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Liposomal Bupivacaine vs Interscalene Nerve Block for Pain Control After Shoulder Arthroplasty: A Retrospective Cohort Analysis
The annual number of total shoulder arthroplasties (TSAs) is rising with the growing elderly population and development of new technologies such as reverse shoulder arthroplasty.1 In 2008, 47,000 shoulder arthroplasties were performed in the US compared with 19,000 in 1998.1 As of 2011, there were 53,000 shoulder arthroplasties performed annually.2 Pain control after shoulder procedures, particularly TSA, is challenging. 3
Several modalities exist to manage pain after shoulder arthroplasty. The interscalene brachial plexus nerve block is considered the “gold standard” for shoulder analgesia. A new approach is the periarticular injection method, in which the surgeon administers a local anesthetic intraoperatively. Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, Inc.) is a nonopioid anesthetic that has been shown to improve pain control, shorten hospital stays, and decrease costs for total knee and hip arthroplasty compared with nerve blocks.4-6 Patients who were treated with liposomal bupivacaine consumed less opioid medication than a placebo group.7
Our purpose was to compare intraoperative local liposomal bupivacaine injection with preoperative single-shot interscalene nerve block (ISNB) in terms of pain control, opioid use, and length of hospital stay (LOS) after shoulder arthroplasty. We hypothesized that patients in the liposomal bupivacaine group would have lower pain scores, less opioid use, and shorter LOS compared with patients in the ISNB group.
Methods
A retrospective cohort analysis was conducted with 58 patients who underwent shoulder arthroplasty by 1 surgeon at our academically affiliated community hospital from January 2012 through January 2015. ISNBs were the standard at the beginning of the study period and were used until Exparel became available on the hospital formulary in 2013. We began using Exparel for all shoulder arthroplasties in November 2013. No other changes were made in the perioperative management of our arthroplasty patients during this period. Patients who underwent TSA, reverse TSA, or hemiarthroplasty of the shoulder were included. Patients who underwent revision TSA were excluded. Twenty-one patients received ISNBs and 37 received liposomal bupivacaine injections. This study was approved by our Institutional Review Board.
Baseline data for each patient were age, sex, body mass index, and the American Society of Anesthesiologists (ASA) Physical Status Classification. The primary outcome measure was the numeric rating scale (NRS) pain score at 4 post-operative time intervals. The NRS pain score has a range of 0 to 10, with 10 representing severe pain. Data were gathered from nursing and physical therapy notes in patient charts. The postoperative time intervals were 0 to 1 hour, 8 to 14 hours, 18 to 24 hours, and 27 to 36 hours. Available NRS scores for these time intervals were averaged. Patients were included if they had pain scores for at least 3 of the postoperative time intervals documented in their charts. Secondary outcome measures were LOS and opioid consumption during hospital admission. Intravenous acetaminophen use was also measured in both groups. All data on opioids were converted to oral morphine equivalents using the method described by Schneider and colleagues.8
A board-certified, fellowship-trained anesthesiologist, experienced in regional anesthesia, administered the single-shot ISNB before surgery. The block was administered under ultrasound guidance using a 44-mm, 22-gauge needle with the patient in the supine position. No indwelling catheter was used. The medication consisted of 30 mL of 5% ropivacaine (5 mg/mL). The surgeon injected liposomal bupivacaine (266 mg diluted into 40 mL of injectable saline) near the end of the procedure throughout the pericapsular area and multiple layers of the wound, per manufacturer guidelines.9 A 60-mL syringe with a 20-gauge needle was used. All operations were performed by 1 board-certified, fellowship-trained surgeon using a standard deltopectoral approach with the same surgical equipment. The same postoperative pain protocol was used for all patients, including intravenous acetaminophen and patient-controlled analgesia. Additional oral pain medication was provided as needed for all patients. Physical therapy protocols were identical between groups.
Statistical Analysis
Mean patient ages in the 2 treatment groups were compared using the Student t test. Sex distribution and the ASA scores were compared using a χ2 test and a Fisher exact test, respectively. Arthroplasty types were compared using a Fisher exact test. The medians and interquartile ranges of the NRS scores at each time point measured were tabulated by treatment group, and at each time point the difference between groups was tested using nonparametric rank sum tests.
We tested the longitudinal trajectory of NRS scores over time, accounting for repeated measurements in the same patients using linear mixed model analysis. Treatment group, time period as a categorical variable, and the interaction between treatment and time period were included as fixed effects, and patient identification number was included as the random effect. An initial omnibus test was performed for all treatment and treatment-by-time interaction effects. Subsequently, the treatment-by-time interaction was tested for each of the time periods. The association of day of discharge (as a categorical variable) with treatment was tested using the Fisher exact test. All analyses were conducted using Stata, version 13, software (StataCorp LP). P values <.05 were considered significant.
Sample Size Analysis
We calculated the minimum detectable effect size with 80% power at an alpha level of 0.05 for the nonparametric rank sum test in terms of the proportion of every possible pair of patients treated with the 2 treatments, where the patient treated with liposomal bupivacaine has a lower pain score than the patient treated with ISNB. For pain score at 18 to 24 hours, the sample sizes of 33 patients treated with liposomal bupivacaine and 20 treated with ISNB, the minimum detectable effect size is 73%.
Results
Fifty-eight patient charts (21 in the ISNB group and 37 in the liposomal bupivacaine group) were reviewed for the study. Patient sex distribution, mean age, mean body mass index, and mean baseline ASA scores were not statistically different (Table 1). 
The primary outcome measure, NRS pain score, showed no significant differences between groups at 0 to 1 hour after surgery (P = .99) or 8 to 14 hours after surgery (P = .208). 
There was no difference in the amount of intravenous acetaminophen given during the hospital stay between groups. There was no significant difference in opioid consumption on postoperative day 1 in the hospital (P = .59) (Figure 2). However, there were significant differences between groups on postoperative days 2 and 3. 
Sixteen of 37 patients in the liposomal bupivacaine group and 2 of 21 in the ISNB group were discharged on the day after surgery (P = .010) (Table 3). 
There were no major cardiac or respiratory events in either group. No long-term paresthesias or neuropathies were noted. There were no readmissions for either group.
Discussion
Postoperative pain control after shoulder arthroplasty can be challenging, and several modalities have been tried in various combinations to minimize pain and decrease adverse effects of opioid medications. The most common method for pain relief after shoulder arthroplasty is the ISNB. Several studies of ISNBs have shown improved pain control after shoulder arthroplasty with associated decreased opioid consumption and related side effects.10 Patient rehabilitation and satisfaction have improved with the increasing use of peripheral nerve blocks.11
Despite the well-established benefits of ISNBs, several limitations exist. Although the superior portion of the shoulder is well covered by an ISNB, the inferior portion of the brachial plexus can remain uncovered or only partially covered.12 Complications of ISNBs include hemidiaphragmatic paresis, rebound pain 24 hours after surgery,13 chronic neurologic complications,14 and substantial respiratory and cardiovascular events.15 Nerve blocks also require additional time and resources in the perioperative period, including an anesthesiologist with specialized training, assistants, and ultrasonography or nerve stimulation equipment contraindicated in patients taking blood thinners.16
Periarticular injections of local anesthetics have also shown promise in reducing pain after arthroplasty.4 Benefits include an enhanced safety profile because local injection avoids the concurrent blockade of the phrenic nerve and recurrent laryngeal nerve and has not been associated with the risk of peripheral neuropathies. Further, local injection is a simple technique that can be performed during surgery without additional personnel or expertise. A limitation of this approach is the relatively short duration of effectiveness of the local anesthetic and uncertainty regarding the best agent and the ideal volume of injection.6 Liposomal bupivacaine is a new agent (approved by the US Food and Drug Administration in 201117) with a sustained release over 72 to 96 hours.18 The most common adverse effects of liposomal bupivacaine are nausea, vomiting, constipation, pyrexia, dizziness, and headache.19 Chondrotoxicity and granulomatous inflammation are more serious, yet rare, complications of liposomal bupivacaine.20
We found that liposomal bupivacaine injections were associated with lower pain scores compared with ISNB at 18 to 24 hours after surgery. This correlated with less opioid consumption in the liposomal bupivacaine group than in the ISNB group on the second postoperative day. These differences in pain values are consistent with the known pharmacokinetics of liposomal bupivacaine.18 Peak plasma levels normally occur approximately 24 hours after injection, leaving the early postoperative period relatively uncovered by anesthetic agent. This finding of relatively poor pain control early after surgery has also been noted in patients undergoing knee arthroplasty.5 On the basis of the findings of this study, we have added standard bupivacaine injections to our separate liposomal bupivacaine injection to cover early postoperative pain. Opioid consumption was significantly lower in the liposomal bupivacaine group than in the ISNB group on postoperative days 2 and 3. We did not measure adverse events related to opioid consumption, so we cannot comment on whether the decreased opioid consumption was associated with the rate of adverse events. However, other studies21,22 have established this relationship.
We found the liposomal bupivacaine group to have earlier discharges to home. Sixteen of 37 patients in the liposomal bupivacaine group compared with 2 of 21 patients in the ISNB group were discharged on the day after surgery. A mean reduction in LOS of 18 hours for the liposomal bupivacaine group was statistically significant (P = .012). This reduction in LOS has important implications for hospitals and value analysis committees considering whether to keep a new, more expensive local anesthetic on formulary. Savings from reduced LOS and improvements in patient satisfaction may justify the expense (approximately $300 per 266-mg vial) of Exparel.
From a societal cost perspective, liposomal bupivacaine is more economical compared with ISNB, which adds approximately $1500 to the cost of anesthesia per patient.23 Eliminating the costs associated with ISNB administration in shoulder arthroplasties could result in substantial savings to our healthcare system. More research examining time savings and exact costs of each procedure is needed to determine the true cost effectiveness of each approach.
Limitations of our study include the retrospective design, relatively small numbers of patients in each group, missing data for some patients at various time points, variation in the types of procedures in each group, and lack of long-term outcome measures. It is important to note that we did not confirm the success of the nerve block after administration. However, this study reflects the effectiveness of each of the modalities in actual clinical conditions (as opposed to a controlled experimental setting). The actual effectiveness of a nerve block varies, even when performed by an experienced anesthesiologist with ultrasound guidance. Furthermore, immediate postoperative pain scores in the nerve block group are consistent with those of prior research reporting pain values ranging from 4 to 5 and a mean duration of effect ranging from 9 to 14 hours.23,24 Additionally, the patients, surgeon, and nursing team were not blinded to the treatment group. Although we did note a significant difference in the types of procedures between groups, this finding is related to the greater number of hemiarthroplasties performed in the ISNB group (N = 5) compared with the liposomal group (N = 1). Because of this variation and the decreased invasiveness of hemiarthroplasties, the bias is against the liposomal group. Finally, our primary outcome variable was pain, which is a subjective, self-reported measure. However, our opioid consumption data and LOS data corroborate the improved pain scores in the liposomal bupivacaine group.
Limiting the study to a single surgeon may limit external validity. Another limitation is the lack of data on adverse events related to opioid medication use. There was no additional experimental group to determine whether less expensive local anesthetics injected locally would perform similarly to liposomal bupivacaine. In total knee arthroplasty, periarticular injections of liposomal bupivacaine were not as effective as less expensive periarticular injections.25 It is unclear which agents (and in what doses or combinations) should be used for periarticular injections. Finally, we acknowledge that our retrospective study design cannot account for all potential factors affecting discharge time.
This is the first comparative study of liposomal bupivacaine and ISNB in TSA. The study design allowed us to control for variables such as surgical technique, postoperative protocols (including use and type of sling), and use of other pain modalities such as patient-controlled analgesia and intravenous acetaminophen that are likely to affect postoperative pain and LOS. This study provides preliminary data that confirm relative equipoise between liposomal bupivacaine and ISNB, which is needed for the ethical conduct of a randomized controlled trial. Such a trial would allow for a more robust comparison, and this retrospective study provides appropriate pilot data on which to base this design and the clinical information needed to counsel patients during enrollment.
Our results suggest that liposomal bupivacaine may provide superior or similar pain relief compared with ISNB after shoulder arthroplasty. Additionally, the use of liposomal bupivacaine was associated with decreased opioid consumption and earlier discharge to home compared with ISNB. These findings have important implications for pain control after TSA because pain represents a major concern for patients and providers after surgery. In addition to clinical improvements, use of liposomal bupivacaine may save time and eliminate costs associated with administering nerve blocks. Local injection may also be used in patients who are contraindicated for ISNB such as those with obesity, pulmonary disease, or peripheral neuropathy. Although we cannot definitively suggest that liposomal bupivacaine is superior to the current gold standard ISNB for pain control after shoulder arthroplasty, our results suggest a relative clinical equipoise between these modalities. Larger analytical studies, including randomized trials, should be performed to explore the potential benefits of liposomal bupivacaine injections for pain control after shoulder arthroplasty.
Am J Orthop. 2016;45(7):424-430. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.
1. Kim SH, Wise BL, Zhang Y, Szabo RM. Increasing incidence of shoulder arthroplasty in the United States. J Bone Joint Surg Am. 2011;93(24):2249-2254.
2. American Academy of Orthopaedic Surgeons. Shoulder joint replacement. http://orthoinfo.aaos.org/topic.cfm?topic=A00094. Accessed June 3, 2015.
3. Desai VN, Cheung EV. Postoperative pain associated with orthopedic shoulder and elbow surgery: a prospective study. J Shoulder Elbow Surg. 2012;21(4):441-450.
4. Springer BD. Transition from nerve blocks to periarticular injections and emerging techniques in total joint arthroplasty. Am J Orthop. 2014;43(10 Suppl):S6-S9.
5. Surdam JW, Licini DJ, Baynes NT, Arce BR. The use of exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. J Arthroplasty. 2015;30(2):325-329.
6. Tong YC, Kaye AD, Urman RD. Liposomal bupivacaine and clinical outcomes. Best Pract Res Clin Anaesthesiol. 2014;28(1):15-27.
7. Chahar P, Cummings KC 3rd. Liposomal bupivacaine: a review of a new bupivacaine formulation. J Pain Res. 2012;5:257-264.
8. Schneider C, Yale SH, Larson M. Principles of pain management. Clin Med Res. 2003;1(4):337-340.
9. Pacira Pharmaceuticals, Inc. Highlights of prescribing information. http://www.exparel.com/pdf/EXPAREL_Prescribing_Information.pdf. Accessed May 7, 2015.
10. Gohl MR, Moeller RK, Olson RL, Vacchiano CA. The addition of interscalene block to general anesthesia for patients undergoing open shoulder procedures. AANA J. 2001;69(2):105-109.
11. Ironfield CM, Barrington MJ, Kluger R, Sites B. Are patients satisfied after peripheral nerve blockade? Results from an International Registry of Regional Anesthesia. Reg Anesth Pain Med. 2014;39(1):48-55.
12. Srikumaran U, Stein BE, Tan EW, Freehill MT, Wilckens JH. Upper-extremity peripheral nerve blocks in the perioperative pain management of orthopaedic patients: AAOS exhibit selection. J Bone Joint Surg Am. 2013;95(24):e197(1-13).
13. DeMarco JR, Componovo R, Barfield WR, Liles L, Nietert P. Efficacy of augmenting a subacromial continuous-infusion pump with a preoperative interscalene block in outpatient arthroscopic shoulder surgery: a prospective, randomized, blinded, and placebo-controlled study. Arthroscopy. 2011;27(5):603-610.
14. Misamore G, Webb B, McMurray S, Sallay P. A prospective analysis of interscalene brachial plexus blocks performed under general anesthesia. J Shoulder Elbow Surg. 2011;20(2):308-314.
15. Lenters TR, Davies J, Matsen FA 3rd. The types and severity of complications associated with interscalene brachial plexus block anesthesia: local and national evidence. J Shoulder Elbow Surg. 2007;16(4):379-387.
16. Park SK, Choi YS, Choi SW, Song SW. A comparison of three methods for postoperative pain control in patients undergoing arthroscopic shoulder surgery. Korean J Pain. 2015;28(1):45-51.
17. Pacira Pharmaceuticals, Inc. Pacira Pharmaceuticals, Inc. announces U.S. FDA approval of EXPAREL™ for postsurgical pain management. http://investor.pacira.com/phoenix.zhtml?c=220759&p=irol-newsArticle_print&ID=1623529. Published October 31, 2011. Accessed June 3, 2015.
18. White PF, Ardeleanu M, Schooley G, Burch RM. Pharmocokinetics of depobupivacaine following infiltration in patients undergoing two types of surgery and in normal volunteers. Paper presented at: Annual Meeting of the International Anesthesia Research Society; March 14, 2009; San Diego, CA.
19. Bramlett K, Onel E, Viscusi ER, Jones K. 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. Knee. 2012;19(5):530-536.
20. Lambrechts M, O’Brien MJ, Savoie FH, You Z. Liposomal extended-release bupivacaine for postsurgical analgesia. Patient Prefer Adherence. 2013;7:885-890.
21. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273.
22. Candiotti KA, Sands LR, Lee E, et al. Liposome bupivacaine for postsurgical analgesia in adult patients undergoing laparoscopic colectomy: results from prospective phase IV sequential cohort studies assessing health economic outcomes. Curr Ther Res Clin Exp. 2013;76:1-6.
23. Weber SC, Jain R. Scalene regional anesthesia for shoulder surgery in a community setting: an assessment of risk. J Bone Joint Surg Am. 2002;84-A(5):775-779.
24. Beaudet V, Williams SR, Tétreault P, Perrault MA. Perioperative interscalene block versus intra-articular injection of local anesthetics for postoperative analgesia in shoulder surgery. Reg Anesth Pain Med. 2008;33(2):134-138.
25. Bagsby DT, Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty. 2014;29(8):1687-1690.
The annual number of total shoulder arthroplasties (TSAs) is rising with the growing elderly population and development of new technologies such as reverse shoulder arthroplasty.1 In 2008, 47,000 shoulder arthroplasties were performed in the US compared with 19,000 in 1998.1 As of 2011, there were 53,000 shoulder arthroplasties performed annually.2 Pain control after shoulder procedures, particularly TSA, is challenging. 3
Several modalities exist to manage pain after shoulder arthroplasty. The interscalene brachial plexus nerve block is considered the “gold standard” for shoulder analgesia. A new approach is the periarticular injection method, in which the surgeon administers a local anesthetic intraoperatively. Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, Inc.) is a nonopioid anesthetic that has been shown to improve pain control, shorten hospital stays, and decrease costs for total knee and hip arthroplasty compared with nerve blocks.4-6 Patients who were treated with liposomal bupivacaine consumed less opioid medication than a placebo group.7
Our purpose was to compare intraoperative local liposomal bupivacaine injection with preoperative single-shot interscalene nerve block (ISNB) in terms of pain control, opioid use, and length of hospital stay (LOS) after shoulder arthroplasty. We hypothesized that patients in the liposomal bupivacaine group would have lower pain scores, less opioid use, and shorter LOS compared with patients in the ISNB group.
Methods
A retrospective cohort analysis was conducted with 58 patients who underwent shoulder arthroplasty by 1 surgeon at our academically affiliated community hospital from January 2012 through January 2015. ISNBs were the standard at the beginning of the study period and were used until Exparel became available on the hospital formulary in 2013. We began using Exparel for all shoulder arthroplasties in November 2013. No other changes were made in the perioperative management of our arthroplasty patients during this period. Patients who underwent TSA, reverse TSA, or hemiarthroplasty of the shoulder were included. Patients who underwent revision TSA were excluded. Twenty-one patients received ISNBs and 37 received liposomal bupivacaine injections. This study was approved by our Institutional Review Board.
Baseline data for each patient were age, sex, body mass index, and the American Society of Anesthesiologists (ASA) Physical Status Classification. The primary outcome measure was the numeric rating scale (NRS) pain score at 4 post-operative time intervals. The NRS pain score has a range of 0 to 10, with 10 representing severe pain. Data were gathered from nursing and physical therapy notes in patient charts. The postoperative time intervals were 0 to 1 hour, 8 to 14 hours, 18 to 24 hours, and 27 to 36 hours. Available NRS scores for these time intervals were averaged. Patients were included if they had pain scores for at least 3 of the postoperative time intervals documented in their charts. Secondary outcome measures were LOS and opioid consumption during hospital admission. Intravenous acetaminophen use was also measured in both groups. All data on opioids were converted to oral morphine equivalents using the method described by Schneider and colleagues.8
A board-certified, fellowship-trained anesthesiologist, experienced in regional anesthesia, administered the single-shot ISNB before surgery. The block was administered under ultrasound guidance using a 44-mm, 22-gauge needle with the patient in the supine position. No indwelling catheter was used. The medication consisted of 30 mL of 5% ropivacaine (5 mg/mL). The surgeon injected liposomal bupivacaine (266 mg diluted into 40 mL of injectable saline) near the end of the procedure throughout the pericapsular area and multiple layers of the wound, per manufacturer guidelines.9 A 60-mL syringe with a 20-gauge needle was used. All operations were performed by 1 board-certified, fellowship-trained surgeon using a standard deltopectoral approach with the same surgical equipment. The same postoperative pain protocol was used for all patients, including intravenous acetaminophen and patient-controlled analgesia. Additional oral pain medication was provided as needed for all patients. Physical therapy protocols were identical between groups.
Statistical Analysis
Mean patient ages in the 2 treatment groups were compared using the Student t test. Sex distribution and the ASA scores were compared using a χ2 test and a Fisher exact test, respectively. Arthroplasty types were compared using a Fisher exact test. The medians and interquartile ranges of the NRS scores at each time point measured were tabulated by treatment group, and at each time point the difference between groups was tested using nonparametric rank sum tests.
We tested the longitudinal trajectory of NRS scores over time, accounting for repeated measurements in the same patients using linear mixed model analysis. Treatment group, time period as a categorical variable, and the interaction between treatment and time period were included as fixed effects, and patient identification number was included as the random effect. An initial omnibus test was performed for all treatment and treatment-by-time interaction effects. Subsequently, the treatment-by-time interaction was tested for each of the time periods. The association of day of discharge (as a categorical variable) with treatment was tested using the Fisher exact test. All analyses were conducted using Stata, version 13, software (StataCorp LP). P values <.05 were considered significant.
Sample Size Analysis
We calculated the minimum detectable effect size with 80% power at an alpha level of 0.05 for the nonparametric rank sum test in terms of the proportion of every possible pair of patients treated with the 2 treatments, where the patient treated with liposomal bupivacaine has a lower pain score than the patient treated with ISNB. For pain score at 18 to 24 hours, the sample sizes of 33 patients treated with liposomal bupivacaine and 20 treated with ISNB, the minimum detectable effect size is 73%.
Results
Fifty-eight patient charts (21 in the ISNB group and 37 in the liposomal bupivacaine group) were reviewed for the study. Patient sex distribution, mean age, mean body mass index, and mean baseline ASA scores were not statistically different (Table 1).
The primary outcome measure, NRS pain score, showed no significant differences between groups at 0 to 1 hour after surgery (P = .99) or 8 to 14 hours after surgery (P = .208).
There was no difference in the amount of intravenous acetaminophen given during the hospital stay between groups. There was no significant difference in opioid consumption on postoperative day 1 in the hospital (P = .59) (Figure 2). However, there were significant differences between groups on postoperative days 2 and 3.
Sixteen of 37 patients in the liposomal bupivacaine group and 2 of 21 in the ISNB group were discharged on the day after surgery (P = .010) (Table 3).
There were no major cardiac or respiratory events in either group. No long-term paresthesias or neuropathies were noted. There were no readmissions for either group.
Discussion
Postoperative pain control after shoulder arthroplasty can be challenging, and several modalities have been tried in various combinations to minimize pain and decrease adverse effects of opioid medications. The most common method for pain relief after shoulder arthroplasty is the ISNB. Several studies of ISNBs have shown improved pain control after shoulder arthroplasty with associated decreased opioid consumption and related side effects.10 Patient rehabilitation and satisfaction have improved with the increasing use of peripheral nerve blocks.11
Despite the well-established benefits of ISNBs, several limitations exist. Although the superior portion of the shoulder is well covered by an ISNB, the inferior portion of the brachial plexus can remain uncovered or only partially covered.12 Complications of ISNBs include hemidiaphragmatic paresis, rebound pain 24 hours after surgery,13 chronic neurologic complications,14 and substantial respiratory and cardiovascular events.15 Nerve blocks also require additional time and resources in the perioperative period, including an anesthesiologist with specialized training, assistants, and ultrasonography or nerve stimulation equipment contraindicated in patients taking blood thinners.16
Periarticular injections of local anesthetics have also shown promise in reducing pain after arthroplasty.4 Benefits include an enhanced safety profile because local injection avoids the concurrent blockade of the phrenic nerve and recurrent laryngeal nerve and has not been associated with the risk of peripheral neuropathies. Further, local injection is a simple technique that can be performed during surgery without additional personnel or expertise. A limitation of this approach is the relatively short duration of effectiveness of the local anesthetic and uncertainty regarding the best agent and the ideal volume of injection.6 Liposomal bupivacaine is a new agent (approved by the US Food and Drug Administration in 201117) with a sustained release over 72 to 96 hours.18 The most common adverse effects of liposomal bupivacaine are nausea, vomiting, constipation, pyrexia, dizziness, and headache.19 Chondrotoxicity and granulomatous inflammation are more serious, yet rare, complications of liposomal bupivacaine.20
We found that liposomal bupivacaine injections were associated with lower pain scores compared with ISNB at 18 to 24 hours after surgery. This correlated with less opioid consumption in the liposomal bupivacaine group than in the ISNB group on the second postoperative day. These differences in pain values are consistent with the known pharmacokinetics of liposomal bupivacaine.18 Peak plasma levels normally occur approximately 24 hours after injection, leaving the early postoperative period relatively uncovered by anesthetic agent. This finding of relatively poor pain control early after surgery has also been noted in patients undergoing knee arthroplasty.5 On the basis of the findings of this study, we have added standard bupivacaine injections to our separate liposomal bupivacaine injection to cover early postoperative pain. Opioid consumption was significantly lower in the liposomal bupivacaine group than in the ISNB group on postoperative days 2 and 3. We did not measure adverse events related to opioid consumption, so we cannot comment on whether the decreased opioid consumption was associated with the rate of adverse events. However, other studies21,22 have established this relationship.
We found the liposomal bupivacaine group to have earlier discharges to home. Sixteen of 37 patients in the liposomal bupivacaine group compared with 2 of 21 patients in the ISNB group were discharged on the day after surgery. A mean reduction in LOS of 18 hours for the liposomal bupivacaine group was statistically significant (P = .012). This reduction in LOS has important implications for hospitals and value analysis committees considering whether to keep a new, more expensive local anesthetic on formulary. Savings from reduced LOS and improvements in patient satisfaction may justify the expense (approximately $300 per 266-mg vial) of Exparel.
From a societal cost perspective, liposomal bupivacaine is more economical compared with ISNB, which adds approximately $1500 to the cost of anesthesia per patient.23 Eliminating the costs associated with ISNB administration in shoulder arthroplasties could result in substantial savings to our healthcare system. More research examining time savings and exact costs of each procedure is needed to determine the true cost effectiveness of each approach.
Limitations of our study include the retrospective design, relatively small numbers of patients in each group, missing data for some patients at various time points, variation in the types of procedures in each group, and lack of long-term outcome measures. It is important to note that we did not confirm the success of the nerve block after administration. However, this study reflects the effectiveness of each of the modalities in actual clinical conditions (as opposed to a controlled experimental setting). The actual effectiveness of a nerve block varies, even when performed by an experienced anesthesiologist with ultrasound guidance. Furthermore, immediate postoperative pain scores in the nerve block group are consistent with those of prior research reporting pain values ranging from 4 to 5 and a mean duration of effect ranging from 9 to 14 hours.23,24 Additionally, the patients, surgeon, and nursing team were not blinded to the treatment group. Although we did note a significant difference in the types of procedures between groups, this finding is related to the greater number of hemiarthroplasties performed in the ISNB group (N = 5) compared with the liposomal group (N = 1). Because of this variation and the decreased invasiveness of hemiarthroplasties, the bias is against the liposomal group. Finally, our primary outcome variable was pain, which is a subjective, self-reported measure. However, our opioid consumption data and LOS data corroborate the improved pain scores in the liposomal bupivacaine group.
Limiting the study to a single surgeon may limit external validity. Another limitation is the lack of data on adverse events related to opioid medication use. There was no additional experimental group to determine whether less expensive local anesthetics injected locally would perform similarly to liposomal bupivacaine. In total knee arthroplasty, periarticular injections of liposomal bupivacaine were not as effective as less expensive periarticular injections.25 It is unclear which agents (and in what doses or combinations) should be used for periarticular injections. Finally, we acknowledge that our retrospective study design cannot account for all potential factors affecting discharge time.
This is the first comparative study of liposomal bupivacaine and ISNB in TSA. The study design allowed us to control for variables such as surgical technique, postoperative protocols (including use and type of sling), and use of other pain modalities such as patient-controlled analgesia and intravenous acetaminophen that are likely to affect postoperative pain and LOS. This study provides preliminary data that confirm relative equipoise between liposomal bupivacaine and ISNB, which is needed for the ethical conduct of a randomized controlled trial. Such a trial would allow for a more robust comparison, and this retrospective study provides appropriate pilot data on which to base this design and the clinical information needed to counsel patients during enrollment.
Our results suggest that liposomal bupivacaine may provide superior or similar pain relief compared with ISNB after shoulder arthroplasty. Additionally, the use of liposomal bupivacaine was associated with decreased opioid consumption and earlier discharge to home compared with ISNB. These findings have important implications for pain control after TSA because pain represents a major concern for patients and providers after surgery. In addition to clinical improvements, use of liposomal bupivacaine may save time and eliminate costs associated with administering nerve blocks. Local injection may also be used in patients who are contraindicated for ISNB such as those with obesity, pulmonary disease, or peripheral neuropathy. Although we cannot definitively suggest that liposomal bupivacaine is superior to the current gold standard ISNB for pain control after shoulder arthroplasty, our results suggest a relative clinical equipoise between these modalities. Larger analytical studies, including randomized trials, should be performed to explore the potential benefits of liposomal bupivacaine injections for pain control after shoulder arthroplasty.
Am J Orthop. 2016;45(7):424-430. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.
The annual number of total shoulder arthroplasties (TSAs) is rising with the growing elderly population and development of new technologies such as reverse shoulder arthroplasty.1 In 2008, 47,000 shoulder arthroplasties were performed in the US compared with 19,000 in 1998.1 As of 2011, there were 53,000 shoulder arthroplasties performed annually.2 Pain control after shoulder procedures, particularly TSA, is challenging. 3
Several modalities exist to manage pain after shoulder arthroplasty. The interscalene brachial plexus nerve block is considered the “gold standard” for shoulder analgesia. A new approach is the periarticular injection method, in which the surgeon administers a local anesthetic intraoperatively. Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, Inc.) is a nonopioid anesthetic that has been shown to improve pain control, shorten hospital stays, and decrease costs for total knee and hip arthroplasty compared with nerve blocks.4-6 Patients who were treated with liposomal bupivacaine consumed less opioid medication than a placebo group.7
Our purpose was to compare intraoperative local liposomal bupivacaine injection with preoperative single-shot interscalene nerve block (ISNB) in terms of pain control, opioid use, and length of hospital stay (LOS) after shoulder arthroplasty. We hypothesized that patients in the liposomal bupivacaine group would have lower pain scores, less opioid use, and shorter LOS compared with patients in the ISNB group.
Methods
A retrospective cohort analysis was conducted with 58 patients who underwent shoulder arthroplasty by 1 surgeon at our academically affiliated community hospital from January 2012 through January 2015. ISNBs were the standard at the beginning of the study period and were used until Exparel became available on the hospital formulary in 2013. We began using Exparel for all shoulder arthroplasties in November 2013. No other changes were made in the perioperative management of our arthroplasty patients during this period. Patients who underwent TSA, reverse TSA, or hemiarthroplasty of the shoulder were included. Patients who underwent revision TSA were excluded. Twenty-one patients received ISNBs and 37 received liposomal bupivacaine injections. This study was approved by our Institutional Review Board.
Baseline data for each patient were age, sex, body mass index, and the American Society of Anesthesiologists (ASA) Physical Status Classification. The primary outcome measure was the numeric rating scale (NRS) pain score at 4 post-operative time intervals. The NRS pain score has a range of 0 to 10, with 10 representing severe pain. Data were gathered from nursing and physical therapy notes in patient charts. The postoperative time intervals were 0 to 1 hour, 8 to 14 hours, 18 to 24 hours, and 27 to 36 hours. Available NRS scores for these time intervals were averaged. Patients were included if they had pain scores for at least 3 of the postoperative time intervals documented in their charts. Secondary outcome measures were LOS and opioid consumption during hospital admission. Intravenous acetaminophen use was also measured in both groups. All data on opioids were converted to oral morphine equivalents using the method described by Schneider and colleagues.8
A board-certified, fellowship-trained anesthesiologist, experienced in regional anesthesia, administered the single-shot ISNB before surgery. The block was administered under ultrasound guidance using a 44-mm, 22-gauge needle with the patient in the supine position. No indwelling catheter was used. The medication consisted of 30 mL of 5% ropivacaine (5 mg/mL). The surgeon injected liposomal bupivacaine (266 mg diluted into 40 mL of injectable saline) near the end of the procedure throughout the pericapsular area and multiple layers of the wound, per manufacturer guidelines.9 A 60-mL syringe with a 20-gauge needle was used. All operations were performed by 1 board-certified, fellowship-trained surgeon using a standard deltopectoral approach with the same surgical equipment. The same postoperative pain protocol was used for all patients, including intravenous acetaminophen and patient-controlled analgesia. Additional oral pain medication was provided as needed for all patients. Physical therapy protocols were identical between groups.
Statistical Analysis
Mean patient ages in the 2 treatment groups were compared using the Student t test. Sex distribution and the ASA scores were compared using a χ2 test and a Fisher exact test, respectively. Arthroplasty types were compared using a Fisher exact test. The medians and interquartile ranges of the NRS scores at each time point measured were tabulated by treatment group, and at each time point the difference between groups was tested using nonparametric rank sum tests.
We tested the longitudinal trajectory of NRS scores over time, accounting for repeated measurements in the same patients using linear mixed model analysis. Treatment group, time period as a categorical variable, and the interaction between treatment and time period were included as fixed effects, and patient identification number was included as the random effect. An initial omnibus test was performed for all treatment and treatment-by-time interaction effects. Subsequently, the treatment-by-time interaction was tested for each of the time periods. The association of day of discharge (as a categorical variable) with treatment was tested using the Fisher exact test. All analyses were conducted using Stata, version 13, software (StataCorp LP). P values <.05 were considered significant.
Sample Size Analysis
We calculated the minimum detectable effect size with 80% power at an alpha level of 0.05 for the nonparametric rank sum test in terms of the proportion of every possible pair of patients treated with the 2 treatments, where the patient treated with liposomal bupivacaine has a lower pain score than the patient treated with ISNB. For pain score at 18 to 24 hours, the sample sizes of 33 patients treated with liposomal bupivacaine and 20 treated with ISNB, the minimum detectable effect size is 73%.
Results
Fifty-eight patient charts (21 in the ISNB group and 37 in the liposomal bupivacaine group) were reviewed for the study. Patient sex distribution, mean age, mean body mass index, and mean baseline ASA scores were not statistically different (Table 1).
The primary outcome measure, NRS pain score, showed no significant differences between groups at 0 to 1 hour after surgery (P = .99) or 8 to 14 hours after surgery (P = .208).
There was no difference in the amount of intravenous acetaminophen given during the hospital stay between groups. There was no significant difference in opioid consumption on postoperative day 1 in the hospital (P = .59) (Figure 2). However, there were significant differences between groups on postoperative days 2 and 3.
Sixteen of 37 patients in the liposomal bupivacaine group and 2 of 21 in the ISNB group were discharged on the day after surgery (P = .010) (Table 3).
There were no major cardiac or respiratory events in either group. No long-term paresthesias or neuropathies were noted. There were no readmissions for either group.
Discussion
Postoperative pain control after shoulder arthroplasty can be challenging, and several modalities have been tried in various combinations to minimize pain and decrease adverse effects of opioid medications. The most common method for pain relief after shoulder arthroplasty is the ISNB. Several studies of ISNBs have shown improved pain control after shoulder arthroplasty with associated decreased opioid consumption and related side effects.10 Patient rehabilitation and satisfaction have improved with the increasing use of peripheral nerve blocks.11
Despite the well-established benefits of ISNBs, several limitations exist. Although the superior portion of the shoulder is well covered by an ISNB, the inferior portion of the brachial plexus can remain uncovered or only partially covered.12 Complications of ISNBs include hemidiaphragmatic paresis, rebound pain 24 hours after surgery,13 chronic neurologic complications,14 and substantial respiratory and cardiovascular events.15 Nerve blocks also require additional time and resources in the perioperative period, including an anesthesiologist with specialized training, assistants, and ultrasonography or nerve stimulation equipment contraindicated in patients taking blood thinners.16
Periarticular injections of local anesthetics have also shown promise in reducing pain after arthroplasty.4 Benefits include an enhanced safety profile because local injection avoids the concurrent blockade of the phrenic nerve and recurrent laryngeal nerve and has not been associated with the risk of peripheral neuropathies. Further, local injection is a simple technique that can be performed during surgery without additional personnel or expertise. A limitation of this approach is the relatively short duration of effectiveness of the local anesthetic and uncertainty regarding the best agent and the ideal volume of injection.6 Liposomal bupivacaine is a new agent (approved by the US Food and Drug Administration in 201117) with a sustained release over 72 to 96 hours.18 The most common adverse effects of liposomal bupivacaine are nausea, vomiting, constipation, pyrexia, dizziness, and headache.19 Chondrotoxicity and granulomatous inflammation are more serious, yet rare, complications of liposomal bupivacaine.20
We found that liposomal bupivacaine injections were associated with lower pain scores compared with ISNB at 18 to 24 hours after surgery. This correlated with less opioid consumption in the liposomal bupivacaine group than in the ISNB group on the second postoperative day. These differences in pain values are consistent with the known pharmacokinetics of liposomal bupivacaine.18 Peak plasma levels normally occur approximately 24 hours after injection, leaving the early postoperative period relatively uncovered by anesthetic agent. This finding of relatively poor pain control early after surgery has also been noted in patients undergoing knee arthroplasty.5 On the basis of the findings of this study, we have added standard bupivacaine injections to our separate liposomal bupivacaine injection to cover early postoperative pain. Opioid consumption was significantly lower in the liposomal bupivacaine group than in the ISNB group on postoperative days 2 and 3. We did not measure adverse events related to opioid consumption, so we cannot comment on whether the decreased opioid consumption was associated with the rate of adverse events. However, other studies21,22 have established this relationship.
We found the liposomal bupivacaine group to have earlier discharges to home. Sixteen of 37 patients in the liposomal bupivacaine group compared with 2 of 21 patients in the ISNB group were discharged on the day after surgery. A mean reduction in LOS of 18 hours for the liposomal bupivacaine group was statistically significant (P = .012). This reduction in LOS has important implications for hospitals and value analysis committees considering whether to keep a new, more expensive local anesthetic on formulary. Savings from reduced LOS and improvements in patient satisfaction may justify the expense (approximately $300 per 266-mg vial) of Exparel.
From a societal cost perspective, liposomal bupivacaine is more economical compared with ISNB, which adds approximately $1500 to the cost of anesthesia per patient.23 Eliminating the costs associated with ISNB administration in shoulder arthroplasties could result in substantial savings to our healthcare system. More research examining time savings and exact costs of each procedure is needed to determine the true cost effectiveness of each approach.
Limitations of our study include the retrospective design, relatively small numbers of patients in each group, missing data for some patients at various time points, variation in the types of procedures in each group, and lack of long-term outcome measures. It is important to note that we did not confirm the success of the nerve block after administration. However, this study reflects the effectiveness of each of the modalities in actual clinical conditions (as opposed to a controlled experimental setting). The actual effectiveness of a nerve block varies, even when performed by an experienced anesthesiologist with ultrasound guidance. Furthermore, immediate postoperative pain scores in the nerve block group are consistent with those of prior research reporting pain values ranging from 4 to 5 and a mean duration of effect ranging from 9 to 14 hours.23,24 Additionally, the patients, surgeon, and nursing team were not blinded to the treatment group. Although we did note a significant difference in the types of procedures between groups, this finding is related to the greater number of hemiarthroplasties performed in the ISNB group (N = 5) compared with the liposomal group (N = 1). Because of this variation and the decreased invasiveness of hemiarthroplasties, the bias is against the liposomal group. Finally, our primary outcome variable was pain, which is a subjective, self-reported measure. However, our opioid consumption data and LOS data corroborate the improved pain scores in the liposomal bupivacaine group.
Limiting the study to a single surgeon may limit external validity. Another limitation is the lack of data on adverse events related to opioid medication use. There was no additional experimental group to determine whether less expensive local anesthetics injected locally would perform similarly to liposomal bupivacaine. In total knee arthroplasty, periarticular injections of liposomal bupivacaine were not as effective as less expensive periarticular injections.25 It is unclear which agents (and in what doses or combinations) should be used for periarticular injections. Finally, we acknowledge that our retrospective study design cannot account for all potential factors affecting discharge time.
This is the first comparative study of liposomal bupivacaine and ISNB in TSA. The study design allowed us to control for variables such as surgical technique, postoperative protocols (including use and type of sling), and use of other pain modalities such as patient-controlled analgesia and intravenous acetaminophen that are likely to affect postoperative pain and LOS. This study provides preliminary data that confirm relative equipoise between liposomal bupivacaine and ISNB, which is needed for the ethical conduct of a randomized controlled trial. Such a trial would allow for a more robust comparison, and this retrospective study provides appropriate pilot data on which to base this design and the clinical information needed to counsel patients during enrollment.
Our results suggest that liposomal bupivacaine may provide superior or similar pain relief compared with ISNB after shoulder arthroplasty. Additionally, the use of liposomal bupivacaine was associated with decreased opioid consumption and earlier discharge to home compared with ISNB. These findings have important implications for pain control after TSA because pain represents a major concern for patients and providers after surgery. In addition to clinical improvements, use of liposomal bupivacaine may save time and eliminate costs associated with administering nerve blocks. Local injection may also be used in patients who are contraindicated for ISNB such as those with obesity, pulmonary disease, or peripheral neuropathy. Although we cannot definitively suggest that liposomal bupivacaine is superior to the current gold standard ISNB for pain control after shoulder arthroplasty, our results suggest a relative clinical equipoise between these modalities. Larger analytical studies, including randomized trials, should be performed to explore the potential benefits of liposomal bupivacaine injections for pain control after shoulder arthroplasty.
Am J Orthop. 2016;45(7):424-430. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.
1. Kim SH, Wise BL, Zhang Y, Szabo RM. Increasing incidence of shoulder arthroplasty in the United States. J Bone Joint Surg Am. 2011;93(24):2249-2254.
2. American Academy of Orthopaedic Surgeons. Shoulder joint replacement. http://orthoinfo.aaos.org/topic.cfm?topic=A00094. Accessed June 3, 2015.
3. Desai VN, Cheung EV. Postoperative pain associated with orthopedic shoulder and elbow surgery: a prospective study. J Shoulder Elbow Surg. 2012;21(4):441-450.
4. Springer BD. Transition from nerve blocks to periarticular injections and emerging techniques in total joint arthroplasty. Am J Orthop. 2014;43(10 Suppl):S6-S9.
5. Surdam JW, Licini DJ, Baynes NT, Arce BR. The use of exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. J Arthroplasty. 2015;30(2):325-329.
6. Tong YC, Kaye AD, Urman RD. Liposomal bupivacaine and clinical outcomes. Best Pract Res Clin Anaesthesiol. 2014;28(1):15-27.
7. Chahar P, Cummings KC 3rd. Liposomal bupivacaine: a review of a new bupivacaine formulation. J Pain Res. 2012;5:257-264.
8. Schneider C, Yale SH, Larson M. Principles of pain management. Clin Med Res. 2003;1(4):337-340.
9. Pacira Pharmaceuticals, Inc. Highlights of prescribing information. http://www.exparel.com/pdf/EXPAREL_Prescribing_Information.pdf. Accessed May 7, 2015.
10. Gohl MR, Moeller RK, Olson RL, Vacchiano CA. The addition of interscalene block to general anesthesia for patients undergoing open shoulder procedures. AANA J. 2001;69(2):105-109.
11. Ironfield CM, Barrington MJ, Kluger R, Sites B. Are patients satisfied after peripheral nerve blockade? Results from an International Registry of Regional Anesthesia. Reg Anesth Pain Med. 2014;39(1):48-55.
12. Srikumaran U, Stein BE, Tan EW, Freehill MT, Wilckens JH. Upper-extremity peripheral nerve blocks in the perioperative pain management of orthopaedic patients: AAOS exhibit selection. J Bone Joint Surg Am. 2013;95(24):e197(1-13).
13. DeMarco JR, Componovo R, Barfield WR, Liles L, Nietert P. Efficacy of augmenting a subacromial continuous-infusion pump with a preoperative interscalene block in outpatient arthroscopic shoulder surgery: a prospective, randomized, blinded, and placebo-controlled study. Arthroscopy. 2011;27(5):603-610.
14. Misamore G, Webb B, McMurray S, Sallay P. A prospective analysis of interscalene brachial plexus blocks performed under general anesthesia. J Shoulder Elbow Surg. 2011;20(2):308-314.
15. Lenters TR, Davies J, Matsen FA 3rd. The types and severity of complications associated with interscalene brachial plexus block anesthesia: local and national evidence. J Shoulder Elbow Surg. 2007;16(4):379-387.
16. Park SK, Choi YS, Choi SW, Song SW. A comparison of three methods for postoperative pain control in patients undergoing arthroscopic shoulder surgery. Korean J Pain. 2015;28(1):45-51.
17. Pacira Pharmaceuticals, Inc. Pacira Pharmaceuticals, Inc. announces U.S. FDA approval of EXPAREL™ for postsurgical pain management. http://investor.pacira.com/phoenix.zhtml?c=220759&p=irol-newsArticle_print&ID=1623529. Published October 31, 2011. Accessed June 3, 2015.
18. White PF, Ardeleanu M, Schooley G, Burch RM. Pharmocokinetics of depobupivacaine following infiltration in patients undergoing two types of surgery and in normal volunteers. Paper presented at: Annual Meeting of the International Anesthesia Research Society; March 14, 2009; San Diego, CA.
19. Bramlett K, Onel E, Viscusi ER, Jones K. 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. Knee. 2012;19(5):530-536.
20. Lambrechts M, O’Brien MJ, Savoie FH, You Z. Liposomal extended-release bupivacaine for postsurgical analgesia. Patient Prefer Adherence. 2013;7:885-890.
21. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273.
22. Candiotti KA, Sands LR, Lee E, et al. Liposome bupivacaine for postsurgical analgesia in adult patients undergoing laparoscopic colectomy: results from prospective phase IV sequential cohort studies assessing health economic outcomes. Curr Ther Res Clin Exp. 2013;76:1-6.
23. Weber SC, Jain R. Scalene regional anesthesia for shoulder surgery in a community setting: an assessment of risk. J Bone Joint Surg Am. 2002;84-A(5):775-779.
24. Beaudet V, Williams SR, Tétreault P, Perrault MA. Perioperative interscalene block versus intra-articular injection of local anesthetics for postoperative analgesia in shoulder surgery. Reg Anesth Pain Med. 2008;33(2):134-138.
25. Bagsby DT, Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty. 2014;29(8):1687-1690.
1. Kim SH, Wise BL, Zhang Y, Szabo RM. Increasing incidence of shoulder arthroplasty in the United States. J Bone Joint Surg Am. 2011;93(24):2249-2254.
2. American Academy of Orthopaedic Surgeons. Shoulder joint replacement. http://orthoinfo.aaos.org/topic.cfm?topic=A00094. Accessed June 3, 2015.
3. Desai VN, Cheung EV. Postoperative pain associated with orthopedic shoulder and elbow surgery: a prospective study. J Shoulder Elbow Surg. 2012;21(4):441-450.
4. Springer BD. Transition from nerve blocks to periarticular injections and emerging techniques in total joint arthroplasty. Am J Orthop. 2014;43(10 Suppl):S6-S9.
5. Surdam JW, Licini DJ, Baynes NT, Arce BR. The use of exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. J Arthroplasty. 2015;30(2):325-329.
6. Tong YC, Kaye AD, Urman RD. Liposomal bupivacaine and clinical outcomes. Best Pract Res Clin Anaesthesiol. 2014;28(1):15-27.
7. Chahar P, Cummings KC 3rd. Liposomal bupivacaine: a review of a new bupivacaine formulation. J Pain Res. 2012;5:257-264.
8. Schneider C, Yale SH, Larson M. Principles of pain management. Clin Med Res. 2003;1(4):337-340.
9. Pacira Pharmaceuticals, Inc. Highlights of prescribing information. http://www.exparel.com/pdf/EXPAREL_Prescribing_Information.pdf. Accessed May 7, 2015.
10. Gohl MR, Moeller RK, Olson RL, Vacchiano CA. The addition of interscalene block to general anesthesia for patients undergoing open shoulder procedures. AANA J. 2001;69(2):105-109.
11. Ironfield CM, Barrington MJ, Kluger R, Sites B. Are patients satisfied after peripheral nerve blockade? Results from an International Registry of Regional Anesthesia. Reg Anesth Pain Med. 2014;39(1):48-55.
12. Srikumaran U, Stein BE, Tan EW, Freehill MT, Wilckens JH. Upper-extremity peripheral nerve blocks in the perioperative pain management of orthopaedic patients: AAOS exhibit selection. J Bone Joint Surg Am. 2013;95(24):e197(1-13).
13. DeMarco JR, Componovo R, Barfield WR, Liles L, Nietert P. Efficacy of augmenting a subacromial continuous-infusion pump with a preoperative interscalene block in outpatient arthroscopic shoulder surgery: a prospective, randomized, blinded, and placebo-controlled study. Arthroscopy. 2011;27(5):603-610.
14. Misamore G, Webb B, McMurray S, Sallay P. A prospective analysis of interscalene brachial plexus blocks performed under general anesthesia. J Shoulder Elbow Surg. 2011;20(2):308-314.
15. Lenters TR, Davies J, Matsen FA 3rd. The types and severity of complications associated with interscalene brachial plexus block anesthesia: local and national evidence. J Shoulder Elbow Surg. 2007;16(4):379-387.
16. Park SK, Choi YS, Choi SW, Song SW. A comparison of three methods for postoperative pain control in patients undergoing arthroscopic shoulder surgery. Korean J Pain. 2015;28(1):45-51.
17. Pacira Pharmaceuticals, Inc. Pacira Pharmaceuticals, Inc. announces U.S. FDA approval of EXPAREL™ for postsurgical pain management. http://investor.pacira.com/phoenix.zhtml?c=220759&p=irol-newsArticle_print&ID=1623529. Published October 31, 2011. Accessed June 3, 2015.
18. White PF, Ardeleanu M, Schooley G, Burch RM. Pharmocokinetics of depobupivacaine following infiltration in patients undergoing two types of surgery and in normal volunteers. Paper presented at: Annual Meeting of the International Anesthesia Research Society; March 14, 2009; San Diego, CA.
19. Bramlett K, Onel E, Viscusi ER, Jones K. 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. Knee. 2012;19(5):530-536.
20. Lambrechts M, O’Brien MJ, Savoie FH, You Z. Liposomal extended-release bupivacaine for postsurgical analgesia. Patient Prefer Adherence. 2013;7:885-890.
21. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273.
22. Candiotti KA, Sands LR, Lee E, et al. Liposome bupivacaine for postsurgical analgesia in adult patients undergoing laparoscopic colectomy: results from prospective phase IV sequential cohort studies assessing health economic outcomes. Curr Ther Res Clin Exp. 2013;76:1-6.
23. Weber SC, Jain R. Scalene regional anesthesia for shoulder surgery in a community setting: an assessment of risk. J Bone Joint Surg Am. 2002;84-A(5):775-779.
24. Beaudet V, Williams SR, Tétreault P, Perrault MA. Perioperative interscalene block versus intra-articular injection of local anesthetics for postoperative analgesia in shoulder surgery. Reg Anesth Pain Med. 2008;33(2):134-138.
25. Bagsby DT, Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty. 2014;29(8):1687-1690.
