Prolongation of epidural bupivacaine effects with hyaluronic acid in rabbits.

To assess the prolongation of epidural bupivacaine by hyaluronic acid viscous formulations we designed a cross-over study in rabbits. Different doses of bupivacaine (3 or 6 mg) either as a solution (bupivacaine hydrochloride), or as viscous formulations with hyaluronic acid (bupivacaine base and bupivacaine hydrochloride) were administered in a rabbit model of epidural anesthesia. In the first part of the study, in vitro release characteristics were determined. Then pharmacodynamic effects and pharmacokinetic profiles of each bupivacaine formulation were studied. The rank order release rate of bupivacaine in vitro was always hydrochloride solution >> viscous physical mixture of bupivacaine with hyaluronic acid > viscous ionic complex of bupivacaine base with hyaluronic acid. Onset time of epidural anesthesia was similar whatever the formulation of bupivacaine used. We did not find any blockade prolongation when 3mg bupivacaine was administered, but significant blockade prolongations were observed with viscous formulations incorporating 6 mg bupivacaine. The observed reduction in the absorption rate of bupivacaine into the systemic circulation for both viscous hyaluronic formulations after 6 mg of bupivacaine may explain the prolongation of spinal effects. Drug release and duration of action were found to be viscosity controlled as linear relationships were found between pharmacodynamic effects and viscosity. Our results were in accordance with those reported with bupivacaine-cyclodextrin complex, another formulation with a molecular dispersion of the drug, resulting in a moderate prolongation of action.