Duloxetine, a serotonin-norepinephrine dual reuptake inhibitor, may improve analgesia after total knee arthroplasty (TKA). Previous studies had one primary outcome, did not consistently use multimodal analgesia, and used patient-controlled analgesia devices, potentially delaying discharge. We investigated whether duloxetine would reduce opioid consumption or pain with ambulation. A total of 160 patients received 60 mg duloxetine or placebo daily, starting from the day of surgery and continuing 14 days postoperatively. Patients received neuraxial anesthesia, peripheral nerve blocks, acetaminophen, nonsteroidal anti-inflammatory drugs, and oral opioids as needed. The dual primary outcomes were Numeric Rating Scale (NRS) scores with movement on postoperative days 1, 2, and 14, and cumulative opioid consumption surgery through postoperative day14. Duloxetine was noninferior to placebo for both primary outcomes and was superior to placebo for opioid consumption. Opioid consumption (mean ± SD) was 288 ± 226 mg OME [94, 385] vs 432 ± 374 [210, 540] (duloxetine vs placebo) P= .0039. Pain scores on POD14 were 4.2 ± 2.0 vs 4.8 ± 2.2 (duloxetine vs placebo) P= .018. Median satisfaction with pain management was 10 (8, 10) and 8 (7, 10) (duloxetine vs placebo) P= .046. Duloxetine reduced interference by pain with walking, normal work, and sleep. The 29% reduction in opioid use corresponds to 17 fewer pills of oxycodone, 5 mg, and was achieved without increasing pain scores. Considering the ongoing opioid epidemic, duloxetine can be used to reduce opioid usage after knee arthroplasty in selected patients that can be appropriately monitored for potential side effects of the medication.

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