Increased clearance of morphine in sickle cell disease: implications for pain management

Acute vaso-occlusive painful episodes associated with sickle cell disease (SCD) are frequently treated with morphine. Many SCD individuals require relatively higher doses of morphine to achieve optimal analgesia. We studied pharmacokinetics of morphine in SCD to explore if altered disposition could be a factor contributing to increased requirement of morphine in this population. The study subjects were in steady state of health to avoid the effect of hemodynamic changes associated with vaso-occlusion on morphine disposition. The plasma concentrations of morphine and its major metabolites were measured at timed intervals in 21 SCD subjects after they received a single .1 mg/Kg infusion of morphine sulfate. USCPACK software was used to fit candidate pharmacokinetic models. Noncompartmental pharmacokinetic parameters for morphine were calculated. Morphine clearance was 2.4-3.6 L/h, half-life was .3-.7 hours, AUC(0-∞) was 27.7-42.5 ng∗h/mL, and volume of distribution was .96-3.38 L/kg. Clearance of morphine in the study population was 3-10 folds higher than published estimates in the non-SCD population, with correspondingly lower AUC and half-life. Volume of distribution was similar. This observation suggests that due to increased clearance SCD individuals may require higher dose and frequency of morphine to achieve comparable plasma levels.

Perspective: Accelerated clearance of morphine likely related to increased hepatic and renal blood flow may be responsible for increased requirement of morphine in SCD. Although SCD individuals may require higher and more frequent doses of morphine, inter-individual variability of morphine disposition highlights the importance of individualization of the therapy.