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Introduction and Objectives Refractory chronic cough (RCC) persists despite guideline-based treatment for any comorbid cough-associated conditions and carries a high burden of disease and impact on patients’ lives. Nalbuphine extended-release (NAL ER, oral tablet form) is a kappa receptor agonist and mu receptor antagonist which acts on the cough reflex arc centrally and peripherally, targeting opioid receptors involved in chronic cough. The RIVER trial ( NCT05962151) evaluated NAL ER in patients with refractory chronic cough (RCC).Methods This double-blind, placebo (PBO)-controlled, crossover study enrolled patients with RCC stratified into 2 subgroups based on 24-h cough frequency at screening (10–19 coughs/h [moderate] and ≥20 coughs/h [severe]) measured by a cough monitor. Patients were randomly assigned to one of two 21-day treatment sequences: NAL ER to PBO or PBO to NAL ER, with a 21-d washout between treatment periods. NAL ER was titrated every 7 d (27 mg, 54 mg, and 108 mg, all BID). The primary endpoint was relative change from baseline in 24-h objective cough frequency at day 21 in all patients.Results Sixty-six patients were randomized (mean age, 60.2 y; mean cough frequency, 34.7 coughs/h). There was a significant difference in the relative change from baseline in 24-hour cough frequency with NAL ER 108 mg compared to PBO (-65% and -9%, respectively with a PBO-adjusted improvement of 57%; P<.0001; figure 1). Cough frequency subgroups of 10–19 and ≥ 20 coughs/hr achieved PBO-adjusted improvements of 75% and 51%, respectively (both P<.0001), with NAL ER at day 21 (108 mg). Significant reductions in 24-h cough frequency occurred at day 7 with 27-mg NAL ER BID (P<.0001). No serious treatment-emergent adverse events (TEAEs) were reported; 10 patients discontinued treatment due to TEAEs. The most common (≥10%) TEAEs were constipation, somnolence, nausea, dizziness, headache, and fatigue.Abstract P113 Figure 1Relative Change from Baseline at Day 21 (108 mg BID)Conclusions The significant reduction in 24-h cough frequency supports further investigation of NAL ER for RCC.