Healthy volunteers were given morphine as an i.v. infusion (10 mg), immediate release (IR) tablets (3 x 10 mg), and as a new controlled release (CR) tablet (30 mg) on separate occasions. Venous blood samples were analyzed for morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) using high-performance liquid chromatography (HPLC). Pupil size, salivation, and central nervous system (CNS) effects were evaluated serially. Pharmacokinetic parameters, calculated using a two-compartment model, were in accordance with previous results for i.v. administration of morphine. The absolute bioavailability of morphine in both IR and in CR tablets was, 32%, and the relative bioavailability of the CR tablet versus the IR tablets was 103% (91-115%, 95% confidence interval). Pupil size and unstimulated saliva production were significantly reduced and CNS effects most pronounced following i.v. infusion of morphine, but were only moderately affected after oral administration with IR or CR tablets. Miosis and reduction of salivation were observed at moderate concentrations of morphine and M6G. A pharmacokinetic/pharmacodynamic model based on previous studies of receptor binding and potency of morphine and its metabolites was used to assess the concentration-effect relationships. According to this model, M6G was four and eight times more potent than morphine in producing miosis and reduction of saliva production, respectively. The same model indicated that intrinsic activities of M6G and morphine were similar for both effect parameters, whereas M3G was either inactive or even opposed the effects of morphine and M6G.