Pharmacodynamics and pharmacokinetics of methadone during the perioperative period

Abstract

The duration of postoperative pain relief was assessed in 23 general surgical or orthopedic patients administered 20 mg methadone as an iv bolus following induction of anesthesia. Nine patients (39%) were pain-free and required no additional analgesia for the control of their postoperative pain (Group 1). Eight patients (35%) required additional narcotic injections (Group 3) but the duration of adequate analgesia was 18.4 ± 6.6 h (mean ± SD). The remaining six patients (26%) requested non-narcotic analgesia (Group 2) for the control of their postoperative pain and the mean (± SD) time to the first supplementary dose was 26.5 ± 4.8 h in these patients. The overall median duration of analgesia resulting from the 20 mg methadone was 27 h (n = 23). The mean (± SD) minimum effective analgetic blood methadone concentration was 30 ± 11 ng/ml for the narcotic-supplemented group, and 33 ± 12 ng/ml for the non-narcotic-supplemented group. The results obtained suggest there is a relationship between the blood methadone concentration and the control of postoperative pain. Patients were sedated in the immediate postoperative period, but their respiratory rate was not depressed significantly (i.e., rate < 10 breaths/min). In no case was it necessary to antagonize methadone with naloxone to initiate spontaneous respiration at the termination of the anesthetic. Nausea or vomiting occurred in 11 patients, but they responded to conventional antiemetic therapy. Sequential blood samples were collected in 19 of the patients for estimation of methadone pharmacokinetics. The mean (± SD) methadone clearance was 178 ± 100 ml/min (i.e., 2.7 ± 1.7 ml.min-1.kg-1), while the terminal half-life was 35 ± 22 h. These results suggest that methadone analgesia is related to the blood concentration of the drug and prolonged postoperative analgesia was consistent with the long half-life of the drug. There was a positive correlation between the methadone initial volume of distribution (76 ± 49 l) and volume of distribution at steady-state (410 ± 156 l) and body weight. Although there was a positive correlation between age of the patient and terminal half-life, no relationship existed between methadone clearance and age of the patient. Surprisingly, there was a highly significant negative correlation between methadone clearance and the minimum effective analgetic blood methadone concentration. The variables of duration of analgesia and minimum effective analgetic blood methadone concentration were subjected to multivariable regression analysis. The aim of this analysis was to provide equations to predict the value of these variables prior to surgery. The patient variables which had most influence included age, weight and the Eysenck Personality Inventory dimensions of neuroticism (N score), extroversion (E score), and social conformity (L score). The authors conclude that methadone has the desirable pharmacokinetic (such as a long half-life and low clearance) and pharmacodynamic properties such that a single dose of 20 mg can result in prolonged postoperative analgesia.