Electronic Thesis and Dissertation Repository


Doctor of Philosophy


Pharmacology and Toxicology


Dr. Gideon Koren


Young children are sometimes prescribed opioids and may be exposed to opioids in utero and through breast milk. Clinical and genetic factors create large inter- individual variability in opioid response and have been associated with life threatening and often fatal adverse drug reactions in young children. Genetic factors have been studied in adults but there is little clinical evidence in young children. The focus of this thesis is on three commonly prescribed opioids: codeine, morphine and methadone. The objective of this work was to investigate risk factors associated with opioid related morbidity and mortality in young children. Risk factors were examined in three populations of children including neonates exposed to opioids in utero, infants exposed to codeine in breast milk as well as young children receiving codeine and morphine for post-surgical pain relief. We hypothesize that genetics and clinical factors will affect opioid response in young children.

As the prevalence of opioid use increases it is important to investigate clinical and genetic risk factors as well as cost-effective treatment options. Neonates exposed to opioids in utero do not show an increased risk for mortality. Genetics may play a role in the development of neonatal withdrawal symptoms following in utero methadone exposure. Further work is necessary in order to corroborate the role of genetic and clinical factors in predicting neonatal abstinence syndrome. Codeine use during lactation has been shown to result in a significant neonatal sedation, much of which was associated with maternal genotype and dose. Guidelines based on predetermined clinical risk factors were able to mitigate the previously identified increased genetic risk. Several fatalities have been reported following codeine use in children post-tonsillectomy. In a randomized clinical trial we found that standard morphine doses (0.2-0.5mg/kg) may not be a safe alternative in children with obstructive sleep apnea. The safety and effectiveness of lower morphine doses should be investigated.

Genetic variability in drug metabolizing enzymes, drug transporters and receptors, influence opioid response and create risks for adverse effects in young children. Standard doses of opioids are not safe in all children, and should be dosed on an individual basis.