With continuous advancements and refinements in medical technology, treatment guidelines for foot and ankle injuries have been significantly improved. Comprehensive surgical protocols have now been established for various conditions, including fractures of the medial, lateral, and posterior malleoli; tibiofibular fractures; midfoot and forefoot fractures (such as metatarsal and phalangeal fractures); as well as ligamentous injuries (1, 2). Surgery serves as a vital tool for treating and preventing diseases, plays a critical role in fracture healing, joint reconstruction, and ligament repairs, and enhances patient quality of life (3, 4). However, patients with foot and ankle disorders frequently experience severe perioperative pain (5), if suboptimally managed, this may even lead to chronic pain, resulting in persistent articular discomfort and functional impairment (6).

Recognized as a primary complication of surgery, postoperative pain represents a substantial challenge for healthcare systems worldwide (7). Inadequate pain control not only triggers fluctuations in intraoperative blood pressure and heart rate but also, through a cascade of stress responses (8, 9), increases postoperative adverse events, prolongs hospital stays, and heightens the financial burden on patients. Studies indicate that the incidence of moderate to severe postoperative pain following orthopedic surgery exceeds 50% (10). As a critical subset of orthopedic procedures, foot and ankle surgery presents unique challenges due to the anatomically complex structure of the joint. Concurrent injuries to tendons, cartilage, and ligaments at fracture sites (11) further exacerbate patients’ postoperative pain. Thus, implementing targeted interventions to improve pain management in foot and ankle surgery patients is clinically imperative.

Peripheral nerve blocks provide effective analgesia and reduce the need for opioid analgesics, playing a critical role in postoperative pain management (12). Owing to the inherent pharmacological properties of local anesthetics, nerve blocks typically cannot provide prolonged analgesic effects (13). Consequently, strategies to extend the duration of analgesia have become a major research focus in recent years, aiming to better harness the clinical benefits of nerve blocks. Liposomal bupivacaine features a unique multivesicular structure that enables the slow release of encapsulated bupivacaine, thereby extending the duration of analgesia (14). Reportedly, liposomal bupivacaine can provide analgesic effects for up to 72 h (15), making it an emerging agent for perioperative pain management. Recent studies have demonstrated that liposomal bupivacaine, when administered via an interscalene brachial plexus block for shoulder surgery, significantly reduces postoperative pain compared with both placebo and standard bupivacaine (16). In thoracic surgery patients, intercostal nerve blocks utilizing liposomal bupivacaine have markedly prolonged the analgesic duration (17). Additionally, the administration of liposomal bupivacaine for transversus abdominis plane (TAP) blocks reduces opioid-related side effects in patients undergoing cesarean delivery and enhances postoperative recovery quality (18). However, no studies have investigated the application of liposomal bupivacaine in foot and ankle surgery populations.

Therefore, we conducted this randomized controlled trial to evaluate the efficacy of liposomal bupivacaine in patients undergoing foot and ankle surgery. Our primary hypothesis is that for patients undergoing foot and ankle surgery, popliteal sciatic and saphenous nerve blocks using liposomal bupivacaine will reduce postoperative opioid consumption and prolong analgesic efficacy. Second, we hypothesize that the use of liposomal bupivacaine will mitigate postoperative pain-related adverse effects and enhance postoperative recovery quality in this patient population.

This randomized controlled trial was conducted at Xuzhou Renci Hospital, enrolling 152 patients scheduled for elective foot and ankle surgeries between September 1, 2024 and January 1, 2025. Four participants experienced last-minute surgery cancelations, while one patient refused to sign the informed consent form. Following randomization, protocol deviations occurred in 5 cases: three subjects in Group R and two in Group L did not undergo the intended nerve block procedures. Consequently, 142 patients (71 per group) were ultimately included in the final analysis. Figure 1 presents the complete participant flow diagram.

In this single-center, double-blind, randomized controlled trial, we demonstrated that, compared with ropivacaine, liposomal bupivacaine significantly reduced postoperative opioid consumption, prolonged the duration of nerve blockade, and improved both postoperative sleep quality and recovery quality. Furthermore, preoperative sleep quality, type of surgery, and pain catastrophizing scale scores were predictive of the development of a rapidly increasing pain trajectory.

Foot and ankle surgery frequently results in significant postoperative pain (24). As a major postoperative complication, optimizing postoperative pain management is paramount for facilitating patient recovery and mitigating the risk of pain-related adverse outcomes (25). Over 80% of patients experience postoperative pain of varying intensity, with peak pain severity typically persisting for 24–72 h (26). Owing to their inherent pharmacological profiles, conventionally used local anesthetics often fail to provide adequate coverage throughout this critical period of maximal postoperative pain (13). Extending the duration of peripheral nerve blocks is pivotal for achieving superior postoperative analgesia, which in turn enhances the quality of postoperative recovery—a cornerstone of Enhanced Recovery After Surgery (ERAS) protocols. Dexamethasone as an adjuvant can prolong the analgesic duration; however, its use in patients with hyperglycemia remains controversial (27, 28). Continuous nerve blocks provide analgesia comparable to that of liposomal bupivacaine but carry risks of infection and catheter dislodgement, along with higher costs (29). Liposomal bupivacaine has emerged as an active area of research in recent years and, owing to its reported prolonged duration of analgesia, represents a novel option for perioperative pain management. In this study, the administration of liposomal bupivacaine via popliteal sciatic and saphenous nerve blocks significantly reduced sufentanil consumption during the 24 to 48 h postoperative period. Furthermore, our results revealed that sufentanil requirements within the first 6 h after surgery were comparable to those observed with ropivacaine. However, from 6 h onward and continuing until postoperative day 3, the group receiving liposomal bupivacaine demonstrated a significantly decreased need for sufentanil. As previously reported (30), liposomal bupivacaine transversus abdominis plane (TAP) block significantly reduces total opioid consumption within the first 72 h following cesarean delivery. Similarly, our study demonstrated that it effectively reduces opioid consumption in patients undergoing foot and ankle surgery. Furthermore, in our study, the application of liposomal bupivacaine significantly prolonged the duration of analgesia (38.63 ± 4.05 h). This result confirms the efficacy of liposomal bupivacaine in extending analgesic duration among patients undergoing foot and ankle surgery. Although the observed duration did not reach the marketed claim of 72 h (31), it nevertheless resulted in a statistically significant prolongation of the analgesic effect compared with the control group receiving ropivacaine (10.91 ± 2.12 h). Liposomal bupivacaine employs multivesicular liposome technology to encapsulate bupivacaine within lipid vesicles. Upon administration, liposomes provide sustained drug release through sequential disruption of their vesicular layers (32), which accounts for their prolonged analgesic efficacy in foot and ankle surgeries.

The sciatic nerve bifurcates superior to the popliteal fossa into the tibial nerve and the common peroneal nerve, which predominantly innervate the posterior leg and plantar foot and the anterolateral leg and dorsum of the foot, respectively. Sciatic nerve blockade in the popliteal fossa is widely employed for patients undergoing lower limb and ankle procedures (33). However, a single sciatic nerve block does not provide analgesic coverage for the medial ankle or lower leg. Combining this technique with a saphenous nerve block effectively addresses this gap. The saphenous nerve, a pure sensory cutaneous branch of the femoral nerve, primarily innervates the skin of the medial aspect of the lower leg and ankle. A study by Maagaard et al. (34) demonstrated that a popliteal sciatic nerve block combined with a saphenous nerve block provides optimal analgesia for patients undergoing foot and ankle surgery. In our cohort, the findings support the efficacy of this combined regional anesthetic technique. It appears to be a safe and effective perioperative analgesic strategy for this specific patient population.

Liu et al. (18) reported that transversus abdominis plane (TAP) block with liposomal bupivacaine resulted in greater recovery at 24 h postcesarean delivery than bupivacaine alone. Consistent with these findings, our study demonstrated that the liposomal bupivacaine group achieved significantly higher QoR-40 scores on postoperative day 1 than did the ropivacaine group. Furthermore, our findings indicate that liposomal bupivacaine, relative to ropivacaine, was associated with superior sleep quality on the first postoperative day. In terms of adverse events, the incidence of observed adverse reactions such as infection, fever, and diarrhea during the hospitalization period following treatment was low in both groups, with no unexpected adverse events reported. These findings suggest that the safety profiles of liposomal bupivacaine and ropivacaine are comparable. Notably, patients in the L group exhibited an approximate 9.9% absolute risk reduction in postoperative nausea and vomiting (PONV) and an 11.3% reduction in dizziness compared to those in the R group, a reduction that can be attributed to the decreased consumption of sufentanil and its associated opioid-related adverse events. The presentation of these absolute risk differences further substantiates the clinical value of liposomal bupivacaine in mitigating adverse postoperative outcomes.

Findings from our exploratory subgroup analyses indicated that the favorable effects of liposomal bupivacaine were consistent across subgroups stratified by sex and age. Despite previous reports suggesting that age and sex can impact drug metabolism (35–37), our interaction analysis revealed that these demographic factors did not significantly modify the treatment effect. Given the exploratory nature of these analyses, however, this observation requires confirmation in adequately powered, prospective studies.

The study by Shankarappa et al. demonstrated (38) that the combination of site 1 sodium channel blockers with quaternary lidocaine derivatives (QLDs) could extend sciatic nerve blockade by 8- to 10-fold. However, QLDs alone induced significant myotoxicity, and even with combination therapy, residual muscle toxicity remained a concern. Their findings highlighted the need for a cautious risk–benefit assessment of such prolonged blocks, questioning whether the duration of blockade justifies the potential cellular-level risks. In contrast, the motor blockade achieved with liposomal bupivacaine in the present study, which lasted approximately 41.24 ± 3.82 h, was not associated with the severe local tissue toxicity concerns reported with QLDs. Current clinical evidence supports the favorable safety profile of liposomal bupivacaine in peripheral nerve blocks (15, 16). The extended duration observed with liposomal bupivacaine is attributed to its multivesicular liposome technology (18, 19), representing a clinically viable approach to achieving long-acting blockade that may circumvent the myotoxicity concerns associated with chemical modifications such as QLDs, as discussed by Shankarappa et al. Furthermore, future investigations should focus on the influence of genetic factors on block duration to facilitate the development of individualized analgesic strategies.

While liposomal bupivacaine significantly prolongs postoperative analgesia, it is important to acknowledge that sciatic nerve blockade, particularly with this formulation (motor block duration: 41.24 ± 3.82 h), can lead to pronounced motor weakness—a factor that warrants careful consideration in clinical practice (39). Early postoperative ambulation is a cornerstone of Enhanced Recovery After Surgery (ERAS) protocols, and evidence suggests (40) that mobilization on postoperative day one or even the day of surgery can significantly shorten hospital stays and accelerate functional recovery. Prolonged motor blockade may therefore conflict with ERAS principles, potentially increasing the risk of patient falls and placing an additional burden on nursing staff. Consequently, we advocate for an individualized approach to the application of this technique. For patient populations requiring strict postoperative immobilization—such as those undergoing complex joint reconstruction or requiring postoperative casting—this prolonged blockade can provide superior analgesia while avoiding pain-related limitations to immobilization. In these patients, with the assistance of family members or ward nurses, ankle pump exercises and gentle joint flexion and extension can be performed. These activities may help reduce swelling in the operated joint, prevent ankle stiffness and adhesions, decrease the incidence of deep vein thrombosis (DVT) in the lower extremities (41), and ultimately enhance functional recovery, recovery quality, and patient satisfaction. Conversely, for patients on a clear ERAS pathway anticipated to ambulate within 6 to 12 h post-surgery, this approach should be used with caution. In such cases, adjustments to local anesthetic concentration may be considered to strike a balance between effective analgesia and the preservation of motor function. Future research should focus on optimizing drug dosages or exploring combination therapies that can shorten the duration of motor blockade while preserving the analgesic benefits. In our study, latent trajectory modeling revealed two distinct pain trajectories within the ropivacaine group. These findings demonstrate heterogeneity in postoperative pain progression among patients receiving ropivacaine nerve block. Further multivariate logistic regression analysis revealed that surgical type, sleep quality, and pain catastrophizing scale scores were independently associated with distinct pain trajectory patterns. Specifically, patients who underwent fracture-related surgery, those reporting poorer sleep quality, and those with higher pain catastrophizing scale scores were more likely to develop a rapidly increasing pain trajectory. Preoperative sleep disorders can induce patient anxiety, which increases sensitivity to pain and subsequently exacerbates postoperative pain intensity (42). Pain catastrophizing refers to exaggerated and negative mental rumination concerning actual or anticipated pain experiences. It represents a maladaptive psychological response closely linked to pain perception (43). Moreover, persistent pain catastrophizing has been shown to exacerbate patients’ pain experience and diminish analgesic efficacy (44), which aligns with the findings of our study. Identifying high-risk factors for rapidly increasing postoperative pain trajectories and implementing personalized interventions such as liposomal bupivacaine nerve blocks holds greater clinical significance for improving postoperative pain management outcomes.

This study has several limitations. First, at the time of study design, our objective was to compare two clinically relevant local anesthetic strategies widely used in practice: liposomal bupivacaine (133 mg) versus standard ropivacaine (50 mg). It is important to emphasize that these doses were selected based on routine clinical dosages recommended by their respective prescribing information and clinical guidelines. Consequently, this study represents a comparison of two clinical strategies rather than a pharmacological equipotent comparison of the formulations themselves. We acknowledge that the 133 mg dose of liposomal bupivacaine and the 50 mg dose of ropivacaine are not matched for potency or pharmacokinetics, complicating the attribution of the observed analgesic benefits specifically to the liposomal formulation rather than the higher equipotent dose. Future studies should consider employing pharmacologically equivalent doses to more accurately isolate the clinical benefits attributable to the formulation itself. Furthermore, while the control group in the present study received 50 mg of ropivacaine, clinicians in real-world settings may adjust the dose or employ adjuncts based on individual patient needs. Therefore, future research should investigate whether our findings remain applicable under conditions involving adjunctive agents or higher ropivacaine doses. Second, the duration of analgesia and motor blockade was recorded based on patient self-assessment, particularly during nighttime hours, which may have introduced a degree of measurement bias and potential overestimation. Although more frequent clinical assessments or portable objective monitoring tools could theoretically provide more precise data, their implementation in routine clinical practice poses significant challenges, including disruption of patient sleep, limitations in personnel resources, and a lack of portable devices suitable for continuous monitoring. Therefore, future research should focus on developing patient-friendly continuous monitoring technologies. In the context of the present study, this measurement bias may have led to a systematic overestimation of block durations. Nevertheless, because the same assessment method was applied across all groups, any bias is likely to be non-differential, and thus the relative differences between groups remain informative. Third, although Xuzhou Renci Hospital is a Grade A tertiary orthopedic hospital and the anesthesiologists possess specialized expertise in peripheral nerve blocks for foot and ankle surgery, we cannot guarantee that every block was performed with perfect technical consistency throughout the study period. This variability in technical execution may have influenced the consistency and efficacy of the nerve blocks. Fourth, it should be acknowledged that latent class trajectory modeling was applied only to the control group, which limits our ability to directly compare pain trajectories between the two groups. The trajectory analysis in this study should therefore be considered exploratory and hypothesis-generating, aimed at uncovering underlying patterns of pain heterogeneity under conventional analgesia, rather than a formal evaluation of the intervention effect. Future studies should consider applying trajectory modeling to larger interventional cohorts to further elucidate how liposomal bupivacaine may differentially modulate analgesic outcomes across distinct pain trajectory subtypes.

Liposomal bupivacaine for popliteal sciatic and saphenous nerve blocks significantly reduced postoperative opioid consumption, prolonged block duration, and improved postoperative sleep quality and functional recovery. As a novel technique for providing postoperative analgesia in patients undergoing foot and ankle surgery, it demonstrated acceptable safety and efficacy under the conditions of this study. Preoperative sleep quality, type of foot and ankle surgery, and Pain Catastrophizing Scale scores serve as independent predictors of pain trajectories, which could help identify patients more likely to benefit from this specific technique.