Extended-release morphine formulations are widely used in the management of chronic pain. Avinza (morphine sulfate extended-release [MSER, Morphelan]) is a new, once-a-day, extended-release morphine formulation designed to reach target concentrations rapidly and maintain concentrations throughout a 24-hour period. The primary objective of this study was to compare the 24-hour steady-state pharmacokinetic (PK) profiles of morphine and its metabolites (morphine-6-glucuronide [M6G] and morphine-3-glucuronide [M3G]) following ingestion of MSER once-a-day and MS Contin (controlled-release morphine sulfate [CRM]) twice-a-day in patients with chronic moderate-to-severe pain. Ten patients with chronic moderate-to-severe pain were recruited into an open-label, multiple-dose, nonrandomized, two-period, single-center study. All patients were stabilized for a minimum of 7 days on a twice-daily dose of CRM associated with an optimal balance between pain control and side effects. Patients were then switched to the closest equivalent once-daily dose of MSER for a minimum of 10 days. Twenty-four hour steady-state PK profiles were obtained on the last day of each treatment period and additional clinical and safety assessments were performed. PK data were normalized to a 100-mg total daily dose prior to statistical analysis. Nine of the 10 patients completed the entire study. MSER and CRM demonstrated similar bioavailability (AUC) of morphine and its metabolites. Compared to CRM, MSER demonstrated a 19% lower maximum concentration (C(max)), a 66% higher minimum concentration (C(min)), and a 44% lower peak-to-trough fluctuation (%FI) over the 24-hour period. In addition, MSER maintained concentrations above 50% and 75% of the C(max) longer than CRM. Clinical efficacy and safety were comparable for MSER and CRM. Once-daily MSER approaches maximum morphine concentration more quickly, approximates maximum concentration longer, and demonstrates less fluctuation in morphine concentration during a 24-hour period than CRM dosed twice daily. The pharmacodynamic implications of this profile deserve further study.