Morphine concentrations in plasma in five patients following intrathecal (i.t.) administration and in five other patients following intravenous (i.v.) administration were measured by a specific RIA sensitive to 0.1 ng/ml. Pharmacokinetic analysis showed a similar apparent total body clearance of morphine following both i.t. and i.v. administration, and complete bioavailability of i.t. morphine to the systemic circulation. This indicates that morphine is probably not metabolised in the CNS and that all of an i.t. dose diffuses from CSF to the plasma compartment. However a marked decrease in the i.t. terminal rate constants, involving a flip-flop phenomenon, contributed to the prolonged terminal half-life of i.t. morphine. The slow diffusion of morphine from the i.t. space to the plasma compartment can account for the prolonged analgesia following i.t. administration.