Use of a von Frey device for evaluation of pharmacokinetics and pharmacodynamics of morphine after intravenous administration as an infusion or multiple doses in dogs

Objective-To evaluate the pharmacokinetics and pharmacodynamics of morphine after IV administration as an infusion or multiple doses in dogs by use of a von Frey (vF) device. Animal-6 dogs. Procedure-In the first 2 crossover experiments of a 3-way crossover study, morphine or saline (0.9%) solution was administered via IV infusion. Loading doses and infusion rates were administered to attain targeted plasma concentrations of 10, 20, 30, and 40 ng/mL. In the third experiment, morphine (0.5 mg/kg) was administered IV every 2 hours for 3 doses. The vF thresholds were measured hourly for 8 hours. Plasma concentrations of morphine were measured by high-pressure liquid chromatography. Results-No significant changes in vF thresholds were observed during infusion of saline solution. The vF thresholds were significantly increased from 5 to 8 hours during the infusion phase, corresponding to targeted morphine plasma concentrations > 30 ng/mL and infusion rates >= 0.15 +/- 0.02 mg/kg/h. The maximal effect (E-MAX) was 78 +/- 11% (percentage change from baseline), and the effective concentration to attain a 50% maximal response (EC50) was 29.5 +/- 5.4 ng/mL. The vF thresholds were significantly increased from 1 to 7 hours during the multiple-dose phase; the EC50 and EMAX were 23.9 +/- 4.7 ng/mL and 173 +/- 58%, respectively. No significant differences in half-life, volume of distribution, or clearance between the first and last dose of morphine were detected. Conclusions and Clinical Relevance-Morphine administered via IV infusion (0.15 0.02 mg/kg/h) and multiple doses (0.5 mg/kg, IV, every 2 hours for 3 doses) maintained significant antinociception in dogs.