Sublingual sufentanil versus femoral nerve catheter analgesia with ropivacaine after primary total knee arthroplasty: a randomized, prospective, clinical comparative phase IV trial

Sublingual sufentanil versus femoral nerve catheter analgesia with ropivacaine after primary total knee arthroplasty: a randomized, prospective, clinical comparative phase IV trial | 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 Short Report Sublingual sufentanil versus femoral nerve catheter analgesia with ropivacaine after primary total knee arthroplasty: a randomized, prospective, clinical comparative phase IV trial David Johanio Avila Castillo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8709340/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) represents one of the most commonly performed orthopedic procedures and requires structured and effective perioperative pain management. Patients typically present with chronic, long-standing pain that substantially impairs quality of life and necessitates surgical joint replacement. Optimal intraoperative and postoperative analgesia is essential to ensure functional recovery and to minimize the risk of persistent postoperative chronic pain. In this context, the present study compares non-invasive sublingual sufentanil (SUF-SL) with invasive ropivacaine-based regional anesthesia administered via a femoral nerve catheter (ROP-RA) for postoperative pain control following TKA. Methods In this randomized, prospective, phase IV clinical trial, 56 patients were assigned to receive either sublingual sufentanil (SUF-SL) (n = 28; patient-controlled administration of 15 µg sufentanil with a lockout interval of 20 minutes) or ropivacaine-based regional anesthesia via a femoral nerve catheter (ROP-RA) (n = 28; ropivacaine 0.2% administered at a continuous infusion rate of 5 mL/h with an additional 5 mL bolus and a lockout interval of 30 minutes) for 72 hours postoperatively. Pain intensity was assessed three times daily during the first five postoperative days using the Numerical Rating Scale (NRS). Daily mean NRS scores were calculated separately for pain at rest and during physical activity. Adverse effects, additional non-opioid analgesic consumption, perioperative time parameters, and length of hospital stay were also recorded. Results Both SUF-SL and ROP-RA significantly reduced postoperative pain after TKA. At rest, NRS scores decreased from 3.66 ± 1.73 to 1.56 ± 1.53 in the SUF-SL group and from 3.09 ± 1.73 to 1.92 ± 1.31 in the ROP-RA group between the day of surgery and postoperative day 5. During exercise, pain scores decreased from 5.64 ± 2.06 to 2.77 ± 1.90 in the SUF-SL group and from 5.64 ± 1.94 to 3.55 ± 2.01 in the ROP-RA group between postoperative days 1 and 5 (all p < 0.001). Both treatment modalities demonstrated similarly low and mild adverse effect profiles, with no significant differences in the consumption of additional non-opioid analgesics. Induction of anesthesia time was approximately 78.6% longer in the ROP-RA group due to femoral catheter placement (p < 0.001). No significant differences were observed in intraoperative time, postoperative recovery time, or length of hospital stay. Conclusion Sublingual sufentanil (SUF-SL) offers an effective, safe, and non-invasive alternative to ropivacaine-based regional anesthesia (ROP-RA) for postoperative pain control after primary total knee arthroplasty and may be integrated into multimodal, patient-centered pain management strategies. From the patient’s perspective, non-invasive analgesic techniques are often preferred, while from a clinical standpoint, sublingual sufentanil demonstrates a reliable efficacy and safety profile. Anesthesiology & Pain Medicine total knee arthroplasty postoperative pain management sublingual sufentanil ropivacaine regional anesthesia comparative study Figures Figure 1 Introduction The knee joint is the largest joint in the human body and plays a central role in mobility and stability. Due to the high mechanical stress, the knee joint is particularly susceptible to degenerative diseases, trauma, and inflammatory processes, which are often associated with significant pain and functional limitations (Aparisi Gómez et al., 2023). When conservative and medical treatments no longer promise sufficient relief, surgical treatment with a new implant remains the only option. The implantation of a knee endoprosthesis is now one of the most frequently planned surgical procedures performed (German Endoprosthesis Registry (EPRD) Report, 2024). It is the method of choice for advanced joint destruction as a result of osteoarthritis in the broadest sense, regardless of its causality (Wu et al., 2022). Treatment success is measured by pain relief, preservation of knee mobility, and return to daily activities (Fawaz and Masri, 2020). Although minimally invasive surgical techniques and improved implant materials are increasingly being used, satisfactory pain relief cannot be observed in 15–20% of cases (Wylde et al., 2013). In this context, there is a significant risk of developing chronic pain. The aim of this study was to compare non-invasive sublingual sufentanil (SUF-SL) with invasive ropivacaine regional anesthesia (ROP-RA) in acute postoperative pain management with regard to their pain reduction potential after primary total knee arthroplasty (TKA). Material and Methods Study Design This study is a randomized, prospective, open-label, Phase IV clinical trial. It compares the administration of SUF-SL via the patient-controlled application system Zalviso® with the patient-controlled administration of ROP-RA via femoral catheter for acute postoperative pain treatment after primary TKA. The study was conducted at the University Hospital Halle (Germany) in collaboration between the Department of Anesthesiology and Surgical Intensive Care and the Department of Orthopaedics, Trauma and Reconstructive Surgery between April 29, 2021, and May 22, 2023. Conduct of anesthesia and surgery technique Anesthesia was induced according to clinical practice standards with 1) sufentanil (analgesia), propofol (sedative), and rocuronium (muscle relaxant). Sevofluran was used to maintain general anesthesia as part of a balanced anesthetic approach. All surgeries were performed as primary TKAs, using either a mini-mid-vastus approach or a standard medial or lateral parapatellar approach, depending on individual anatomy. Tourniquets and cementation of the prosthetic components were performed according to standard surgical procedures. Before wound closure, an intra-articular and a subcutaneous drain were placed and left in place until the second postoperative day. Preoperatively, patients in the ROP-RA group received an ultrasound-guided femoral nerve catheter prior to sedation. This catheter was used to administer a single-shot femoral nerve block with 20 mL of 0.2% ropivacaine (total dose: 40 mg ). Subsequently, a single-shot sciatic nerve block was performed using 10 mL of 0.75% ropivacaine (total dose: 75 mg ). Following completion of the regional anesthetic procedures, general anesthesia was induced and maintained for the surgical intervention. Patients in the SUF-SL group received intraoperative local infiltration analgesia consisting of 150 mL of 0.2% ropivacaine (total dose: 300 mg ) combined with 0.75 mL of adrenaline (total dose: 0.75 mg ) for vasoconstriction, infiltrated into the surgical site according to a standardized protocol. In both groups, perioperative antibiotic prophylaxis consisted of a single intravenous dose of cefuroxime 1.5 g , administered 30 minutes prior to skin incision . At the end of surgery and before emergence from anesthesia, patients in both groups received parecoxib 40 mg intravenously for postoperative analgesia. Metamizole 1 g intravenously was administered additionally as needed , with a short temporal interval between administrations when required. Inclusion and exclusion criteria Based on the inclusion and exclusion criteria (Table 1), 28 patients per treatment arm were enrolled during the study period (total n=56). Table 1: Inclusion and exclusion criteria Inclusion criteria Exclusion criteria - Minimum age 18 years - Capacity to consent - Signed informed consent - Unilateral total knee arthroplasty - American Society of Anesthesiologists score: 1-3 - Revision total knee replacement - American Society of Anesthesiologists score: >3 - Previous spinal surgery - Chronic opioid use - Obstructive sleep apnea syndrome - Chronic obstructive pulmonary disease - Coagulopathy - Contraindications to peripheral nerve block - Allergies or intolerance to sufentanil - Allergies or intolerance to amide local anesthetics - Infections at the injection site for regional anesthesia - Liver cirrhosis Child-Pugh grades B and C - Glomerular filtration rate <30 ml/min - Pregnancy or breastfeeding patient - Women of childbearing potential without contraception - Alcohol or drug abuse Postoperative pain management Patients in the SUF-SL group received a sublingual patient-controlled analgesia (PCA) system (Zalviso®, Grünenthal, Aachen, Germany) in the post-anesthesia care unit. The device delivered single doses of 15 µg sufentanil with a lockout interval of 20 minutes , in accordance with the approved dosing regimen. The maximum duration of use was limited to 72 hours , as specified in the marketing authorization. Patients in the ROP-RA group received ropivacaine 0.2% postoperatively via a PCA pump connected to the femoral nerve catheter. A continuous infusion rate of 5 mL per hour (equivalent to 10 mg ropivacaine per hour ) was administered. In addition, patient-controlled bolus doses of 5 mL ropivacaine 0.2% ( 10 mg ) were permitted with a lockout interval of 30 minutes . To ensure methodological comparability between groups, the maximum duration of regional analgesia was likewise limited to 72 hours . All patients received standardized instruction in the use of their respective PCA systems by a specialized anesthesiology team prior to initiation. In accordance with the German S3 guideline for multimodal treatment of acute perioperative and post-traumatic pain , both groups received scheduled systemic basic analgesia with non-opioid agents, consisting of metamizole 1 g intravenously four times daily and ibuprofen 600 mg oral three times daily . In patients with contraindications or intolerance, paracetamol 1 g intravenously was administered as an alternative, up to a maximum of four doses per day . All co-analgesic medications were gradually tapered within the first five postoperative days . The predefined analgesic target was a Numerical Rating Scale (NRS) score below 4 . The hospital’s acute pain service conducted structured ward rounds twice daily , and trained personnel were available at all times to address patient concerns or technical issues related to PCA use. Overdose of sublingual sufentanil was not possible due to the fixed dosing parameters and lockout intervals programmed into the device. Endpoints The primary endpoint of the study was the assessment of postoperative pain at rest and during physical exertion (stress) between SUF-SL and ROP-RA using NRS (0=no pain, 10=maximum pain). At rest, NRS was recorded on the day of surgery (postoperatively) and on the first, second, third, fourth and fifth days after surgery. The first physical exertion after TKA occurred on the first postoperative day. Therefore, the NRS was recorded during exercise on the first, second, third, fourth, and fifth postoperative days, not on the day of surgery. Discharge from the hospital was scheduled for the 6th postoperative day. The NRS was recorded during the morning visit and thus at the same time for all patients to exclude daily fluctuations. In addition, possible adverse effects of the study medication were recorded. The secondary endpoint was the consumption of additional non-opioid analgesics at the above-mentioned time points. The assessment was based on whether these were necessary at the respective time points or not. The third endpoint was whether the use of SUF-SL or ROP-RA had an influence on the pre-, intra-, and postoperative procedures as well as on the total hospital stay. Statistics Randomization was performed the day before surgery using secuTrail® software. Statistical analysis was conducted with IBM SPSS Statistics version 29.0.1.1. To evaluate postoperative pain progression (NRS scores from day 0 to day 5), a mixed ANOVA with within- and between-subject factors was used, comparing pain development over time and between the two study groups (sufentanil vs. ropivacaine). Additionally, separate group comparisons were performed for each postoperative day using independent t-test, following confirmation of normal distribution (Shapiro-Wilk test) and homogeneity of variance (Levene test). For baseline comparisons (age, body mass index (BMI), gender), independent t-tests and chi-square tests were applied accordingly. Group differences in the daily frequency of additional non-opioid analgesic use were analyzed using chi-square tests. Time variables (pre-, intra-, postoperative) were compared using independent t-test after confirming test assumptions. Bonferroni correction was applied for multiple testing. A p-value <0.05 was considered statistically significant. Ethical approval This study was approved by the Ethics Committee of Martin Luther University Halle-Wittenberg (Germany) (approval: 30.10.2019; processing number: 2019-081; EudraCT number: 2019-001725-27; Protocol number: KKSH152). The ethical principles of Good Medical Practice and the Declaration of Helsinki in their current version were fully observed. Results The entire patient collective (n=56, male: n=22, female: n=34, mean age: 65.1±9.7 years (range: 40-83)) is presented in Table 2, with their patient variables gender, age and BMI and with their NRS pain level at the different assessment time points. The SUF-SL group was on average younger (62.5±9.0 years; range: 40-80) than the ROP-RA group (67.7±9.8 years; range: 53-83) (p=0.043), with higher BMI values (32.8±6.3 kg/m²; range: 25.1-47.3 vs. 29.1±5.9 kg/m²; range: 19.4-43.3; p=0.027). There were no differences in gender distribution between the two groups (male/female: SUF-SL: n=14/14 vs. ROP-RA: n=8/20; p=0.10). Both the SUF-SL and ROP-RA groups demonstrated significant postoperative pain reduction after TKA, at rest and during exercise. At rest, pain decreased with SUF-SL from 3.66±1.73 (surgery day) to 1.56±1.53 (postoperative day 5) on the NRS (p<0.001). Under physical exercise, pain decreased with SUF-SL from 5.64±2.06 (postoperative day 1) to 2.77±1.90 (postoperative day 5) on the NRS (p<0.001). At rest, pain decreased with ROP-RA from 3.09±1.73 (surgery day) to 1.92±1.31 (postoperative day 5) on the NRS (p<0.001). Under physical exertion, pain decreased with ROP-RA from 5.64±1.94 (postoperative day 1) to 3.55±2.01 (postoperative day 5) on the NRS (p<0.001) (Table 2). There was no significant difference in pain reduction between the SUF-SL and ROP-RA groups (p=0.55). Thus, the postoperative pain reduction was significant and consistent in both groups, at rest and during exercise. These findings are graphically represented in Figure 1. Adverse effects in the SUF-SL group (4/28, 14%) included dizziness (n=1), nausea (n=1), and constipation (n=2). The ROP-RA group experienced motor impairment in the quadriceps femoris muscle (n=1) and nausea (n=1) (2/28, 7%). Table 2: Patient variables and NRS pain level Postoperative Pain Management Sufentanil n=28 Ropivacaine n=28 Patient Data Gender Male n=14 n=8 Female n=14 n=20 Age (in years) Mean±SD (Min-Max) 62.5±9.0 (40-80) 67.7±9.8 (53-83) BMI (in kg/m²) Mean±SD (Min-Max) 32.8±6.3 (25.1-47.3) 29.1±5.9 (19.4-43.3) NRS-Levels (Mean±SD) Rest / Under stress Day of surgery 3.66±1.73 / omitted 3.09±1.73 / omitted Day 1 3.48±2.20 / 5.64±2.06 3.08±2.02 / 5.64±1.94 2 2.36±1.80 / 5.05±1.98 2.54±1.21 / 4.18±1.62 3 1.92±1.57 / 3.77±1.97 2.08±2.18 / 3.95±2.57 4 2.08±2.01 / 3.05±2.08 1.79±1.06 / 4.09±1.77 5 1.56±1.53 / 2.77±1.90 1.92±1.31 / 3.55±2.01 Figure 1: Numerical Rating Scale pain level in total knee arthroplasty The anesthesia induction time in the operating room averaged 36.9±13.2 minutes (range: 5-59) in the SUF-SL group, while it averaged 65.9±25.4 minutes (range: 25-137) in the ROP-RA group, which was significantly longer (p<0.001) due to catheter placement. In contrast, operative time (SUF-SL: mean: 87.9±21.1 minutes (range: 56-135); ROP-RA: mean: 85.8±29.7 minutes (range: 49-147); p=0.77), recovery room stay (SUF-SL: mean: 138.3±65.3 minutes (range: 65-342); ROP-RA: mean: 160.3±57.4 minutes (range: 90-352); p=0.21), and total postoperative hospital stay (SUF-SL: mean: 6.3±1.3 days (range: 5-12); ROP-RA: mean: 6.8±1.2 days (range: 6-10); p=0.14) showed no significant differences. The analysis of additional postoperative non-opioid analgesic consumption per day revealed no significant difference between the two groups (p>0.3). Discussion The present study compared two postoperative pain management strategies following primary total knee arthroplasty (TKA): a non-invasive, patient-controlled sublingual sufentanil system combined with local infiltration analgesia (SUF-SL) and an invasive regional anesthesia technique using continuous femoral nerve catheterization combined with a single-shot sciatic nerve block (ROP-RA). The primary aim was to evaluate analgesic efficacy, safety, feasibility, and perioperative workflow implications in the context of modern, multimodal perioperative care pathways. Effective management of acute postoperative pain is essential not only for patient comfort but also for the prevention of persistent postsurgical pain syndromes (Chen et al., 2021; Katz and Seltzer, 2009; Kehlet et al., 2006). Insufficient pain control may induce peripheral and central sensitization through neuroplastic changes mediated by N-methyl-D-aspartate receptor activation, release of pro-inflammatory cytokines, and sustained central hyperexcitability (Kehlet et al., 2006; Werner and Kongsgaard, 2014; Woolf, 2011). These mechanisms are particularly relevant after major orthopedic procedures such as TKA, where 20–30% of patients may develop chronic postoperative pain despite technically successful surgery outcome (Lewis et al., 2012; Wylde et al., 2013). High pain intensity during the early postoperative phase has consistently been identified as a key risk factor for pain chronification (Brummett et al., 2017). Regional anesthesia techniques have long been integral components of perioperative analgesia in lower extremity surgery (Hebl, 2006). Continuous femoral nerve blocks provide effective analgesia, reduce systemic opioid requirements, and are associated with favorable short-term pain outcomes (Ilfeld et al., 2009; Mariano et al., 2021). In our study, ROP-RA demonstrated significant pain reduction at rest and during mobilization, confirming its well-established analgesic efficacy. However, a major and clinically relevant finding was the high rate of unplanned therapy discontinuation or deviation in the ROP-RA group. Overall, 64.3% of patients experienced premature termination or protocol deviations, with catheter dislocation being the predominant cause (35.7%), highlighting the vulnerability of catheter-based techniques in routine clinical practice. Although femoral nerve block is a simple, proven, and low-risk anesthesiological procedure with a good pain-reducing success rate (Albrecht and Birnbaum, 2008), with correct redistribution of the local anesthetic, such blocks are anesthesiologically very efficient, and the local spread of effects within the affected extremity is highly predictable. With correct procedure, motor function/mobility and vigilance remain unaffected, which significantly reduces the need for a urinary catheter as well as the occurrence of positional injuries, hypothermia, and systemic sympathetic activation (Capdevila et al., 1999; Lu et al., 2023). Particularly in cases of opiate intolerance or addiction, peripheral regional anesthesia procedures are a highly effective alternative (Kalachian et al., 2024), with a low complication rate (nerve damage: <0.02%; infections: 0.2%; superficial redness of the injection site: 5%) (Shams et al., 2022; Zaballos et al., 2022). In postoperative pain management, catheter-dependent continuous administration of local anesthetics (e.g., amide-type ropivacaine (Gromov et al., 2021)) via pump is available. PCA is preferred, allowing the patient to administer medication independently and as needed (Sonawane and Dixit, 2021). Compared with single-shot nerve blocks, continuous nerve blocks resulted in lower pain levels during exercise within 24 hours after TKA (Chan et al., 2013). Compared with intravenous patient-controlled opioid analgesia, continuous nerve blocks resulted in better pain reduction within 24 hours after TKA, with lower opioid consumption, less nausea and vomiting, and faster knee mobilization (Chan et al., 2013). However, invasive catheter-based regional anesthesia techniques can be technically challenging for intracorporeal placement and carry the risk of catheter malfunction, dislocation, and infection (Ilfeld, 2009; 2011; Jaeger et al. 2013; Kalimeris et al., 2020; Liu et al., 2005; Neal et al., 2008; Rawal, 2016). These findings are particularly relevant in the context of evolving surgical and rehabilitation concepts. Modern TKA pathways increasingly emphasize minimally invasive surgical techniques, early mobilization, and accelerated rehabilitation protocols. Continuous femoral nerve blockade may counteract these goals due to catheter-related complications, impaired mobility, or technical failure. Our data suggest that under real-world conditions, the theoretical advantages of continuous regional anesthesia may be offset by practical limitations that compromise treatment continuity and reliability. In contrast, the SUF-SL approach provided comparable analgesic efficacy without invasive instrumentation. Both treatment groups showed significant and clinically meaningful reductions in postoperative pain at rest and during exercise, with no statistically significant differences between modalities. Importantly, SUF-SL was associated with a significantly shorter anesthesia induction time, reflecting its ease of use and elimination of catheter placement. This advantage did not translate into differences in operative duration, postoperative recovery time, or length of hospital stay, indicating that SUF-SL integrates seamlessly into established perioperative workflows. Sufentanil is a highly potent μ-opioid receptor agonist with favorable pharmacokinetic properties for sublingual administration (Hutchings et al., 2023). While traditionally restricted to intraoperative intravenous use, its application as a sublingual, patient-controlled system has expanded its role into postoperative analgesia. In our cohort, SUF-SL was well tolerated, with only mild and infrequent adverse effects and no clinically relevant respiratory or neurological complications. The absence of significant differences in additional non-opioid analgesic consumption further supports its analgesic equivalence to regional anesthesia. This study investigated a SUF-SL PCA application for its use in postoperative pain management after TKA and compared with ROP-RA. Both SUF-SL and ROP-RA demonstrated significant postoperative pain reduction after TKA, at rest and during exercise (p0.5), with a low side effect profile and no significant difference in the additional need for non-opioid analgesics (p>0.3). Due to the non-invasive and easy administration of SUF-SL, a significantly shorter anesthesia induction time was observed compared to catheter-based ROP-RA (p<0.001). Regarding total operating time and postoperative hospital stay, there were no disadvantages for the SUF-SL group. Previous studies have demonstrated superior patient satisfaction, lower side-effect profiles, and improved mobilization with SUF-SL compared to intravenous morphine PCA (Hutchins et al., 2020). Our findings extend this evidence by directly comparing SUF-SL with catheter-based regional anesthesia in TKA patients. The markedly lower rate of therapy discontinuation and protocol deviations in the SUF-SL group underscores its robustness and practicality in everyday clinical use. Non-invasive analgesia procedures, such as SUF-SL administration, promote earlier mobilization, shorter hospital stays, lower thrombosis risks, and faster functional recovery (Kehlet and Wilmore, 2008; Wainwright et al., 2016), with lower complication rates and lower personnel costs (Di Martino et al., 2023; Faldini et al., 2024). From a broader perspective, non-invasive, patient-controlled analgesic strategies align well with enhanced recovery after surgery (ERAS) concepts. Earlier mobilization, reduced complication rates, simplified logistics, and potentially lower personnel costs make SUF-SL an attractive alternative within multimodal pain management frameworks. Especially in patients with contraindications to regional anesthesia or in settings where catheter management is resource-intensive, SUF-SL represents a viable and effective option. Conclusion Despite their established use and known advantages, regional anesthesia procedures should be reconsidered in the context of modern Fast track treatment concepts aimed at early mobilization, especially when alternative, non-invasive analgesic methods with comparable efficacy and low side effect profile are available. In postoperative pain management, the use of SUF-SL as a non-invasive, simple and patient-controlled anesthesia should be considered, provided there are no contraindications, as an equivalent, effective, safe, and feasible alternative within the framework of multimodal, patient-centered pain management concepts. Declarations Ethics Statement This study was approved by the Ethics Committee of Martin Luther University Halle-Wittenberg (Germany) (approval: 30.10.2019; processing number: 2019-081; EudraCT number: 2019-001725-27; Protocol number: KKSH152). The ethical principles of Good Medical Practice and the Declaration of Helsinki in their current version were fully observed. Funding The publication of this article received financial support from the Open Access Publication Fund of the Martin Luther University Halle-Wittenberg. Acknowledgments We acknowledge the financial support of the Open Access Publication Fund of the Martin-Luther-University Halle-Wittenberg. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Conflicts of Interest The authors declare no conflicts of interest. Author Contributions David Johanio Avila Castillo: Conceptualization, Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing. Andreas Posa: Conceptualization, Methodology, Data curation, Formal analysis, Investigation, Supervision, Writing – original draft preparation. Annett Christel: Methodology, Data curation, Writing – review and editing. Michael Bucher: Methodology, Data curation, Formal analysis, Ressources, Writing – review and editing. Walter Alexander Wohlgemuth: Methodology, Data curation, Formal analysis, Writing – review and editing. David Wohlrab: Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing. Alexander Zeh: Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing. Lilit Flöther: Conceptualization, Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing. References Albrecht R, Birnbaum J (editors). Femoral nerve block. 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Anesthesia via peripheral nerve blocks during total knee replacement has no effect on postoperative inflammation in elderly patients. J Orthop Surg. 2023;31(3):10225536231217539. Mariano ER, El-Boghdadly K, Ilfeld BM. Using postoperative pain trajectories to define the role of regional analgesia in personalised pain medicine. Anaesthesia. 2021;76(2):165–9. Neal JM, Bernards CM, Hadzic A, et al. ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine. Reg Anesth Pain Med. 2008;33(5):404–15. Porela-Tiihonen S, Kokki M, Kokki H. Sufentanil sublingual formulation for the treatment of acute, moderate to severe postoperative pain in adult patients. Expert Rev Neurother. 2017;17(2):101–11. Rawal N. Current issues in postoperative pain management. Eur J Anaesthesiol. 2016;33(3):160–71. Reddi D, Curran N. Chronic pain after surgery: pathophysiology, risk factors and prevention. Postgrad Med J. 2014;90(1062):222–7. Sacerdote P, Coluzzi F, Fanelli A. Sublingual sufentanil, a new opportunity for the improvement of postoperative pain management in Italy. Eur Rev Med Pharmacol Sci. 2016;20(7):1411–22. Shams D, Sachse K, Statzer N, et al. Regional Anesthesia Complications and Contraindications. Clin Sports Med. 2022;41(2):329–43. Sonawane K, Dixit H, Balavenkatasubramanian J. Regional analgesia technique for postoperative analgesia in total knee arthroplasty: have we hit the bull’s eye yet? Braz J Anesthesiol. 2021;71(3):307–9. Wainwright TW, Immins T, Middleton RG. Enhanced recovery after surgery (ERAS) and its applicability for major spine surgery. Best Pract Res Clin Anaesthesiol. 2016;30(1):91–102. Werner MU, Kongsgaard UE. I. Defining persistent post-surgical pain: is an update required? BJA Br J Anaesth. 2014;113(1):1–4. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2–15. Wu R, Ma Y, Yang Y, et al. A clinical model for predicting knee replacement in early-stage knee osteoarthritis: data from osteoarthritis initiative. Clin Rheumatol. 2022;41(4):1199–210. Wylde V, Bruce J, Beswick A, et al. Assessment of chronic postsurgical pain after knee replacement: a systematic review. Arthritis Care Res. 2013;65(11):1795–803. Zaballos M, Fernández I, Rodríguez L, et al. Effects of intravenous lipid emulsions on the reversal of pacing-induced ventricular arrhythmias and electrophysiological alterations in an animal model of ropivacaine toxicity. Clin Toxicol Phila Pa. 2022;60(8):902–11. Additional Declarations The authors declare no competing interests. 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8709340","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":581088438,"identity":"b6bc467a-7111-4ceb-a96c-5d2239859b62","order_by":0,"name":"David Johanio Avila Castillo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABP0lEQVRIie2RMWvCQBTH3/EgWYJdlYL5CicOItJ+FkMgLgqdSqAlngiXJXV28EP4ES4c1EXqmlEROjlkKoKl9EXtktZ27XA/Du64//3u3uMADIb/iKLh0GzZ5w3LRgE5dIEDjijFy8o5qlrIBJseFSYuKVAoX1EVSEHnF6WyWDbUDm69CeIa9o9RVEE22t7IAFp2KlQOnXpJqS37PJ2B70m0OEuedVHYuDmQfWgnnkin0GuWFK6CrnYAm9RL6wCWKhR5PZDhcK48QZH2RElZvRbKkBQ7R/iITkpbhhRthH4HPSwrma+Kq+oWOpwO40lhVBjP6BUA3S33km1VOuOLQrljTxNdk9RLI3kJSNmINOG9RumVysob57vwwXHjeA77t+jKjcfpen/vU2E+LcKO++1jjuX9uPtXZDAYDIaLfAKS3G4MVo3MBAAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Anesthesiology and Surgical Intensive Care, University Hospital Halle (Saale)","correspondingAuthor":true,"prefix":"","firstName":"David","middleName":"Johanio Avila","lastName":"Castillo","suffix":""}],"badges":[],"createdAt":"2026-01-27 10:45:13","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8709340/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8709340/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101630246,"identity":"3b0a8872-2d3c-4b53-b8e5-05ffef25dfa9","added_by":"auto","created_at":"2026-02-02 05:25:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":53669,"visible":true,"origin":"","legend":"\u003cp\u003eNumerical Rating Scale pain level in total knee arthroplasty\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8709340/v1/1b0d03021d5efa174c2c01dc.png"},{"id":101752659,"identity":"bfb0755c-dab2-46fe-8d35-96a759191903","added_by":"auto","created_at":"2026-02-03 10:28:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1087906,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8709340/v1/44a2e19f-2832-415e-b4e7-09f001ee6fbe.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSublingual sufentanil versus femoral nerve catheter analgesia with ropivacaine after primary total knee arthroplasty: a randomized, prospective, clinical comparative phase IV trial\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe knee joint is the largest joint in the human body and plays a central role in mobility and stability. Due to the high mechanical stress, the knee joint is particularly susceptible to degenerative diseases, trauma, and inflammatory processes, which are often associated with significant pain and functional limitations (Aparisi G\u0026oacute;mez et al., 2023). When conservative and medical treatments no longer promise sufficient relief, surgical treatment with a new implant remains the only option. The implantation of a knee endoprosthesis is now one of the most frequently planned surgical procedures performed (German Endoprosthesis Registry (EPRD) Report, 2024). It is the method of choice for advanced joint destruction as a result of osteoarthritis in the broadest sense, regardless of its causality (Wu et al., 2022). Treatment success is measured by pain relief, preservation of knee mobility, and return to daily activities (Fawaz and Masri, 2020). Although minimally invasive surgical techniques and improved implant materials are increasingly being used, satisfactory pain relief cannot be observed in 15\u0026ndash;20% of cases (Wylde et al., 2013). In this context, there is a significant risk of developing chronic pain.\u003c/p\u003e \u003cp\u003eThe aim of this study was to compare non-invasive sublingual sufentanil (SUF-SL) with invasive ropivacaine regional anesthesia (ROP-RA) in acute postoperative pain management with regard to their pain reduction potential after primary total knee arthroplasty (TKA).\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e\u003cem\u003eStudy Design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a randomized, prospective, open-label, Phase IV clinical trial. It compares the administration of SUF-SL via the patient-controlled application system Zalviso® with the patient-controlled administration of ROP-RA via femoral catheter for acute postoperative pain treatment after primary TKA. The study was conducted at the University Hospital Halle (Germany) in collaboration between the Department of Anesthesiology and Surgical Intensive Care and the Department of Orthopaedics, Trauma and Reconstructive Surgery between April 29, 2021, and May 22, 2023.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConduct of anesthesia and surgery technique\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAnesthesia was induced according to clinical practice standards with 1) sufentanil (analgesia), propofol (sedative), and rocuronium (muscle relaxant). Sevofluran was used to maintain general anesthesia as part of a balanced anesthetic approach.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll surgeries were performed as primary TKAs, using either a mini-mid-vastus approach or a standard medial or lateral parapatellar approach, depending on individual anatomy. Tourniquets and cementation of the prosthetic components were performed according to standard surgical procedures. Before wound closure, an intra-articular and a subcutaneous drain were placed and left in place until the second postoperative day.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePreoperatively, patients in the \u003cstrong\u003eROP-RA group\u003c/strong\u003e received an ultrasound-guided femoral nerve catheter prior to sedation. This catheter was used to administer a single-shot femoral nerve block with \u003cstrong\u003e20 mL of 0.2% ropivacaine\u003c/strong\u003e (total dose: \u003cstrong\u003e40 mg\u003c/strong\u003e). Subsequently, a single-shot sciatic nerve block was performed using \u003cstrong\u003e10 mL of 0.75% ropivacaine\u003c/strong\u003e (total dose: \u003cstrong\u003e75 mg\u003c/strong\u003e). Following completion of the regional anesthetic procedures, \u003cstrong\u003egeneral anesthesia\u003c/strong\u003e was induced and maintained for the surgical intervention.\u003c/p\u003e\n\u003cp\u003ePatients in the \u003cstrong\u003eSUF-SL group\u003c/strong\u003e received \u003cstrong\u003eintraoperative local infiltration analgesia\u003c/strong\u003e consisting of \u003cstrong\u003e150 mL of 0.2% ropivacaine\u003c/strong\u003e (total dose: \u003cstrong\u003e300 mg\u003c/strong\u003e) combined with \u003cstrong\u003e0.75 mL of adrenaline\u003c/strong\u003e (total dose: \u003cstrong\u003e0.75 mg\u003c/strong\u003e) for vasoconstriction, infiltrated into the surgical site according to a standardized protocol.\u003c/p\u003e\n\u003cp\u003eIn both groups, \u003cstrong\u003eperioperative antibiotic prophylaxis\u003c/strong\u003e consisted of a single intravenous dose of \u003cstrong\u003ecefuroxime 1.5 g\u003c/strong\u003e, administered \u003cstrong\u003e30 minutes prior to skin incision\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAt the end of surgery and before emergence from anesthesia, patients in both groups received \u003cstrong\u003eparecoxib 40 mg intravenously\u003c/strong\u003e for postoperative analgesia. \u003cstrong\u003eMetamizole 1 g intravenously\u003c/strong\u003e was administered additionally \u003cstrong\u003eas needed\u003c/strong\u003e, with a short temporal interval between administrations when required.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion and exclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBased on the inclusion and exclusion criteria (Table 1), 28 patients per treatment arm were enrolled during the study period (total n=56).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Inclusion and exclusion criteria\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e- Minimum age 18 years\u003c/p\u003e\n \u003cp\u003e- Capacity to consent\u003c/p\u003e\n \u003cp\u003e- Signed informed consent\u003c/p\u003e\n \u003cp\u003e- Unilateral total knee arthroplasty\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e- American Society of Anesthesiologists score: 1-3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e- Revision total knee replacement\u003c/p\u003e\n \u003cp\u003e- American Society of Anesthesiologists score: \u0026gt;3\u003c/p\u003e\n \u003cp\u003e- Previous spinal surgery\u003c/p\u003e\n \u003cp\u003e- Chronic opioid use\u003c/p\u003e\n \u003cp\u003e- Obstructive sleep apnea syndrome\u003c/p\u003e\n \u003cp\u003e- Chronic obstructive pulmonary disease\u003c/p\u003e\n \u003cp\u003e- Coagulopathy\u003c/p\u003e\n \u003cp\u003e- Contraindications to peripheral nerve block\u003c/p\u003e\n \u003cp\u003e- Allergies or intolerance to sufentanil\u003c/p\u003e\n \u003cp\u003e- Allergies or intolerance to amide local anesthetics\u003c/p\u003e\n \u003cp\u003e- Infections at the injection site for regional anesthesia\u003c/p\u003e\n \u003cp\u003e- Liver cirrhosis Child-Pugh grades B and C\u003c/p\u003e\n \u003cp\u003e- Glomerular filtration rate \u0026lt;30 ml/min\u003c/p\u003e\n \u003cp\u003e- Pregnancy or breastfeeding patient\u003c/p\u003e\n \u003cp\u003e- Women of childbearing potential without contraception\u003c/p\u003e\n \u003cp\u003e- Alcohol or drug abuse\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003ePostoperative pain management\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients in the \u003cstrong\u003eSUF-SL group\u003c/strong\u003e received a \u003cstrong\u003esublingual patient-controlled analgesia (PCA) system\u003c/strong\u003e (Zalviso®, Grünenthal, Aachen, Germany) in the post-anesthesia care unit. The device delivered single doses of \u003cstrong\u003e15 µg sufentanil\u003c/strong\u003e with a \u003cstrong\u003elockout interval of 20 minutes\u003c/strong\u003e, in accordance with the approved dosing regimen. The \u003cstrong\u003emaximum duration of use was limited to 72 hours\u003c/strong\u003e, as specified in the marketing authorization.\u003c/p\u003e\n\u003cp\u003ePatients in the \u003cstrong\u003eROP-RA group\u003c/strong\u003e received \u003cstrong\u003eropivacaine 0.2%\u003c/strong\u003e postoperatively via a PCA pump connected to the femoral nerve catheter. A \u003cstrong\u003econtinuous infusion rate of 5 mL per hour\u003c/strong\u003e (equivalent to \u003cstrong\u003e10 mg ropivacaine per hour\u003c/strong\u003e) was administered. In addition, patient-controlled bolus doses of \u003cstrong\u003e5 mL ropivacaine 0.2%\u003c/strong\u003e (\u003cstrong\u003e10 mg\u003c/strong\u003e) were permitted with a \u003cstrong\u003elockout interval of 30 minutes\u003c/strong\u003e. To ensure methodological comparability between groups, the \u003cstrong\u003emaximum duration of regional analgesia was likewise limited to 72 hours\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAll patients received standardized instruction in the use of their respective PCA systems by a \u003cstrong\u003especialized anesthesiology team\u003c/strong\u003e prior to initiation. In accordance with the \u003cstrong\u003eGerman S3 guideline for multimodal treatment of acute perioperative and post-traumatic pain\u003c/strong\u003e, both groups received scheduled systemic basic analgesia with non-opioid agents, consisting of \u003cstrong\u003emetamizole 1 \u0026nbsp;g intravenously four times daily\u003c/strong\u003e and \u003cstrong\u003eibuprofen 600 mg oral three times daily\u003c/strong\u003e. In patients with contraindications or intolerance, \u003cstrong\u003eparacetamol 1 g intravenously\u003c/strong\u003e was administered as an alternative, up to a maximum of \u003cstrong\u003efour doses per day\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAll co-analgesic medications were \u003cstrong\u003egradually tapered within the first five postoperative days\u003c/strong\u003e. The predefined analgesic target was a \u003cstrong\u003eNumerical Rating Scale (NRS) score below 4\u003c/strong\u003e. The hospital’s \u003cstrong\u003eacute pain service\u003c/strong\u003e conducted structured ward rounds \u003cstrong\u003etwice daily\u003c/strong\u003e, and trained personnel were available at all times to address patient concerns or technical issues related to PCA use. \u003cstrong\u003eOverdose of sublingual sufentanil was not possible\u003c/strong\u003e due to the fixed dosing parameters and lockout intervals programmed into the device.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEndpoints\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of the study was the assessment of postoperative pain at rest and during physical exertion (stress) between SUF-SL and ROP-RA using NRS (0=no pain, 10=maximum pain). At rest, NRS was recorded on the day of surgery (postoperatively) and on the first, second, third, fourth and fifth days after surgery. The first physical exertion after TKA occurred on the first postoperative day. Therefore, the NRS was recorded during exercise on the first, second, third, fourth, and fifth postoperative days, not on the day of surgery. Discharge from the hospital was scheduled for the 6th postoperative day. The NRS was recorded during the morning visit and thus at the same time for all patients to exclude daily fluctuations. In addition, possible adverse effects of the study medication were recorded. The secondary endpoint was the consumption of additional non-opioid analgesics at the above-mentioned time points. The assessment was based on whether these were necessary at the respective time points or not. The third endpoint was whether the use of SUF-SL or ROP-RA had an influence on the pre-, intra-, and postoperative procedures as well as on the total hospital stay.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRandomization was performed the day before surgery using secuTrail® software. Statistical analysis was conducted with IBM SPSS Statistics version 29.0.1.1. To evaluate postoperative pain progression (NRS scores from day 0 to day 5), a mixed ANOVA with within- and between-subject factors was used, comparing pain development over time and between the two study groups (sufentanil vs. ropivacaine). Additionally, separate group comparisons were performed for each postoperative day using independent t-test, following confirmation of normal distribution (Shapiro-Wilk test) and homogeneity of variance (Levene test). For baseline comparisons (age, body mass index (BMI), gender), independent t-tests and chi-square tests were applied accordingly. Group differences in the daily frequency of additional non-opioid analgesic use were analyzed using chi-square tests. Time variables (pre-, intra-, postoperative) were compared using independent t-test after confirming test assumptions. Bonferroni correction was applied for multiple testing. A p-value \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthical approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Martin Luther University Halle-Wittenberg (Germany) (approval: 30.10.2019; processing number: 2019-081; EudraCT number: 2019-001725-27; Protocol number: KKSH152). The ethical principles of Good Medical Practice and the Declaration of Helsinki in their current version were fully observed.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe entire patient collective (n=56, male: n=22, female: n=34, mean age: 65.1±9.7 years (range: 40-83)) is presented in Table 2, with their patient variables gender, age and BMI and with their NRS pain level at the different assessment time points. The SUF-SL group was on average younger (62.5±9.0 years; range: 40-80) than the ROP-RA group (67.7±9.8 years; range: 53-83) (p=0.043), with higher BMI values (32.8±6.3 kg/m²; range: 25.1-47.3 vs. 29.1±5.9 kg/m²; range: 19.4-43.3; p=0.027). There were no differences in gender distribution between the two groups (male/female: SUF-SL: n=14/14 vs. ROP-RA: n=8/20; p=0.10).\u003c/p\u003e\n\u003cp\u003eBoth the SUF-SL and ROP-RA groups demonstrated significant postoperative pain reduction after TKA, at rest and during exercise. At rest, pain decreased with SUF-SL from 3.66±1.73 (surgery day) to 1.56±1.53 (postoperative day 5) on the NRS (p\u0026lt;0.001). Under physical exercise, pain decreased with SUF-SL from 5.64±2.06 (postoperative day 1) to 2.77±1.90 (postoperative day 5) on the NRS (p\u0026lt;0.001). At rest, pain decreased with ROP-RA from 3.09±1.73 (surgery day) to 1.92±1.31 (postoperative day 5) on the NRS (p\u0026lt;0.001). Under physical exertion, pain decreased with ROP-RA from 5.64±1.94 (postoperative day 1) to 3.55±2.01 (postoperative day 5) on the NRS (p\u0026lt;0.001) (Table 2). There was no significant difference in pain reduction between the SUF-SL and ROP-RA groups (p=0.55). Thus, the postoperative pain reduction was significant and consistent in both groups, at rest and during exercise. These findings are graphically represented in Figure 1. Adverse effects in the SUF-SL group (4/28, 14%) included dizziness (n=1), nausea (n=1), and constipation (n=2). The ROP-RA group experienced motor impairment in the quadriceps femoris muscle (n=1) and nausea (n=1) (2/28, 7%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u003c/strong\u003e Patient variables and NRS pain level\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostoperative Pain Management\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSufentanil\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003en=28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRopivacaine\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003en=28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient Data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFemale\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003en=20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003cp\u003e(in years)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMean±SD\u003c/p\u003e\n \u003cp\u003e(Min-Max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e62.5±9.0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(40-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e67.7±9.8\u003c/p\u003e\n \u003cp\u003e(53-83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003cp\u003e(in kg/m²)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMean±SD\u003c/p\u003e\n \u003cp\u003e(Min-Max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e32.8±6.3\u003c/p\u003e\n \u003cp\u003e(25.1-47.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29.1±5.9\u003c/p\u003e\n \u003cp\u003e(19.4-43.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRS-Levels\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(Mean±SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRest \u0026nbsp;/ \u0026nbsp;Under stress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay of surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.66±1.73 \u0026nbsp;/ \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; omitted \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.09±1.73 \u0026nbsp;/ \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; omitted\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.48±2.20 \u0026nbsp;/ \u0026nbsp;5.64±2.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.08±2.02 \u0026nbsp;/ \u0026nbsp;5.64±1.94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.36±1.80 \u0026nbsp;/ \u0026nbsp;5.05±1.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.54±1.21 \u0026nbsp;/ \u0026nbsp;4.18±1.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.92±1.57 \u0026nbsp;/ \u0026nbsp;3.77±1.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.08±2.18 \u0026nbsp;/ \u0026nbsp;3.95±2.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.08±2.01 \u0026nbsp;/ \u0026nbsp;3.05±2.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.79±1.06 \u0026nbsp;/ \u0026nbsp;4.09±1.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.56±1.53 \u0026nbsp;/ \u0026nbsp;2.77±1.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.92±1.31 \u0026nbsp;/ \u0026nbsp;3.55±2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1:\u003c/strong\u003e Numerical Rating Scale pain level in total knee arthroplasty\u003c/p\u003e\n\u003cp\u003eThe anesthesia induction time in the operating room averaged 36.9±13.2 minutes (range: 5-59) in the SUF-SL group, while it averaged 65.9±25.4 minutes (range: 25-137) in the ROP-RA group, which was significantly longer (p\u0026lt;0.001) due to catheter placement. In contrast, operative time (SUF-SL: mean: 87.9±21.1 minutes (range: 56-135); ROP-RA: mean: 85.8±29.7 minutes (range: 49-147); p=0.77), recovery room stay (SUF-SL: mean: 138.3±65.3 minutes (range: 65-342); ROP-RA: mean: 160.3±57.4 minutes (range: 90-352); p=0.21), and total postoperative hospital stay (SUF-SL: mean: 6.3±1.3 days (range: 5-12); ROP-RA: mean: 6.8±1.2 days (range: 6-10); p=0.14) showed no significant differences. The analysis of additional postoperative non-opioid analgesic consumption per day revealed no significant difference between the two groups (p\u0026gt;0.3).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study compared two postoperative pain management strategies following primary total knee arthroplasty (TKA): a non-invasive, patient-controlled sublingual sufentanil system combined with local infiltration analgesia (SUF-SL) and an invasive regional anesthesia technique using continuous femoral nerve catheterization combined with a single-shot sciatic nerve block (ROP-RA). The primary aim was to evaluate analgesic efficacy, safety, feasibility, and perioperative workflow implications in the context of modern, multimodal perioperative care pathways.\u003c/p\u003e\n\u003cp\u003eEffective management of acute postoperative pain is essential not only for patient comfort but also for the prevention of persistent postsurgical pain syndromes (Chen et al., 2021; Katz and Seltzer, 2009; Kehlet et al., 2006). Insufficient pain control may induce peripheral and central sensitization through neuroplastic changes mediated by N-methyl-D-aspartate receptor activation, release of pro-inflammatory cytokines, and sustained central hyperexcitability (Kehlet et al., 2006; Werner and Kongsgaard, 2014; Woolf, 2011). These mechanisms are particularly relevant after major orthopedic procedures such as TKA, where 20–30% of patients may develop chronic postoperative pain despite technically successful surgery outcome (Lewis et al., 2012; Wylde et al., 2013). High pain intensity during the early postoperative phase has consistently been identified as a key risk factor for pain chronification (Brummett et al., 2017).\u003c/p\u003e\n\u003cp\u003eRegional anesthesia techniques have long been integral components of perioperative analgesia in lower extremity surgery (Hebl, 2006). Continuous femoral nerve blocks provide effective analgesia, reduce systemic opioid requirements, and are associated with favorable short-term pain outcomes (Ilfeld et al., 2009; Mariano et al., 2021). In our study, ROP-RA demonstrated significant pain reduction at rest and during mobilization, confirming its well-established analgesic efficacy. However, a major and clinically relevant finding was the high rate of unplanned therapy discontinuation or deviation in the ROP-RA group. Overall, 64.3% of patients experienced premature termination or protocol deviations, with catheter dislocation being the predominant cause (35.7%), highlighting the vulnerability of catheter-based techniques in routine clinical practice.\u003c/p\u003e\n\u003cp\u003eAlthough femoral nerve block is a simple, proven, and low-risk anesthesiological procedure with a good pain-reducing success rate (Albrecht and Birnbaum, 2008), with correct redistribution of the local anesthetic, such blocks are anesthesiologically very efficient, and the local spread of effects within the affected extremity is highly predictable. With correct procedure, motor function/mobility and vigilance remain unaffected, which significantly reduces the need for a urinary catheter as well as the occurrence of positional injuries, hypothermia, and systemic sympathetic activation (Capdevila et al., 1999; Lu et al., 2023). Particularly in cases of opiate intolerance or addiction, peripheral regional anesthesia procedures are a highly effective alternative (Kalachian et al., 2024), with a low complication rate (nerve damage: \u0026lt;0.02%; infections: 0.2%; superficial redness of the injection site: 5%) (Shams et al., 2022; Zaballos et al., 2022). In postoperative pain management, catheter-dependent continuous administration of local anesthetics (e.g., amide-type ropivacaine (Gromov et al., 2021)) via pump is available. PCA is preferred, allowing the patient to administer medication independently and as needed (Sonawane and Dixit, 2021). Compared with single-shot nerve blocks, continuous nerve blocks resulted in lower pain levels during exercise within 24 hours after TKA (Chan et al., 2013). Compared with intravenous patient-controlled opioid analgesia, continuous nerve blocks resulted in better pain reduction within 24 hours after TKA, with lower opioid consumption, less nausea and vomiting, and faster knee mobilization (Chan et al., 2013). However, invasive catheter-based regional anesthesia techniques can be technically challenging for intracorporeal placement and carry the risk of catheter malfunction, dislocation, and infection (Ilfeld, 2009; 2011; Jaeger et al. 2013; Kalimeris et al., 2020; Liu et al., 2005; Neal et al., 2008; Rawal, 2016). These findings are particularly relevant in the context of evolving surgical and rehabilitation concepts. Modern TKA pathways increasingly emphasize minimally invasive surgical techniques, early mobilization, and accelerated rehabilitation protocols. Continuous femoral nerve blockade may counteract these goals due to catheter-related complications, impaired mobility, or technical failure. Our data suggest that under real-world conditions, the theoretical advantages of continuous regional anesthesia may be offset by practical limitations that compromise treatment continuity and reliability.\u003c/p\u003e\n\u003cp\u003eIn contrast, the SUF-SL approach provided comparable analgesic efficacy without invasive instrumentation. Both treatment groups showed significant and clinically meaningful reductions in postoperative pain at rest and during exercise, with no statistically significant differences between modalities. Importantly, SUF-SL was associated with a significantly shorter anesthesia induction time, reflecting its ease of use and elimination of catheter placement. This advantage did not translate into differences in operative duration, postoperative recovery time, or length of hospital stay, indicating that SUF-SL integrates seamlessly into established perioperative workflows.\u003c/p\u003e\n\u003cp\u003eSufentanil is a highly potent μ-opioid receptor agonist with favorable pharmacokinetic properties for sublingual administration (Hutchings et al., 2023). While traditionally restricted to intraoperative intravenous use, its application as a sublingual, patient-controlled system has expanded its role into postoperative analgesia. In our cohort, SUF-SL was well tolerated, with only mild and infrequent adverse effects and no clinically relevant respiratory or neurological complications. The absence of significant differences in additional non-opioid analgesic consumption further supports its analgesic equivalence to regional anesthesia.\u003c/p\u003e\n\u003cp\u003eThis study investigated a SUF-SL PCA application for its use in postoperative pain management after TKA and compared with ROP-RA. Both SUF-SL and ROP-RA demonstrated significant postoperative pain reduction after TKA, at rest and during exercise (p\u0026lt;0.001). However, no significant difference in pain reduction was found between these two pain management modalities (p\u0026gt;0.5), with a low side effect profile and no significant difference in the additional need for non-opioid analgesics (p\u0026gt;0.3). Due to the non-invasive and easy administration of SUF-SL, a significantly shorter anesthesia induction time was observed compared to catheter-based ROP-RA (p\u0026lt;0.001). Regarding total operating time and postoperative hospital stay, there were no disadvantages for the SUF-SL group.\u003c/p\u003e\n\u003cp\u003ePrevious studies have demonstrated superior patient satisfaction, lower side-effect profiles, and improved mobilization with SUF-SL compared to intravenous morphine PCA (Hutchins et al., 2020). Our findings extend this evidence by directly comparing SUF-SL with catheter-based regional anesthesia in TKA patients. The markedly lower rate of therapy discontinuation and protocol deviations in the SUF-SL group underscores its robustness and practicality in everyday clinical use. Non-invasive analgesia procedures, such as SUF-SL administration, promote earlier mobilization, shorter hospital stays, lower thrombosis risks, and faster functional recovery (Kehlet and Wilmore, 2008; Wainwright et al., 2016), with lower complication rates and lower personnel costs (Di Martino et al., 2023; Faldini et al., 2024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFrom a broader perspective, non-invasive, patient-controlled analgesic strategies align well with enhanced recovery after surgery (ERAS) concepts. Earlier mobilization, reduced complication rates, simplified logistics, and potentially lower personnel costs make SUF-SL an attractive alternative within multimodal pain management frameworks. Especially in patients with contraindications to regional anesthesia or in settings where catheter management is resource-intensive, SUF-SL represents a viable and effective option.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDespite their established use and known advantages, regional anesthesia procedures should be reconsidered in the context of modern Fast track treatment concepts aimed at early mobilization, especially when alternative, non-invasive analgesic methods with comparable efficacy and low side effect profile are available. In postoperative pain management, the use of SUF-SL as a non-invasive, simple and patient-controlled anesthesia should be considered, provided there are no contraindications, as an equivalent, effective, safe, and feasible alternative within the framework of multimodal, patient-centered pain management concepts.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Martin Luther University Halle-Wittenberg (Germany) (approval: 30.10.2019; processing number: 2019-081; EudraCT number: 2019-001725-27; Protocol number: KKSH152). The ethical principles of Good Medical Practice and the Declaration of Helsinki in their current version were fully observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe publication of this article received financial support from the Open Access Publication Fund of the Martin Luther University Halle-Wittenberg.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the financial support of the Open Access Publication Fund of the Martin-Luther-University Halle-Wittenberg.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDavid Johanio Avila Castillo:\u003c/strong\u003e Conceptualization, Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing. \u003cstrong\u003eAndreas Posa:\u0026nbsp;\u003c/strong\u003eConceptualization, Methodology, Data curation, Formal analysis, Investigation, Supervision, Writing – original draft preparation. \u003cstrong\u003eAnnett Christel:\u003c/strong\u003e Methodology, Data curation, Writing – review and editing. \u003cstrong\u003eMichael Bucher:\u003c/strong\u003e Methodology, Data curation, Formal analysis, Ressources, Writing – review and editing. \u003cstrong\u003eWalter Alexander Wohlgemuth:\u003c/strong\u003e Methodology, Data curation, Formal analysis, Writing – review and editing.\u0026nbsp;\u003cstrong\u003eDavid Wohlrab:\u003c/strong\u003e Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing. \u003cstrong\u003eAlexander Zeh:\u003c/strong\u003e Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing.\u0026nbsp;\u003cstrong\u003eLilit Flöther:\u003c/strong\u003e Conceptualization, Methodology, Data curation, Formal analysis, Investigation, Writing – review and editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlbrecht R, Birnbaum J (editors). 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Clin Toxicol Phila Pa. 2022;60(8):902\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"total knee arthroplasty, postoperative pain management, sublingual sufentanil, ropivacaine regional anesthesia, comparative study","lastPublishedDoi":"10.21203/rs.3.rs-8709340/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8709340/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) represents one of the most commonly performed orthopedic procedures and requires structured and effective perioperative pain management. Patients typically present with chronic, long-standing pain that substantially impairs quality of life and necessitates surgical joint replacement. Optimal intraoperative and postoperative analgesia is essential to ensure functional recovery and to minimize the risk of persistent postoperative chronic pain. In this context, the present study compares non-invasive sublingual sufentanil (SUF-SL) with invasive ropivacaine-based regional anesthesia administered via a femoral nerve catheter (ROP-RA) for postoperative pain control following TKA.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this randomized, prospective, phase IV clinical trial, 56 patients were assigned to receive either sublingual sufentanil (SUF-SL) (n\u0026thinsp;=\u0026thinsp;28; patient-controlled administration of 15 \u0026micro;g sufentanil with a lockout interval of 20 minutes) or ropivacaine-based regional anesthesia via a femoral nerve catheter (ROP-RA) (n\u0026thinsp;=\u0026thinsp;28; ropivacaine 0.2% administered at a continuous infusion rate of 5 mL/h with an additional 5 mL bolus and a lockout interval of 30 minutes) for 72 hours postoperatively. Pain intensity was assessed three times daily during the first five postoperative days using the Numerical Rating Scale (NRS). Daily mean NRS scores were calculated separately for pain at rest and during physical activity. Adverse effects, additional non-opioid analgesic consumption, perioperative time parameters, and length of hospital stay were also recorded.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBoth SUF-SL and ROP-RA significantly reduced postoperative pain after TKA. At rest, NRS scores decreased from 3.66\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73 to 1.56\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53 in the SUF-SL group and from 3.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73 to 1.92\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31 in the ROP-RA group between the day of surgery and postoperative day 5. During exercise, pain scores decreased from 5.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.06 to 2.77\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90 in the SUF-SL group and from 5.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.94 to 3.55\u0026thinsp;\u0026plusmn;\u0026thinsp;2.01 in the ROP-RA group between postoperative days 1 and 5 (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Both treatment modalities demonstrated similarly low and mild adverse effect profiles, with no significant differences in the consumption of additional non-opioid analgesics. Induction of anesthesia time was approximately 78.6% longer in the ROP-RA group due to femoral catheter placement (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant differences were observed in intraoperative time, postoperative recovery time, or length of hospital stay.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSublingual sufentanil (SUF-SL) offers an effective, safe, and non-invasive alternative to ropivacaine-based regional anesthesia (ROP-RA) for postoperative pain control after primary total knee arthroplasty and may be integrated into multimodal, patient-centered pain management strategies. From the patient\u0026rsquo;s perspective, non-invasive analgesic techniques are often preferred, while from a clinical standpoint, sublingual sufentanil demonstrates a reliable efficacy and safety profile.\u003c/p\u003e","manuscriptTitle":"Sublingual sufentanil versus femoral nerve catheter analgesia with ropivacaine after primary total knee arthroplasty: a randomized, prospective, clinical comparative phase IV trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-02 05:25:01","doi":"10.21203/rs.3.rs-8709340/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":"aa359310-403c-417c-8701-8f5168acfd17","owner":[],"postedDate":"February 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61814822,"name":"Anesthesiology \u0026 Pain Medicine"}],"tags":[],"updatedAt":"2026-02-02T05:25:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-02 05:25:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8709340","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8709340","identity":"rs-8709340","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}