Lowenstein, O., Leyendecker, P., Hopp, M., Schutter, U., Rogers, P.D., Uhl, R., . . . Reimer, K. (2009). Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: A randomised controlled trial. Expert Opinion on Pharmacotherapy, 10, 531-543.

To show the addition of naloxone improves constipation symptoms in patients with non-malignant pain receiving high-dose oxycodone prolonged release (PR).

Patients were randomized to receive either oxycodone PR and naloxone PR or oxycodone PR plus matched oxycodone PR/naloxone placebo. Patients had oxycodone PR titrated to an effective analgesic dose over a 7- to 28-day period and were converted to the study laxative, bisacodyl. Oxycodone immediate release was used as pain rescue medication. Patients were eligible to participate in a 52-week open-label extension. Mean pain over the past 24 hours and bowel function were measured at each study visit and in patient diaries on a daily basis.

• The study reported on a sample of 222 patients (81.5% female and 18.5% male).
• Mean age was 56.2 to 57.5 years (SD = 10.5) across both study groups.
• Patients with cancer-related pain were excluded.
• Predominant problems were musculoskeletal and connective tissue disorders.
• Patients required 60 to 80 mg oxycodone PR equivalent per day and had constipation.

• Multi-site
• Outpatient
• Germany

This was a double-blind, placebo-controlled, randomized study with an extension phase.

• Bowel Function Index (BFI)
• Pain Intensity Scale (numeric rating 0-10)
• Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYMN)
• Subjective Opioid Withdrawal Scale (SOWS)
• Patient diary

• During the first four weeks of the study in the double-blind phase, the difference in mean BFI scores was significantly different (PR = -14.9, p < 0.0001, 95% confidence interval [-17.9, -11.9]) in favor of the oxycodone-PR/naloxone-PR group.
• There were no differences between groups in mean pain measures.
• There were no substantial differences between groups in supplemental analgesic use.
• Significantly fewer patients in the oxycodone-PR/naloxone-PR group took laxatives (p = 0.0009).
• Most common events were nausea, pain, and headache in both groups.
• Withdrawal scores were stable, low, and similar between groups.

Oxycodone PR/naloxone PR was superior to oxycodone PR at improving bowel function and symptoms of constipation. That improvement was achieved without affecting the analgesic efficacy of the oxycodone component.

• The study period of 12 weeks is limited in the setting of much longer-term opioid use.
• Although the study design specified a maximum number of laxative rescue doses, actual rescue laxatives taken were not described and were not analyzed between the two groups.
• Patients with cancer-related pain were specifically excluded; therefore, application to that group is not clear.

The combination of oxycodone PR/naloxone PR in patients with cancer warrants investigation to determine potential benefits in reducing opioid-induced constipation in this population.