Liposomal bupivacaine in peri-articular injection reduces opioid consumption and improves early prognosis of total knee arthroplasty: a randomized controlled trial

Abstract

Background

Total knee arthroplasty (TKA) has become a common surgical procedure for alleviating pain caused by end-stage osteoarthritis and improving joint dysfunction, but the optimal postoperative analgesic regimen remains controversial. This study aimed to evaluate the efficacy and safety of liposomal bupivacaine(LB) for peri-articular injection (PAI) in TKA, focusing on its impact on early postoperative outcomes, and comparing it with traditional ropivacaine hydrochloride (RH).

Methods

From February to June 2025, 121 patients undergoing total knee arthroplasty at Qingdao University Affiliated Hospital were enrolled. This single-center, parallel-group, double-blind study randomly assigned patients in a 1:1 ratio using a random number table to the LB or RH group. Prime outcomes include the visual analogue scale (VAS) within 72 h after surgery and the consumption of opioid drugs. Secondary outcomes comprised postoperative knee range of motion (ROM), time to first ambulation (TFA), Timed Up-and-Go (TUG) test, 2-minute walk test(2MWT), length of hospital stay (LHT), and postoperative adverse events.

Results

Demographic and clinical characteristics were comparable between groups. The LB group demonstrated lower postoperative pain scores and opioid consumption. Additionally, LB group patients exhibited markedly greater joint range of motion and earlier time to first ambulation compared to the RH group. The incidence of adverse events was similar between groups. One patient in the LB group and two in the RH group experienced early postoperative complications, none of which were considered related to analgesic selection.

Conclusion

This study demonstrates that LB may alleviate postoperative knee pain, reduce the consumption of opioid drugs, and thereby facilitate recovery.

Trial registration

Clinicaltrials.gov. Identifier ChiCTR2400082998, 12/04/2024.

Introduction

Total knee arthroplasty (TKA) has become one of the primary surgical interventions for alleviating severe knee pain and improving end-stage knee joint damage [1].Pain management following total knee arthroplasty remains a challenging yet critical component, significantly impacting surgical success. Effective postoperative pain management directly influences limb recovery and overall patient satisfaction [2–5]. Inadequate postoperative pain management may lead to increased opioid use, heightened incidence of nausea and vomiting, delayed ambulation increasing the risk of deep vein thrombosis, and prolonged hospital stays.

Clinical practice guidelines recommend multimodal analgesia (MMA) [6] combining preoperative, intraoperative, and postoperative medications, utilizing low doses of multiple drugs with different mechanisms of action to maximize pain control while minimizing side effects. Multimodal analgesia is central to pain management under the ERAS concept [6, 7], with analgesic measures initiated preoperatively and extending throughout the intraoperative and postoperative periods. Analgesic modalities can be categorized into central analgesia, regional analgesia, local analgesia, and systemic analgesia. Commonly used approaches include oral or intravenous analgesics, epidural analgesia (EDA), patient-controlled epidural analgesia (PCIA) [8], and periarticular injection of local anesthetic (PAIs). A frequently employed modality in multimodal pain management is PAIs. PAIs presents an attractive approach for providing analgesia at the surgical site with minimal systemic side effects. Studies demonstrate that [9] PAIs significantly improves pain relief and reduces opioid consumption. Adductor canal block (ACB) is effective for postoperative pain management in TKA, causing minimal motor blockage but carrying a risk of rebound pain after block resolution. PAIs can provide analgesia for knee regions not covered by ACB. MMA combining ACB with PAIs is an effective strategy for improving postoperative pain after TKA [10, 11].However, the efficacy of MMA protocols typically begins to decline 12 to 24 h postoperatively. To provide prolonged analgesia, we introduced liposomal bupivacaine for periarticular injection [12].

Numerous studies have evaluated the efficacy of LB in hospitalized patients undergoing TKA. Some studies report advantages, while others do not. For example, Mont et al. reported that [12–14] periarticular injection of LB provided superior pain control at 6 and 12 h post-TKA. Lima et al. demonstrated that [15] LB significantly reduced toxicity and adverse reactions compared to conventional local anesthetics. Conversely, Bagsby et al. found that [16, 17] periarticular injection of LB offered no clear advantage in postoperative pain management.

In attempting to reconcile these conflicting findings, we identified various differences in study design and methodology across the literature, including variations in infiltration techniques, opioid usage, and pain assessment methods—all of which could contribute to divergent outcomes. Therefore, we designed and conducted this study to compare the efficacy of periarticular injection of LB versus our institution’s conventional RH in alleviating pain and reducing opioid consumption within 72 h post-primary TKA.

Methods

Study design

This study aimed to evaluate the efficacy of LB versus o our institution’s conventional RH in primary TKA. Patients were randomly assigned to the LB group or RH group. All patients provided written informed consent prior to participation. Patients were unaware of their group assignment. This study adhered to the ethical principles of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of The Affiliated Hospital of Qingdao University (QYFY WZLL 30888) and registered with the (ChiCTR2400082998). All patients were managed postoperatively using standardized MMA pathways as depicted in Fig. 1. Following surgery, patients were provided with a patient-controlled analgesia pump containing morphine for opioid analgesia.

Fig. 1.

Multimodal analgesic pathway used for all patients during the study period. PRN = pro re nata (as needed), IV = intravenous, IP=Intravenous pumping, SJ=Subcutaneous injection, PACU = post-anesthesia care unit

Sample size calculation

The sample size was determined based on the total MME [18] consumption of the LB and RH groups within 72 h after surgery, as observed in the preliminary study conducted from November to December 2024. With a significance level of α = 0.05 and a power of 1-β = 0.80, the analysis revealed that each group requires 46 participants. Considering an anticipated 10% dropout rate, the target enrollment increased to 50 patients per group, resulting in a total sample size of 100 participants to meet the requirements of the power analysis.

Patients

Adult patients presenting with knee pain, difficulty in daily activities, radiographically diagnosed stage IV knee osteoarthritis, and undergoing primary total knee arthroplasty were enrolled. All patients received a MMA regimen comprising preoperative nerve block anesthesia, prophylactic oral analgesics throughout hospitalization until discharge, and intraoperative periarticular anesthetic injections. Postoperative preemptive analgesia with paracetamol sodium was administered to all patients except those with contraindications.

Interventions

Throughout the study period, the only modification to the perioperative multimodal pain protocol was the use of two different periarticular injection medications, minimizing confounding variables and isolating the impact of univariate changes on outcomes. Participants received anesthetic formulations according to the randomization scheme: (i) the LB group received 266 mg of LB diluted with saline to 100mL, the dosage of 266 mg of LB was selected as it is the standard FDA-approved single-dose regimen for local infiltration in total joint arthroplasty [19, 20], and it is also the modified protocol described by Bramlet et al. [21]; (ii) The RH group received 200 mg of ropivacaine + 1mL of Depo-Medrol (5 mg betamethasone dipropionate and 2 mg betamethasone sodium phosphate) + 0.5 mg of epinephrine [18] diluted with saline to 100mL. Depo-Medrol and epinephrine were excluded from the LB group because co-administration of these adjuvants can disrupt the lipid bilayer membrane of the liposomes. This disruption may lead to the premature release of lidocaine (i.e., dose spillover), compromising the drug’s sustained-release properties [22, 23]. After the surgery is completed and the prosthesis is in place, use a syringe to inject the anesthetic into the posterior joint capsule; before closing the incision, inject the remaining anesthetic into the suprapatellar bursa, the quadriceps tendon, the medial and lateral collateral ligaments, and the area around the incision. When injecting, ensure proper aspiration and take care not to inject into the popliteal vessels.

Randomization and blinding

Participants were randomly assigned in a 1:1 ratio using fixed-block randomization with a block size of 4. The random sequence was generated by an independent statistician. To mask the obvious physical differences between the milky-white LB and the clear RH, we used the same opaque syringe to conceal the appearance of the medication and maintain blinding. Patients, intervention providers, outcome assessors, and data analysts were blinded to group assignments.

Efficacy analysis

During routine rounds while patients are hospitalized, their self-reported pain scores are measured. Pain scores are assessed using the Visual Analog Scale (VAS), which ranges from 0 to 10, where 0 indicates no pain and 10 represents the most severe pain possible. To more accurately describe pain intensity, pain scores are defined as follows: mild: 0.00–3.99; Moderate: 4.00–6.99; Severe: 7.00–10.0. All continuous outcomes are presented with 95% confidence intervals (95% CI), and clinical significance is interpreted using the Minimum Clinically Important Difference (MCID) for the VAS. The MCID was calculated using anchor-based ROC analysis, with the PGIC serving as the external anchor. The optimal cutoff value, determined by the maximum Youden index, was defined as the MCID for the VAS. The MCID was calculated to be 1.5 points. During pain assessment in the rescue analgesia period, patients’ VAS scores were measured at specific times each day, and the mean was calculated to ensure the accuracy of the raw data. The PAI formulations for both groups were clearly defined and standardized, and injections were performed by the same surgeon to eliminate technical bias. Statistical methods: All statistical analyses were performed using SPSS Statistics 31.0 software and R 4.4.0 software (the LME4 package for longitudinal data analysis). A two-sided p-value < 0.05 was considered statistically significant. Baseline characteristics: Continuous variables with normal distributions were compared using independent samples t-tests; non-normally distributed variables were compared using the Mann-Whitney U test; and categorical variables were compared using the chi-square test or Fisher’s exact test. At each time point, pairwise comparisons between groups were performed using independent samples t-tests. Clinical significance: All statistically significant differences between groups were interpreted in conjunction with the Minimum Clinically Important Difference (MCID); a difference was considered clinically significant only if it was both statistically significant and exceeded the MCID.

Perioperative care

All surgeries were performed at the same surgical institution. All patients received adjunctive medications according to a standardized MMA pathway (Fig. 1). Postoperatively, patients were transferred to the Post-Anesthesia Care Unit (PACU) for continuous monitoring and management. Both groups received electronic patient-controlled intravenous analgesia (PCIA) (Jiangsu Rain Medical Technology Co., Ltd., China) (total volume 100mL, no background infusion, single bolus dose 2mL, lockout time 15 min, maximum bolus dose 10 mL). PCIA was available from PACU through 72 h postoperatively. If pain remained uncontrolled after PCIA use with a VAS score of 7 or higher, pethidine 50 mg IM was administered as rescue analgesia, with a maximum daily dose of 100 mg. Postoperative analgesia primarily involved acetaminophen-NSAID combination therapy, elevation of the affected limb, and ultrasound therapy.

The MMA protocol remained unchanged throughout the study period. During hospitalization, all patients received standardized physical therapy services emphasizing early ambulation and range-of-motion exercises, with similar home exercise programs prescribed for all.

Demographic characteristics

Initially, 121 patients (121 knees) were enrolled. After screening, 21 patients were excluded due to contraindications for surgery. Among the remaining 100 patients, 5 were discarded due to missing data, and 2 were discarded due to medication dosage errors. The final analysis cohort comprised 93 patients: 46 in the LB group (liposomal bupivacaine group) and 47 in the RH group (traditional periarticular injection group) (Fig. 2). All demographic data are presented in Table 1. No statistically significant differences existed between the control and experimental groups in demographic characteristics.

Fig. 2.

CONASORT diagram

Table 1.

Baseline demographic characteristics

Variable	LB (Bupivacaine N=46)	RH (Ropivacaine N = 47)
			P Value
Age(years)	67.91 ± 6(56–78)	68.09 ± 6(55–80)	0.25
Age category
≥ 70 years	24(52%)	15(32%)
< 70 years	22(48%)	32(68%)
Sex
Male	12(32%)	20(40%)
Female	34(64%)	30(60%)
Height (cm)	159.74 ± 7	163.26 ± 7
Weight (kg)	69.27 ± 14	75 ± 10
BMI	27 ± 4	28 ± 3	0.08

The LB group (n = 46) and the RH group (n = 47) were highly matched in terms of baseline demographic and clinical characteristics, with no statistically significant differences in age, age group, sex, height, weight, BMI, or BMI category ( p > 0.05; Table 1). The two groups were comparable at baseline, thereby eliminating confounding factors associated with individual differences.

Results

Pain scores

At rest, the postoperative VAS score in the LB group was significantly lower than that in the RH group. Within 24 h postoperatively, the VAS score in the LB group (1.26 ± 1.18) was significantly lower than that in the RH group (3.11 ± 1.34) (mean difference = − 1.83 > MCID; 95% CI: −2.41, − 1.24; P < 0.01). Between 24 and 48 h postoperatively, the LB group’s score of 0.91 (± 0.92) was significantly lower than the RH group’s score of 2.70 (± 1.44) (mean difference = − 1.78 > MCID; 95% CI: −2.35, − 1.21; P < 0.01). Between 48 and 72 h postoperatively, the LB group’s score of 0.35 (± 0.60) was significantly lower than the RH group’s 2.04 (± 1.26) (mean difference = − 1.70 > MCID; 95% CI: −2.13, − 1.26; P < 0.01)(Fig. 3).

Fig. 3.

The VAS of the experimental group and the control group during the resting state. The standard deviation is represented by the lines

At motion, the postoperative VAS score in the LB group remained lower than that in the RH group. Within 24 h postoperatively, the VAS score in the LB group (3.87 ± 2.04) was lower than that in the RH group (5.04 ± 1.53) (mean difference = − 1.17 < MCID; 95% CI: −1.98, − 0.36; P < 0.01). Between 24 and 48 h postoperatively, the LB group’s score of 3.28 (± 1.67) was lower than the RH group’s 4.20 (± 1.78) (mean difference = − 0.91 < MCID; 95% CI: −1.63, − 0.20; P > 0.01). Between 48 and 72 h postoperatively, the LB group (2.28 ± 1.52) was lower than the RH group (3.15 ± 1.61) (mean difference = − 0.87 < MCID; 95% CI: −1.46, − 0.28; P < 0.01)(Fig. 4). Most notably, from the first 24 h postoperatively through the remainder of the hospital stay until discharge, patients’ pain scores showed a downward trend both at rest and during activity, with the decrease at rest being more pronounced than during activity. The analgesic advantage of bupivacaine liposomes was more evident at rest. During activity, although the analgesic advantage was less pronounced due to typically higher pain scores, a difference between the two groups still persisted.

Fig. 4.

The pain scores of the experimental group and the control group during the exercise state. The standard deviation is represented by lines

Pain intensity was categorized using the highest observed score as the daily pain rating. Categorized pain scores yielded results similar to mean numerical pain ratings. At 72 h postoperatively, there was no significant difference between the bupivacaine liposome and conventional injection groups in the percentage of patients reporting mild or moderate pain. Similarly, no significant difference existed in the percentage of patients reporting severe postoperative pain between the two groups. However, within the initial 24 h, 32% of patients receiving bupivacaine liposome injections rated their pain as moderate on average, compared to 49% in the conventional injection group. During the same period, 52% of patients administered bupivacaine liposomes rated their pain as mild, whereas only 35% of patients in the conventional injection group reported mild pain (Fig. 5).

Fig. 5.

The pain scores of the experimental group and the control group were classified and graded according to the degree of pain

Opioid consumption

Figure 6 shows the overall temporal trends in opioid consumption for the two treatment groups. The results regarding opioid consumption between the two groups were consistent with the mean pain scores. In the postoperative recovery room (PACU), opioid consumption was low in both the experimental and control groups, and there was no significant difference between the two groups, which may be attributed to the effects of general anesthesia. The MME consumption within 24 h postoperatively in the LB group (32.76 ± 16.12 mg) was significantly lower than that in the RH group (42.22 ± 16.40 mg) (mean difference = − 9.46 mg; 95% CI: −15.70, − 3.21 mg; P < 0.01). Between 24 and 48 h, the mean total MME consumption in the LB group was (23.61 ± 11.66 mg), and in the RH group was (30.59 ± 14.56 mg) (mean difference = -6.98 mg; 95% CI: -12.70, -1.26 mg; P > 0.01). At 72 h, the mean total MME consumption was (15.96 ± 9.13 mg) in the LB group and (19.39 ± 12.41 mg) in the RH group (mean difference = − 3.44 mg; 95% CI: −7.71, − 0.84 mg; P > 0.01). Figure 5 shows that after the effects of anesthesia wore off on the first postoperative day (POD-1), opioid consumption exhibited a significant upward trend. As time progressed, the effects of local infiltration gradually became apparent, leading to a gradual decrease in opioid consumption. At the same time, liposomal bupivacaine demonstrated a more pronounced advantage in providing long-acting postoperative analgesia.

Fig. 6.

Overall opioid dose (MME), by time period after total knee arthroplasty; MME, milligram morphine equivalents; PACU, post-anesthesia care unit; POD, postoperative day (defined as consecutive 24 h periods following discharge from the PACU); Mean (SE) opioid dose at each time point was estimated by repeated measures ANOVA; MME was entered as zero when a participant did not receive opioids

Functional outcomes

Compared with the RH group, patients in the LB group took less time to get out of bed for the first time: 22.17 (± 5.59)hours in the LB group versus 24.55 (± 3.46)hours in the RH group (mean difference = − 2.38 h; 95% CI: -4.24, -0.52; P < 0.01). Patients in the LB group had a shorter length of hospital stay (difference: -0.68; 95% CI: -1.14, -0.22; P = 0.01). There were no significant differences between the LB and RH groups in ROM, TUG, 2MWT, postoperatively. The lack of a significant difference between TUG and 2MWT may be related to the use of tourniquets during surgery [20, 21]. Prolonged use of tourniquets during surgery can lead to ischemic injury of the thigh muscles, resulting in difficulty raising the leg postoperatively [22]. (Table 2).

Table 2.

Knee joint function indicators

Variable	LB( N=46)	RH( N = 47)	Difference or OR (95% CI)	P
ROM	98.72°(±17.86)	92.13°(±9.93)	7.02(1.37,12.67)	0.02
TUG	8.38s(±6.20)	8.96s(±5.49)	-0.57(-3.01,1.86)	0.64
TFA	22.17 h(±5.59)	24.55(±3.46)	-2.38(-4.24,--0.52)	0.01
2MWT	27.21(±18.56)	21.19(±13.06)	6.02(-1.23,13.27)	0.10
LHT	6.00(±1.22)	6.68(±0.84)	-0.68(-1.14,-0.22)	0.01

Adverse reactions

Three adverse events occurred: one in the experimental group and two in the control group. All three patients experienced nausea during postoperative physical therapy, which did not necessitate additional medical intervention. None of these events were determined to be directly related to the studied drugs.

Discussion

Liposomes [24]are lipid-based multivesicular particles that function as drug carriers, providing controlled delivery of medications such as bupivacaine to produce prolonged effects. It enables controlled delivery of bioactive drugs, resulting in prolonged efficacy and reduced toxicity [25]. Utilizing Depo Foam technology, it achieves steady-state drug release for postoperative analgesia lasting up to 72 h [25]. Composed of minute, multi-vesicular lipid particles forming honeycomb-like aqueous cavities, this design permits drug diffusion exceeding 96 h after a single administration [26, 27].As a natural evolution, liposomal bupivacaine is now proposed for TKA [28]. One study compared the effects of different doses of liposomal (i.e., Depo Foam) bupivacaine versus bupivacaine hydrochloride on wound infiltration. It found that the highest dose of bupivacaine was the only dose that improved patients’ resting pain scores, and this improvement was found to be dose-dependent [21].

This study aimed to determine whether liposomal bupivacaine PAIs, compared to traditional ropivacaine hydrochloride PAIs, provided benefits as part of an established multimodal pain management regimen. Results showed that after the initial 24 h, hospitalized patients in the LB group reported significantly lower pain scores, and a significantly higher proportion of patients in the liposomal bupivacaine group rated their pain as “mild” compared to the RH group. Compared with the RH group, patients treated with LB showed a downward trend in mean pain scores, opioid consumption, and antiemetic use. However, we found that the analgesic advantage of the LB group began to diminish 48 h postoperatively. The results showed a statistically significant reduction in VAS scores in the LB group, but these reductions did not reach the MCID threshold. Opioid consumption decreased significantly between 48 and 72 h postoperatively, but not clinically significant. This phenomenon is likely multifactorial. First, early joint mobilization dictated by modern ERAS protocols increases regional tissue perfusion [7, 29], which may accelerate the systemic clearance of the local bupivacaine depot. Second, the implementation of a robust multimodal analgesia (MMA) regimen produced a synergistic effect [30], in that systemic analgesics masked the subtle differences between local anesthetic techniques, this approach may establish a high level of pain control and functional readiness, thereby reducing the incremental benefits of any single component. Finally, the delayed pharmacokinetic profile of Depo-Medrol (intra-articular corticosteroid) in the control group must be considered [31], its anti-inflammatory and analgesic effects typically peak between 24 and 72 h, effectively closing the efficacy gap as the ropivacaine block wears off. Our findings are consistent with several previous studies. Hubler et al. reported that, compared with ropivacaine, the use of liposomal bupivacaine in the early postoperative period following total knee arthroplasty may offer advantages in terms of pain relief and reduced opioid use [32]. Yuan et al. reported that liposomal bupivacaine provided a pharmacologically prolonged but clinically irrelevant analgesic effect [20]. Belli et al. recently reported, however, that bupivacaine did not demonstrate a significant clinical advantage over ropivacaine in postoperative pain management following TKA [33]. In contrast, we believe that LB offers a clear analgesic advantage in the early postoperative period. This discrepancy may stem from the fact that their study included conventional bupivacaine but did not perform a separate subgroup analysis for lipid-based formulations, whereas our study focused specifically on LB. Furthermore, their analysis combined the peripheral nerve block (PNB) and PAI groups, whereas our study used PAI as the sole route of administration.

For advanced dynamic functional indicators such as the Timed Up-and-Go (TUG) test and the 2-minute walk test (2MWT), no significant differences were observed between the groups, the only significant difference was observed for the time to first ambulation (TFA). This lack of significant functional differentiation is likely multifactorial and extends beyond simple pain management. First, the application of a surgical tourniquet during TKA predictably induces ischemia-reperfusion injury [34, 35], which significantly impairs early postoperative quadriceps strength and limits mobility regardless of the analgesic regimen utilized. Second, performance in tests like TUG and 2MWT is heavily dependent on overall postoperative muscle strength recovery and neuromuscular control, which are primarily dictated by surgical trauma rather than isolated pain reduction. Third, early rehabilitation training compliance plays a crucial role; variations in patient motivation, psychological resilience, and postoperative kinesiophobia introduce considerable variability into functional performance. Finally, individual differences among patients—including preoperative functional baselines, age, BMI, and pain tolerance—often exert a more profound impact on advanced mobility milestones than the specific formulation of periarticular injection. These results indicate that LB provides only short-term statistical benefits for early postoperative pain control and functional recovery in TKA, with limited clinical value for improving long-term postoperative outcomes. This finding is consistent with the results of Bagsby et al. and Schumer et al. [16, 17]. Yang et al. reported that, compared with RH, LB did not significantly reduce postoperative opioid use or shorten hospital stay; LB showed no clear clinical advantage, and they concluded that its significantly higher cost was difficult to justify [36]. In contrast, our trial demonstrated that LB had statistically significant advantages, including lower early postoperative pain scores, reduced opioid requirements, and earlier ambulation. Differences in the evaluation methods may be one reason for this discrepancy. Another possible explanation is that Yang’s evaluation included multiple routes of administration (PNB, PAI, local infiltration) and surgical procedures (TKA, TSA, THA), introducing clinical heterogeneity. Our cost-effectiveness analysis aligns with their conclusion that LB is more expensive; however, we identified selective short-term benefits that may justify the targeted use of LB rather than its blanket rejection. From a cost-effectiveness perspective, LB is more expensive than conventional regional anesthesia (RH); given the limited short-term clinical benefits of LB, its routine use for all TKA patients is not cost-effective, and it should be used selectively based on patient characteristics and clinical needs. This study provides a balanced and evidence-based interpretation of the clinical value of LB, clarifying that LB is a valuable adjunct to MMA for early postoperative pain control but cannot replace conventional regional anesthesia.

This study does have limitations, and results should be interpreted within this context. First, LB its routine clinical application still requires further validation in large-scale, multicenter studies. Single-center studies are prone to selection bias, whereas multicenter studies involve a more heterogeneous population and are better representative of clinical practice. Second, despite utilizing opaque syringes for intraoperative administration, the operating surgeon might have discerned differences in the viscosity or flow characteristics of the suspensions during infiltration. This represents a potential source of surgeon performance bias. Third, the exclusion of a small subset of patients post-randomization (due to intraoperative surgical adjustments or early post-operative protocol deviations) represents a study limitation. Such exclusions can introduce attrition bias and may limit the generalizability of our intention-to-treat analysis, future trials should strive to minimize post-randomization dropouts and report sensitivity analyses to address this factor. Finally, a potential study design alternative would be to establish a third control group evaluating LB combined with corticosteroids or alternative dosages. However, due to the pharmaceutical incompatibility of liposomal structures with standard adjuvants, we restricted our comparison to the standard clinical formulations of each drug to isolate the univariate impact of the analgesic agents safely, while pharmacologically justified to prevent liposomal disruption, this asymmetry in the local injection cocktail introduces a potential confounding variable when comparing the two groups. Despite these limitations, the authors believe the study’s scientific validity and efficacy are strengthened by minimizing bias through consecutive patient selection within each group, standardized perioperative anesthesia and medical protocols, consistent surgical techniques, and a multimodal pain management regimen.

Conclusions

In summary, this study demonstrates that periarticular injection of liposomal bupivacaine in patients undergoing primary total knee arthroplasty can alleviate postoperative pain or reduce the use of analgesics. However, due to limited clinical benefits and high costs, its clinical advantages are inconsistent, and its routine use is not recommended for all TKA patients. Currently, these findings support the inclusion of liposomal bupivacaine in modern multimodal pain management protocols, but further research may be needed.

Abbreviations

LB

Liposomal Bupivacaine

RH

Ropivacaine Hydrochloride

MME

Morphine milligram equivalent

ROM

Range of motion

TFA

Time to first ambulation

TUG

Timed Up-and-Go test

2MWT

2-minute walk test

LHT

Length of hospital stay

POD

Postoperative day

POH

Postoperative hour

PACU

Post-anesthesia care unit

Authors’ contributions

Tao Li conceptualized and designed the study, secured funding, and provided overall supervision. Tianlong Gao and Ke Xiao was responsible for the formal statistical analysis and drafted the original manuscript. Data collection, patient screening, and follow-up assessments were conducted by Tianlong Gao, Jiaqi Dong, Kunyi Zhao and Zheng Tang. The standardized surgical procedures and periarticular injections were performed and supervised by Tao Li and Haining Zhang. All authors participated in the interpretation of the results, contributed to the critical revision of the manuscript for important intellectual content, and approved the final version for submission.

Funding

This work was supported by grants from National Natural Science Foundation of China; Grant number: 82272489, 82203588; TaiShan Scholars Project Special Fund; Grant number: NO.tsqn202306396; Qingdao Science and Technology Benefiting the People Demonstration Special Project; Grant number: 24-1-8-smjk-3-nsh. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study adhered to ethical principles of the Declaration of Helsinki was approved by the Ethics Committee of Qingdao University (QYFY WZLL 308888) and registered with the(ChiCTR2400082998, 12/04/2024). All participants signed informed consent forms and voluntarily agreed to participate.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.