Bupivacaine Liposome (Exparel)
Number: 0941
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses bupivacaine liposome (Exparel).
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Medical Necessity
Aetna considers bupivacaine liposome injectable suspension (Exparel) medically necessary, with or without ultrasound guidance, for the following indications:
- In members 6 years of age and older as a single-dose infiltration to produce postsurgical local analgesia; or
- In adult members as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia; or
- In adult members as an adductor canal block; or
- In adult members as a sciatic nerve block in the popliteal fossa.
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Experimental, Investigational, or Unproven
Bupivacaine liposome injectable suspension is considered experimental, investigational, or unproven for all other indications including the following (not an-all inclusive list) because of insufficient evidence in peer-reviewed published literature:
- Bilateral transversus abdominis plane (TAP) and rectus sheath blocks for men undergoing robotic prostatectomy
- Combined regimen with bupivacaine hydrochloride for dorsal penile block during ambulatory pediatric urologic surgery
- Erector spinae plane block in adult pectus surgery
- Instillation in laparoscopy ports
- Intercostal injection for Nuss procedure/rib fractures
- Infra-clavicular block for post-operative analgesia in open reduction and internal fixation (ORIF) of the upper extremity
- Intra-cervical block for hysterectomy
- Intra-operative peri-articular injection during reverse shoulder arthroplasty
- Use in peripheral nerve block for epigastric incision for major oncologic surgery
- Use in supra-clavicular nerve block (NB) for fracture surgery
- Use in TAP blocks for deep inferior epigastric artery perforator (DIEP) flap breast reconstruction
- Use in TAP blocks in laparoscopic colorectal resections.
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Related Policies
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).
The recommended dose of Exparel for single-dose infiltration in pediatric persons, aged 6 to less than 17 years, is 4 mg/kg (up to a maximum of 266 mg), which is based upon two studies of pediatrics undergoing either spine surgery or cardiac surgery.
Source: Pacira Pharmaceuticals, 2022
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
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Exparel is indicated:
- In patients 6 years of age and older for single-dose infiltration to produce postsurgical local analgesia;
- In adults as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia.
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 multi-vesicular 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. Post-surgically, 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.
Pediatric Use
In 2022, the U.S. FDA approved a label expansion for patients 6 years of age and older for single-dose infiltration to produce postsurgical local analgesia. This approval is based upon two studies of pediatric patients undergoing either spine surgery or cardiac surgery.
Tirotta et al (2021) conducted a multi-center, open-label, phase 3, randomized study to evaluate the pharmacokinetics and safety of liposomal bupivacaine for postsurgical analgesia in pediatric patients aged 6 to less than 17 years. The pediatric population were divided into two age groups (group 1 (n=61): patients 12 to less than 17 years undergoing spine surgery; group 2 (n=34): patients 6 to less than 12 years undergoing spine or cardiac surgery). The authors randomized allocation of liposomal bupivacaine 4 mg/kg or bupivacaine hydrochloride (HCl) 2 mg/kg via local infiltration at the end of spine surgery (group 1); liposomal bupivacaine 4 mg/kg via local infiltration at the end of spine or cardiac surgery (group 2). The primary and secondary objectives were to evaluate the pharmacokinetics (e.g., maximum plasma bupivacaine concentrations [Cmax], time to Cmax) and safety of liposomal bupivacaine, respectively. Mean Cmax after liposomal bupivacaine administration was found to be lower versus bupivacaine HCl in group 1 (357 vs 564 ng/mL); mean Cmax in group 2 was 320 and 447 ng/mL for spine and cardiac surgery, respectively. Median time to Cmax of liposomal bupivacaine occurred later with cardiac surgery versus spine surgery (22.7 vs 7.4 h). In group 1, the incidence of adverse events (AEs) was comparable between liposomal bupivacaine (61% [19/31]) and bupivacaine HCl (73% [22/30]). In group 2, 100% (5/5) and 31% (9/29) of patients undergoing spine and cardiac surgery experienced AEs, respectively. AEs were generally mild or moderate, with no discontinuations due to AEs or deaths. The authors concluded that plasma bupivacaine levels following local infiltration with liposomal bupivacaine remained below the toxic threshold in adults (approximately 2000-4000 ng/mL) across age groups and procedures. AEs were mild to moderate, supporting the safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery.
"The safety of Exparel in 110 pediatric patients between the age of 6 and 17 years old undergoing spine or cardiac surgical procedures was evaluated in one randomized, open-label, clinical study in which Exparel was administered by infiltration into the surgical site and one single-arm, open-label study in which Exparel was administered by infiltration into the surgical site. Patients were administered a weight-based dose of Exparel at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg (maximum dose of 175 mg). In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, vision blurred, pruritus, and tachycardia" Pacira Pharmaceuticals, 2022).
Common adverse reactions (incidence greater than or equal to 2% to less than 10%) included bradycardia, muscle spasms, tachypnea, hypoesthesia oral, anemia postoperative, dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain, hematuria, incontinence, muscular weakness, and visual impairment.
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) post surgery and total opioid consumption 0-48 hours post surgery. 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 post surgery 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 multi-vesicular 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. Post-surgically, 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. Post-surgically, 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) post-surgically. 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 3 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). Post-surgically, 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, sub-muscular 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 post injection 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.
Adductor Canal Block / Sciatic Nerve Block in the Popliteal Fossa
Yayac et al (2019) noted that since its FDA approval in 2011 as a local anesthetic for post-surgical analgesia, LB has been incorporated into the PAI of many knee surgeons. The slow release of this medication from vesicles should significantly extend the duration of its analgesic effect; however, current evidence has not clearly demonstrated this benefit. These investigators 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 PNB (mean difference [MD] = 0.45, p = 0.02) and LB over a traditional PAI (standard MD [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 prospective, double-blinded RCT, Malige et al (2022) compared the use of LB (Exparel) versus ropivacaine in adductor canal blocks (ACB) before TKAs. From April 2020 to September 2021, a total of 147 patients undergoing unilateral primary TKA were asked to participate in this study. Each patient received an iPACK block utilizing ropivacaine and was additionally randomized to receive an ACB with Exparel or ropivacaine. For each patient, demographic information, inpatient hospital information, post-operative opioid use, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire scores were collected. A total of 100 patients were included (50 in each cohort). The Exparel group had a lower hospital LOS compared to the Control group (36.3 versus 49.7 hours, p < 0.01). Patients in the Exparel group reported an increased amount of NRS pain score improvement at all post-operative time-points. These subjects also used a lower amount of inpatient opioids (40.9 versus 47.3 MME/day, p = 0.04) but a similar amount of outpatient opioids (33.4 versus 32.1 MME/day, p = 0.351). Finally, the Exparel group had increased improvements in all WOMAC sub-scores and total scores at most time-points compared to the Control group (p < 0.05). The authors concluded that Exparel PNBs resulted in decreases in pain levels, shorter hospital LOS, inpatient opioid usage, and improved WOMAC scores. These investigators stated that Exparel can be safely used in ACB blocks before TKA to aid in controlling post-operative pain and reducing LOS.
Chen et al (2022) noted that ACB is advantageous for post-operative analgesia in TKA because it leads to minimal motor block. Liposomal bupivacaine is FDA-approved extended-release formulation of bupivacaine for interscalene PNBs. Its use is increasing in the TKA setting, mainly as a local infiltration agent. In a retrospective, single-center study, these researchers compared the effectiveness of ACB using LB versus ropivacaine in TKA. Duration of LB-ACB, time to 1st opioid use post-recovery room, amount of opioid use post-recovery room, hospital LOS, and average and highest pain scores were collected. A total of 91 and 142 TKA patients received ropivacaine and LB for ACB, respectively. At 8 hours post-recovery room, more patients in the LB group required no opioids compared with the ropivacaine group (p = 0.026). Mean opioid consumption was lower in the LB group than in the ropivacaine group at 8 and 24 hours post-recovery room, although statistical significance was only observed at 8 hours (p = 0.022). The highest pain score for patients in the 2 groups was not statistically different. The average pain score for patients with a 2-day LOS was higher in the LB group; however, average pain scores were similar for patients with 1- and 3-day LOS. Median LOS for the LB and ropivacaine groups was 1 and 2 days, respectively (p < 0.0001). Significantly lower opioid use at 8 hours post-recovery room was observed in the LB group compared with the ropivacaine group. There was no difference in opioid use at 24 and 48 hours. There was also no advantage with LB ACB in decreasing pain scores; however, the LB-ACB group showed a significantly shorter hospital LOS compared with the ropivacaine ACB group.
On November 10, 2023, the FDA, based on the results of 2 randomized, double-blind, active-controlled, multi-center phase-III clinical trials, granted bupivacaine liposome (Exparel) 2 new indications: for use in adults as an adductor canal block and as a sciatic nerve block in the popliteal fossa.
Analgesic Adjunct in Adult Pectus Surgery
Malan et al (2023) stated that pain management may be challenging in patients undergoing pectus excavatum (PE) bar removal surgery. To enhance recovery, opioid sparing strategies with regional anesthesia including ultrasound (US)-guided erector spinae plane block (ESPB) have been implemented. In a retrospective review, these investigators examined the safety and effectiveness of bilateral ESPB with a LB/traditional bupivacaine mixture as part of an enhanced patient recovery pathway. This review included adult patients who underwent PE bar removal from January 2019 to December 2020. Peri-operative data were reviewed and recorded. Patients who received ESPB were compared to historical controls (non-ESPB patients). A total of 202 patients were included (non-ESPB: 124 patients; ESPB: 78 patients); no AEs were attributed to ESPB. Non-ESPB patients received more intra-operative opioids (MMEs; 41.8 ± 17.0 mg versus 36.7 ± 17.1, p = 0.05) and were more likely to present to the emergency department within 7 days post-operatively (4.8 % versus 0 %, p = 0.05) when compared to ESPB patients. No significant difference in total peri-operative MMEs, severe pain in PACU, time from PACU arrival to analgesic administration, PACU-LOS, or post-procedure admission rates between groups were observed. The authors concluded that in patients undergoing PE bar removal surgery, bilateral ESPB with LB was carried out without complications. ESPB with LB may be considered as an analgesic adjunct to enhance recovery in patients undergoing cardiothoracic procedures; however, further prospective, randomized clinical trials comparing LB to traditional local anesthetics with and without indwelling nerve catheters are needed.
Bilateral Transversus Abdominis Plane and Rectus Sheath Blocks for Patients Undergoing Robotic Prostatectomy
Kazior et al (2023) noted that as robotic prostatectomy surgery becomes more prevalent, it is important to identify any regional techniques to optimize patient's recovery. These researchers examined the effectiveness of bilateral transversus abdominis plane (TAP) and rectus sheath (RS) blocks with LB. They hypothesized that these blocks would reduce peri-operative opioid use and pain scores. A retrospective cohort of patients from May 2018 and May 2021 at a single, large VA hospital were studied. These investigators compared those not receiving a nerve block (NB) against those receiving the TAP and RS as part of an Enhanced Recovery After Surgery (ERAS) pathway starting in May 2019. The primary outcome was post-operative opioid use; and secondary outcomes were post-operative pain scores and hospital LOS. A total of 134 patients were included in the final analysis; 81 did not receive a block and 53 patients did receive a block. No difference existed between the groups in regard to median oral MME used in PACU or any post-operative day. No difference was observed in median opioid usage (mg) or pain scores between the 2 groups on any post-operative day. There was no difference in temporal association of median pain scores or narcotic usage between the 2 groups. The authors concluded that bilateral TAP and RS with LB did not significantly decrease post-operative opioid use, improve pain scores, or decrease hospital LOS for patients undergoing robotic prostatectomy. These researchers stated that further studies are needed to examine the effect of these blocks with LB.
Combined Regimen with Bupivacaine Hydrochloride for Dorsal Penile Block During Ambulatory Pediatric Urologic Surgery
Gabrielson et al (2023) examined the tolerability and effectiveness of pre-operative dorsal penile nerve block with LB plus bupivacaine hydrochloride in children 6 years of age or older undergoing ambulatory urologic surgery. These researchers showed that the drug combination was well-tolerated, with appropriate analgesic effectiveness in the recovery room as well as at 48-hour and 10- to 14-day follow-up periods. The authors concluded that these preliminary data justify the need to conduct a prospective, randomized study comparing LB plus bupivacaine hydrochloride to other common local anesthetic regimens used in pediatric urologic surgery.
Deep Inferior Epigastric Artery Perforator (DIEP) Flap Breast Reconstruction
Nguyen et al (2024) stated that pain control following autologous breast reconstruction is important for patient satisfaction and early recovery. Transversus Abdominis Plane (TAP) blocks are commonly used as part of an Enhanced Recovery After Surgery (ERAS) pathway for breast reconstruction. It is unclear if LB used in TAP blocks offer additional advantages. In a prospective, double-blinded RCT, these researchers compared the effectiveness of LB versus plain bupivacaine for patients undergoing deep inferior epigastric perforator (DIEP) flap breast reconstruction. This trial included patients undergoing abdominally based autologous breast reconstruction between June 2019 to August 2020. Subjects were randomly assigned LB or plain bupivacaine, carried out using ultrasound (US)-guided TAP block technique. All subjects were managed according to an ERAS protocol. Primary outcomes were post-operative narcotic analgesia required measured in oral morphine equivalents (OME) from post-operative day (POD) 1 to 7. Secondary outcomes included POD 1 to 7 pain Numeric Pain Scale (NPS), non-narcotic pain medication usage, time to 1st narcotic use, return of bowel function, and hospital LOS. A total of 60 patients were enrolled; 30 received LB, while 30 received plain bupivacaine. There were no significant differences in demographics, daily OME narcotic use, non-narcotic pain medication use, time to narcotic use, NPS, time to bowel function, or hospital LOS. The authors concluded that LB did not confer advantages over plain bupivacaine when used in TAP blocks for abdominally based micro-vascular breast reconstruction in patients under ERAS protocols and multi-modal approaches for pain control.
Intra-Operative Peri-Articular Injection During Reverse Shoulder Arthroplasty
Schumaier et al (2023) stated that interscalene nerve blocks (ISNBs) and local anesthetic infiltration are 2 methods commonly used in multi-modal analgesia regimens for shoulder arthroplasty; LB is a novel anesthetic that can be detected more than 24 hours following local administration. Studies comparing LB with conventional analgesic methods have found mixed results regarding pain and narcotic consumption, and there is little information available regarding patient satisfaction and the role of psychosocial variables. In a randomized study of 76 adult patients undergoing reverse shoulder arthroplasty who were assigned to receive a pre-operative ISNB with ropivacaine (Block; n = 38) or an intra-operative peri-articular injection of LB (Local; n = 38). The primary outcomes were narcotic consumption (mEq, morphine equivalents), VAS pain scores, and satisfaction (0 to 10). The secondary outcomes were the effect of patient group preference (Block versus Local) and psychosocial variables (Pain Catastrophizing Scale, Brief Resilience Scale) on satisfaction. Hospital LOS, pain-related phone calls, pain-related re-admissions, and the number of narcotic refills were tracked from the day of surgery through the 1st post-operative appointment, which was routinely 7 to 14 days after surgery. Intra-operative and day 0 narcotic consumption was lower in the Block group by 17.3 and 21.6 mEq (p < 0.001, p = 0.035) with no differences on day 1 or 2. There was no difference in VAS pain scores, hospital LOS, pain-related phone calls, pain-related re-admissions, or the number of narcotic refills. Patient satisfaction was higher in the Block group (8.3 versus 6.8, p = 0.017). Pain catastrophizing, resilience, and patient group preference did not have any significant relationship with patient satisfaction. The authors concluded that patients undergoing reverse shoulder arthroplasty exhibited higher satisfaction with a conventional ISNB compared to a peri-articular injection of LB. There were no clinically important differences in narcotic consumption, VAS pain scores, hospital LOS, pain-related phone calls, pain-related re-admissions, or the number of narcotic refills. The Pain Catastrophizing Scale, Brief Resilience Scale, and patient preferences did not have any relationship with patient satisfaction. Level of Evidence = I.
Pain Management After Anterior Cervical Discectomy and Fusion
Neufeld et al (2022) stated that despite its widespread use, definitive data showing the effectiveness of LB is limited especially in patients undergoing anterior cervical discectomy and fusion (ACDF). In a retrospective study, these investigators examined if ACDF patients who received intra-operative LB (LB cohort) would exhibit reduced post-operative opioid use and hospital LOS compared to ACDF patients who did not receive intra-operative LB (controls). A total of 82 patients who underwent primary ACDF by a single surgeon from 2016 to 2019 were identified from an institutional database; 59 patients received intra-operative LB while 23 did not. Patient characteristics, medical co-morbidities, complications, post-operative opioid consumption, and hospital LOS data were collected. The LB cohort did not require fewer opioids on post-operative day (POD) 0, POD1, POD2, or throughout the hospital course after normalizing by hospital LOS (total per LOS). The number of cervical vertebrae involved in surgery, but not LB use, predicted opioid consumption on POD0, POD1, and total per LOS. For every vertebral level involved, 242 additional MMEs were consumed on POD0, 266 additional MMEs were used on POD1, and 130 additional MMEs were consumed in total per LOS. The authors concluded that ACDF patients who received intra-operative LB did not require fewer post-operative opioids or exhibit a reduced hospital LOS compared to controls. Patients whose procedures involved a greater number of cervical vertebrae were associated with greater opioid consumption on POD0, POD1, and total per LOS. ACDF patients, especially those who had a high number of vertebrae involved, may require alternative analgesia to LB.
The authors stated that this study had several drawbacks. Notably, this was a retrospective analysis focused on examining the body of work of a single surgeon. While this allowed for the surgeries to be relatively standardized, it did require caution in generalizing the results to all ACDF patients as there is surgeon procedural variability. Second, the lack of post-operative pain scores, e.g., VAS, due to their absence in the EMR. Future studies should include VAS scores that would further elucidate the possible role of LB during ACDF. Third, these researchers were unable to stratify patients quantitatively (only qualitatively) based on pre-operative opioid use. That is, the authors procured documentation of whether study participants used opioids before surgery or not (i.e., opioid naive) but not the amount of MME consumed. This factor deserves consideration as prior opioid sensitivity or misuse could affect the quantities of narcotic medications needed for effective analgesia. Pre-operative opioid consumption is associated with not only greater opioid requirements during hospitalization but also inferior patient outcomes overall. These investigators stated that future investigations should consider surveying patients for prior opioid use and examining the potential effects of LB in this population.
Pain Management After Bariatric Surgery
Becker et al (2023) noted that minimization of opiate use is an important focus in the setting of the severe national opioid crisis. In a prospective, double-blind, institutional review board (IRB)-approved RCT, these investigators examined the role of LB in decreasing post-operative opioid use before and after implementation of a bariatric enhanced recovery after surgery (ERAS) program. This study included patients undergoing elective, minimally invasive, weight loss surgery at a comprehensive metabolic and bariatric surgery center from November 2017 to December 2019. Primary outcomes were post-operative MME/day and average subjective inpatient pain level. Secondary outcomes were hospital LOS and AEs. Of the 100 patients enrolled, 78 were randomly assigned to LB (n = 42) or plain bupivacaine (PB) (n = 36); 34 received the ERAS protocol, and 44 did not. The mean MME/day use did not differ significantly by the bupivacaine group [median, IQR PB: 20.3 (40.95); LB: 33.0 (42.9); p = 0.314]; however, it did differ by the ERAS group [median, IQR no ERAS 33.2 (47.1), ERAS 24.0 (34.0); p = 0.049]. Hospital LOS, inpatient pain score, and AEs did not differ significantly by either the bupivacaine or the ERAS group. The authors concluded that in this trial, LB did not significantly reduce post-operative opioid use either before implementation of ERAS or as part of an enhanced recovery after surgery program for minimally invasive bariatric surgery procedures.
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 [inter-quartile 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 Fracture Surgery
Brown et al (2023) stated that distal radius fractures (DRFs) are common fractures requiring surgical fixation. The literature varies regarding opioid prescribing habits, opioid consumption, and post-operative pain scores. In a single-center study, these researchers hypothesized that the pre-operative administration of a LB supra-clavicular nerve block (NB) would be safe and effective in managing post-operative pain. A standardized pain management protocol was implemented from July 2021 to March 2022 for patients undergoing open reduction internal fixation (ORIF) of DRF. Protocol elements included a pre-operative LB supra-clavicular NB and a multi-modal post-operative pain regimen. Primary clinical outcomes included post-operative pain scores and number of opioid tablets consumed. A total of 20 patients underwent a newly implemented protocol; the average age was 56 years. Mean number of oxycodone 5-mg tablets consumed was 4.1 (median of 2.5), and mean VAS pain score at 1st post-operative appointment was 2.8. There were no incidences of missed acute carpal tunnel post-operatively. When compared with an institutional historical control (n = 189), number of opioid pills prescribed was reduced by 60 % (21.4 versus 8.6 tablets, p < 0.0001), and no patients had unscheduled healthcare contact because of uncontrolled pain (22 % versus 0 %, p < 0.016). The authors concluded that LB supra-clavicular NBs were safe and effective in the treatment of post-operative pain following ORIF of DRF. Patients consumed less than 5 oxycodone tablets on average, which was less than many recommended prescribed quantities (more than 20 to 30 tablets). Patients had low pain scores (2.8/10) at the 1st post-operative follow-up. These researchers noted that to their knowledge, this was the 1st study showing the use of LB in this clinical setting.
Gailey and Ostrum (2023) noted that historically, opioids have played a major role in the treatment of post-operative pain in orthopedic surgery. A multitude of AEs have been associated with opioid use and alternative approaches to pain relief are being examined, with particular focus on multi-modal pain management regimens. Liposomal bupivacaine (Exparel) is a component of some multi-modal regimens. This formulation of bupivacaine encapsulates the local anesthetic into a multi-vesicular liposome to theoretically deliver a consistent amount of drug for up to 72 hours. Although the use of liposomal bupivacaine has been studied in many areas of orthopedics, there is little evidence examining its use in patients with fractures. In a systematic review, these investigators identified a total of 8 studies evaluating the use of liposomal bupivacaine in patients with fractures. Overall, these studies showed mixed results: 3 studies found no difference in post-operative pain scores on post-operative days 1 to 4, while 2 studies found significantly lower pain scores on the day of surgery; 3 studies examined the quantity of narcotic consumption post-operatively and failed to find a significant difference between control groups and groups treated with liposomal bupivacaine. Furthermore, significant variability in comparison groups and study designs made interpretation of the available data difficult. The authors concluded that given this lack of clear evidence, there is a need for prospective, randomized clinical trials focused on fully examining the use of liposomal bupivacaine in fracture patients. These researchers stated that these studies should analyze many variables and at a minimum record data on the potential benefits of liposomal bupivacaine. These variables include post-operative pain scores, total narcotic consumption, LOS, AEs, and total hospitalization cost. There is also significant potential to further examine the injection technique used during the administration of liposomal bupivacaine in order to create a more standardized procedure that may contribute to more reliable results. Specifically, this may entail studying if the effectiveness of liposomal bupivacaine changes based on how and where it is administered. For example, studies may compare administering liposomal bupivacaine directly into soft tissues versus intra-articular injection versus as an adjunct to peripheral nerve blocks. Throughout these studies, the safety of liposomal bupivacaine should continue to be monitored to ensure there are no detrimental effects that have not been previously identified.
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.
Li et al (2022) stated that TSA and RCR surgery result in considerable post-operative pain. Optimal post-operative pain management based on a multi-disciplinary approach is needed to promote early post-operative rehabilitation. In a systematic review and meta-analysis, these investigators compared LB with traditional, non-LB agents following TSA or RCR surgery. Two independent authors searched the PubMed Central, Google Scholar, and Cochrane Library websites for suitable studies. They included RCTs comparing outcomes after the administration of LB and non-LB agents for RCR or TSA. The outcome measures for this meta-analysis were VAS pain scores at 24 and 48 hours after surgery, opioid consumption 24 and 48 hours after surgery, hospital LOS, as well as complications within 48 hours following surgery. These researchers used the GRADE approach to examine the degree of evidence for the outcomes, and they used the Cochrane risk-of-bias assessment tool to evaluate the risk of bias. The current meta-analysis comprised 11 RCTs with 846 subjects; 7 studies used local infiltration to administer LB, and 3 used a block. The pooled analysis results showed no significant difference in VAS pain scores at 24 hours after surgery (SMD, -0.27; 95 % CI: -0.55 to 0.01; prediction interval, -1.25 to 0.70), VAS pain scores at 48 hours after surgery (SMD, -0.18; 95 % CI: -0.46 to 0.09; prediction interval, -1.10 to 0.73), opioid consumption at 24 hours after surgery (SMD, 0.04; 95 % CI: -0.27 to 0.34; prediction interval, -1.01 to 1.09), and opioid consumption at 48 hours after surgery (SMD, 0.10; 95 % CI: -0.44 to 0.64; prediction interval, -1.76 to 1.96) between the LB and non-LB groups. The LB and non-LB groups had similar hospital LOS (SMD, -0.38; 95 % CI: -1.51 to 0.74; prediction interval, -14.7 to 13.9) and AEs (RR, 0.89; 95 % CI: 0.42 to 1.36) following the shoulder procedures. The level of evidence was low according to the GRADE analysis. The authors concluded that this meta-analysis provided evidence indicating that LB was similar to non-LB agents in terms of overall pain relief and opioid requirements. The hospital LOS and complication rates were also similar in the 2 groups. These researchers stated that future well-designed, and adequately powered RCTs are needed to confirm these findings and to be able to recommend LB for various types of shoulder operations. Level of Evidence = II.
Elmer et al (2023) noted that interscalene brachial plexus blocks are frequently carried out to decrease pain following TSA; LB has been purported to prolong the duration of brachial plexus blocks for up to 72 hours; however, there has been controversy surrounding the analgesic benefits of this drug. These researchers hypothesized that an interscalene block carried out with bupivacaine alone would be non-inferior to a combination of LB and bupivacaine with respect to opioid consumption following TSA. Patients presenting for primary TSA were randomized in a 1:1 ratio to an ultrasound-guided, single-injection interscalene block with either a combination of LB and bupivacaine (LB group) or bupivacaine without additive (Bupi group). The primary outcome of this study was 72-hour post-operative cumulative opioid consumption (in oral morphine equivalents) with a non-inferiority margin of 22.5 mg. Secondary outcomes included pain scores, patient satisfaction with analgesia and patient reported duration of sensory block. A total of 76 subjects, 38 from the Bupi group and 38 from the LB group, completed the study. Analysis of the primary outcome showed a 72-hour cumulative geometric mean oral morphine equivalent consumption difference of 11.9 mg (95 % CI: -6.9 to 30.8) between groups (calculated on the log scale). This difference constituted approximately 1.5 tablets of oxycodone over 3 days. No secondary outcomes showed meaningful differences between groups. The authors concluded that interscalene brachial plexus blocks carried out with bupivacaine alone did not demonstrate non-inferiority compared to a mixture of LB plus bupivacaine with regards to 72-hour cumulative opioid consumption following TSA. Moreover, the difference between groups did not appear to be clinically meaningful.
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.
Chen et al (2023) stated that LB is a relatively new formulation that slowly releases bupivacaine to extend its effectiveness for 72 to 96 hours. It is inconclusive whether LB offers better effectiveness than traditional peri-articular injection (TPAI) following TKA. Relevant RCTs were searched using electronic databases, including PubMed, Cochrane Library, Embase, and Web of Science. Review Manager 5.4.1 was used for calculations. A total of 16 RCTs were included in this meta-analysis; LB exhibited better effects on morphine consumption equivalents during post-operative 24 to 48 hours than TPAI. No significant difference was observed in pain relief, incidence of nausea and vomiting, or hospital LOS between the 2 groups. The authors concluded that LB administration during TKA was not superior to TPAI. Moreover, these researchers stated that studies with larger sample size are needed to validate these findings.
The authors stated that this meta-analysis had several drawbacks. First, there were multiple TPAI components, and differences of the components were observed in most of the RCTs, contributing to the risk of bias when comparing them to each other. Second, different RCTs used different time units. For example, some studies used POD 1, POD 2, and POD 3. In other studies, the time units were the first 24 hours, second 24 hours, at 24 hours, or at 48 hours. There might be some bias introduced by combining these different time units. Third, this study contained only a small number of RCTs. Although 16 RCTs were identified, not every study provided the outcomes expected. For example, only 5 RCTs provided the VAS score on the operation day. furthermore, because the majority of RCTs had fewer than 50 subjects, it was challenging to determine the incidence rate of nausea and vomiting, which may be better observed in a large study population. Fourth, various anesthesia methods were adopted in these RCTs, with spinal anesthesia being the most common choice. However, spinal anesthesia may also have an effect on post-operative pain, and this issue was not addressed in this study. Fifth, all of the RCTs were carried out in the U.S.; thus, it was difficult to generalize the results to other countries or races.
Dodson et al (2023) noted that peripheral nerve catheters are used to provide analgesia following TKA; and have been shown to decrease pain and opioid use, to facilitate participation with PT, and to hasten discharge. More recently, peri-capsular infiltration using LB has been used as an alternative analgesic approach. In a retrospective study, these investigators compared outcomes for 3 analgesic approaches: femoral nerve catheter (FNC), adductor canal catheter (ACC), and intra-operative LB infiltration. The primary outcome was NRS pain scores at 24 hours. Secondary outcomes included pain scores at 12, 36, and 48 hours, time-to-first opioid, cumulative opioid use, distance walked, and time-to-discharge. Pain scores at 24 hours were significantly lower in both the ACC and FNC cohorts when compared to the LB cohort (3.1 versus 4.6 [p = 0.017] and 2.4 versus 4.6 [p < 0.0001]). The ACC and FNC groups did not differ significantly at that time-point (p = 0.27). Similar comparisons were found at 12 and 36 hours, while at 48 hours the FNC group was superior. Time to 1st opioid and opioid consumption favored the ACC and FNC groups. Walking distance favored the ACC group. Both the ACC and LB groups had a faster time-to-discharge than the FNC group. The authors concluded that both ACCs and FNCs provided superior analgesia at 24 hours compared to LB, while being equivalent to each other. Pain scores at 12 hours and 36 hours as well as opioid consumption through 48 hours mirrored this finding. These investigators stated that although various differences were observed between groups in terms of time-to-first analgesic, walking distance and time-to-discharge, the ACC approach appeared to optimally balance analgesia, ambulation, and time-to-discharge.
Minimally Invasive Supra-Cervical 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 supra-cervical hysterectomy. This trial examined intracervical injection of combination liposomal bupivacaine and bupivacaine for post-operative pain among patients undergoing laparoscopic and robotic supra-cervical 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.
Surgical Wound Infiltration
Jiang et al (2023) noted that LB has consistently been considered a potential analgesic for surgical wound infiltration; however, the evidence of its analgesic effectiveness remains unclear. In a meta-analysis, these researchers examined the potential use of LB wound infiltration in different surgical procedures; RCTs comparing LB with non-liposomal local anesthetics and placebos were retrieved from 6 electronic databases. The primary outcome was cumulative morphine equivalent consumption within 24-, 48-, and 72-hour following surgery. Approximately 2,659 patients from 22 studies were included in the meta-analysis. Compared to the control, LB-wound infiltration did not reduce the post-operative morphine consumption at 24 hours (weighted mean difference [WMD], -0.60 mg; 97.5 % CI: -2.78 to 1.59 mg; p = 0.54), 48 hours (WMD, -1.00 mg; 97.5 % CI: -3.23 to 1.24; p = 0.32) or 72 hours (WMD, 0.50 mg; 97.5 % CI: -0.67 to 1.67; p = 0.33). Similarly, secondary outcome analysis did not reveal any additional benefits of LB in any other pain-related outcomes. LB was not associated with any adverse effects. The authors concluded that LB did not appear to improve the post-operative analgesic, rehabilitation, or safety outcomes. Current evidence does not support the routine use of LB for wound infiltration following surgical procedures.
Transversus Abdominis Plane Blocks in Laparoscopic Colorectal Resections
Chevrollier et al (2023) stated that TAP blocks improve post-operative pain following colorectal resections; however, the benefits of LB use for these blocks have not been clearly demonstrated. In a prospective, single-blinded, single-center RCT, these investigators examined if the use of LB in TAP blocks would improve post-operative pain control and reduce opioid use in patients undergoing elective colorectal resections compared to standard bupivacaine. This study was conducted at a single-institution academic medical center with 6 staff colorectal surgeons and 2 colorectal surgery fellows. A total of 96 patients aged 18 to 85 years were evaluated for eligibility; 76 were included and randomly assigned to 2 groups of 38 patients. Subjects in the experimental group received LB TAP blocks, whereas the control group received standard bupivacaine blocks. The primary outcome was maximum pain score on post-operative day 2; and secondary outcomes included daily maximum and average pain scores in the 3 days after surgery, as well as daily MME use and hospital LOS. Patients receiving LB blocks had lower maximum pain scores on the day of surgery (mean of 6.5 versus 7.7; p = 0.008). No other difference was observed between groups with respect to maximum or average pain scores at any time point post-operatively, nor was there any difference in MMEs used or hospital LOS (median of 3.1 days). The authors concluded that LB use in TAP blocks for patients undergoing laparoscopic colorectal resections did not appear to improve post-operative pain, nor does it reduce narcotic use or decrease hospital LOS. Moreover, these researchers stated that given its cost, use of LB in TAP blocks is not justified for colorectal resections. These investigators noted that the main drawbacks of this study were that it was a single-center study with only patients blinded to group assignment.
Infra-Clavicular Block for Post-Operative Analgesia in Open Reduction and Internal Fixation (ORIF) of the Upper Extremity
StatPearls’ review on “Infraclavicular nerve block” (Williams et al, 2023) noted that the infra-clavicular block is a brachial plexus block used as an alternative or adjunct to general anesthesia. It could be employed for post-operative pain control for upper extremity (UE) surgeries such as the elbow, forearm, and hand, but not the shoulder. The infra-clavicular block is a regional anesthetic technique developed to avoid the side effects and complications of supra-clavicular blocks, especially pneumothorax.
UpToDate reviews on “Infraclavicular brachial plexus block procedure guide” (Bansal and Allen, 2024), and “Upper extremity nerve blocks: Techniques” (Jeng and Rosenblatt, 2024) do not mention the use of bupivacaine liposome injectable suspension formulation.
Pain Management Associated with Gynecological and/or Urological Surgeries
In a retrospective, single-center study, Hutchins et al (2015) examined the effect of a subcostal transversus abdominis plane (TAP) block with liposomal bupivacaine on post-operative maximal pain score and hospital LOS among women undergoing robotic-assisted hysterectomy. This trial compared patients before and after consistent implementation of TAP blocks with liposomal bupivacaine during robotic-assisted hysterectomies. Analysis compared patient demographic and operative characteristics by TAP block use, along with outcomes of interest, including post-operative pain and hospital LOS. There was a statistically significant decrease in maximal NRS pain scores, presence of nausea and vomiting, and hospital LOS in those who had a TAP block with liposomal bupivacaine (n = 30) compared with those who did not receive a TAP block (n = 30). These differences remained even after adjustment for potential confounders. The authors concluded that liposomal bupivacaine used in a TAP block was a useful method to provide post-operative pain control in patients undergoing robotic-assisted hysterectomy and was associated with lower post-operative maximal pain scores and hospital LOS. Moreover, these researchers stated that prospective, randomized trials that follow pain medication requirements of patients beyond hospital discharge are currently underway.
The authors stated that this study had several drawbacks. First, this was not a randomized trial and while these investigators attempted to account for potential confounding, these findings may be biased due to other unmeasured confounders; thus, reflecting a difference in the patient population that these researchers did not measure or a change in surgical practices over time independent of the use of TAP blocks. Second, the sample size was fairly small (n = 30 in the TAP group) and patients were not followed beyond hospital discharge for pain experience and medication use. Third, these data represented the experience at a single center and may not be generalizable to the broader population.
In a double-masked, single-center RCT, Barron et al (2017) examined if pre-incision infiltration with extended-release liposomal bupivacaine would provide improved overall pain relief compared with 0.25 % bupivacaine after laparoscopic or robotic-assisted hysterectomy. Subjects were recruited from July 2015 through January 2016; a total of 64 patients were randomized, and 59 were analyzed for the primary outcome. Women scheduled to undergo multi-port laparoscopic or robotic-assisted total hysterectomy for benign indications were randomized to receive pre-incision infiltration with undiluted liposomal bupivacaine or 0.25 % bupivacaine. The primary outcome was overall average pain intensity by NRS (0 to 10) using the Brief Pain Inventory (BPI) via telephone survey on post-operative day (POD) 3. A sample size of 28 per group (n = 56) was planned to detect a 30 % change in pain scores. Secondary outcomes were overall average and worst numeric pain scores on PODs 1, 2, and 14; pain scores in hospital; BPI pain interference scores; and total opioid use. There were no demographic differences between the 2 groups. For the primary outcome, these investigators found a decrease in the average (p = 0.02) pain scores on POD 3 in the liposomal bupivacaine group. They also found a decrease in worst pain scores on POD 2 (p = 0.03) and POD 3 (p = 0.01). There were no differences in pain scores while in the hospital or on POD 1 or POD 14. There were no differences in BPI pain interference scores, opioid use, or reported adverse effects. The authors concluded that liposomal bupivacaine may provide additional pain relief on POD2 and POD3; however, they did not find any significant improvements in opioid use or QOL and did not believe its routine use for port site analgesia in laparoscopic or robotic multi-port hysterectomy was justified.
The authors stated that this study had several drawbacks. First, generalizability of this study was limited due to the fact that only 1 type of gynecologic surgery (minimally invasive hysterectomy) was studied. Second, difficulty in collecting information regarding NSAID use as the majority of patients did not fill their prescriptions and these researchers could not verify the amount of over-the-counter use. Clinically, however, opioid use is more meaningful than NSAID use. Third, while this trial was powered to detect differences in opioid consumption and BPI pain interference score, it was not designed with those results as primary outcomes.
Seagle et al (2017) determined the cost-effectiveness of TAP block with liposomal bupivacaine compared to oral opioids alone for acute post-operative pain following laparoscopic hysterectomy for early endometrial cancer. These investigators employed a decision-tree structure with a 30.5 day time-horizon to calculate incremental cost-effectiveness ratio (ICER) values per quality-adjusted life-year (QALY). Base-case costs, probabilities, and QALY values were identified from recently published all-payer national database studies, 2017 Medicare fee-schedules, randomized trials, institutional case series, or assumed, when published values were not available; 1-way, 2-way, and multiple probabilistic sensitivity analyses were carried out. The TAP strategy dominated the oral opioid-only strategy, with decreased costs, and increased effectiveness. Specifically, the TAP strategy saved $235.90 under the base-case assumptions. Threshold analyses showed that if the relative same-day discharge probability was 12 % or more higher in the TAP group, then TAP was cost-saving over oral opioids-alone. Similarly, TAP was cost-saving whenever the costs saved by same-day discharge compared to admission were $1,115.22 or greater. Cost-effectiveness of the TAP strategy was highly robust of a variety of sensitivity analyses. The authors concluded that TAP with liposomal bupivacaine was robustly cost-effective at conventional willingness-to-pay thresholds. In addition, TAP was cost-saving compared to opioids-only when the same-day discharge rate among TAP users was greater than among opioid-only users.
The authors noted that in addition to limitations related to the base-case model assumptions, limitations of this study included that not all possible specific complications were modeled. For instance, post-operative pneumonia and venous thrombo-embolism (VTE)were not specifically considered. However, these complications would presumably occur more often among women who were admitted to the hospital, favoring the TAP block strategy. Furthermore, cost estimates used for the surgical admission were total inpatient cost estimates including costs related to the full-spectrum of complications experienced, based on a nationally-representative all-payer database analysis, and thus included costs of other additional complications. In addition, because major complications were uncommon, consistent with the 1-way sensitivity analysis results, the results were not sensitive to major complication costs. Therefore, disagreement regarding assumptions of modeling uncommon major complications, resulting in alternative modeling of complications, would not meaningfully change the result that the TAP strategy is robustly cost-effective and often cost-saving. Surgical procedure costs used pertained to women undergoing hysterectomy for benign disease rather than for cancer. If higher surgical admission costs specifically for cancer or for robotic hysterectomy were used, the results would be very similar because the difference in same-day discharge (SDD) probabilities and cost-saving associated with SDD would be the same. These SDD parameters were the most important factors for determining the relative cost-effectiveness and the cost-savings of the TAP strategy. As for the potential concerns regarding assumptions of effectiveness estimates (QALY values) used here, it should be noted that no case report of death resulting from a TAP block with a local analgesic has been reported, and therefore the probability of death due to the TAP strategy that was assumed could arguably be removed from the model. This would allow these researchers to transform the analysis to a cost-minimization, without consideration of effectiveness estimates or alternative time-horizons. A cost-minimization would show the TAP strategy to be most often cost-saving, consistent with the cost-effectiveness analysis results. Finally, use of non-opioid analgesic agents was assumed to be similar among the model arms in this decision analysis and thus was not modeled. Given modern enhanced recovery protocols, it is likely that any center using TAP blocks routinely also uses multi-modal oral analgesia strategies as part of good practice.
In a prospective, randomized study, Hutchins et al (2019) examined if a TAP block with liposomal bupivacaine would reduce total post-operative opioid use in the first 72 hours following laparoscopic or robotic hysterectomy compared to port-site infiltration with 0.25 % bupivacaine. Patients received either a true TAP block procedure with 266 mg liposomal bupivacaine and 50 mg of 0.25 % bupivacaine and sham port infiltration or sham TAP block procedure with true port-site infiltration with 100 to 125 mg of 0.25 % bupivacaine. All patients had a standardized, scheduled, non-opioid pain management plan. The primary outcome was total IV morphine equivalents used in the first 72 hours following surgery. Secondary outcomes included assessment of post-operative pain over the study period and quality of recovery measures. Patients undergoing TAP blockade required fewer total opioid equivalents during the observation period than patients allocated to infiltration (median of 21 versus 25 mg IV morphine equivalents, p = 0.03). Opioid use was highest in the first 24 hours after surgery, with less difference between the groups during days 2 and 3 post-operatively. There were 5 in the TAP group and 0 in the infiltration group were opioid-free at 72 hours. Those in the TAP group had improved quality of recovery (QoR15) with no change in overall benefit of analgesia score. The authors concluded that TAP blockade reduced the requirement for opioid pain medication in the first 72 hours after surgery, had more patients opioid-free at 72 hours, and improved patients' quality of their recovery. Moreover, these researchers stated that further investigation is needed to optimize both the technique and patient selection to optimize the cost:benefit ratio of using peri-operative TAP blocks.
The authors stated that this study had several drawbacks. First, all surgeries were carried out by experienced surgeons; however, specific strategies, including the number of ports used were not mandated. It was hoped that randomization and blinding would mitigate these differences, but standardization would potentially have assured this. Second, although the infiltration strategies were specified in the protocol, compliance was not measured; however as both the TAP infusate and local infusate were labeled to preclude identification, it was thought that non-compliance was unlikely to bias these findings. Third, these investigators used between 100 and 125 mg of bupivacaine in the control group site versus 50 mg of bupivacaine and 266 mg of liposomal bupivacaine in the experimental group, and this disparity of dosing may have impacted outcomes. Fourth, the sham TAP procedure may have resulted in unintended pain just from the saline expansion of the TAP space. Fifth, as most patients were treated in an out-patient setting, these researchers relied on patient reporting of opioid use. While the accuracy of the reports could not be confirmed, blinding of both the observer and reporter in this case was thought to decrease potential bias.
Burnes et al (2021) noted that reducing post-operative opioid consumption is a main objective of enhanced recovery following colorectal surgery protocols. Potential solutions include anesthetic techniques such as local infiltration of anesthetic agents or TAP blocks. In a systematic review and network meta-analysis, these investigators examined the effectiveness of liposomal bupivacaine (LB) for colorectal resections, across a variety of anesthetic techniques. PubMed, Scopus and Embase databases were searched for relevant studies assessing LB, administered by any anesthetic technique. The primary outcome was post-operative morphine consumed (mg) and the secondary outcome was LOS (days). A Bayesian network meta-analysis comparing LB versus non-LB analgesia was carried out alongside meta-regression for different surgical approaches. A total of 12 studies were included, with a total of 2,512 patients. LB-based wound infiltration was most likely to reduce LOS followed by TAP block with LB (sum under the cumulative ranking [SUCRA] 85.55 and 70.26, respectively). TAP block with LB was most likely to reduce morphine requirements, followed by wound infiltration with LB (SUCRA 83.94 and 75.73, respectively). Compared to standard analgesia, LB-based wound infiltration reduced morphine usage (mean difference [MD] 36.64 mg, 95 % CI: 15.64 to 59.20) and LOS (MD 1.79 days, 95 % CI: 0.59 to 3.81). On meta-regression, the findings held for minimally invasive surgery only. The authors concluded that although LB-based interventions were associated with reduced post-operative morphine requirements and LOS in this network meta-analysis, the confidence in these estimates was graded as very low. These researchers stated that further well-designed studies are needed before LB can be recommended as a 1st-line agent.
In a randomized, double-blinded, placebo-controlled study, Son et al (2022) examined the effectiveness of intra-cervical injection of LB for post-operative pain control among women undergoing minimally invasive supra-cervical hysterectomy. This trial entailed intra-cervical injection of combination LB and bupivacaine for post-operative pain among patients undergoing laparoscopic and robotic supra-cervical 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 participants 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 LB and bupivacaine intra-cervical block and those receiving placebo in the first 48 hours after surgery. There was no difference in analgesic use between the 2 study groups.
The authors stated that one of the drawbacks of this trial was that only 39 out of 60 patients completely filled their pain diaries limiting their secondary outcome assessment. These researchers were only able to comment on the use of opioid medication, but could not evaluate possible dosage differences between the 2 groups. Another drawback was the statistically significant difference in body mass index (BMI) between the control and intervention arms of the study after randomization. The BMI difference between the groups was small (average of 29.65 in the control group, and 27 in the intervention group), which brought into question the clinical significance of this finding. Furthermore, cervical injection in this study was carried out by resident physicians under the guidance of a minimally invasive gynecologic surgery fellow or the fellow alone. Injections were carried out by various providers with different levels of training. Everyone who performed the injection watched a video demonstrating the proper technique; however, this did not ensure uniformity among injections.
Copperthwaite et al (2023) stated that enhanced recovery programs in laparoscopic colorectal surgery (LCS) use combined approaches to achieve post-operative analgesia; and TAP block is a loco-regional anesthetic technique that may reduce post-operative pain. These researchers carried out a systematic review and meta-analysis to compare the effectiveness of laparoscopic- versus US-guided TAP block in LCS. Databases were searched for relevant articles from inception until March 2022. All RCTs that compared laparoscopic (LTB) versus US-guided (UTB) TAP blocks in LCS were included. The primary outcome was narcotic consumption at 24 hours post-operatively, while secondary outcomes included pain scores at 24 hours post-operatively, operative time, post-operative nausea and vomiting (PONV) and complication rates. Random effects models were used to calculate pooled effect size estimates. A total of 3 RCTs were included capturing 219 patients. Studies were clinically heterogenous. On random effects analysis, LTB was associated with significantly lower narcotic consumption (SMD - 0.30 mg, 95 % CI: - 0.57 to - 0.03, p = 0.03) and pain scores (SMD - 0.29, 95 % CI: - 0.56 to - 0.03, p = 0.03) at 24 hours. However, there were no differences in operative time (SMD - 0.09 mins, 95 % CI: - 0.40 to 0.22, p = 0.56), PONV (OR = 0.97, 95 % CI: 0.36 to 2.65, p = 0.96) or complication (OR = 1.30, 95 % CI: 0.64 to 2.64, p = 0.47) rates. The authors concluded that LTB was associated with significantly less narcotic usage and pain at 24 hours post-operatively but similar PONV, operative time, and complication rates, compared to UTB. Moreover, these researchers stated that these findings were inconsistent, and require further investigation.
The clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) (Irani et al, 2023) stated that analgesic blocks and wound infiltration have shown benefit in opioid reduction among patients undergoing open and laparoscopic colorectal surgery. There are an increasing number of block options, including but not limited to TAP, quadratus lumborum (QL), erector spinae, and rectus sheath blocks. Two meta-analyses of TAP blocks showed decreased LOS compared with systemic opioid use in laparoscopic colorectal surgery. A recent systematic review and meta-analysis showed that laparoscopic-guided TAP block was safe and effective for pain management in minimally invasive surgery and appeared to be as effective as US-guided TAP blocks with respect to early pain control and reducing post-operative opioid use. However, data remain controversial regarding the purported extended duration of benefit with long-acting local anesthetics such as LB in reducing post-operative opioid consumption.
Use as Local Anesthesia After Urologic Surgery
Cotta et al (2016) stated that a new extended-release suspension bupivacaine (ERSB) delivers 3 days of local anesthetic, and has been shown to reduce pain and narcotic usage in some patient groups; however, this issue is largely unstudied in urologic surgery. In a pilot study, these researchers carried out a retrospective, single-surgeon chart review of patients who underwent penile prosthesis implantation. Pain scores and standardized morphine equivalent (ME) dose data were collected during a 23-hour observation period. Subjects who received ERSB were compared with those who received standard bupivacaine or no local anesthesia. In 37 patients, those who received (n = 13), and those who did not receive (n = 24) ERSB were grouped, respectively. These 2 groups were comparable demographically. ME was used 3.2-fold more frequently in the non-ERSB group (18.0, and 5.6 for non-ERSB, and ESRB groups, respectively (p = 0.04). Mean overall pain scores were 3.8/10 for ERSB and 3.9/10 for non-ERSB group, respectively. Per patient medication cost for the control, and ERSB groups were $5.16 and $285.54, respectively. The authors concluded that the use of a new ERSB in inflatable penile prosthesis resulted in a 3.2-fold decrease in consumption of narcotics by patients and led to equivalent post-operative pain control when compared with traditional post-operative pain control protocols. These investigators stated that considering the cost of the ERSB ($285/dose) in comparison to the inexpensive intravenous and oral pain medication used ($5.16), this new medication may not be cost-effective for patients undergoing implantation of an inflatable penile prosthesis.
The authors stated that drawbacks of this pilot study included limited statistical power due to a low number of enrollees (n = 13 in the ERSB group) and the subjective nature of pain scores. The retrospective design of the study and a lack of ensured blinding by the urology residents caring for the patients decreased the strength of the conclusions and restricted objective findings reported by the residents. Although the patients’ nurses were not intentionally blinded to the identities of the patients who did or did not receive ERSB, it was very unlikely that they would have altered care based on differences in peri-operative local anesthetic use. These researchers stated that future studies should seek to increase the sample size of participants, evaluate pain scores in a more uniform fashion, and blind both nurses and residents taking care of the patient to the study protocol.
Britton et al (2021) stated that novel strategies have been proposed to minimize post-operative opioid use; however, many patients experience significant pain following penile surgery. In a pilot study, these investigators examined post-operative opioid use in patients undergoing penile ring block with long-acting LB (Exparel) during surgery for Peyronie's disease (PD). They identified patients who underwent tunica albuginea plication (TAP) and plaque excision/grafting (PEG) for PD between July 2019 and September 2020. Intra-operatively, a ring block was administered at the penile base with 20 cc of LB. Patients were instructed to use over the counter (OTC) pain medications as 1st-line treatment for post-operative pain, and opioids were available for severe break-through pain as needed (7.5 oral ME [OME] = 5 mg oxycodone). Opioid use was assessed during the first 5 days post-operatively. A total of 28 patients met inclusion criteria including 18/28 (64 %) who underwent TAP and 10/28 (36 %) who underwent PEG. Median patient age was 56 years (IQR: 51 to 61). Median post-operative 10-point VAS was 0 (range of 0 to 3). Duration of penile anesthesia ranged from 1.5 to 4 days. In total, 9/28 patients (32 %) used opioids during the first 5days post-operatively (range of 7.5 to 75 OME); 2 patients (7 %) needed opioids during the first 2 days after surgery; and 27/28 (96 %) were satisfied or highly satisfied with post-operative pain control. The authors concluded that intra-operative penile ring block with LB resulted in excellent pain control with local anesthetic duration of 1.5 to 4 days. The majority of patients did not require any opioids during the early post-operative period. Moreover, these researchers stated that further investigations comparing outcomes with shorter-acting local anesthetics are needed to balance pain control benefits with additional cost.
The authors stated that drawbacks of this study included the small sample size (n = 28) that lacked statistical power to identify potential factors associated with opioid use. There was no control group with which to compare post-operative opioid use following administration of shorter-acting local anesthetics; thus, these investigators did not truly know if LB limited opioid use relative to alternative shorter acting local anesthetics. These researchers stated that future comparative studies are needed. These investigators also relied on patient recall regarding the quantity of opioids consumed, which introduced bias, and they lacked data on post-operative pain scores beyond the initial immediate post-operative assessments. Lastly, in the current era of increasing medical expenditures, LB remains a more expensive option at $180 for 133 mg (10 ml) and $334 for 255 mg (20 ml) compared to short-acting bupivacaine ($3 per dose), and this medication is not readily available at all institutions.
Gabrielson et al (2023) examined the tolerability and effectiveness of pre-operative dorsal penile NB with Exparel plus bupivacaine hydrochloride in children over 6 years of age undergoing ambulatory urologic surgery. These researchers showed that the drug combination was well-tolerated, with appropriate analgesic effectiveness in the recovery room as well as at 48-hour, and 10 to 14 day follow-up periods. The authors concluded that these preliminary findings justified the need to perform a prospective, randomized trial comparing Exparel plus bupivacaine hydrochloride to other common local anesthetic regimens used in pediatric urologic surgery.
Findlay et al (2023) noted that surgeons play an important role in the opioid epidemic. These investigators examined the effectiveness of a standardized peri-operative pain management pathway and post-operative opioid requirements in men undergoing outpatient anterior urethroplasty. Patients undergoing outpatient anterior urethroplasty by a single surgeon from August 2017 to January 2021 were prospectively followed. Standardized non-opioid pathways were implemented based on location (penile versus bulbar) and need for buccal mucosa graft. A practice change in October 2018 transitioned (i) from oxycodone to tramadol, a weak mu opioid receptor agonist, post-operatively; and (ii) from 0.25 % bupivacaine to liposomal bupivacaine intra-operatively. Post-operative validated questionnaires included 72-hour pain level (Likert 0 to 10), pain management satisfaction (Likert 1 to 6), and opioid consumption. A total of 116 eligible men underwent outpatient anterior urethroplasty during the study period; 1/3 of patients did not use opioids post-operatively, and nearly 78 % of patients used 5 or less tablets. The median number of unused tablets was 8 (IQR 5 to 10). The only predictor for use of less than 5 tablets was pre-operative opioid use (75 % versus 25 %, p < 0.01). Overall, patients using tramadol post-operatively reported higher satisfaction (6 versus 5, p < 0.01) and greater percentages of pain reduction (80 % versus 50 %, p < 0.01) compared to those using oxycodone. The authors concluded that for opioid-naïve men, 5 tablets or less of opioid medication with a non-opioid care pathway provided satisfactory pain control following outpatient urethral surgery without excessive over-prescribing of narcotic medication. Overall, multi-modal pain pathways and peri-operative patient counseling should be optimized to further limit post-operative opioid prescribing.
In a prospective, randomized, single-blinded, single-center, phase-III clinical trial, Gabrielson et al (2024) examined if the addition of LB to bupivacaine hydrochloride would improve opioid-free rate and post-operative pain scores among children undergoing ambulatory urologic surgery. This study was carried out in children 6 to 18 years undergoing ambulatory urologic procedures between October 2021 and April 2023. Subjects were randomized 1:1 to receive dorsal penile NB (penile procedures) or incisional infiltration with spermatic cord block (inguinal/scrotal procedures) with weight-LB plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The primary outcome was opioid-free rate at 48 hours; and secondary outcomes included parents' post-operative pain measure scores, NPS scores, and weight-based opioid utilization at 48 hours, and 10 to 14 days. These researchers randomized 104 participants, with greater than 98 % (102/104) with complete follow-up data at 48 hours and 10 to 14 days. At interim analysis, there was no significant difference in opioid-free rate at 48 hours between arms (60 % in the intervention versus 62 % in the control group; estimated difference in proportion -1.9 % [95 % CI: -20 % to 16 %]; p = 0.8). These investigators observed no increased odds of patients being opioid-free at 48 hours with the intervention compared to the control group (odds ratio [OR] 0.96; 95 % CI: 0.41 to 2.3; p = 0.9). This trial met the pre-determined futility threshold for early stopping. There was no difference in parents' post-operative pain measure scores, NPS scores, or opioid utilization at 48 hours or 10 to 14 days; and no difference in AEs was observed. The authors concluded that the addition of LB to bupivacaine hydrochloride did not significantly improve opioid-sparing effect or post-operative pain compared with bupivacaine hydrochloride alone among children 6 years of age or older undergoing ambulatory urologic surgery.
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:
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