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Objectives: Recent data suggest concomitant gabapentinoid use increases opioid-related overdose (ORO) risk; however, this association has not been well studied in the hospital setting. The primary objective of this study was to compare ORO risk, indicated by naloxone administration, in patients receiving opioids plus gabapentinoids versus opioids alone. Methods: In this retrospective case-control study of adults admitted to a large community hospital from 1/1/20 to 12/31/21, all cases (defined as patients who received naloxone more than 24 hours after admission) identified were matched 1:1 to randomly selected controls (defined as patients on opioids who did not receive naloxone). The primary outcome was the percentage of cases and controls with concomitant inpatient gabapentinoid use. Logistic regression was performed to determine the independent association between gabapentinoids and ORO (as evidenced by inpatient naloxone administration). Results: Baseline characteristics were similar between the 144 cases and 144 controls. Gabapentinoid exposure was greater for cases than controls (34.0%vs 20.8%, P =.0118). Median hospital length of stay (11vs 4 days, P <.0001) and mortality (19%vs 5%; P =.0018) were also higher for cases. In logistic regression analysis, ORO (adjusted OR 4.91; 95% CI 1.86-12.96) and serotonergic medication exposure (adjusted OR 4.31; 95% CI 1.50-12.38) were significantly associated with gabapentinoid use. Conclusions: Concomitant gabapentinoid use with opioids was associated with increased ORO risk in the inpatient setting. When considering prescribing gabapentinoids in conjunction with opioids in the hospital setting, potential benefits should be weighed against increased overdose risk. [ABSTRACT FROM AUTHOR]