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.

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.

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.

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.

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.

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.

Clinical practice guideline: CYP2D6 genotyping for safe and efficacious codeine therapy.

This guideline is intended to provide a basis for informed decision-making regarding genetic testing to identify those individuals who will not benefit from codeine therapy, as well as those who are at an increased risk for codeine-induced toxicity. This guideline addresses the following key questions: 1) Should genetic testing for CYP2D6 be performed in patients prior to the initiation of codeine therapy? 2) How should patients with an indication for codeine therapy be managed based on their genotyping results for CYP2D6?

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.

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.

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.

Life-threatening adverse events following therapeutic opioid administration in adults: is pharmacogenetic analysis useful?

BACKGROUND: Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life-threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed. METHODS: A panel of 20 functional candidate polymorphisms in genes involved in the opioid biotransformation pathway (CYP2D6, UGT2B7, ABCB1, OPRM1, COMT) were genotyped in these two patients using commercially available genotyping assays. RESULTS: In case 1, the patient experienced adverse outcomes when administered codeine and morphine, but not hydromorphone. Genetic test results suggested that this differential response may be due to an inherent propensity to generate active metabolites from both codeine and morphine. These active metabolites are not generated with hydromorphone. In case 2, the patient experienced severe respiratory depression during postoperative recovery following standard doses of morphine. The patient was found to carry genetic variations that result in decreased morphine efflux transporter activity at the blood-brain barrier and increased sensitivity to opioids. CONCLUSIONS: Knowledge of the relative contribution of pharmacogenetic biomarkers and their influence on opioid response are continually evolving. Pharmacogenetic analysis, together with clinical history, has the potential to provide mechanistic insight into severe respiratory depressive events in patients who receive opioids at therapeutic doses.

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.

Actionable theranostics for global maternal health: a focus on HIV and malaria.

A new wave of rapid and accurate molecular diagnostics, which harness the power of genomics and proteomics, hold great potential to improve aspects of maternal health on a global scale. This review will provide a context to issues related to global maternal health and highlight international endeavors aimed to alleviate morbidity and mortality during pregnancy, childbirth and into the postnatal period. The authors will couple these efforts to actionable and promising theranostic advancements in the detection and treatment of HIV and malaria through the lens of maternal global health strategies.

Apnea and oxygen desaturations in children treated with opioids after adenotonsillectomy for obstructive sleep apnea syndrome: a prospective pilot study.

BACKGROUND: Recent case reports have alerted the medical community of fatality in children receiving codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. OBJECTIVE: The objective of this study was to compare the rates of oxygen desaturation before and after adenotonsillectomy in children with obstructive sleep apnea syndrome (OSAS), and to examine the relationship between cytochrome P450 2D6 (CYP2D6) genotype and respiratory events. STUDY DESIGN: This was a prospective observational study. METHODS: Twenty-six children with OSAS (mean age 78 months, range 1.8-17 years) who underwent adenotonsillectomy were studied. CYP2D6 genotype was characterized in 21 of these children. The primary endpoints of the study were the change in the rate of desaturation and in the nadir oxygen saturation values before and in the first 24 hours after surgery as measured by pulse oximetry. RESULTS: Twenty-two children received codeine and four were managed with hydrocodone. There was no post-operative improvement in the mean rate of desaturation (1.84 ± 1.45/hour pre-operative vs 2.97 ± 3.3/hour post-operative; p = 0.119; 95% CI -2.56, 0.313), or the post-operative nadir of oxygen saturation (85.2 ± 5.8% pre-operative vs 84.0 ± 6.8% post-operative; p = 0.632; 95% CI -3.00, 4.84) on the night after surgery. Prior to surgery, six children had an oxygen saturation nadir <80%, while post-surgery, the number increased to eight children. Ten children improved their parameters after surgery. CYP2D6 genotype by itself did not predict the changes in desaturation or nadir. CONCLUSION: Post-operative use of opioids following OSAS may not be safe for all children. It is conceivable that if the child is among the significant proportion that experiences increased oxygen desaturations, the CNS depressing effects of codeine or hydrocodone and their respectively potent morphine or hydromorphone metabolites can further compromise respiratory drive. Larger studies are needed to investigate the potential contribution of CYP2D6 genotype.

Patterns of paediatric analgesic use in Africa: a systematic review.

We conducted a systematic literature review with two objectives: (1) to assess reported patterns of analgesic use in African children and compare these observed patterns to the analgesics given in the WHO Essential Medicines List for Children (EMLc); and (2) to summarise outcomes related to effectiveness, adverse events, cost and accessibility of these analgesics. Eligible participants were children (≤12 years) living in any African country who received an analgesic administered with the intention of relieving pain in any setting. Thirty-four peer-reviewed, observational studies representing 7772 African children were accepted. Studies were conducted in 25 different regions of 12 countries. Pain was attributed to surgery, burns, sickle cell anaemia and conditions requiring palliation in 32% of children, and was unspecified in the other 68%. Of the three EMLc analgesics, paracetamol and ibuprofen were widely employed, constituting ∼60% of all analgesics, while morphine was used in 20 children (0.2%). There were 455 suspected adverse drug reactions which included 17 deaths. Analgesic use reported in African children appears to fall short of WHO standards.

Tacrolimus-induced nephrotoxicity and genetic variability: a review.

BACKGROUND: Calcineurin inhibition (CNI) is the mainstay of immunosuppressant therapy for most solid organ transplant patients. High tacrolimus levels are related with acute nephrotoxicity, but the relationship with chronic toxicity is less clear. Variation in disposition of tacrolimus is associated with genetic variation in CYP3A5. Hence, could genetic variation in CYP3A5 or other genes involved in tacrolimus disposition and effect be associated with a risk for tacrolimus-induced nephrotoxicity? To perform a review of the literature and to identify if genetic variation in CYP3A5 or other genes involved in tacrolimus disposition or effect may be associated with tacrolimus-induced nephrotoxicity and/or renal dysfunction in solid organ transplant recipients. MATERIAL/METHODS: Pubmed/Medline, Embase and Google were searched from their inception till November 8th 2010 with the search terms 'tacrolimus', 'genetics', and 'nephrotoxicity' or 'renal dysfunction'. References of relevant articles were screened as well. RESULTS: We identified 13 relevant papers. In kidney recipients, associations between donor ABCB1, recipient CCR5 genotype and tacrolimus-induced nephrotoxicity were found. CYP3A5 genotype studies in kidney recipients yielded contradictory results. In liver recipients, a possible association between recipient ACE, CYP3A5, ABCB1 and CYP2C8 genetic polymorphisms and tacrolimus-induced nephrotoxicity was suggested. In heart recipients, TGF-ß genetic polymorphisms were associated with tacrolimus-induced nephrotoxicity. The quality of the studies varied considerably. CONCLUSIONS: Limited evidence suggests that variation in genes involved in pharmacokinetics (ABCB1 and CYP3A5) and pharmacodynamics (TGF-ß, CYP2C8, ACE, CCR5) of tacrolimus may impact a transplant recipients' risk to develop tacrolimus-induced nephrotoxicity across different transplant organ groups.

Are infants exposed to methadone in utero at an increased risk for mortality?

BACKGROUND: The prevalence of opioid abuse is increasing in North America. Opioid abuse during pregnancy can cause medical, obstetric and psychosocial complications. Neonates exposed to opioids in utero often develop the neonatal abstinence syndrome. Methadone maintenance therapy is the treatment of choice for maternal opioid dependency. There have been unsupported concerns that infants cared for by mothers treated with methadone have higher mortality rates during the first year of life than in the general population. OBJECTIVES: To compare the mortality rates of infants exposed to methadone in utero to those of general population in Ontario, Canada. METHODS: We utilized several provincial and national databases including those of the Office of the Chief Coroner of Ontario, the Canadian Institute for Health Information, and the Ontario Infant Mortality Rate Report. Reference organ weights were obtained from the peer reviewed literature. RESULTS: The Office of the Chief Coroner of Ontario has reported 8 deaths in children under one associated with in utero methadone exposure between January 1, 2006 and December 31, 2010. Over the same period there have been a total of 1103 cases of neonatal abstinence syndrome recorded in the province. The mean infant mortality rate in Ontario for children under the age of 1year over the same period was 5.2 per 1000 live births. The odds ratio for mortality among children with neonatal abstinence syndrome was not different from that in the general population [OR 1.45 (95% confidence interval 0.471-4.459)] (p=0.56). CONCLUSION: The available data do not support the concerns that children under the age of one year, born to mothers on methadone maintenance therapy (MMT) are at an increased risk for mortality.

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.

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.