The management of acute postoperative pain remains suboptimal. Systematic reviews and Cochrane analysis can assist with collating evidence about treatment efficacy, but the results are limited in part by heterogeneity of endpoints in clinical trials. In addition, the chosen endpoints may not be entirely clinically relevant. To investigate the endpoints assessed in perioperative pain trials, we performed a systematic literature review on outcome domains assessing effectiveness of acute pain interventions in trials after total knee arthroplasty (TKA). We followed the Cochrane recommendations for systematic reviews, searching Pubmed, Cochrane, and Embase, resulting in the screening of 1590 potentially eligible studies. After final inclusion of 295 studies, we identified 11 outcome domains and 45 subdomains/descriptors with the domain “pain”/”pain intensity” most commonly assessed (98.3%), followed by “analgesic consumption” (88.8%) and “side effects” (75.3%). In contrast, “physical function” (53.5%), “satisfaction” (28.8%) and “psychological function” (11.9%) were given much less consideration. The combinations of outcome domains were inhomogeneous throughout the studies, regardless of the type of pain management investigated. In conclusion, we found that there was high variability in outcome domains and inhomogeneous combinations, as well as inconsistent subdomain description and utilization in trials comparing for effectiveness of pain interventions after TKA. This point towards the need for harmonizing outcome domains, e.g. by consenting on a core outcome set (COS) of domains which are relevant for both stakeholders and patients. Such a COS should include at least 3 domains from 3 different health core areas like pain intensity, physical function and one psychological domain.