Bupivacaine Liposome (Exparel)

Number: 0941

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


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 (intracervical injection for hysterectomy, as a nerve block for knee arthroplasty, epigastric incision for major oncologic surgery, intercostal injection for Nuss procedure/rib fractures, skin graft donor sites in individuals with burn, sternotomy pain from cardiac surgery; not an all-inclusive list) 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.


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

Other CPT codes related to the CPB:

15200 - 15201 Full thickness graft, free, including direct closure of donor site, trunk
15220 - 15221 Full thickness graft, free, including direct closure of donor site, scalp, arms, and/or legs
15240 - 15241 Full thickness graft, free, including direct closure of donor site, forehead, cheeks, chin, mouth, neck, axillae, genitalia, hands, and/or feet
15260 - 15261 Full thickness graft, free, including direct closure of donor site, nose, ears, eyelids, and/or lips
15760 Graft; composite (eg, full thickness of external ear or nasal ala), including primary closure, donor area
20605 Arthrocentesis, aspiration and/or injection, intermediate joint or bursa (eg, temporomandibular, acromioclavicular, wrist, elbow or ankle, olecranon bursa); without ultrasound guidance [POP control after sternotomy]
21742 - 21743 Reconstructive repair of pectus excavatum or carinatum
27440 - 27447 Arthroplasty
33510 – 33516 Coronary artery bypass, vein only; coronary venous grafts
33533 – 33536 Coronary artery bypass, using arterial graft(s); coronary arterial grafts
58150 - 58152 Total abdominal hysterectomy (corpus and cervix)
58180 Supracervical abdominal hysterectomy (subtotal hysterectomy), with or without removal of tube(s), with or without removal of ovary(s)
58200 Total abdominal hysterectomy, including partial vaginectomy, with para-aortic and pelvic lymph node sampling, with or without removal of tube(s), with or without removal of ovary(s)
58210 Radical abdominal hysterectomy, with bilateral total pelvic lymphadenectomy and para-aortic lymph node sampling (biopsy), with or without removal of tube(s), with or without removal of ovary(s)
58260 - 58294 Vaginal hysterectomy
58541 - 58575 Laparoscopy
64420 - 64421 Injection(s), anesthetic agent(s) and/or steroid; intercostal nerve
64435 Injection(s), anesthetic agent(s) and/or steroid; paracervical (uterine) nerve [POP control after hysterectomy]
64447 Injection(s), anesthetic agent(s) and/or steroid; femoral nerve [POP control after knee arthroplasty]
64450 Injection(s), anesthetic agent(s) and/or steroid; other peripheral nerve or branch [POP control after hysterectomy] [POP control after epigastric incision for major oncologic surgery]
64454 Injection(s), anesthetic agent(s) and/or steroid; genicular nerve branches, including imaging guidance, when performed [POP control after knee arthroplasty]
64486 - 64487 Transversus abdominis plane (TAP) block (abdominal plane block, rectus sheath block) unilateral [POP control after epigastric incision for major oncologic surgery]
64488 - 64489 Transversus abdominis plane (TAP) block (abdominal plane block, rectus sheath block) bilateral [POP control after epigastric incision for major oncologic surgery]
64517 Injection, anesthetic agent; superior hypogastric plexus [POP control after epigastric incision for major oncologic surgery]
64530 Injection, anesthetic agent; celiac plexus, with or without radiologic monitoring [POP control after epigastric incision for major oncologic surgery]
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular [POP control after Nuss procedure/rib fractures]

HCPCS codes covered if selection criteria are met:

C9290 Injection, bupivacaine liposome, 1 mg

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 Management After Cesarean Delivery / Vaginal Surgery / Open Gynecologic 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.

Meyer and colleagues (2021) stated that value in healthcare is reflected by patient-centered outcomes of care per health dollar expended.  Although LB is more expensive, it has been shown to provide prolonged analgesia (up to 72 hours).  In a prospective, single-blinded RCT, these researchers examined if the addition of LB to standard bupivacaine could decrease opioid intake and improve pain control after laparotomy for gynecologic surgery compared with standard bupivacaine alone in an enhanced recovery after surgery pathway.  This trial entailed the use of wound infiltration with LB plus 0.25 % bupivacaine (study arm) versus 0.25 % bupivacaine (control arm) at a National Cancer Institute (NCI)-designated tertiary referral cancer center.  Participants were patients aged greater than or equal to 18 years undergoing exploratory laparotomy for a gynecologic indication.  All patients were treated on an enhanced recovery pathway including local wound infiltration before closure.  In this study, 266-mg of LB (free base; equal to 300 mg bupivacaine HCL) + 150-mg of bupivacaine mixed in the same syringe was used in the study arm, and 150-mg of bupivacaine was used in the control arm.  The primary outcome was the proportion of patients who were opioid-free within 48 hours after surgery.  Secondary outcomes included number of opioid-free days from post-operative day 0 to post-operative day 3, days to 1st opioid administration, morphine equivalent daily dose, and patient-reported outcomes collected with the MD Anderson Symptom Inventory.  The MD Anderson Symptom Inventory was administered as a pre-operative baseline, daily while hospitalized, and at least weekly for 8 weeks after discharge.  All outcomes were pre-specified before data collection.  A total of 102 patients were evaluated; among them, 16.7 % of patients in the study arm received no opioids up to 48 hours compared with 14.8 % in the control arm (p = 0.99).  There were no significant differences in the amounts of intra-operative opioids administered or days to 1st opioid use.  There was no significant difference between the 2 arms in median cumulative morphine equivalent daily dose (21.3 [study arm] versus 33.8 [control arm]; p = 0.36) or between the groups in morphine equivalent daily dose per individual day.  There were no significant differences in patient-reported pain or interference with walking between the 2 arms or other patient-reported outcomes.  The authors concluded that within an enhanced recovery after surgery pathway, adding LB to 0.25 % bupivacaine wound infiltration did not decrease the proportion of patients who were opioid-free within 48 hours after surgery, did not decrease opioid intake, or did not improve patient's self-reported pain and functional recovery compared with standard bupivacaine.

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.

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.

In a systematic review and meta-analysis, Zhou and associates (2020) examined the effectiveness of LB against the traditional bupivacaine infiltration in the post-operative management of THA.  Various databases including PubMed Central, Medline, Scopus, Embase, Google Scholar, Cochrane library and ScienceDirect (inception date till August 2020) were searched.  The quality of published trials was evaluated using Cochrane risk of bias tool, and a random-effects model was used for meta-analysis.  These investigators reported pooled risk ratios (RR) or pooled SMD with 95 % CIs.  They analyzed a total of 13 studies with 62,582 subjects.  The majority of the studies were retrospective with lower bias risks; LB was significantly associated with the reduction in mEq at 48 hours (SMD = -0.25; 95 % CI: -0.40 to -0.09; p = 0.002) and LOS (SMD = -0.25; 95 % CI: -0.43 to -0.07, p = 0.006) following THA compared with the control group.  However, there was no statistically significant difference between the effect of LB and other agents for pain score (24 and 48 hours), mEq at 24 hours and incidence of nausea.  The authors concluded that LB exhibited selective benefits in terms of mEq and LOS against the traditional bupivacaine among the patients undergoing THA.  Moreover, these researchers stated that RCTs or prospective investigation with larger numbers of subjects are needed to examine the effectiveness, optimal dose and post-operative management.

The authors stated that this study had several drawbacks.  Different peri-operative pain management protocols were used in all the included studies, contributing to the heterogeneity.  Limitations of the included studies did not allow these investigators to perform subgroup analysis and meta-regression to evaluate other possible sources of heterogeneity.  Most of the studies used a dosage of 266-mg LB; however, there is no evidence that this dose is optimal for the full effect of the drug.  These researchers found a possibility of publication bias in this study.  Since they only included studies comparing the effect of LB with the traditional bupivacaine, it was possible that unpublished studies might influence the findings.  Over 50 % of the included studies were retrospective; thus, It was possible that these findings may be influenced by the potential participant’s selection bias.  Finally, the generalizability of these findings was limited, since the majority of the selected studies were carried out in the United States.

Zamora and colleagues (2021) 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.

Hussain and colleagues (2021) stated that peri-articular LIA is integral to multi-modal analgesia following TKA; however, the duration of analgesia using traditional long-acting local anesthetics is often insufficient.  LIA with slow-release LB may provide extended analgesia, but evidence of efficacy beyond the first 24 hours is conflicting.  In a meta-analysis, these investigators compared the effects of peri-articular LB and plain bupivacaine LIA on day 2 analgesic outcomes post-TKA.  Studies comparing liposomal and plain bupivacaine LIA for TKA were sought.  The 2 co-primary outcomes were cumulative oral mEq consumption as well as difference in AUC of pooled rest pain scores on day 2 (24 to 48 hours) post-TKA.  These researchers also examined pain and analgesic consumption on day 3 (48 to 72 hours), functional recovery, LOS, patient satisfaction; and opioid-related side effects.  Data were pooled using random-effects modeling; a total of 17 studies (1,836 subjects) were analyzed.  Comparing LB versus plain bupivacaine LIA for TKA failed to detect differences in mEq and pain AUC on day 2 post-operatively, with mean differences (MDs) of 0.54 mg (95 % CI: -5.09 to 6.18) and 0.08 cm/hour (95 % CI: -0.19 to 0.35), respectively (high-quality evidence).  Secondary outcome analysis did not uncover any additional analgesic, functional or safety advantages to LB on post-operative day 2 or 3.  The authors concluded that findings of this study indicated that LB and plain bupivacaine LIAs were not different for extended post-operative analgesic outcomes, including pain control, opioid consumption, as well as functional and safety outcomes on days 2 and 3 post-TKA.  These researchers stated that high-quality evidence does not support using LB LIA for TKA.

Feng and co-workers (2021) examined the effect of discontinuing the use of LB in a peri-articular protocol on immediate post-operative pain scores, mEq, and objective functional outcomes.  On July 1, 2019, these researchers discontinued the use of intra-operative LB as part of a peri-articular injection protocol.  A consecutive group of patients who received LB as part of the protocol (Protocol 1) and a subsequent group who did not (Protocol 2) were compared.  All patients received the same opioid-sparing protocol.  Verbal rating scale (VRS) pain scores were collected from the authors’ electronic data warehouse and averaged per patient per 12-hour interval.  Events relating to the opiate administration were derived as morphine milligram equivalences (MMEs) per patient per 24-hour interval.  The Activity Measure for Post-Acute Care (AM-PAC) tool was used to examine the immediate post-operative function.  A total of 888 subjects received Protocol 1, while 789 received Protocol 2.  The mean age of the patients was significantly higher in those who did not receive LB (66.80 versus 65.57 years, p = 0.006).  The sex, BMI, American Society of Anesthesiologists (ASA) physical status score, race, smoking status, marital status, operating time, LOS, and discharge disposition were similar in the 2 groups.  Compared with the LB group, discontinuing LB showed no significant difference in post-operative VRS pain scores up to 72 hours (p > 0.05), mEq up to 96 hours (p > 0.05), or AM-PAC scores within the first 24 hours (p > 0.05).  The authors concluded that the control of pain after TKA with a multi-modal management protocol was not improved by the addition of LB compared with traditional bupivacaine.

Pain Management After Minimally Invasive Lung Resection

Weksler and colleagues (2021) stated that thoracic surgery can cause significant pain, and multiple strategies have been developed to control pain following surgery.  In a randomized, open-label study, these researchers compared 2 bupivacaine formulations given intra-operatively: bupivacaine with epinephrine (1,200,000) or LB.  Eligible patients were adults scheduled for a minimally invasive lung procedure.  Incision sites were injected with bupivacaine with epinephrine or LB before incision, and each intercostal space was injected with 1-ml of bupivacaine with epinephrine or LB entering the thoracic cavity; PCA was initiated in the recovery room.  Pain was recorded using a VAS.  The primary outcome was the amounts of narcotics taken during the post-operative hospital stay.  These investigators recruited 50 patients; 25 received bupivacaine with epinephrine, and 25 received LB.  The treatment groups were similar in age, histology, and procedure performed.  There were no statistical differences between the treatment groups in the amounts of narcotics needed during the hospital stay (36.3 mg for bupivacaine and 38 mg for LB) or in pain assessed the day of surgery (5 and 5), the 1st day (3.5 and 2.3), 2nd day (3 and 2.6), 2 weeks (0 and 1), or 3 months (0 and 0) post-operatively; LOS and complications were also similar.  The authors did not find significant differences between bupivacaine with epinephrine or LB in mitigating pain following minimally invasive lung resection.  These researcher currently favor using the non-liposomal bupivacaine preparations until additional data are available.

Pain Management After Lower-Extremity Amputation

Domitrascu and colleagues (2021) noted that optimizing peri-operative analgesia for patients undergoing major lower-extremity amputation remains a considerable challenge.  The use of LB as a component of peripheral nerve blockade for lower-extremity amputation is unknown.  In an observational study, these researchers compared 3 different peri-operative analgesic techniques for adults undergoing major lower-extremity amputation under general anesthesia between 2012 and 2017 at an academic medical center: no regional anesthesia; peripheral nerve blockade (PNB) with standard bupivacaine; and PNB with a mixture of LB and standard bupivacaine.  The primary outcome of cumulative opioid oral morphine milligram equivalent utilization in the first 72 hours post-operatively was compared across groups by means of multi-variable linear regression.  A total of 631 unique anesthetics were included for 578 patients, including 416 (66 %) without regional anesthesia, 131 (21 %) with PNB with a mixture of LB and standard bupivacaine, and 84 (13 %) with PNB with standard bupivacaine alone.  Cumulative morphine equivalents were lower in those receiving PNB with combined LB and standard bupivacaine compared with those not receiving regional anesthesia (multiplicative increase 0.67; 95 % CI: 0.50 to 0.90; p = 0.007).  There were no significant differences in opioid use between PNB groups (p = 0.59).  The authors concluded that PNB was associated with reduced opioid requirements after lower-extremity amputation compared with general anesthesia alone; however, the incorporation LB was not significantly different to blockade employing only standard bupivacaine.

Pain Management After Truncal Incisions

Sandhu and colleagues (2021) stated that LB for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine; however, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.  In a randomized clinical trial, these researchers compared the effectiveness of single-administration standard bupivacaine versus LB in patients undergoing truncal incisions.  This study enrolled patients undergoing sternotomy, thoracotomy, mini-thoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018.  The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80 %.  Data analysis was carried out from July to December 2018.  Patients were randomized to LB or standard bupivacaine.  Pain was assessed over 3 post-operative days by the NRS.  Adjunctive opioids were converted to morphine equivalents units (MEU); NRS scores were compared using Wilcoxon rank-sum (3-day AUC) and 2-way non-parametric mixed models (daily scale score) to assess time-by-group interaction.  Secondary outcomes included cumulative opioid consumption.  A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine versus LB).  Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36 %) were women.  Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression p < 0.001).  Incision type was associated with pain with patients undergoing thoracotomy (including mini-thoracotomy) reporting highest median (IQR) pain scores on post-operative days 1 (LB versus standard bupivacaine, 6 [4 to 8] versus 5 [3 to 7]; p = 0.049, Wilcoxon rank-sum) and 2 (LB versus standard bupivacaine, 5 [4 to 7] versus 4 [2 to 6]; p = 0.003, Wilcoxon rank-sum) but not day 3 (LB versus standard bupivacaine, 3 [2 to 6] versus 3 [1 to 5]; p = 0.10, Wilcoxon rank-sum), irrespective of treatment group.  Median (IQR) 3-day cumulative NRS was 12.0 (8.0 to 16.5) for bupivacaine and 13.5 (9.0-17.0) for LB (p = 0.15, Wilcoxon rank-sum).  Furthermore, use of opioids was greater following LB compared with standard bupivacaine (median [IQR], 41.5 [21.3 to 73.8] MEU versus 33.0 [17.8 to 62.5] MEU; p = 0.03, Wilcoxon rank-sum).  On multi-variable analysis, no interaction by incision type was observed for mean pain scores or opioid use.  The authors concluded that the heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of LB versus conventional formulations of bupivacaine, underscored the importance of independent comparative effectiveness research, conducted with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators.  These researchers stated that the findings of this study did not support the use of liposomal formulation over the standard formulation of bupivacaine for post-operative pain control in major truncal surgery.

Prevention of Post-Operative Pain

Dinges and colleagues (2021) noted that LB is a prolonged release formulation of conventional bupivacaine designed for prolonging local or peripheral regional single injection anesthesia; however, the benefit of the new substance on relevant endpoints is controversial.  In a systematic review and meta-analysis, these researchers examined if there is a difference in post-operative pain scores and morphine consumption between patients treated with LB and bupivacaine hydrochloride.  They identified RCTs in Embase, CENTRAL, Medline and Web of Science up to May 2020.  Risk of bias was evaluated using Cochrane methodology.  Primary endpoints were the mean pain score difference and the mEq consumption expressed as the ratio of means (ROM) 24 and 72 hours post-operatively.  A total of 23 RCTs including 1,867 subjects were eligible for meta-analysis.  The mean pain score difference at 24 hours post-operatively was significantly lower in the LB group, at -0.37 (95 % CI: -0.56 to -0.19).  The relative mEq consumption after 24 hours was also significantly lower in the LB group, at 0.85 (0.82 to 0.89).  At 72 hours, the pain score difference was not significant at -0.25 (-0.71 to 0.20) and the mEq ratio was 0.85 (0.77 to 0.95).  The authors concluded that the beneficial effect on pain scores and opioid consumption was small and not clinically relevant, despite statistical significance.  The effect was stable among all studies, indicating that it was independent of the application modality.

Major Oncologic Surgery with an Epigastric Incision

Aiken et al (2022) stated that thoracic epidurals are commonly recommended in enhanced recovery protocols, although they may cause hypotension and urinary retention.  Peripheral nerve blocks (PNBs) using liposomal bupivacaine are a potential alternative, though they have not been extensively studied in major cancer operations with an epigastric incision.  In a retrospective review, these investigators examined collected data following the transition from thoracic epidural to liposomal PNBs in patients undergoing major oncologic surgery.  Patients receiving PNBs were compared to those receiving thoracic epidural.  Outcome variables included post-operative opioid use (MMEs), severe pain, and post-operative complications.  A total of 47 of 102 patients studied (46 %) received PNBs.  Opioid use was higher in the PNB group during the 0 to 24 hours (116 versus 94 MMEs, p = 0.04) and 24 to 48 hours post-operative period (94 versus 23 MMEs, p < 0.01).  There was no significant difference in severe pain, hypotension, urinary retention, or ileus.  PNBs were associated with earlier ambulation (1 versus 2 days, p = 0.04), although other milestones were similar.  The authors concluded that liposomal PNBs were associated with increased opioid use compared to thoracic epidural.  On the basis of these findings, thoracic epidural might be preferred in surgical oncology patients with an epigastric incision.

Patients Undergoing Hemorrhoidectomy

Chitty et al (2022) noted that the effectiveness of infiltration of liposomal bupivacaine against an active comparator, such as bupivacaine, remains debated on acute post-operative pain control.  These investigators examined the analgesic effectiveness, patient satisfaction, and side effects of liposomal bupivacaine compared to bupivacaine during hemorrhoidectomy procedures.  A total of 94 consecutive adult patients with hemorrhoid surgery between October 2019 and November 2020. Were included in this study.  Interventions entailed a pre-intervention control group of 0.25 % bupivacaine (50 ml, 125 mg, n = 47) and a post-intervention group of liposomal bupivacaine (30 ml, 266 mg, n = 47) for perianal local anesthetic administration.  The primary endpoint was analgesic effectiveness of liposomal bupivacaine compared to bupivacaine based on a reduction in the number of patients administered opioids and patient-reported pain scores in the post-anesthesia care unit (PACU).  Secondary endpoints included constipation, post-discharge patient-reported pain management satisfaction, and opioid prescription refill requests in telephonic interviews 3 days after surgery.  PACU peak pain scores were significantly higher in the bupivacaine compared to the liposomal bupivacaine group (median 3 [IQR 0 to 6] versus 0 [IQR 0 to 4], p = 0.03), respectively with no differences in PACU discharge pain scores.  There was no difference in the frequency of rescue opioid use (38.2 % versus 25.5 %, p = 0.18) or the MMEs administered to each of those patients (median 15 [IQR 10 to 23] versus 15 [IQR 15 to 25], p = 0.39) in the PACU comparing the bupivacaine and liposomal bupivacaine groups, respectively.  Secondary endpoints were similar in each group with respect to requests for opioid refills (10.6 % versus 12.8 %, p = 0.75), greater than 75 % satisfied with their pain management (p = 0.94), and constipation reported on day 3 after surgery (p = 0.07).  The authors concluded that liposomal bupivacaine was not superior to 0.25 % bupivacaine for pain control, there was no difference in rescue opioid use in the PACU between groups, patient satisfaction was comparable (greater than 75 %) between liposomal bupivacaine and bupivacaine, and there was no difference in PACU discharge pain scores, constipation, or post-operative requests for narcotic refills.

Patients Undergoing Knee Arthroplasty

Hamilton et al (2022) stated that more than 50 % of patients who undergo knee replacement surgery reported substantial acute post-operative pain.  In a randomized, patient-blinded, multi-center, clinical superiority trial, these researchers examined the effectiveness and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management following knee replacement.  This study entailed 533 subjects at 11 institutions within the National Health Service in England.  Adults undergoing primary unilateral knee replacement for symptomatic end-stage OA were enrolled between March 29, 2018, and February 29, 2020, and followed-up for 1 year after surgery.  Follow-up was completed March 1, 2021.  A per-protocol analysis for each co-primary outcome was carried out in addition to the main intention-to-treat (ITT) analysis.  Interventions were 266 mg of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery.  The co-primary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain VAS score AUC from 6 to 72 hours.  Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life (QOL) at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year.  AEs and serious AEs up to 12 months after randomization were also assessed.  Among the 533 subjects included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8 %) and 246 were men (46.2 %).  Baseline characteristics were balanced between study groups.  There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted MD, 0.54 [97.5 % CI: -2.05 to 3.13]; p = 0.64) or the pain VAS score AUC at 6 to 72 hours (-21.5 [97.5 % CI: -46.8 to 3.8]; p = 0.06).  Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery (adjusted difference -0.54 [97.5 % CI: -1.07 to -0.02]; p = 0.02).  No difference in cumulative opioid consumption and functional outcomes was detected.  Liposomal bupivacaine was not cost-effective compared with the control treatment.  No difference in AEs or serious AEs was found between the liposomal bupivacaine and control groups.  The authors concluded that this study found no difference in post-operative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery.

Minimally Invasive Supracervical Hysterectomy

In a randomized, double-blinded, placebo-controlled trial, Son et al (2022) examined the effectiveness of intracervical injection of liposomal bupivacaine for post-operative pain control among women undergoing minimally invasive supracervical hysterectomy.  This trial examined intracervical injection of combination liposomal bupivacaine and bupivacaine for post-operative pain among patients undergoing laparoscopic and robotic supracervical hysterectomy.  Patients were enrolled between October 1, 2018 and April 30, 2019.  The primary outcome was pain at 12 hours post-operatively using a NRS from 0 to 10.  Pain scores were also recorded pre-operatively, immediately post-operatively, at 12, 24, and 48 hours post-operatively.  The secondary outcome was the number of patients who required opioid analgesic medications up to 48 hours post-operatively.  A total of 60 subjects were randomized into the control (n = 30) and intervention (n = 30) groups.  Pain scores were 1 and 1.75 (p = 0.89) immediately post-operatively, 3 and 3.5 (p = 0.85) at 12 hours, 3.5 and 5 (p = 0.22) at 24 hours, and 2.75 and 4 (p = 0.18) at 48 hours for the control and intervention groups, respectively.  Within the first 24 hours, 10 patients in the control and 14 patients in the intervention group used narcotics (p = 0.37).  From the 24 to 48 hours window, 6 and 8 patients in the control and intervention groups used narcotics (p = 0.74), respectively.  The authors concluded that there was no statistically significant difference in pain scores between patients receiving combination liposomal bupivacaine and bupivacaine intracervical block and those receiving placebo in the first 48 hours after surgery.  There was no difference in analgesic use between the 2 study groups.

Nuss Procedure / Rib Fractures

Jeziorczak et al (2021) noted that the Nuss procedure has provided a minimally invasive surgical solution for pectus excavatum with excellent long-term outcomes; however, opioid avoidance, cost reduction, and length of stay (LOS) still offer room for improvement.  In a retrospective study, these investigators examined the impact of bupivacaine liposome injectable suspension (Exparel) on outcomes.  This trial was carried out at a pediatric specialty hospital from October 1, 2014 to December 31, 2019.  All subjects underwent a Nuss procedure (n = 19) for pectus excavatum.  The cohort comprised a control group that did not use liposomal bupivacaine (standard, n = 9) and an interventional group that received liposomal bupivacaine (n = 10).  Non-parametric Wilcoxon rank-sum tests and Chi-squared or Fisher's exact tests were used to evaluate significance (p < 0.05).  Overall, the entire population was 68.4 % male and had an average age of 15 years.  There was a significant difference between the standard and liposomal bupivacaine groups for total cost ($60,746 versus $13,289), total MMEs (282 versus 76.8 MMEs) and epidural catheter usage (100 % versus 0 %).  There was also a significant difference between groups for LOS (5.00 days versus 3.00 days) and Foley catheter usage (100 % versus 20 %).  The authors concluded that there was a significant impact of liposomal bupivacaine usage on epidural catheter avoidance and opioid administration correlating with a significantly decreased total cost and decreased LOS.  Moreover, these researchers stated that while more study is needed, liposomal bupivacaine for Nuss procedure offers improvement of post-operative patient outcomes.

Wallen et al (2022) stated that blunt chest wall injury accounts for 15 % of trauma admissions.  Previous studies have reported that the number of rib fractures predicts inpatient opioid requirements, raising concerns for pharmacologic consequences, including hypotension, delirium, and opioid dependence.  In a prospective, double-blinded, randomized placebo-control trial, these researchers hypothesized that intercostal injection of liposomal bupivacaine would reduce analgesia needs and improve spirometry metrics in trauma patients with rib fractures.  This study was carried out at a Level I trauma center as a Food and Drug Administration (FDA) investigational new drug study.  Enrollment criteria included patients 18 years or older admitted to the intensive care unit (ICU) with blunt chest wall trauma who could not achieve greater than 50 % goal inspiratory capacity.  Patients were randomized to liposomal bupivacaine or saline injections in up to 6 intercostal spaces.  Primary outcome was to examine pain scores and breakthrough pain medications for 96-hour duration.  The secondary endpoint was to evaluate the effects of analgesia on pulmonary physiology.  A total of 100 patients were enrolled, 50 per cohort, with similar demographics (Injury Severity Score, 17.9 bupivacaine 17.6 control) and co-morbidities.  Enrolled patients had a mean age of 60.5 years, and 47 % were women.  Rib fracture number, distribution, and targets for injection were similar between groups.  While both groups displayed a decrease in opioid use over time, there was no change in mean daily pain scores.  The bupivacaine group achieved higher incentive spirometry volumes over Days 1 and 2 (1,095 ml, 1,063 ml bupivacaine versus 900 ml, 866 ml control).  Hospital and ICU-LOS were similar and there were no differences in post-injection pneumonia, use of epidural catheters or AEs between groups.  The authors concluded that while intercostal liposomal bupivacaine injection was a safe method for rib fracture-related analgesia, it was not effective in reducing pain scores, opioid requirements, or hospital LOS.  Bupivacaine injection transiently improved incentive spirometry volumes, but without a reduction in the development of pneumonia.  Level of Evidence = II.

Reconstructive Skin Graft Donor Sites in Burn Patients

Sadeq et al (2022) noted that post-operative pain at skin graft donor sites is frequently under-treated in burn patients, which could impair reconstructive outcomes and result in harmful psychological consequences.  There is a need to examine and promote non-opioid, multi-modal analgesics.  Donor site infiltration of the local anesthetic liposomal bupivacaine in adolescent and young adult burn patients has not been previously examined.  In a retrospective analysis, these researchers examined intra-operative liposomal bupivacaine infiltration for post-operative donor site pain control in adolescent and young adult burn patients undergoing reconstructive skin graft procedures.  This trial included patients aged 14 to 25 years, who underwent at least 2 reconstructive skin graft procedures, 1 that received donor site infiltration of the standard treatment (bupivacaine hydrochloride) and 1 that received donor site infiltration of liposomal bupivacaine.  The final sample included 30 patients with a total of 44 liposomal bupivacaine cases and 53 standard treatment cases analyzed.  In these investigators’ 5-year experience, the use of liposomal bupivacaine compared to standard treatment was associated with statistically significant decreases in 0 to 4 hours post-operative pain scores (mean of 1.4/10 versus 2.3/10, p = 0.04) and 0 to 24 hours post-operative pain scores (mean of 1.7/10 versus 2.4/10, p = 0.02).  Neither analgesic was associated with AEs.  Differences in LOS and inpatient post-operative opioid usage were not regarded as significant.  The authors reported the 1st results that suggested intra-operative liposomal bupivacaine donor site infiltration may be associated with statistically improved patient outcomes in adolescent and young adult burn patients.  However, the reported differences were most likely not clinically significant, establishing the need for further investigations of using liposomal bupivacaine in this unique patient population.

Spine Surgery

Nguyen et al (2021) noted that spine surgery with posterior approaches may involve extensive manipulation of native structures, resulting in significant post-operative pain.  In a systematic review, these investigators examined the findings of retrospective cohort-matched studies and prospective RCTs examining the use of liposomal bupivacaine (LB) in spine surgery compared with a control/no treatment group.  Medline, Cochrane controlled trials register, and Google Scholar were searched to identify all studies that examined the effect of LB use on outcomes in spine surgery.  The search identified 10 articles that independently examined the effect of LB on reduction of post-operative opioid use, pain scores, hospital LOS, cost, and incidence of adverse effects.  The principles of GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) were applied to evaluate the quality of evidence from each study.  A total of 10 studies were analyzed (1,112 total patients).  LB was associated with significantly lower MMEs of post-operative opioids, especially in opiate-tolerant patients, VAS scores, AUC of cumulative pain scores, numeric pain scale scores, and hospital LOS, with comparable or lower odds of adverse effects relative to controls.  The authors concluded that low-quality evidence suggested that liposomal bupivacaine may safely decrease post-operative opioid requirements, pain scores, and LOS in patients undergoing spine surgery, whereas moderate-quality evidence did not support its use at this time.  Moreover, these researchers stated that additional prospective, well-powered studies are needed to examine the effectiveness of LB in spine surgery.

Sternotomy Pain from Cardiac Surgery

Patel et al (2022) stated that multi-modal analgesia is a cornerstone of post-operative pain management.  Different formulations of local anesthetics are available.  Data to support these therapeutic options are limited.  In a retrospective, observational single-center study, these researchers examined the effectiveness of liposomal bupivacaine compared with bupivacaine or ropivacaine in patients undergoing sternotomy for coronary artery bypass graft (CABG) and/or valve surgery.  Patients included were 18 years of age or older undergoing CABG and/or valve surgery via median sternotomy and received either liposomal bupivacaine or an active comparator.  The primary outcome was opioid utilization in MMEs from 0 to 72 hours.  A total of 376 patients were included, 223 in the liposomal bupivacaine arm and 153 in the active comparator arm.  There was no difference in the MME use from 0 to 72 hours among patients in the liposomal bupivacaine group compared with the comparator group (114.2 mg [75.55] versus 107.6 mg [68.4], p = 0.38).  After Bonferroni correction, there was no difference in pain scores at individual time-points.  At 24 and 48 hours after surgery, pain scores were higher with liposomal bupivacaine at 4.4 (2.7) versus 3.5 (2.8) (p = 0.01) and 3.1 (2.9) versus 2.4 (2.6) (p = 0.02).  The authors concluded that based on these findings and previous studies, liposomal bupivacaine should not be routinely used for CABG and/or valve surgery through a median sternotomy given lack of superiority.

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.


References

The above policy is based on the following references:

  1. Aiken TJ, Padilla E, Lemaster D, et al. Peripheral nerve blocks with liposomal bupivacaine are associated with increased opioid use compared to thoracic epidural in patients with an epigastric incision. J Surg Oncol. 2022;125(3):387-391.
  2. 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.
  3. 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.
  4. 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.
  5. Chahar P, Cummings KC. Liposomal bupivacaine: a review of a new bupivacaine formulation. Journal of Pain Research. 2012;5:257-264.
  6. Chitty L, Ridley B, Johnson B, et al. Liposomal compared to 0.25% bupivacaine in patients undergoing hemorrhoidectomy: A pre- and post-implementation quality improvement evaluation. J Clin Anesth. 2022;80:110868.
  7. Dinges H-C, Wiesmann T, Otremba B, et al. The analgesic efficacy of liposomal bupivacaine compared with bupivacaine hydrochloride for the prevention of postoperative pain: A systematic review and meta-analysis with trial sequential analysis. Reg Anesth Pain Med. 2021;46(6):490-498.
  8. Dumitrascu CI, Warner NS, Stewart TM, et al. Peripheral nerve blockade with combined standard and liposomal bupivacaine in major lower-extremity amputation. Pain Pract. 2021;21(3):299-307.
  9. Feng JE, Ikwuazom CP, Mahure SA, et al. Discontinuation of the liposomal delivery of bupivacaine has no effect on pain management after primary total knee arthroplasty: No effect on pain scores, opioid consumption, or functional status. Bone Joint J. 2021;103-B(6 Supple A):102-107.
  10. 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.
  11. 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.
  12. 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.
  13. Hamilton TW, Knight R, Stokes JR, et al; Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK) Study Group. Efficacy of liposomal bupivacaine and bupivacaine hydrochloride vs bupivacaine hydrochloride alone as a periarticular anesthetic for patients undergoing knee replacement: A randomized clinical trial. JAMA Surg. 2022;157(6):481-489.
  14. Hussain N, Brull R, Sheehy BT, et al. The mornings after-periarticular liposomal bupivacaine infiltration does not improve analgesic outcomes beyond 24 hours following total knee arthroplasty: A systematic review and meta-analysis. Reg Anesth Pain Med. 2021;46(1):61-72.
  15. 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.
  16. Jeng CL and Rosenblatt MA. Upper extremity nerve blocks: Techniques. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017.
  17. Jeziorczak PM, Frenette RS, Aprahamian CJ, et al. Liposomal bupivacaine injection in Nuss procedure allows narcotic avoidance and improved outcomes. J Laparoendosc Adv Surg Tech A. 2021;31(12):1384-1388.
  18. 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.
  19. 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.
  20. Lieblich SE, Danesi H. Liposomal bupivacaine use in third molar impaction surgery: INNOVATE Study. Anesth Prog. Fall 2017;64(3):127-135.
  21. 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.
  22. Meyer LA, Corzo C, Iniesta MD, et al. A prospective randomized trial comparing liposomal bupivacaine vs standard bupivacaine wound infiltration in open gynecologic surgery on an enhanced recovery. Am J Obstet Gynecol. 2021;224(1):70.e1-70.e11.
  23. 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.
  24. Nguyen TH, Iturriaga C, Verma R, et al. Efficacy of liposomal bupivacaine in spine surgery: A systematic review. Spine J. 2021;21(9):1450-1459.
  25. Patel J, Medas R, Donnelly J, Mullins B. Efficacy of liposomal bupivacaine for sternotomy pain after cardiac surgery: A retrospective analysis. Ann Pharmacother. 2022;56(10):1113-1118.
  26. 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.
  27. 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.
  28. Sadeq F, DePamphilis MA, Dabek RJ, et al. Evaluation of liposomal bupivacaine infiltration at reconstructive skin graft donor sites in adolescent and young adult burn patients: A retrospective analysis. Burns. 2022;48(5):1166-1171.
  29. Sandhu HK, Miller CC, 3rd 1 , Tanaka A, et al. Effectiveness of standard local anesthetic bupivacaine and liposomal bupivacaine for postoperative pain control in patients undergoing truncal incisions: A randomized clinical trial. JAMA Netw Open. 2021;4(3):e210753.
  30. 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.
  31. 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.
  32. Son MA, Jiggetts S, Elfeky A, et al. Liposomal bupivacaine injection for analgesia during minimally invasive supracervical hysterectomy. JSLS. 2022;26(2):e2022.00008.
  33. 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.
  34. U.S. Food and Drug Administration (FDA). Exparel (bupivacaine liposome injectable suspension). Prescribing Information. Reference ID: 4247612. Rockville, MD: FDA; revised April 2018.
  35. 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. 
  36. 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.
  37. 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.
  38. Wallen TE, Singer KE, Makley AT, et al. Intercostal liposomal bupivacaine injection for rib fractures: A prospective randomized controlled trial. J Trauma Acute Care Surg. 2022;92(2):266-276.
  39. Weksler B, Sullivan JL, Schumacher LY, et al. Randomized trial of bupivacaine with epinephrine versus bupivacaine liposome suspension in patients undergoing minimally invasive lung resection. J Thorac Cardiovasc Surg. 2021;161(5):1652-1661.
  40. 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.
  41. 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.
  42. 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.
  43. Zamora FJ, Madduri RP, Philips AA, et al. Evaluation of the efficacy of liposomal bupivacaine in total joint arthroplasty. J Pharm Pract. 2021;34(3):403-406.
  44. 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.
  45. Zhou S-C, Liu B-G, Wang Z-H. Efficacy of liposomal bupivacaine vs. traditional anaesthetic infiltration for pain management in total hip arthroplasty: A systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2020;24(21):11305-11314.