Bupivacaine Liposome (Exparel)

Number: 0941

Policy

Aetna considers bupivacaine liposome injectable suspension (Exparel) medically necessary, with or without ultrasound guidance, as
  1. a single-dose infiltration in adults to produce postsurgical local analgesia; and
  2. an interscalene brachial plexus nerve block to produce postsurgical regional analgesia.



Aetna considers bupivacaine liposome injectable suspension experimental and investigational for all other indications because of insufficient evidence in peer-reviewed published literature.

See also: CPB 0863 - Nerve Blocks.

Dosing Recommendations

Exparel is intended for single-dose administration only.  Do not dilute Exparel with water for injection or other hypotonic solution.  Different formulations of bupivacaine are not bio-equivalent even if the milligram strength is the same.  It is not possible to convert dosing from other formulations of bupivacaine to Exparel.

The recommended dose of Exparel for local infiltration in adults is up to a maximum dose of 266 mg (20 mL).

The recommended dose of Exparel for interscalene brachial plexus nerve block in adults is 133 mg (10 mL).

Source: Prescribing Information. Exparel (bupivacaine liposome injectable suspension). 2018.

Background

In 2011, the FDA approved bupivacaine liposome injectable suspension (Exparel) for local administration via infiltration to provide post-surgical analgesia. On April 6, 2018, the FDA also approved Exparel for use as an interscalene brachial plexus nerve block to produce post-surgical regional analgesia following shoulder surgery in adults. The interscalene block is used for surgery of the shoulder and proximal upper extremity. It anesthetizes the C5 through C7 nerve roots as well as the superficial cervical plexus (C3 and C4, including the supraclavicular nerve). Depending on the volume of local anesthetic injected, the roots of C8 and T1, which form the lower trunk, are often not blocked so the interscalene block may not provide analgesia for medial (ulnar distribution) hand surgery. Local anesthetics include lidocaine, mepivacaine, ropivacaine, and bupivacaine and are chosen according to the goal of the block (surgical anesthesia or analgesia) and the desired duration of the effect of the block.

Liposomal bupivacaine (Exparel) consists of vesicles of bupivacaine loaded in the aqueous chambers using DepoFoam technology (Pacira Pharmaceuticals Inc, San Diego, CA). Each particle is composed of a honeycomb-like structure of numerous internal aqueous chambers containing encapsulated bupivacaine. Bupivacaine is present at a concentration of 13.3 mg/mL. After injection of Exparel, bupivacaine is released from the multivesicular liposomes over a period of time. Bupivacaine is related chemically and pharmacologically to the amide-type local anesthetics. It is a homologue of mepivacaine and is related chemically to lidocaine. 

The efficacy of Exparel compared to placebo was demonstrated in three multicenter, randomized, double-blinded clinical studies. For local analgesia via infiltration, a study by Golf et al (2011) evaluated the treatment in patients undergoing bunionectomy and a study by Gorfine et al (2011) evaluated the treatment in patients undergoing hemorrhoidectomy. The FDA deemed these two trials to be representative of orthopedic procedures and soft tissue procedures.

For regional analgesia, a third study evaluated the use of Exparel as a brachial plexus nerve block via interscalene or supraclavicular approach in patients undergoing total shoulder arthroplasty (TSA) or rotator cuff repair (RCR), however, only two subjects had nerve blocks via the supraclavicular approach. In accordance with recommendations made by an FDA advisory committee, the agency has determined that clinical trial data is not sufficient to support the general use of Exparel for regional nerve blocks for post-surgical analgesia other than shoulder surgery.

Golf et al (2011) compared DepoFoam bupivacaine (Pacira Pharmaceuticals, Inc., San Diego, CA, USA), an extended-release liposomal bupivacaine-based analgesic, with placebo for the prevention of pain after bunionectomy in a randomized, multicenter, double-blind phase 3 clinical study. Patients received placebo (n = 96) or DepoFoam bupivacaine 120 mg (n = 97) via wound infiltration prior to closure. Pain intensity was assessed using a numeric rating scale (NRS) from time 0 through to 72 hours postsurgically. The primary efficacy measure was area under the curve (AUC) of NRS scores through 24 hours. Other efficacy measures included AUC of NRS at other time points, proportion of patients who were pain-free, time to first opioid use, and total postsurgical consumption of supplemental opioid medication. Adverse events were also assessed. The AUC for NRS scores was significantly less in patients treated with DepoFoam bupivacaine versus patients receiving placebo at 24 hours (P = 0.0005) and 36 hours (P < 0.0229). More patients treated with DepoFoam bupivacaine avoided use of opioid rescue medication during the first 24 hours (7.2% vs. 1%; P < 0.0404) and were pain-free (NRS ≤ 1) at 2, 4, 8, and 48 hours. Median time-to-first-opioid use was delayed in favor of DepoFoam bupivacaine (4.3 vs. 7.2 hours; P < 0.0001). Fewer adverse events were reported by patients treated with DepoFoam bupivacaine (59.8%) versus placebo (67.7%). The authors concluded that DepoFoam bupivacaine, a long-acting local analgesic, provided extended pain relief and decreased opioid use after bunionectomy, compared with placebo.

Gorfine et al (2011) stated bupivacaine extended-release liposome injection is a novel formulation of bupivacaine designed to achieve long-acting postoperative analgesia. The aim of this study was to compare the magnitude and duration of postoperative analgesia from a single dose of bupivacaine extended-release injection with placebo administered intraoperatively in patients undergoing hemorrhoidectomy. This evaluation was a multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 study. Data were obtained from 13 centers in the Republic of Georgia, Poland, and Serbia. Included in this study were patients aged 18 to 86 years undergoing excisional hemorrhoidectomy. All patients received either a single dose of bupivacaine extended-release 300 mg or placebo administered intraoperatively via wound infiltration. The cumulative pain score was assessed by measurement of the area under the curve of pain intensity through 72 hours after study drug administration. One hundred eighty-nine patients were randomly assigned and treated; 186 completed the study. Pain intensity scores were significantly lower in the bupivacaine extended-release group in comparison with the group receiving placebo (141.8 vs 202.5, P < .0001). More patients in the bupivacaine extended-release group remained opioid free from 12 hours (59%) to 72 hours (28%) after surgery compared with patients receiving placebo (14% and 10%; P < .0008 through 72 h). The mean total amount of opioids consumed through 72 hours was 22.3 mg and 29.1 mg in the bupivacaine extended-release and placebo groups (P ≤ .0006). The median time to first opioid use was 14.3 hours in the bupivacaine extended-release group vs 1.2 hours in the placebo group (P < .0001). A greater proportion of patients in the bupivacaine extended-release group were satisfied with their postsurgical analgesia (95% vs 73%, P = .0007) than in the placebo group. The authors concluded that bupivacaine extended-release demonstrated a statistically significant reduction in pain through 72 hours, decreased opioid requirements, delayed time to first opioid use, and improved patient satisfaction compared with placebo after hemorrhoidectomy.

A TAP  block is a regional anesthetic technique used for post-surgical analgesia of the anterolateral abdomen. The local anesthetic is placed in the fascial plane between the internal oblique and the transverse abdominus muscles. The end result is a field block. In a field block, local anesthetic is infiltrated around the border of the surgical field, leaving the operative area undisturbed. In a December 2015 rescission letter from the FDA to the manufacturer of Exparel, Pacira Pharmaceuticals, the FDA states field block is consistent with the procedure described in the hemorrhoidectomy trial submitted in support of Exparel's approval. Therefore, TAP blocks are covered by the FDA-approved Exparel labeling. Also in this letter, the FDA states Exparel’s indication does encompass use for postoperative analgesia when administered as local infiltration at the site of oral surgical procedures, including tooth extractions. Exparel’s indication also includes local anesthetic deposited near a terminal branch of the maxillary or mandibular branch of the trigeminal nerve, also referred to as periapical injections. However, the approved indication does not include its use as a nerve block prior to dental restorative procedures or oral surgical procedures.

Exparel’s new indication as an interscalene nerve block for shoulder surgery was approved based on the results of one multicenter, randomized, double-blind, placebo-controlled study (NCT02713230) in 156 patients undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with general anesthesia. The mean age was 61 years (range 33 to 80). Prior to the surgical procedure, patients received 10 mL of Exparel (133 mg) expanded with normal saline to 20 mL as a brachial plexus nerve block via interscalene or supraclavicular approach with ultrasound guidance. Only two patients received nerve block with EXPAREL by supraclavicular approach. Postsurgically, patients were administered acetaminophen/paracetamol up to 1000 mg PO or IV every 8 hours (q8h) unless contraindicated. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5-10 mg every 4 hours or as needed). If a patient could not tolerate oral medication, IV morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) could be administered every 4 hours or as needed. In this study, there was a statistically significant treatment effect for Exparel compared to placebo in cumulative pain scores through 48 hours as measured by the AUC of the visual analog scale (VAS) pain intensity scores. There were statistically significant, but small differences in the amount of opioid consumption through 48 hours, the clinical benefit of which has not been demonstrated. For those patients who required rescue medication, the mean amount of morphine-equivalent opioid rescue used over 48 hours was 12 mg for patients treated with Exparel and 54 mg for patients treated with placebo and 23 mg with Exparel vs. 70 mg for placebo over 72 hours. Although at 48 hours, 9 subjects (13%) in the Exparel group remained opioid-free compared to 1 subject (1%) in the placebo group, a difference which was statistically significant, at 72 hours, there were 4 (6%) subjects in the Exparel group who remained opioid-free compared to 1 (1%) subject in the placebo group, a difference that is not statistically significant. 

Cao and Pan (2017) conducted a meta-analysis to compare the efficiency and safety of liposomal bupivacaine infiltration and interscalene nerve block for pain control after total shoulder arthroplasty. A systematic search was performed in Medline (1966 to May 2017), PubMed (1966 to May 2017), Embase (1980 to May 2017), ScienceDirect (1985 to May 2017) and the Cochrane Library. Only randomized controlled trials (RCTs) were included. Reported surgical outcomes, including visual analogue scale (VAS) scores, opioid consumption, length of stay, and postoperative adverse effects including the risk of nausea and vomiting. Meta-analysis was performed using Stata 11.0 software. Four RCTs including 510 patients met the inclusion criteria. The present meta-analysis indicated that there were no significant differences between groups in terms of VAS score at 12 hours (standard mean difference [SMD] = 0.272, 95% CI: -0.150 to 0.695, P = .207), 24 hours (SMD = -0.056, 95% CI: -0.458 to 0.346, P = 0.785), and 48 hours (SMD = 0.183, 95% CI: -0.148 to 0.513, P = .278). Liposomal bupivacaine infiltration groups required an equivalent amount of opioids at postoperative 12 hours (SMD = -0.039, 95% CI: -0.222 to 0.143, P = .672), 24 hours (SMD = 0.046, 95% CI: -0.136 to 0.228, P = .618) and 48 hours (SMD = -0.025, 95% CI: -0.207 to 0.157, P = .785). The authors concluded that liposomal bupivacaine infiltration provides equivalent postoperative pain control compared with interscalene nerve block following total shoulder arthroplasty. Both of them can reduce the consumption of opioids without severe adverse effects. More high-quality RCTs with long follow-up period are necessary for proper comparisons of the efficacy and safety of liposomal bupivacaine infiltration with interscalene nerve block.

Bupivacaine Liposome Compared With Bupivacaine Hydrochloride

Mont et al (2018; PILLAR Trial) stated local infiltration analgesia (LIA) with liposomal bupivacaine in patients undergoing total knee arthroplasty (TKA) has yielded mixed results. This study was designed to minimize limitations associated with previous studies and compared the effects of LIA with or without liposomal bupivacaine on pain scores, opioid consumption, including proportion of opioid-free patients, time to first opioid rescue, and safety after primary unilateral TKA. Patients (N = 140) were randomized to LIA with liposomal bupivacaine 266 mg/20 mL (admixed with bupivacaine HCl 0.5%, 20 mL) or LIA with bupivacaine HCl 0.5%, 20 mL. Standardized infiltration techniques and a standardized multimodal pain management protocol were used. The coprimary efficacy endpoints were area under the curve (AUC) of visual analog scale pain intensity scores 12-48 hours (AUC12-48) postsurgery and total opioid consumption 0-48 hours postsurgery. Mean AUC12-48 of visual analog scale pain intensity score was 180.8 with liposomal bupivacaine and 209.3 without liposomal bupivacaine (least squares [LS] mean treatment difference -26.88, P = .0381). LS mean total opioid consumption 0-48 hours postsurgery was 18.7 mg with and 84.9 mg without liposomal bupivacaine (LS ratio 0.220, P = .0048). Significant differences in favor of liposomal bupivacaine were observed for the percentage of opioid-free patients (P < .01) and time to first opioid rescue (P = .0230). Treatments were similarly well tolerated. The authors concluded that this study provides data on LIA with LB administered using optimal techniques specific to TKA. In this setting, LIA with liposomal bupivacaine significantly improved postsurgical pain, opioid consumption, and time to first opioid rescue, with more opioid-free patients and no unexpected safety concerns

Vandepitte et al (2017) examined whether liposome bupivacaine (Exparel) given in the interscalene brachial plexus block lowers pain in the setting of multimodal postoperative pain management for major shoulder surgery. Fifty-two adult patients were randomized to receive either 5 mL of 0.25% bupivacaine HCl immediately followed by 10 mL of liposome bupivacaine 133 mg (n = 26) or 15 mL of 0.25% standard bupivacaine alone (n = 26) in interscalene brachial plexus block. The primary outcome (worst pain in the first postoperative week) was assessed by the Modified Brief Pain Inventory short form. Secondary outcomes were overall satisfaction with analgesia (OBAS), functionality of the surgical arm, sleep duration, time to first opioid (tramadol) request and opioid consumption (mEq), sensory-motor block characteristics, and the occurrence of adverse effects. Worst pain was lower in patients given liposome bupivacaine added to standard bupivacaine than in patients given standard bupivacaine alone (generalized estimating equation [GEE] estimated marginal mean values, 3.6 ± 0.3 vs 5.3 ± 0.4 points on the Numeric Rating Scale, respectively, although the effect was modest, 1.6 ± 0.5; 95% confidence interval, 0.8-2.5). Total OBAS scores indicated greater satisfaction (GEE estimated marginal mean values, 1.8 ± 0.3 vs 3.3 ± 0.4 on total OBAS, respectively, with modest effect, difference, 1.4 ± 0.5; 95% confidence interval, 0.5-2.4). There were no differences in any of the other secondary outcomes. The authors concluded that liposome bupivacaine added to standard bupivacaine may lower pain and enhance patient's satisfaction in the first postoperative week even in the setting of multimodal analgesia for major shoulder surgery. This study was registered with clinicaltrials.gov (NCT02554357).

Chahar and Cummings (2012) reviewed liposomal bupivacaine and stated many attempts have been made to increase the duration of local anesthetic action. One avenue of investigation has focused on encapsulating local anesthetics within carrier molecules to increase their residence time at the site of action. This article aims to review the literature surrounding the recently approved formulation of bupivacaine, which consists of bupivacaine loaded in multivesicular liposomes. This preparation increases the duration of local anesthetic action by slow release from the liposome and delays the peak plasma concentration when compared to plain bupivacaine administration. Liposomal bupivacaine has been approved by the US Food and Drug Administration for local infiltration for pain relief after bunionectomy and hemorrhoidectomy. Studies have shown it to be an effective tool for postoperative pain relief with opioid sparing effects and it has also been found to have an acceptable adverse effect profile. Its kinetics are favorable even in patients with moderate hepatic impairment, and it has been found not to delay wound healing after orthopedic surgery. More studies are needed to establish its safety and efficacy for use via intrathecal, epidural, or perineural routes. The authors concluded that liposomal bupivacaine is effective for treating postoperative pain when used via local infiltration when compared to placebo with a prolonged duration of action, predictable kinetics, and an acceptable side effect profile. However, more adequately powered trials are needed to establish its superiority over plain bupivacaine. 

Studies That Do Not Support An Indication For Exparel (Bupivacaine Liposome)

Exparel was administered via a femoral nerve block in patients undergoing total knee arthroplasty (TKA) in two placebo-controlled studies. The results of these studies did not support a femoral nerve block indication due to inadequate safety data (Study 4 and Study 5) or due to inadequate efficacy findings (Study 5). In addition, patient falls were reported only in the Exparel treatment groups and none was reported in placebo groups.Study 4 was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study (NCT01683071) conducted in 196 patients undergoing primary unilateral total knee arthroplasty (TKA) under general or spinal anesthesia. The mean age was 65 years (range 42 to 88). Prior to the surgical procedure, 20 mL of Exparel (266 mg) was administered as a femoral nerve block with ultrasound guidance. Postsurgically, patients were allowed opioid rescue medication administered initially by intravenous injection of hydromorphone and subsequently by a patient-controlled analgesia (PCA) pump containing morphine or hydromorphone only. Once patients were tolerating oral medication, oral immediate-release oxycodone was administered on an as-needed basis (but not more than 10 mg every 4 hours) or, if that was insufficient, a third rescue of bupivacaine HCl (0.125%, 1.25 mg/mL) was administered at a rate of 8 mL per hour via the previously placed femoral nerve catheter. In this study, there was a statistically significant treatment effect for Exparel compared to placebo in cumulative pain scores through 72 hours as measured by the AUC of the NRS pain (at rest) intensity scores. There was a statistically significant, although small decrease in opioid consumption for the Exparel treatment group compared to the placebo group, the clinical benefit of which has not been established. All patients in both the Exparel and placebo treatment groups required opioid rescue medication during the first 72 hours. The mean amount of opioid rescue used over 72 hours was 76 mg for patients treated with Exparel and 103 mg for patients treated with placebo. The study was inadequate to fully characterize the safety of Exparel when used for femoral nerve block due to patient falls, which occurred only in the Exparel-treated patients and not the placebo-treated patients.

Study 5 was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study (NCT02713178), was conducted in 230 patients undergoing primary unilateral total knee arthroplasty (TKA) under general or spinal anesthesia. The mean age was 65 years (range 39 to 89). Prior to the surgical procedure, either 20 mL of Exparel (266 mg) or 10 mL of Exparel (133 mg) plus 10 mL of normal saline was administered as a femoral nerve block with ultrasound guidance. In addition to study drug, 8 mL of bupivacaine HCl (0.5%) diluted with 8 mL of normal saline was administered by the surgeon as a periarticular infiltration to the posterior capsule (8 mL each behind the medial and lateral condyles) before placement of the prosthesis. Postsurgically, patients were allowed opioid rescue medication consisting of oral immediate-release oxycodone (initiated at 5 to 10 mg every 4 hours or as needed). If a subject could not tolerate oral medication, IV morphine (2.5 to 5 mg) or hydromorphone (0.5 to 1 mg) was permitted every 4 hours or as needed. Patient-controlled analgesia was not permitted. No other analgesic agents, including NSAIDs, were permitted through 108 hours. However, to reflect the current standard of care of postsurgical multimodal therapy, all subjects received cyclobenzaprine (a single dose of 10 mg orally or as needed) and acetaminophen/paracetamol (up to 1000 mg orally or IV every 8 hours for a maximum total daily dose of 3000 mg) postsurgically. In this study there were no statistically significant treatment effects for the Exparel group compared to the placebo group in cumulative pain intensity scores or total opioid consumption. All patients in the Exparel and placebo treatment groups required opioid rescue medication over 72 hours. The mean amount of opioid rescue used over 72 hours was 69 mg for patients treated with Exparel 133 mg; 74 mg for patients treated with Exparel 266 mg, and 81 mg for patients treated with placebo. The median Tmax of bupivacaine observed in this study was 72 h with a range of 2.5 h to 108 h. Similarly to Study 4, patient falls only occurred in the Exparel-treated patients and not the placebo-treated patients.

Study 6 was a multicenter, randomized, double-blind, placebo-controlled study was conducted in 191 patients undergoing posterolateral thoracotomy under general anesthesia (NCT01802411). The mean age was 58 years (range 18 to 82). After the surgical procedure was completed but prior to the surgical site closure, 20 mL of Exparel was administered by the surgeon as an intercostal nerve block divided into three equal doses in three syringes of approximately 88 mg in 6.6 mL volume per nerve, and administered to each of three nerve segments (index nerve, nerve above, and nerve below). Postsurgically, patients were allowed opioid rescue medication administered initially by intravenous fentanyl 100 mcg, which was to be administered once via bolus only. For the US sites, the second rescue medication was to be PCA-administered morphine or hydromorphone. For the European sites, the second rescue medication was to be intramuscular administered morphine up to10 mg every 4 hours. At all sites, once a subject was tolerating oral medication, oral immediate-release oxycodone was administered (but not more than 10 mg every 4 hours). Subjects who did not achieve adequate pain relief with this regimen were to be withdrawn from the study and followed for safety only. In this study there were no statistically significant treatment effects for Exparel 266 mg compared to placebo in cumulative pain intensity scores or total opioid consumption. Four percent of patients treated with Exparel required no rescue medication at 72 hours compared to 1% treated with placebo. For those patients who did require rescue medication, the mean amount of opioid rescue used over 72 hours was 71 mg for patients treated with Exparel and 71 mg for patients treated with placebo. The median Tmax of bupivacaine observed in this study was 1 h with a range of 0.5 h to 50 h.

Smoot et al (2012) stated breast augmentation can result in significant postsurgical pain. The authors evaluate the extent and duration of analgesia achieved with extended-release DepoFoam bupivacaine (Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty under general anesthesia. In this randomized, multicenter, double-blind study, patients received a single dose of DepoFoam bupivacaine 600 mg or bupivacaine HCl 200 mg divided into the implant pockets at the conclusion of surgery. The primary efficacy measure was cumulative pain score with activity through 72 hours postoperatively. Secondary efficacy measures included pain intensity with activity and at rest, postsurgical consumption of rescue opioids, and integrated rank analysis combining pain scores at rest with the amount of opioid used. One hundred thirty-six patients were randomized and treated (DepoFoam bupivacaine, n = 66; bupivacaine HCl, n = 70). Reflecting the underpowered nature of the study, the mean cumulative pain score (numeric rating scale with activity through 72 hours) was 441.5 with DepoFoam bupivacaine versus 468.2 with bupivacaine HCl (P = .3999). Total amounts of opioid consumed were significantly lower in the DepoFoam bupivacaine group through 24 hours (P = .0211) and through 48 hours (P = .0459). The prespecified integrated rank analysis showed statistically-significant differences at multiple time points up to and including 60 hours; results on most other efficacy measures trended in favor of DepoFoam bupivacaine. No serious adverse events were reported, and no patients discontinued the study due to adverse events. The authors concluded that DepoFoam bupivacaine trended toward benefit versus bupivacaine HCl on most efficacy measures. Due to early termination, the study was underpowered to achieve statistical significance.

Bultema et al (2016) stated that in the treatment of patients with symptomatic irreversible pulpitis, endodontic debridement is a predictable method to relieve pain. However, there are clinical situations in which emergency care cannot be provided immediately. An unexplored treatment option in these cases may be the use of a long-acting anesthetic to reduce pain in untreated irreversible pulpitis. Some medical studies have shown potential for infiltrations of liposomal bupivacaine (Exparel; Pacira Pharmaceuticals, San Diego, CA) to prolong pain relief and reduce opioid use postoperatively. The purpose of this study was to compare an infiltration of liposomal bupivacaine versus bupivacaine for pain control in untreated, symptomatic irreversible pulpitis. Ninety-five emergency patients received 2% lidocaine with 1:100,000 epinephrine via infiltration or an inferior alveolar nerve block to relieve their initial presenting pain. Patients then randomly received either 4 mL liposomal bupivacaine (13.3 mg/mL) or 4 mL 0.5% bupivacaine with 1:200,000 epinephrine by infiltration. Patients received a diary for the day of the appointment and 3 days postinjection to record soft tissue numbness, pain levels, and analgesic (non-narcotic and narcotic) use. No significant differences (P < .05) were found between the 2 anesthetic formulations for pain or the use of pain medications. A statistically higher level of soft tissue numbness was found on days 1 to 3 for the liposomal bupivacaine group. The author concluded that although liposomal bupivacaine had some effect on soft tissue anesthesia, it did not reduce pain to manageable clinical levels in patients presenting with untreated, symptomatic irreversible pulpitis.

Lieblich et al (2017) evaluated the analgesic efficacy and safety of liposomal bupivacaine (LB) in third molar extraction in this phase 3, double-blind, placebo-controlled study of subjects undergoing bilateral third molar extraction. Subjects were randomized 2:1 to infiltration with LB (133 mg/10 mL) or placebo, and received opioid rescue medication as needed. Primary efficacy measure was cumulative area under the curve (AUC) of numeric rating scale (NRS) pain severity scores through 48 hours (AUC of NRS0-48) post-surgery. Other measures included AUC of NRS0-24, AUC of NRS0-72, and AUC of NRS0-96, and incidence of adverse events. There were 150 subjects in the primary efficacy population (n = 99 LB, n = 51 placebo) and 89 in the per-protocol population (n = 59 LB, n = 30 placebo). Least-squares mean for AUC of NRS0-48 was 172.3 LB versus 194.7 placebo (P = .227) in the primary efficacy population and 120.8 LB versus 183.3 placebo (P = .023) in the per-protocol population. At all time points, between-group differences in AUC of NRS scores were significant in the per-protocol population (LB lower than placebo, P < .05) but not in the primary efficacy population. The adverse event profile was similar between groups. LB produced significantly lower cumulative pain scores versus placebo at all time points in the per-protocol analysis but not in the primary efficacy analysis because of protocol violations. The authors concluded that this study indicates significant improvement in pain scores in the third molar model, but because of extensive protocol violations additional studies are warranted to demonstrate effectiveness.

Pain Managment After Cesarean Delivery / Vaginal Surgery

Jones and colleagues (2018) noted that effective post-operative pain management is a crucial component of recovery following surgery.  Narcotics are a cornerstone of post-operative analgesia, but can require a re-dosing requirement, encompass a lengthy list of side effects and adverse reaction risks, as well as carry a dependency potential.  The national focus on decreasing opioid use has directly impacted post-operative pain management.  Previous studies have reported the beneficial use of a single intra-operative injection of extended-release liposomal bupivacaine in post-operative pain management, however the same results have not been extensively studied in the urogynecology literature.  In a randomized, double-blinded, placebo-controlled trial, these researchers evaluated cumulative post-operative vaginal pain on days 1 and 3 after posterior vaginal wall surgery comparing study medication (extended-release liposomal bupivacaine) to placebo (saline).  Secondary aims were to evaluate vaginal pain on post-operative day 7 and total morphine-equivalent narcotic usage on days 1, 3, and 7.  This trial entailed 100 subjects who were recruited from Walter Reed National Military Medical Center urogynecology clinic.  All subjects were of age greater than 18 years and scheduled for surgery involving the posterior vaginal wall or muscularis (including posterior colporrhaphy, colpocleisis, sphincteroplasty, perineorrhaphy), excluding those with regular narcotic usage or concurrent pain management requiring the use of epidural anesthesia . A sample size of 96 patients was calculated.  Subjects were randomized to receive either 20 ml of extended-release liposomal bupivacaine (Exparel) or 20 ml of placebo (saline) at the end of surgery.  Concealed syringes were used and injected immediately post-operative into the lateral vaginal wall/levator muscle area and perineal body.  In-house morphine-equivalent narcotic usage was recorded along with the post-operative day 1 pain scores.  Patients were contacted by telephone on post-operative days 3 and 7.  Vaginal pain scores were evaluated using the Defense and Veterans Pain Rating Scale, cumulatively and on days 1, 3, and 7.  Overall morphine-equivalent narcotics were compared between the 2 groups.  From October 2014 through August 2017, a total of 100 patients were enrolled and completed the study; 49 (49 %) of the patients were randomized to the study group and 51 (51 %) were in the placebo group.  There was no significant difference between vaginal pain scores between the study group and the placebo group (post-operative day 1: study medication median score 1 [interquartile range [IQR] 0 to 3], placebo median score 1 [IQR 0 to 3] [p = 0.59]; post-operative day 3: study medication median score 2 [IQR 0 to3], placebo median score 1 [IQR 0 to 3] [p = 0.20]; post-operative day 7: study medication median score 3 [IQR 1 to 4], placebo median score 1.5 [IQR 0 to 3] [p = 0.06]).  Cumulative pain scores post-operative day 1 to 7 were also not significant (study medication median score 6 [IQR 1 to 10], placebo median score 4 [IQR 1 to 8] [p = 0.14]).  Multi-variate model for the presence of vaginal pain was calculated and after controlling for body mass index (BMI), age, and combined laparoscopy surgery, there was no significant difference between the study and the placebo groups (p = 0.62).  There was no statistically significant difference in morphine equivalents for the 2 groups: study medication 112.5 (IQR 45 to 207) and placebo 101.5 (IQR 37.5 to 195); p = 0.81.  The authors concluded that the use of extended-release liposomal bupivacaine in posterior vaginal wall surgeries, injected into the lateral posterior vaginal wall and perineal body, did not provide a significant decrease in post-operative pain or decrease narcotic medication usage when compared to saline.

In a randomized, patient-blinded, placebo-controlled study, Yeung and associates (2018) examined the effect of liposomal bupivacaine on post-operative pain among patients undergoing robotic sacrocolpopexy with posterior repair.  This trial recruited women who underwent robotic sacrocolpopexy with posterior repair.  Liposomal bupivacaine or normal saline placebo was injected into laparoscopic and vaginal incisions at completion of surgery.  Peri-operative care was standardized; VAS were collected at 4, 18, and 24 hours post-operatively in hospital.  Starting on post-operative day 1, participants completed twice-daily pain scales and a pain medication diary up until the evening of post-operative day 3.  The primary outcome was a 20-mm change in the VAS 18 hours post-operatively.  Secondary measures included additional pain scores, satisfaction, and narcotic use.  Sample size calculation revealed that 32 patients per arm were required to detect the 20-mm difference with 90 % power and an α of 0.05.  To allocate for drop-out, a goal of 70 was set.  Between March 2015 and April 2016, a total of 100 women were screened and 70 women were enrolled: 35 women were randomized to liposomal bupivacaine and 35 to placebo, of whom 64 (91 %) were included in the final analysis: 33 liposomal bupivacaine and 31 placebo.  No difference in demographics, surgical data, or satisfaction between groups was noted.  Median VAS at 18 hours after surgery was not statistically different in those who received liposomal bupivacaine compared with normal saline (15 mm compared with 20 mm; p = 0.52).  Other pain scales and total morphine equivalents were also similar (p = 0.90).  The authors concluded that in this study of robotic sacrocolpopexy with posterior repair, there were no differences in pain scores or narcotic use between liposomal bupivacaine and placebo injected into laparoscopic and vaginal incisions.  These researchers stated that given its lack of clinical benefit, routine use of liposomal bupivacaine is not supported for this surgical intervention.

In a single-blind, RCT, Prabhu and co-workers (2018) examined if a liposomal bupivacaine incisional block decreases post-operative pain and represents an opioid-minimizing strategy following scheduled cesarean delivery.  This trial included opioid-naive women undergoing cesarean delivery; liposomal bupivacaine or placebo was infiltrated into the fascia and skin at the surgical site, before fascial closure.  Using an 11-point numeric rating scale (NRS), the primary outcome was pain score with movement at 48 hours post-operatively.  A sample size of 40 women per group was needed to detect a 1.5-point reduction in pain score in the intervention group.  Pain scores and opioid consumption, in oral morphine milligram equivalents, at 48 hours post-operatively were summarized as medians (IQR and compared using the Wilcoxon rank-sum test.  Between March and September 2017, a total of 249 women were screened, 103 women enrolled, and 80 women were randomized; 1 woman in the liposomal bupivacaine group was excluded after randomization as a result of a vertical skin incision, leaving 39 patients in the liposomal bupivacaine group and 40 in the placebo group.  Baseline characteristics between groups were similar.  The median (IQR) pain score with movement at 48 hours post-operatively was 4 (2 to 5) in the liposomal bupivacaine group and 3.5 (2 to 5.5) in the placebo group (p = 0.72).  The median (IQR) opioid use was 37.5 (7.5 to 60) morphine milligram equivalents in the liposomal bupivacaine group and 37.5 (15 to 75) morphine milligram equivalents in the placebo group during the first 48 hours post-operatively (p = 0.44).  The authors concluded that compared with placebo, a liposomal bupivacaine incisional block at the time of cesarean delivery resulted in similar post-operative pain scores in the first 48 hours post-operatively.

Pain Management After Laparotomy

Yalamanchili and colleagues (2019) stated that efforts to achieve balance between effective pain management and opioid-related adverse events (ORAEs) have led to multi-modal analgesia regimens.  In a prospective RCT, these researchers compared opioids delivered via patient-controlled analgesia (PCA) plus liposomal bupivacaine to opioids delivered through PCA alone or PCA plus subcutaneous bupivacaine infusion (ONQ), following laparotomy.  This trial included a total of 100 patients who underwent non-emergent laparotomy.  Patients were randomly assigned to 1 of 3 study treatments: PCA only (PCAO), PCA with ONQ, or PCA with injectable liposomal bupivacaine suspension (EXP).  Main outcome measures included cumulative opioid use, daily mean patient-reported pain scores, and ORAEs through 72 hours post-operatively.  On average, the EXP (n = 31) group exhibited less than 50 % of the total opioid consumption of the PCAO (n = 36) group, and less than 60 % of that for the ONQ (n = 33) group.  Post-operative days 1 and 3 pain scores were significantly lower for the EXP group as compared to the ONQ and PCAO groups (p ≤ 0.005).  Fewer patients in the EXP group (19.4 %) experienced ORAEs compared to the PCAO (41.1 %) and ONQ (45.5 %) groups (p = 0.002).  The authors concluded that laparotomy patients treated with liposomal bupivacaine as part of a multi-modal regimen consumed less opioids, had lower pain scores, and had fewer ORAEs.  These researchers stated that the role of liposomal bupivacaine in the post-operative care of laparotomy patients merits further study.

Pain Management After Total Joint (Hip, Knee, and Shoulder) Arthroplasty

In a meta-analysis, Zhang and associates (2017) compared the safety and efficiency of local liposomal bupivacaine infiltration and traditional cocktail analgesia for pain management in total hip arthroplasty (THA).  PubMed, Embase, Web of science, Medline, and Cochrane library databases were systematically searched.  Participants were patients planned for a THA with a diagnosis of hip osteoarthritis (OA); liposomal bupivacaine was administrated in the experimental groups for pain control.  Comparisons: the control groups received local infiltration of traditional analgesics.  Outcome measures included pain scores, opioids consumption, and post-operative complications among the patients; RCTs and non-RCTs were included in this analysis.  Methodological Index for non-randomized studies scale was used to assess the methodological quality of the included studies.  Meta-analysis was conducted by Stata 11.0 software.  Systematic review registration number is CRD42017120981.  A total of 4 articles involving 308 participants were included.  Current meta-analysis revealed that there were significant differences regarding post-operative pain score at 12 hours (standard mean difference [SMD] = -0.496, 95 % CI: -0.717 to -0.275, p = 0.000), 24 hours (SMD = -0.537, 95 % CI: -0.760 to -0.313, p = 0.000), and 48 hours (SMD = -0.802, 95 % CI: -1.029 to -0.576, p = 0.000).  Liposomal bupivacaine intervention was found to significantly decrease opioid consumption at 12 hours (SMD = -0.544, 95 % CI: -0.766 to -0.323, p = 0.000), 24 hours (SMD = -0.357, 95 % CI: -0.577 to -0.138, p = 0.001), and 48 hours (SMD = -0.370, 95 % CI: -0.589 to -0.151, p = 0.001).  The authors concluded that local liposomal bupivacaine infiltration could significantly reduce VAS scores and opioid consumption within the first 48 hours following THA surgery.  In addition, there was a decreased risk of nausea and vomiting in liposomal bupivacaine groups.  The overall evidence level was low, which meant that further research is likely to significantly alter confidence levels in the effect, as well as potentially changing the estimates.  In any subsequent research, further studies should focus on the optimal dose of local anesthetics and the potential adverse side effects.  In addition, surgeries that can improve pain relief and enable faster rehabilitation and earlier discharges should also be explored.  Several potential limitations of this study should be noted; 4 articles were included and the sample size in each trial was small.  Some important outcome parameters such as ROM were not fully described and could not be included in the meta-analysis.  All included studies were retrospectives that may decrease evidence levels for the meta-analysis.  The evidence quality for each outcome was low that may influence the results of the meta-analysis.  Short-term follow-ups may lead to the under-estimation of complications, such as neurotoxicity and cardiotoxicity.  Publication bias was an inherent weakness that existed in all meta-analyses.

Kuang and colleagues (2017) noted that total knee arthroplasty (TKA) is gradually emerging as the treatment of choice for end-stage OA.  In the past, the method of liposomal bupivacaine by peri-articular injection (PAI) showed better effects on pain reduction and opioid consumption after surgery.  However, some recent studies have reported that liposomal bupivacaine by PAI did not improve pain control and functional recovery in patients undergoing TKA.  In a meta-analysis, these researchers examined if liposomal bupivacaine provided better pain relief and functional recovery after TKA.  Web of Science, PubMed, Embase, and the Cochrane Library were comprehensively searched; RCTs, controlled clinical trials, and cohort studies were included in this meta-analysis.  A total of 11 studies that compared liposomal bupivacaine using the PAI technique with the conventional PAI method were included in this meta-analysis.  The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and Cochrane Handbook were applied to assess the quality of the results published in all included studies to ensure that the results of our meta-analysis were reliable and veritable.  The pooled data analysis demonstrated that liposomal bupivacaine was as effective as the control group in terms of VAS score at 24 hours (p = 0.46), 48 hours (p = 0.43), 72 hours (p = 0.21), total amount of opioid consumption (p = 0.25), ROM (p = 0.28), length of hospital stay (LOS; p = 0.53), post-operative nausea (p = 0.34), and ambulation distance (p = 0.07).  The authors concluded that compared with the conventional PAI method, liposomal bupivacaine showed similar pain control and functional recovery following TKA.  Moreover, these investigators stated that considering the cost for pain control, liposomal bupivacaine is not worthy of being recommended as a long-acting alternative analgesic agent using the PAI method.

Alijanipour and co-workers (2017) noted that PAI of liposomal bupivacaine has been adopted as part of multi-modal pain management after TKA.  In a prospective, randomized clinical trial, these researchers enrolled 162 patients undergoing primary TKA in a single institution between January 2014 and May 2015; 87 patients were randomized to liposomal bupivacaine (experimental group), and 75 patients were randomized to free bupivacaine (control group).  All patients received spinal anesthesia and otherwise identical surgical approaches, pain management, and rehabilitation protocols.  Outcomes evaluated include the patient-reported VAS pain scores, narcotic consumption, and narcotic-related side effects (Brief Pain Inventory) within 96 hours after surgery as well as functional outcomes using the Knee Society Score (KSS) and the Short-Form 12 (SF-12) measured pre-operatively and at 4 to 6 weeks after surgery.  There were no statistically significant differences between the groups in terms of post-operative daily pain scores, narcotic consumption (by-day and overall), or narcotic-related side effects.  There were no statistically significant differences between the groups in terms of surgical (p = 0.76) and medical complications or LOS (p = 0.35).  There were no statistically significant differences in satisfaction between the groups (p = 0.56) or between the groups in post-operative KSS (p = 0.53) and the SF-12 at 4 to 6 weeks (p = 0.82, p = 0.66).  The authors concluded that as part of multi-modal pain management protocol, PAI of liposomal bupivacaine compared with bupivacaine HCl did not result in any clinically or statistically significant improvement of the measured outcomes following TKA.

Hyland and associates (2019) stated that liposomal bupivacaine (Exparel) is a long-acting local anesthetic preparation with demonstrated efficacy over placebo in reducing post-operative pain and opioid requirement.  Limited comparative efficacy and cost-effectiveness data exist for its use in TKA when used in a multi-modal, opioid-sparing analgesic and anesthetic approach.  In a prospective, randomized, single-blinded, controlled trial, these researchers examined if liposomal bupivacaine offers no clinical advantage over r standard of care but carries significant economic impact.  This trial compared liposomal bupivacaine PAI to current approach including conventional bupivacaine PAI, in the setting of regional anesthesia.  All adult unilateral TKA patients of the collaborating surgeon were eligible to participate in the study.  Patients were randomized 1:1 to either the liposomal bupivacaine protocol or the standard-of-care protocol.  All patients received regional anesthesia and standard post-operative analgesia protocols.  Patients and all post-operative healthcare providers were blinded to study arm assignment.  A total of 59 patients were enrolled per the authors’ a priori power calculation after 1 exclusion for randomization error.  No significant demographic differences between the study arms were found.  There was no statistically significant difference in the primary outcome of number of physical therapy (PT) sessions needed to achieve home-going discharge goals (3.0 ± 1.2 versus 3.6 ± 1.3, p = 0.137), nor in the clinical secondary outcomes.  A significant difference in medication charges was found.  The authors concluded that the findings of this study supported earlier literature suggesting no significant clinical benefit of using liposomal bupivacaine over standard of care in TKA and underscored cost-of-care concerns with this agent.

In a Cochrane review, Hamilton and co-workers (2017) examined the analgesic efficacy and adverse effects of liposomal bupivacaine infiltration at the surgical site for the management of post-operative pain.  The authors concluded that liposomal bupivacaine at the surgical site did not appear to reduce post-operative pain compared to placebo, however, at present the limited evidence did not demonstrate superiority to bupivacaine hydrochloride (HCl).  There were no reported drug-related serious AEs and no study withdrawals due to drug-related AEs.  Overall due to the low quality and volume of evidence their confidence in the effect estimate was limited and the true effect may be substantially different from their estimate.

Sun and associates (2019) stated that liposomal bupivacaine is a novel method for pain control following TKA, but recent studies showed no advantage for patients undergoing TKA compared with traditional PAI.  These researchers compared the clinical outcomes between liposomal bupivacaine treatment and traditional PAI.  They retrospectively reviewed data from 16 clinical trials in published databases from their inception to June 2017.  The primary outcome was post-operative VAS score and secondary outcomes included opiate usage, narcotic consumption, ROM, and LOS.  A total of 9 RCTs and 7 non-RCTs involving 924 liposomal bupivacaine cases and 1,293 traditional PAI cases were eligible for inclusion in the meta-analysis.  No differences were detected in most of the clinical outcomes, except for post-operative VAS within 12 hours and LOS.  The authors concluded that this analysis showed that liposomal bupivacaine was not associated with significant improvement in post-operative pain control or other outcomes in TKA compared with PAI.

Zamora and colleagues (2019) stated that appropriate pain control is one of the cornerstones necessary to promote positive clinical outcomes.  A new bupivacaine liposomal formulation was designed to extend its analgesic effect for up to 72-hours post-surgery, reportedly leading to significant opioid-sparing.  These researchers carried out a retrospective and prospective chart review in a 178-bed academic institution between January 2013 to December 2013 and August 2014 to November 2014, in 115 patients who received hip and knee arthroplasty.  The primary outcome was the measurement of average daily pain score on post-operative days 1 and 2.  Secondary outcomes included LOS, overall opioid use post-surgery and pain control satisfaction using Press-Ganey scores.  The average pain scores in the HCl group were 4.64 and 4.38 (Likert score: 0 to 10) for POD 1 and POD 2, compared to 4.72 POD 1 and 4.2 POD 2 in the liposome group (POD 1: p = 0.413; POD 2: p = 0.303).  The difference in LOS for knee arthroplasty was statistically significant [HCl group: 1.94 days (± 0.66) versus liposome group: 2.27 days (± 0.77) p = 0.038)] favoring the standard of care (SOC).  For hip arthroplasty or bilateral knee arthroplasty the differences in LOS were not statistically significant (p = 0.052 and p = 0.484, respectively); 93 % of the patients in the HCl group, pain was well controlled, versus 88.5 % in the liposome group with similar oxycodone IR use among groups.  The authors concluded that liposome bupivacaine did not offer a notable benefit compared to the HCl formulation in this study.

Sethi and associates (2019) noted that arthroscopic rotator cuff repair (ARCR) provides excellent clinical outcomes but is often associated with significant post-operative pain.  The use of intra-operative anesthesia in conjunction with multi-modal pharmacologic strategies is a widely accepted approach for managing surgical pain and reducing opiate use.  These researchers examined if using a combined field and supra-scapular nerve block with liposomal bupivacaine (LB) in addition to an interscalene block would provide greater pain relief and a reduction in opiate consumption compared with an interscalene block alone.  The study enrolled 50 patients with full-thickness rotator cuff tears undergoing primary ARCR surgery.  Patients were randomized to receive intra-operative LB (n = 25) or not (n = 25) and given post-operative "pain journals" to document VAS pain scores and to track their daily opioid consumption during the first 5 post-operative days.  Patients in the LB group reported statistically and clinically lower pain scores during post-operative days 1 and 2 (p < 0.0001 and p = 0.03, respectively).  In addition, patients in the LB group consumed significantly fewer narcotics than the control group during the 5-day period, demonstrating a 64 % reduction in total narcotic consumption (p = 0.002).  The authors concluded that the findings of this study suggested that the addition of LB to multi-modal anesthetic protocols significantly reduced the acute peri-operative pain experienced following rotator cuff repair and the number of narcotic pills consumed in the first 5 days following ARCR.  This was a relatively small study (n = 25 in the liposomal bupivacaine + multi-modal anesthetic group).

Yayac and co-workers (2019) noted that since its FDA approval in 2011 as a local anesthetic for post-surgical analgesia, liposomal bupivacaine (LB) has been incorporated into the peri-articular injection (PAI) of many knee surgeons.  The slow release of this medication from vesicles should significantly extend the duration of its analgesic effect, but current evidence has not clearly demonstrated this benefit.  These researchers systematically searched electronic databases including PubMed, Medline, Cochrane Library, Embase, ScienceDirect, and Scopus, as well as the Journal of Arthroplasty web page for relevant articles.  All calculations were made using Review Manager 5.3.  They identified 42 studies that compared LB to an alternate analgesic modality; 17 of these studies were controlled trials that were included in meta-analysis.  Significant differences were observed in pain scores with LB over a peripheral nerve block (MD = 0.45, p = 0.02) and LB over a traditional PAI (SMD = -0.08, p = 0.004).  The authors concluded that while LB may offer a statistically significant benefit over a traditional PAI, the increase in pain control may not be clinically significant and it did not appear to offer a benefit in reducing opioid consumption.  However, there is no standardization among current studies, as they varied greatly in design, infiltration technique, and outcome measurement, which precluded any reliable summarization of their results.  These researchers stated that future independent studies using a standardized protocol are needed to provide clear unbiased evidence.

Warnings and Precautions

Exparel is contraindicated in obstetrical paracervical block anesthesia.

Monitor cardiovascular status, neurological status, and vital signs during and after injection of Exparel.

Adverse reactions reported with an incidence greater than or equal to 10% following Exparel administration via infiltration were nausea, constipation, and vomiting; adverse reactions reported with an incidence greater than or equal to 10% following Exparel administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation.

If Exparel and other non-bupivacaine local anesthetics, including lidocaine, are administered at the same site, there may be an immediate release of bupivacaine from Exparel. Therefore, Exparel may be administered to the same site 20 minutes after injecting lidocaine.

Avoid additional use of local anesthetics within 96 hours following administration of Exparel.

Exparel is not recommended to be used in the following patient population: patients <18 years old and/or pregnant patients.

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, Exparel should be used cautiously in patients with hepatic disease.

Exparel is not recommended for the following types or routes of administration: epidural, intrathecal, regional nerve blocks (other than interscalene brachial plexus nerve block), or intravascular or intra-articular use.

The potential sensory and/or motor loss with Exparel is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days, as seen in clinical trials.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

CPT codes covered if selection criteria are met:

64415 Injection, anesthetic agent; brachial plexus, single

HCPCS codes covered if selection criteria are met:

C9290 Injection, bupivacaine liposome, 1 mg

ICD-10 codes covered if selection criteria are met (not all-inclusive):

Numerous options Single-dose infiltration in adults and postsurgical local analgesia

The above policy is based on the following references:

  1. Alijanipour P, Tan TL, Matthews CN, et al. Periarticular injection of liposomal bupivacaine offers no benefit over standard bupivacaine in total knee arthroplasty: A prospective, randomized, controlled trial. J Arthroplasty. 2017;32(2):628-634.
  2. Bultema K, Fowler S, Drum M, et al. Pain reduction in untreated symptomatic irreversible pulpitis using liposomal bupivacaine (Exparel): A prospective, randomized, double-blind trial. J Endod. 2016;42(12):1707-1712.
  3. Cao X, Pan F. Comparison of liposomal bupivacaine infiltration versus interscalene nerve block for pain control in total shoulder arthroplasty: A meta-analysis of randomized control trails. Medicine (Baltimore). 2017;96(39):e807.
  4. Chahar P, Cummings KC. Liposomal bupivacaine: a review of a new bupivacaine formulation. Journal of Pain Research. 2012;5:257-264.
  5. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. 2011;28(9):776-88.
  6. Gorfine SR, Onel E, Patou G, et al. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011;54(12):1552–1559.
  7. Hamilton TW, Athanassoglou V, Mellon S, et al. Liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain. Cochrane Database Syst Rev. 2017 Feb 1;2:CD011419.
  8. Hyland SJ, Deliberato DG, Fada RA, et al. Liposomal bupivacaine versus standard periarticular injection in total knee arthroplasty with regional anesthesia: A prospective randomized controlled trial. J Arthroplasty. 2019;34(3):488-494.
  9. Jeng CL and Rosenblatt MA. Upper extremity nerve blocks: Techniques. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017.
  10. Jones CL, Gruber DD, Fischer JR, et al. Liposomal bupivacaine efficacy for postoperative pain following posterior vaginal surgery: A randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 2018;219(5):500.e1-500.e8.
  11. Kuang MJ, Du Y, Ma JX, et al. The efficacy of liposomal bupivacaine using periarticular injection in total knee arthroplasty: A systematic review and meta-analysis. J Arthroplasty. 2017;32(4):1395-1402.
  12. Lieblich SE, Danesi H. Liposomal bupivacaine use in third molar impaction surgery: INNOVATE Study. Anesth Prog. Fall 2017;64(3):127-135.
  13. Liu Y, Zeng JF, Zeng Y, et al. Comprehensive comparison of liposomal bupivacaine with femoral nerve block for pain control following total knee arthroplasty: An Updated Systematic Review and Meta-Analysis. Orthop Surg. 2019;11(6):943-953.
  14. Mont MA, Beaver WB, Dysart SH, et al. Local infiltration analgesia with liposomal bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: Results of a randomized controlled trial. J Arthroplasty. 2018;33(1):90-96.
  15. Prabhu M, Clapp MA, McQuaid-Hanson E, et al. Liposomal bupivacaine block at the time of Cesarean delivery to decrease postoperative pain: A randomized controlled trial. Obstet Gynecol. 2018;132(1):70-78.
  16. Raman S, Lin M, Krishnan N. Systematic review and meta-analysis of the efficacy of liposomal bupivacaine in colorectal resections. J Drug Assessment. 2018;7(1):43-50.
  17. Sethi PM, Brameier DT, Mandava NK, Miller SR. Liposomal bupivacaine reduces opiate consumption after rotator cuff repair in a randomized controlled trial. J Shoulder Elbow Surg. 2019;28(5):819-827.
  18. Smoot JD, Bergese SD, Onel E, et al. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: a randomized, double-blind, active-control study. Aesthet Surg J. 2012;32(1):69-76.
  19. Sun H, Huang Z, Zhang Z, Liao W. A meta-analysis comparing liposomal bupivacaine and traditional periarticular injection for pain control after total knee arthroplasty. J Knee Surg. 2019;32(3):251-258.
  20. U.S. Food and Drug Administration (FDA). Exparel (bupivacaine liposome injectable suspension). Prescribing Information. Reference ID: 4247612. Rockville, MD: FDA; revised April 2018.
  21. U.S. Food and Drug Administration (FDA). FDA In Brief: FDA approves new use of Exparel for nerve block pain relief following shoulder surgeries. Silver Spring, MD: FDA; April 6, 2018. 
  22. U.S. Food and Drug Administration (FDA). Exparel rescission letter. Silver Spring, MD; FDA; December 14, 2015. Available at: https://www.fda.gov/media/95042/download. Accessed November 17, 2020.
  23. Yalamanchili H, Thorns J, Buchanan S, et al. Post laparotomy pain management: Patient controlled analgesia pump alone versus adjunctive continuous subcutaneous bupivacaine infusion or
    injection of liposomal bupivacaine suspension. J Opioid Management. 2019;15(2):169-175.
  24. Vandepitte C, Kuroda M, Witvrouw R, et al. Addition of liposome bupivacaine to bupivacaine HCl versus bupivacaine HCl alone for interscalene brachial plexus block in patients having major shoulder surgery. Reg Anesth Pain Med. 2017;42(3):334-341.
  25. Yayac M, Li WT, Ong AC, et al. The efficacy of liposomal bupivacaine over traditional local anesthetics in periarticular infiltration and regional anesthesia during total knee arthroplasty: A systematic review and meta-analysis. J Arthroplasty. 2019;34(9):2166-2183.
  26. Yeung J, Crisp CC, Mazloomdoost D, et al. Liposomal bupivacaine during robotic colpopexy and posterior repair: A randomized controlled trial. Obstet Gynecol. 2018;131(1):39-46.
  27. Zamora FJ, Madduri RP, Philips AA, et al. Evaluation of the efficacy of liposomal bupivacaine in total joint arthroplasty. J Pharm Pract. 2019 Sep 16 [Epub ahead of print].
  28. Zhang X, Yang Q, Zhang Z. The efficiency and safety of local liposomal bupivacaine infiltration for pain control in total hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(49):e8433.