Introduction: OIC affects 40-80% of patients taking chronic opioid therapy. Naloxegol (Movantik®), a peripherally acting mu-opioid receptor antagonist (PAMORA) is effective in treating OIC symptoms in adults with chronic non-cancer pain as shown in two pivotal phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This pooled analysis evaluated symptom improvement utilizing the Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM) in these two randomized, placebo-controlled trials. Methods: PAC-SYM scores were collected during KODIAC 4/5 as supportive efficacy measures. Scores range from 0 (absence of symptoms) to 4 (very severe) for each domain (abdominal, rectal, and stool symptoms). Minimal clinically important difference (MCID) thresholds of 0.5 based on literature and naloxegol real world studies, and 0.8 based on anchor method assessment were used to identify responders and non-responders. Results: 1337 patients (naloxegol (25mg, 12.5mg) or placebo (PBO)) were assessed in this analysis. The overall mean baseline values for PAC-SYM total, abdominal, rectal, and stool symptoms scores were 1.8, 1.7, 1.3, and 2.3, respectively, and were similar across groups. For MCID ≥0.5, there was a significantly higher proportion of PAC-SYM responders with naloxegol (25 mg: 69.49%; 12.5 mg: 65.63%) vs PBO (57.66%) at week 12. Odds ratios (OR) were 1.776 (p=0.0010) for 25mg and 1.501 (p=0.0143) for 12.5mg vs PBO. For MCID ≥0.8, higher proportions of PAC-SYM responders were also observed for naloxegol (25mg: 53.47%; 12.5mg: 45.74%) vs PBO (42.34%) at week 12. ORs were 1.709 (p=0.002) for 25mg and 1.217 (p=0.2368) for 12.5mg vs PBO ORs were generally consistent between MCID >0.8 and 0.5 (Table). At 12 weeks for both MCID thresholds, patients receiving naloxegol 25mg were >70% more likely to achieve clinically meaningful symptom improvement than with PBO.Subdomain analyses revealed dose-dependent responses; significantly greater responses in rectal and stool symptoms were achieved for 25mg vs. PBO (p< 0.05) at both MCID cut-offs (Figure 1a-d). Conclusion: OIC patients achieved clinically meaningful, constipation-related symptom improvement with naloxegol. These changes were dose dependent, with significant gains noted for 25mg at both MCID thresholds. Rectal and stool symptoms appear to drive these improvements consistent with the known effects of PAMORAs.Figure 1.: a-d. Likelihood of Achieving PAC-SYM MCID at Week 12: Naloxegol vs. Placebo (KODIAC 4/5; ITT Population) Table 1. - PAC-SYM Total Score: Proportion of Responders Achieving MCID at Week 12 (KODIAC 4/5; ITT Population) Placebo(N=359) a n(%) Naloxegol 12.5 mg(N=352) a n(%) Naloxegol 25 mg(N=331) a n(%) Naloxegol 12 mg vs. PlaceboOR(95% CI)p-value Naloxegol 25 mg vs. PlaceboOR(95% CI)p-value Proportion of PAC-SYM Responders Achieving MCID ≥ 0.5 207 (57.66%) 231 (65.63%) 230 (69.49%) 1.501(1.085, 2.078)0.0143 1.776(1.263, 2.497)0.0010 Proportion of PAC-SYM Responders Achieving MCID ≥ 0.8 152 (42.34%) 161 (45.74%) 177 (53.47%) 1.217(0.879, 1.687)0.2368 1.709(1.216, 2.401)0.0020 aNumber of analyzable subjects with complete PAC-SYM data for 12-wks.PAC-SYM, Patient Assessment of Constipation Symptoms questionnaire; MCID, minimal clinically important difference; OR, odds ratio; CI, confidence interval.