Liposomal bupivacaine in head and neck fibula flap reconstruction: current evidence and future directions

Introduction

The opioid crisis remains a major public health concern in the United States. Although deaths attributed to opioids have declined modestly, approximately 75,000 fatalities were still reported in 2024 (1,2). Postoperative opioid prescriptions contribute substantially to this epidemic and carry risks of misuse, abuse, and diversion (3). Among opioid-naïve surgical patients, three to six percent continue using opioids more than 90 days after surgery (4,5). Moreover, chronic opioid use is associated with worse clinical outcomes, including increased mortality and higher rates of opioid-related hospital readmissions (6).

Despite these concerns, opioids remain central to perioperative analgesia in oral and maxillofacial surgery (OMS) (7-12). This is true not only for routine outpatient procedures, but also for complex operations such as orthognathic surgery, ablative oncologic resections, and microvascular reconstructive surgery (8,13,14). These patients typically receive high opioid doses in the immediate post-operative period and are discharged with additional opioid prescriptions (14). This reliance on opioids contributes to postoperative morbidity and also places patients at risk for persistent opioid use and associated complications.

Given these challenges, multimodal analgesia and opioid-sparing strategies have gained widespread interest. This has prompted a paradigm shift in perioperative pain management towards approaches that optimize analgesia while minimizing opioid exposure (15). One treatment modality that has gained traction are long-acting local anesthetics such as liposomal bupivacaine (LB), which have shown potential to reduce opioid requirements in various surgical settings (13,16-18). However, data supporting the effectiveness of this therapy in OMS remains limited, and further research is needed to guide best practices.

Recently, Wu et al. investigated the use of LB in conjunction with preoperative popliteal sciatic nerve block (PSNB) in maxillomandibular reconstruction using a free fibula flap (19). Their findings highlight the potential role of long-acting regional anesthesia techniques as well as LB in enhancing recovery pathways for major OMS procedures. Given the growing emphasis on opioid stewardship and enhanced recovery, a critical appraisal of emerging evidence is warranted to guide clinical adoption and identify future research opportunities. As such, the purpose of this commentary is to examine the findings of Wu et al. (19) and synthesize the current evidence on the use of LB in head and neck reconstruction as well as OMS more broadly.

LB for PSNB

Wu et al. conducted a randomized controlled trial (RCT) to evaluate whether preoperative PSNB using LB could reduce postoperative opioid consumption and improve recovery in patients undergoing fibula flap reconstruction of the maxillomandibular complex (19). Seventy-four patients undergoing maxillary or mandibular resection with fibula flap reconstruction were randomized to receive either general anesthesia (GA) with PSNB or GA alone. All patients received standardized anesthetic care and those in the intervention group were administered 133 mg LB via ultrasound-guided PSNB after induction. The control group underwent sham preparation without injection or administration of LB. Postoperative pain was managed according to post-anesthesia care unit (PACU) or intensive care unit (ICU) protocols with pain at both the donor and recipient sites assessed at 6, 12, 24, and 48 hours using an 11-point numerical rating scale (NRS).

The primary outcome was cumulative perioperative opioid use (converted to remifentanil equivalents), including intraoperative and postoperative consumption over 48 hours. Secondary outcomes included incidence of post-operative moderate to severe pain (NRS >3), sleep quality, postoperative nausea and vomiting (PONV), length of stay, and complications during the hospitalization.

The study found no significant difference in total or intraoperative opioid consumption between groups. However, PSNB significantly reduced the need for rescue opioids within 48 hours (median 0 vs. 50 µg remifentanil equivalents, p=0.007). This was attributed to significantly lower incidences of moderate to severe pain (27% vs. 57%, p=0.01), particularly at the donor site (8% vs. 49%, p<0.001). As expected, there was no difference in pain scores at the resection site. The PSNB group also reported better sleep quality and lower rates of PONV (0% vs. 13.5%, p=0.021). No serious adverse events were observed in either group. Minor side effects in the PSNB group included transient paresthesia (1 patient) and mild headaches (2 patients), all of which were self-limited.

The trial was methodologically robust, employing a randomized controlled design with blinding of patients, care teams (except the block administrator), and outcome assessors. The nerve block was performed by a single experienced clinician using a standardized ultrasound guided technique. Uniform anesthesia protocols and intraoperative management reduced confounding variables. However, several limitations should be acknowledged. Since the PSNB was administered after induction of GA, the study could not clinically confirm a successful nerve block. The administration of multiple medications, both for sedation and analgesia, may also confound the effects of the PSNB. Further, given that patients experience pain at both the resection and donor sites, isolating the opioid-sparing effect of PSNB alone is difficult. Finally, the 48-hour study period did not allow analysis of subsequent opioid use during the remainder of the hospitalization and longer-term opioid use during recovery.

In summary, while preoperative PSNB with LB did not reduce overall perioperative opioid consumption, it was associated with clinically meaningful improvements in donor site pain, reduced use of rescue opioids, lower rates of PONV, and improved sleep quality. These findings suggest that PSNB in conjunction with LB may be an effective adjunct for improving perioperative recovery after complex maxillofacial procedures, and highlight the need for further research to define its role within anesthesia protocols in OMS.

Perioperative LB

LB is a long-acting local analgesic formulated with a sustained-release delivery system to provide prolonged pain management (20-22). It is typically administered via peripheral nerve block or local infiltration during surgery and is often incorporated into multimodal analgesia protocols (19,23,24). Its use has been evaluated in various surgical settings, with particular interest in its potential to reduce postoperative pain and opioid consumption in the first 72 hours after surgery (17,21,24,25). However, systematic reviews and RCTs have demonstrated variable efficacy depending on the procedure and analgesic technique.

The opioid-sparing effects of LB have been well studied but remain inconsistent across surgical disciplines. To date, a number of studies have shown clear benefit. In breast surgery, LB has been associated with significant reductions in opioid consumption in addition to postoperative recovery benefits. In shoulder surgeries such as arthroscopic rotator cuff repair, LB administered via brachial plexus block was associated with decreased cumulative postoperative opioid use (26,27). Finally, in hemorrhoidectomy, LB has been associated with significant reductions in postoperative opioid use and delayed opioid initiation (17). Conversely, the evidence is less favorable in other surgical specialties. In thoracic surgery, LB did not show significant benefit compared to conventional local anesthetics for opioid use or pain control (28,29). Similarly, meta-analyses in total knee arthroplasty (TKA) and total hip arthroplasty found only transient and modest reductions in opioid consumption, without consistent clinical benefit (30,31). These mixed results suggest that the efficacy of LB may be procedure specific rather than providing a universal benefit.

A growing body of literature has explored LB in OMS. A recent review found LB to be generally favorable for reducing postoperative pain and opioid usage across several OMS procedures (32). For instance, in full-arch implant surgery, LB was associated with clinically relevant reductions in opioid use (33). In orthognathic surgery, LB reduced postoperative opioid use from 25 to 9.3 morphine milligram equivalents (MME) with similar effects in patients with cleft lip and palate undergoing orthognathic surgery or alveolar bone grafting (13,18,34,35). In third molar extraction, findings are more variable. One retrospective study found reduced opioid prescriptions (44.9 vs. 109.5 adjusted MME) and refills (3.3% vs. 7.7%) among patients who received intraoperative LB (36). However, another randomized clinical trial in third molar extractions found no significant differences in opioid usage (37). Overall, emerging evidence suggests that LB may reduce postoperative opioid use in OMS, though effect size may vary.

Beyond total opioid consumption, LB may provide other benefits for postoperative recovery such as improved patient satisfaction, sleep quality, reduced length of hospital stay, and fewer postoperative adverse effects. Trials in hemorrhoidectomy, bunionectomy, shoulder surgery, and breast surgery demonstrate improved postoperative pain scores and patient satisfaction (16,17,25-27). In OMS, studies have shown mixed but generally modest benefits. In third molar extractions, parallel-arm studies reported improved pain scores in the LB group (36,37). Split-mouth RCTs have shown variable results. One study found significant pain reduction on the LB side, while another found no significant difference (38,39). In full-arch implant surgery, LB reduced postsurgical pain and improved patient satisfaction, especially the evening after surgery (33). In orthognathic surgery for cleft lip and palate patients, LB was associated with earlier oral intake and increased fluid consumption in the immediate postoperative period (13). Alveolar bone graft patients receiving LB demonstrated increased mobility after iliac crest bone grafting during the first three postoperative days, although hospital length of stay was unchanged (34). Similarly, no difference in length of stay was observed in bimaxillary surgery (18). Additionally, LB generally exhibits a favorable safety profile. Most studies report no increase in adverse events compared to conventional local anesthetics. Reported side effects are typically mild and self-limited, including transient paresthesia, lightheadedness, headache, fever, chills, and constipation (19,21,39-41).

Cost remains a major limitation to widespread adoption of LB. In joint replacement and minimally invasive thoracic lobectomy, LB nearly doubled pharmacy costs without a corresponding improvement in outcomes (29,31,41,42). In the case of TKA, LB increased costs by approximately $300 per operation (31). Evidence in OMS is limited, but surveys suggest cost is a key obstacle as LB is typically not covered by insurance (43,44). While over 75% of patients undergoing third molar extraction expressed interest in LB for its opioid sparing effects, 88% were willing to pay up to only $200, and fewer than 20% were willing to pay current market prices (43,44). High acquisition costs and limited reimbursement thus pose significant barriers to LB adoption.

Donor site analgesia after fibula flap reconstruction

Maxillofacial reconstruction using a fibula flap is a well-established technique for restoring facial form and function. It involves harvesting a segment of the fibula with its vascular pedicle and surrounding soft tissue followed by microvascular transfer to the recipient site (45). Postoperative pain typically peaks within the early postoperative period but may persist for weeks to months (46). Importantly, donor site pain is often more severe than the recipient site and can significantly impact recovery (47).

Regional anesthesia for the lower extremity has consistently reduced pain and perioperative opioid use (47-51). Techniques include popliteal, sciatic, or combined femoral and common peroneal nerve blocks, traditionally performed with continuous infusions of bupivacaine or ropivacaine (8,19,47,50,51). For example, in a randomized trial, donor site ropivacaine nerve blocks reduced opioid use after free flap reconstruction of oral cavity defects (118.4 vs. 166.32 MME) (49). Similarly, Zhang et al. found that femoral and common peroneal nerve blocks with ropivacaine in fibula flap reconstruction reduced the incidence of severe donor site pain (15% vs. 85%) and decreased sufentanil consumption (89.6 vs. 110.4 µg) (47). In another trial, Persson et al. found that continuous popliteal block with levobupivacaine and ropivacaine halved opioid consumption (109 vs. 202 mg) and reduced episodes of breakthrough pain (17% vs. 33%) after fibula flap harvest (50). The safety profile for regional anesthesia techniques is generally favorable, with only rare complications reported (49,50). Currently, utilization of these techniques varies across centers, influenced by institutional protocols, provider expertise, and resource availability.

LB offers several potential advantages compared with continuous catheter-based local anesthetic infusions. As a single injection formulation, it provides analgesia for up to 72 hours without the need for pumps, tubing, or catheter management, thereby eliminating risk of dislodgement or infection. Another benefit includes potentially earlier mobilization without tethering to an infusion system. This is particularly important for fibula flap harvest as patients are typically expected to ambulate with an orthopedic boot on postoperative day 1. In contrast, analgesic efficacy can be limited as LB is not titratable. Furthermore, increased cost is also an issue compared to traditional infusions. Regardless, the simplicity, safety, and reduced resource utilization make LB a promising alternative in certain surgical patients.

Chronic pain has been reported as a potential outcome following fibula flap reconstruction. One study reported that persistent donor site pain in a subset of patients up to two years postoperatively (46). Similarly, de Lange et al. found that 21% of patients who underwent fibula flap harvest developed neuropathic leg pain, and 27% had chronic leg pain, with symptoms such as hypoesthesia, paresthesia, and burning which diminished function and quality of life (52). Moreover, many patients undergo fibula flap reconstruction for oncologic reasons, where the combination of radiotherapy, trismus, and high incidence of hardware issues among others may further exacerbate pain (53-55). These long-term sequelae underscore the need for effective acute pain control strategies to potentially mitigate chronic pain development.

In summary, while the fibula flap is a workhorse reconstructive option, it has been associated with significant perioperative and potentially even chronic pain. Multimodal analgesia including regional nerve blocks can mitigate some of this pain burden, but opioids remain necessary for many patients. These findings highlight the need for continued efforts to optimize pain management strategies in maxillofacial reconstruction, including exploring longer-acting regional techniques such as LB nerve blocks to improve both perioperative recovery and long-term outcomes.

Knowledge gaps & future directions

Wu et al.’s study contributes to the literature surrounding the use of LB for regional anesthesia within multimodal regimens after maxillomandibular free flap reconstruction. However, several key knowledge gaps remain. While LB has been studied in procedures such as third molar extraction, alveolar bone grafting, and orthognathic surgery, its effectiveness in other settings such as facial reconstruction after trauma or pathology remains more sparsely studied (13,32-39). These procedures typically involve severe and more variable pain or multiple surgical sites, both of which may affect LB’s efficacy.

Another gap in the literature is the effect of LB on functional recovery and long-term outcomes. Most studies focus on short-term endpoints such as pain scores and opioid consumption in the first 24–72 hours postoperatively (34,35,37). To date, few studies have addressed broader functional recovery outcomes including return to oral intake, speech, mobility, persistent opioid use, or overall quality of life. Although early improvements in ambulation and oral intake have been reported in orthognathic and alveolar bone grafting procedures, these benefits have not been systematically evaluated in more extensive surgeries (13,34). Further, important logistical considerations remain regarding optimal dosing, timing, and route of administration of LB, particularly within existing pain protocols. As a result, it remains unclear how LB can best optimize functional recovery in other OMS procedures, or whether short-term improvements translate into sustained long-term benefits.

In summary, the use of LB in maxillofacial reconstruction and OMS as a whole is promising but nascent. Addressing the above knowledge gaps will require procedure-specific clinical trials that evaluate not only analgesic efficacy, but also long-term recovery, patient outcomes, and economic feasibility. Such data will represent the cornerstone of evidence-based guidelines and perioperative pathways for patients undergoing both ambulatory and major OMS procedures.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Oral and Maxillofacial Anesthesia. The article has undergone external peer review.

Peer Review File: Available at https://joma.amegroups.com/article/view/10.21037/joma-2025-1-35/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-2025-1-35/coif). D.A.K. had received payment for lecture for facial pain from Massachusetts Dental Society. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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