Randomized Controlled Trial of Interscalene Block Compared with Injectable Liposomal Bupivacaine in Shoulder Arthroplasty

Namdari, Surena MD, MSc; Nicholson, Thema MSc; Abboud, Joseph MD; Lazarus, Mark MD; Steinberg, Dean MD; Williams, Gerald MD

Journal of Bone & Joint Surgery - American Volume: 5 April 2017 - Volume 99 - Issue 7 - p 550–556
doi: 10.2106/JBJS.16.00296
Scientific Articles
Commentary
Disclosures

Background: Shortcomings of interscalene brachial plexus blockade include technical failure and rebound pain. Bupivacaine liposome injectable suspension, a sustained release preparation, is used for surgical-site administration. The purpose of this study was to evaluate these 2 postoperative pain management strategies in patients undergoing shoulder arthroplasty.

Methods: In a non-blinded, randomized controlled trial of participants undergoing primary shoulder arthroplasty, patients were randomized to interscalene brachial plexus blockade or intraoperative soft-tissue infiltration of bupivacaine liposome injectable suspension. The primary outcome variable was morphine equivalent units consumed over the first 24 hours postoperatively. Secondary outcomes included morphine equivalent units consumed intraoperatively and a visual analog scale (VAS) for pain at 0, 8, 16, and 24 hours.

Results: Seventy-eight patients were randomized to interscalene brachial plexus blockade treatment (the blockade group) and 78 patients were randomized to bupivacaine liposome injectable suspension treatment (the suspension group). The mean total postoperative narcotic consumption (and standard deviation) over 24 hours after the surgical procedure was 14.8 ± 11.3 morphine equivalent units in the blockade group compared with 14.4 ± 16.8 morphine equivalent units in the suspension group (p = 0.849). Intraoperative narcotics were significantly lower (p < 0.001) in the blockade group (8.9 ± 4.1 morphine equivalent units) compared with the suspension group (16.2 ± 7.0 morphine equivalent units). The mean VAS pain score was significantly lower in the blockade group than in the suspension group at 0 hours postoperatively (0.8 ± 2.2 compared with 3.3 ± 2.7 points; p < 0.001) and at 8 hours postoperatively (1.4 ± 2.4 compared with 3.2 ± 2.2 points; p < 0.001), but it was not significantly different at 16 hours postoperatively (4.3 ± 2.8 compared with 3.8 ± 2.4 points; p = 0.348). The VAS pain scores were significantly higher (p = 0.021) in the blockade group (4.9 ± 2.7 points) compared with the suspension group (3.9 ± 2.3 points) at 24 hours postoperatively.

Conclusions: Patients treated with bupivacaine liposome injectable suspension required an equivalent amount of postoperative narcotics and greater intraoperative narcotics compared with patients treated with interscalene brachial plexus blockade. Although interscalene brachial plexus blockade provided improved pain scores for the first 8 hours after the surgical procedure, pain scores were worse at 24 hours. The optimal postoperative pain regimen for shoulder arthroplasty and the cost-effectiveness of analgesic techniques require further investigation.

Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

1Department of Orthopaedic Surgery, Rothman Institute, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania

2Department of Anesthesia, Sidney Kimmel Medical College at Thomas Jefferson University-Methodist Hospital Division, Philadelphia, Pennsylvania

E-mail address for S. Namdari: surena.namdari@rothmaninstitute.com

Article Outline

The optimal postoperative pain control regimen after shoulder arthroplasty has not been well studied; however, the recent use of regional anesthetics has been shown to improve the patient experience, with lower postoperative pain scores and improved patient satisfaction1. Interscalene brachial plexus blockade has been shown to be an effective anesthetic technique for inpatient shoulder surgical procedures2-4. Compared with patients receiving only general anesthesia, patients who undergo preoperative interscalene brachial plexus blockade have shorter hospital stays5 and a reduced need for analgesics6,7. Patients undergoing interscalene brachial plexus blockade also experience less time in the postanesthesia care unit (PACU)7-9 and high levels of satisfaction8,10. Despite the potential analgesic benefits of an interscalene brachial plexus blockade, risks include a failure rate as high as 10% to 20%11 and complications from the procedure12. What is less known is the extent to which patients encounter rebound pain (a quantifiable difference in pain scores when the interscalene brachial plexus blockade is working compared with the increase in acute pain that is encountered during the first few hours after the effects of perineural local anesthetics resolve)13.

The use of an intraoperative, periarticular, soft-tissue local anesthetic or analgesic injection cocktail has been studied in the hip and knee arthroplasty literature and has been shown to decrease in-hospital narcotic consumption and the prevalence of postoperative nausea and to improve patient satisfaction14. A 2004 study by Lombardi et al. demonstrated lower postoperative in-hospital narcotic needs in patients who were undergoing total knee arthroplasty and had received a single intra-articular soft-tissue injection at the time of the surgical procedure15. Furthermore, a 2006 randomized controlled trial of patients who underwent total knee arthroplasty and had received spinal anesthetic in conjunction with local infiltration of local anesthetic and analgesic had superior pain scores and reduced narcotic needs compared with patients who underwent the procedure with spinal anesthetic alone14.

Bupivacaine liposome injectable suspension is a local analgesic that has been approved by the U.S. Food and Drug Administration (FDA) for administration into the surgical site, with proven safety in both animal and human studies16-21. This suspension is created using a lipid-based delivery system that encapsulates the drug in multivesicular liposomal particles that then release the drug over a 72-hour time period22,23. Although this suspension has the theoretical ability to provide sustained analgesia over the first 72 hours after administration, several randomized controlled trials have indicated that the primary analgesic period is 24 hours after administration, with no significant reduction in pain intensity between 24 and 72 hours22,23. In this study, we used Exparel (Pacira Pharmaceuticals) for all patients.

The purpose of this current study was to evaluate in-hospital postoperative pain scores and narcotic consumption over the first 24 hours after the surgical procedure in patients undergoing shoulder arthroplasty using either interscalene brachial plexus blockade or intraoperative periarticular local anesthetic infiltration with bupivacaine liposome injectable suspension.

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Materials and Methods

The study was approved by the institutional review board, was registered at ClinicalTrials.gov (NCT02695758), and followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines (Fig. 1). This study was designed as a non-blinded randomized controlled trial of participants undergoing primary total shoulder arthroplasty for osteoarthritis or reverse arthroplasty for cuff tear arthropathy. All surgical procedures were performed at a single institution by 1 of 4 fellowship-trained shoulder surgeons. Excluded from the study were patients with psychiatric illness, as defined by comorbid diagnosis of bipolar disorder or schizophrenia; those who underwent revision arthroplasty; those who underwent a surgical procedure for a diagnosis of fracture; those who had Workers’ Compensation, disability, or a litigation claim; those who were unable to consent for enrollment; those who were unable to complete a postoperative pain survey; those who had a known adverse drug reaction or allergy to the medications used; those who had chronic pain syndromes (including reflex sympathetic dystrophy, fibromyalgia, and chronic diffuse musculoskeletal pain); those who were taking long-acting narcotic pain medications (including extended-release narcotic pain medications and methadone); and those who had hepatic disease.

Patients preoperatively provided consent to be included in the study. Data regarding demographic characteristics, medical comorbidities, short-acting narcotic usage, and non-narcotic analgesic usage were collected prospectively. Patients were randomized to interscalene brachial plexus blockade treatment or intraoperative periarticular local anesthetic infiltration with bupivacaine liposome injectable suspension treatment by a computer random number generator. No preoperative oral analgesic regimen was used. Baseline preoperative visual analog scale (VAS) pain scores were obtained on the day of the surgical procedure. Preoperatively, interscalene brachial plexus blockades were performed by 1 of 6 anesthesiologists, experienced in ultrasound-guided regional anesthesia, using 30 mL of 0.5% ropivacaine. Patients in the bupivacaine liposome injectable suspension group did not undergo a preoperative interscalene brachial plexus blockade and instead underwent intraoperative infiltration of an Exparel suspension (20 mL of fluid, which includes 266 mg of 1.3% bupivacaine)18,24 diluted in 20 mL of saline solution. Injections were performed via a technique that was standardized among the 4 surgeons. A 22-gauge needle was utilized and multiple aliquots of 0.5 mL were injected into the anterior capsule, subscapularis, deltoid, pectoralis major, and subcutaneous fat layer along the extent of both sides of the deltopectoral incision. Care was taken to inject slowly in order to prevent the extravasation of the suspension from the soft tissues. If a complete anterior capsulectomy was performed or if the anterior capsule was insufficient, the inferior and posterior portions of the shoulder capsule were alternatively injected. All injections were performed after final implantation of components and prior to subscapularis repair and wound closure. Intraoperative narcotic administration was at the discretion of the anesthesiologist. The need for narcotic was generally determined on the basis of physiologic indicators for pain, which include hypertension and tachycardia. All patients were provided a patient-controlled analgesic pump in the PACU. The pump dispensed hydromorphone with the dosage and frequency titrated on the basis of the patient’s pain. No additional oral narcotics were routinely ordered over the first 24 hours after the surgical procedure. In cases of ineffectiveness or reactions to hydromorphone, patient-controlled analgesic pumps were altered to dispense either morphine or fentanyl. Acetaminophen was utilized to treat fever in the perioperative setting on an as-needed basis. No other analgesic or nonsteroidal anti-inflammatory medications were given during the first 24 hours.

The primary outcome variable was the morphine equivalent units consumed over the first 24 hours after the surgical procedure. The sample size estimation of 78 patients per group was based on a 2-tailed t test with 80% power, assuming an effect size (net difference normalized by within-group standard deviation) of 0.5 and a p value for significance of 0.025, which adjusts for 2 primary outcomes being tested independently. Additional outcomes measures included intraoperative morphine equivalent units consumed; VAS for pain at 0, 8, 16, and 24 hours postoperatively; time in the operating room; hospital length of stay; intraoperative complications (fracture, vascular injury, anesthesia-related); and acute postoperative complications (medical, nerve injury, dislocation, hematoma, wound). Crossover between groups was addressed via an intention-to-treat analysis.

Comparative statistics between groups were performed using the Mann-Whitney test for continuous variables and the Fisher exact test for non-continuous variables. A linear regression model was utilized to determine associations between demographic variables and morphine equivalent units utilized in the first 24 hours after the surgical procedure and VAS pain score at 24 hours after the surgical procedure. All analyses were performed using R 3.2.3 (R Foundation).

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Results

Seventy-eight patients were randomized to the interscalene brachial plexus blockade treatment (the blockade group) and 78 patients were randomized to intraoperative periarticular local anesthetic infiltration treatment (the suspension group) from January 12, 2015, to February 1, 2016. The mean patient age (and standard deviation) was 70.9 ± 9.3 years in the blockade group and 68.4 ± 8.2 years in the suspension group (p = 0.069). There were no significant differences (p > 0.05) in sex, body mass index, arthroplasty type performed, or Charlson Comorbidity Index (Table I). Similarly, there were no significant differences (p > 0.05) in preoperative oral short-acting narcotic usage, non-narcotic analgesic usage, or VAS pain scores between groups (Table I).

The mean total postoperative narcotic consumption in the first 24 hours after the surgical procedure was 14.8 ± 11.3 morphine equivalent units in the blockade group compared with 14.4 ± 16.8 morphine equivalent units in the suspension group (p = 0.849). Intraoperative narcotics were significantly lower (p < 0.001) in the blockade group (8.9 ± 4.1 morphine equivalent units) compared with the suspension group (16.2 ± 7.0 morphine equivalent units). The overall narcotic usage (intraoperative plus postoperative) was significantly lower (p < 0.001) in the blockade group (23.4 ± 12.7 morphine equivalent units) compared with the suspension group (30.8 ± 18.5 morphine equivalent units) (Fig. 2). The mean VAS pain score was significantly lower in the blockade group at 0 hours postoperatively (0.8 ± 2.2 compared with 3.3 ± 2.7 points; p < 0.001) and at 8 hours postoperatively (1.4 ± 2.4 compared with 3.2 ± 2.2 points; p < 0.001), but it was not significantly different at 16 hours postoperatively (4.3 ± 2.8 compared with 3.8 ± 2.4 points; p = 0.348) (Fig. 3). Six patients (8%) in the blockade group and 15 patients (19%) in the suspension group had VAS pain scores of >5 points in the PACU. The mean VAS pain scores were significantly higher (p = 0.021) in the blockade group (4.9 ± 2.7 points) compared with the suspension group (3.9 ± 2.3 points) at 24 hours postoperatively. There were no significant differences in time in the operating room (170.2 ± 30.8 compared with 172.7 ± 32.3 minutes; p = 0.627) or hospital length of stay (1.8 ± 0.6 compared with 1.6 ± 0.8 days; p = 0.293) between the blockade group and the suspension group. No intraoperative complications or acute postoperative complications occurred in either group. Two patients (3%) in the suspension group underwent an interscalene brachial plexus blockade postoperatively (p = 0.276) early in the series; however, because of concern for bupivacaine toxicity, this practice was discontinued thereafter.

The regression model for the VAS pain score at 24 hours postoperatively was significant (p < 0.001, r2 = 0.19); however, the model for total postoperative narcotic requirement (morphine equivalent units over 24 hours) (p = 0.49, r2 = 0.05) was not significant. On linear regression analysis, higher VAS pain score at 24 hours postoperatively was significantly associated with younger age (p = 0.005, −0.1 VAS point per year of age), history of depression (p = 0.038), higher Charlson Comorbidity Index score (p = 0.035, +0.4 VAS point per point of Charlson Comorbidity Index score), and higher preoperative VAS pain score (p = 0.003, +0.2 VAS point per point of preoperative VAS score).

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Discussion

Patients treated with periarticular local anesthetic infiltration of bupivacaine liposome injectable suspension required equivalent postoperative narcotics and greater intraoperative narcotics compared with patients treated with interscalene brachial plexus blockade. Although interscalene brachial plexus blockade provided improved pain scores for the first 8 hours postoperatively, pain scores were higher at 24 hours compared with local anesthetic infiltration of bupivacaine liposome injectable suspension. We attribute these findings to the experience of rebound pain in patients undergoing interscalene brachial plexus blockade.

The benefits of interscalene brachial plexus blockade in shoulder surgical procedures have been reported25,26. Abdallah et al. performed a meta-analysis to examine the effect of interscalene brachial plexus blockade on analgesic outcomes during the first 48 hours after a shoulder surgical procedure25. A total of 23 randomized controlled trials, including 1,090 patients, were analyzed. Similar to our findings, the authors demonstrated that interscalene brachial plexus blockade can provide effective analgesia up 8 hours after a shoulder surgical procedure, with no demonstrable benefits thereafter. Additionally, they showed that patients who received an interscalene brachial plexus blockade experienced rebound pain at 24 hours. We demonstrated a change in pain score from 1.4 to 4.9 points between 8 and 24 hours after a surgical procedure in the interscalene brachial plexus blockade group, which was consistent with the experience of rebound pain. It was this increased pain during the first 24 hours after a surgical procedure that we believe accounted for the increased postoperative narcotic usage in patients who underwent an interscalene brachial plexus blockade.

Bupivacaine liposome injectable suspension has been shown in previous studies to be safe for local soft-tissue infiltration at the time of the surgical procedure18,19. Interestingly, the analgesic effect of this suspension remained consistent for the first 24 hours after shoulder arthroplasty. Despite this, approximately 19% of patients in the local soft-tissue infiltration group had pain scores of >5 in the PACU; it does not appear that bupivacaine liposome injectable suspension alone is sufficient for optimal postoperative pain control after shoulder arthroplasty in all patients. Interestingly, despite improved pain relief at 0 hours postoperatively in the interscalene brachial plexus blockade group, almost 8% of patients had VAS pain scores of >5 in the PACU. Possible reasons for this include failure of the interscalene brachial plexus blockade or pain in the axillary region of the shoulder that is typically not addressed by an interscalene brachial plexus blockade.

It is important to note that alternative methods of soft-tissue infiltration, such as non-liposome injectable bupivacaine or previously described infiltration cocktails15, were not compared in this study. As a result, it is unknown whether the lack of rebound pain experience seen in patients in the soft-tissue infiltration group was due to the injection of bupivacaine liposome injectable suspension or simply a consequence of patients in this group not undergoing an interscalene brachial plexus blockade. Abdallah et al. reported that, after a shoulder surgical procedure, the mean pain scores were 4.96 at 8 hours postoperatively and 4.62 at 16 hours postoperatively in control subjects who did not undergo interscalene brachial plexus blockade25. This is compared with 3.2 at 8 hours postoperatively and 3.8 at 16 hours postoperatively in our subjects who underwent periarticular local anesthetic infiltration of bupivacaine liposome injectable suspension. On the basis of these historic data, there may be an analgesic benefit provided by the bupivacaine liposome injectable suspension.

Based on the regression analysis, it appears that certain demographic factors are associated with higher pain scores at 24 hours after a surgical procedure, regardless of the analgesic technique used. Younger patients were noted to have higher pain scores at 24 hours after a surgical procedure. Gold et al. showed that younger patients were more likely to require long-acting opioids after undergoing a joint replacement surgical procedure27. Depression and greater Charlson Comorbidity Index scores were also associated with greater pain scores at 24 hours after the surgical procedure. Menendez et al. showed that psychological distress is associated with greater perceived disability and pain in patients with shoulder disease28. Tashjian et al. showed that medical comorbidities can have a negative impact on self-reported pain experience in patients with chronic rotator cuff tears29, but that the ultimate outcome of a surgical procedure is not necessarily impacted by greater comorbid conditions30. Finally, a higher preoperative VAS pain score was associated with a higher VAS pain score at 24 hours after a surgical procedure. Similarly, Williams et al. reported that higher preoperative pain scores were correlated with higher acute postoperative pain scores after rotator cuff repair31. Because these factors were associated with higher pain scores regardless of the analgesic technique used, it appears that patients at high risk for postoperative pain experience may not be adequately treated with either interscalene brachial plexus blockade or local soft-tissue infiltration with bupivacaine liposome injectable suspension.

This study had a number of weaknesses. As discussed above, this study did not include a negative control group of subjects who did not undergo local soft-tissue infiltration or interscalene brachial plexus blockade. The study was designed in this manner because of ethical concerns related to denying patients pain management strategies known to be effective. Additionally, we utilized single-injection interscalene brachial plexus blockade in this study, as it is the standard of care at our hospital. It is likely that interscalene brachial plexus blockade with placement of a catheter for continuous infusion of analgesic medication would have resulted in longer-lasting pain relief. Another weakness is that patient pain scores and narcotic utilization were only evaluated over the first 24 hours after a surgical procedure. Although it is possible that differences between the interscalene brachial plexus blockade and local soft-tissue infiltration would be significant beyond the first 24 hours after a surgical procedure, previous studies have indicated no difference between pain intensity between 24 and 72 hours after a surgical procedure in control subjects and those receiving soft-tissue infiltration with bupivacaine liposome injectable suspension22,23. With regard to the rebound pain after 24 hours, multiple studies of soft-tissue infiltration with liposomal bupivacaine in orthopaedic and non-orthopaedic surgery have not demonstrated the presence of rebound pain experience beyond 24 hours32-35. Also, because many patients were discharged on the first postoperative day, additional data acquisition would have required greater resources for data collection. Given a goal to perform this investigation without industry support, we chose to fund this study internally and to evaluate patients only during the first 24 hours. Although reported narcotic usage in terms of morphine equivalent units is common in the literature14,32-34, there is growing concern that a single, effective method does not exist that allows opioids to be accurately and consistently converted to another opioid36. A cost analysis would be an important adjunct to this investigation; however, the necessary charge and reimbursement data were not available and this study was not designed in a manner to perform an accurate cost-effectiveness analysis. Finally, although the injection technique was standardized among the investigators, there were no predicate data from the literature to guide an optimal injection technique; additionally, a formal evaluation of the success of our standardization process was not performed. As a result, it is possible that variability in injection techniques could lead to greater difference in outcomes in the soft-tissue infiltration group. Despite this, we believe that this variability more closely replicates the true clinical situation and would not be expected to be substantially different from the variability present in the performance of interscalene brachial plexus blockade.

On the basis of our findings, bupivacaine liposome injectable suspension appears to be a viable alternative to interscalene brachial plexus blockade. Although interscalene brachial plexus blockade provides optimal pain relief for the first 8 hours after a surgical procedure, there is an associated cost of rebound pain after 8 hours. Bupivacaine liposome injectable suspension does not result in rebound pain during the first 24 hours after a surgical procedure, but pain relief for the first 8 hours after a surgical procedure is less predictable. As a result, the optimal pain regimen for shoulder arthroplasty and the cost-effectiveness of analgesic techniques require further investigation.

NOTE: The authors acknowledge the efforts of Daniel Sholder in patient recruitment and enrollment in this investigation and Mitchell Maltenfort for statistical support.

Investigation performed at the Department of Orthopaedic Surgery, Rothman Institute, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania

A commentary by Ranjan Gupta, MD, is linked to the online version of this article at jbjs.org.

Disclosure: There was no external funding source for this study. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work (http://links.lww.com/JBJS/B593).

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