Introduction

Orthopedic procedures have increased globally due to several factors, including an aging population, advances in surgical techniques and the introduction of new technologies. For instance, the absolute number of hip fracture surgery increased rapidly between 2012 and 2016,¹ and a previous study has indicated that the incidence of hip fractures is expected to increase to more than 1 million annually by 2050 in the USA.² Meanwhile, the number of knee arthroplasty procedures increased by 32.2% between 2012 and 2018 in France.³ Orthopedic procedures are strongly associated with severe postoperative pain and subsequently significant opioid consumption.^4,5 Even arthroscopic rotator cuff repair could give rise to pain that persists from 8 to 16 hours.⁶ Moderate-to-severe pain has been reported even in foot and ankle surgery, the most severe of which occurring up to 3 days postoperatively.⁷ Inadequate analgesia would be even expected to develop chronic postsurgical pain lasting up to a year and increase the rate of occurrence of chronic postoperative pain after a year.⁸ Thus, multimodal analgesia has become one of the effective alternative methods of pain management.⁹ Peripheral nerve blocks (PNBs) are an important component of multimodal analgesia regimens, especially in orthopedic surgery,¹⁰ as regional anesthesia block the nociceptive signal transmission in sensory neurons prior to its start.¹¹ PNBs are commonly used to decrease total and rescue opioid consumption, offer comfortable postoperative care settings, improve analgesic outcomes and shortens hospital length of stay.^10,12,13 Both single-shot PNBs and continuous PNBs are effective for postoperative pain. Although continuous PNBs are increasingly used, there are some limitations including infectious risk, local anesthetic systemic toxicity and the requirement for precise catheter placement.^14–16 As for the length of duration, single-shot PNBs are shorter than continuous PNBs, which is the main limitation of single-shot approach.¹⁷ Researchers found adjuvants, such as dexamethasone, could be added to the local anesthetic to prolong the duration of sense block by 6 to 8 h.¹⁸ However, when the analgesic effect of single-shot blocks wears off, it often leads to a phenomenon of rebound pain, which could increase in opioid consumption, hamper patient satisfaction and rehabilitation.¹⁹ Chan et al reported that conventional bupivacaine carried a high risk of rebound pain upon discontinuation.²⁰ To address these limitations, extended-release local anesthetics such as liposomal bupivacaine (LB) have emerged as a promising alternative in single-shot PNBs.

Liposomal bupivacaine (LB), encapsulated by lipid-based particle layers and slowly released into the surrounding tissue,²¹ can provide analgesia lasting up to over 72 h, longer than the duration of the analgesic effect of plain bupivacaine hydrochloride (PB) (<24 hours).^22,23 Liposomal bupivacaine was first approved by the Food and Drug Administration (FDA) in 2011 for postoperative pain management in surgical infiltration and transversus abdominis plane block (TAP) at doses up to 266 mg. In 2018, the FDA Anesthetic and Drug Products Advisory Committee authorized the requisition of liposomal bupivacaine for a new indication for interscalene brachial plexus block regimens.^24,25 Since then, liposomal bupivacaine has been approved for even more indications, such as field block infiltration, brachial plexus block and femoral nerve block, adductor canal block and sciatic nerve block in the popliteal fossa.^26,27 Consequently, the number of published trials focused on perineural liposomal bupivacaine in orthopedic surgery is substantially increasing.

Although previous meta-analyses have concluded that liposomal bupivacaine is not clinically superior to bupivacaine hydrochloride regardless of the regional anesthesia technique used,^26,28 no published data are available on the effective of perineural liposomal bupivacaine in orthopedic surgery. Since this meta-analysis exclusively focuses on RCTs evaluating perineural LB in orthopedic procedures to minimize heterogeneity.

The aim of our meta-analysis is to evaluate whether liposomal bupivacaine for peripheral nerve block provides superior efficacy compared to bupivacaine hydrochloride in orthopedic procedures, as demonstrated by high-quality randomized controlled trials (RCTs). We assessed postoperative pain scores and opioid consumption as the primary outcomes and importantly focused on the potential clinical efficacy of liposomal bupivacaine. Our findings may guide clinicians in selecting optimal nerve block agents to balance analgesia efficacy and opioid-sparing effects.

Material and Methods

Study Design and Registration

We searched for RCTs involving orthopedic surgery to evaluate the analgesic effect of liposomal bupivacaine and compare it with standard bupivacaine after a nerve block. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.²⁹ The meta-analysis protocol was registered on 27 October 2024 on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024600643).

Search Strategy

A detailed literature search was performed on EMBASE, PubMed, Web of Science, Scopus, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews to identify eligible studies published in print or online. The search strategy included MeSH and exploded terms related to liposomal bupivacaine, nerve block and postoperative analgesia; the last search was conducted on 11 October 2024. We also searched the reference lists of all the retrieved articles and reviewed them as supplemental trials. We employed the PICOS strategy as follows: P (patients) were defined as adult patients who underwent orthopedic surgery; I (intervention) was defined as peripheral nerve block with LB. C (comparison/control) was defined as peripheral nerve block with PB. O (outcome) was defined as pain reduction, opioid consumption, duration of analgesia, patient satisfaction and adverse events. S (study design) was the only RCTs that satisfied our inclusion criteria. During the actual search, we ignored the specificity of P, C and O to avoid missing relevant studies.

Eligibility Criteria

The inclusion criteria were as follows: 1) adult patients (≥18 years of age); 2) orthopedic surgery; 3) single-injection peripheral nerve block with liposomal bupivacaine and/or plain bupivacaine; 4) a control group consisting of patients treated only with bupivacaine hydrochloride; and 5) a study type of RCT.

The exclusion criteria were as follows: 1) unavailable full text; 2) non-orthopedic surgery; 3) perineural adjuvants other than epinephrine; 4) infiltration techniques and/or field block with liposomal bupivacaine; and 5) continuous nerve block. No limitations on publication language were set.

Study Selection and Data Extraction

Two reviewers (Dr. Wan and Dr. Meng) independently searched the titles and abstracts on 13 October 2024 in Endnote 21. The full-text versions of eligible studies were then retrieved, and any duplicates were removed. The same reviewers evaluated the studies for potential inclusion, and any discrepancies were settled by a third reviewer (Dr. Xi). A pilot-tested extraction form was created by one of the reviewers (Dr. Wan) in Microsoft Excel for Mac, V.16.9. Data from the included studies were subsequently extracted by two independent reviewers (Dr. Wan and Dr. Xi). Any discrepancies in this process were discussed between the two reviewers or resolved by a third reviewer (Dr. Liang) until a consensus was reached. The collected information included the study authors, publication year, sample size, type of nerve block, type of surgery, surgical anesthetic, time of nerve block, dose and volume administered to the control group and intervention group, postoperative multimodal analgesia, primary outcomes, resting and dynamic pain scores, postoperative opioid consumption, liposomal bupivacaine-related adverse effects, duration of nerve block, patient satisfaction, length of hospital stay, functional recovery and quality of life outcomes. To facilitate the quantitative analyses, any median values and their interquartile ranges (IQRs) from the included studies were converted to means and standard deviations (SDs).

Risk of Bias Assessment and GRADE

The risk of bias (RoB) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) were independently assessed by two reviewers (Dr. Wan and Dr. Wu). The RoB was assessed with the Cochrane Risk of Bias Tool V.2.0³⁰ according to five aspects: 1) bias related to the randomization process; 2) bias due to deviations from the intended interventions; 3) bias due to missing outcome data; 4) bias in the measurement of the outcome; and 5) bias in the selection of the reported result. One of the four options can be selected for each of these aspects: “yes” “probably yes” “probably no” “no” and “no information.” For those studies that did not provide a sufficiently detailed methodology, we considered them to have an “unclear risk of bias”. The overall risk of bias was calculated by the system based on the summary of the five different domains. If the study was judged to have a high risk of bias in at least one of these domains, it was considered to have an overall high risk of bias. Any discrepancies in the quality assessment were ultimately resolved by a third reviewer (Dr. Xi).

GRADE was performed with the online Guideline Development Tool (GRADEpro GDT) to assess the quality of outcomes. According to the GRADE system, the quality of evidence was initially classified as high or low on the basis of whether the outcomes were derived from an experimental or observational trial; subsequently, the level of evidence was classified as high, moderate, low, or very low by considering five different factors.³¹ In accordance with our prespecified criteria, the initial quality was high, because the included studies were all experimental trials.

As liposomal bupivacaine prolongs the duration of regional analgesia (up to 72 hours) over plain bupivacaine,³² the primary outcomes were the mean pain scores according to a numeric rating scale (NRS) ranging from 0 to 10 (no pain to the worst pain imaginable, respectively) from 24 hours to 72 hours postoperatively. To evaluate the analgesic efficacy of the drugs more comprehensively, we also designated the postoperative oral morphine equivalents (OMEs) consumed each day from 24 hours to 72 hours postoperatively as another primary outcome.

The secondary outcomes included the duration of nerve block, incidence of nerve block-related adverse events, patient satisfaction, length of hospital stay, motor function and postoperative quality of recovery. All data related to time were measured in hours.

Statistical Methods

Continuous data, including pain scores and OMEs, are presented as the means ± SDs. The medians and IQRs or ranges were converted to estimated values of the means and SDs if the latter were unavailable from the original articles.^33,34 According to the Cochrane handbook, if the mean and 95% confidence interval (CI) were provided, the data were also converted to the mean and SD. Data from graphs were extracted with GetData Graph Digitizer version 2.24. In some cases, unavailable SDs were estimated as the average SD across similar studies.³⁵ We also contacted the authors of the included studies to obtain as much missing but potentially useful original data as possible.

Heterogeneity was assessed according to the P and I² values,³⁶ in which I² > 50% indicated significant heterogeneity. For primary outcomes with high heterogeneity, we performed subgroup analysis or excluded one specific study with confounding factors at a time to determine the source of heterogeneity. As different evaluation systems may be used in individual studies, some heterogeneity is expected. Consequently, a random-effects model was used to eliminate the influence of this heterogeneity. If I² < 50% with low heterogeneity, a fix-effects model could be used. In addition, we conducted sensitivity analyses for the primary outcomes. Leave-one-study-out analysis and Egger’s regression³⁷ were carried out in StataCorp Stata version 18.0 for Mac.

For continuous outcomes, the weighted mean difference (WMD) was used to weigh the effect size for pain scores and OMEs, and statistical pooling was performed using the inverse variance method due to the presence of experimental heterogeneity. For dichotomous outcomes, the risk ratio (RR) was calculated, and statistical pooling was performed using the Mantel–Haenszel random effects model.³⁸ Forest plots were created to visualize and evaluate the analgesic effects of the different studies. All results were depicted as the 95% CI, and a two-tailed P value of <0.05 was considered to indicate statistical significance. In this meta-analysis, calculations and graphics were generated with Review Manager Software for Mac 5.4 (Nordic Cochrane Centre, The Cochrane Collaboration 2020, Copenhagen, Denmark). The risk of publication bias was assessed by examining the results of Egger’s regression test for the primary endpoints.

In addition, the definition of a minimal clinically meaningful change in the pain score can differ in different studies;^39–43 thus, a minimum difference of 2.0 points on a 0–10 scale was considered clinically relevant in this meta-analysis. For postoperative opioid consumption, a minimum 30-mg difference in OME consumption was considered clinically relevant.^26,28

Trial Sequential Analysis

Trial sequential analysis (TSA) allows quantification of the statistical reliability of the data in the overall meta-analysis and was used here to assess the reliability of the primary outcomes. The strength of available evidence as assessed by TSA can determine the required information size (RIS) for an expected meta-analysis.

TSA was performed using software developed by the Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.^44,45 Because the DerSimonian‒Laird (DL) estimator tends to underestimate between-trial variance, the Biggerstaff and Tweedie (BT) random-effects model was applied.^46,47 A two-sided α of 0.05 and β of 0.2 with a power of 80% were used to calculate the RIS, and heterogeneity was corrected for variance-based.

Results

Study Characteristics

We identified 2386 publications through a search of the aforementioned databases and 9 publications through manual searches of the reference lists of related literature reviews, for a total of 2395 studies. After removing duplicates and screening based on the titles and abstracts, 169 reports with available full text were assessed for eligibility. Ultimately, ten RCTs^{5–7,48–54} were included in this systematic review. The flow diagram for study inclusion is shown in Figure 1. A grid depicting the risk of bias assessment is depicted in Figure 2. Five studies were rated as having low overall risks of bias. In particular, two reports noted that their funding was provided by pharmaceutical companies.^7,48

Figure 1 PRISMA 2020 Flow Diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PRISMA figure adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021 Mar 29;10(1):89.55

Figure 2 Risk of Bias Assessment for Included Studies.5–7,48–54

The baseline characteristics of the patients and the main outcomes of the ten included studies are summarized in Table 1 and Table 2, respectively. A total of 782 patients were enrolled, 60.9% (n = 476) of whom were female, and the average age was 58.75 years. Eight of the ten included studies were from the USA,^{5–7,49–52,54} one was from China,⁵³ and one was from Belgium.⁴⁸ The types of orthopedic surgery included total shoulder arthroplasty,^48,49,51,52 rotator cuff repair,^6,48 total knee arthroplasty,^50,54 hip arthroscopy,⁵ distal metaphyseal osteotomy,⁷ and distal radial fracture fixation.⁵³ The types of peripheral nerve block used included brachial nerve block,^{6,48,49,51–53} adductor canal block,^50,54 fascia iliaca blockade,⁵ and sciatic nerve block in the popliteal fossa.⁷ Owing to different operative sites involved, the volume of perineural liposomal or plain bupivacaine varied from 15 to 40 mL. Two doses of liposomal bupivacaine were used: 133 mg or 266 mg. Except for two studies^7,50 in which liposomal bupivacaine alone was used in the experimental groups, a mixture of plain and liposomal bupivacaine was administered to the patients. Regarding basic anesthesia, the majority of the included patients underwent general anesthesia, and some studies were designed with field block^7,53 or spinal anesthesia⁵⁴ as background technologies.

Table 1 Characteristics and Analgesic Regiments of Included Studies

Table 2 Outcomes of Included Studies

Primary Outcomes

Mean Pain Score at 24 Hours

All ten studies^{5–7,48–54} included in this meta-analysis (769 patients) reported pain scores 24 hours after surgery. One trial⁷ failed to be included in statistics because of a different measuring unit. The liposomal bupivacaine group did not have significantly lower pain scores than the control group from 0 to 24 hours (MD = −0.72, 95% CI: [−1.51, 0.06], P = 0.07; GRADE: moderate; Figure 3). The heterogeneity was high, with an I² of 91%. As shown in Figure 3, pooled weighted mean differences with 95% CIs; diamonds represent effect estimates and lines indicate the confidence intervals. By the method of leave-one-out analysis, we found the sources of heterogeneity from Chan et al,⁵³ excluding this trial (MD = −0.48, 95% CI: [−1.06, 0.09], P = 0.10; I² = 62%).

Figure 3 Forest plot of mean pain scores after 24 hours.5–7,48–54

Mean Pain Score at 48 Hours

Nine studies^{5–7,48–51,53,54} included in this meta-analysis (744 patients) reported pain scores 48 hours after surgery. One trial⁷ failed to be included in statistics because of a different measuring unit. The liposomal bupivacaine group had statistically lower pain scores than the control group from 24 to 48 hours (MD = −0.86, 95% CI: [−1.19, −0.45], P < 0.001; GRADE: moderate; Figure 4). The heterogeneity was low, with an I² of 44%.

Figure 4 Forest plot of mean pain scores after 48 hours.5–7,48–51,53,54

Mean Pain Score at 72 Hours

Eight studies^{5–7,48–51,53} including 676 patients reported pain scores at 72 hours after surgery. One trial⁷ failed to be included in statistics because of a different measuring unit. Compared with the control group, the liposomal bupivacaine group had statistically lower pain scores from 48 to 72 hours (MD = −0.38, 95% CI: [−0.54, −0.21], P < 0.001; GRADE: moderate; Figure 5). Regrettably, this difference failed to meet the standard of clinical importance. The heterogeneity was low, with an I² of 4%.

Figure 5 Forest plot of mean pain scores after 72 hours.5–7,48–51,53

Opioid Consumption at 24 Hours

Seven trials^{5–7,48,50,51,54} including 567 patients reported OME consumption from 0 to 24 hours postoperatively. No significant difference was identified between the two groups (MD = −1.50, 95% CI: [−3.65, 0.66], P = 0.17; GRADE: moderate; Figure 6). The heterogeneity was high, with an I² of 78%. After one study⁴⁸ that reported industry funding was excluded, statistically significant differences were detected by a fixed-effects model (MD = −2.45, 95% CI: [−3.66, −1.24], P < 0.001, I² = 46%; GRADE: high). However, this difference was not clinically relevant.

Figure 6 Forest plot of opioid consumption after 24 hours.5–7,48,50,51,54

Opioid Consumption at 48 Hours

Seven trials^{5–7,48,50,51,54} including 566 patients reported OME consumption from 24 to 48 hours postoperatively. The difference between the two groups was significant (MD = −5.51, 95% CI: [−9.97, −1.06], P = 0.02; GRADE: moderate; Figure 7). The heterogeneity was high, with an I² of 93%. After excluding the study by Vandepitte et al,⁴⁸ which reported industry funding, patients treated with LB were shown to have consumed significantly less OMEs than those treated with PB according to a fixed-effects model (MD = −5.53, 95% CI: [−6.96, −4.11], P < 0.001, I² = 50%; GRADE: high). However, this difference was not clinically relevant.

Figure 7 Forest plot of opioid consumption after 48 hours.5–7,48,50,51,54

Opioid Consumption at 72 Hours

Seven trials^5-7,48–51 including 596 patients reported OME consumption from 48 to 72 hours postoperatively. The difference between the two groups was significant (MD = −3.62, 95% CI: [−6.04, −1.21], P = 0.003; GRADE: moderate; Figure 8). The heterogeneity was high, with an I² of 78%. After one study that reported industry funding was excluded, notably fewer OMEs were consumed by LB-treated patients than by PB-treated patients when a fixed-effects model was used (MD = −4.16, 95% CI: [−5.39, −2.93], P < 0.001, I² = 14%; GRADE: high). Regrettably, this difference failed to meet the threshold of clinical importance.

Figure 8 Forest plot of opioid consumption after 72 hours.5–7,48–51

Secondary Outcomes

Length of Stay

Four trials^5,49,50,54 including 305 patients reported the length of stay, one of which⁴⁹ was excluded due to missing detailed data. No significant difference was found between the two groups according to a fixed-effects model (MD = −0.32, 95% CI: [−1.51, 0.86], P = 0.59, I² = 31%; GRADE: moderate).

Patient Satisfaction

Six studies^7,48–51,53 (532 patients) involving different reporting tools provided data on patient satisfaction with analgesia. Vandepitte et al⁴⁸ reported the Overall Benefit of Analgesia Score (OBAS) to assess satisfaction with pain treatment. Patients given liposome bupivacaine reported lower total scores than those given plain bupivacaine, indicating greater benefits from the former (difference, 1.4 ± 0.5; 95% CI, 0.5–2.4). A 10-point scale, with 10 being the highest level of comfort, was used to measure patient satisfaction in three included studies,^7,49,50 all of which reported similar scores between the two groups. Chan et al⁵³ also evaluated patient satisfaction with the OBAS and reported that patients given liposomal bupivacaine had significantly lower scores than patients given plain bupivacaine in the first 48 hours.

Duration of Nerve Block

We extracted the duration of sensory block data from three studies^5,7,51 involving 309 patients. We defined the outcome as the ratio of thigh numbness reported at postoperative 72 hours. The results of the meta-analysis revealed significant differences between the two groups both when the nerve block duration was treated as a dichotomous^5,7 (RR = 3.35, 95% CI: [1.92, 5.84], P < 0.001 I² = 0; GRADE: moderate) and a continuous variable⁵¹ (geometric mean 24.3 ± 0.9 hours vs 39.9 ± 0.6 hours, P < 0.001).

Motor Function

Four studies^7,48,50,53 involving 356 patients reported the outcome. Hubler et al⁵⁰ reported gait velocity through a 10-meter walk test on postoperative day 1 as the primary outcome of the efficacy of LB (0.46 ± 0.32 m/s) versus PB (0.52 ± 0.26 m/s) and found no significant difference between the two groups (P = 0.271). Vandepitte et al,⁴⁸ Hubler et al⁵⁰ and Chan et al,⁵³ meanwhile, reported muscle power according to extension strength, but none reported a significant difference between the two groups. Schwartz et al⁷ assessed the duration of motor block prior to restoration of complete foot movement and similarly did not report significant differences between the groups. Because different assessments were performed for motor function in these studies, these data failed to be analyzed.

Quality of Life Outcomes

Only two studies^6,53 reported the results of the quality of recovery (QoR) test. Chan et al⁵³ found no statistically significant difference between the two groups after the first 48 hours postoperatively. However, an improved QoR was reported after 72 hours (114.3 ± 19.0 vs 125.8 ± 15.9) for patients given liposome bupivacaine over plain bupivacaine by Flaherty et al.⁶

Nerve Block-Related Adverse Effects

Eight studies^{5–7,48,50–53} with 594 patients reported complications of the nerve block. No significant difference was identified between the two groups (RR = 1.15, 95% CI: [0.82 1.62], P = 0.41, I² = 29%). Some common adverse effects included nausea and vomiting (LB 16.0% vs PB 20.6%), shortness of breath (LB 6.2% vs PB 3.0%), falling while standing unassisted (LB 5.1% vs PB 1.9%), and dizziness (LB 4.1% vs PB 4.8%). In addition, three studies^6,7,48 reported serious adverse events, including symptoms of systemic toxicity and neurological complications. Berg et al⁵² did not report any adverse events in their trials. No deaths occurred in all included trials.

Sensitivity Analysis and Publication Bias

A sensitivity analysis regarding all primary endpoints was performed. The results, shown in online Supplemental Content 1, indicated robustness to the exclusion of any single study at a time. The risk of publication bias was low for any point-in-time we included (P = 1.00).

TSA

The results of the TSA for the mean pain score at postoperative 24 hours are presented in online supplemental content 2. In this meta-analysis, the 606 included patients did not meet the requisite sample size of 890 patients at postoperative 24 hours. The cumulative Z curve crossed the conventional boundary (Z = 1.96; P = 0.05) but failed to cross the O’Brien–Fleming boundary. The power of the present meta-analysis therefore indicated that more trials are needed to make valid conclusions.

Discussion

This systematic review and meta-analysis of RCTs demonstrated that the efficacy of liposomal bupivacaine significantly differed from that of plain bupivacaine, especially in the first 72 hours postoperatively. However, no clinically relevant differences were found, which aligns with the findings of previous meta-analyses.^26,28 The lack of standardization in experimental designs and outcome measurement as well as the exclusion of studies funded by industries or institutions may have contributed to the reported lack of clinical effectiveness for liposomal bupivacaine. Therefore, further large-scale clinical trials are needed to evaluate the effectiveness of liposomal bupivacaine and form the standardized rating indicators including pain scores, patient satisfaction scores and motor function.

Postoperative Pain

The primary outcomes of this meta-analysis demonstrate the statistically greater efficacy of perineural liposomal bupivacaine over plain bupivacaine after postoperative 48 hours, but the difference was not clinically relevant. Similarly, an increasing number of randomized controlled trials have reported that liposomal bupivacaine does not seem to present advantages over plain bupivacaine in terms of postoperative analgesia effects. Besides, no significant reduction in pain scores was observed over the first 72 hours after shoulder arthroplasty. Similar results⁵⁵ were obtained following the injection of periarticular Exparel compared with plain bupivacaine, which did not demonstrate clinically relevant differences in the visual analog scale (VAS) pain scores for the first 96 hours after knee arthroplasty. Moreover, the use of liposomal bupivacaine alone could lead to worse pain scores early in the postoperative period because the local anesthetic exhibits limited activity.⁵⁶ Although these trials demonstrated that liposomal bupivacaine is not superior to plain bupivacaine in controlling postoperative pain, it should be noted that the drugs were predominantly administered via infiltration techniques or field block instead of nerve block in the strictest sense. Notably, a triple-blinded pharmacodynamic study⁵⁷ demonstrated that volunteers receiving plain bupivacaine did not consistently perceive residual blockade, whereas those given liposomal bupivacaine experienced intermittent episodes of sensory loss alternating with normal sensation, potentially indicating incomplete or inconsistent sensory and motor blockade. Moreover, among the published studies and indications, most uses of perineural liposomal bupivacaine in orthopedic surgery involved larger nerves rather than smaller nerves. A potential explanation is that the use of liposomal bupivacaine is characterized by an extended duration of loss of sense and motion, leading to aggravated discomfort and delayed convalescence, which is more notable for smaller peripheral nerves. In addition, we noticed one form of postoperative pain following nerve block resolution is rebound pain, described by a delayed increase in patient-reported pain scores, often accompanied by increased analgesic consumption, corresponding to the resolution of the analgesic effect of single-injection blocks.¹⁹ The structure of liposomal bupivacaine allows the steady release of anesthetic medication for up to 72 hours. We also hypothesized that according to existing theories on its functioning, the liposomal bupivacaine used in nerve block could reduce the occurrence of postoperative rebound pain in orthopedic surgery by prolonging the duration of the nerve block, helping decrease opioid rescue and achieve satisfactory pain management. Therefore, the optimal nerve block sites for liposomal bupivacaine, which balance postoperative analgesia with motor function, need to be further explored.

Opioid Consumption

To evaluate the analgesic effect, the opioid consumption was another important outcome. For liposomal bupivacaine, the reduction of postoperative narcotic consumption was considered a potential superiority, especially after postoperative 48 hours. Four included studies^7,50,51,54 demonstrated the lower total opioid consumption in the early postoperative period, but all of them failed to meet the clinical threshold of difference. However, five included studies^5,6,48,49,53 found the total opioid consumption postoperatively did not statistically differ between two groups. Chan et al⁵³ considered that decreasing pain intensity was insufficient to affect outcomes such as postoperative opioid consumption and quality of recovery, chronic pain, upper limb functional scores, and health-related quality of life scores. Namdari et al⁵⁸ reported that treated with interscalene brachial plexus blockade, patients administered Exparel significantly required more postoperative narcotics. These differences of results among the included studies can be attributed to several factors, including patient demographics, surgical procedures and anesthetic protocols. For instance, age is an important factor leading to clinical differences in the sensation of postoperative pain. A retrospective cohort study⁴³ reported that older patients were insensitive to pain when performing activities in bed, breathing deeply, coughing, sleeping, and experiencing side effects and severe emotions and were unwilling to receive more treatment, including opioids. Furthermore, the type of surgery is a crucial determinant of pain intensity. Major procedures such as hip arthroplasty or spinal surgery were generally associated with high pain scores,⁵⁹ probably resulting in more opioid consumption. Given these observations, establishing uniform criteria for patient selection, types of surgery, and outcome measures will be critical in reducing heterogeneity and enhancing the comparability of results. Additional RCTs with large sample sizes are essential to better determine whether perineural liposomal bupivacaine has any clinical effects of postoperative pain improvement in orthopedic surgery.

Nerve Block-Related Adverse Effects

As an important part of secondary outcomes in this meta-analysis, there was no statistical difference between two groups. Only one study⁶ indicated there were more cases of complications in the liposomal bupivacaine group. For upper extremity surgery, Vandepitte et al,⁴⁸ Elmer et al⁵¹ and Flaherty et al⁶ reported shortness of breath associated with nerve block in both groups. These complications including shortness of breath, numbness in the affected extremity, and Horner’s syndrome are block-related with and without the addition of LB.⁶⁰ However, two cases of falls in LB group were reported by Flaherty et al,⁶ for which additional studies are required to determine whether liposomal bupivacaine contributed. For lower extremity surgery, Purcell et al⁵ and Hubler et al⁵⁰ reported falls associated with nerve block in both groups. Xing et al⁶¹ also found 22% of patients who received femoral nerve block reported falls compared with 0% in placebo in the first postoperative day. This complication may be due to muscle weakness and numbness, in combination with narcotics of a general anesthetic.⁶² As for liposomal bupivacaine, it may prolong motor and sense blocks resulting to increase the risk of falls. Therefore, nerve block with or without the addition of LB must be used with caution to decrease the incidence of adverse events.

Economic Problems

According to the secondary outcomes such as length of hospital stay and the duration of nerve block in this meta-analysis, the total cost of hospitalization could not be ignored between two groups. Evaluating the actual clinical importance of liposomal bupivacaine is challenging because of the significant publication bias and that related to industrial fundings. According to McCann et al,²⁴ Pacira Biosciences developed a massive market for Exparel in 2013. The financial report of this company revealed that sales of liposomal bupivacaine increased by one quarter in 2019 over 2018. Our meta-analysis included two studies sponsored by industrial or departmental funding. After these studies were excluded, the degree of statistical heterogeneity was notably decreased. In addition, for the clinical application of new drugs, expenses such as direct costs and health care costs must be considered. Gailey et al⁶³ considered that liposomal bupivacaine utilization could shorten the length of stay and duration of recovery, thus reducing overall hospital expenditures. Critically, the lack of clinical importance of the outcomes for Exparel was ignored, as were the extremely higher per-dose costs associated with liposomal bupivacaine ($334) than with nonliposomal bupivacaine ($3) in the USA. Consequently, future studies should focus on a comparison of the medical expenditures related to liposomal bupivacaine versus plain bupivacaine.

Strengths and Limitations of the Study

First, this is a comprehensive systematic review and meta-analysis of RCTs evaluating the potential clinical value of perineural liposomal bupivacaine. Our inclusion criteria were strict and precise to ensure that the results were sufficiently convincing. Second, for those outcomes with high levels of heterogeneity, we attempted to eliminate the heterogeneity and identify its sources. Third, to draw valuable conclusions and provide future directions in this field, we performed a TSA. The meta-analysis for pain scores at 24 hours was not conclusive because the required sample size was not reached. Therefore, additional RCTs are required in the future.

Our meta-analysis also has several potential limitations. First, owing to the limited number of studies, we failed to perform subgroup analyses including liposomal bupivacaine alone or in combination with bupivacaine hydrochloride, different surgical type and block site. If more RCTs have been included, the subgroup analyses would be more precise. Second, the dosing regimens (eg, 133 mg vs 266 mg) differed across the ten clinical studies because of the type of operation. However, the relatively low heterogeneity undermined this possibility. Third, the disparate multimodal analgesia regimens used in the included studies may have influenced the outcomes of the nerve blocks. Finally, we only assessed the main outcomes over three days after surgery, and additional, longer-term follow-up studies are needed to better assess motor function recovery, chronic pain status, opioid dependence, and health-related quality of life postoperatively.

Conclusion

Current evidence suggests that existing RCTs in patients undergoing orthopedic surgery are insufficient to support the use of liposomal bupivacaine as a clinically meaningful alternative to bupivacaine hydrochloride for postoperative pain management. Although some statistically significant differences were observed in pain scores and opioid consumption, these differences did not meet the thresholds for clinical importance. Overall, liposomal bupivacaine did not demonstrate clinically relevant advantages over bupivacaine hydrochloride in terms of analgesia. Given the high cost, further studies need to specifically consider which types of orthopedic surgery are more suitable for the use of perineural liposomal bupivacaine.