Differential Gastrointestinal Effects of Who-Step III Opioids in Low Back Pain Patients with vs. Without Constipation: Post-Hoc Analysis of Data from a 12-Week Prospective, Open-Label Blinded Endpoint Streamlined Study

Objective: Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with longer-term opioid use and interferes with analgesic efficacy, functionality, quality-of-life, and patient compliance. To compare effects of prolonged release (PR) oxycodone and PR naloxone (OXN), vs. PR oxycodone (OXY) vs. PR morphine (MOR) on bowel function under real-life conditions in chronic low back pain (LBP) patients with vs. those without pre-existent constipation.

Research design and methods: Post-hoc analysis of data from a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study, carried out in 88 centres in Germany, where a total of 901 patients, requiring WHO-step III opioids to treat low back pain, were enrolled, and prospectively observed for 3 months. Bowel function was graded with respect to the bowel function index and characterized as normal (NCP; n=643) or constipated (COP; n=258). Treatment doses could be adjusted as per the German prescribing information and physicians were free to address all side-effects and tolerability issues as usual.

Main outcome measures: Primary endpoint was the proportion of patients experiencing a decrease of ≥1 complete spontaneous bowel movements (CSBMs) per week at end of observation vs. baseline. Secondary analyses addressed absolute/relative BFI changes, proportion of patients with ≤3 CSBMs per week, use of laxatives, treatment emergent adverse events (TEAEs), analgesic effects, and differences between initially non-constipated vs. constipated patient groups.

Results: CSBMs decreased with all three WHO-step III treatments, however, significantly less with OXN vs. OXY and MOR despite a significantly higher use of laxatives with the latter ones (p<0.001). Overall, percentage of patients who met the primary endpoint was 10.3% (31/301) with OXN and significantly inferior to those seen with OXY (42.3%, 127/300; OR: 6.39, 95%-CI: 14.13-9.89; p<0.001) or MOR (42.0%, 126/300; OR: 6.31, 95%-CI: 4.08-9.77; p<0.001). CSBM changes varied with baseline BFI scores and were higher for COP vs. NCP. Primary endpoint for NCP/COP was met with MOR in 40.1/47.0%, with OXY in 39.6/48.9%, and with OXN in 6.5/19.5%. An absolute (relative) BFI deterioration of ≥12 mm VAS (≥50%) vs. baseline was seen for NCP with OXN/OXY/MOR in 40.7/67.5/72.8% (25.7/36.3/43.8%; p<0.001 for OXN vs. OXY and MOR), and for COP in 43.7/71.6/71.1% (21.8/53.4/54.2%; p<0.001 for OXN vs OXY and MOR). Pain intensity, pain-related functionality in daily life as well as quality-of-life improved significantly with all three opioids, however significantly superior with OXN vs. OXY vs. MOR independent of the constipation status at baseline. Overall 359 TEAEs (OXN: 78, OXY: 134, MOR: 147) in 204 patients (OXN: 41, OXY: 80, MOR: 83) occurred, most affecting the gastrointestinal (49.3%) and the nervous system (39.3%). With exception of constipation, related treatment TEAE contrasts between NCP vs. COP were insignificant.

Conclusion: In this post-hoc analysis of data from a real-life 12-week study, OXN treatment was associated with a significantly lower risk of OIC, superior tolerability and significantly better analgesic efficacy compared with OXY and MOR both in patients with and without a pre-existent constipation.