Reevaluating Pain Perception in Staged Bilateral Total Knee Arthroplasty: A 72-Hour Postoperative Analysis

Reevaluating Pain Perception in Staged Bilateral Total Knee Arthroplasty: A 72-Hour Postoperative Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reevaluating Pain Perception in Staged Bilateral Total Knee Arthroplasty: A 72-Hour Postoperative Analysis Khanin Iamthanaporn, Arnan Wiwatboworn, Pawin Wanasitchaiwat, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7974018/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Total knee arthroplasty (TKA) is a well-established treatment for end-stage knee osteoarthritis (OA) that significantly alleviates pain and improves joint function. In staged bilateral TKA, previous studies suggest that patients may experience greater pain in the second knee; however, the evidence and underlying mechanisms remain inconsistent and unclear. This study re-evaluated pain perception during the initial 72 h following staged bilateral TKA and examines factors influencing postoperative pain levels, including opioid consumption and the interval between surgeries. Methods This retrospective analysis included 175 patients who underwent staged bilateral TKA between 2015 and 2020. Pain was assessed using a verbal numerical rating scale (VNRS) every 4 h for 72 h postoperatively. A linear mixed-effect model compared pain levels between the first and second surgeries, adjusting for time, opioid consumption, nerve block type, femorotibial angle, and osteoarthritis severity. A subgroup analysis was conducted based on the interval between surgeries ( 12 months). Results The mean interval between the surgeries was 12.34 months. Analysis revealed no significant difference in pain levels between the first and second TKAs (β = -0.070, p = 0.198). However, pain significantly decreased over time (β = -0.076 per 4-hour interval, p < 0.001), and femoral nerve block was associated with reduced pain (β = -0.335, p < 0.001). Sensitivity analysis indicated a slight reduction in pain during the second surgery ( p = 0.041). Subgroup analysis showed no significant differences in pain trajectories across the surgical intervals. Conclusions Pain following second-stage TKA was not significantly higher and was slightly lower than that following first-stage TKA. Additionally, the interval between surgeries did not appear to significantly influence pain outcomes. These findings suggest flexibility in scheduling the second procedure without concern for increased pain and provide valuable insights for optimizing pain management in staged bilateral TKA. Knee osteoarthritis Total knee arthroplasty Staged bilateral TKA Pain perception Postoperative pain management Figures Figure 1 Figure 2 INTRODUCTION Total knee arthroplasty (TKA) is an effective treatment for end-stage knee osteoarthritis (OA), providing substantial pain relief and improving joint function and quality of life. Bilateral symptoms are present in approximately one-third of the patients with knee OA. [ 1 ] Among those undergoing primary unilateral TKA, approximately 40% will eventually require contralateral knee TKA within 10 years. [ 2 ] Staged bilateral TKA is a common approach considered both safe and effective, with fewer complications and lower mortality rates compared with simultaneous bilateral TKA.[ 3 , 4 ] Patients undergoing a second surgery often report increased pain relative to their initial surgery, regardless of the anatomical site.[ 5 ] This heightened pain sensitivity may result from central sensitization, where the nervous system becomes more responsive to nociceptive stimuli following previous surgical exposure. Several studies have reported increased postoperative pain in the second knee following staged bilateral TKA; however, the underlying factors contributing to this phenomenon remain unclear. Kim et al. and Sun et al. observed that patients reported higher pain levels after second-stage TKA.[ 6 , 7 ] Koh et al. also found that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that prevents central sensitization, did not significantly reduce pain during second-stage surgery. [ 8 ] By contrast, Huang et al. demonstrated that patients undergoing simultaneous bilateral TKA experienced less pain in the second knee.[ 9 ] These conflicting findings highlight the ongoing debate regarding pain differences between the first- and second-stage TKA procedures. Given these inconsistencies in literature, we conducted a retrospective study to compare postoperative pain levels in patients undergoing staged bilateral TKA. This study primarily determined whether there was a significant difference in postoperative pain between the first and second stages of the TKA procedure. We hypothesized no significant differences in pain levels between the two stages. Secondary outcomes included opioid consumption and length of hospital stay. These findings provide further insight into postoperative pain management and contribute to optimizing care for patients undergoing staged bilateral TKA. MATERIAL AND METHODS In this retrospective review of anonymised electronic medical records from patients who underwent total knee arthroplasty (ICD-9 code 81.54) between January 2015 and December 2020, the study protocol was reviewed and approved by the Human Research Ethics Committee of the Faculty of Medicine, Prince of Songkla University (approval no. 63-261-11-1) and conducted in accordance with the 1964 Declaration of Helsinki and its later amendments ; because the research relied on de-identified, retrospective data and involved no direct patient contact, the committee waived the requirement for written informed consent, so separate consent to participate or consent for publication was not applicable, and since this was an observational study rather than an interventional trial, no clinical trial registration number applies. Patient Selection Patients undergoing staged bilateral TKA under spinal anesthesia were included. The exclusion criteria included secondary osteoarthritis, previous knee surgery or infection, and revision surgery during follow-up, as well as patients requiring revision surgery owing to infection or other complications. Surgical Procedure All surgeries were performed by two experienced joint surgeons at a university hospital. A tourniquet was applied during each surgery. Prophylactic antibiotics and tranexamic acid (750 mg) were intravenously administered. A minimally invasive medial parapatellar approach was employed, followed by a measured resection technique. Cemented posterior-stabilized prostheses were implanted, with patellar resurfacing selectively performed based on the severity of patellofemoral joint osteoarthritis, at the surgeon’s discretion. Anesthesia and Postoperative Care Spinal anesthesia was administered in all cases with either femoral nerve or adductor canal block, depending on the anesthesiologist’s preference. Dexamethasone or periarticular injections were not administered. Postoperative pain management included scheduled paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids (morphine, fentanyl, and tramadol) used for rescue pain relief as needed. Aspirin was administered as a prophylaxis for deep vein thrombosis. The patients were encouraged to use a walker the morning after surgery and to follow a standardized rehabilitation program that included a range of motion and muscle-strengthening exercises. Outcome Measures The primary outcome was a 10-point verbal numerical rating score (VNRS) for pain at rest, recorded every 4 h for 48 h postoperatively. Secondary outcomes included cumulative opioid consumption, conversion to morphine-equivalent units, and length of hospital stay. The discharge criteria were based on achieving 90° knee flexion, the absence of intravenous pain medication, and readiness for independent mobility and rehabilitation. Data Collection Demographic and clinical data were collected, including age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) classification, Charlson comorbidity index, Kellgren–Lawrence classification for osteoarthritis severity, [ 10 ] femorotibial angle, and peripheral nerve block type. Statistical Analysis Continuous variables were tested for normality using the Shapiro–Wilk test. McNemar’s chi-square test or the Stuart–Maxwell test was applied for categorical variables, whereas paired t-tests were used for normally distributed continuous variables. Non-normally distributed data were analyzed using the Wilcoxon signed-rank test. Mixed-effects models were employed to analyze VNRS and opioid consumption. Patients were stratified by the interval between surgeries ( 12 months), and analysis of variance or Kruskal–Wallis tests were used to compare postoperative VNRS changes between the subgroups. Sample Size Following Sun et al.[ 7 ]’s study, a sample size of 72 patients per group was required to achieve 80% statistical power at a 95% confidence level. Given the retrospective design, all eligible patients were included in this study. RESULTS The study analysis included 175 patients, with a mean interval of 12.34 months (SD = 9.21) between the first and second stages. Significant differences between the groups included a higher average age in the second TKA group (69.5 vs. 68.4 years, p < 0.001), greater use of adductor canal blocks in the second TKA group (48.6% vs. 26.4%, p < 0.001), and a shorter hospital stay for the second TKA group (3.6 vs. 3.8 days, p < 0.001), as presented in Table 1 . Other factors, such as BMI, Charlson Comorbidity Index, and Kellgren–Lawrence classification, were similar between the groups. Table 1 Demographic data First TKA (n = 175) (mean[SD]) Second TKA (n = 175) (mean[SD]) p -value Age 68.4 (8.2) 69.5 (8.1) < 0.001 Gender Female 165 (94.3) 165 (94.3) 1 Male 10 (5.7) 10 (5.7) BMI 28.2 (4.5) 28.4 (4.4) 0.103 Charlson Comorbidity Index 2.8 (1.1) 2.9 (1.2) 0.006 Femorotibial angle (degree) 10.5 (5.8) 9.7 (5.0) 0.078 Kellgren-Lawrence classification 0.134 Grade 3 13 (7.4) 19 (10.9) Grade 4 162 (92.6) 156 (89.1) Preoperative VNRS 2.1 (2.6) 2.5 (2.6) 0.1475 ASA classification 0.951 Class 1 2 (1.2) 2 (1.1) Class 2 126 (73.3) 131 (74.9) Class 3 44 (25.6) 42 (24) Type of anesthesia 0.342 General anesthesia 14 (8.1) 10 (5.8) Spinal anesthesia 159 (91.9) 162 (94.2) Peripheral nerve block < 0.001 None 53 (30.5) 28 (16.2) Femoral nerve block 75 (43.1) 61 (35.3) Adductor canal block 46 (26.4) 84 (48.6) Operating time (min) 100 (23.9) 99 (24.3) 0.455 Length of hospital stay (day) 3.8 (0.8) 3.6 (0.8) < 0.001 Blood transfusion (unit) 0.3 (1.6) 0.2 (0.5) 0.026 BMI, body mass index kg/m 2 ; VNRS, visual numeric rating scale; ASA, American Society of Anesthesiologists. Significant p -values are written in bold letters. Pain Levels and Opioid Consumption Pain levels following each TKA stage are illustrated in Fig. 1 , which presents the VNRS scores recorded at 4 h intervals up to 72 h postoperatively. The Wilcoxon signed-rank test revealed a significant difference at 48 h, with lower VNRS scores for the second TKA compared with the first ( p = 0.036). However, opioid consumption at 72 h was comparable between the two groups (Table 2 ). Table 2 Comparison of opioid consumption (median [IQR]) in morphine equivalent units for each group First TKA Second TKA p -value 0–24 h 15 (7,21.5) 14.2 (4.4,24.4) 0.634 24–48 h 6 (0,12.5) 4 (0,12.5) 0.446 48–72 h 3 (0,8.3) 0 (0,6) 0.727 0–72 h 26 (10,40.3) 21.5 (6,43.5) 0.308 IQR, interquartile range. Significant p -values are written in bold letters. Linear Mixed-Effects Model Analysis We used a linear mixed-effects model, incorporating 5,301 observations from 175 patients, to analyze the factors influencing pain levels. The model was adjusted for the time since surgery, peripheral nerve block type, femorotibial angle, Kellgren–Lawrence classification, surgeon, and opioid consumption. Fixed effects analysis indicated no significant difference in pain levels between the first and second TKA stages (β = -0.070, p = 0.198). However, there was a significant reduction in pain over time (β = -0.076 per 4-hour interval, p < 0.001). The femoral nerve block was significantly associated with a reduction in pain (β = -0.335, p < 0.001), whereas the adductor canal block had no significant effect (β = -0.046, p = 0.630). Femorotibial angle and Kellgren–Lawrence classification had no significant influence on pain outcomes, whereas opioid consumption strongly predicted increased pain (β = 0.017, p < 0.001). Random effects indicated significant inter-patient variability, with a standard deviation of 0.785 and 1.799 for intercept and residuals, respectively. Sensitivity Analysis A sensitivity analysis using the last observation carried forward (LOCF) method, including 6,498 observations, supported the primary model's findings with some variations. This analysis revealed a significant reduction in pain during the second TKA stage compared with the first (β = -0.094, p = 0.041). The trend of decreasing pain over time remained significant (β = -0.071, p < 0.001), and the femoral nerve block continued to show a significant pain-relieving effect (β = -0.241, p = 0.003). The adductor canal block had no significant effect (β = -0.037, p = 0.654), whereas the effect of the surgeon approached significance ( p = 0.054). The relationship between opioid use and increased pain was also confirmed (β = 0.016, p < 0.001). Variability in pain levels across patients, as indicated by random effects, was consistent with the primary analysis, reinforcing the robustness of these findings. Subgroup Analysis A subgroup analysis was conducted based on the interval between the first- and second-stage TKAs, dividing the patients into three groups: 12 months (n = 69). No significant differences in demographic characteristics, including BMI and ASA classification, were observed across the groups, although the “>12 months” group was slightly younger ( p = 0.011) and had a higher proportion of Grade 3 Kellgren–Lawrence classification ( p = 0.016). Pain trajectories from the immediate postoperative period to 68 h after surgery did not differ significantly between the groups, although fluctuations in the VNRS scores were observed over time (Fig. 2 ). DISCUSSION This study examined postoperative pain levels following first- and second-stage bilateral TKA, focusing on temporal changes and evaluating the impact of various factors. The primary analysis showed no significant difference in pain levels between the two stages after adjusting for opioid consumption and peripheral nerve block type. However, sensitivity analysis using the LOCF approach indicated a subtle but statistically significant reduction in pain following the second TKA ( p = 0.041), suggesting that pain following the second procedure may be slightly lower than that following the first, particularly when accounting for potential data biases. These findings differ from most current literature, where higher pain levels after a second TKA are commonly reported and often attributed to central sensitization. Kim et al. and Sun et al. highlighted heightened pain sensitivity in the second knee owing to sensitization after the first surgery. [ 6 , 7 ] Koh et al. also reported increased pain in the second knee, even when ketamine was used to block central sensitization. [ 8 ] Conversely, our results closely aligned with the findings of Sun et al. that pain differences between the two surgeries decreased over time. [ 7 ] In their subgroup analysis, patients with less than six months between surgeries experienced more pain after the second TKA, whereas no significant differences were observed in patients with intervals of 6–12 months or > 12 months. The average interval in our study was 12.34 months, which may explain the lack of significant differences in pain between the first and second TKA procedures. Our data provide useful insights for surgeons when counseling patients about postoperative pain after second-stage TKA. The absence of significant pain differences suggests that patients can undergo a second procedure once they have adequately recovered from the first stage, without concerns about increased pain. However, a longer interval between surgeries may be beneficial, potentially leading to lower postoperative pain levels. This observation aligned with previous research suggesting that complications associated with the second-stage TKA decreased when surgery was delayed beyond six months. Ji et al. highlighted that although the complication rate was highest in patients who underwent a second procedure within 6 months (11.11%), no significant differences in complication rates or functional outcomes were observed across different surgical intervals[ 1 , 11 , 12 ]. These findings highlight the complexity of the relationship between the intersurgical interval and patient outcomes. Surgeons should consider individual patient factors, health status, and recovery from the first TKA, rather than relying solely on time-based protocols. Our study contributes to related literature by emphasizing that pain levels are not significantly influenced by the inter-surgical interval, offering reassurance to both patients and clinicians when planning staged bilateral TKA. Our results challenge the prevailing hypothesis that second-stage TKA is inherently more painful due to central sensitization. This divergence from previous studies underscores the complexity of pain perception in staged procedures, suggesting that factors such as recovery time, individual patient characteristics, and advancements in surgical and pain management techniques may influence the pain variability between the two stages. This study has several limitations. The observational design and reliance on subjective pain scores may not fully capture the nuances of postoperative pain influenced by psychological and recovery factors. During the study period, there was a transition from femoral nerve block to adductor canal block, potentially influencing pain control, although the meta-analysis indicated similar pain relief between the two techniques[ 13 – 16 ]. Additionally, the retrospective nature of the study limited control over potential confounders. Long-term functional outcomes and patient satisfaction, which could provide further insights into pain-related findings, were not assessed. Future research should explore the mechanisms underlying pain perception in staged bilateral TKA, particularly the influence of inter-surgical intervals on recovery. Prospective randomized controlled trials are needed to definitively assess the impact of surgical interval on pain and other outcomes. Additionally, long-term functional outcomes and patient satisfaction, along with the role of preoperative pain management strategies, should be investigated to provide a comprehensive understanding of patient experiences with staged bilateral TKA. Overall, our study suggests that pain following second-stage TKA is insignificant and slightly lower than that after the first stage, particularly with longer intervals between surgeries. The inter-surgical interval did not significantly affect pain outcomes, offering flexibility in scheduling the second surgery based on individual patient factors. These findings offer valuable insights for clinical decision-making and patient counseling in staged bilateral TKA procedures, although further research is required to fully assess the factors influencing pain and overall outcomes. CONCLUSIONS Pain following second-stage TKA was not significantly higher and was slightly lower than that following first-stage TKA. Additionally, the interval between surgeries did not appear to significantly influence pain outcomes. These findings suggest flexibility in scheduling the second procedure without concern for increased pain and provide valuable insights for optimizing pain management in staged bilateral TKA. Declarations Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Correspondence telephone +66 74 451601 Correspondence email [email protected] Conflict -of-Interest Statement Fundings No funding was received for conducting this study. Funding No funding was received for conducting this study. Author Contribution Khanin Iamthanaporn, MD: Conceptualization, Studay design, data analysis, manuscript drafting, and revision.Arnan Wiwatboworn, MD: Data collection, methodology, and manuscript editing.Pawin Wanasitchaiwat, MD: Data acquisition, statistical analysis, and manuscript review.Peeranut Purngpiputtrakul, MD: Study design, interpretation of results, and manuscript drafting.Varah Yuenyongviwat, MD: Supervision, project administration, final manuscript approval, and corresponding author. Acknowledgement I sincerely appreciate Ms. Jirawan Jayuphan, whose expertise as a statistician greatly contributed to the accurate analysis and interpretation of the data in this study. Her invaluable efforts were crucial to the success of this research, and her commitment to precision and excellence is deeply acknowledged. References Ji F, Zhao Z, Zhang L, Liu T, Xu B, Li W, et al. 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Dahl JB, Erichsen CJ, Fuglsang-Frederiksen A, Kehlet H. Pain sensation and nociceptive reflex excitability in surgical patients and human volunteers. Br J Anaesth. 1992;69:117–21. https://doi.org/10.1093/bja/69.2.117 . Kim MH, Nahm FS, Kim TK, Chang MJ, Do SH. Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: Clinical evidence of enhanced pain sensitivity after surgical injury. Pain. 2014;155:22–7. https://doi.org/10.1016/j.pain.2013.08.027 . Sun J, Li L, Yuan S, Zhou Y. Analysis of early postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: A retrospective controlled study. PLoS ONE. 2015;10:1–10. https://doi.org/10.1371/journal.pone.0129973 . Koh HJ, In Y, Kim ES, Hwang JW, Kim JY, Lim SJ, et al. Does central sensitization affect hyperalgesia after staged bilateral total knee arthroplasty? A randomized controlled trial. J Int Med Res. 2020;48:1–12. https://doi.org/10.1177/0300060520938934 . Huang S, Li X, Tang Y, Stiphan S, Yan B, He P, et al. Different patient satisfaction levels between the first and second knee in the early stage after simultaneous bilateral total knee arthroplasty (TKA): A comparison between subjective and objective outcome assessments. J Orthop Surg Res. 2017;12:4–9. https://doi.org/10.1186/s13018-017-0605-0 . Kellgren JH, Lawrence JS. Radiological Assessment of Osteo-Arthrosis. Ann Rheum Dis. 1957;16:494–502. https://doi.org/10.1136/ard.16.4.494 . Sun K, Pi J, Wu Y, Zeng Y, Xu J, Wu L, et al. The Optimal Period of Staged Bilateral Total Knee Arthroplasty Procedures under Enhanced Recovery: A Retrospective Study. Orthop Surg. 2023;15:1249–55. https://doi.org/10.1111/os.13684 . Ali Ghasemi S, Rashidi S, Rasouli MR, Parvizi J. Staged Bilateral Total Knee Arthroplasty: When Should the Second Knee be Replaced? Archives Bone Joint Surg. 2021;9:633–40. https://doi.org/10.22038/abjs.2021.49007.2432 . Grevstad U, Mathiesen O, Valentiner LS, Jaeger P, Hilsted KL, Dahl JB. Effect of adductor canal block versus femoral nerve block on quadriceps strength, mobilization, and pain after total knee arthroplasty: A randomized, blinded study. Reg Anesth Pain Med. 2015;40:3–10. https://doi.org/10.1097/AAP.0000000000000169 . Gao F, Ma J, Sun W, Guo W, Li Z, Wang W. Adductor canal block versus femoral nerve block for analgesia after total knee arthroplasty. Clin J Pain. 2017;33:356–68. https://doi.org/10.1097/AJP.0000000000000402 . Gong J, Tang L, Han Y, Liu P, Yu X, Wang F. Continuous adductor canal block versus continuous femoral nerve block for postoperative pain in patients undergoing knee arthroplasty: An updated meta-analysis of randomized controlled trials. PLoS ONE. 2024;19:e0306249. https://doi.org/10.1371/journal.pone.0306249 . Jæger P, Zaric D, Fomsgaard JS, Hilsted KL, Bjerregaard J, Gyrn J, et al. Adductor canal block versus femoral nerve block for analgesia after total knee arthroplasty a randomized, double-blind study. Reg Anesth Pain Med. 2013;38:526–32. https://doi.org/10.1097/AAP.0000000000000015 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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07:33:56","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":72593,"visible":true,"origin":"","legend":"","description":"","filename":"e39d6680134146d8b40b0d070a4d16431structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7974018/v1/2b72db75ce54add6b1c775a8.xml"},{"id":96156119,"identity":"a5eb1483-0aa9-480a-9eb4-af96c7b0f930","added_by":"auto","created_at":"2025-11-18 08:27:23","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80990,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7974018/v1/45e9561281684a53f12be115.html"},{"id":96156115,"identity":"b27fe78f-90ad-4929-99fa-3c365b4558b1","added_by":"auto","created_at":"2025-11-18 08:27:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":221466,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of mean pain levels following first- and second-stage total knee arthroplasty (TKA) from the immediate postoperative period to 72 h, measured at 4-hour intervals. The pain levels were recorded using a visual numeric rating scale (VNRS), with higher values indicating more intense pain. The solid red line represents the mean pain levels after the first TKA, and the green dotted line represents those after the second TKA. Error bars indicate 95% confidence intervals for each time point, illustrating the variability in pain levels between the two stages.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7974018/v1/ac2009208b14181eaa2341d0.png"},{"id":96156113,"identity":"d172dba1-7178-43e7-8c9c-ab1262842003","added_by":"auto","created_at":"2025-11-18 08:27:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":203140,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup comparison of Δ visual numeric rating scale (VNRS) scores (second knee VNRS minus first knee VNRS) based on inter-surgery intervals, from immediate postoperative period to 68 hs. Group 1 (solid red) represents patients with an interval of \u0026lt; 6 months, group 2 (dotted green) represents patients with an interval of 6–12 months, and group 3 (dashed black) represents patients with an interval \u0026gt; 12 months. Error bars represent 95% confidence intervals at each time point, illustrating the variability in pain scores across the subgroups.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7974018/v1/d09ce8e9f16451e568845343.png"},{"id":97148665,"identity":"6b4f35b7-c142-45eb-8c59-cb8d14a216a6","added_by":"auto","created_at":"2025-12-01 10:19:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1308343,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7974018/v1/4eb115a6-fe8c-4a13-af3d-256396a1c436.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Reevaluating Pain Perception in Staged Bilateral Total Knee Arthroplasty: A 72-Hour Postoperative Analysis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eTotal knee arthroplasty (TKA) is an effective treatment for end-stage knee osteoarthritis (OA), providing substantial pain relief and improving joint function and quality of life. Bilateral symptoms are present in approximately one-third of the patients with knee OA. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Among those undergoing primary unilateral TKA, approximately 40% will eventually require contralateral knee TKA within 10 years. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Staged bilateral TKA is a common approach considered both safe and effective, with fewer complications and lower mortality rates compared with simultaneous bilateral TKA.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e\u003cp\u003ePatients undergoing a second surgery often report increased pain relative to their initial surgery, regardless of the anatomical site.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] This heightened pain sensitivity may result from central sensitization, where the nervous system becomes more responsive to nociceptive stimuli following previous surgical exposure. Several studies have reported increased postoperative pain in the second knee following staged bilateral TKA; however, the underlying factors contributing to this phenomenon remain unclear.\u003c/p\u003e\u003cp\u003eKim et al. and Sun et al. observed that patients reported higher pain levels after second-stage TKA.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Koh et al. also found that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that prevents central sensitization, did not significantly reduce pain during second-stage surgery. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] By contrast, Huang et al. demonstrated that patients undergoing simultaneous bilateral TKA experienced less pain in the second knee.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] These conflicting findings highlight the ongoing debate regarding pain differences between the first- and second-stage TKA procedures.\u003c/p\u003e\u003cp\u003eGiven these inconsistencies in literature, we conducted a retrospective study to compare postoperative pain levels in patients undergoing staged bilateral TKA. This study primarily determined whether there was a significant difference in postoperative pain between the first and second stages of the TKA procedure. We hypothesized no significant differences in pain levels between the two stages. Secondary outcomes included opioid consumption and length of hospital stay. These findings provide further insight into postoperative pain management and contribute to optimizing care for patients undergoing staged bilateral TKA.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003e In this retrospective review of anonymised electronic medical records from patients who underwent total knee arthroplasty (ICD-9 code 81.54) between January 2015 and December 2020, the study protocol was reviewed and approved by the Human Research Ethics Committee of the Faculty of Medicine, Prince of Songkla University (approval no. 63-261-11-1) and conducted in accordance with the 1964 Declaration of Helsinki and its later amendments ; because the research relied on de-identified, retrospective data and involved no direct patient contact, the committee waived the requirement for written informed consent, so separate consent to participate or consent for publication was not applicable, and since this was an observational study rather than an interventional trial, no clinical trial registration number applies.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatient Selection\u003c/h2\u003e\u003cp\u003ePatients undergoing staged bilateral TKA under spinal anesthesia were included. The exclusion criteria included secondary osteoarthritis, previous knee surgery or infection, and revision surgery during follow-up, as well as patients requiring revision surgery owing to infection or other complications.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSurgical Procedure\u003c/h3\u003e\n\u003cp\u003eAll surgeries were performed by two experienced joint surgeons at a university hospital. A tourniquet was applied during each surgery. Prophylactic antibiotics and tranexamic acid (750 mg) were intravenously administered. A minimally invasive medial parapatellar approach was employed, followed by a measured resection technique. Cemented posterior-stabilized prostheses were implanted, with patellar resurfacing selectively performed based on the severity of patellofemoral joint osteoarthritis, at the surgeon\u0026rsquo;s discretion.\u003c/p\u003e\n\u003ch3\u003eAnesthesia and Postoperative Care\u003c/h3\u003e\n\u003cp\u003eSpinal anesthesia was administered in all cases with either femoral nerve or adductor canal block, depending on the anesthesiologist\u0026rsquo;s preference. Dexamethasone or periarticular injections were not administered. Postoperative pain management included scheduled paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids (morphine, fentanyl, and tramadol) used for rescue pain relief as needed. Aspirin was administered as a prophylaxis for deep vein thrombosis. The patients were encouraged to use a walker the morning after surgery and to follow a standardized rehabilitation program that included a range of motion and muscle-strengthening exercises.\u003c/p\u003e\n\u003ch3\u003eOutcome Measures\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was a 10-point verbal numerical rating score (VNRS) for pain at rest, recorded every 4 h for 48 h postoperatively. Secondary outcomes included cumulative opioid consumption, conversion to morphine-equivalent units, and length of hospital stay. The discharge criteria were based on achieving 90\u0026deg; knee flexion, the absence of intravenous pain medication, and readiness for independent mobility and rehabilitation.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eDemographic and clinical data were collected, including age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) classification, Charlson comorbidity index, Kellgren\u0026ndash;Lawrence classification for osteoarthritis severity, [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] femorotibial angle, and peripheral nerve block type.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eContinuous variables were tested for normality using the Shapiro\u0026ndash;Wilk test. McNemar\u0026rsquo;s chi-square test or the Stuart\u0026ndash;Maxwell test was applied for categorical variables, whereas paired t-tests were used for normally distributed continuous variables. Non-normally distributed data were analyzed using the Wilcoxon signed-rank test. Mixed-effects models were employed to analyze VNRS and opioid consumption. Patients were stratified by the interval between surgeries (\u0026lt;\u0026thinsp;6 months, 6\u0026ndash;12 months, and \u0026gt;\u0026thinsp;12 months), and analysis of variance or Kruskal\u0026ndash;Wallis tests were used to compare postoperative VNRS changes between the subgroups.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSample Size\u003c/h3\u003e\n\u003cp\u003eFollowing Sun et al.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u0026rsquo;s study, a sample size of 72 patients per group was required to achieve 80% statistical power at a 95% confidence level. Given the retrospective design, all eligible patients were included in this study.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe study analysis included 175 patients, with a mean interval of 12.34 months (SD\u0026thinsp;=\u0026thinsp;9.21) between the first and second stages. Significant differences between the groups included a higher average age in the second TKA group (69.5 vs. 68.4 years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), greater use of adductor canal blocks in the second TKA group (48.6% vs. 26.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and a shorter hospital stay for the second TKA group (3.6 vs. 3.8 days, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Other factors, such as BMI, Charlson Comorbidity Index, and Kellgren\u0026ndash;Lawrence classification, were similar between the groups.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic data\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eFirst TKA (n\u0026thinsp;=\u0026thinsp;175) (mean[SD])\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eSecond TKA (n\u0026thinsp;=\u0026thinsp;175) (mean[SD])\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(8.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e69.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(8.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e165\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(94.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e165\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(94.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.103\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharlson Comorbidity Index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemorotibial angle (degree)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(5.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(5.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.078\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKellgren-Lawrence classification\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.134\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(7.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(10.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(92.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e156\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(89.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative VNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.1475\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eASA classification\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.951\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClass 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClass 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(73.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e131\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(74.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClass 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(25.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType of anesthesia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.342\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGeneral anesthesia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(8.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(5.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpinal anesthesia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e159\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(91.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(94.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeripheral nerve block\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(30.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(16.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemoral nerve block\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(43.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(35.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdductor canal block\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(26.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(48.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOperating time (min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(23.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(24.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.455\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of hospital stay (day)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood transfusion (unit)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBMI, body mass index kg/m\u003csup\u003e2\u003c/sup\u003e; VNRS, visual numeric rating scale; ASA, American Society of Anesthesiologists.\u003c/p\u003e\u003cp\u003eSignificant \u003cem\u003ep\u003c/em\u003e-values are written in bold letters.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePain Levels and Opioid Consumption\u003c/h2\u003e\u003cp\u003ePain levels following each TKA stage are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, which presents the VNRS scores recorded at 4 h intervals up to 72 h postoperatively. The Wilcoxon signed-rank test revealed a significant difference at 48 h, with lower VNRS scores for the second TKA compared with the first (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036). However, opioid consumption at 72 h was comparable between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of opioid consumption (median [IQR]) in morphine equivalent units for each group\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eFirst TKA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eSecond TKA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u0026ndash;24 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(7,21.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(4.4,24.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.634\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u0026ndash;48 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(0,12.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0,12.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.446\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e48\u0026ndash;72 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(0,8.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0,6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.727\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u0026ndash;72 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e(10,40.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(6,43.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.308\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIQR, interquartile range.\u003c/p\u003e\u003cp\u003eSignificant \u003cem\u003ep\u003c/em\u003e-values are written in bold letters.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eLinear Mixed-Effects Model Analysis\u003c/h2\u003e\u003cp\u003eWe used a linear mixed-effects model, incorporating 5,301 observations from 175 patients, to analyze the factors influencing pain levels. The model was adjusted for the time since surgery, peripheral nerve block type, femorotibial angle, Kellgren\u0026ndash;Lawrence classification, surgeon, and opioid consumption.\u003c/p\u003e\u003cp\u003eFixed effects analysis indicated no significant difference in pain levels between the first and second TKA stages (β = -0.070, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.198). However, there was a significant reduction in pain over time (β = -0.076 per 4-hour interval, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The femoral nerve block was significantly associated with a reduction in pain (β = -0.335, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas the adductor canal block had no significant effect (β = -0.046, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.630). Femorotibial angle and Kellgren\u0026ndash;Lawrence classification had no significant influence on pain outcomes, whereas opioid consumption strongly predicted increased pain (β\u0026thinsp;=\u0026thinsp;0.017, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Random effects indicated significant inter-patient variability, with a standard deviation of 0.785 and 1.799 for intercept and residuals, respectively.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSensitivity Analysis\u003c/h2\u003e\u003cp\u003eA sensitivity analysis using the last observation carried forward (LOCF) method, including 6,498 observations, supported the primary model's findings with some variations. This analysis revealed a significant reduction in pain during the second TKA stage compared with the first (β = -0.094, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041). The trend of decreasing pain over time remained significant (β = -0.071, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the femoral nerve block continued to show a significant pain-relieving effect (β = -0.241, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). The adductor canal block had no significant effect (β = -0.037, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.654), whereas the effect of the surgeon approached significance (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.054). The relationship between opioid use and increased pain was also confirmed (β\u0026thinsp;=\u0026thinsp;0.016, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Variability in pain levels across patients, as indicated by random effects, was consistent with the primary analysis, reinforcing the robustness of these findings.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup Analysis\u003c/h2\u003e\u003cp\u003eA subgroup analysis was conducted based on the interval between the first- and second-stage TKAs, dividing the patients into three groups: \u0026lt; 6 months (n\u0026thinsp;=\u0026thinsp;49), 6\u0026ndash;12 months (n\u0026thinsp;=\u0026thinsp;57), and \u0026gt;\u0026thinsp;12 months (n\u0026thinsp;=\u0026thinsp;69). No significant differences in demographic characteristics, including BMI and ASA classification, were observed across the groups, although the \u0026ldquo;\u0026gt;12 months\u0026rdquo; group was slightly younger (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and had a higher proportion of Grade 3 Kellgren\u0026ndash;Lawrence classification (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016). Pain trajectories from the immediate postoperative period to 68 h after surgery did not differ significantly between the groups, although fluctuations in the VNRS scores were observed over time (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study examined postoperative pain levels following first- and second-stage bilateral TKA, focusing on temporal changes and evaluating the impact of various factors. The primary analysis showed no significant difference in pain levels between the two stages after adjusting for opioid consumption and peripheral nerve block type. However, sensitivity analysis using the LOCF approach indicated a subtle but statistically significant reduction in pain following the second TKA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041), suggesting that pain following the second procedure may be slightly lower than that following the first, particularly when accounting for potential data biases.\u003c/p\u003e\u003cp\u003eThese findings differ from most current literature, where higher pain levels after a second TKA are commonly reported and often attributed to central sensitization. Kim et al. and Sun et al. highlighted heightened pain sensitivity in the second knee owing to sensitization after the first surgery. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Koh et al. also reported increased pain in the second knee, even when ketamine was used to block central sensitization. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eConversely, our results closely aligned with the findings of Sun et al. that pain differences between the two surgeries decreased over time. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] In their subgroup analysis, patients with less than six months between surgeries experienced more pain after the second TKA, whereas no significant differences were observed in patients with intervals of 6\u0026ndash;12 months or \u0026gt;\u0026thinsp;12 months. The average interval in our study was 12.34 months, which may explain the lack of significant differences in pain between the first and second TKA procedures.\u003c/p\u003e\u003cp\u003eOur data provide useful insights for surgeons when counseling patients about postoperative pain after second-stage TKA. The absence of significant pain differences suggests that patients can undergo a second procedure once they have adequately recovered from the first stage, without concerns about increased pain. However, a longer interval between surgeries may be beneficial, potentially leading to lower postoperative pain levels.\u003c/p\u003e\u003cp\u003eThis observation aligned with previous research suggesting that complications associated with the second-stage TKA decreased when surgery was delayed beyond six months. Ji et al. highlighted that although the complication rate was highest in patients who underwent a second procedure within 6 months (11.11%), no significant differences in complication rates or functional outcomes were observed across different surgical intervals[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThese findings highlight the complexity of the relationship between the intersurgical interval and patient outcomes. Surgeons should consider individual patient factors, health status, and recovery from the first TKA, rather than relying solely on time-based protocols. Our study contributes to related literature by emphasizing that pain levels are not significantly influenced by the inter-surgical interval, offering reassurance to both patients and clinicians when planning staged bilateral TKA.\u003c/p\u003e\u003cp\u003eOur results challenge the prevailing hypothesis that second-stage TKA is inherently more painful due to central sensitization. This divergence from previous studies underscores the complexity of pain perception in staged procedures, suggesting that factors such as recovery time, individual patient characteristics, and advancements in surgical and pain management techniques may influence the pain variability between the two stages.\u003c/p\u003e\u003cp\u003eThis study has several limitations. The observational design and reliance on subjective pain scores may not fully capture the nuances of postoperative pain influenced by psychological and recovery factors. During the study period, there was a transition from femoral nerve block to adductor canal block, potentially influencing pain control, although the meta-analysis indicated similar pain relief between the two techniques[\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, the retrospective nature of the study limited control over potential confounders. Long-term functional outcomes and patient satisfaction, which could provide further insights into pain-related findings, were not assessed.\u003c/p\u003e\u003cp\u003eFuture research should explore the mechanisms underlying pain perception in staged bilateral TKA, particularly the influence of inter-surgical intervals on recovery. Prospective randomized controlled trials are needed to definitively assess the impact of surgical interval on pain and other outcomes. Additionally, long-term functional outcomes and patient satisfaction, along with the role of preoperative pain management strategies, should be investigated to provide a comprehensive understanding of patient experiences with staged bilateral TKA.\u003c/p\u003e\u003cp\u003eOverall, our study suggests that pain following second-stage TKA is insignificant and slightly lower than that after the first stage, particularly with longer intervals between surgeries. The inter-surgical interval did not significantly affect pain outcomes, offering flexibility in scheduling the second surgery based on individual patient factors. These findings offer valuable insights for clinical decision-making and patient counseling in staged bilateral TKA procedures, although\u003c/p\u003e\u003cp\u003efurther research is required to fully assess the factors influencing pain and overall outcomes.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003ePain following second-stage TKA was not significantly higher and was slightly lower than that following first-stage TKA. Additionally, the interval between surgeries did not appear to significantly influence pain outcomes. These findings suggest flexibility in scheduling the second procedure without concern for increased pain and provide valuable insights for optimizing pain management in staged bilateral TKA.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflict of Interests:\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCorrespondence telephone\u003c/h2\u003e\u003cp\u003e+66 74 451601\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCorrespondence email\u003c/strong\u003e\u003cp\[email protected]\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eConflict\u003c/h2\u003e\u003cp\u003e\u003cb\u003e-of-Interest Statement\u003c/b\u003e\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eFundings\u003c/h2\u003e\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKhanin Iamthanaporn, MD: Conceptualization, Studay design, data analysis, manuscript drafting, and revision.Arnan Wiwatboworn, MD: Data collection, methodology, and manuscript editing.Pawin Wanasitchaiwat, MD: Data acquisition, statistical analysis, and manuscript review.Peeranut Purngpiputtrakul, MD: Study design, interpretation of results, and manuscript drafting.Varah Yuenyongviwat, MD: Supervision, project administration, final manuscript approval, and corresponding author.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eI sincerely appreciate Ms. Jirawan Jayuphan, whose expertise as a statistician greatly contributed to the accurate analysis and interpretation of the data in this study. Her invaluable efforts were crucial to the success of this research, and her commitment to precision and excellence is deeply acknowledged.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJi F, Zhao Z, Zhang L, Liu T, Xu B, Li W, et al. The interval between staged bilateral total knee arthroplasties does not affect early complications of the second knee or long-term function of the first and second knees. BMC Surg. 2024;24:152. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12893-024-02442-y\u003c/span\u003e\u003cspan address=\"10.1186/s12893-024-02442-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcMahon M, Block JA. The risk of contralateral total knee arthroplasty after knee replacement for osteoarthritis. 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Reg Anesth Pain Med. 2013;38:526\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/AAP.0000000000000015\u003c/span\u003e\u003cspan address=\"10.1097/AAP.0000000000000015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Knee osteoarthritis, Total knee arthroplasty, Staged bilateral TKA, Pain perception, Postoperative pain management","lastPublishedDoi":"10.21203/rs.3.rs-7974018/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7974018/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTotal knee arthroplasty (TKA) is a well-established treatment for end-stage knee osteoarthritis (OA) that significantly alleviates pain and improves joint function. In staged bilateral TKA, previous studies suggest that patients may experience greater pain in the second knee; however, the evidence and underlying mechanisms remain inconsistent and unclear. This study re-evaluated pain perception during the initial 72 h following staged bilateral TKA and examines factors influencing postoperative pain levels, including opioid consumption and the interval between surgeries.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis retrospective analysis included 175 patients who underwent staged bilateral TKA between 2015 and 2020. Pain was assessed using a verbal numerical rating scale (VNRS) every 4 h for 72 h postoperatively. A linear mixed-effect model compared pain levels between the first and second surgeries, adjusting for time, opioid consumption, nerve block type, femorotibial angle, and osteoarthritis severity. A subgroup analysis was conducted based on the interval between surgeries (\u0026lt;\u0026thinsp;6 months, 6\u0026ndash;12 months, and \u0026gt;\u0026thinsp;12 months).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe mean interval between the surgeries was 12.34 months. Analysis revealed no significant difference in pain levels between the first and second TKAs (β = -0.070, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.198). However, pain significantly decreased over time (β = -0.076 per 4-hour interval, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and femoral nerve block was associated with reduced pain (β = -0.335, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Sensitivity analysis indicated a slight reduction in pain during the second surgery (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041). Subgroup analysis showed no significant differences in pain trajectories across the surgical intervals.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePain following second-stage TKA was not significantly higher and was slightly lower than that following first-stage TKA. Additionally, the interval between surgeries did not appear to significantly influence pain outcomes. These findings suggest flexibility in scheduling the second procedure without concern for increased pain and provide valuable insights for optimizing pain management in staged bilateral TKA.\u003c/p\u003e","manuscriptTitle":"Reevaluating Pain Perception in Staged Bilateral Total Knee Arthroplasty: A 72-Hour Postoperative Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 08:27:18","doi":"10.21203/rs.3.rs-7974018/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1d3f09eb-ed50-49f2-9fa4-c96f472ed7c3","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T10:17:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-18 08:27:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7974018","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7974018","identity":"rs-7974018","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}