Simpson, K., Leyendecker, P., Hopp, M., Muller-Lissner, S., Lowenstein, O., De Andres, J., . . . Reimer, K. (2008). Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Current Medical Research and Opinion, 24, 3503-3512.

To demonstrate improvement in constipation in individuals on prolonged-release (PR) oxycodone and PR naloxone compared with individuals receiving single-agent PR oxycodone.

Prerandomization comprised a run-in phase for conversion and titration of prestudy pain medication regimen to the PR oxycodone and bisacodyl laxative regimen. In the double-blind phase, patients were randomized to receive one of the following for 12 weeks: PR oxycodone/PR naloxone in a 2:1 ratio and PR oxycodone placebo, or PR oxycodone alone and PR oxycodone/PR naloxone placebo. All patients completing the double-blind phase were eligible to enter a 52-week extension phase and receive PR oxycodone/PR naloxone.

• The study reported on a sample of 277 patients aged 18 years or older.
• Patients had a documented history of the following:
  • Moderate-to-severe chronic noncancer pain (eg, musculoskeletal, neuropathic, visceral), needing 24-hour coverage with an oxycodone equivalent of 20 to 50 mg/day
  • Constipation caused or worsened by an opioid
  • Expectation of benefit from the World Health Organization (WHO) step III opioid therapy treatment for the duration of the study.

• Multi-site
• Outpatient
• 4 European countries

This was a randomized, double-blind, parallel-group, phase III study.

• Bowel Function Index (BFI)
• Patient Assessment of Opioid Induced Constipation (PACOI)
• Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM)
• Pain Intensity Scale
• Brief Pain Inventory (Short Form) (BPI-SF)

• At week 4, the mean BFI score for the PR oxycodone/PR naloxone group decreased by 26.9 points. In contrast, the mean BFI score for the PR oxycodone group decreased by 9.4 points. The difference between those scores was significantly in favor of the PR oxycodone/PR naloxone group (p < 0.0001).
• At week 4, the mean PACOI score in the PR oxycodone/PR naloxone group decreased to 6.4% compared to 9.4% in the PR oxycodone group, showing statistically significant improvement (p < 0.0001).
• During the first four weeks, significantly fewer patients in the PR oxycodone/PR naloxone group took bisacodyl compared with the PR oxycodone group (p < 0.0001).
• No statistically significant difference existed between the two groups for efficacy of pain control.
• Mean pain intensity scores remained stable throughout the study.
• Twelve patients (three in the PR oxycodone/PR naloxone group and 9 in the PR oxycodone group) experienced serious adverse events, including gastrointestinal bleeding, headache, and cerebrovascular accident.

PR oxycodone/PR naloxone demonstrated superiority in the management of constipation in patients with chronic noncancer pain without compromising analgesia.

The study only included patients with noncancer pain.

PR oxycodone/PR naloxone may be effective in the management of constipation without compromising pain control for patients with chronic pain. However, the study did not include patients with cancer or patients receiving doses of oxycodone equivalent higher than 50 mg/day. Additional studies are warranted with higher doses of opioids and the inclusion of patients with cancer.