PAMORAs in Cancer and Non-Cancer Opioid-Induced Constipation: A Systematic Review, Meta-Analysis, and Personalized Value-Based Evaluation Integrating Clinical and Patient-Reported Outcomes

Background: Opioid-induced constipation (OIC) is a frequent and clinically relevant complication of long-term opioid therapy in both cancer and non-cancer populations, negatively affecting symptoms, treatment adherence, and health-related quality of life. Peripherally acting μ-opioid receptor antagonists (PAMORAs) represent a mechanism-based therapeutic approach targeting peripheral opioid effects while preserving analgesic activity. However, the overall value of PAMORAs, integrating clinical outcomes, patient-reported benefits, and health-economic implications, has not been comprehensively assessed. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) comparing PAMORAs versus placebo in adults with OIC was performed. PubMed, Embase, Cochrane CENTRAL, and Web of Science were searched up to June 2025. Studies were stratified according to clinical setting (cancer versus non-cancer populations). The primary outcome was the change in mean weekly spontaneous bowel movements (SBMs). Secondary outcomes included constipation-related quality of life assessed by the Patient Assessment of Constipation–Quality of Life (PAC-QOL) questionnaire and health utility estimation through EQ-5D mapping. A two-step exploratory framework linking SBM improvement to PAC-QOL and subsequently to EQ-5D utilities was applied to extend the economic evaluation across the available evidence base. Results: Nineteen RCTs including 5565 patients (2785 PAMORA-treated and 2780 placebo-treated patients) were included. PAMORAs significantly increased weekly SBMs compared with placebo (mean difference [MD] 1.49; 95% CI 1.04–1.95; p < 0.0001). The treatment effect was highly consistent in non-cancer populations (MD 1.28; 95% CI 1.10–1.46; I2 = 0%) and larger but more heterogeneous in cancer populations (MD 2.67; 95% CI −0.001 to 5.35; I2 = 93.7%). In five trials reporting quality-of-life outcomes, PAMORAs were associated with a statistically significant improvement in PAC-QOL scores compared with placebo (MD −0.25; 95% CI −0.41 to −0.10); however, only one study demonstrated an improvement approaching a clinically meaningful threshold, limiting the certainty regarding the clinical relevance of the pooled effect. Mapping analyses provided an exploratory estimate of the relationship between bowel function, patient-reported quality of life, and EQ-5D utilities, allowing estimation of illustrative value-based treatment thresholds. Estimated acceptable monthly treatment costs ranged from approximately €25 to €101 depending on population and trial characteristics. Conclusions: PAMORAs consistently improve bowel function in patients with opioid-induced constipation across cancer and non-cancer settings. Available evidence also suggests an improvement in constipation-related quality of life, although the clinical relevance of this effect remains uncertain because of the limited number of studies and the lack of consistently clinically meaningful changes. The exploratory integration of clinical outcomes, patient-reported measures, and health-economic parameters provides a potential framework for personalized treatment evaluation, but the estimated economic thresholds should be interpreted cautiously and should not be considered direct estimates of cross-country cost-effectiveness.