Summarize the literature available for the use of Exparel in various indications, including ankle fractures, forefoot reconstruction procedures, and ankle reconstruction including arthroplasty and fusion.

Comment by InpharmD Researcher

There is a moderate body of literature evaluating Exparel (liposomal bupivacaine) in foot and ankle surgery overall, although procedure-specific evidence is limited, particularly for ankle arthrodesis and other ankle reconstruction procedures. In ankle fracture fixation, randomized evidence demonstrated lower early postoperative pain scores with Exparel, while significant reductions in opioid consumption were limited to the immediate postoperative period. In forefoot procedures, Exparel has been associated with reduced early postoperative opioid consumption, with randomized bunionectomy data demonstrating reductions in both postoperative pain and opioid requirements. For total ankle arthroplasty, Exparel produced similar pain scores, opioid refills, and complication rates compared with continuous popliteal sciatic nerve blockade. Data for ankle arthrodesis are limited to one small prospective study (Table 5), which reported stabilization of pain after postoperative day 1, high patient satisfaction, and no Exparel-associated wound complications or persistent paresthesias. Overall, Exparel may provide postoperative analgesic and opioid-sparing benefits across these procedures, but the magnitude and consistency of benefit appear to vary by procedure and comparator.

Background

A 2026 systematic review evaluated liposomal bupivacaine (LB; Exparel) for postoperative analgesia in lower-extremity arthroplasty using 9 randomized controlled trials (N= 828), including 1 total ankle arthroplasty study. The review states that evidence for LB in foot and ankle surgery remains limited. In ankle procedures, LB provided pain control comparable to continuous nerve blocks (mean VAS difference, −0.4 points; 95% confidence interval [CI] −1.2 to 0.3; p> 0.05) and was associated with a 12.9% absolute reduction in catheter-related complications (95% CI 2.1%–23.7%; p= 0.04). Forefoot surgery data similarly showed comparable analgesic efficacy between LB and conventional local anesthetics; specific outcomes for ankle fractures or ankle arthrodesis were not reported. [1]

Literature Review

A search of the published medical literature revealed 10 studies investigating the researchable question:

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-10 for your response.

Efficacy of Liposomal Bupivacaine in Ultrasound-Guided Peripheral Nerve Blocks for Postoperative Pain Management in Foot and Ankle Surgery
Design	Prospective, randomized, single-anonymized controlled study N= 248
Objective	To compare the efficacy of liposomal bupivacaine (LB) in ultrasound (US)-guided peripheral nerve blocks, surgeon-administered LB field blocks, and a control group using peripheral nerve block (PNB) with local anesthetic only
Study Groups	US-guided PNB with local anesthetic only (n= 70) US-guided PNB with LB (n= 98) Surgeon-administered LB field block (n= 80)
Inclusion Criteria	Age >18 years; undergoing elective foot and ankle surgery
Exclusion Criteria	Surgery resulting from traumatic injury; inability to consent for surgery; inability to be reached via phone during postoperative course
Methods	Patients were randomized to 1 of 3 interventions: Group 1, US-guided PNB with conventional bupivacaine alone, administered as a popliteal block (20–30 mL of 0.5% bupivacaine) or combined popliteal/adductor canal blocks (20 mL of 0.5% and 15 mL of 0.25% bupivacaine, respectively); Group 2, US-guided PNB with LB plus conventional bupivacaine, administered as a popliteal block (20 mL LB + 10 mL of 0.5% bupivacaine) or combined popliteal/adductor canal blocks (15 mL LB + 10 mL of 0.5% bupivacaine and 5 mL LB + 15 mL of 0.25% bupivacaine, respectively); or Group 3, surgeon-administered infiltrative field block with 20 mL LB + 10 mL of 0.25% bupivacaine.
Duration	March 2022 to January 2023
Outcome Measures	Primary: Number of opioid pills taken from POD 0 to POD 4 S Secondary: Opioid requirements in oral morphine equivalents, block duration, PROMIS scores
Baseline Characteristics		US-guided PNB with local anesthetic only (n= 70)	US-guided PNB with LB (n= 98)	Surgeon-administered LB field block (n= 80)
	Female	39 (55.7%)	58 (59.2%)	41 (51.2%)
	BMI	31.77 ± 6.85	33.07 ± 7.05	30.95 ± 7.05
	Smoking status - No	40 (57.1%)	55 (56.1%)	50 (62.5%)
	Smoking status - Yes	6 (8.6%)	10 (10.2%)	7 (8.8%)
	Smoking status - Previous	24 (34.3%)	33 (33.7%)	23 (28.7%)
	Diabetes	3 (4.3%)	8 (8.2%)	8 (10.0%)
	ASA classification - 1	8 (11.4%)	10 (10.3%)	13 (61.3%)
	ASA classification - 2	42 (60.0%)	57 (58.8%)	46 (57.5%)
	ASA classification - 3	20 (28.6%)	29 (29.9%)	21 (26.3%)
	ASA classification - 4	0	1 (1.0%)	0
	Procedure based on area of foot - Ankle	36 (51.4%)	48 (49.0%)	31 (38.8%)
	Procedure based on area of foot - Forefoot	15 (21.4%)	18 (18.4%)	22 (27.5%)
	Procedure based on area of foot - Hindfoot	15 (21.4%)	23 (23.5%)	15 (18.8%)
	Procedure based on area of foot - Midfoot	4 (5.7%)	9 (9.2%)	12 (15.0%)
	Popliteal vs popliteal/adductor - Popliteal only	23 (32.9%)	28 (28.6%)	0
	Popliteal vs popliteal/adductor - Popliteal/adductor	47 (67.1%)	70 (71.4%)	0
	Popliteal vs popliteal/adductor - N/A	0	0	80 (100%)
	Revision/prior surgery	9 (12.9%)	19 (19.4%)	11 (13.8%)
	90-d readmission	2 (2.9%)	4 (4.1%)	5 (6.3%)
	Weightbearing after surgery - WBAT	18 (25.7%)	25 (25.8%)	22 (27.5%)
	Weightbearing after surgery - NWB	47 (67.1%)	71 (73.2%)	53 (66.3%)
	Weightbearing after surgery - PWB	5 (7.1%)	1 (1.0%)	4 (5.0%)
	Weightbearing after surgery - TTWB	0	0	1 (1.3%)
	Abbreviations: BMI, body mass index; NWB, nonweightbearing; PWB, partial weightbearing; TTWB, toetouch weightbearing; WBAT, weightbearing as tolerated.
Results		US-guided PNB with local anesthetic only (n= 70)	US-guided PNB with LB (n= 98)	Surgeon-administered LB field block (n= 80)	p-value
	PACU OME, median (range)	0 (0-57.5)	0 (0-67.5)	7.5 (0-102)	0.017
	Number of opioid pills taken from PACU, POD 4, median (range)	6.5 (0-26)	4 (0-21)	5.5 (0-64)	0.025
	Length of block, d, median (range)	1.25 (0.42-2.5)	3 (1-7)	1.5 (0.04-3.0)	<0.001
	Length of block, h, median (range)	30 (10-60)	72 (24-168)	36 (1-72)	<0.001
	Daily average OME, POD 1-4, median (range)	48.75 (0-195)	30 (0-157.5)	37.5 (0-480)	0.011
	Abbreviations: OME, oral morphine equivalents; PACU, postanesthesia care unit. Six major complications occurred, none related to the nerve blocks; 1 nerve block–related minor complication occurred in the ultrasound-guided LB PNB group (foot drop that resolved by POD 10).
Adverse Events	Six major complications were reported, none of which were related to the nerve blocks. One nerve block–related minor complication occurred in the ultrasound-guided LB PNB group: temporary foot drop that resolved by POD 10. Other minor complications included wound-healing issues and superficial infection.
Study Author Conclusions	US-guided peripheral nerve blocks using liposomal bupivacaine were associated with reduced postoperative opioid consumption and prolonged block duration in patients undergoing foot and ankle surgery. Compared with both local anesthetic–only blocks and surgeon-administered field blocks with liposomal bupivacaine, US-guided delivery provided more sustained analgesia. These findings suggest a potential benefit of liposomal bupivacaine in regional anesthesia protocols, though further studies are warranted to assess its generalizability across surgical subtypes and to evaluate long-term safety.
Critique	The study's prospective, randomized design is a strength, providing robust data on the efficacy of liposomal bupivacaine in reducing opioid use and prolonging analgesia. However, the study's limitations include unequal group sizes due to randomization, potential recall bias in patient-reported outcomes, and lack of stratification by specific surgical procedures or weightbearing status. The modest differences between groups and the study's design may limit the generalizability of the findings. Further research is needed to explore the long-term safety and efficacy of liposomal bupivacaine in various surgical contexts.

Table 1 References:
[2] McKeeman J, Smith B, Malige A, Bates R, Pellegrino AN, Lachman J. Efficacy of Liposomal Bupivacaine in Ultrasound-Guided Peripheral Nerve Blocks for Postoperative Pain Management in Foot and Ankle Surgery. Foot Ankle Int. 2025;46(10):1147-1155. doi:10.1177/10711007251359634

The Use of Liposomal Bupivacaine Administered With Standard Bupivacaine in Ankle Fractures Requiring Open Reduction Internal Fixation: A Single-Blinded Randomized Controlled Trial
Design	Prospective single-blinded randomized control trial N= 76
Objective	To determine the efficacy of liposomal bupivacaine (Exparel) compared to placebo for postoperative pain control in patients undergoing operative fixation of ankle fractures
Study Groups	General anesthesia alone (n= 39) General anesthesia with liposomal bupivacaine + bupivacaine (n= 37)
Inclusion Criteria	Patients with acute ankle fractures (OTA/AO 44A-C) requiring operative fixation, surgically managed on a nonelective basis, over 18 years of age
Exclusion Criteria	Patients on chronic opioids or with a neurologic condition that could interfere with pain sensation
Methods	Patients were randomly assigned to receive either local intraoperative liposomal bupivacaine (intervention) or normal saline (control) under general anesthesia. Liposomal bupivacaine was administered as a 40-mL 1:1 mixture of 1.3% liposomal bupivacaine and sterile saline, while the control consisted of 40 mL of normal saline. The assigned solution was infiltrated into the periosteum, tendon sheaths, exposed muscle, subcutaneous tissue, and skin along the surgical incision(s).
Duration	December 2014 to May 2016
Outcome Measures	Pain scores; Percocet ingestion; overall satisfaction with pain control
Baseline Characteristics		General anesthesia with liposomal bupivacaine + bupivacaine (n= 39)	General anesthesia alone (n= 37)
	Mean age, years	41.9	42.6
	OTA/AO Fracture Classification - 44A	8	12
	OTA/AO Fracture Classification - 44B	19	16
	OTA/AO Fracture Classification - 44C	10	11
	Mean Charlson Comorbidity Index	0.8	0.9
	Mean length of stay, h	120.5	92.3
	Abbreviations: OTA, Orthopaedic Trauma Association.
Results		General anesthesia with liposomal bupivacaine + bupivacaine (n= 39)	General anesthesia alone (n= 37)	p-value
	Percocet ingestion at 4 hours	0.7	1.3	0.004
	Percocet ingestion at 48 hours	2.8	3.69	0.07
	Pain scores were significantly lower with liposomal bupivacaine than with saline at each assessed time point. Percocet use was significantly lower with liposomal bupivacaine at 4 hours (0.7 vs 1.3 doses; p= 0.004), but differences were not significant at 24, 48, or 72 hours or for total use over postoperative days 1–3 (8.8 vs 11.1; p= 0.12). There were no significant differences between groups in post-anesthesia care unit (PACU) morphine use (p= 0.22), pain scores or total pain medication use between postoperative day 3 and day 14 (p= 0.79 and p= 0.15, respectively), satisfaction with pain control (p= 0.93), or PACU or hospital length of stay. Results primarily presented in figures.
Adverse Events	No adverse events or major complications were reported; 1 patient receiving liposomal bupivacaine experienced generalized ankle pruritus that resolved within 24 hours without medication.
Study Author Conclusions	Local intraoperative infiltration of liposomal bupivacaine administered with standard bupivacaine for ankle fractures requiring ORIF affords improved pain relief in the immediate postoperative period resulting in a reduction in Percocet ingestion, with resultant effects seen up to 2 days postoperatively. Continued investigation of this drug for use with extremity fractures is warranted.
Critique	The study's strength lies in its design as a single-blinded, prospective, randomized control trial, allowing for direct observation of the effects of liposomal bupivacaine. However, limitations include the lack of standardization of adjuvant pain medication in the immediate postoperative period and potential inaccuracies due to patient-reported data. Additionally, the study did not find a significant reduction in hospital length of stay, which may limit the perceived cost-effectiveness of the intervention.

Table 2 References:
[3] Davidovitch R, Goch A, Driesman A, Konda S, Pean C, Egol K. The Use of Liposomal Bupivacaine Administered With Standard Bupivacaine in Ankle Fractures Requiring Open Reduction Internal Fixation: A Single-Blinded Randomized Controlled Trial. J Orthop Trauma. 2017;31(8):434-439. doi:10.1097/BOT.0000000000000862

Liposomal Bupivacaine Versus Continuous Popliteal Sciatic Nerve Block in Total Ankle Arthroplasty
Design	Retrospective comparative study N= 75
Objective	To compare use of intraoperative liposomal bupivacaine (LB) injection to continuous popliteal sciatic nerve block (CPSNB) as a regional anesthetic for total ankle arthroplasty, focusing on postoperative pain scores, narcotic use, and complications
Study Groups	LB (n= 41) CPSNB (n= 34)
Inclusion Criteria	Patients who underwent primary total ankle arthroplasty with available medical records and follow-up for at least 90 days
Exclusion Criteria	Patients undergoing revision ankle arthroplasty, younger than 18 years, pregnant or nursing
Methods	Retrospective review of patients undergoing primary total ankle arthroplasty (TAA) who received either a preoperative single-shot popliteal sciatic nerve block with 0.2% ropivacaine followed by intraoperative LB infiltration or a preoperative CPSNB with 0.2% ropivacaine. In the LB group, 10 mL was injected into the posterior capsule/pericapsular tissues, 4 mL into the anterior capsule/pericapsular tissues, and 3 mL into each of the medial and lateral subcutaneous tissues. The CPSNB group received continuous 0.2% ropivacaine through an indwelling catheter, with catheter removal at 48–72 hours.
Duration	3-year period
Outcome Measures	VAS pain score at 8 hours, 24 hours, 1 week, and 3 weeks; need for opioid pain medication refill; physician office notification for pain issues; complications within 90 days
Baseline Characteristics		LB (n= 41)	CPSNB (n= 34)
	Age, years	56.7	62.2
	Gender (Male/Female)	27/14	21/13
	Body mass index	32.5	29.2
	ASA	2.2	2.2
	Laterality (R/L)	26/15	24/10
	Diagnosis - Primary osteoarthritis	11 (27%)	6 (18%)
	Diagnosis - Posttraumatic arthritis	26 (63%)	27 (79%)
	Diagnosis - Rheumatoid arthritis	4 (10%)	1 (3%)
	Additional procedures	1.6	2.1
	All patients had end-stage ankle arthritis with clinical and radiographic indications for total ankle arthroplasty.
Results		LB (n= 41)	CPSNB (n= 34)	P Value
	Complications	2 (5%)	4 (12%)	0.40
	Readmissions	1 (2%)	0	>0.99
	Emergency department visits without admission	0	0	>0.99
	Reoperations	0	0	>0.99
	VAS pain score (8 h)	1.8	2.1	0.59
	VAS pain score (24 h)	3.5	3.2	0.65
	VAS pain score (1 wk)	2.6	2.2	0.27
	VAS pain score (3 wk)	2.2	1.9	0.40
	Narcotic refills	16 (39%)	12 (35%)	0.81
	Physician office contact episodes	2 (5%)	5 (15%)	0.23
Adverse Events	No anesthetic-specific complications or adverse medical events were reported. Superficial anterior wound breakdown occurred in 2 LB patients and 4 CPSNB patients; 1 LB patient was readmitted 4 days after surgery for rehabilitation placement.
Study Author Conclusions	Liposomal bupivacaine was safe and effective as an option for regional anesthetic and postoperative pain control, with comparable results to continuous popliteal sciatic nerve block.
Critique	The study provides valuable insights into the use of liposomal bupivacaine in total ankle arthroplasty, showing it as a viable alternative to continuous popliteal sciatic nerve block. However, the retrospective design and small sample size limit the generalizability of the findings. Additionally, the variability in opioid prescriptions and the lack of blinding may have influenced the results.

Table 3 References:
[4] Mulligan RP, Morash JG, DeOrio JK, Parekh SG. Liposomal Bupivacaine Versus Continuous Popliteal Sciatic Nerve Block in Total Ankle Arthroplasty. Foot Ankle Int. 2017;38(11):1222-1228. doi:10.1177/1071100717722366

EXPAREL® (Long-Acting Liposomal Bupivacaine) Use for Popliteal Nerve Block in Postoperative Pain Control after Ankle Fracture Fixation
Design	Case series
Case 1	A 46-year-old female presented with a lateral malleolus fracture after a fall and underwent ankle open reduction and internal fixation (ORIF). She received a preoperative popliteal nerve block with 20 mL of 1.3% EXPAREL (liposomal bupivacaine; 266 mg). On arrival to the Postoperative Anesthesia Care Unit (PACU), she had absent cold sensation in the targeted dermatomes but reported pain of 10/10, which decreased to 3/10 at 60 minutes and 0/10 at 120 minutes after IV hydromorphone; she also received IV diphenhydramine for pruritus. Her highest pain scores were 8/10 on postoperative day (POD) 1, 10/10 on POD 2, and 4/10 on POD 3; she used 2 doses of Percocet 5/325 on POD 1 and subsequently used Advil for breakthrough pain because of pruritus with Percocet. Overall satisfaction was 4/5.
Case 2	A 48-year-old female presented with a bimalleolar ankle fracture after a fall and underwent ankle ORIF. She received a preoperative nerve block with 20 mL of 1.3% EXPAREL (266 mg). Her pain remained 0/10 throughout the PACU stay; her highest pain score was 8/10 on POD 1 without use of pain medication, followed by 0/10 on POD 2 and POD 3 with no oral pain medication use. She reported that the block lasted approximately 84 hours and rated her overall satisfaction 5/5.
Case 3	A 54-year-old female presented with a left bimalleolar fracture after a fall and underwent ankle ORIF. She received 20 mL of 1.3% EXPAREL (266 mg) as a nerve block. Her pain score was 3/10 initially, 5/10 at 60 minutes, and 0/10 at 120 minutes, with no pain medication required in the PACU. She reported 0/10 pain on POD 1–3 with no breakthrough pain medication, reported a block duration of approximately 72 hours, and rated her overall satisfaction 5/5.
Case 4	A 49-year-old female presented with a right bimalleolar fracture after a fall and underwent ankle ORIF. She received 20 mL of 1.3% EXPAREL (266 mg) as a nerve block and reported 0/10 pain at 60 and 120 minutes; the block was reported to wear off approximately 12 hours after placement. Her highest pain scores were 2/10 on postoperative day (POD) 1, 10/10 on POD 2, and 4/10 on POD 3, with Percocet (oxycodone/acetaminophen) and Motrin (ibuprofen) used for breakthrough pain. Numbness returned on POD 2 with inability to move her toes, persisted to the calf on POD 3, and subsequently resolved except for numbness and hyperesthesia in the sural nerve distribution that lasted 3 months; overall satisfaction was 4/5.
Study Author Conclusions	Liposomal bupivacaine (EXPAREL®) has shown to be effective at prolonging postoperative pain control when administered by wound infiltration; however, the effectiveness of this medication in use through nerve blocks is yet to be established. The results of this case series of EXPAREL® use in sciatic nerve block appear to be similar to those of previous studies conducted on healthy volunteers suggesting that there is a large degree of variability in response to the medication. These inconsistent results and the possibility of bimodal kinetics creating analgesic gaps as seen in two of our patients indicate that more studies with larger sample size are needed to better characterize these phenomena and determine if more consistent results can be obtained in a future clinical trial.

Table 4 References:
[5] Discepola P, Bouhara M, Kwon M, et al. EXPAREL (Long-Acting Liposomal Bupivacaine) Use for Popliteal Nerve Block in Postoperative Pain Control after Ankle Fracture Fixation. Pain Res Manag. 2020;2020:5982567. Published 2020 Jul 23. doi:10.1155/2020/5982567

Use of Liposomal Bupivacaine in Major Ankle and Hindfoot Surgery
Design	Prospective, single-arm observational study; meeting abstract N= 28
Objective	To evaluate the effect of surgeon-applied liposomal bupivacaine on post-operative pain in patients undergoing major ankle and hindfoot surgery.
Study Groups	All patients (N= 28)
Inclusion Criteria	Patients scheduled to undergo ankle arthrodesis, tibiotalocalcaneal arthrodesis, hindfoot arthrodesis, or a flatfoot procedure
Exclusion Criteria	Not reported in abstract
Methods	Patients received a single-shot popliteal block before surgery, followed at the conclusion of surgery by surgeon infiltration of 20 mL liposomal bupivacaine mixed with 10 mL normal saline at the surgical site.
Duration	Day of surgery (DOS) to postoperative day (POD) 3
Outcome Measures	VAS pain scores, narcotic use, antiemetic use, Post-Anesthesia Care Unit (PACU) length of stay, patient satisfaction with postoperative pain relief, and complications.
Baseline Characteristics	Mean age was 55.6 years (range, 20–80 years). No other baseline characteristics were reported in abstract.
Results	Postoperatively, 18/28 patients (64%) rated satisfaction >4 on a 5-point scale. The greatest increase in VAS pain scores occurred from the DOS to POD 1 at 4:00 PM, and satisfaction with pain control was most strongly associated with pain scores at midday on POD 3 (R=−0.68). Mean pain medication use was lowest on DOS (28.83 mg), with mean total morphine equivalents of 236.68 mg from DOS through POD 3.
Adverse Events	No complications associated with liposomal bupivacaine were reported, including postoperative wound complications, skin necrosis, or persistent paresthesias.
Study Author Conclusions	Extended-release liposomal bupivacaine-based analgesics when utilized during major ankle or hindfoot surgery, did not provide complete pain relief as demonstrated by the sharp rise in pain scores seen after the resolution of the analgesic effect of the popliteal block. However, it seemed that the effect of liposomal bupivacaine did contribute to lower pain scores at the conclusion of the period of efficacy, as there was no further rise in pain complaints after POD1 and lowest pain scores were seen on POD3. Application of liposomal bupivacaine appears to be safe without an increase in complications, wound problems, or adverse reactions.
InpharmD Researcher Critique	This study is limited by its small sample size and absence of a comparator group, limiting assessment of the effect of liposomal bupivacaine. All patients also received a single-shot popliteal block, making the contribution of liposomal bupivacaine to postoperative analgesia difficult to distinguish from the regional block. The study included multiple different ankle and hindfoot procedures, but outcomes were not reported separately by procedure. Additionally, the available publication is a conference abstract, with limited methodological and outcome detail.

Table 5 References:
[6] Adair CR, Cohen BE, Anderson RB, Davis WH, Jones CP, Ellington JK. Use of liposomal bupivacaine in major ankle and hindfoot surgery. Foot Ankle Orthop. 2016;1(1 suppl). doi:10.1177/2473011416S00320

A phase 3 active-controlled trial of liposomal bupivacaine via sciatic nerve block in the popliteal fossa after bunionectomy
Design	Two-part, randomized, double-blind, active-controlled trial (NCT05157841) N= 185
Objective	To investigate the efficacy, safety, pharmacodynamics, and pharmacokinetics of liposomal bupivacaine (LB) administered via ultrasound-guided sciatic nerve block in the popliteal fossa in participants undergoing bunionectomy
Study Groups	Part A: LB 266 mg (n= 22), LB 133 mg (n= 22), bupivacaine (n= 22) Part B: LB 133 mg (n= 59), bupivacaine (n= 60)
Inclusion Criteria	Adults with American Society of Anesthesiologists physical status classification ≤3 and body mass index ≥18 to <40 kg/m2 undergoing elective distal metaphyseal osteotomy
Exclusion Criteria	Allergy, hypersensitivity, intolerance, or contraindication to any study medications; concurrent painful physical condition requiring analgesic treatment; inadequate sensory function of the foot/ankle; history of addiction or abuse of substances; long-term opioid use within 30 days before randomization
Methods	The two-part trial randomized participants in Part A 1:1:1 to liposomal bupivacaine (LB) 266 mg, LB 133 mg, or bupivacaine HCl 50 mg; Part B randomized participants 1:1 to the LB dose selected from Part A or bupivacaine HCl 50 mg. Study drug was administered by ultrasound-guided sciatic nerve block in the popliteal fossa 90 ± 30 minutes before surgery. All participants also received celecoxib 200 mg preoperatively, a Mayo field block with 20 mL of 0.5% bupivacaine HCl immediately before incision, and IV acetaminophen 1000 mg at incision and approximately 8 hours later; oxycodone, IV morphine, or hydromorphone were permitted as needed for breakthrough pain.
Duration	February 15, 2022, to August 17, 2022
Outcome Measures	Primary: AUC of NRS pain intensity scores 0–96 h after surgery Secondary: Total postsurgical opioid consumption, opioid-free status 0–96 h after surgery, pharmacokinetic endpoints
Baseline Characteristics		LB 266 mg (n= 22)	LB 133 mg (n= 81)	Bupivacaine (n= 82)
	Age, years	48.4 ± 10.90	50.2 ± 12.82	47.2 ± 11.95
	Female	95.5%	91.4%	82.9%
	Not Hispanic or Latino	54.5%	67.9%	61.0%
	White	72.7%	58.0%	59.8%
	BMI, kg/m2	26.42 ± 4.02	28.74 ± 5.02	27.86 ± 4.82
	Abbreviations: BMI, body mass index. Most participants had an American Society of Anesthesiologists (ASA) physical status classification of 1 (57.8%). Mean worst and average pain intensity scores during the previous 30 days were 5.5 and 3.7, respectively.
Results	In Part A, LB 133 mg significantly reduced the least-squares mean (LSM) area under the curve (AUC) of numerical rating scale (NRS) pain scores from 0–96 hours versus bupivacaine HCl 50 mg (difference, −189.0; p= 0.0012), whereas LB 266 mg did not (difference, −63.0; p= 0.1515); therefore, LB 133 mg was selected for Part B. In the combined Part A+B population, LB 133 mg produced a 44% lower LSM pain AUC from 0–96 hours versus bupivacaine HCl (207.4 vs 371.4; difference, −164.0; p< 0.00001) and 61% lower LSM total opioid consumption (17.68 vs 45.34 MME; p< 0.00001). Adjusted opioid use through 96 hours was 75.6% vs 94.0%, with approximately 5-fold higher odds of being opioid-free with LB 133 mg (p=0.0003). Pain-management satisfaction was similar between groups (LSM score, 9.0 vs 9.0; p= 0.4308).
Adverse Events	Overall AE incidence was similar with LB 266 mg (59.1%), LB 133 mg (51.9%), and bupivacaine HCl (54.9%), and all AEs were mild or moderate; no deaths occurred. Treatment-related AEs occurred in 18.2%, 6.2%, and 2.4%, respectively. Two cases of peroneal nerve palsy occurred with LB 133 mg and resolved within 6 days. Study drug-related serious AEs leading to discontinuation included hypertension and pyrexia in 1 participant receiving LB 266 mg and second-degree atrioventricular block in 1 participant receiving bupivacaine HCl; all resolved the same day.
Study Author Conclusions	LB 133 mg administered via sciatic nerve block in the popliteal fossa after bunionectomy demonstrated superior and long-lasting postsurgical pain control versus bupivacaine. The clinical relevance of these findings is supported by concurrent reductions in pain and opioid consumption over 4 days after surgery and a significantly greater percentage of participants remaining opioid-free.
Critique	The study's strengths include its robust design and clear demonstration of LB's efficacy in reducing pain and opioid use. However, the study's generalizability may be limited by its specific population and setting. Additionally, the reasons for the lack of additional benefit with the higher LB dose are unclear, suggesting a potential ceiling effect or other influencing factors.

Table 6 References:
[7] Schwartz G, Gadsden JC, Gonzales J, et al. A phase 3 active-controlled trial of liposomal bupivacaine via sciatic nerve block in the popliteal fossa after bunionectomy. J Clin Anesth. 2024;94:111402. doi:10.1016/j.jclinane.2024.111402

Liposomal Bupivacaine in Forefoot Surgery
Design	Prospective therapeutic cohort study N= 40
Objective	To quantify the reduction in opioid consumption as well as postoperative pain scores in the postoperative period when liposomal bupivacaine is used at the conclusion of forefoot surgery
Study Groups	Liposomal bupivacaine group (n= 20) Bupivacaine (n= 20)
Inclusion Criteria	Patients who underwent isolated forefoot surgery from October 2013 to April 2014
Exclusion Criteria	Patients whose insurance did not cover the use of liposomal bupivacaine were placed into the control cohort
Methods	All patients received celecoxib 400 mg preoperatively and an ankle block with 10 mL of 1% lidocaine plus 0.5% bupivacaine; the LB group received 15 mL and the control group received 20 mL of 0.5% bupivacaine for the ankle block. The LB group additionally received 20 mL of LB injected into the operative wound at closure. Postoperatively, all patients received oral narcotic pain medication and celecoxib 200 mg twice daily for 3 days.
Duration	October 2013 to April 2014
Outcome Measures	Reduction in opioid consumption; postoperative pain scores; need for medication refill; time to first refill; wound complications
Baseline Characteristics		Liposomal bupivacaine group (n= 20)	Bupivacaine (n= 20)
	Mean age, years	58.0	58.0
	Female	82.5%	82.5%
Results		Liposomal bupivacaine group (n= 20)	Bupivacaine (n= 20)	p-value
	Mean pills consumed POD1	1.4	3.6	0.002
	Mean pills consumed POD2	1.8	3.6	0.021
	Patients requiring refill	3 (15.0%)	7 (35.0%)	0.273
	Wound complications	1 (5.0%)	4 (20.0%)	0.342
	Mean narcotic pill consumption was significantly lower with liposomal bupivacaine versus control on postoperative day (POD) 1 (1.4 vs 3.6; p= 0.002) and POD 2 (1.8 vs 3.6; p= 0.021), with no significant differences on POD 3 or 4. Pain scores were lower with liposomal bupivacaine on POD 1–4, but differences were not statistically significant, including cumulative pain scores (AUC, 9.2 vs 11.2; p= 0.362). Narcotic refills were required by 15% (3/20) vs 35% (7/20) of patients (p= 0.273), with a median time to refill of 20 vs 8 days (p= 0.206).
Adverse Events	No increase in wound complications in the liposomal bupivacaine group compared to control (1 vs 4).
Study Author Conclusions	Liposomal bupivacaine appears to be a useful adjunct in the treatment of postoperative pain when used as part of a multimodal analgesic regimen in patients undergoing forefoot surgery. Additional large randomized controlled trials are needed to definitively determine its utility.
Critique	The study showed a significant reduction in opioid consumption with liposomal bupivacaine, but the small sample size limits the statistical power for pain score differences. The lack of randomization due to insurance constraints and the single-surgeon experience may limit generalizability. Further large-scale randomized trials are needed to confirm findings.

Table 7 References:
[8] Robbins J, Green CL, Parekh SG. Liposomal bupivacaine in forefoot surgery. Foot Ankle Int. 2015;36(5):503-507. doi:10.1177/1071100714568664

A Phase I Study of the Pharmacokinetics, Pharmacodynamics, and Safety of Liposomal Bupivacaine for Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy
Design	Phase 1, single-center, open-label, dose-escalation trial N= 45
Objective	To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of liposomal bupivacaine (LB) alone and admixed with bupivacaine (BUPI) HCl for popliteal sciatic nerve blocks in patients having bunionectomies
Study Groups	LB 266 mg + BUPI HCl 50 mg (n= 15) LB 133 mg + BUPI HCl 50 mg (n= 10) LB 266 mg (n= 10) BUPI HCl 100 mg (n= 10)
Inclusion Criteria	Adults scheduled for bunionectomy procedures, ASA physical status classification I-III, BMI ≥18 and ≤40 kg/m2
Exclusion Criteria	Inadequate sensory function on the operative foot, concurrent physical conditions requiring analgesic treatment, history of diabetes or severe peripheral vascular disease, renal or hepatic dysfunction, long-term opioid use (≥30 morphine equivalents per day in the last 30 days)
Methods	Participants were sequentially enrolled into 4 cohorts receiving an ultrasound-guided popliteal sciatic nerve block 60 ± 30 minutes before surgery with LB 266 mg + BUPI HCl 50 mg (30 mL), LB 133 mg + BUPI HCl 50 mg (20 mL), LB 266 mg alone (20 mL), or BUPI HCl 100 mg alone (20 mL). Bunionectomy was performed under general anesthesia or propofol sedation; only short-acting opioids were permitted intraoperatively. Postoperatively, patients with pain scores <5 received nonsteroidal anti-inflammatory drugs, while those with scores ≥5 received immediate-release oxycodone, IV morphine, or hydromorphone; no other analgesics were permitted within 96 hours of the nerve block.
Duration	July 26, 2019 to December 2, 2019
Outcome Measures	Pharmacokinetics (Cmax, Tmax, AUC); onset and duration of motor and sensory nerve block; safety and tolerability; adverse events
Baseline Characteristics		LB 266 mg + BUPI HCl 50 mg (n= 15)	LB 133 mg + BUPI HCl 50 mg (n= 10)	LB 266 mg (n= 10)	BUPI HCl 100 mg (n= 10)
	Age, years	48 ± 11	48 ± 13	51 ± 12	48 ± 14
	Female	14 (93%)	8 (80%)	8 (80%)	6 (60%)
	White	12 (80%)	6 (60%)	7 (70%)	7 (70%)
	ASA physical status classification - I	13 (87%)	4 (40%)	4 (40%)	9 (90%)
	ASA physical status classification - II	2 (13%)	6 (60%)	6 (60%)	1 (10%)
	BMI, kg/m2	29 ± 4	29 ± 5	30 ± 6	28 ± 4
	Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index.
Results		LB 266 mg + BUPI HCl 50 mg (n= 10)	LB 133 mg + BUPI HCl 50 mg (n= 9)	LB 266 mg (n= 10)	BUPI HCl 100 mg (n= 10)
	Early Cmax, ng/mL	421 ± 44	235 ± 44	97 ± 36	496 ± 59
	Late Cmax, ng/mL	291 ± 42	123 ± 22	226 ± 34	NA
	All 45 participants completed the study; 6 were excluded from the pharmacokinetic analysis because of incomplete pharmacokinetic data. Median sensory block onset was similar across treatment cohorts (0.3–0.5 hours), while median sensory block duration was 119–167 hours with liposomal bupivacaine-containing regimens versus 67 hours with bupivacaine HCl 100 mg. Median motor block onset was also similar across cohorts (0.4–0.5 hours), with median duration of 119, 119, and 156 hours for liposomal bupivacaine 266 mg + bupivacaine HCl 50 mg, liposomal bupivacaine 133 mg + bupivacaine HCl 50 mg, and liposomal bupivacaine 266 mg, respectively, versus 64 hours with bupivacaine HCl 100 mg. Plasma bupivacaine concentrations appeared dose proportional based on dose-normalized AUC, and liposomal bupivacaine regimens demonstrated prolonged bupivacaine exposure. Pain scores were not formally compared statistically; mean pain AUC from 24–96 hours was numerically greater with bupivacaine HCl 100 mg than with the other cohorts.
Adverse Events	Nausea was the most common adverse event. No serious adverse events were reported. Adverse events were mild to moderate in severity. No discontinuations due to adverse events.
Study Author Conclusions	Liposomal bupivacaine provided prolonged sensory nerve block when given as popliteal sciatic nerve blocks with or without bupivacaine hydrochloride. Plasma concentrations were well below the toxicity threshold, supporting its safety and efficacy for prolonged analgesia.
Critique	The study was limited by its non-randomized design and lack of blinding, which may introduce bias. The small sample size may limit the detection of rare adverse events. However, the study provides valuable pharmacokinetic and pharmacodynamic data supporting the use of liposomal bupivacaine for prolonged analgesia in bunionectomy procedures.

Table 8 References:
[9] Sessler DI, Bao X, Leiman D, et al. A Phase I Study of the Pharmacokinetics, Pharmacodynamics, and Safety of Liposomal Bupivacaine for Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy. J Clin Pharmacol. 2025;65(4):441-451. doi:10.1002/jcph.6159

Single-Shot Liposomal Bupivacaine is a Safe and Effective Alternative to Continuous Catheter-Based Analgesia For Postoperative Pain Management of Foot and Ankle Surgery
Design	Retrospective analysis; meeting abstract N= 404
Objective	To compare the efficacy and safety of single-shot liposomal bupivacaine (Exparel) versus continuous catheter-based analgesia in managing postoperative pain in foot and ankle surgery
Study Groups	Catheter group (n= 203) Exparel (n= 201)
Inclusion Criteria	Patients who underwent foot and ankle surgery from January 2023 through December 2024 and received either continuous peripheral nerve catheter-based analgesia or a single-shot Exparel peripheral nerve block.
Exclusion Criteria	Not reported in abstract
Methods	Patients received either continuous peripheral nerve catheter-based analgesia or a single-shot liposomal bupivacaine peripheral nerve block.
Duration	January 2023 to December 2024
Outcome Measures	Postoperative opioid consumption through postoperative day 7; complication rates, including catheter-related complications such as leakage, dislodgement, and paresthesias
Baseline Characteristics	Baseline characteristics not reported in abstract
Results	The Exparel group had significantly lower postoperative opioid consumption than the continuous catheter group during the first 6 postoperative days (p< 0.001), with no significant difference on postoperative day 7 (p= 0.834).
Adverse Events	Complications occurred in 22.17% of the catheter group versus 0% of the Exparel group (p< 0.001); reported catheter-related complications included leakage, dislodgement, and paresthesias.
Study Author Conclusions	Single-shot liposomal bupivacaine offers effective postoperative pain relief with fewer complications compared to continuous catheter-based analgesia in foot and ankle surgery. The findings support its use as an opioid-sparing, cost-effective, and practical alternative to continuous infusion catheters.
InpharmD Researcher Critique	This study is limited by its retrospective design. The specific foot and ankle procedures were not reported, and outcomes were not stratified by procedure, limiting conclusions for individual surgical indications. Additionally, only an abstract was available, limiting assessment of the study.

Table 9 References:
[10] Fiore P, Kiriluk S, Baquero S, Gonzalez T, Vulcano E. Single-shot liposomal bupivacaine is a safe and effective alternative to continuous catheter-based analgesia for postoperative pain management of foot and ankle surgery. Foot Ankle Orthop. 2026;11(1 suppl). doi:10.1177/2473011426S00050

Liposomal bupivacaine for popliteal sciatic and saphenous nerve blocks in patients undergoing foot and ankle surgery: a single-center, double-blind, randomized controlled trial
Design	Single-center, double-blind, randomized controlled trial N= 142
Objective	To assess the efficacy of liposomal bupivacaine for popliteal sciatic and saphenous nerve blocks in managing pain after foot and ankle surgery
Study Groups	Ropivacaine group (R group; n= 71) Liposomal bupivacaine group (L group; n= 71)
Inclusion Criteria	BMI ranging from 18.5 to 35.0 kg/m2, aged 18 years or older, ASA I-III, and scheduled for foot and ankle surgery
Exclusion Criteria	Contraindications to nerve block anesthesia, pregnancy status, inability to cooperate, liver and kidney dysfunction, participation in other drug trials, infection at the puncture site, abnormal coagulation function, and incomplete case data
Methods	Patients were randomized 1:1 to liposomal bupivacaine or ropivacaine. Following induction of general anesthesia, patients received ultrasound-guided popliteal sciatic and saphenous nerve blocks with either liposomal bupivacaine 133 mg or ropivacaine 50 mg (0.25%), each diluted to a total volume of 20 mL; 15 mL was administered for the popliteal sciatic block and 5 mL for the saphenous block, without adjuvants. Postoperative patient-controlled analgesia contained sufentanil 100 μg plus tropisetron 10 mg in 100 mL normal saline, with IV tramadol 50 mg permitted as rescue analgesia. Procedures included primarily ankle, tibiofibular, and foot fractures, as well as wound suturing, soft-tissue reconstruction, and arthroscopic ankle ligament repair.
Duration	September 1, 2024 to January 1, 2025
Outcome Measures	Primary: Cumulative sufentanil consumption during the 24 to 48 h postoperatively Secondary: Sufentanil consumption at 6, 12, 24, 48, and 72 h; duration of analgesia; duration of motor blockade; sleep quality; quality of recovery; incidence of postoperative adverse events
Baseline Characteristics		Group R (n= 71)	Group L (n= 71)
	Age, years	39.86 ± 13.39	37.62 ± 11.54
	Female	38 (53.5%)	36 (50.7%)
	BMI, kg/m2	24.74 ± 2.25	25.07 ± 2.72
	ASAII	65 (91.5%)	63 (88.7%)
	ASAIII	6 (8.5%)	8 (11.3%)
	Smoking history	12 (16.9%)	8 (11.3%)
	Alcohol history	11 (15.5%)	13 (18.3%)
	Operation history - Primary Surgery	53 (74.6%)	57 (80.3%)
	Operation history - Multiple Surgeries	18 (25.4%)	14 (19.7%)
	Operative type - Fracture	46 (64.8%)	50 (70.4%)
	Operative type - Non-fracture injuries	25 (35.2%)	21 (29.6%)
	Sleep quality (IQR)	3 (1–8)	4 (2–7)
	Anxiety scale - Low	11 (15.5%)	7 (9.9%)
	Score of Pain Catastrophizing Scale (IQR)	34 (32–40)	33 (29–38)
	Vasoactive medications - Ephedrine	5 (7.0%)	4 (5.6%)
	Vasoactive medications - Phenylephrine	9 (12.7%)	7 (9.9%)
	Surgery duration, min (IQR)	125 (100–142)	136 (112–147)
	Anesthesia duration, min (IQR)	19 (16–22)	18 (17–22)
Results	Sufentanil consumption	Group R (n= 71)	Group L (n= 71)	Mean Difference (95% CI)	p-value
	24 h–48 h	39.27 ± 7.14	34.45 ± 4.72	4.82 (2.81, 6.83)	<0.001
	Within 6 h	7.62 ± 1.30	7.54 ± 1.27	0.09 (−0.34, 0.51)	0.697
	Within 12 h	16.80 ± 2.65	14.56 ± 2.24	2.24 (1.42, 3.06)	<0.001
	Within 24 h	50.93 ± 5.00	28.96 ± 3.41	21.97 (20.55, 23.39)	<0.001
	Within 48 h	90.20 ± 4.70	63.41 ± 3.37	26.79 (25.43, 28.15)	<0.001
	Within 72 h	106.83 ± 4.15	82.46 ± 3.45	24.36 (23.10, 25.63)	<0.001
	Abbreviations: CI, confidence interval. Liposomal bupivacaine prolonged analgesic block (38.63 vs 10.91 hours; p< 0.001) and motor block (41.24 vs 12.45 hours; p< 0.001). On postoperative day 1, the liposomal bupivacaine group had a significantly lower Pittsburgh Sleep Quality Index (PSQI) score than the ropivacaine group (5.00 vs 9.00; p< 0.001) and a significantly higher Quality of Recovery-40 (QoR-40) score (166.00 vs 162.00; p< 0.001). No significant between-group differences in sleep quality or quality of recovery were observed at the other assessed time points.
Adverse Events	The incidence of postoperative nausea and vomiting (PONV) was significantly lower in Group L than in Group R (4.2% vs. 14.1%; p= 0.042). The incidence of dizziness was significantly reduced in Group L compared with Group R (5.6% vs. 16.9%; p= 0.034). Other postoperative complications occurred at low rates (< 5%) with no significant differences between groups.
Study Author Conclusions	The administration of liposomal bupivacaine for popliteal sciatic and saphenous nerve blocks significantly reduces postoperative opioid consumption and extends nerve block duration, providing a safe and effective technique for postoperative analgesia in patients undergoing foot and ankle surgery. Preoperative sleep quality, surgical type, and Pain Catastrophizing Scale score are independent predictors of the pain trajectory that can identify patients more likely to benefit from liposomal bupivacaine.
Critique	While the study demonstrated significant reductions in opioid consumption and prolonged analgesia with liposomal bupivacaine, the doses of liposomal bupivacaine and ropivacaine were not matched for potency or pharmacokinetics, complicating the attribution of benefits specifically to the liposomal formulation. Additionally, the study relied on patient self-assessment for duration of analgesia and motor blockade, which may introduce measurement bias. The study included heterogeneous foot and ankle procedures, and outcomes were not stratified by procedure, limiting conclusions for individual surgical indications.

Table 10 References:
[11] Wang J, Yang Y, Chen FQ, Wang K, Meng XC, Zheng J. Liposomal bupivacaine for popliteal sciatic and saphenous nerve blocks in patients undergoing foot and ankle surgery: a single-center, double-blind, randomized controlled trial. Front Med (Lausanne). 2026;13:1753354. Published 2026 Mar 3. doi:10.3389/fmed.2026.1753354