Materials and Methods SB-767905/011 was carried out in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practices. The protocol and related documents were approved by an Institutional Review Board or Independent Ethics Committee at each center, and all subjects provided voluntary written informed consent. The study was a double-blind study of the investigational, peripherally active mu-opioid receptor (PAM-OR) antagonist, alvimopan, in 522 chronic pain patients randomized to alvimopan 0.5mg BID, 1mg QD, 1mg BID, or placebo for 6 weeks. Patients requiring analgesia equivalent to ≥30mg oral morphine daily, reporting <3 bowel movements/week without laxatives and symptomatic in 25% of stools, were eligible. Patients described weekly changes in GIS for constipation, using a 7-point Likert scale, relative to pre-treatment. Responders reported moderate or substantial improvement. Severity of constipation symptoms and impact on quality of life (QoL) were assessed by the Patient Assessment of Constipation Scales, PAC-SYM and PAC-QoL, respectively.

Results Mean GIS responder rates, defined as proportion of weeks a patient was a responder, were ~40% in the alvimopan groups vs 14% for placebo (p<0.001). Percentage of responders each week was typically ≥20% higher than placebo (p≤0.003). OBD global improvement was significantly correlated with bowel movement frequency (p<0.0001), straining (p<0.0001), incomplete evacuation (p<0.0001), stool consistency (p<0.0001), and each domain (p<0.0001) of PAC-SYM and PAC-QoL.

Conclusion This analysis demonstrates that Global Improvement is an important endpoint that integrates patients' assessment of a range of OBD symptom changes.