Perioperative gabapentinoid use during total knee arthroplasty is associated with higher rates of postoperative complications compared to no use.

Background: Gabapentinoids are commonly incorporated into multimodal analgesia protocols for total knee arthroplasty (TKA) to reduce opioid use, yet new evidence suggests important safety concerns. Past studies often label gabapentinoid exposure as a binary variable, without taking into account factors such as chronic continuation, perioperative initiation, and no use, which may carry distinct postoperative risks. Methods: Adults undergoing primary TKA in a large federated EHR network were classified into three perioperative gabapentinoid exposure groups: continuation, new-start, or never use. Postoperative outcomes were evaluated at 30 and 90 days, with risks summarized as risk ratios and hazard ratios with 95% confidence intervals. Results: After matching, 126,941 patients were included in the continuation vs never comparison, 6,227 in continuation vs new start, and 6,221 in new start vs never. Compared with never users, continuation was associated with higher 30- and 90-day risks of acute respiratory failure, acute renal failure, sepsis, venous thromboembolism, emergency department utilization, and postoperative infection. New-start use showed a consistently adverse profile, with increased risks of acute renal failure, postoperative infection, venous thromboembolism, and emergency department utilization at both time points vs never use. Continuation and new-start users had largely similar complication rates, with no clear benefits of continuation. Conclusions: Perioperative gabapentinoid exposure following TKA is associated with higher short-term postoperative complication rates than no exposure, greatest with new initiation and intermediate with continuation. These findings argue against routine perioperative gabapentinoid use in TKA enhanced recovery pathways and support a patient-specific approach pending further randomized evaluation.