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This study reports the results of a double-blind, parallel-group comparison of intravenous methadone with morphine for the control of postoperative pain. Twenty patients (ASA Status 1 or 2) undergoing a surgical procedure involving an upper abdominal incision were randomly allocated to the methadone (n = 10) or morphine (n = 10) treatment groups. The patients were administered a 20-mg intraopeative opioid dose and 5-mg intravenous increments of opioid from precoded syringes in response to pain in the recovery and surgical wards. There was no significant difference between the mean ± SD amount of supplementary methadone (8 ± 6.3 mg) and morphine (9 ± 9 mg) required in the recovery ward to provide initial pain control. The time from initial pain control to the first supplementary dose in the surgical ward was significantly different (P < 0.01) in the methadone group (20.7 ± 20.2 h) when compared to the morphine group (6.2 ± 3.0 h). Further, patients required significantly less (P < 0.001) methadone (11.5 ± 8.5 mg) than morphine (41 ± 14.1 mg) in the surgical ward to provide adequate pain relief throughout the duration of the study (i.e., 60 h). There was a significant difference in visual analogue pain scores between the methadone and morphine groups on postoperative days 1 and 2, suggesting the quality of pain relief was similar for both treatment groups. Blood opioid-concentration monitoring indicated that there was a relationship between blood opioid concentration and pain relief. The minimum effective concentration (MEC) (mean ± SD) values of methadone and morphine were 59.2 ± 24.1 ng/ml and 14.7 ± 4.8 ng/ml, respectively. However, there was a significantly larger (P < 0.001) intrasubject variability in the coefficient of variation in MEC for morphine (39.4 ± 6.6%) compared with methadone (17.8 ± 10.4%).