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Background: The purpose of this study was investigate the dose proportionality of a novel, oncedaily, controlled-release formulation of hydromorphone that utilizes the OROS® Push-PullTM osmotic pump technology. Methods: In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS® hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals preand post-OROS® hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0–∞). An analysis of variance (ANOVA) model on untransformed and dosenormalized data for AUC0-t, AUC0–∞, and Cmax was used to establish dose linearity and proportionality. Results: The study was completed by 31 of 32 subjects. Median Tmax (12.0–16.0 hours) and mean t1/2 (10.6–11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0– 48, and AUC0–∞ by dose indicated that the relationship was linear (slope, P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05). Conclusion: The pharmacokinetics of OROS® hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses. Trial Registration: Clinical Trials.gov NCT00398957 Background Hydromorphone hydrochloride (HCl), which is available in immediateand extended-release formulations, is a semi-synthetic opioid agonist that has been used widely for many years in the treatment of acute and chronic pain. A number of studies have demonstrated the efficacy and tolerability of hydromorphone in comparison with morphine and other opioid analgesic agents [1]. When formuPublished: 2 February 2007 BMC Clinical Pharmacology 2007, 7:3 doi:10.1186/1472-6904-7-3 Received: 5 May 2006 Accepted: 2 February 2007 This article is available from: http://www.biomedcentral.com/1472-6904/7/3 © 2007 Sathyan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.