Methadone is a synthetic opioid used to treat pain and as maintenance therapy for opiate addicted individuals. Methadone does not have the euphoric properties of morphine and thus is less addictive. Its use in the treatment of both acute and chronic pain, thus offers advantage. However, limiting methadones clinical use is its prolongation of the cardiac cells repolarization time, manifested as QT prolongation which is associated with ventricular arrhythmia and sudden cardiac death. Female patients are especially at risk due to an already longer repolarization time than in men. Additionally, low serum potassium, cardiac ion channel abnormalities, as well as low magnesium can increase the patients risk when taking methadone. We have found in pre-clinical studies that the R-isomer of methadone causes significantly less QT prolongation, reducing arrhythmia risk. Given the potential for lethal arrhythmias, methadone poses a serious public health problem with potentially tens of thousands of patients at risk. R-methadone would be a safer alternative for pain therapy. This proposal entails studying an abuse deterrent formulation of methadone as to its pharmacokinetic properties. Studies would be initiated in Beagle dogs to evaluate kinetics along with QT effects of R-methadone as contrasted to R,S methadone(the standard mixture available for therapeutic use in the U.S.). These studies will initiate the development of a cardiac safer formulation of methadone that could not be tampered with and that would be safer for patients, especially women and those with potassium channelopathies, or patients with hypokalemia, or hypomagnesemia.
Public Health Relevance Statement: Project Narrative Methadone is an effective drug, used as a pain killer and to help patients addicted to opiates to avoid illicit substances when placed on a methadone maintenance program. However, methadone causes QT prolongation and is a risk factor for sudden death (more so in women and patients with certain hereditary conditions). One isolated minor image of the compound, called the R-isomer causes much less QT prolongation and thus less arrhythmic risk. We propose to study the R-isomer in an abuse deterrent formulation as to its pharmacokinetics initially in dogs as a prelude to human studies. So we know the amount to give and how often.
Project Terms: Absence of pain sensation; Acute Pain; Analgesics; Animal Model; Animals; Arrhythmia; base; Biological Assay; Canis familiaris; Cardiac; Cells; Cessation of life; chronic pain; Clinical; Communities; Data; Death, Sudden, Cardiac; Development; drug addiction therapy; Drug Kinetics; Drug usage; Electrocardiogram; Female; Formulation; Germany; Health; Heart Diseases; Hour; Human; Hypokalemia; Hypomagnesemia; Image; Individual; Inherited; Ion Channel; Isomerism; Kinetics; Laboratories; Lead; Life; Magnesium; Maintenance Therapy; Measures; men; Methadone; methadone maintenance; milligram; Minor; Morphine; Naltrexone; Opiates; opioid use; Oral; Package Insert; Pain; Pain management; Patient risk; Patients; Pharmaceutical Preparations; Pharmacologic Actions; Potassium; preclinical study; Preparation; programs; Property; Public Health; Quetiapine fumarate; Reporting; response; Risk; Risk Factors; Sampling; Seroquel; Serum; Sudden Death; System; Therapeutic; Therapeutic Uses; Time; Torsades de Pointes; United States; Ventricular Arrhythmia; Ventricular Tachycardia; Woman
