A randomized, double-blind comparison of OROS(R) hydromorphone and controlled-release morphine for the control of chronic cancer pain

Abstract

Background: Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS(R) hydromorphone is a sustained-release formulation of hydromorphone that requires dosing once daily to maintain therapeutic concentrations. The objective of this study was to demonstrate the clinical equivalence of immediate-release and sustained-release formulations of hydromorphone and morphine for chronic cancer pain.

Methods: 200 patients with cancer pain (requiring </= 540 mg/d of oral morphine) participated in this double-blind, parallel-group trial. Patients were randomized to receive hydromorphone or morphine (immediate-release for 2-9 days, sustained-release for 10-15 days). Efficacy was assessed with the Brief Pain Inventory (BPI), investigator and patient global evaluations, Eastern Cooperative Oncology Group performance status, and the Mini-Mental State Examination. The primary endpoint was the 'worst pain in the past 24 hours' item of the BPI, in both the immediate-release and sustained-release study phases, with treatments deemed equivalent if the 95% confidence intervals (CI) of the between-group differences at endpoint were between -1.5 and 1.5. No equivalence limits were defined for secondary endpoints.

Results: Least-squares mean differences (95% CI) between groups were 0.2 (-0.4, 0.9) in the immediate-release phase and -0.8 (-1.6, -0.01) in the sustained-release phase (intent-to-treat population), indicating that the immediate-release formulations met the pre-specified equivalence criteria, but that the lower limit of the 95% CI (-1.6) was outside the boundary (-1.5) for the sustained-release formulations. BPI 'pain now PM' was significantly lower with OROS(R) hydromorphone compared with controlled-release morphine (least-squares mean difference [95% CI], -0.77 [-1.49, -0.05]; p = 0.0372). Scores for other secondary efficacy variables were similar between the two sustained-release treatments. At endpoint, > 70% of investigators and patients rated both treatments as good to excellent. The safety profiles of hydromorphone and morphine were similar and typical of opioid analgesics.

Conclusion: Equivalence was demonstrated for immediate-release formulations of hydromorphone and morphine, but not for the sustained-release formulations of OROS(R) hydromorphone and controlled-release morphine. The direction of the mean difference between the treatments (-0.8) and the out-of-range lower limit of the 95% CI (-1.6) were in favor of OROS(R) hydromorphone.

Trial registration: ClinicalTrials.gov: NCT0041054.

Trial registration: ClinicalTrials.gov NCT00041054.

Figure 1

Study design. BID, twice daily; CR, controlled-release; IR, immediate-release; QD, once-daily; q4h, every 4 hours.

Figure 2

Patient disposition. IR, immediate-release; SR, sustained-release.

Figure 3

Least-squares mean differences and 95% confidence intervals between the OROS^® hydromorphone and controlled-release (CR) morphine groups at end of the sustained-release (SR) phase.

Figure 4

Mean Brief Pain Inventory (BPI) interference scores at baseline, end of immediate-release (IR) phase, and end of sustained-release (SR) phase. Values at baseline represent means; values at other time points represent least-squares means. At baseline: hydromorphone, n = 99; morphine, n = 101. In IR phase: IR hydromorphone, n = 99; IR morphine, n = 101. In SR phase: OROS^® hydromorphone, n = 77; controlled-release (CR) morphine, n = 86.

Figure 5

Mean (standard error, SE) pain now scores in the morning during the sustained-release (SR) phase. Pain was rated using the 11-point Brief Pain Inventory (BPI), ranging from 0 (no pain) to 10 (worst pain imaginable). CR, controlled-release.

Figure 6

Mean (standard error, SE) pain now scores in the evening during the sustained-release (SR) phase. Pain was rated using the 11-point Brief Pain Inventory (BPI), ranging from 0 (no pain) to 10 (worst pain imaginable). CR, controlled-release.

Figure 7

Patient (A) and investigator (B) global evaluations of treatment effectiveness at the end of the sustained-release (SR) phase. CR, controlled-release.