Changes in methadone concentration, opiod effects, and opioid withdrawal during induction onto maintenance treatment

Abstract

Objective: Deaths of people on methadone maintenance due to respiratory depression most commonly occur during the first week of dosing. This paper describes the changes in opioid withdrawal, respiratory rate, and pupil diameter that occur during the first 8 days of methadone treatment. The changes in plasma concentration of the active enantiomer, R-methadone, are also described and related to the changes in opioid effects and withdrawal. Methods: Five heroin dependent subjects were assessed each day over the first 8 days of methadone administration. Blood samples were collected and measures made of withdrawal severity, respiration, and pupil diameter prior to methadone dosing and 3 hours after; additional sampling and testing were carried out on days 1, 3, 5, and 8. Blood samples were analyzed to determine the plasma concentration of R-methadone. Results: Over the first 8 days plasma concentration of R-methadone increased, withdrawal severity decreased, and both pupil diameter and respiratory rate decreased. Each of the 3 measures of opioid effect/withdrawal was significantly correlated with plasma R-methadone concentration. Respiratory depression was marked in some subjects and was maximal at time of peak R-methadone concentration. Conclusion: Caution needs to be exercised during the first days of methadone dosing as some degree of respiratory depression is common in non-problematic patients. Observation of patients around time of peak methadone concentration would reduce risk.