Wallace, M., Moulin, D.E., Rauck, R.L., Khanna, S., Tudor, I.C., Skowronski, R., & Thipphawong, J. (2009). Long-term safety, tolerability, and efficacy of OROS hydromorphone in patients with chronic pain. Journal of Opioid Management, 5(2), 97–105.

To assess the safety and efficacy of long-term repeated dosing of osmotic extended-release oral delivery system (OROS) hydromorphone used to relieve chronic pain

A patient who entered this study after completing a comparative dose-conversion study with OROS hydromorphone continued taking OROS hydromorphone at his or her stable dose. This study also included patients who had participated in a comparison of hydromorphone immediate release (IR) and OROS hydromorphone. These patients began the OROS hydromorphone study by taking 50%–100% of their established dose; dose adjustments were allowed after a minimum of two days. Dose adjustments were usually in 8 mg increments. The target duration of treatment was at least one year. Adverse events were assessed monthly, and physical exams were conducted and vital signs assessed every three months.

• Of all patients in the study, 106 completed the study (388 had enrolled, and 72.7% withdrew). The study sponsor terminated 80 patients (28.4%) from the study because of a decreasing supply of study medication.
• Mean patient age was 50 years. Age range was 27–91 years.
• Of all patients, 50.8% were female and 49.2% were male.
• Patients in the study were adults, with chronic cancer pain or chronic pain unrelated to malignancies, who were receiving stable doses of OROS hydromorphone equal to at least 8 mg/day. Approximately 20% of the initial sample had cancer-related pain.

• Multisite
• Outpatient
• 56 centers in the United States and Canada

Multicenter open-label extension trial

• Brief Pain Inventory (BPI), patient ratings on a 0–10 scale (0 = no pain, 10 = worst pain imaginable)
• Pain relief as measured by the patient on a 0%–100% scale
• Scale measuring extent to which pain interfered with physical activity or social functioning (0 = no interference, 10 = complete interference)
• Global ratings, by patient and investigator, of overall medication effectiveness (1 = poor, 2 = fair, 3 = good, 4 = very good, 5 = excellent

BPI ratings of worst pain, least pain, and average pain were essentially stable throughout the study. Median daily dose of study medication increased from 32 mg at baseline to 40 mg at month 3 and 48 mg at months 6, 9, and 12. The most frequently reported adverse events were nausea (which 24% of patients experienced) and constipation (which 19.3% of patients experienced). The side-effect profile was similar to that of other sustained-release opioids. Most side effects usually resolved over time, although constipation was did not resolve. Laxatives can manage constipation effectively.

Authors concluded that the benefits of OROS hydromorphone were maintained when daily administration was continued. Once-daily OROS hydromorphone appeared to be safe and effective in controlling moderate to severe chronic pain.

• Only 20% of patients in the study had cancer-related pain upon study entry. Authors did not specify the number of patients with cancer-related pain who completed the study and were included in analysis. Given the relatively small number of patients with cancer-related pain, the degree to which overall findings are generalizable to the oncology patient population is unclear.
• The study had risks of bias due to no blinding and no comparison group. 
• Authors did not discuss rescue medication or breakthrough pain.

Of patients who entered the study, 52.3% experienced a treatment-related event. (The side effects experienced by anyone who entered the study and who took at least one dose of OROS hydromorphone were reported.) Therefore, the tolerability of OROS hydromorphone, used long term, appears limited. The single dose required for pain management may be advantageous for patients who must consume multiple oral medications.