Parvaz Madadi

Pharmacogenetics of Neonatal Opioid Toxicity Following Maternal Use of Codeine During Breastfeeding: A Case–Control Study

A large number of women receive codeine for obstetric pain while breastfeeding. Following a case of fatal opioid poisoning in a breastfed neonate whose codeine prescribed mother was a CYP2D6 ultrarapid metabolizer (UM), we examined characteristics of mothers and infants with or without signs of central nervous system (CNS) depression following codeine exposure while breastfeeding in a case–control study. Mothers of symptomatic infants (n = 17) consumed a mean 59% higher codeine dose than mothers of asymptomatic infants (n = 55) (1.62 (0.79) mg/kg/day vs. 1.02 (0.54) mg/kg/day; P = 0.004). There was 71% concordance between maternal and neonatal CNS depression. Two mothers whose infants exhibited severe neonatal toxicity were CYP2D6 UMs and of the UGT2B7*2/*2 genotype. There may be a dose–response relationship between maternal codeine use and neonatal toxicity, and strong concordance between maternal‐infant CNS depressive symptoms. Breastfed infants of mothers who are CYP2D6 UMs combined with the UGT2B7*2/*2 are at increased risk of potentially life‐threatening CNS depression.

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.

Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use

Codeine has been used medicinally since the 1800s as an analgesic and antitussive agent. Although very few studies have methodically examined the safety of codeine use in the pediatric age group, it is nonetheless commonly prescribed to children and breastfeeding mothers. Empirical evidence over the last century has suggested variability in the efficacy of codeine, and recent genomic advancements have shed important light on the mechanisms leading to such variability. Aside from evaluating the role of genetic variability in drug-metabolizing enzymes, receptors and transporters, the development of the blood-brain-barrier and the ontogeny of drug-metabolizing enzymes must also be considered in newborns and young children.

Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in Ontario, Canada.

Background The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. Methods This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. Results Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. Significance/Conclusion These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users.

Fatal Hydrocodone Overdose in a Child: Pharmacogenetics and Drug Interactions

Fatal opioid toxicity occurred in a developmentally delayed child aged 5 years 9 months who was inadvertently administered high doses of hydrocodone for a respiratory tract infection. The concentration of hydrocodone in postmortem blood was in the range associated with fatality; however, hydromorphone, a major metabolite catalyzed by cytochrome P450 2D6 (CYP2D6), was not detected when using mass spectrometry. Genetic analysis revealed that the child had a reduced capability to metabolize the drug via the CYP2D6 pathway (CYP2D6*2A/*41). Coadministration of clarithromycin (a potent cytochrome P450 3A4 inhibitor) for an ear infection and valproic acid for seizures since birth further prevented drug elimination from the body. This case highlights the interplay between pharmacogenetic factors, drug-drug interactions, and dose-related toxicity in a child.

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.

Establishing causality of CNS depression in breastfed infants following maternal codeine use.

AbstractBackground: We recently reported on a breastfed infant who succumbed to opioid toxicity following exposure 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.

Prediction of Codeine Toxicity in Infants and Their Mothers Using a Novel Combination of Maternal Genetic Markers

Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life‐threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP‐glucuronosyltransferase 2B7 (UGT2B7), P‐glycoprotein (ABCB1), mu‐opioid receptor (OPRM1), and catechol O‐methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61–4.48; Ptrend = 0.0002) and their mothers (OR 2.74; 95% CI 1.55–4.84; Ptrend = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.

CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study.

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.