INTRODUCTION: Opioid-induced constipation (OIC) is a common side effect of chronic opioid therapy that significantly impacts quality of life and healthcare costs. Naldemedine, a peripherally acting mu-opioid receptor antagonist, has shown efficacy in treating OIC. However, real-world evidence on naldemedine use in the United States is limited, particularly in older adults. We aimed to describe naldemedine use in real-world settings in the US, focusing on clinical characteristics, comorbidity profiles, co-prescribed medications, and healthcare resource utilization (HCRU), with a specific emphasis on older adults. METHODS: This retrospective study analyzed data from the 2017-2022 Merative™ MarketScan RESULTS: The study cohort (66% women, median age 56 years, 14% aged ≥ 65 years) presented a significant comorbidity burden, with 57% having hypertension, 36% diabetes, and 25% chronic pulmonary disease with a Charlson Comorbidity Index ≥ 2 in 38% of subjects. Polypharmacy (i.e., use of five or more distinct drugs, excluding naldemedine) was very common (76%, 82% in ≥ 65 years). The most frequent indications for naldemedine were chronic back pain and radiculopathy. Oxycodone, hydrocodone, and morphine were the most commonly prescribed opioids. After initiating naldemedine, 30% of patients showed a reduction in hospitalizations per patient per year, with a more pronounced effect in older adults (37%). Potential drug-drug interactions with CYP3A4 inducers or inhibitors were infrequent and did not appear to impact HCRU. CONCLUSIONS: This real-world study demonstrates that naldemedine is predominantly used in middle-aged adults with comorbidities and polypharmacy. Naldemedine use was associated with reduced HCRU, particularly in older adults, suggesting potential benefits in managing OIC. The findings support the safety and effectiveness of naldemedine in real-world settings, including in older patients with multiple comorbidities.