Repeat-dose steady-state pharmacokinetic evaluation of once-daily hydromorphone extended-release (OROS® hydromorphone ER) in patients with chronic pain

OBJECTIVE To characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications. METHODS This open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3-14 days and stabilized between 8-48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration-time curve from 0-24 hours (AUC(0-24)), maximum plasma concentration (C(max)), trough plasma concentration (C(min)), average plasma concentration (C(avg)), and degree of fluctuation (100 × [(C(max) - C(min)) ÷ C(avg)]) were calculated based on data from 14 patients. RESULTS Dose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC(0-24), 41.1 ng · h/mL; C(max), 2.6 ng/mL; C(min), 1.1 ng/mL; C(avg), 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2-21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred. CONCLUSION These findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications.