Article History

Published: Fri 01, Aug 2025
Received: Wed 16, Apr 2025
Accepted: Mon 12, May 2025

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Irada Mamukadze McKenzie Miller Preetha Pamidighantam Sajjaad Samat Sam Manski Thais Fortes

Abstract

Background: There is inconclusive evidence regarding whether liposomal bupivacaine plus bupivacaine hydrochloride (LB-BH) confers better post-lumpectomy analgesia than standard bupivacaine hydrochloride (BH). This study aimed to compare patient-reported pain control and clinical outcomes.
Methods: This single-center, patient-blinded, prospective, randomized controlled trial included 76 patients who underwent lumpectomy between April 2023 and February 2024. Participants were randomized to receive either an LB-BH combination or BH alone during surgery. The sample size was calculated to ensure the statistical power for equivalence testing. Pain scores were assessed using the Numerical Rating Scale (NRS) on postoperative days (POD) 2 (phone follow-up) and 9 (clinic visit). Cost analysis compares the relative financial impacts of both interventions.
Results: LB-BH and BH reported equivalent pain scores during phone visits (1.28 ± 1.61 vs. 1.94 ± 2.3, P = .002) and office visits (1.04 ± 1.83 vs. 1.90 ± 1.83, P < .001). None of the patients required opioid medications within 72 h of surgery, contacted the office with pain-related questions, or requested opioid prescriptions. None of the groups had pain-related emergency room visits within 30 days of surgery or reported adverse clinical outcomes. Cost analysis revealed that LB-BH was 33.11 times more expensive than BH for commercially insured patients.
Conclusion: LB-BH and BH are clinically equivalent in terms of postoperative pain control. However, BH was significantly more cost-effective, supporting its use in the enhanced recovery after surgery (ERAS) protocol to reduce opioid exposure and minimize the risk of narcotic dependence in post-lumpectomy patients.

Keywords

Lumpectomy, Liposomal bupivacaine, Bupivacaine hydrochloride, ERAS, Marcaine, Exparel, postoperative pain control

Synopsis

This randomized controlled trial compares postoperative pain control using an ERAS protocol with liposomal bupivacaine (LB) versus bupivacaine hydrochloride (BH) after lumpectomy. Findings show no clinical advantage of LB over BH, with BH being significantly more cost-effective.

1. Introduction

Breast cancer remains one of the most prevalent cancers worldwide, with an estimated 310,720 new cases reported by 2024 [1]. Lumpectomy is a common breast-conserving procedure used to treat localized breast tumors [2]. While lumpectomy offers good cosmetic outcomes, postoperative pain is a significant concern that affects 40-50% of patients [3, 4]. After lumpectomy, patients are often discharged with opioids, although only 15-25% of patients require this level of pain control [5, 6]. Overprescription of opioids poses a risk of opioid dependence and misuse [5, 7, 8], underscoring the need for alternative analgesia methods [9].

One such alternative is liposomal bupivacaine (LB), a slow-release formulation of bupivacaine created to provide extended analgesia [6]. However, evidence of its efficacy over standard bupivacaine hydrochloride (BH) remains inconclusive, with mixed findings regarding its benefit [10-13]. Additionally, LB is significantly more expensive than BH, and some cost-utility analyses have shown LB to be non-cost-effective, particularly when there is no perceived clinical benefit [14, 15]. Nevertheless, LB remains a candidate for pain control within the enhanced recovery after surgery (ERAS) protocol because of its reported association with limited opioid dependence [16]. Given the potential to optimize cost savings and opioid-sparing effects, this study aimed to determine whether LB provides superior pain control and clinical outcomes compared with BH alone when used within the post-lumpectomy ERAS protocol. We hypothesized that both the analgesic regimens would be clinically equivalent.

2. Methods

This single-center, randomized, patient-blinded, active, comparator-controlled study was conducted at the University of Michigan Health Sparrow Hospital. The local Institutional Review Board (IRB 2228) approved the study in September 2023, and all participants provided informed consent during their preoperative visit. This study was deemed to have minimal risk.

2.1. Participants and Randomization

Adult patients (ages ≥ 18 years) scheduled for lumpectomy with or without sentinel lymph node biopsy (SLNB) were eligible to participate. Exclusion criteria included inability to provide informed consent, cognitive impairment, active substance use, and known anesthetic allergy. Patients with bilateral breast cancer, irrespective of tumor size or malignancy status, were allowed to participate as long as the other exclusion criteria were not met. Subjects were randomized to LB-BH or BH in a 1:1 ratio, facilitating balanced allocation between groups using the National Cancer Institute clinical trial randomization tool, stratified by type of surgery (lumpectomy alone or lumpectomy with SLNB) and recruitment site to achieve a balanced allocation of participants in the treatment arms. Patients in the intervention group received a combination of liposomal bupivacaine (LB) and bupivacaine hydrochloride (BH) for intraoperative analgesia (LB-BH), whereas those in the control group received only bupivacaine hydrochloride (BH) for intraoperative analgesia. This randomization strategy was designed to minimize confounding variables, ensure comparability between groups, and enhance the reliability of outcome comparisons.

2.2. Interventions

Following the induction of general anesthesia and surgical preparation, all participants underwent standard lumpectomy with or without SLNB. Finally, the participants in each group received the following interventions:

• LB-BH Group: 10 ml liposomal bupivacaine mixed with 10 ml bupivacaine hydrochloride was injected into the surgical site and surrounding breast tissue for postoperative analgesia.

• BH Group: 0.25% bupivacaine hydrochloride alone (2 mg/kg maximum dose) infiltrated similarly.

The analgesic regimens in both groups adhered to a standardized ERAS protocol with preoperative acetaminophen, intraoperative euvolemia and normothermia, and postoperative antiemetic and non-opioid pain control. No narcotics were administered postoperatively.

2.3. Outcome Measures

Postoperative follow-up was conducted through a phone call on postoperative day (POD) 2 and an in-person clinic visit on POD 9. During these encounters, the patients were asked to report their pain using a numerical rating scale (NRS), a clinically valid pain score measure that served as the primary outcome. Secondary outcomes included opioid analgesia requirement in the first 72 h postoperatively, ED visits, pain-related consultation or prescription requests, and adverse clinical events, which were recorded at pre-scheduled visits or monitored through chart review for 30 days postoperatively. A cost analysis comparing LB-BH and BH pricing based on institutional and insurance data is also conducted. The mean cost per dose was derived from the average price of each analgesic across all insurance programs. The maximum cost per dose was calculated as the maximum cost of each analgesic as recorded in the institutional database.

2.4. Outcomes

The primary purpose of this study was to compare postoperative pain levels between the two groups using the NRS from POD 2 during the telephone call and POD 9 during the clinic visit. This outcome was chosen based on its validity in measuring postoperative pain and clinically assessing analgesic efficacy. These secondary outcomes were tracked to assess not only the efficacy of pain management but also the potential impact of the two analgesic regimens on recovery-related complications. Clinical outcomes were assessed using equivalence testing based on predefined pain score margins. The equivalence margin was set at two points on the NRS, which was considered clinically significant based on previous studies [17-19].

2.5. Sample Size Calculation and Statistical Analysis

The sample size was calculated to detect equivalence in pain scores (margin of ±2 points on the NRS) with 80% power and two-sided significance level of 0.05. The calculations were based on an assumed standard deviation of 2 points on the NRS, derived from prior studies of similar analgesic treatments. In total 76 participants required adequate statistical robustness. Equivalence testing using two-sample t-tests assessed the clinical equivalence of pain control (±2 points NRS) between the two analgesic modalities. Sensitivity analyses were performed to assess the potential impact of missing data. Additionally, chi-squared tests of independence were employed to explore any relationship between treatment and missing data for pain scale responses, ensuring that any missingness did not introduce bias into the results. A descriptive analysis of the preoperative and postoperative outcomes was performed. Continuous variables are reported as mean ± standard deviation (SD) or median with interquartile range (IQR) and compared using t-tests or Wilcoxon rank-sum tests, as appropriate. Categorical variables were presented as counts (percent). Group comparisons will be made using t-tests or Mann-Whitney U tests for continuous variables and Chi-square or Fisher's exact tests for categorical variables, depending on the data distribution and expected cell counts.

3. Results

3.1. Participant Demographics and Study Flow

A total of 118 participants were initially assessed for eligibility between April 21, 2023, and February 23, 2024. After screening, 42 participants were excluded based on the predefined eligibility criteria, resulting in 76 patients being randomly assigned to either the intervention group (liposomal bupivacaine mixed with plain bupivacaine hydrochloride, LB-BH) or the control group (plain bupivacaine hydrochloride, BH) (Figure 1).

3.2. Missing Data

Missing data for key outcome variables (pain scale during telephone and clinic visits) were assessed to determine potential bias. Chi-squared tests of independence showed no significant relationship between treatment assignment and missingness for pain scale responses at either visit (phone-call, P = 1.000, office-visit, P = 0.7428), indicating that missingness was not systemically different. Recorded variables were examined for their ability to predict missingness in the pain scores. Logistic regression models identified lymph node status as a predictor of missing pain scores on telephone visits, suggesting that patients with SLNB were less likely to have missing pain. However, no significant predictors were found for clinic visits and overall missingness did not affect the equivalence analysis. The results were visualized by plotting the expected distribution of mean differences, effect size, confidence intervals, and equivalence bounds. In all cases, the point estimate for the mean difference was near zero, with 90% and 95% confidence intervals within the equivalence bounds. The attritional analysis confirmed that missing data did not affect the study’s primary conclusions.

3.3. Primary and Secondary Outcomes

The baseline characteristics of the study population, including age, sex, and surgery type (lumpectomy with or without SLNB), were well balanced between the two groups (Table 1). This ensured that the groups were comparable at baseline and that any differences in outcomes could be attributed to the interventions being studied. The secondary outcomes are shown in (Table 1). The postoperative days of call and office visits did not differ between cohorts. None of the patients in either group required postoperative opioid medication. Both groups reported no adverse clinical outcomes, and no pain medication prescription requests occurred. Two LB-BH patients and one BH patient had non-pain-related emergency visits within 30 days: one for breast seroma, one for a rheumatoid arthritis flare, and one (BH group) for surgical site infection.

TABLE 1: Patient demographics and postoperative outcomes.

Patient Characteristics		Group Assignment
			BH (N=28)	LB-BH (N=48)	P
Age (Years)			57.1±17.8	62.2±14.6)	0.183
Race	White		25 (89.3)	45 (93.8)	0.267
	Asian/Pacific Islander		2 (7.1)
	Unknown		1 (3.6)	1 (2.1)
	Black/African American/African Diaspora			2 (4.2)
Hispanic	No		26 (92.9)	46 (95.8)	0.717
	Unknown		1 (3.6)	2 (4.2)
	Yes		1 (3.6)
Pathology	Malignant		20 (71.4)	36 (75.0)	0.790
	Benign		8 (28.6)	12 (25.0)
Type of Surgery	Lumpectomy alone		16 (57.1)	26 (54.2)	0.816
	Lumpectomy with SLNB		12 (42.9)	22 (45.8)
Chronic Opioid Use	Yes		3 (10.7)	8 (16.7)	0.737
Intraoperative Toradol	Yes		13 (46.4)	17 (35.4)	0.446
Post-operative outcomes
Phone Call POD			2.17	2.20	0.932
Office Visit POD			9.93	9.83	0.961
Opioids Prescribed at Discharge	Yes		1 (3.6)	1 (2.1)	0.604
Side Effects	No		27 (96.4)	40 (83.3)	0.916
	Missing		1 (3.6)	3 (6.2)
	Seroma			2 (4.2)
	Persistent inflammation			3 (6.3)
ED Visit	Yes		1 (3.6)	2 (4.2)	1.000
Request for additional pain control	No		0 (0)	0(0)	1.000

Categorical variables were expressed as counts (%). Numerical variables are expressed as the mean (SD).

BH: Bupivacaine Hydrochloride; LB-BH: Liposomal Bupivacaine; POD: Postoperative Day; ED: Emergency Department.

Table 2 summarizes the per-protocol equivalence test results comparing the pain scores at telephone and clinic visits between the intervention (LB-BH) and control (BH) groups. The mean pain score for LB-BH and BH on POD 2 was 1.28 ± 1.61 vs. 1.94 ± 2.30 (P = .002) and on POD 9 was 1.04 ± 1.83 vs. 1.90 ± 1.83 (P < .001) (Figure 2). The mean differences were near zero, with confidence intervals fully contained within the predefined equivalence margin ([-2.2]). The effect size estimates (Hedges’ g) also confirmed the clinical equivalence, with standardized bounds of [-0.92, 0.92]. The analysis demonstrated that the pain scores between the LB-BH and BH groups were clinically equivalent at both postoperative call and visit. Figure 3 displays a visual comparison of the pain scores over the follow-up period for each treatment group.

TABLE 2: Equivalence testing of mean pain scores at postoperative encounter by intervention group.

	Mean Pain Score (SD)		Equivalence Test	Raw Mean Pain Score Difference	Effect Size (Hedge’s g)
By Encounter	BH	LB-BH	Test Statistic (P-value)	Estimate [90%CI]	Estimate [90%CI]
Postop Call	1.94 (2.30)	1.28 (1.61)	3.04 (0.002)	-0.059 [-1.134, 1.016]	-0.027 [-0.502, 0.449]
Postop Visit	1.90 (1.83)	1.04 (1.83)	4.41 (<0.001)	-0.145 [-0.851, 0.561]	-0.085 [-0.490, 0.321]

BH: Bupivacaine Hydrochloride; LB: Liposomal Bupivacaine; CI: Confidence Interval.

The cost analyses of LB-BH and BH are presented in (Table 3). Mean cost of BH is $7.29 versus LB-BH $468.20; maximum possible costs were $15.20 and $664.60 respectively. The minimum cost per dose per patient comparison showed that LB-BH is 33.11 times more expensive than BH.

TABLE 3: Cost-benefit analysis between LB-BH and BH.

	BH	LB-BH
Vial volume (ml)	5	10
Cost per vial (USD)	$20	$874.48
Standard dose per patient (ml)	10	20 (10 LB + 10 BH)
Mean insurance-covered cost	$7.29	$468.20
Maximum possible cost	$15.20	$664.60
Min cost per dose per patient (USD)	$14.58	$482.78
Max cost per dose per patient (USD)	$30.40	$695
Max Charge Dosage Cost Ratio		22.86:1

BH: Bupivacaine Hydrochloride; LB: Liposomal Bupivacaine.

4. Discussion

This randomized controlled trial compared patient-reported pain control, side effects, clinical outcomes, and opioid prescription needs in patients who received LB and BH after lumpectomy. The primary aim of this study was to investigate whether there is a difference in pain control between patients receiving BH and those receiving LB plus BH. Our findings revealed no discernible advantage of LB combined with BH over BH alone in postoperative pain management after lumpectomy. Additionally, LB is not cost-effective in comparison to BH, further questioning its widespread use given its higher cost and similar efficacy. While some earlier studies suggested LB’s efficacy in reducing postoperative pain and hospital stays [20-22], our results align with those of other studies, indicating no meaningful differences in pain control or opioid usage between LB and BH [11].

Pain management remains a challenge following breast surgery, because postoperative pain is a major factor contributing to delayed mobilization and prolonged hospital stay in the acute period following surgery. Up to 60% of women experience postoperative pain syndrome after breast surgery [3, 21, 23, 24], which can complicate recovery due to delayed wound healing, a higher risk of infection, long-term hospitalization, readmission, and cardiovascular complications [7]. Lumpectomy was chosen as the study procedure because it is a common breast-conserving surgery with lower expected opioid requirements than mastectomy. However, postoperative pain remains a significant concern for a substantial proportion of patients.

LB analgesics have been used in several surgical procedures with an overall reduction in postoperative opioid use and improved pain control. This translates to improved patient satisfaction, fewer opioid-related complications, and lower patient pain indices, which are especially important given the ongoing opioid crisis. Current evidence on the effectiveness of LB compared with BH is inconclusive owing to the small study size and non-standardized comparators [15]. This prompted this randomized controlled trial to assess not only the statistical significance of LB efficacy compared to BH but also to evaluate the clinical equivalence of both drugs.

Our study conducted equivalence and non-inferiority tests to compare LB and BH in terms of pain control, opioid use, side effects, and clinical outcomes. Although LB demonstrated effective pain management and opioid-sparing effects, no significant differences were observed between LB and BH. This aligns with previous randomized studies that reported no significant differences in the pain scores or other parameters [11, 12, 24]. Although LB offers a 72-hour extended release, participants reported diminishing local anesthetic effects within the first 24-48 hours [11, 25].

Equivalence testing showed that LB-BH and BH alone were clinically equivalent in terms of postoperative pain relief. Pain scores did not differ significantly between the groups, and the differences observed were within the clinically accepted range of 2 points on the numerical rating scale (NRS). The statistically significant reduction in postoperative pain with LB was clinically insignificant and did not require a higher cost. Cost-utility analyses have shown LB to be non-cost-effective, with many believing that its benefits do not warrant expense [14, 15]. Ultimately, the substantial cost difference between LB and BH and their similar efficacies suggests that BH is a more economical choice, leading to significant savings without compromising patient outcomes. Prioritizing BH can enhance patient care, while minimizing healthcare expenses.

5. Conclusion

LB-BH and BH alone were determined to be equivalent for postoperative pain control and recovery in patients post-lumpectomy. However, given that BH is more cost-effective and has similar efficacy, it is the preferred analgesic choice in lumpectomy procedures. With ongoing opioid crises, this study supports the use of ERAS protocols and intraoperative BH to minimize opioid use, while maintaining effective pain management.

Limitations

This study has several limitations. First, this was a single-center, single-surgeon study with a limited sample size. Larger multicenter multi-surgeon studies are required to validate these findings. Second, equivalence tests were performed only on the complete case data, thus reducing the sample size and potentially limiting the analysis. However, the attrition analysis indicated that missing data likely did not bias the results. Third, follow-up was limited to 30 days postoperatively, necessitating a longer follow-up period to assess the long-term treatment effects of LB, adverse events, and overall long-term costs of the treatment compared to BH. Additionally, lumpectomy was chosen over other breast surgery procedures associated with higher pain levels, such as total mastectomy or cosmetic breast enhancements/reconstruction, which may have affected the generalizability of the results. Future studies should be adequately powered to evaluate treatment differences based on procedure type and examine LB’s role of LB in more extensive breast cancer surgeries.

Funding

The study was internally funded through the research program University of Michigan Health- Sparrow.

Data Access Statement

Research data supporting this publication are available upon request.

Author Contributions

IM and PP contributed to the design and implementation of the research; IM contributed to the analysis of the results; and to the original writing of the manuscript. PP, SS, and MM helped with the manuscript revision. TF conceived and supervised the original project.

Conflicts of Interest

None.

Acknowledgements

We would like to thank our research team and the participants for their support.

REFERENCES

[1]  Kathleen A Cronin, Susan Scott, Albert U Firth, et al. “Annual report to the nation on the status of cancer, part 1: National cancer statistics.” Cancer, vol. 128, no. 24, pp. 4251-4284, 2022. View at: Publisher Site | PubMed

[2]  Quan D Nguyen, Anahita Tavana, Sarfaraz Sadruddin, et al. “Successful lumpectomy in a patient with multicentric breast cancer.” Cureus, vol. 12, no. 8, pp. e10072, 2020. View at: Publisher Site | PubMed

[3]  Reza Alizadeh, Ziba Aghsaeifard, Nasrin Alavi, et al. “A cross-sectional study on the postoperative analgesic-associated side effects and clinical parameters following partial mastectomy.” Int J Surg Open, vol. 27, pp. 114-118, 2020. View at: Publisher Site

[4]  Uzma Shamim Seth, Sughra Perveen, Tanweer Ahmed, et al. “Postoperative Analgesia in Modified Radical Mastectomy Patients After Instillation of Bupivacaine Through Surgical Drains.” Cureus, vol. 14, no. 4, pp. e24125, 2022. View at: Publisher Site | PubMed

[5]  Claudya Morin, Yamini Patel, Munazza Javid, et al. “Opioid-sparing multimodal analgesia protocol for lumpectomy patients results in superior postoperative pain control.” Ann Surg Oncol, vol. 28, no. 11, pp. 5855-5864, 2021. View at: Publisher Site | PubMed

[6]  Andrew D Gailey, Robert F Ostrum “The use of liposomal bupivacaine in fracture surgery: a review.” J Orthop Surg Res, vol. 18, no. 1, pp. 267, 2023. View at: Publisher Site | PubMed

[7]  Jowkar S, Farbood A, Amini A. Effect of continuous intra-incisional bupivacaine on postoperative pain in non-traumatic spinal fixation surgeries: a randomized controlled trial.” Braz J Anesth, vol. 72, no. 5, pp. 599-604, 2023. View at: Publisher Site | PubMed

[8]  Melissa Hite, Nancy Klauber-DeMore, Andrea M. Abbott “Narcotics and breast surgery: a review of current literature.” J Unexplored Med Data, vol. 4, pp. 9, 2019. View at: Publisher Site

[9]  Roshni Rao, Rubie Sue Jackson, Barry Rosen, et al. “Pain control in breast surgery: survey of current practice and recommendations for optimizing management—American Society of Breast Surgeons Opioid/Pain Control Workgroup.” Ann Surg Oncol, vol. 27, no. 4, pp. 985-990, 2020. View at: Publisher Site | PubMed

[10]      Donald A Elmer, John R Coleman, Christian M Renwick, et al. “Comparing bupivacaine alone to liposomal bupivacaine plus bupivacaine in interscalene blocks for total shoulder arthroplasty: a randomized, non-inferiority trial.” Reg Anesth Pain Med, vol. 48, no. 1, pp. 1-6, 2023. View at: Publisher Site | PubMed

[11]      Andrew T Gabrielson, Logan Galansky, Tamir Sholklapper, et al. “Effectiveness of liposomal bupivacaine with bupivacaine hydrochloride vs bupivacaine hydrochloride alone as a local anesthetic for children undergoing ambulatory urologic surgery: the Baby ORIOLES randomized clinical trial.” J Urol, vol. 211, no. 1, pp. 37-47, 2024. View at: Publisher Site | PubMed

[12]      Yar L Yeap, John Wolfe, Jennifer Stewart, et al. “Liposomal bupivacaine addition versus standard bupivacaine alone for colorectal surgery: a randomized controlled trial.” Pain Manag, vol. 12, no. 1, pp. 35-43, 2022. View at: Publisher Site | PubMed

[13]      Atul Dilawri, Marcia Wyman, Sneha Shah “Liposomal bupivacaine versus immediate-release bupivacaine for postoperative pain control.” Ann Pharmacother, vol. 56, no. 6, pp. 664-670, 2022. View at: Publisher Site | PubMed

[14]      Meghan H Nadeau, Anju Saraswat, Alexander Vasko, et al. “Bupivacaine versus liposomal bupivacaine for postoperative pain control after augmentation mammaplasty: a prospective, randomized, double-blind trial.” Aesthetic Surg J, vol. 36, no. 2, pp. NP47-NP52, 2016. View at: Publisher Site | PubMed

[15]      Thomas W Hamilton, Ruth Knight, Jamie R Stokes, et al. “Efficacy of liposomal bupivacaine and bupivacaine hydrochloride vs bupivacaine hydrochloride alone as a periarticular anesthetic for patients undergoing knee replacement: a randomized clinical trial.” JAMA Surg, vol. 157, no. 6, pp. 481-489, 2022. View at: Publisher Site | PubMed

[16]      Mark Lambrechts, Michael J O'Brien, Felix H Savoie, et al. “Liposomal extended-release bupivacaine for postsurgical analgesia.” Patient Prefer Adherence, vol. 7, pp. 885-890, 2013. View at: Publisher Site | PubMed

[17]      Mette Frahm Olsen, Eik Bjerre, Maria Damkjær Hansen, et al. “Pain relief that matters to patients: systematic review of empirical studies assessing the minimum clinically important difference in acute pain.” BMC Med, vol. 15, no. 1, pp. 35, 2017. View at: Publisher Site | PubMed

[18]      Gilda Piaggio, Diana R Elbourne, Stuart J Pocock, et al. “Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement.” JAMA, vol. 308, no. 24, pp. 2594-2604, 2012. View at: Publisher Site | PubMed

[19]      Hidenori Suzuki, Shuichi Aono, Shinsuke Inoue, et al. “Clinically significant changes in pain along the pain intensity numerical rating scale in patients with chronic low back pain.” PLoS One, vol. 15, no. 3, pp. e0229228, 2020. View at: Publisher Site | PubMed

[20]      Keith Candiotti “Liposomal bupivacaine: an innovative nonopioid local analgesic for the management of postsurgical pain.” Pharmacotherapy, vol. 32, no. 9 Suppl, pp. 19S-26S, 2012. View at: Publisher Site | PubMed

[21]      Eric Haas, Erol Onel, Howard Miller, et al. “A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation.” Am Surg, vol. 78, no. 5, pp. 574-581, 2012. View at: Publisher Site | PubMed

[22]      Juan Portillo, Nawal Kamar, Somayah Melibary, et al. “Safety of liposome extended-release bupivacaine for postoperative pain control.” Front Pharmacol, vol. 5, pp. 90, 2014. View at: Publisher Site | PubMed

[23]      Mona Gad Mostafa Elebieby, Mohammed Nashaat Mohammd, Khaled Abdelwahab, et al. “Analgesic effect of adding calcitonin to bupivacaine in erector spine plane block for breast surgery: a double-blind randomized study.” Egypt J Anaesth, vol. 39, no. 1, pp. 446-452, 2023. View at: Publisher Site

[24]      Saba Motakef, Wendy W Wong, Michael J Ingargiola, et al. “Liposomal bupivacaine in implant-based breast reconstruction.” Plast Reconstr Surg Glob Open, vol. 5, no. 11, pp. e1559, 2017. View at: Publisher Site | PubMed

[25]   Hyebin Yoo, Jun Seok Park, Seung Soo Oh, et al. “Osmotically balanced, large unilamellar liposomes that enable sustained bupivacaine release for prolonged pain relief in in vivo rat models.” Sci Rep, vol. 11, no. 1, pp. 12096, 2021. View at: Publisher Site | PubMed