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

Magdi Hanna,John Thipphawong

doi:10.1186/1472-684x-7-17

Abstract

BackgroundLong-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS® 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.Methods200 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.ResultsLeast-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® 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.ConclusionEquivalence was demonstrated for immediate-release formulations of hydromorphone and morphine, but not for the sustained-release formulations of OROS® 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® hydromorphone.Trial registrationClinicalTrials.gov: NCT0041054

Highlights

Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain
Withdrawal from the study owing to lack of efficacy was more common in patients randomized to hydromorphone (n = 11) compared with morphine (n = 4)
This study demonstrates that while IR hydromorphone is equivalent to IR morphine for relieving chronic cancer pain, equivalence was not demonstrated for OROS® hydromorphone and CR morphine in the SR phase of the study

Summary

Introduction

Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS® hydromorphone is a sustained-release formulation of hydromorphone that requires dosing once daily to maintain therapeutic concentrations. The European Association for Palliative Care [4] and the American Pain Society [5] advocate the use of long-acting oral agents for maintaining analgesia once individual dose requirements have been established. For these reasons, long-acting opioids have become the mainstay of chronic cancer pain therapy. OROS® hydromorphone is a unique long-acting opioid formulation that utilizes Push-PullTM active osmotic technology developed by ALZA Corporation (Mountain View, CA, USA). The pharmacokinetics of OROS® hydromorphone are minimally affected by alcohol; one study found that plasma hydromorphone concentrations were slightly higher after alcohol (240 mL solutions of 4%, 20%, and 40% alcohol and orange juice) compared with no alcohol, but there was no clear alcohol dose-response relationship and no dose dumping of hydromorphone occurred [12]

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