The Journal of Arthroplasty xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
The Journal of Arthroplasty journal homepage: www.arthroplastyjournal.org
Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty Deren T. Bagsby, MD, Phillip H. Ireland, MD, R. Michael Meneghini, MD Department of Orthopaedic Surgery, Indiana University Health Physicians, Indiana University School of Medicine, Indianapolis, Indiana
a r t i c l e
i n f o
Article history: Received 10 January 2014 Accepted 29 March 2014 Available online xxxx Keywords: knee arthroplasty knee arthroplasty periarticular injection pain control bupivacaine liposomal
a b s t r a c t The purpose of this study was to compare a novel liposomal bupivacaine to traditional peri-articular injection (PAI) in a multi-modal pain protocol for total knee arthroplasty (TKA). A retrospective cohort study compared 85 consecutive patients undergoing TKA with a traditional PAI of ropivacaine, epinephrine and morphine to 65 patients with a liposomal bupivacaine PAI. After the initial 24 h, inpatient self-reported pain scores were higher in the liposomal bupivacaine group compared to the traditional PAI group (P = 0.04) and a smaller percentage (16.9%) of patients in the liposomal bupivacaine group rated their pain as “mild” compared to the traditional group (47.6%). Liposomal bupivacaine PAI provided inferior pain control compared to the less expensive traditional PAI in a multi-modal pain control program in patients undergoing TKA. © 2014 Elsevier Inc. All rights reserved.
A substantial number of patients experience severe pain after total knee arthroplasty (TKA). Appropriate postsurgical pain management promotes healing and recovery, faster patient mobilization, shortened hospital stays, and reduced healthcare costs. Other potential benefits of optimal pain control in surgical patients include improving cardiac, respiratory, and gastrointestinal function; minimizing thromboembolic complications; reducing chronic post surgical pain; reducing mortality in high-risk patients; improving patient participation in physical therapy and reducing healthcare costs [1]. While parenteral narcotics were the mainstay in pain management strategies of the past, utility as the sole analgesic technique was limited by side effects and inconsistent pain relief [2]. Multimodal pain control programs, which utilize lower doses of multiple drugs that work via different mechanisms, have recently been popularized to maximize pain control while minimizing side effects [1–9]; however, the optimal components of such programs remain unknown. One modality that is frequently used in the multi-modal pain protocols is a periarticular injection of local anesthetic. Liposomal bupivacaine had recently emerged for periarticular injection with proposed benefits of longer acting pain control in TKA [10]. Liposomes are lipid-based multi-vesicular particles that function as drug carriers and offer a controlled delivery of drugs, such as bupivacaine, with a resultant longer term effect [11]. However, there is no study to date that examines the effectiveness
The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2014.03.034. Reprint requests: R. Michael Meneghini, MD, Department of Orthopaedic Surgery, Indiana University School of Medicine, 13100 136th Street, Suite 2000, Fishers, IN 46037.
of this modality on postoperative pain levels or outcomes in TKA. The purpose of this study is to assess the efficacy of liposomal bupivacaine versus a traditional periarticular injection in minimizing opiate consumption and postoperative pain levels following primary total knee arthroplasty. Methods IRB approval was obtained to retrospectively review the inpatient hospital medical records of all patients who underwent unilateral primary TKA by two joint arthroplasty specialists at a single hospital from January through September 2013. A multimodal pain protocol consisting of pre-emptive oral pain medications preoperatively and throughout the hospital stay until discharge, a preoperative singleshot spinal, and an intraoperative periarticular anesthetic injection was employed in all patients. All patients received pre-emptive and postoperative oral analgesia in the form of acetaminophen and celecoxib unless contraindicated. If the patients were 65 years old or younger, all received oral sustained release oxycodone and pregabalin preoperatively and postoperatively. Patients greater than 65 years old were given tramadol preoperatively and postoperatively. A single shot spinal consisting of intrathecal morphine was administered in all patients, along with light general anesthesia per the discretion of the anesthesiologist. Hydroxyzine and famotidine were administered in all patients to counteract the side effects of the intrathecal morphine. Postoperatively, all patients were managed with oral acetaminophen, celecoxib, pregabalin and narcotics. Intravenous narcotics and patient-controlled analgesia were avoided and only administered when necessary for breakthrough pain. Intra-operatively, all patients received a periarticular injection consisting of ropivacaine, morphine
http://dx.doi.org/10.1016/j.arth.2014.03.034 0883-5403/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
2
D.T. Bagsby et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
and epinephrine or liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, Parsipanny, NJ). During the entire study period, the only modification in the perioperative multi-modal pain protocol was the two different periarticular injections, which minimized confounding variables and isolated the outcome effects of the single variable change. From January through June the periarticular injection consisted of 400 mg ropivacaine, 5 mg morphine and 0.4 mg epinephrine in 100 cc solution. From July 1st, 2013 through September 30th, 2013, the periarticular injection consisted of liposomal bupivacaine per the instruction of use by the liposomal bupivacaine manufacturer. An initial syringe of 30 cc of 0.5% marcaine with 1:200,000 epinephrine was injected into the periarticular tissues to provide initial pain control during the immediate postoperative period due to the delayed onset of action of the liposomal bupivacaine. Subsequently 20 cc of 1.3% liposomal bupivacaine (1 vial; 266 mg) added to 30 cc normal saline to a total of 50 cc solution was injected into the periarticular tissues at the conclusion of the surgical procedure. All patients completed perioperative patient education specifically to address pain control, physical therapy and discharge expectations. All patients were encouraged to ambulate the afternoon day of surgery and discharge home on postoperative day two. A standard rehabilitation protocol was followed for all patients. Patients were deemed ready for discharge when medically stable, they satisfied physical therapy requirements and demonstrated adequate pain control. During the hospital stay, patient self-rated pain scores were taken during regular nursing rounds per the protocol established on the orthopaedic surgery inpatient floor. Pain scores were recorded in the EMR approximately every 2–4 h, unless the patient was asleep. The pain scores were averaged during two time periods, the first 24 h and during the remainder of hospital stay. The self-reported pain score at the time of discharge was also recorded. Pain scores were evaluated on the visual analog scale of 0 to 10, with 0 indicating no pain and 10 indicating the worst possible pain. In order to further characterize pain levels, categorical pain scores were defined as: none 0; mild 0.01–3.99; moderate 4.00–6.99; severe 7.00–10.0. Oral narcotics were given to patients per standardized protocols developed and implemented by a perioperative medical specialist and utilized hydrocodone at various dosages depending on the pain level of the patient. In order to accurately and comparatively assess the total opioid usage by the patients during their hospital stay, the oral narcotics and intravenous opioids were converted to intravenous equivalents of morphine through the following formula: 0.33 [PO hydrocodone] + 0.57 [mg PO oxycodone] + 0.33 [mg PO morphine] + 0.05 [mg PO codeine 3] + [mg IV morphine] + 0.1 [mcg IV fentanyl] + 6.67 [mg IV hydromorphone] + 1.8 [mcg fentanyl patch/24 h]. Standard statistical Student’s t-tests were utilized to compare the mean outcome variables between groups. Mean pain scores at the different time periods and the mean morphine equivalents of narcotic usage between the two groups were compared. Statistically significant difference was considered at a P value less than or equal to 0.05 between groups.
Table 1 Patient Variables. Liposomal Bupivicaine
Age (years) BMI Length of Stay Gender: Male Female Side: Left Right
(n = 85)
P Value
63.13 ± 10.32 34.64 ± 7.81 2.32 ± 0.53
65.19 ± 9.21 35.25 ± 8.49 2.31 ± 0.93
0.20 0.60 0.93
18 (27.7%) 47 (72.3%)
25 (29.1%) 61 (70.9%)
34 (52.3%) 31 (47.7%)
49 (57.0%) 37 (43.0%)
With respect to the outcome variables, there was no statistical difference between groups in mean postoperative opiate usage in morphine equivalents between groups at any time frame, mean antiemetic doses, or mean naloxone doses (Table 2). With regard to postoperative patient-reported pain scores, during the first 24 h after surgery there was no statistical difference between the 1.94 (±2.1) in the traditional group compared to the 1.93 (±2.1) in the liposomal bupivacaine group (P = 1.0), likely due to the spinal anesthetic. At the time of discharge, the mean pain scores in the traditional injection group were 3.6 (±2.1) compared 4.1 (± 1.9) in the liposomal bupivacaine injection group and this difference did not reach statistical significance (P = 0.14). Most notably, the mean patient reported pain scores during the remaining hospitalization after the first 24 h until discharge were lower in the traditional injection group at 4.4 (± 1.6) compared to 4.9 (±1.4) in the liposomal bupivacaine, which reached statistical significance (P = 0.04) (Fig. 1). Categorical pain scores demonstrate similar findings as the mean numerical pain scores (Table 3). There was no substantial difference in the percentage of patients who rated their pain as either mild or moderate between the traditional and liposomal bupivacaine groups during the first 24 h after surgery or at the time of discharge. However, during the time interval after the initial 24 h, 81.5% of patients in the liposomal bupivacaine rated their pain an average of “moderate”, compared with only 46.4% in the traditional injection group. Conversely, during the same time period only 16.9% of patients in the liposomal bupivacaine rated their pain as mild, compared to 47.6% of patients in the traditional injection group (Table 3). In the traditional injection group, there were no cases of reoperation or revision during the follow up period. However, in the
Table 2 Patient Drug Outcome Measures. Liposomal Bupivacaine
Ropivicaine Injection
P Value
505 ± 417
486 ± 447
0.79
First 24 h Remaining Stay Final
1.94 ± 2.10 4.89 ± 1.35 4.11 ± 1.86
1.93 ± 2.14 4.38 ± 1.60 3.62 ± 2.09
0.97 0.04 0.14
First 24 h Remaining Stay
6.21 ± 18.30 79.40 ± 62.97
13.75 ± 13.42 65.53 ± 65.00
0.34 0.19
First 24 h Remaining Stay
0.72 ± 1.14 1.03 ± 1.85
0.47 ± 0.85 0.81 ± 1.55
0.12 0.43
First 24 h Remaining Stay
0.03 ± 0.25 0.00 ± 0.00
0.00 ± 0.00 0.02 ± 0.15
0.25 0.22
Time until 1st opiod (min) Self-Rated Pain
Results 150 consecutive patients underwent total knee arthroplasty. There were 85 patients in the traditional periarticular injection group and 65 patients in the liposomal bupivacaine group. All patient demographic data are found in Table 1. The mean age of the traditional group was 65.2 (±9.2) years comprised of 71% female, and the mean age of the liposomal bupivacaine group was 63.1 years (±0.3) with 72% female. The mean body mass index in the traditional injection group was 35.4 (±8.5) compared to 34.6 (± 7.8) in the liposomal bupivacaine group (P = 0.6). There were no statistically significant differences between comparison groups demographically with the numbers available.
Ropivicaine Injection
(n = 65)
Opiate Usage (Meq)
Anti-Emetic Doses
Naloxone Doses
Meq = Intravenous Morphine Equivalents.
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
D.T. Bagsby et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
3
Fig. 1. Mean patient reported pain scores during the first 24 h post-op, the remainder of the hospital stay, and at discharge.
liposomal bupivacaine injection group, three of the 65 patients (4.6%) suffered onset of wound drainage at 3–4 weeks postop and acute postoperative methicillin sensitive staph infection that required reoperation. One patient underwent successful open irrigation and debridement, polyethylene liner exchange and component retention with prolonged antibiotics. Two of the three patients were considered high risk for failure due to medical co-morbidities and underwent resection knee arthroplasty with successful two-stage reimplantation.
Discussion In an effort to optimize pain control after TKA and reduce the side effects associate with opioid consumption, multimodal pain management protocols utilize multiple agents with varying mechanism to modulate nociceptors and different regions of the common pain pathways, reducing the use of opioid agents and their adverse effects. A modality frequently employed in multimodal pain management protocols is a peri-articular injection of local analgesia. The efficacy of periarticular injections in reducing postoperative pain in TKA has been established [8,12]. Peri-articular injections that have successful results of pain control in TKA have consisted of a local anesthetic such as bupivacaine [13] or ropivacaine [8,14], as well as adjuvant morphine and epinephrine to delay its systemic absorption and prolong local tissue effects. Bupivacaine is a long acting local anesthetic with a half-life of 3.5 h and effects that typically last 9 h Table 3 Categorical Pain Scores. Liposomal Bupivacaine (n = 65)
Ropivicaine Injection (n = 85)
14 38 12 1
(21.54%) (58.46%) (18.46%) (1.54%)
21 (25.00%) 46 (54.76%) 12 (15.48%) 4 (4.76%)
0 11 49 5
(0%) (16.92%) (75.38%) (7.69%)
0 (0%) 40 (47.62%) 39 (46.43%) 5 (5.95%)
3 17 38 7
(4.62%) (26.15%) (58.46%) (10.77%)
9 (10.71%) 26 (30.95%) 31 (36.90%) 8 (9.52%)
First 24 h None Mild Moderate Severe Remaining Stay None Mild Moderate Severe Final None Mild Moderate Severe
or less [15,16], and has also been used successfully as a continuous infusion to control pain after TKA [17]. Liposomal bupivacaine has recently been introduced and shown to provide up to 72 h of analgesia after hemorrhoidectomy, reducing consumption of opioids [18,19]. Liposomes are a commonly used drug carrier that offers a controlled delivery of biologically active drugs with resulting long-term potency and reduction in toxicity [11]. They consist of microscopic, spherical multi-vesicular lipid based particles forming honeycomb-like aqueous chambers. This design allows diffusion of the drug over 96 h after a single administration. As a natural evolution, liposomal bupivacaine is now being proposed to offer benefit in TKA [10]. In a study of 138 TKA comparing various doses of liposomal (i.e. DepoFoam) bupivacaine versus bupivacaine HCL in wound infiltration, the highest dose of liposomal bupivacaine (532 mg) was the only dose that produced improved pain scores in patients at rest over the bupivacaine, and was found to be dose-related [10]. This retrospective study was undertaken to determine whether a PAI of liposomal bupivacaine provided a benefit as a component of an established multi-modal pain management protocol compared to a traditional PAI of ropivacaine, epinephrine and morphine. The results demonstrate that after the initial 24 h, inpatient self-reported pain scores were actually higher in the liposomal bupivacaine group compared to the traditional PAI group (P = 0.04) and a smaller percentage (16.9%) of patients in the liposomal bupivacaine group rated their pain as “mild” compared to the traditional group (47.6%). Therefore, liposomal bupivacaine PAI provided inferior pain control compared to the less expensive traditional PAI in a multi-modal pain control program in patients undergoing TKA. In fact, the results demonstrated a trend toward greater mean pain scores, opiate consumption and anti-emetic usage in those patients who were administered liposomal bupivacaine compared to standard ropivacaine and morphine in the PAI, yet these trends did not reach statistical significance. The inferior pain control in the liposomal bupivacaine group may be explained by slow release of the drug from the liposomes, which limits the amount of free bupivacaine present at the site of action. Mashimoto et al demonstrated that slow release of drugs from liposomes can modify the pharmacodynamics properties of lidocaine, a structural cousin of bupivacaine [20]. This study does have limitations and the results should be taken in within that context. First, this is not a randomized, prospective study, but rather a retrospective cohort study. Second, the effect of the periarticular injection may be technique dependent and could have affected the results. However, the technique of injection was identical in both treatment groups and was carried out by two different
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
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D.T. Bagsby et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
surgeons, which minimized the potential confounding effect on injection technique. Thirdly, patient reported pain scores documented in the electronic medical record and the administration of opiates and anti-emetic drugs could theoretically be affected by the variability of the nurses recording and administering them. However, in this particular study, a limited core group of nurses was maintained in all patients in both groups due to the relatively small size of this specialty-based hospital, which minimized the nursing variability. Despite these limitations, the authors believe the scientific methodology and validity of this study are strengthened by the consecutive selection of patients in each group to avoid bias, as well as the standardized perioperative anesthesia and medical protocols, and maintaining an identical surgical technique and multimodal pain management protocol in order to minimize bias through isolation of a single variable (PAI composition) to assess its effect on outcome. In summary, this study demonstrates that a periarticular injection of liposomal bupivacaine in primary TKA patients is not associated with a significant improvement in post-operative pain or narcotic usage. This study found no benefit to intra-articular injection of liposomal bupivacaine, with the possible negative effect of increased pain throughout the remaining hospital course after the initial 24 h. Based on the results of this study, the authors conclude that pain control after TKA with a multimodal pain management protocol is not improved with the addition of liposomal bupivacaine compared to a traditional injection of ropivacaine and epinephrine. In addition, the additional cost of liposomal bupivacaine does not appear to be warranted over the less expensive ropivacaine injection. While the results of this study do not support the routine use of liposomal bupivacaine as a component of modern multi-modal pain management programs at this time, further study is likely warranted. Based on the results of this study, the authors would specifically recommend future prospective, randomized controlled trials be performed in order to enhance the scientific methodology. References 1. Jiang J, Teng Y, Fan Z, et al. The efficacy of periarticular multimodal drug injection for postoperative pain management in total knee or hip arthroplasty. J Arthroplast 2013;28(10):1882.
2. Krych AJ, Horlocker TT, Hebl JR, et al. Contemporary pain management strategies for minimally invasive total knee arthroplasty. Instr Course Lect 2010;59:99. 3. Meftah M, Wong AC, Nawabi DH, et al. Pain management after total knee arthroplasty using a multimodal approach. Orthopedics 2012;35(5):e660. 4. Duellman TJ, Gaffigan C, Milbrandt JC, et al. Multi-modal, pre-emptive analgesia decreases the length of hospital stay following total joint arthroplasty. Orthopedics 2009;32(3):167. 5. Hebl JR, Dilger JA, Byer DE, et al. A pre-emptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery. Reg Anesth Pain Med 2008;33(6):510. 6. Ranawat AS, Ranawat CS. Pain management and accelerated rehabilitation for total hip and total knee arthroplasty. J Arthroplast 2007;22(7 Suppl. 3):12. 7. Horlocker TT, Kopp SL, Pagnano MW, et al. Analgesia for total hip and knee arthroplasty: a multimodal pathway featuring peripheral nerve block. J Am Acad Orthop Surg 2006;14(3):126. 8. Busch CA, Shore BJ, Bhandari R, et al. Efficacy of periarticular multimodal drug injection in total knee arthroplasty. A randomized trial. J Bone Joint Surg Am 2006;88(5):959. 9. Kissin I. Preemptive analgesia. Anesthesiology 2000;93(4):1138. 10. Bramlett K, Onel E, Viscusi ER, et al. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extendedrelease liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee 2012;19(5):530. 11. Ranade VV. Drug delivery systems. 1. Site-specific drug delivery using liposomes as carriers. J Clin Pharmacol 1989;29(8):685. 12. Vendittoli PA, Makinen P, Drolet P, et al. A multimodal analgesia protocol for total knee arthroplasty. A randomized, controlled study. J Bone Joint Surg Am 2006;88 (2):282. 13. Parvataneni HK, Shah VP, Howard H, et al. Controlling pain after total hip and knee arthroplasty using a multimodal protocol with local periarticular injections: a prospective randomized study. J Arthroplast 2007;22(6 Suppl 2):33. 14. Ng FY, Ng JK, Chiu KY, et al. Multimodal periarticular injection vs continuous femoral nerve block after total knee arthroplasty: a prospective, crossover, randomized clinical trial. J Arthroplast 2012;27(6):1234. 15. Babst CR, Gilling BN. Bupivacaine: a review. Anesth Prog 1978;25(3):87. 16. Moiniche S, Mikkelsen S, Wetterslev J, et al. A qualitative systematic review of incisional local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth 1998;81(3):377. 17. Williams D, Petruccelli D, Paul J, et al. Continuous infusion of bupivacaine following total knee arthroplasty: a randomized control trial pilot study. J Arthroplast 2013;28(3):479. 18. Haas E, Onel E, Miller H, et al. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg 2012;78(5):574. 19. Gorfine SR, Onel E, Patou G, et al. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum 2011;54(12):1552. 20. Mashimo T, Uchida I, Pak M, et al. Prolongation of canine epidural anesthesia by liposome encapsulation of lidocaine. Anesth Analg 1992;74(6):827.
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
Contents lists available at ScienceDirect
The Journal of Arthroplasty journal homepage: www.arthroplastyjournal.org
Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty Deren T. Bagsby, MD, Phillip H. Ireland, MD, R. Michael Meneghini, MD Department of Orthopaedic Surgery, Indiana University Health Physicians, Indiana University School of Medicine, Indianapolis, Indiana
a r t i c l e
i n f o
Article history: Received 10 January 2014 Accepted 29 March 2014 Available online xxxx Keywords: knee arthroplasty knee arthroplasty periarticular injection pain control bupivacaine liposomal
a b s t r a c t The purpose of this study was to compare a novel liposomal bupivacaine to traditional peri-articular injection (PAI) in a multi-modal pain protocol for total knee arthroplasty (TKA). A retrospective cohort study compared 85 consecutive patients undergoing TKA with a traditional PAI of ropivacaine, epinephrine and morphine to 65 patients with a liposomal bupivacaine PAI. After the initial 24 h, inpatient self-reported pain scores were higher in the liposomal bupivacaine group compared to the traditional PAI group (P = 0.04) and a smaller percentage (16.9%) of patients in the liposomal bupivacaine group rated their pain as “mild” compared to the traditional group (47.6%). Liposomal bupivacaine PAI provided inferior pain control compared to the less expensive traditional PAI in a multi-modal pain control program in patients undergoing TKA. © 2014 Elsevier Inc. All rights reserved.
A substantial number of patients experience severe pain after total knee arthroplasty (TKA). Appropriate postsurgical pain management promotes healing and recovery, faster patient mobilization, shortened hospital stays, and reduced healthcare costs. Other potential benefits of optimal pain control in surgical patients include improving cardiac, respiratory, and gastrointestinal function; minimizing thromboembolic complications; reducing chronic post surgical pain; reducing mortality in high-risk patients; improving patient participation in physical therapy and reducing healthcare costs [1]. While parenteral narcotics were the mainstay in pain management strategies of the past, utility as the sole analgesic technique was limited by side effects and inconsistent pain relief [2]. Multimodal pain control programs, which utilize lower doses of multiple drugs that work via different mechanisms, have recently been popularized to maximize pain control while minimizing side effects [1–9]; however, the optimal components of such programs remain unknown. One modality that is frequently used in the multi-modal pain protocols is a periarticular injection of local anesthetic. Liposomal bupivacaine had recently emerged for periarticular injection with proposed benefits of longer acting pain control in TKA [10]. Liposomes are lipid-based multi-vesicular particles that function as drug carriers and offer a controlled delivery of drugs, such as bupivacaine, with a resultant longer term effect [11]. However, there is no study to date that examines the effectiveness
The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2014.03.034. Reprint requests: R. Michael Meneghini, MD, Department of Orthopaedic Surgery, Indiana University School of Medicine, 13100 136th Street, Suite 2000, Fishers, IN 46037.
of this modality on postoperative pain levels or outcomes in TKA. The purpose of this study is to assess the efficacy of liposomal bupivacaine versus a traditional periarticular injection in minimizing opiate consumption and postoperative pain levels following primary total knee arthroplasty. Methods IRB approval was obtained to retrospectively review the inpatient hospital medical records of all patients who underwent unilateral primary TKA by two joint arthroplasty specialists at a single hospital from January through September 2013. A multimodal pain protocol consisting of pre-emptive oral pain medications preoperatively and throughout the hospital stay until discharge, a preoperative singleshot spinal, and an intraoperative periarticular anesthetic injection was employed in all patients. All patients received pre-emptive and postoperative oral analgesia in the form of acetaminophen and celecoxib unless contraindicated. If the patients were 65 years old or younger, all received oral sustained release oxycodone and pregabalin preoperatively and postoperatively. Patients greater than 65 years old were given tramadol preoperatively and postoperatively. A single shot spinal consisting of intrathecal morphine was administered in all patients, along with light general anesthesia per the discretion of the anesthesiologist. Hydroxyzine and famotidine were administered in all patients to counteract the side effects of the intrathecal morphine. Postoperatively, all patients were managed with oral acetaminophen, celecoxib, pregabalin and narcotics. Intravenous narcotics and patient-controlled analgesia were avoided and only administered when necessary for breakthrough pain. Intra-operatively, all patients received a periarticular injection consisting of ropivacaine, morphine
http://dx.doi.org/10.1016/j.arth.2014.03.034 0883-5403/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
2
D.T. Bagsby et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
and epinephrine or liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, Parsipanny, NJ). During the entire study period, the only modification in the perioperative multi-modal pain protocol was the two different periarticular injections, which minimized confounding variables and isolated the outcome effects of the single variable change. From January through June the periarticular injection consisted of 400 mg ropivacaine, 5 mg morphine and 0.4 mg epinephrine in 100 cc solution. From July 1st, 2013 through September 30th, 2013, the periarticular injection consisted of liposomal bupivacaine per the instruction of use by the liposomal bupivacaine manufacturer. An initial syringe of 30 cc of 0.5% marcaine with 1:200,000 epinephrine was injected into the periarticular tissues to provide initial pain control during the immediate postoperative period due to the delayed onset of action of the liposomal bupivacaine. Subsequently 20 cc of 1.3% liposomal bupivacaine (1 vial; 266 mg) added to 30 cc normal saline to a total of 50 cc solution was injected into the periarticular tissues at the conclusion of the surgical procedure. All patients completed perioperative patient education specifically to address pain control, physical therapy and discharge expectations. All patients were encouraged to ambulate the afternoon day of surgery and discharge home on postoperative day two. A standard rehabilitation protocol was followed for all patients. Patients were deemed ready for discharge when medically stable, they satisfied physical therapy requirements and demonstrated adequate pain control. During the hospital stay, patient self-rated pain scores were taken during regular nursing rounds per the protocol established on the orthopaedic surgery inpatient floor. Pain scores were recorded in the EMR approximately every 2–4 h, unless the patient was asleep. The pain scores were averaged during two time periods, the first 24 h and during the remainder of hospital stay. The self-reported pain score at the time of discharge was also recorded. Pain scores were evaluated on the visual analog scale of 0 to 10, with 0 indicating no pain and 10 indicating the worst possible pain. In order to further characterize pain levels, categorical pain scores were defined as: none 0; mild 0.01–3.99; moderate 4.00–6.99; severe 7.00–10.0. Oral narcotics were given to patients per standardized protocols developed and implemented by a perioperative medical specialist and utilized hydrocodone at various dosages depending on the pain level of the patient. In order to accurately and comparatively assess the total opioid usage by the patients during their hospital stay, the oral narcotics and intravenous opioids were converted to intravenous equivalents of morphine through the following formula: 0.33 [PO hydrocodone] + 0.57 [mg PO oxycodone] + 0.33 [mg PO morphine] + 0.05 [mg PO codeine 3] + [mg IV morphine] + 0.1 [mcg IV fentanyl] + 6.67 [mg IV hydromorphone] + 1.8 [mcg fentanyl patch/24 h]. Standard statistical Student’s t-tests were utilized to compare the mean outcome variables between groups. Mean pain scores at the different time periods and the mean morphine equivalents of narcotic usage between the two groups were compared. Statistically significant difference was considered at a P value less than or equal to 0.05 between groups.
Table 1 Patient Variables. Liposomal Bupivicaine
Age (years) BMI Length of Stay Gender: Male Female Side: Left Right
(n = 85)
P Value
63.13 ± 10.32 34.64 ± 7.81 2.32 ± 0.53
65.19 ± 9.21 35.25 ± 8.49 2.31 ± 0.93
0.20 0.60 0.93
18 (27.7%) 47 (72.3%)
25 (29.1%) 61 (70.9%)
34 (52.3%) 31 (47.7%)
49 (57.0%) 37 (43.0%)
With respect to the outcome variables, there was no statistical difference between groups in mean postoperative opiate usage in morphine equivalents between groups at any time frame, mean antiemetic doses, or mean naloxone doses (Table 2). With regard to postoperative patient-reported pain scores, during the first 24 h after surgery there was no statistical difference between the 1.94 (±2.1) in the traditional group compared to the 1.93 (±2.1) in the liposomal bupivacaine group (P = 1.0), likely due to the spinal anesthetic. At the time of discharge, the mean pain scores in the traditional injection group were 3.6 (±2.1) compared 4.1 (± 1.9) in the liposomal bupivacaine injection group and this difference did not reach statistical significance (P = 0.14). Most notably, the mean patient reported pain scores during the remaining hospitalization after the first 24 h until discharge were lower in the traditional injection group at 4.4 (± 1.6) compared to 4.9 (±1.4) in the liposomal bupivacaine, which reached statistical significance (P = 0.04) (Fig. 1). Categorical pain scores demonstrate similar findings as the mean numerical pain scores (Table 3). There was no substantial difference in the percentage of patients who rated their pain as either mild or moderate between the traditional and liposomal bupivacaine groups during the first 24 h after surgery or at the time of discharge. However, during the time interval after the initial 24 h, 81.5% of patients in the liposomal bupivacaine rated their pain an average of “moderate”, compared with only 46.4% in the traditional injection group. Conversely, during the same time period only 16.9% of patients in the liposomal bupivacaine rated their pain as mild, compared to 47.6% of patients in the traditional injection group (Table 3). In the traditional injection group, there were no cases of reoperation or revision during the follow up period. However, in the
Table 2 Patient Drug Outcome Measures. Liposomal Bupivacaine
Ropivicaine Injection
P Value
505 ± 417
486 ± 447
0.79
First 24 h Remaining Stay Final
1.94 ± 2.10 4.89 ± 1.35 4.11 ± 1.86
1.93 ± 2.14 4.38 ± 1.60 3.62 ± 2.09
0.97 0.04 0.14
First 24 h Remaining Stay
6.21 ± 18.30 79.40 ± 62.97
13.75 ± 13.42 65.53 ± 65.00
0.34 0.19
First 24 h Remaining Stay
0.72 ± 1.14 1.03 ± 1.85
0.47 ± 0.85 0.81 ± 1.55
0.12 0.43
First 24 h Remaining Stay
0.03 ± 0.25 0.00 ± 0.00
0.00 ± 0.00 0.02 ± 0.15
0.25 0.22
Time until 1st opiod (min) Self-Rated Pain
Results 150 consecutive patients underwent total knee arthroplasty. There were 85 patients in the traditional periarticular injection group and 65 patients in the liposomal bupivacaine group. All patient demographic data are found in Table 1. The mean age of the traditional group was 65.2 (±9.2) years comprised of 71% female, and the mean age of the liposomal bupivacaine group was 63.1 years (±0.3) with 72% female. The mean body mass index in the traditional injection group was 35.4 (±8.5) compared to 34.6 (± 7.8) in the liposomal bupivacaine group (P = 0.6). There were no statistically significant differences between comparison groups demographically with the numbers available.
Ropivicaine Injection
(n = 65)
Opiate Usage (Meq)
Anti-Emetic Doses
Naloxone Doses
Meq = Intravenous Morphine Equivalents.
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
D.T. Bagsby et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
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Fig. 1. Mean patient reported pain scores during the first 24 h post-op, the remainder of the hospital stay, and at discharge.
liposomal bupivacaine injection group, three of the 65 patients (4.6%) suffered onset of wound drainage at 3–4 weeks postop and acute postoperative methicillin sensitive staph infection that required reoperation. One patient underwent successful open irrigation and debridement, polyethylene liner exchange and component retention with prolonged antibiotics. Two of the three patients were considered high risk for failure due to medical co-morbidities and underwent resection knee arthroplasty with successful two-stage reimplantation.
Discussion In an effort to optimize pain control after TKA and reduce the side effects associate with opioid consumption, multimodal pain management protocols utilize multiple agents with varying mechanism to modulate nociceptors and different regions of the common pain pathways, reducing the use of opioid agents and their adverse effects. A modality frequently employed in multimodal pain management protocols is a peri-articular injection of local analgesia. The efficacy of periarticular injections in reducing postoperative pain in TKA has been established [8,12]. Peri-articular injections that have successful results of pain control in TKA have consisted of a local anesthetic such as bupivacaine [13] or ropivacaine [8,14], as well as adjuvant morphine and epinephrine to delay its systemic absorption and prolong local tissue effects. Bupivacaine is a long acting local anesthetic with a half-life of 3.5 h and effects that typically last 9 h Table 3 Categorical Pain Scores. Liposomal Bupivacaine (n = 65)
Ropivicaine Injection (n = 85)
14 38 12 1
(21.54%) (58.46%) (18.46%) (1.54%)
21 (25.00%) 46 (54.76%) 12 (15.48%) 4 (4.76%)
0 11 49 5
(0%) (16.92%) (75.38%) (7.69%)
0 (0%) 40 (47.62%) 39 (46.43%) 5 (5.95%)
3 17 38 7
(4.62%) (26.15%) (58.46%) (10.77%)
9 (10.71%) 26 (30.95%) 31 (36.90%) 8 (9.52%)
First 24 h None Mild Moderate Severe Remaining Stay None Mild Moderate Severe Final None Mild Moderate Severe
or less [15,16], and has also been used successfully as a continuous infusion to control pain after TKA [17]. Liposomal bupivacaine has recently been introduced and shown to provide up to 72 h of analgesia after hemorrhoidectomy, reducing consumption of opioids [18,19]. Liposomes are a commonly used drug carrier that offers a controlled delivery of biologically active drugs with resulting long-term potency and reduction in toxicity [11]. They consist of microscopic, spherical multi-vesicular lipid based particles forming honeycomb-like aqueous chambers. This design allows diffusion of the drug over 96 h after a single administration. As a natural evolution, liposomal bupivacaine is now being proposed to offer benefit in TKA [10]. In a study of 138 TKA comparing various doses of liposomal (i.e. DepoFoam) bupivacaine versus bupivacaine HCL in wound infiltration, the highest dose of liposomal bupivacaine (532 mg) was the only dose that produced improved pain scores in patients at rest over the bupivacaine, and was found to be dose-related [10]. This retrospective study was undertaken to determine whether a PAI of liposomal bupivacaine provided a benefit as a component of an established multi-modal pain management protocol compared to a traditional PAI of ropivacaine, epinephrine and morphine. The results demonstrate that after the initial 24 h, inpatient self-reported pain scores were actually higher in the liposomal bupivacaine group compared to the traditional PAI group (P = 0.04) and a smaller percentage (16.9%) of patients in the liposomal bupivacaine group rated their pain as “mild” compared to the traditional group (47.6%). Therefore, liposomal bupivacaine PAI provided inferior pain control compared to the less expensive traditional PAI in a multi-modal pain control program in patients undergoing TKA. In fact, the results demonstrated a trend toward greater mean pain scores, opiate consumption and anti-emetic usage in those patients who were administered liposomal bupivacaine compared to standard ropivacaine and morphine in the PAI, yet these trends did not reach statistical significance. The inferior pain control in the liposomal bupivacaine group may be explained by slow release of the drug from the liposomes, which limits the amount of free bupivacaine present at the site of action. Mashimoto et al demonstrated that slow release of drugs from liposomes can modify the pharmacodynamics properties of lidocaine, a structural cousin of bupivacaine [20]. This study does have limitations and the results should be taken in within that context. First, this is not a randomized, prospective study, but rather a retrospective cohort study. Second, the effect of the periarticular injection may be technique dependent and could have affected the results. However, the technique of injection was identical in both treatment groups and was carried out by two different
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
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D.T. Bagsby et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
surgeons, which minimized the potential confounding effect on injection technique. Thirdly, patient reported pain scores documented in the electronic medical record and the administration of opiates and anti-emetic drugs could theoretically be affected by the variability of the nurses recording and administering them. However, in this particular study, a limited core group of nurses was maintained in all patients in both groups due to the relatively small size of this specialty-based hospital, which minimized the nursing variability. Despite these limitations, the authors believe the scientific methodology and validity of this study are strengthened by the consecutive selection of patients in each group to avoid bias, as well as the standardized perioperative anesthesia and medical protocols, and maintaining an identical surgical technique and multimodal pain management protocol in order to minimize bias through isolation of a single variable (PAI composition) to assess its effect on outcome. In summary, this study demonstrates that a periarticular injection of liposomal bupivacaine in primary TKA patients is not associated with a significant improvement in post-operative pain or narcotic usage. This study found no benefit to intra-articular injection of liposomal bupivacaine, with the possible negative effect of increased pain throughout the remaining hospital course after the initial 24 h. Based on the results of this study, the authors conclude that pain control after TKA with a multimodal pain management protocol is not improved with the addition of liposomal bupivacaine compared to a traditional injection of ropivacaine and epinephrine. In addition, the additional cost of liposomal bupivacaine does not appear to be warranted over the less expensive ropivacaine injection. While the results of this study do not support the routine use of liposomal bupivacaine as a component of modern multi-modal pain management programs at this time, further study is likely warranted. Based on the results of this study, the authors would specifically recommend future prospective, randomized controlled trials be performed in order to enhance the scientific methodology. References 1. Jiang J, Teng Y, Fan Z, et al. The efficacy of periarticular multimodal drug injection for postoperative pain management in total knee or hip arthroplasty. J Arthroplast 2013;28(10):1882.
2. Krych AJ, Horlocker TT, Hebl JR, et al. Contemporary pain management strategies for minimally invasive total knee arthroplasty. Instr Course Lect 2010;59:99. 3. Meftah M, Wong AC, Nawabi DH, et al. Pain management after total knee arthroplasty using a multimodal approach. Orthopedics 2012;35(5):e660. 4. Duellman TJ, Gaffigan C, Milbrandt JC, et al. Multi-modal, pre-emptive analgesia decreases the length of hospital stay following total joint arthroplasty. Orthopedics 2009;32(3):167. 5. Hebl JR, Dilger JA, Byer DE, et al. A pre-emptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery. Reg Anesth Pain Med 2008;33(6):510. 6. Ranawat AS, Ranawat CS. Pain management and accelerated rehabilitation for total hip and total knee arthroplasty. J Arthroplast 2007;22(7 Suppl. 3):12. 7. Horlocker TT, Kopp SL, Pagnano MW, et al. Analgesia for total hip and knee arthroplasty: a multimodal pathway featuring peripheral nerve block. J Am Acad Orthop Surg 2006;14(3):126. 8. Busch CA, Shore BJ, Bhandari R, et al. Efficacy of periarticular multimodal drug injection in total knee arthroplasty. A randomized trial. J Bone Joint Surg Am 2006;88(5):959. 9. Kissin I. Preemptive analgesia. Anesthesiology 2000;93(4):1138. 10. Bramlett K, Onel E, Viscusi ER, et al. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extendedrelease liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee 2012;19(5):530. 11. Ranade VV. Drug delivery systems. 1. Site-specific drug delivery using liposomes as carriers. J Clin Pharmacol 1989;29(8):685. 12. Vendittoli PA, Makinen P, Drolet P, et al. A multimodal analgesia protocol for total knee arthroplasty. A randomized, controlled study. J Bone Joint Surg Am 2006;88 (2):282. 13. Parvataneni HK, Shah VP, Howard H, et al. Controlling pain after total hip and knee arthroplasty using a multimodal protocol with local periarticular injections: a prospective randomized study. J Arthroplast 2007;22(6 Suppl 2):33. 14. Ng FY, Ng JK, Chiu KY, et al. Multimodal periarticular injection vs continuous femoral nerve block after total knee arthroplasty: a prospective, crossover, randomized clinical trial. J Arthroplast 2012;27(6):1234. 15. Babst CR, Gilling BN. Bupivacaine: a review. Anesth Prog 1978;25(3):87. 16. Moiniche S, Mikkelsen S, Wetterslev J, et al. A qualitative systematic review of incisional local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth 1998;81(3):377. 17. Williams D, Petruccelli D, Paul J, et al. Continuous infusion of bupivacaine following total knee arthroplasty: a randomized control trial pilot study. J Arthroplast 2013;28(3):479. 18. Haas E, Onel E, Miller H, et al. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg 2012;78(5):574. 19. Gorfine SR, Onel E, Patou G, et al. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum 2011;54(12):1552. 20. Mashimo T, Uchida I, Pak M, et al. Prolongation of canine epidural anesthesia by liposome encapsulation of lidocaine. Anesth Analg 1992;74(6):827.
Please cite this article as: Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.034
