Pharmacokinetics of Morphine and its Glucuronidated Metabolites in Burn Injuries

Abstract

OBJECTIVE: To investigate the effects of major thermal burn injury and continuous intravenous morphine infusion on the disposition of morphine and its glucuronidated metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) once a week for three weeks. CASE SUMMARIES: Five patients with major first-, second-, or third-degree burn injuries received long-term intravenous morphine infusion. The required dose varied greatly (from 4 to 39.5 mg/h). The steady-state concentrations of morphine, M3G, and M6G ranged from 20 to 452, 29 to 3436, and 20 to 1240 μmol/L, respectively. The systemic clearance (Cls) of morphine ranged from 14.8 to 40.3 mL/min/kg and did not change over time. The ratios of M6G and M3G to morphine were not affected by dose, even with the wide variation of intravenous dosage. Morphine kinetics appeared to be first-order. Mean recovery of morphine, M3G, and M6G in urine was 1.7 ± 1.0%, 42.0 ± 16.8%, and 11.8 ± 3.2%, respectively, and renal clearance ranged from 8 to 64, 26 to 325, and 59 to 589 mL/min, respectively. Mean pain intensity ratings at rest remained low and stable (0.7 ± 0.9 on day 7, 0.4 ± 0.3 on day 14, 0 ± 0 on day 21). DISCUSSION: To our knowledge, this is the first published report describing morphine, M3G, and M6G disposition in patients with major thermal burn injury. The Cls of morphine is similar to that observed in other patient populations and healthy subjects, suggesting that the presence of major burn injuries or a continuous morphine infusion over a three-week period may not contribute significantly to the variability among individuals. In these cases, the renal clearance of morphine and its glucuronides was within the range of values reported for other populations of patients and healthy subjects. Recovery of morphine and its glucuronides in urine was also similar to that in healthy individuals. CONCLUSIONS: These cases suggest that the effects of major burn injuries and of long-term intravenous infusion of morphine did not seem to modify morphine, M3G, and M6G disposition. Among patients with burn injuries, the severity of burns or duration of administration are not a cause of nonlinear kinetic of morphine or of morphine resistance. The morphine infusion rate was substantially variable and not directly related to its clearance, suggesting that monitoring of morphine should be focused on the clinical response.