OBJECTIVE: To investigate the concentration-effect relationship of hydromorphone by using two different methods to minimize the hysteresis between concentration and effects.DESIGN: Open study.SUBJECTS: Twelve healthy volunteers.MEASUREMENTS: The analgesic effect of hydromorphone, evaluated as pressure pain thresholds (PPTs), and nonanalgesic effects, miosis and reduction of saliva production, were related to the concentration of the opioid, analyzed by high performance liquid chromatography. Hysteresis between the concentration and the measured effects of hydromorphone was minimized by a link model and system analysis.RESULTS: Parameter estimation was successful using both methods of hysteresis minimization. According to the link model, the mean concentration of hydromorphone at steady state (Css50) producing 50% of the Emax for reduction of saliva production was 6.7±3.0 nmol/L and the mean Emax, given as the fraction of baseline salivation, was -1.1±0.2. Mean Css50 for reduction of pupil size was 15±20 nmol/L, and mean Emax was -0.8±0.2. For analgesia, mean Css50 was 68±42 nmol/L and mean Emax was 1.8±2.2. Similar results were obtained by using system analysis.CONCLUSION: Hydromorphone demonstrated a high intrinsic activity, producing miosis and dryness of the mouth. The analgesic effect of hydromorphone at the dose used in this laboratory setting was transient but significant. The link model and system analysis were equally efficient at evaluating the relation between concentration, and analgesic and nonanalgesic effects of hydromorphone, and gave similar results. Both methods may be useful in the study of pharmacodynamics of opioids.