MORPHINE PHARMACOKINETICS AND EFFECTS ON SALIVATION AND CONTINUOUS REACTION-TIMES IN HEALTHY-VOLUNTEERS

Ten healthy volunteers were given an i.v. infusion of 10 mg morphine H Cl, an oral solution of 20 mg morphine HCl, or a new controlled releas e tablet of 30 mg morphine sulphate on three separate occasions in a c omplete crossover design. Venous blood samples were collected serially for 14-24 h and analyzed for morphine using high-performance liquid c hromatography (HPLC). Continuous reaction times (CRTs) and salivation were measured repeatedly in all subjects. Oxygen saturation remained n ormal throughout the procedure. Five subjects experienced nausea on at least one occasion. Pharmacokinetic parameters, calculated using a tw o-compartment model, were in accordance with previous results for i.v. and oral administration of morphine solutions. The absolute bioavaila bility of morphine in the oral solution was 21.6% (15.4-27.7%; 95% CI) and in the controlled release tablet, 17.1% (12.621. 6%; CI). Seconda ry peaks in the plasma concentration curves strongly indicated an ente rohepatic circulation (EHC) of morphine. Alternative pharmacokinetic c alculations, including EHC, were performed and used in a pharmacokinet ic-pharmacodynamic model, in which the studied effects were well corre lated to the concentrations of morphine.