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The aim of the study was to establish whether there exists a relationship between blood methadone concentration and analgesic response and the intrasubject and intersubject variability in this relationship. Sixteen general surgical (upper abdominal) and orthopedic (spinal fusion) patients were administered methadone (20 mg, iv) as part of the general anesthetic and supplementary methadone doses (usually 5 mg, iv) in the recovery ward until postoperative pain was controlled effectively. The criteria established for the administration of supplementary methadone doses were the coexistence of 1) spontaneous reporting of significant pain by the patient; 2) an unstimulated respiratory rate of greater than 10 breaths/min, and 3) no significant depression of the level of consciousness.A median of two supplementary iv methadone doses (range 13) were administered to the patient by a titration method in the recovery ward to obtain effective pain control. This was achieved by a median dose of 10 mg (range 5-20 mg) in addition to the 20 mg intraoperative dose. Serial blood samples were collected for the estimation of blood methadone concentration following all doses. The methadone concentration in the blood sample collected immediately prior to a supplementary dose was termed the minimum effective concentration (MEC [methadone]). The mean (±SD) coefficient of variation in MEC (methadone) for the 16 patients was 21 ±10% (range: 7-38%), while the mean MEC for methadone was 57.9 ± 15.2 ng/ml (range: 34.5-80.3 ng/ml) in these patients. The small intrapatient coefficient of variation in MEC (range: 7-38%) provides additional experimental evidence in support of the concept that there is a relationship between blood concentration and analgesic response within an individual.Following methadone titration, the mean duration of analgesia (±SD) was 21 ± 13 h (range: 5-48 h), while the mean pain score (visual analogue scale of 0 [no pain] to 10 cm [worst pain]) was 1.5 ±1.3 cm during this period of effective analgesia. After this sustained period of analgesia, additional methadone (usually 5 mg iv) resulted in a further period of prolonged analgesia (range from 7.4 h to prolonged, i.e., no further analgesia required for the hospital stay). The mean (±SD) total methadone dose was 42 ± 10 mg (range: 30-70 mg).These results indicate that prolonged and safe postoperative analgesia can be obtained from methadone following the proposed intravenous titration method, which cautiously and reliably elevates the blood methadone concentration to a level in excess of the MEC, thereby providing prolonged analgesia as a result of the low methadone clearance.