Methadone is an important long-term maintenance therapy for drug addiction and currently is frequently used for analgesia. However, methadone prolongs the QT interval on the electrocardiogram and this increases risk for life threatening arrhythmias and has led to the FDA's placing a "black box" warning on methadone's label. Initial studies in our laboratory have shown that one of the stereoisomers of methadone causes significantly less QT prolongation and this isomer possesses the analgesic effect of methadone. The studies outlined in the grant propose to confirm the safety of the R isomer in a model to access proarrhythmia that the FDA proposes for the animal evaluation of arrhythmic risk and then to determine if the isomer causes less QT prolongation in the dog at therapeutic and higher than routine therapeutic doses of R methadone as compared to racemic methadone. These are necessary steps for the submission of a new drug application and the eventual commercial availability of the methadone isomer as a safer treatment for analgesia and addiction. PUBLIC HEALTH RELEVANCE: Methadone is frequently used for pain treatment and drug addiction, but the current formulation poses a serious risk of arrhythmias. The R isomer of methadone does not cause the same electrophysiologic changes (QT prolongation) and thus would not pose the same risk for arrhythmias. Studies in this grant set out to show that the R isomer is a safer methadone and would pose less of a risk for life threatening arrhythmias to patient.