ALTERED METHADONE ANALGESIA DUE TO CHANGES IN PLASMA-PROTEIN BINDING - ROLE OF THE ROUTE OF ADMINISTRATION

1. The effect of experimental inflammation on methadone analgesia was evaluated in rats, by the tail-flick test, after single intravenous (0 .35 mg/kg) and subcutaneous (3 mg/kg) doses. 2. After i.v. administrat ion a significant decrease (P <0.05) in the area under the methadone t ime-response curve was seen in rats with experimental inflammation, wh en compared with control. However, no differences in the analgesic res ponse to methadone were detected between control rats and rats with in flammation when the drug was administered by s.c. injection. 3. Plasma mucoprotein levels were significantly increased (P <0.001) and methad one free fraction was significantly decreased in rats with inflammatio n (P <0.05). In addition, after i.v. methadone a decrease in brain upt ake in rats with inflammation was detected. A significant correlation between brain uptake index and plasma free fraction was also observed. 4. These results suggest that a decreased immediate response to i.v. methadone may occur in circumstances in which there is an increase in alpha(1) acid glycoprotein, but that this is not likely to be observed when the absorption is not instantaneous.