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Does Extended-Release Liposomal Bupivacaine Better Control Pain Than Bupivacaine After Total Knee Arthroplasty (TKA)? A Prospective, Randomized Clinical Trial
Liposomal bupivacaine periarticular injection (PAI) offers sustained bupivacaine release after TKA, but few prospective independent studies exist. In this prospective, blinded study, liposomal bupivacaine was randomized against bupivacaine and incorporated into a comprehensive multimodal pain management protocol. 111 primary TKAs were randomized to receive PAI: 58 patients received 266 mg (20 cc) liposomal bupivacaine mixed with 75 mg (30 cc) 0.25% bupivacaine, and 53 patients received 150 mg (60 cc) 0.25% bupivacaine. Visual analog pain scores and narcotic use were determined. No pain score differences occurred between study and control patients: Day 1: 4.5/4.6 (P = 0.73); Day 2: 4.4/4.8 (P = 0.27); or Day 3: 3.5/3.7 (P = 0.58). Narcotic use was similar during hospitalization, 51.8/54.2 (P = 0.34). The study medication costs $285, and the control medication costs $2.80. This finding does not justify the routine use of liposomal bupivacaine.
Benefits of prolonged postoperative cycloogenase-2 inhibitor administration on total knee arthroplasty recovery: a double-blind, placebo-controlled study.
]. Rather than starting pain management postoperatively with narcotics alone, these strategies administer multiple medications and modalities given before, during, and after surgery to block the initiation, transmission, and reception of pain at the local, peripheral, and central nervous system levels. A component of most multimodal pain management strategies is periarticular injection (PAI), the injection of local anesthetic and pain medications into the soft tissue of the knee toward the end of the procedure [
Periarticular injection with bupivacaine for postoperative pain control in total knee replacement: a prospective randomized double-blind controlled trial.
Controlling pain after total hip and knee arthroplasty using a multimodal protocol with local periarticular injections: a prospective randomized study.
]. While many papers have been published on the benefit of PAI, no consensus to the optimal injection “cocktail” has been determined.
Liposomal bupivacaine is a local anesthetic recently released for clinical use (Exparel, Pacira, Parsippany, NJ) that is designed to provide extended action of local pain control [
A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty.
]. Liposomes are lipid-based molecules varying in size that act as drug carriers, offering sustained release of drugs over an extended period of time [
]. Liposomal bupivacaine injectable offers sustained release of bupivacaine and has been cleared by the FDA for intraoperative injection in surgical patients. Improved pain management has been reported in general surgery [
A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation.
A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty.
In this blinded prospective study, liposomal bupivacaine was incorporated into a comprehensive multimodal pain management protocol at the authors' institution. Patients were randomized to receive a PAI of either liposomal bupivacaine or bupivacaine. This study sought to determine if a single dose of liposomal bupivacaine injected into the soft tissues around the knee at the end of the total knee arthroplasty procedure would improve pain scores and decrease narcotic use more than bupivacaine alone.
Patients and Methods
Hospital Institutional Review Board (IRB) approval was obtained to compare periarticular injections (PAI) of liposomal bupivacaine versus plain bupivacaine in a prospective, blinded, randomized trial. A total of 111 consecutive patients between March 17, 2014 and May 8, 2014 were invited to participate in the study before undergoing unilateral primary TKA. All patients consented to the study protocol and were randomized to receive either liposomal bupivacaine (Exparel, Pacira, Parsippany, NJ) or bupivacaine. No patient declined participation. Fifty-eight patients (study group) received the liposomal bupivacaine PAI and 53 patients (control group) received the bupivacaine PAI. No difference was seen in preoperative pain level, age, sex, BMI, ASA, knee diagnosis, deformity, and motion between the two groups (Table 1). All patients had a unilateral cemented TKA through a mini-subvastus approach [
All primary total knee patients participated in an extensive multimodal pain management program. Before surgery, patients attended a one-hour group total knee education program covering pre-procedure and post-procedure physical therapy tasks, pain management and expectations, discharge goals, and home health plans upon discharge. Patients were encouraged to take acetaminophen per bottle instructions for 72 hours prior to surgery. On the day of surgery, patients received 400 mg celecoxib, 20 mg oxycontin, and a 6 mg scopolamine patch topically. Spinal anesthesia with 25 μg fentanyl and 2 cc 0.75% (15 mg) bupivacaine was administered in the operating room with moderate conscious sedation of propofol. During surgery, 8 mg dexamethasone, 8 mg ondansetron, and 10 mg/kg (up to 1 g) tranexamic acid were administered intravenously. Prior to implantation, the tourniquet was released, hemostasis obtained, and the periarticular injection given. The leg then was exsanguinated, the tourniquet inflated, and the procedure completed. Postoperatively patients continued celecoxib 400 mg daily, oxycontin 10 mg every 12 hours for two doses, prn medication of hydrocodone or oxycodone, and a patient-controlled anesthesia (PCA) of morphine for breakthrough pain. While all patients had access to on-demand IV narcotic, PCA use was discouraged in preference of oral narcotics and was discontinued the morning after surgery. Patients received 8 mg ondansetron intravenously every 6 hours routinely for 24 hours and then every 6 hours as needed for nausea. All patients were mobilized by physical therapy on the afternoon of surgery and seen twice daily by physical therapists thereafter. Home health, consisting of a visiting nurse and home therapist, saw patients within 48 hours of discharge. Patients were examined in the surgeon's office three weeks postoperatively and knee range of motion was determined.
Prior to the start of this study, a liposomal bupivacaine PAI was used in 192 consecutive primary TKAs by the principal investigator, November 2013–March 2014. During this time, sales representatives of Exparel were invited to educate surgeon and staff on optimal use of the study medication. Despite the routine use of bupivacaine PAI by the principal investigator since 2004, several beneficial changes were made to PAI technique over this “practice” time period. The spinal needle caliber was decreased to 21 gauge to limit backflow of medication from the soft tissue. A more thorough injection of the medication posterolateral, posteromedial, and within the periosteum was developed. During this “practice” period, a standard PAI regimen was developed: with the knee in flexion, medication was injected around the femoral notch and the sub-periosteal femoral tissue. With the knee in extension, medication was injected along the sub-periosteal tibial tissue, throughout the remaining periarticular soft tissues, and subcutaneously around the incision.
Participating patients were randomized at the time of surgery by the circulating nurse whose responsibility was to obtain appropriate medication from the surgical pharmacy for all cases. The medication used was recorded in the patients' electronic medical record. Study patients received a PAI of 266 mg (20 cc) liposomal bupivacaine combined with 75 mg (30 cc) bupivacaine. Control patients received a PAI of 150 mg (60 cc) bupivacaine. Neither the surgeon nor the surgical team was blinded to the PAI.
Data were maintained in a strict intent-to-treat methodology [
]. Preoperative patient demographics and knee data were compared to ensure equality of the study and control groups. The primary endpoint of the study was the Visual Analog Pain Scores [
] obtained twice daily just prior to physical therapy sessions during hospitalization. Secondary measures included hospital length of stay, knee flexion at time of hospital discharge and at three weeks, and narcotic equivalents during hospitalization. Narcotic equivalents were determined by the formula: [mg IV morphine] + 6.7 [mg IV hydromorphone] + 0.33 [PO hydrocodone] + 0.57 [PO oxycodone] [
]. Patients, floor staff, and therapy were blinded to medication given during surgery. Research collection was blinded until all data were tabulated. Categorical measures were compared with chi-square tests. Visual analog pain scores and continuous measures were compared with unpaired student t-tests. Narcotic equivalents were compared with a Mann–Whitney U test. Statistical significance was determined with P < 0.05.
Results
Pain scores were similar for the study and control groups (Table 2 and Fig. 1). On the morning of Day 1, VAS mean pain scores were 4.5 for the study and 4.6 for the control patients (P = 0.73). Afternoon Day 1 scores were 4.1 and 4.5 (P = 0.28). Morning Day 2 scores were 4.4 and 4.8 (P = 0.27). Afternoon Day 2 scores were 4.1 and 4.6 (P = 0.23). Morning Day 3 scores were 3.9 and 4.1 (P = 0.57). Hospital pain scores, narcotic use, and knee motion data were available for all 111 patients at the time of hospital discharge. One hundred eight patients (97%) were discharged directly home. One study and two control patients were discharged to a rehabilitation hospital prior to returning home. Hospital length of stay was 2.9 days for the study patients and 3.0 days for the control patients (P = 0.98). Knee range of motion was 81° versus 77° for the study and control groups at hospital discharge (P = 0.14), and 107° versus 108° (P = 0.47) at three-week follow-up. Narcotic use was similar during hospitalization, 51.8 vs. 54.2 (P = 0.34). Both groups had a slight incidence of postoperative nausea, 3 study patients (5%) and 2 control patients (4%), P = 0.72.
Fig. 1Pain scores were not statistically significantly different for the study group versus the control group at the five postoperative intervals during hospitalization in which Visual Analog Scale pain scores were obtained.
This prospective, blinded, randomized study found no significant benefit from using liposomal bupivacaine instead of standard bupivacaine in periarticular injections (PAI) as part of our multimodal pain management following primary TKA. No difference occurred in pain scores recorded twice daily during hospitalization, no difference in narcotic use during hospitalization, and no change in hospital length of stay. Knee range of motion at the time of hospital discharge and at the 3-week follow-up office visit was the same for both groups.
Similar results have been reported by Bagsby et al [
]. In their evaluation of 150 patients, no difference was found between PAI with liposomal bupivacaine or a combination of ropivacaine, epinephrine and morphine. While their study was a retrospective review of two sequential cohorts, the authors concluded that the pain control afforded by a multimodal pain management protocol was not improved with the change to liposomal bupivacaine [
]. The authors hypothesized that the poor results of the liposomal bupivacaine may be explained by the slow release of medication from the liposomes, limiting the amount of free bupivacaine present at the site of action.
Previous studies have suggested that the slow release of similar medications from liposomes modifies their properties and may limit their effectiveness [
]. Bagsby et al raised their concern that the study medication injected alone could create a window of breakthrough pain prior to the initial breakdown and effect of the smallest liposomes. In the current study, the addition of bupivacaine to the liposomal bupivacaine in the study patients' PAI obviated the concern for a window of pain control prior to initiation of the effects of the liposomal bupivacaine.
Several previously published studies have suggested benefit from liposomal bupivacaine PAI, but their study methodology raises concerns about these conclusions. First, the majority of these studies are retrospective comparisons of sequential cohorts without PAI controls [
]. The only prospective study published to date following TKA demonstrated that liposomal bupivacaine (532 mg), twice the standard tested dose, was superior to plain bupivacaine only when patients were at rest on days one and five [
A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty.
] Secondly, previous studies are limited by comparisons of dissimilar pain treatment modalities. In these studies, liposomal bupivacaine PAI is compared with alternative pain management strategies without a control PAI. Barrington et al. determined that a liposomal bupivacaine PAI provided superior pain management compared with femoral nerve blocks [
Multimodal periarticular injection vs. continuous femoral nerve block after total knee arthroplasty: a prospective, crossover, randomized clinical trial.
]. Together, these studies confirm that PAIs are beneficial, but do not demonstrate a greater benefit from using liposomal bupivacaine with the current study demonstrating equivalent results to bupivacaine alone. Finally, most previous studies on liposomal bupivacaine may be hampered by conflicts of interest in which either the authors, research, or study publication are directly funded by the manufacturer of liposomal bupivacaine [
A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty.
]. Entire journal supplements have been funded by industry. Surgeons with listed conflict of interest give testimonials to the benefit of liposomal bupivacaine without providing data to support opinion [
]. Previous investigations on potential conflict of interest in orthopedic research have demonstrated that positive studies are much more likely to be published than negative studies when potential conflicts of interest exist [
Benefits of prolonged postoperative cycloogenase-2 inhibitor administration on total knee arthroplasty recovery: a double-blind, placebo-controlled study.
]. The protocol outlined in this study is a comprehensive multimodal pain management strategy with more than 15 specific elements designed to decrease pain, nausea, and swelling to improve mobilization after primary TKA. This strategy has been developed and implemented during the past 12 years with success. Mean pain scores associated with physical therapy were maintained at or below a moderate level [
]. Patients were mobilized on the day of surgery and 97% were discharged directly home on or before day three. Nausea prevention strategies, a key component to successful pain management, enabled 95% of patients recover from TKA without the discomfort of nausea. In the face of the current study, with this comprehensive pain management strategy, liposomal bupivacaine had no significant benefit over bupivacaine. The limited effect of liposomal bupivacaine may reflect this relatively small change within an extensive pain management approach.
Increased use of PAI from 61% to 85%, as documented by the surgeon audience response survey at the American Association of Hip and Knee Surgeons (AAHKS) meeting for 2013 and 2014, indicates that more joint arthroplasty surgeons are using PAIs in their pain management programs [
]. A significant contribution of the development of a new proprietary medication such as Exparel has been the marketing that frequently is associated with a new pharmaceutical product. The directed communication of a motivated sales force and specialty specific campaigns can dramatically increase physician awareness of new medications and procedures [
]. Many surgeons' initial experience with PAI has been employing liposomal bupivacaine. A vigorous marketing campaign and sales force associated with this new medication has increased indirectly the exposure of the benefit of PAI following TKA. Certainly, with the extensive literature demonstrating the benefit of PAI, any PAI is better than none.
Previous descriptions of PAI utilize generic medications that are inexpensive to employ during surgery. The results of the current study demonstrate that liposomal bupivacaine, with a cost of $285 at the authors' institution, has no additional benefit over a generic medication costing a hundredth as much, $2.80. At our joint arthroplasty center, the hospital and surgeons have extensive experience in both private payor and Medicare bundled payment programs. With increased cost awareness, we increasingly shift to value-based care models, and the lack of demonstrably improved outcomes does not warrant the increased cost of this medication [
This study has some limitations. First, the surgeon was not blinded at the time of the injection. Liposomal bupivacaine is a cloudy liquid that is more viscous and therefore harder to inject than the clear bupivacaine. Because of this knowledge, the principal investigator was not involved in hospital pain assessment or narcotic prescription, or with knee motion measurement at 3 weeks postoperative. Second, a type 2 error of an inadequate population may be postulated. The population of this study (111 TKAs) is comparable to previous pain management studies [
Benefits of prolonged postoperative cycloogenase-2 inhibitor administration on total knee arthroplasty recovery: a double-blind, placebo-controlled study.
]. A post hoc power analysis determined that this study was adequately powered to identify a VAS difference of 0.5, π = 0.81. A larger study population, greater than 1000 patients, would be required to obtain a ≤0.2 VAS difference, though this difference has little clinical relevance compared with the cost differences between the two medications. Third, a consideration and potential strength of the study is that the surgical technique, PAI administration, and postoperative management of these cases were done by a single surgeon. While this allows complete standardization of TKA technique and the entire perioperative pathway including the multimodal pain management strategy, the PAI technique of the principal investigator could be fallible. The “practice” process of PAI with liposomal bupivacaine, under the view of a trained sales and education force, in nearly 200 primary TKAs prior to initiation of this study attempted to minimize this concern.
Conclusion
This is the first report of a prospective randomized independent study comparing PAI with liposomal bupivacaine versus plain bupivacaine. As a part of a comprehensive pain management protocol, liposomal bupivacaine did not demonstrate improved pain scores, lower narcotic use, or better knee motion during hospitalization.
Benefits of prolonged postoperative cycloogenase-2 inhibitor administration on total knee arthroplasty recovery: a double-blind, placebo-controlled study.
Periarticular injection with bupivacaine for postoperative pain control in total knee replacement: a prospective randomized double-blind controlled trial.
Controlling pain after total hip and knee arthroplasty using a multimodal protocol with local periarticular injections: a prospective randomized study.
A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty.
A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation.
Multimodal periarticular injection vs. continuous femoral nerve block after total knee arthroplasty: a prospective, crossover, randomized clinical trial.
One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to http://dx.doi.org/10.1016/j.arth.2015.01.059.
This IRB approved study was funded by the St. Louis Joint Replacement Institute. Neither the patients nor the authors received anything of value for participation, conduction, or publication of the results of this study. All patients met strict inclusion criteria and signed consent to participate in the study.
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