Abstract

It is very important to set an appropriate dose level and frequency with a sufficient duration of administration to allow for assessment of the physical dependence liability of drugs. The purpose of this study was to investigate the relationship between the physical dependence liability and blood concentrations of morphine following an oral administration. Morphine was administered by oral gavage once daily for 28 days at dose levels of 10 and 30 mg/kg/day, and then withdrawal signs were observed for 7 days. During the withdrawal period, apparent withdrawal signs such as hyper reactivity to handling, loose stools, piloerection and transient, statistically significant decreases in the percent change of body weight gain and food consumption were noted at 30 mg/kg/day. At 10 mg/kg/day, hyperreactivity to handling and piloerection were observed, but transient decreases in the percent change of body weight gain and food consumption were not noted. The mean plasma concentrations of morphine at 24 h post-dosing at 10 and 30 mg/ kg/day were 3.4 and 13.6 ng/mL on Day 1 of dosing and 3.91 and 20.3 ng/mL on Day 28 of dosing, respectively. The plasma concentrations of morphine at 30 mg/kg/day were above the lower limit of the effective blood concentrations in humans. Thus, it was suggested that dose levels that can maintain effective blood concentrations or higher in humans should be selected for evaluation of physical dependence liability.