Pharmacokinetics cannot explain the increased effective dose requirement for morphine and midazolam in rats during their extended administration alone or in combination

Abstract

Abstract Objectives Chronic administration of morphine and midazolam, alone or in combination, can induce tolerance to their effects. Data showed that co-administration of morphine and midazolam increased effective dose requirement of morphine, exceeding that observed with morphine alone. Methods To elucidate the pharmacokinetic component to the tolerance, we administered midazolam (2 mg/kg) and morphine (10 mg/kg) alone or their combination daily to rats for 12 days followed by a pharmacokinetic study on day 13. On the study day, each animal received a single bolus dose of 5 mg/kg morphine, and 2 mg/kg of midazolam 30 s later. Multiple blood samples were obtained for 6 h. Plasma drug concentrations were assayed by mass spectrometry optimized for small samples. Key findings Mean morphine clearance was as follows: 22.2, 27.2, 26.0 and 23.4 l/h per kg in the saline–saline, saline–midazolam, saline–morphine and midazolam–morphine groups, respectively. Corresponding midazolam clearances were 32.8, 23.0, 22.2 and 31.1 l/h per kg. ANOVA indicated no significant differences among the four groups in the clearances, half-lives, and volumes of distribution. Morphine and midazolam clearances were significantly correlated (R2 = 0.48, P < 0.001). Conclusions This animal model suggests that altered pharmacokinetics cannot explain tolerance evidenced as increased dose requirement for morphine or midazolam, when administered alone or combination, for extended periods.