PhD

dissertationMethadone is effective for preventing opioid abstinence syndrome (OAS). Understanding factors that impact this effectiveness is needed to optimize its use in pediatric patients. These factors vary significantly with patient demographics and pathophysiologic characteristics. Thus understanding both the pharmacokinetic and pharmacodynamics factors that influence drug effect is critical. Population modeling was used to evaluate the pharmacokinetics of methadone in critically ill children. The model revealed a rapid distribution half life with a long terminal elimination half life (1.22 and 7 hours, respectively.) The elimination half life (13.3 hours) is significantly less than that reported in adults. Body weight as a covariate for both distribution volumes and clearance improved the model fit, indicating that methadone concentrations can change rapidly in critically ill children due to redistribution and a decreased elimination half life compared to adults. To explore the pharmacodynamics factors related to OAS, morphine, a mu-opioid agonist and inducer of OAS, and methadone, a mu-opioid agonist and NMDA antagonists, were supplied to dorsal root ganglion cells (DRG) extracted from neonatal mice pups which served as a model system for studying pediatric OAS. Following opioid deprivation, methadone was more effective at attenuating calcium ion influx in DRG neurons, which leads to greater inhibition of nociceptive input. Thus, methadone may have a pharmacodynamics impact on controlling OAS besides its pharmacokinetic impact that is generally considered the basis for its use. Further examination of the efficacy of methadone in combination with morphine was carried out in pediatric animal model. Mice pups received methadone, morphine, or methadone and morphine subcutaneously. Pharmacodynamic measurements of withdrawal were quantified and again, the calcium ion influx of DRG cells was measured. Co-administration of methadone and morphine reduced the influx of calcium ions over time compared to morphine alone and methadone alone (p=0.001). However, no difference occurred in the behavioral assessments due to experimental limitations. Methadon's ability to antagonize the NMD receptor appears to impact the formation of opioid tolerance and subsequent withdrawal in both the cellular and animal models. Methadone combined with morphine gives physicians an alternative in making clinical decisions regarding dosing regimens for their patients