Hydromorphone hydrochloride extended release (HHER) is a multiparticulate melt-extrusion pellet capsule formulation administered q24h. Study 1 investigated the bioavailability of 24-mg HHER fed, as well as 24-mg and 12-mg HHER and 8-mg hydromorphone hydrochloride immediate-release (HHIR) tablets fasting. No clinically significant food effect was observed on hydromorphone C(max) or AUC for the 24-mg HHER, and dose proportionality (AUC) was demonstrated between 12- and 24-mg HHER. Study 2 demonstrated dose strength proportionality for 3 x 12-mg HHER versus 1 x 32-mg HHER. Study 3 evaluated 12-mg HHER q24h versus 3-mg HHIR q6h at steady state. HHER produced relatively constant steady-state concentrations over 24 hours. HHER and HHIR were equivalent for AUC(ss). C(ssmax) was 26% lower for HHER than HHIR, C(ssmin) was 43% higher for HHER, and peak-to-trough fluctuation was 126% for HHER versus 328% for HHIR, which are ideal attributes of a once-daily oral extended-release dosage form. HHER administration resulted in fewer adverse events than HHIR in study 3.