Improvement in Central Sensitization Following Total Knee Arthroplasty Is Associated With Severe Preoperative Pain and Affects Postoperative Quality of Life: A Retrospective Study
Introduction Total knee arthroplasty (TKA) is the most common surgical procedure performed for knee osteoarthritis (OA) . TKA is a cost‐effective surgical method and has excellent patient satisfaction and outcomes . However, 8.0%–26.5% of patients are still dissatisfied with the postoperative outcomes . A growing body of evidence suggests that psychological factors contribute to these unexpected negative surgical outcomes . In particular, the presence of central sensitization (CS) has been shown to adversely affect postoperative quality of life (QOL) in many recent studies . CS refers to pain enhancement triggered by modulation of the central nervous system, which occurs when the same stimulus is continued several times over a long period of time . In this pathological condition, neurons in the central nervous system respond to subthreshold stimuli or amplify pain stimuli, causing allodynia or hyperalgesia . It has been reported that 20%–40% of end‐stage knee OA patients scheduled to undergo primary TKA are associated with CS preoperatively . The diagnostic tools used to identify CS are classified into two types: provocation tests using pain‐related stimuli or self‐reported questionnaires . Of these two, diagnosis using questionnaires is simpler and more efficient at predicting postoperative outcomes . The most frequently used questionnaires for diagnosing CS are the Central Sensitization Inventory (CSI) and PainDETECT . Although studies have shown that PainDETECT can be useful for predicting postoperative results, many recent studies using the CSI have also been reported . Despite the extensive research on preoperative CS, there is a noticeable gap in understanding postoperative CS. Previous studies have generally overlooked the investigation of changes in CS after surgery in relation to clinical outcomes. This study aims to fill this gap by examining both preoperative CS levels and postoperative CS changes, and their impacts on QOL and clinical outcomes following TKA. The primary objectives of this study are as follows: (i) To determine the extent of changes in CS following surgery and identify common patient characteristics associated with improved CS after TKA. (ii) To explore whether these changes in CS correlate with enhanced patient QOL and improved clinical outcomes. By addressing these objectives, this study aims to provide valuable insights into the role of CS in postoperative recovery after TKA and inform future interventions aimed at improving patient outcomes in this context. 

Materials and Methods 2.1 Participants We retrospectively reviewed 115 patients who underwent primary unilateral TKA between January 2021 and May 2023 after obtaining approval from our institutional review board. We only included patients with Kellgren–Lawrence Grade IV knee OA between the ages of 50 and 90 years in our study. All participants were followed up for at least 1 year postoperatively and completed all examinations related to outcome measurements. The following patients were excluded:  those diagnosed with secondary knee OA ( n = 3),  those who needed rehospitalization or reoperation due to periprosthetic joint infection ( n = 2),  those who underwent additional surgery within 1 year after TKA for other reasons ( n = 4, one patient had a periprosthetic fracture, and the other underwent TKA on the opposite knee),  those who were diagnosed with any psychiatric disorder ( n = 3), and  those with a history of drug abuse ( n = 0). In addition, we excluded 11 patients with a history of central sensitivity syndromes (fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, chronic low back pain, tension‐type headaches, temporomandibular disorders, myofascial pain syndrome, and restless legs syndrome) and complex regional pain syndrome (Figure ) . Finally, 92 patients were enrolled in the study (male: 11; female: 81). 2.2 Outcome Measures All participants were admitted to the hospital 1 day before surgery. After admission, demographic data including age, sex, weight, and body mass index were collected, and plain radiographs of the knee were taken. We used three scoring systems to evaluate the patients: the CSI, Hospital for Special Surgery (HSS) knee score, and the Short Form Health Survey (SF‐36). These three scoring systems help provide a comprehensive understanding of the patient by evaluating overall health related to pain, the local condition of the knee, and QOL. Therefore, we applied these scoring systems to all patients undergoing surgery. All questionnaires were completed in a self‐reported manner, except for objective examinations to determine the HSS knee score. Physical examinations and analyses of plain radiographs were performed by a clinical researcher, including measurements of flexion contracture, range of motion (ROM), and mechanical axis alignment. The CSI was used to quantify the CS severity of participants . This questionnaire consists of 25 questions, and the result is an integer between 0 and 100 . Based on the CSI score, CS severity was classified as follows: subclinical, 0–29; mild, 30–39; moderate, 40–49; severe, 50–59; and extreme, 60–100 . The HSS knee score was used to assess the overall condition of the knee. This scoring system is divided into a subjective score that evaluates pain and function and an objective score . We recorded the total score of the HSS knee score in addition to the pain score and function score, which are subscores of the HSS subjective score. The maximum scores possible for the pain score and the function score are 30 and 22, respectively. Higher scores indicate better outcomes. The SF‐36 was used to evaluate QOL. The SF‐36 includes 36 questions and eight health scales: limitations of physical functioning (PF), role‐functioning physical (RP), bodily pain (BP), general health (GH), vitality (V), social functioning (SF), role functioning emotional (RE), and mental health (MH). Each score ranges from 0 to 100, with higher scores indicating better conditions . 2.3 Perioperative Pain Control All patients received 5 mg of transdermal buprenorphine via patch (sustained release of 5 μg/h) 12 h before surgery, 200 mg of celecoxib 1 h before surgery, and 10 mg of intravenous dexamethasone at the beginning of surgery. All surgeries were performed at our institution by the senior author under general anesthesia using standard procedures and the same posterior‐stabilized–type implant system (Persona; Zimmer‐Biomet, Warsaw, IN, USA). After surgery, all patients received intravenous patient‐controlled analgesia (PCA). PCA was adjusted to be administered at 2 mL/h and was prepared by mixing 700 μg of fentanyl in 100 mL of normal saline. Two hundred milligrams of celecoxib and 10 mg of intravenous dexamethasone were administered at 8:00 a.m. on postoperative Day 1. After that, 200 mg of celecoxib was maintained until 4 weeks after surgery. To control breakthrough pain, 50 mg of intravenous tramadol was administered at 6‐h intervals only to patients experiencing breakthrough pain with a pain score of 5 or higher on a 10‐point visual analogue scale, for 1 week after surgery. In all other cases, tramadol was not administered. 2.4 Patient Follow‐up All patients were followed up clinically at 1, 3, 6, and 9 months. At 1 year after TKA, the same plain radiographs acquired at the time of admission were taken again. In addition, the questionnaires described above were completed. All physical examinations and analyses of plain radiographs were performed by the same clinical researcher. 2.5 Changes in CS After Surgery and Related Patient Characteristics We compared the CSI scores before and 1 year after surgery. The number and proportion of patients with and without an improvement in CS severity of ≥ 1 level at 1 year after surgery were determined (improved and non‐improved groups, respectively). In addition, the distribution of CS severity levels was compared pre‐ and post‐TKA. To determine whether there were any predictive variables for patients who may have an improved postoperative CS severity, we analyzed whether there were any preoperative variables showing a statistically significant difference between the two groups. These variables included demographic data and underlying conditions that may affect QOL such as diabetes mellitus, coronary artery disease, cerebrovascular accident, and kidney disease, as well as preoperative flexion contracture, ROM, mechanical axis alignment, and HSS knee score. To determine the clinical usefulness of the variables showing a statistically significant difference between the two groups, we analyzed whether there were threshold values for these variables that could distinguish the two groups using the receiver‐operating characteristic (ROC) curve and the area under the ROC curve (AUC). Furthermore, the relationship between these variables and the extent of change in CSI score after TKA was analyzed using two different methods. First, the Pearson correlation coefficient between the change in CSI score and each variable was calculated. Second, to investigate the relationship with changes in CS severity levels, patients were divided into three groups: those with no change (non‐improved group, as previously defined), those with an increase of one level (moderately improved group), and those with an increase of two or more levels (highly improved group). The differences in the means of each variable among these groups were then assessed. 2.6 Changes in CS After Surgery and Its Relationship with Patients' QOL We investigated whether changes in CS were related to patient QOL. The change in SF‐36 scores before and after surgery in the improved and non‐improved groups was compared. We determined whether the mean postoperative changes in the eight scales of SF‐36 for each group achieved the minimal clinically important changes (MIC). Moreover, to determine if the improvement in CS severity level is associated with improvements in SF‐36, we compared the number of SF‐36 scales that achieved the MIC among patients in the non‐improved, moderately improved, and highly improved groups. The MIC values were taken from two previous studies on primary unilateral TKA . 2.7 Statistical Analysis Continuous variables were compared using Student's t ‐test or the Mann–Whitney U ‐test. The chi‐squared test was used to compare categorical variables. For comparisons between multiple groups, one‐way analysis of variance (ANOVA) was used for continuous variables. All analyses were performed with R software (Version 4.2.1; R Development Core Team, Vienna, Austria), and the level of statistical significance was set to p < 0.05. 

Participants We retrospectively reviewed 115 patients who underwent primary unilateral TKA between January 2021 and May 2023 after obtaining approval from our institutional review board. We only included patients with Kellgren–Lawrence Grade IV knee OA between the ages of 50 and 90 years in our study. All participants were followed up for at least 1 year postoperatively and completed all examinations related to outcome measurements. The following patients were excluded:  those diagnosed with secondary knee OA ( n = 3),  those who needed rehospitalization or reoperation due to periprosthetic joint infection ( n = 2),  those who underwent additional surgery within 1 year after TKA for other reasons ( n = 4, one patient had a periprosthetic fracture, and the other underwent TKA on the opposite knee),  those who were diagnosed with any psychiatric disorder ( n = 3), and  those with a history of drug abuse ( n = 0). In addition, we excluded 11 patients with a history of central sensitivity syndromes (fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, chronic low back pain, tension‐type headaches, temporomandibular disorders, myofascial pain syndrome, and restless legs syndrome) and complex regional pain syndrome (Figure ) . Finally, 92 patients were enrolled in the study (male: 11; female: 81). 

Outcome Measures All participants were admitted to the hospital 1 day before surgery. After admission, demographic data including age, sex, weight, and body mass index were collected, and plain radiographs of the knee were taken. We used three scoring systems to evaluate the patients: the CSI, Hospital for Special Surgery (HSS) knee score, and the Short Form Health Survey (SF‐36). These three scoring systems help provide a comprehensive understanding of the patient by evaluating overall health related to pain, the local condition of the knee, and QOL. Therefore, we applied these scoring systems to all patients undergoing surgery. All questionnaires were completed in a self‐reported manner, except for objective examinations to determine the HSS knee score. Physical examinations and analyses of plain radiographs were performed by a clinical researcher, including measurements of flexion contracture, range of motion (ROM), and mechanical axis alignment. The CSI was used to quantify the CS severity of participants . This questionnaire consists of 25 questions, and the result is an integer between 0 and 100 . Based on the CSI score, CS severity was classified as follows: subclinical, 0–29; mild, 30–39; moderate, 40–49; severe, 50–59; and extreme, 60–100 . The HSS knee score was used to assess the overall condition of the knee. This scoring system is divided into a subjective score that evaluates pain and function and an objective score . We recorded the total score of the HSS knee score in addition to the pain score and function score, which are subscores of the HSS subjective score. The maximum scores possible for the pain score and the function score are 30 and 22, respectively. Higher scores indicate better outcomes. The SF‐36 was used to evaluate QOL. The SF‐36 includes 36 questions and eight health scales: limitations of physical functioning (PF), role‐functioning physical (RP), bodily pain (BP), general health (GH), vitality (V), social functioning (SF), role functioning emotional (RE), and mental health (MH). Each score ranges from 0 to 100, with higher scores indicating better conditions . 

Perioperative Pain Control All patients received 5 mg of transdermal buprenorphine via patch (sustained release of 5 μg/h) 12 h before surgery, 200 mg of celecoxib 1 h before surgery, and 10 mg of intravenous dexamethasone at the beginning of surgery. All surgeries were performed at our institution by the senior author under general anesthesia using standard procedures and the same posterior‐stabilized–type implant system (Persona; Zimmer‐Biomet, Warsaw, IN, USA). After surgery, all patients received intravenous patient‐controlled analgesia (PCA). PCA was adjusted to be administered at 2 mL/h and was prepared by mixing 700 μg of fentanyl in 100 mL of normal saline. Two hundred milligrams of celecoxib and 10 mg of intravenous dexamethasone were administered at 8:00 a.m. on postoperative Day 1. After that, 200 mg of celecoxib was maintained until 4 weeks after surgery. To control breakthrough pain, 50 mg of intravenous tramadol was administered at 6‐h intervals only to patients experiencing breakthrough pain with a pain score of 5 or higher on a 10‐point visual analogue scale, for 1 week after surgery. In all other cases, tramadol was not administered. 

Patient Follow‐up All patients were followed up clinically at 1, 3, 6, and 9 months. At 1 year after TKA, the same plain radiographs acquired at the time of admission were taken again. In addition, the questionnaires described above were completed. All physical examinations and analyses of plain radiographs were performed by the same clinical researcher. 

Changes in CS After Surgery and Related Patient Characteristics We compared the CSI scores before and 1 year after surgery. The number and proportion of patients with and without an improvement in CS severity of ≥ 1 level at 1 year after surgery were determined (improved and non‐improved groups, respectively). In addition, the distribution of CS severity levels was compared pre‐ and post‐TKA. To determine whether there were any predictive variables for patients who may have an improved postoperative CS severity, we analyzed whether there were any preoperative variables showing a statistically significant difference between the two groups. These variables included demographic data and underlying conditions that may affect QOL such as diabetes mellitus, coronary artery disease, cerebrovascular accident, and kidney disease, as well as preoperative flexion contracture, ROM, mechanical axis alignment, and HSS knee score. To determine the clinical usefulness of the variables showing a statistically significant difference between the two groups, we analyzed whether there were threshold values for these variables that could distinguish the two groups using the receiver‐operating characteristic (ROC) curve and the area under the ROC curve (AUC). Furthermore, the relationship between these variables and the extent of change in CSI score after TKA was analyzed using two different methods. First, the Pearson correlation coefficient between the change in CSI score and each variable was calculated. Second, to investigate the relationship with changes in CS severity levels, patients were divided into three groups: those with no change (non‐improved group, as previously defined), those with an increase of one level (moderately improved group), and those with an increase of two or more levels (highly improved group). The differences in the means of each variable among these groups were then assessed. 

Changes in CS After Surgery and Its Relationship with Patients' QOL We investigated whether changes in CS were related to patient QOL. The change in SF‐36 scores before and after surgery in the improved and non‐improved groups was compared. We determined whether the mean postoperative changes in the eight scales of SF‐36 for each group achieved the minimal clinically important changes (MIC). Moreover, to determine if the improvement in CS severity level is associated with improvements in SF‐36, we compared the number of SF‐36 scales that achieved the MIC among patients in the non‐improved, moderately improved, and highly improved groups. The MIC values were taken from two previous studies on primary unilateral TKA . 

Statistical Analysis Continuous variables were compared using Student's t ‐test or the Mann–Whitney U ‐test. The chi‐squared test was used to compare categorical variables. For comparisons between multiple groups, one‐way analysis of variance (ANOVA) was used for continuous variables. All analyses were performed with R software (Version 4.2.1; R Development Core Team, Vienna, Austria), and the level of statistical significance was set to p < 0.05. 

Results 3.1 Changes in CS After Surgery Demographic data for all participants are shown in Table . The mean CSI was 36.5 ± 9.79 before surgery and 24.2 ± 13.2 at 1 year thereafter ( p < 0.001) (Figure ). At 1 year after TKA, the number of patients with subclinical CS increased by more than twofold, whereas the number of patients in the other CS severity categories decreased (Figure ). Postoperative CS severity was statistically significantly lower than before surgery ( p < 0.001). In total, 57 patients (62.0%) belonged to the improved group and 35 (38.0%) to the non‐improved group. 3.2 Common Patient Characteristics Associated with Improved CS After Surgery There were no differences in preoperative characteristics between the two groups (Table ). However, there were significant differences in preoperative pain and total HSS knee scores between the two groups, and these differences disappeared after surgery (Table ). The optimal HSS knee pain score for distinguishing the two groups was 7.5 (sensitivity: 82.9%; specificity: 54.4%) according to ROC analysis. The AUC value was 0.744, exceeding the reliable threshold of 0.7 . In addition, the optimal HSS knee total score for distinguishing the two groups was 58.8 (sensitivity: 85.7%; specificity: 57.9%) (Figure ). The AUC value was 0.719, exceeding the accepted threshold . The Pearson correlation coefficient between the HSS knee pain score and the amount of change in CSI after TKA was 0.321 (95% CI: [0.125–0.494]; p = 0.002; r 2 = 0.103). Meanwhile, the Pearson correlation coefficient between the HSS knee total score and the amount of change in CSI after TKA was 0.140 (95% CI: [−0.067 to 0.335]; p = 0.186; r 2 = 0.019). Therefore, only the pain score showed a correlation with the change in CSI . In addition, the greater the improvement in CS severity level after surgery, the lower the preoperative HSS pain score (Table ). 3.3 Postoperative Changes in CS and Their Association with Patients' QOL The preoperative SF‐36 scores were significantly lower in the improved group compared to the non‐improved group. However, similar to the lack of a significant difference in postoperative HSS knee scores between the two groups, there were no differences in postoperative SF‐36 scores between the groups. Specifically, SF scores increased significantly in the improved group, surpassing those in the non‐improved group. Consequently, the mean postoperative increases in the scores for all eight SF‐36 scales were greater in the improved group than in the non‐improved group, and significance was observed for the PF, RP, BP, SF, and MH. The mean postoperative increases in the scores for all eight SF‐36 scales exceeded the MIC in the improved group. However, in the non‐improved group, the mean postoperative increases in PF, RP, and SF were below the MIC suggested by Clement et al. and Escobar et al. In addition, the values for V were lower than the MIC suggested by Escobar et al.  (Table ). Moreover, the number of SF‐36 scales that achieved the MIC increased as CS severity improved more significantly in each patient (Figure ). 

Changes in CS After Surgery Demographic data for all participants are shown in Table . The mean CSI was 36.5 ± 9.79 before surgery and 24.2 ± 13.2 at 1 year thereafter ( p < 0.001) (Figure ). At 1 year after TKA, the number of patients with subclinical CS increased by more than twofold, whereas the number of patients in the other CS severity categories decreased (Figure ). Postoperative CS severity was statistically significantly lower than before surgery ( p < 0.001). In total, 57 patients (62.0%) belonged to the improved group and 35 (38.0%) to the non‐improved group. 

Common Patient Characteristics Associated with Improved CS After Surgery There were no differences in preoperative characteristics between the two groups (Table ). However, there were significant differences in preoperative pain and total HSS knee scores between the two groups, and these differences disappeared after surgery (Table ). The optimal HSS knee pain score for distinguishing the two groups was 7.5 (sensitivity: 82.9%; specificity: 54.4%) according to ROC analysis. The AUC value was 0.744, exceeding the reliable threshold of 0.7 . In addition, the optimal HSS knee total score for distinguishing the two groups was 58.8 (sensitivity: 85.7%; specificity: 57.9%) (Figure ). The AUC value was 0.719, exceeding the accepted threshold . The Pearson correlation coefficient between the HSS knee pain score and the amount of change in CSI after TKA was 0.321 (95% CI: [0.125–0.494]; p = 0.002; r 2 = 0.103). Meanwhile, the Pearson correlation coefficient between the HSS knee total score and the amount of change in CSI after TKA was 0.140 (95% CI: [−0.067 to 0.335]; p = 0.186; r 2 = 0.019). Therefore, only the pain score showed a correlation with the change in CSI . In addition, the greater the improvement in CS severity level after surgery, the lower the preoperative HSS pain score (Table ). 

Postoperative Changes in CS and Their Association with Patients' QOL The preoperative SF‐36 scores were significantly lower in the improved group compared to the non‐improved group. However, similar to the lack of a significant difference in postoperative HSS knee scores between the two groups, there were no differences in postoperative SF‐36 scores between the groups. Specifically, SF scores increased significantly in the improved group, surpassing those in the non‐improved group. Consequently, the mean postoperative increases in the scores for all eight SF‐36 scales were greater in the improved group than in the non‐improved group, and significance was observed for the PF, RP, BP, SF, and MH. The mean postoperative increases in the scores for all eight SF‐36 scales exceeded the MIC in the improved group. However, in the non‐improved group, the mean postoperative increases in PF, RP, and SF were below the MIC suggested by Clement et al. and Escobar et al. In addition, the values for V were lower than the MIC suggested by Escobar et al.  (Table ). Moreover, the number of SF‐36 scales that achieved the MIC increased as CS severity improved more significantly in each patient (Figure ). 

Discussion 4.1 Key Findings of This Study and Their Implications This study investigated whether CS changes 1 year after TKA, and assessed the clinical significance of such changes. About two‐thirds of our patients showed a clinically significant improvement in CS after TKA. These patients (the improved group) had more severe preoperative pain than the non‐improved group. Furthermore, the improved group showed a more significant improvement in SF‐36 scores after TKA than the non‐improved group. This improvement appeared to be clinically relevant. Taken together, these results indicate that patients with severe preoperative pain are more likely to show clinically meaningful improvement in CS and QOL postoperatively. This study may provide another perspective, namely that the improvement in QOL after TKA is not only due to the resolution of local knee problems but may also be related to an improvement in CS, which is associated with the deterioration of multiple parts of the body. 4.2 Extent of Changes in CS After Surgery Few studies have investigated the changes that occur in CS after TKA using the CSI score, and conflicting results have been reported. Koh et al. found that CS in patients did not change after TKA . However, Sasaki et al. reported that 47.5% of patients were diagnosed with CS before surgery, which decreased to 10.0% after TKA . In a study by Fitzsimmons et al., using other diagnostic tools for neuropathic pain, 35.5% of patients showed neuropathic pain before surgery, and 23.6% of patients showed neurogenic pain 6 months after TKA . It is difficult to identify the cause of these conflicting conclusions drawn from the results of previous studies. Since the prevalence of fibromyalgia, which is highly related to CS, is higher in patients with a lower socioeconomic status, the results of studies on CS in patients with knee OA may also differ depending on the location or situation of the institution where the study was conducted . Therefore, a larger‐scale study involving multiple regions will be needed to reach a clear conclusion. 4.3 Common Patient Characteristics Associated with Improved CS After Surgery: Preoperative Pain as a Key Factor In this study, patients who showed improvement in CS severity after surgery had more severe preoperative pain. The optimal preoperative HSS knee pain score for discriminating between the improved and non‐improved groups was 7.5, where higher scores indicate less severe pain. Scores of < 10 indicate that the pain is severe when resting, walking, or both. Therefore, patients experiencing severe pain at rest or while walking were more likely to show an improvement in CS after TKA. This finding can be explained by the fact that persistent activation of peripheral nociceptors is the cause of CS . The results of our study can be interpreted as indicating that CS severity improved in part because the strong peripheral pain that caused CS was eliminated after TKA. Of course, there are limitations to this explanation. The Pearson correlation coefficient between the amount of improvement in CSI score and the preoperative pain score was 0.321, which is a weak correlation. In addition, since the r 2 for this correlation coefficient was 0.103, only about 10.3% of the variability in changes in CSI can be explained by the preoperative HSS knee pain score. Moreover, while the specificity was high (82.9%), the sensitivity was low (54.4%), such that some patients with a pain score above the threshold value were included in the improved group. Thus, even patients with less severe preoperative pain may show improvements in CS. Nevertheless, we believe that the results of this study are sufficient to conclude that the level of pain before TKA is one of several factors associated with changes in CS severity after TKA. There was also a significant group difference in the preoperative HSS knee total scores between the two groups. However, as there were no significant differences between the groups in subscores of the HSS knee score other than the pain score, this seemed to be entirely attributable to differences in pain scores. 4.4 Postoperative Changes in CS and Their Association with Patients' QOL with Clinical Implications Patients in the improved group, who reported more severe pain before surgery, had lower preoperative QOL as assessed by SF‐36 compared to the non‐improved group. However, 1 year after surgery, their SF‐36 scores showed a significant increase compared to the non‐improved group, reaching a level of recovery that was similar to or even higher than the non‐improved group. Thus, more severe pain before surgery may predict a greater improvement in QOL as well as CS after TKA. Since postoperative QOL appears to be related to postoperative satisfaction , these results may explain the finding in previous studies that the more severe the preoperative pain, the higher the patient's satisfaction after TKA . However, definitive conclusions cannot be drawn based on our results because we did not analyze the relationship between changes in CS severity and patient satisfaction after TKA. The improved group exhibited particularly significant improvements in the PF, RP, and SF scales of the SF‐36 compared to the non‐improved group. These scales are indicators related to the patients' social well‐being . Therefore, the observed enhancement in QOL in the improved group may be related to the improvement in physical function, which had previously been limited by knee issues, thereby leading to better social well‐being after TKA. However, further detailed studies are needed to specify which aspects of QOL the patients in the improved group benefited from. Based on our findings, patients with HSS knee pain scores below 7.5, indicating severe pain during walking or at rest before surgery, tend to experience significant improvement in CS severity levels. This improvement correlates with enhanced postoperative QOL. Therefore, accurately assessing preoperative pain may greatly contribute to achieving favorable postoperative outcomes. Evaluating preoperative pain does not require extensive effort or time but may significantly influence surgical outcomes. Hence, meticulous assessment of pain in preoperative patients is crucial. 4.5 The Impact of Gender Bias in the Study on the Interpretation of Findings In this study, there was a predominance of women, which could potentially bias the study results. This outcome arises because in the area where this study was conducted, the incidence of women undergoing TKA is nearly five to ten times higher than that of men . The female predominance among TKA patients is a characteristic observed in most Asian countries and has also been noted in Western countries, where women undergo TKA at more than twice the rate of men . Therefore, when selecting TKA patients as the study population, there will always be a female‐biased group, making studies that strive to balance the gender ratio actually fail to adequately reflect the characteristics of the population. Consequently, studies related to TKA patients with CS often show a female bias. However, these findings are still accepted as scientific results, taking into account the potential limitations in interpretation . Hence, while our study may have a female bias, it might still be generalizable to populations in other regions. However, as the female predominance among TKA patients may vary by region, caution is required when interpreting the results of this study. 4.6 Limitations and Strengths Our study had several limitations. First, we used the HSS knee score for pain assessment, which is less commonly applied than certain other diagnostic instruments. However, the HSS knee score has been validated and exhibits sufficient sensitivity for pain assessment . Second, there is no consensus on the MIC for the SF‐36, as the MIC varies among populations . Therefore, we referred to studies that calculated the MIC specifically for patients who underwent primary unilateral TKA. Despite the aforementioned limitations, our study has strengths in its focus on changes in CS after surgery and in identifying these changes, as well as recognizing their impact on postoperative outcomes. Furthermore, the study offers specific guidelines for patient selection prior to surgery aimed at improving patients' QOL. 

Key Findings of This Study and Their Implications This study investigated whether CS changes 1 year after TKA, and assessed the clinical significance of such changes. About two‐thirds of our patients showed a clinically significant improvement in CS after TKA. These patients (the improved group) had more severe preoperative pain than the non‐improved group. Furthermore, the improved group showed a more significant improvement in SF‐36 scores after TKA than the non‐improved group. This improvement appeared to be clinically relevant. Taken together, these results indicate that patients with severe preoperative pain are more likely to show clinically meaningful improvement in CS and QOL postoperatively. This study may provide another perspective, namely that the improvement in QOL after TKA is not only due to the resolution of local knee problems but may also be related to an improvement in CS, which is associated with the deterioration of multiple parts of the body. 

Extent of Changes in CS After Surgery Few studies have investigated the changes that occur in CS after TKA using the CSI score, and conflicting results have been reported. Koh et al. found that CS in patients did not change after TKA . However, Sasaki et al. reported that 47.5% of patients were diagnosed with CS before surgery, which decreased to 10.0% after TKA . In a study by Fitzsimmons et al., using other diagnostic tools for neuropathic pain, 35.5% of patients showed neuropathic pain before surgery, and 23.6% of patients showed neurogenic pain 6 months after TKA . It is difficult to identify the cause of these conflicting conclusions drawn from the results of previous studies. Since the prevalence of fibromyalgia, which is highly related to CS, is higher in patients with a lower socioeconomic status, the results of studies on CS in patients with knee OA may also differ depending on the location or situation of the institution where the study was conducted . Therefore, a larger‐scale study involving multiple regions will be needed to reach a clear conclusion. 

Common Patient Characteristics Associated with Improved CS After Surgery: Preoperative Pain as a Key Factor In this study, patients who showed improvement in CS severity after surgery had more severe preoperative pain. The optimal preoperative HSS knee pain score for discriminating between the improved and non‐improved groups was 7.5, where higher scores indicate less severe pain. Scores of < 10 indicate that the pain is severe when resting, walking, or both. Therefore, patients experiencing severe pain at rest or while walking were more likely to show an improvement in CS after TKA. This finding can be explained by the fact that persistent activation of peripheral nociceptors is the cause of CS . The results of our study can be interpreted as indicating that CS severity improved in part because the strong peripheral pain that caused CS was eliminated after TKA. Of course, there are limitations to this explanation. The Pearson correlation coefficient between the amount of improvement in CSI score and the preoperative pain score was 0.321, which is a weak correlation. In addition, since the r 2 for this correlation coefficient was 0.103, only about 10.3% of the variability in changes in CSI can be explained by the preoperative HSS knee pain score. Moreover, while the specificity was high (82.9%), the sensitivity was low (54.4%), such that some patients with a pain score above the threshold value were included in the improved group. Thus, even patients with less severe preoperative pain may show improvements in CS. Nevertheless, we believe that the results of this study are sufficient to conclude that the level of pain before TKA is one of several factors associated with changes in CS severity after TKA. There was also a significant group difference in the preoperative HSS knee total scores between the two groups. However, as there were no significant differences between the groups in subscores of the HSS knee score other than the pain score, this seemed to be entirely attributable to differences in pain scores. 

Postoperative Changes in CS and Their Association with Patients' QOL with Clinical Implications Patients in the improved group, who reported more severe pain before surgery, had lower preoperative QOL as assessed by SF‐36 compared to the non‐improved group. However, 1 year after surgery, their SF‐36 scores showed a significant increase compared to the non‐improved group, reaching a level of recovery that was similar to or even higher than the non‐improved group. Thus, more severe pain before surgery may predict a greater improvement in QOL as well as CS after TKA. Since postoperative QOL appears to be related to postoperative satisfaction , these results may explain the finding in previous studies that the more severe the preoperative pain, the higher the patient's satisfaction after TKA . However, definitive conclusions cannot be drawn based on our results because we did not analyze the relationship between changes in CS severity and patient satisfaction after TKA. The improved group exhibited particularly significant improvements in the PF, RP, and SF scales of the SF‐36 compared to the non‐improved group. These scales are indicators related to the patients' social well‐being . Therefore, the observed enhancement in QOL in the improved group may be related to the improvement in physical function, which had previously been limited by knee issues, thereby leading to better social well‐being after TKA. However, further detailed studies are needed to specify which aspects of QOL the patients in the improved group benefited from. Based on our findings, patients with HSS knee pain scores below 7.5, indicating severe pain during walking or at rest before surgery, tend to experience significant improvement in CS severity levels. This improvement correlates with enhanced postoperative QOL. Therefore, accurately assessing preoperative pain may greatly contribute to achieving favorable postoperative outcomes. Evaluating preoperative pain does not require extensive effort or time but may significantly influence surgical outcomes. Hence, meticulous assessment of pain in preoperative patients is crucial. 

The Impact of Gender Bias in the Study on the Interpretation of Findings In this study, there was a predominance of women, which could potentially bias the study results. This outcome arises because in the area where this study was conducted, the incidence of women undergoing TKA is nearly five to ten times higher than that of men . The female predominance among TKA patients is a characteristic observed in most Asian countries and has also been noted in Western countries, where women undergo TKA at more than twice the rate of men . Therefore, when selecting TKA patients as the study population, there will always be a female‐biased group, making studies that strive to balance the gender ratio actually fail to adequately reflect the characteristics of the population. Consequently, studies related to TKA patients with CS often show a female bias. However, these findings are still accepted as scientific results, taking into account the potential limitations in interpretation . Hence, while our study may have a female bias, it might still be generalizable to populations in other regions. However, as the female predominance among TKA patients may vary by region, caution is required when interpreting the results of this study. 

Limitations and Strengths Our study had several limitations. First, we used the HSS knee score for pain assessment, which is less commonly applied than certain other diagnostic instruments. However, the HSS knee score has been validated and exhibits sufficient sensitivity for pain assessment . Second, there is no consensus on the MIC for the SF‐36, as the MIC varies among populations . Therefore, we referred to studies that calculated the MIC specifically for patients who underwent primary unilateral TKA. Despite the aforementioned limitations, our study has strengths in its focus on changes in CS after surgery and in identifying these changes, as well as recognizing their impact on postoperative outcomes. Furthermore, the study offers specific guidelines for patient selection prior to surgery aimed at improving patients' QOL. 

Conclusion In conclusion, 1 year after TKA, our patients experienced an improvement in CS, particularly those with more severe preoperative pain. In addition, this improvement appeared to be related to an improvement in postoperative QOL. Before deciding whether to perform TKA on a given patient, pain at rest or during walking should be assessed, as patients with severe preoperative pain are more likely to benefit from TKA in terms of CS and QOL. 

Y.H.C. and H.S.K.: contributed to the conceptualization. Y.C.K. and Y.H.C.: contributed to the methodology and formal analysis. M.H.K. and D.J.P.: contributed to the investigation. M.H.K.: contributed to the resources and visualization. H.S.K. and Y.C.K.: contributed to writing the original draft. Y.H.C. and D.J.P.: contributed to the review and editing of the manuscript. Y.H.C.: contributed to supervision. Y.C.K.: contributed to funding acquisition. 

This study was approved by the Institutional Review Board of St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea (Study No. VC22RISI0142). 

Because this was a retrospective study, the need for informed consent was waived with the approval of our Institutional Review Board for the following reasons: The study involved no more than minimal risk. The waiver of informed consent was not considered to adversely affect the rights and welfare of the subjects. It was not practical to conduct the study without the waiver or alterations to the study design. Whenever appropriate, participants were provided with additional pertinent information after their participation. 

The authors declare no conflicts of interest. 

