Fetal and perinatal exposure to drugs and chemicals: novel biomarkers of risk.

Pregnant women are almost always excluded from randomized controlled clinical trials, as the risks to the fetus posed by most new chemical entities or approved drugs cannot be sufficiently ruled out. Hence, a major scientific challenge in this field is to discover and validate alternative tools that will fill the knowledge gap created by the lack of participation in gold-standard randomized trials. This review focuses on novel tools that allow estimation of fetal risks after exposure to therapeutic agents, such as placental perfusion studies, biomarkers of fetal exposure, and novel epidemiological and pharmacogenetic tools, all of which have been tested successfully in recent years.

Suicide by means of opioid overdose in patients with chronic pain.

Deaths from prescription opioid use continue to rise in North America. The main focus to date has been developing strategies to prevent nonintentional (accidental) fatalities, which constitute the majority of opioid deaths across all jurisdictions. Often overlooked is the complex group of individuals whose cause of death was suicide by opioid overdose. Although most opioid prescribing tools focus on identifying risk factors for potential abuse, diversion, and propensity for opioid addiction, physicians who consider prescribing opioids should also screen and optimize chronic pain treatment for patients at risk for suicide.

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.

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.

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.

Is there a role for therapeutic drug monitoring with codeine?

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.

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.

Perinatal exposure to maternal lamotrigine: clinical considerations for the mother and child.

QUESTION: The question of neonatal safety during breastfeeding when mothers are taking lamotrigine (LTG) has become more prevalent in my practice. There are some theoretical concerns about breastfeeding while taking LTG, which have been compounded by a published case report of toxicity in the breastfed neonate of a mother taking LTG. How should I advise my patients who wish to breastfeed while taking LTG? ANSWER: Most neonates born to mothers taking LTG have already been exposed to the drug for 9 months in utero, given the chronic indications for which the drug is intended. Lamotrigine exposure via breast milk is considerably less than placental transfer, with serum LTG concentrations in neonates higher at birth than during lactation. While a single case of toxicity has been reported in a neonate exposed to LTG via breast milk, in most circumstances, breastfeeding can be initiated and maintained given the tremendous benefits of mothers' milk. On the other hand, toxicity during breastfeeding might occur more commonly in the mother, if sufficient and gradual dose readjustments are not undertaken in the weeks following delivery.

Guidelines for maternal codeine use during breastfeeding.

QUESTION: In light of the recent evidence of adverse events in infants whose mothers use codeine medication, we have been struggling with the issue of how to manage codeine analgesia in our postpartum patients. What are some guidelines for the safe use of codeine during breastfeeding? ANSWER: Motherisk has summarized recent scientific evidence into suggested guidelines for the safe use of codeine during breastfeeding.

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

BACKGROUND: 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.

Timolol concentrations in breast milk of a woman treated for glaucoma: calculation of neonatal exposure.

A 32-year-old lactating woman with open-angle glaucoma used timolol maleate 0.5% eye drops twice daily to her right eye for 6 months. Four milk samples were collected over a span of 6 days. Timolol maleate milk levels were examined by liquid chromatography tandem mass spectrometry and found to be at a mean of 0.12 ng/mL (range, 0 to 0.37 ng/mL). At this level, the theoretical maximum relative infant dose expressed as a percentage of the weight-adjusted maternal dose was 0.012%. As most glaucoma patients administer drops to both eyes, the dosage was duplicated to reflect the more pertinent calculated theoretical relative infant dose of 0.024%. This dose of timolol is unlikely to cause systemic side effects to the healthy breastfed infant.

Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine.

QUESTION: Recently a newborn died from morphine poisoning when his mother used codeine while breastfeeding. Many patients receive codeine for postlabour pain. Is it safe to prescribe codeine for nursing mothers? ANSWER: When a mother is an ultrarapid metabolizer of cytochrome P450 2D6, she produces much more morphine when taking codeine than most people do. In this situation, newborns might be exposed to toxic levels of morphine when breastfeeding. Options to reduce this risk include discontinuing codeine after 2 to 3 days of use and being aware of symptoms of potential opioid toxicity in both mothers and newborns.

Forensic Investigation of Methadone Concentrations in Deceased Breastfed Infants.

There is a paucity of data to aid in assessing whether postmortem methadone findings in breastfed infants are clinically and/or toxicologically significant. Two cases are reported in which methadone was detected in deceased neonates whose mothers were enrolled in methadone maintenance programs and were breastfeeding. In addition to a complete autopsy and toxicological testing for alcohol, prescription medications, and drugs of abuse, pharmacogenetic analysis was performed for variants in genes related to methadone metabolism and response. In both cases, the postmortem methadone concentration measured in neonatal heart blood was higher than the maximum serum methadone concentration reported in living breastfed infants whose mothers were receiving methadone. However, additional analysis of antemortem blood indicated postmortem redistribution of methadone. Pharmacogenetic results were suggestive of a potential predisposition to methadone toxicity based on studies in adults; the significance of these findings in breastfed neonates requires further research. The medical cause of death was unascertained in both cases.

Drug Toxicity Deaths after Release from Incarceration in Ontario, 2006-2013: Review of Coroner's Cases.

BACKGROUND: There is an increased risk of death due to drug toxicity after release from incarceration. The purpose of this study was to describe the timing, rate and circumstances of drug toxicity deaths following release from incarceration. This information can be used to help design potential preventive interventions. METHODS AND FINDINGS: We reviewed coroner's files to identify deaths in adults in Ontario between 2006 and 2013 caused by drug toxicity (n = 6,978) and these records were matched with provincial correctional records to identify individuals who died within one year of being released from incarceration (n = 702). Twenty percent (n = 137) of the 702 deaths occurred within one week of release. The majority (77%, n = 538) of deaths after release involved one or more opioids. Of the deaths involving opioids, intervention by another person may have been possible in 318 cases. CONCLUSIONS: Between 2006 and 2013 in Ontario, one in ten drug toxicity deaths in adults occurred within one year of release from provincial incarceration. These findings may help to inform the implemention and assessment of interventions aimed at reducing drug toxicity deaths following release from incarceration.

Ethical perspectives on translational pharmacogenetic research involving children.

Children represent a special population characterized by dynamic changes which may affect drug safety and efficacy. The interplay of pharmacogenetics with physiological alterations that occur throughout development is an area of increasing research focus. Given the translational nature of pharmacogenetic research, it is possible that pharmacogenetic research results may possess clinically actionable information. The potential long-term implications of pharmacogenetic test results throughout the lifespan of the child, and the potential impact of the results for other members of the family need to be considered. Comprehensive counselling and communication strategies may need to be integrated as part of pharmacogenetic research studies in children.

Codeine-related deaths: The role of pharmacogenetics and drug interactions.

The objective of this study was to assess the relationship between genetic polymorphisms and drug interactions on codeine and morphine concentrations in codeine-related deaths (CRD). All CRD in Ontario, Canada between 2006 and 2008 were identified. Post-mortem blood was analyzed for 22 polymorphisms in 5 genes involved in codeine metabolism and response. Sixty-eight CRD were included in this study. The morphine-to-codeine ratio was significantly correlated with the presence of a CYP2D6 inhibitor at varying potencies (p=0.0011). The presence of other central nervous system (CNS) depressants (i.e. benzodiazepines, hypnotics, and/or alcohol) was significantly associated with lower codeine concentration as compared to CRD in which other CNS depressants were not detected (p=0.0002). Individuals who carried the ABCB1 1236T variant had significantly lower morphine concentrations (p=0.004). In this population of individuals whose cause of death was related to codeine, drug interactions and genetic polymorphisms were significantly associated with post-mortem codeine and morphine concentrations.

Pregnancy and pharmacogenomics in the context of drug metabolism and response.

It is well-known that profound physiological and biochemical changes occur throughout the course of pregnancy. At the same time, the role of pharmacogenomics in modulating the metabolism and response profile to numerous medications has been elucidated. Yet, the clinical impact of pharmacogenomics during pregnancy is less well understood. We present an overview of factors modulating the pharmacokinetics and pharmacodynamics of medications throughout the time span of pregnancy while providing insights on how pharmacogenomics may contribute to interindividual variability in drug metabolism and response amongst pregnant women.

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.