clinical trial recruited children who had sleep disordered breathing who were scheduled for tonsillectomy +/− adenoid removal. Parents were provided with a pulse oximeter to measure oxygen saturation and apnea events the night before and the night after surgery. Children were randomized to receive acetaminophen with either 0.2–0.5 mg/kg oral morphine or 10 mg/kg of oral ibuprofen. The Objective Pain Scale and Faces Scale were used to assess effectiveness on postoperative day 1 and day 5. The primary endpoint was changes in respiratory parameters during sleep. RESULTS: A total of 91 children aged 1 to 10 years were randomized. On the first postoperative night, with respect to oxygen desaturations, 86% of children did not show improvement in the morphine group, whereas 68% of ibuprofen patients did show improvement (14% vs 68%; P < .01). The number of desaturation events increased substantially in the morphine group, with an average increase of 11.17 ± 15.02 desaturation events per hour (P < .01). There were no differences seen in analgesic effectiveness, tonsillar bleeding, or adverse drug reactions. CONCLUSIONS: Ibuprofen in combination with acetaminophen provides safe and effective analgesia in children undergoing tonsillectomy. Post-tonsillectomy morphine use should be limited, as it may be unsafe in certain children.

Neonatal Benzodiazepines Exposure during Breastfeeding

OBJECTIVE To assess central nervous system depression and other adverse effects in infants exposed to benzodiazepines through breast milk. STUDY DESIGN A prospectively recruited, retrospectively assessed cohort study of mothers who contacted the Motherisk program regarding the safety of benzodiazepines and were invited to participate in a follow-up program regarding the effects of these medications on their infants during lactation. RESULTS A total of 124 consenting women participated. Adverse outcomes, specifically sedation, was identified in only 1.6% (2 of 124) of infants and was not associated with benzodiazepine dose, number of hours breastfed, or any demographic trait. Mothers reporting adverse outcomes in themselves (26% [32 of 124]) were more likely to be taking concomitantly a greater number of central nervous system depressants. CONCLUSIONS This study supports the continued recommendation to initiate breastfeeding while taking benzodiazepines postpartum.

A Clinical Tool for Reducing Central Nervous System Depression among Neonates Exposed to Codeine through Breast Milk

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. Methods and Findings Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines. Conclusions The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity.

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

Background:Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp) may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. The objective of the study was to determine the ontogeny of P-gp in the human brain.Methods:Postmortem cortex samples from gestational age (GA) 20–26 wk, GA 36–40 wk, postnatal age (PNA) 0–3 mo, PNA 3–6 mo, and adults were immunostained for P-gp.Results:The intensity of P-gp staining in adults was significantly higher compared to at GA 20–26 wk (P < 0.05), GA 36–40 wk (P < 0.05), and PNA 0–3 mo (P < 0.05). P-gp intensity at GA 20–26 wk (P < 0.05), GA 36–40 wk (P < 0.05), and PNA 0–3 mo (P < 0.05) was significantly lower compared to at PNA 3–6 mo.Conclusion:P-gp expression in the brain is limited at birth, increases with postnatal maturation, and reaches adult levels at ~3–6 mo of age. Given the immaturity of blood–brain barrier (BBB) P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

Is there a role for therapeutic drug monitoring with codeine

Abstract: Codeine is an old and commonly used analgesic agent for mild to moderate pain. It is the prototypical “prodrug” in that its analgesic effect is almost wholly dependent on its biotransformation to morphine, a process that is mediated by the polymorphic cytochrome P450 2D6 enzyme. As such, interindividual variability in codeine metabolism and response is a clinical reality, and there has been much progress in characterizing the genetic causes of this variability in diverse populations. Yet despite the potential for both life-threatening adverse reactions and lack of therapeutic effect, codeine is not commonly indicated for therapeutic drug monitoring. This review will discuss the relative role of pharmacogenetics and therapeutic drug monitoring in predicting and/or maintaining adequate and safe analgesia with codeine. The review will end on a discussion of how the marriage of these 2 fields may provide new insights into the mechanisms of codeine-induced toxicity and analgesia.

The pharmacogenetics of codeine pain relief in the postpartum period

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 manage postpartum pain.

Putative association of ABCB1 2677G>T/A with oxycodone-induced central nervous system depression in breastfeeding mothers.

Objective: To assess the effect of maternal CYP2D6, CYP3A5, ABCB1, and OPRM1 polymorphisms in predicting both neonatal and maternal central nervous system depression after oxycodone use during lactation. Study design: A nested case–control study in 67 breastfeeding mother–infant pairs exposed to oxycodone was conducted. Cases were defined as parental reports of lethargy in the infant temporally related to oxycodone exposure via breastmilk. Maternal saliva samples were analyzed for 18 polymorphisms in 4 genes, CYP2D6, CYP3A5, OPRM1, ABCB1, involved in oxycodone metabolism and response. Results: Mothers of symptomatic infants were using oxycodone for a longer period of time during breastfeeding compared with those of asymptomatic infants (P < 0.0001). None of the maternal genetic variants in the 4 genes were associated with oxycodone-induced depression in neonates. However, mothers carrying at least one copy of the ABCB1 2677 T variant had an increased risk of experiencing sedation themselves (odds ratio, 2.35; 95% confidence interval, 1.06–5.28; P = 0.03). Conclusions: The ABCB1 2677 T variant may predict oxycodone-induced central nervous system depression in breastfeeding mothers.

A core outcome set for neonatal abstinence syndrome: Study protocol for a systematic review, parent interviews and a Delphi survey

BackgroundThe prevalence of neonatal abstinence syndrome (NAS) is increasing globally resulting in an increased incidence of adverse neonatal outcomes and health system costs. Evidence regarding the effectiveness of NAS prevention and management strategies is very weak and further research initiatives are critically needed to support meta-analysis and clinical practice guidelines. In NAS research, the choice of outcomes and the use of valid, responsive and feasible measurement instruments are crucial. There is currently no consensus and evidence-based core outcome set (COS) for NAS.Methods/designThe development of the NAS-COS will include five stages led by an international Multidisciplinary Steering Committee: (1) qualitative interviews with parents/families and a systematic review (SR) to identify items for inclusion in a COS. The SR will also identify participants for the Delphi survey, (2) a three-round Delphi survey to gain expert opinion on the importance of health outcomes influencing NAS management decisions, (3), a consensus meeting to finalize the items and definitions with experts and COS users, (4) feasibility and pilot testing, development of the COS and explanatory document and (5) implementation planning.DiscussionSince standardized outcome measurement and reporting will improve NAS clinical research consistency, efficacy and impact, this COS will reflect the minimum set of health outcomes which should be measured in trials evaluating interventions for preventing or treating NAS.