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Total knee arthroplasty is a painful procedure, with approximately half of patients reporting severe pain during the early postoperative period. Gabapentinoids are used as an adjunct for the management of acute pain in approximately half of enhanced recovery programs. We performed a meta-analysis to assess the effectiveness and safety of gabapentinoids for the treatment of acute postoperative pain following total knee arthroplasty.Randomized controlled trials of patients undergoing elective primary total knee arthroplasty that compared the use of the gabapentinoid class of drugs (gabapentin [Neurontin; Pfizer]) or pregabalin [Lyrica; Pfizer]) with that of placebo were retrieved, with 12 studies meeting inclusion criteria. The primary outcome was pain intensity with activity at 48 hours following the surgical procedure. The secondary outcomes included pain intensity at other time points, opioid consumption, knee function, incidence of chronic pain, and adverse events.No difference in pain score at 12, 24, 48, or 72 hours following the surgical procedure was seen between gabapentin and placebo. Although pregabalin was associated with reduced pain scores at 24 and 48 hours, this corresponded to a reduction of 0.5 point (95% confidence interval, 0 to 1.0 point) at 24 hours and 0.3 point (95% confidence interval, 0 to 0.6 point) at 48 hours on an 11-point numeric rating scale, which was assessed as not clinically important. Overall, no clinically relevant reduction in pain scores was associated with the use of gabapentinoids. Likewise, gabapentinoids were associated with a small, but not clinically important, reduction in cumulative opioid consumption at 48 hours (mean difference, −23.2 mg [95% confidence interval, −40.9 to −5.4 mg]). There was no difference in knee flexion at 48 hours (p = 0.63) or in the incidence of chronic pain at 3 months (p = 0.31) or 6 months (p = 0.54) associated with the use of gabapentinoids. Although gabapentinoids were associated with a significant reduction in the incidence of nausea (risk ratio, 0.7 [95% confidence interval, 0.6 to 0.9]; p < 0.001), pregabalin was also associated with a significant, clinically relevant increase in the risk of sedation (risk ratio, 1.4 [95% confidence interval, 1.1 to 1.9]; p = 0.02).On the basis of this meta-analysis, we found no evidence to support the routine use of gabapentinoids in the management of acute pain following total knee arthroplasty.Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.