Periarticular Injection of Liposomal Bupivacaine Offers No Benefit Over Standard Bupivacaine in Total Knee Arthroplasty: A Prospective, Randomized, Controlled Trial

Accepted Manuscript Peri-articular Injection of Liposomal Bupivacaine offers no Benefit over Standard Bupivacaine in Total Knee Arthroplasty: A Prospective, Randomized, Controlled Trial Pouya Alijanipour, MD, Timothy L. Tan, MD, Christopher N. Matthews, BS, Jessica R. Viola, BS, James J. Purtill, MD, Richard H. Rothman, MD, PhD, Javad Parvizi, MD, FRCS, Matthew S. Austin, MD PII:

S0883-5403(16)30445-4

DOI:

10.1016/j.arth.2016.07.023

Reference:

YARTH 55322

To appear in:

The Journal of Arthroplasty

Received Date: 24 February 2016 Revised Date:

22 July 2016

Accepted Date: 26 July 2016

Please cite this article as: Alijanipour P, Tan TL, Matthews CN, Viola JR, Purtill JJ, Rothman RH, Parvizi J, Austin MS, Peri-articular Injection of Liposomal Bupivacaine offers no Benefit over Standard Bupivacaine in Total Knee Arthroplasty: A Prospective, Randomized, Controlled Trial, The Journal of Arthroplasty (2016), doi: 10.1016/j.arth.2016.07.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Peri-articular Injection of Liposomal Bupivacaine offers no Benefit over Standard

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Pouya Alijanipour MD Timothy L. Tan MD Christopher N. Matthews BS Jessica R. Viola BS James J. Purtill MD Richard H. Rothman MD PhD Javad Parvizi MD FRCS Matthew S. Austin MD

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Bupivacaine in Total Knee Arthroplasty: A Prospective, Randomized, Controlled Trial

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The Rothman Institute of Orthopaedics at Thomas Jefferson University Hospital Philadelphia, PA, 19107

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Correspondence to: Matthew S. Austin MD The Rothman Institute of Orthopedics at Thomas Jefferson University Hospital 925 Chestnut Street Philadelphia, PA 19107 Phone: 267-399-3617 Fax: 215-503-0580 E-mail: [email protected]

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ABSTRACT Background: Peri-articular injection of liposomal bupivacaine has been adopted as part of

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multimodal pain management after total knee arthroplasty (TKA). Methods: In this prospective, randomized clinical trial, we enrolled 162 patients undergoing primary TKA in a single institution between January 2014 to May 2015. Eighty-seven patients

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were randomized to liposomal bupivacaine (experimental group) and 75 patients were

randomized to free bupivacaine (control group). All patients received spinal anesthesia and

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otherwise identical surgical approaches, pain management and rehabilitation protocols. Outcomes evaluated include the patient-reported visual analogue pain scores, narcotic consumption and narcotic-related side effects (Brief Pain Inventory) within 96 hours after surgery as well as functional outcomes using the Knee Society Score (KSS) and the Short-Form

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12 (SF-12) measured preoperatively and at 4-6 weeks after surgery.

Results: There were no statistically significant differences between the groups in terms of postoperative daily pain scores, narcotic consumption (by-day and overall), or narcotic-related

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side effects. There were no statistically significant differences between the groups in terms of surgical (p=0.76) and medical complications or length of hospital stay (p=0.35). There were no

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statistically significant differences in satisfaction between the groups (p=0.56) or between the groups in postoperative KSS (p=0.53) and the SF-12 at 4-6 weeks (p=0.82, p=0.66). Conclusion: As part of multimodal pain management protocol, periarticular injection of liposomal bupivacaine compared with bupivacaine HCl did not result in any clinically or statistically significant improvement of the measured outcomes following TKA.

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Keywords: Pain, Total Knee Arthroplasty, Randomized Controlled Trial, Periarticular Injection,

Level of Evidence: 1 Randomized Controlled Trial

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Bupivacaine, Pain, Liposomal

Trial Registration: ClinicalTrials.gov Identifier: NCT02060591: Comparison of Two

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Periarticular Injection Medications for Adjunctive Pain Management Following Total Knee

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Arthroplasty (TKA)

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Acknowledgements

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Pouya Alijanipour and Timothy L. Tan had full access to all of the data in the study

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and take responsibility for the integrity of the data and the accuracy of the data

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analysis. Each author certifies that our institution has approved the human protocol

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for this investigation and that all investigations were conducted in conformity with

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ethical principles of research. Each Author has contributed substantially to the

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research, preparation and production of the paper and approves of its submission to

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the Journal. None of the authors have potential conflict of interest relevant to the

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subject of this manuscript. This project did not receive any financial funding from

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external resources. The authors would like to appreciate the contribution of Stephanie

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Buchel and John Cibenko (for consultancy and assistance with the logistics), Mitchell

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G Maltenfort PhD (for performing the statistical analysis), Tiffany Morrison (for

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consultancy regarding Institutional Review Board approval) and Camilo Restrepo MD

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(for consultancy regarding study design, logistics and statistical analysis).

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Peri-articular injection of liposomal bupivacaine offers no benefit over standard

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bupivacaine in total knee arthroplasty: a prospective, randomized, controlled trial

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ABSTRACT Introduction: Peri-articular injection of liposomal bupivacaine has been adopted as part

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of multimodal pain management after total knee arthroplasty (TKA). Materials and Methods:

In this prospective, randomized clinical trial, we enrolled 162 patients undergoing

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primary TKA in a single institution between January 2014 to May 2015. Eighty-seven

patients were randomized to liposomal bupivacaine (experimental group) and 75 patients

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were randomized to free bupivacaine (control group). All patients received spinal anesthesia and otherwise identical surgical approaches, pain management and rehabilitation protocols. Outcomes evaluated include the patient-reported visual analogue pain scores, narcotic consumption and narcotic-related side effects (Brief Pain Inventory)

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within 96 hours after surgery as well as functional outcomes using the Knee Society Score (KSS) and the Short-Form 12 (SF-12) measured preoperatively and at 4-6 weeks after surgery.

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Results: There were no statistically significant differences between the groups in terms

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of postoperative daily pain scores, narcotic consumption (by-day and overall), or narcotic-related side effects. There were no statistically significant differences between the groups in terms of surgical (p=0.76) and medical complications or length of hospital stay (p=0.35). There were no statistically significant differences in satisfaction between the groups (p=0.56) or between the groups in postoperative KSS (p=0.53) and the SF-12 at 4-6 weeks (p=0.82, p=0.66).

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Discussion: As part of multimodal pain management protocol, periarticular injection of liposomal bupivacaine compared with bupivacaine HCl did not result in any clinically or

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statistically significant improvement of the measured outcomes following TKA.

Injection, Bupivacaine, Pain, Liposomal

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Level of Evidence: 1 Randomized Controlled Trial

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Keywords: Pain, Total Knee Arthroplasty, Randomized Controlled Trial, Periarticular

Trial Registration: ClinicalTrials.gov Identifier: NCT02060591: Comparison of Two Periarticular Injection Medications for Adjunctive Pain Management Following Total

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Knee Arthroplasty (TKA)

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INTRODUCTION Despite the considerable success of total knee arthroplasty (TKA), pain control during the initial postoperative period can be challenging. Adequate postsurgical

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analgesia is crucial for early mobilization, rehabilitation, and timely discharge. Adequate

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analgesia has also been associated with improved patient satisfaction and functional

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outcome. [1,2] Inadequate pain relief results in an increased use of rescue analgesics,

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particularly opioids, potentiating the risk of narcotic-related side effects (cognitive,

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gastrointestinal, and urinary disturbances) and increasing the risk of developing chronic

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pain syndromes. [3]

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Multimodal perioperative pain management consists of various adjunctive yet potentially synergistic analgesic methods that act at different locations of the pain

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pathway. [4] These techniques have been implemented in pain management protocols

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following TKA with success and can include some or all of the following elements: pre-

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and postoperative administration of systemic anti-inflammatory medications,

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gabapentinoids, [5,6] intrathecal and epidural spinal analgesia, [7] peripheral nerve block,

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[8] continuous intraarticular infusion or periarticular injection of local analgesics or

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anesthetics, [9,10] cryotherapy, [11] and transdermal patches. [12]

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Among drug formulations for periarticular injection, liposomal bupivacaine

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(Exparel, Pacira Pharmaceuticals Inc, San Diego, CA) has recently gained popularity

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because of its potential to provide extended pain relief following surgical procedures.

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[13] The proposed benefit is attributed to its novel delivery system (DepoFoam particles,

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Pacira Pharmaceuticals Inc, San Diego, CA), which encapsulates drugs into

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nonconcentric multi-vesicular liposomes. This system provides the possibility of

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sustained release with an extended analgesia duration compared with free non-

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encapsulated bupivacaine HCl (72 versus 12 hours, respectively). [14] The US Food and

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Drug Administration has approved liposomal bupivacaine for local injection into the

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surgical site. The formulation is a single-dose administration that provides local analgesia

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or anesthesia following various surgical procedures (general surgical, plastic, and foot)

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with successful outcomes reported in several randomized controlled trials (RCTs). [15–

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19] A few comparative studies with inconsistent results have also been published

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regarding the efficacy of periarticular liposomal bupivacaine injections in TKA. [19,20]

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In a phase II RCT, local periarticular infiltration of liposomal bupivacaine at doses above

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266mg seemed to have superior pain outcomes compared with bupivacaine HCl.

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However, the comparisons of pain scores were inconsistent between the groups, and

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despite reaching the level of clinically significant pain relief in some occasions, they did

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not reach statistical significance. [19] In another retrospective study, the pain scores of

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patients in the liposomal bupivacaine group were paradoxically worse than those in the

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ropivicaine group during the postoperative hospital stay, except for the first and last day,

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during which the pain scores were similar between the groups. [20] In both studies,

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liposomal bupivacaine use did not reduce the overall opioid consumption.

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We conducted this RCT to compare the efficacy of liposomal bupivacaine with

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that of non-encapsulated free bupivacaine HCl using an otherwise identical, standardized,

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perioperative TKA protocol. We hypothesized that the primary endpoint, pain scores

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measured by visual analogue scores (VAS), would be lower during the hospital stay for

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the liposomal bupivacaine group compared with the bupivacaine HCl group.

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MATERIALS AND METHODS This study was a prospective single-center, two-arm, parallel-group RCT. The study proposal was approved by our institutional review board and registered at

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clinicaltrials.gov (ID number: NCT02060591).

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Eligible participants ranged between 18 and 80 years old and underwent unilateral primary TKA for osteoarthritis. Patients with the following conditions were excluded:

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body mass index greater than 40 kg/m2; weight less than 50 kg; and history of

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hypotension, fibromyalgia, opioid-dependence, or alcohol abuse. Additionally, patients

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undergoing bilateral TKA, unicondylar arthroplasty, surgical approach other than a

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medial parapatellar approach, and TKA due to post-traumatic arthritis or avascular

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necrosis were not included. Patients with allergy or a contraindication to the study

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medications were also excluded. Four adult reconstruction surgeons performed the

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surgeries at a single academic institution.

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The study interventions were periarticular injection of either liposomal bupivacaine (experimental group) or bupivacaine HCl (control group). Other components

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of perioperative care such as spinal anesthesia, surgical technique, knee implant fixation,

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prophylactic antibiotics, pain management protocol, venous thromboembolism

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prophylaxis, postoperative rehabilitation, and follow-up interval were similar for all

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patients. Patients received a cemented, posterior stabilized prosthesis with patellar

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resurfacing under uniform spinal anesthesia with bupivacaine (15mg). The specific

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implant model and manufacturer utilized was left to the surgeon’s discretion.

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In the experimental group, the infiltration solution consisted of 20ml (266 mg) of liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, San Diego, CA) with 40 ml of

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sterile normal saline and 0.5 ml of epinephrine (1mg/ml). For the control group

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(bupivacaine HCl), 20ml (50mg) of free bupivacaine solution (Marcaine 0.25% with

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epinephrine 1:200000, Hospira Inc. Lake Forest, IL) was diluted with 40ml of normal

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saline. The volume of injected solution was consistent in both groups, and the infiltration

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protocol was adapted from the technique video provided by the liposomal bupivacaine

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manufacturer. The injection technique was standardized among the four surgeons prior to

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initiation of the study. Following implantation of the knee prosthesis, the solution was

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injected by the attending surgeon into the vastus medialis (5ml), medial retinaculum

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(5ml), origin of medial collateral ligament (5ml) and lateral collateral ligament (5ml),

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lateral portion of the quadriceps tendon (5ml), vastus lateralis (5ml), and subcutaneous

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tissues, especially along saphenous nerve distribution (30ml). An 18-gauge needle was

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utilized as per the instruction of the manufacturer to use a bore size needle of at least a 25

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gauge, and each injection site was penetrated multiple times during infiltration. The

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injected volume was spread throughout the surface area of the site rather than

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concentrated.

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Preoperatively, patients received oral acetaminophen (975mg), celecoxib

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(400mg), and pregabalin (75mg) within two hours of surgery. Patients received a

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cemented, posterior stabilized prosthesis with patellar resurfacing under uniform spinal

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anesthesia with bupivacaine (15mg). Surgical drains were not used. Postoperatively,

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standing doses of oral acetaminophen (650mg) every 6 hours, pregabalin (75mg) every

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12 hours, and intravenous ketorolac (30mg) were administered. Oral narcotics (mainly

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oxycodone 10mg) and tramadol (50mg) were administered for residual breakthrough

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pain. Aspirin (81mg or 325mg) or warfarin (target international normalized ratio [INR]:

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1.5-2.0) was administered for thromboembolism prophylaxis. All patients were mobilized

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on the day of surgery. All patients completed a VAS-based pain questionnaire adapted from the

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American Pain Society’s Patient Outcome Questionnaire, [21] Short Form (SF)-12, Knee

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Society Score (KSS), and a validated psychological questionnaire known as the Distress

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and Risk Assessment Method (DRAM). [22]

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Postoperatively, patients completed the questionnaires in the morning (8am) and

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the evening (5pm) on postoperative days (PODS) 1 and 2, and in the morning on days 3

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and 4. If the patients were discharged earlier than POD 4, they were required to complete

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the questionnaire at home and mail it back to us. The study questionnaires have been

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utilized in a published study. [10]

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The primary outcome measure was the change in subjective pain perception recorded via VAS on a scale of 0 (no pain) to 100mm (extreme pain) within 96 hours

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after surgery. Time zero was defined as the time of complete resolution of regional

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anesthesia. The orthopaedic floor nurses, who were blinded to the group assignment,

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assessed pain during the first 24 hours.

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Secondary outcomes were narcotic consumption (in oral morphine equivalents), opioid-related side effects (based on the Brief Pain Inventory), [23] and satisfaction level

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during the first 96 hours post-surgery (scale: 0: very dissatisfied, 1: dissatisfied, 2:

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neutral, 3: satisfied, and 4: very satisfied); and functional outcomes including SF-12

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scores and KSS and postoperative complications upon follow up at 4-6 weeks after

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surgery.

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Power analysis was based on a minimal clinically important difference (MCID) of

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9mm-13mm, with a standard deviation of 13-25 as reported by previous studies. [24–26]

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Using a MCID of 12, standard deviation of 20, and setting the power level at 0.90 with an

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alpha error of 0.05, an effect size of 0.60 and sample size of 118 (59 in each group) was

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calculated.

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An Excel random number generator (Excel 2013; Microsoft, Redmond,

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Washington) was used to determine the allocation order using sequentially numbered

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sealed envelopes that were opened just prior to the intervention in a consecutive fashion

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irrespective of the surgeon. Separate individuals did the random allocation sequence,

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patient enrollment and allocation, and outcome assessment.

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The patients, outcome assessors (including the floor nursing staff and clinical assessors), data collectors, and statistician were blinded. Because the gross appearance of

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the two injection solutions is different (liposomal bupivacaine is cloudy and bupivacaine

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HCl is clear), it was impossible to blind the surgeons and operating room staff.

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Using R software 2.15.1 (R Foundation for Statistical Computing, Vienna,

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Austria), the statistical analysis was performed when the outcomes were available for 118

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subjects (59 in each group) as per a priori power analysis. Data regarding satisfaction

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level and severity of side effects were collected in Likert scales and converted to

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numerical values of 0-4 for statistical comparison. P-values less than 0.05 awere

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considered statistically significant, and Student’s t-test and Wilcoxon signed-rank test

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were used for variables with normal and non-parametric distribution, respectively.

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Fisher’s exact test was utilized for categorical variables, and Spearman’s rho was

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calculated for correlation analysis.

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Sources of Funding

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This project did not receive any financial funding from external sources.

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RESULTS Between January 2014 and May 2015, 259 consecutive candidates undergoing

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unilateral primary TKA were assessed for eligibility. One hundred sixty two patients

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consented to participate in the study and received the intervention. In the cohort, 42

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patients did not complete postoperative questionnaires and two were retrospectively

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excluded because they did not meet inclusion criteria and had been included in error.

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Recruitment was completed once outcomes were available for enough patients to meet

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the required sample size. There were 59 patients each in the liposomal bupivacaine

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(experimental) and bupivacaine HCl (control) groups (Figure 1).

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The groups were not statistically different in terms of demographics,

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comorbidities, operative time, preoperative functional scores (KSS and SF-12), and

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emotional status (DRAM test) (Table 1). There were better preoperative scores for the

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experimental group compared with the control group in terms of average daily pain

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(38mm versus 42mm, respectively p=0.09), worst daily pain (53mm versus 62mm,

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respectively, p=0.06), and KSS scores (53 versus 46, respectively p=0.06).

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No statistically significant difference was observed between the groups at any

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time point in terms of the least, worst, and average daily pain. Generally, similar trends

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were observed for the average and worst daily pain in both groups. There was a peak in

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the average pain levels in both groups 6-12 hours following surgery, followed by a

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gradual decline at subsequent time points, although the decline in the control group was

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delayed starting on the morning of POD 2. For the worst pain, the trend was similar to the

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average pain with a less noticeable peak, although the experimental patients seemed to

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experience slightly more intense maximum pain compared with those in the control

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group. The control patients seemed to experience more intense minimum pain during the

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first POD compared with those in the experimental group. As mentioned earlier,

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however, none of the comparisons for the average, least, and worst pain scores reached

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statistical significance (Figure 2).

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Secondary Outcomes

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Similar trends existed for narcotic consumption between the two groups with no statistically significant difference in daily and overall narcotic consumption (Figure 3).

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Peak narcotics consumption was observed in both groups on POD 2 followed by a

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decreasing slope throughout the postoperative period. In the experimental and control

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groups, 12% (7/59) and 11% (6/55), respectively, did not require narcotics during the

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postoperative hospital stay (p=1.0). No statistically significant difference was observed

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between the groups for narcotic-related side effects (Table 2).

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Based on scale of satisfaction (0: very dissatisfied, 1: dissatisfied, 2: neutral, 3: satisfied and 4: very satisfied), the median satisfaction level regarding pain management

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during the first 96 hours after the surgery was 3.2 (interquartile range [IQR]: 2.8–3.8) in

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the experimental group and 3.0 (IQR: 2.8–3.6) in the control group, meaning both groups

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reached the “satisfied” level without a statistically significant difference (p=0.56).

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As shown in Table 3, improvement of physical function (KSS and SF-12) occurred in

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both groups during the follow-up period, but no statistically significant difference was

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observed between the groups in terms of the final scores or improvement (∆ values).

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The incidence of overall postoperative complications was similar in both groups

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(11%, p=1.0)(Table 4). The incidence of surgical complications (including manipulation

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under anesthesia, irrigation and debridement for persistent drainage from a hematoma,

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neurologic complications, periprosthetic joint infection, and wound healing issues) was

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5/87 (6%) and 6/74 (8%) in the experimental and control groups, respectively (p=0.76).

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The median length of stay was 2 days (IQR: 1-2) in both groups (p=0.35).

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DISCUSSION

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The quality of pain management has an influential role on patient postoperative

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recovery and the outcome of any surgical procedure. This is especially true after TKA.

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Studies have reported successful results with the use of locally-injected solutions into

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periarticular tissues following TKA. [27,28] Multi-vesicular liposomal bupivacaine as a

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long-acting local anesthetic appears attractive for single periarticular injection in TKA as

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it is safe and compatible with implants, does not influence surgical wound healing, and

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can be co-administered with other locally-injected medications such as epinephrine.

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[14,29,30] Despite its promising potential, however, the efficacy of liposomal

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bupivacaine compared with free bupivicaine remains unknown. The results of this

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prospective randomized study found no significantly measureable difference between

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liposomal bupivacaine and free bupivacaine when used as part of a multimodal pain

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management protocol. These findings resemble those of a recently published prospective

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randomized trial [31] and another retrospective study [32] on TKA patients, in which the

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implementation of periarticular liposomal bupivacaine in different multimodal pain

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management protocols was not associated with extra benefit compared to bupivacaine

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HCl or ropivacaine injection, respectively.

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Furthermore, we did not observe clinically significant improvements in pain perception, narcotic consumption, and narcotic-related side effects in patients who

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received periarticular infiltration of liposomal bupivacaine compared with bupivacaine

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HCl following TKA. In both groups, the peak narcotic consumption on POD 1 was

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associated with a higher intensity of average and worse daily pain compared with

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subsequent PODs. Previous studies on TKA patients receiving periarticular injections

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similarly reported that maximum in-hospital perioperative pain scores or narcotic

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consumption occur on the first POD. [10,27,33] In our study, the functional outcomes

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were similar in the experimental and control groups, and we generally did not observe

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any superiority or inferiority of liposomal bupivacaine compared with bupivacaine HCl.

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In addition, patients in both the experimental and control groups were equally satisfied

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with their pain management.

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Periarticular injection of both bupivacaine solutions had an acceptable safety

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profile in this study. The overall incidence of manipulation under anesthesia was 3% (1%

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and 5% for the experimental and control groups, respectively), which is similar to recent

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findings. [34,35] Similarly, the incidences of thromboembolic events (<1%), surgical

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wound-related complications (2%), and neurologic complications (1%) in our cohort

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were compatible with those in other reports. [36,37] One patient in the control group had

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a periprosthetic infection. Finally, the incidence of major coronary complications in our

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cohort during the study period (1.2%) was higher than what has been reported in

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nationwide large-scale studies (0.2%-0.4%). [38,39] However, given the underlying

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condition of our patients, previous safety reports of local injections of bupivacaine, and

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the small size of our study, we cannot establish a connection with the injection.

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Liposomal bupivacaine did not result in shorter length of hospital stay compared with

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bupivacaine HCl.

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We acknowledge this study has some limitations. First, our pain assessment schedule at 8am and 5pm was based on the patients’ daily routines in order to obtain

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better compliance. It was impractical to adjust the time of pain assessment to the time of

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surgical procedure, end of administration of anesthesia, routine daily activity, physical

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therapy, or rescue analgesic administration. Any of these factors may have influenced the

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patients’ responses to the pain questionnaire. Because the patients, therapists, and nursing

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staff were blinded to the medication group, however, the experimental and control groups

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had similar risk for the potential confounding influence of those factors. Second, the

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surgeons who did the infiltration could not be blinded to the medication due to the

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difference in gross appearance of the formulas. Third, we retrospectively discovered that

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there were two patients (one in each group) who did not meet the inclusion criteria. The

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patient in the experimental group had a remote history of narcotic addiction and the

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patient in the control group had multiple surgeries in his knee 20 years before undergoing

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TKA. These patients were considered for the analysis of postoperative complications

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only because they received the intervention. Finally, we had a high overall dropout rate of

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26%; however, this dropout rate was comparable to that of similarly designed studies.10

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In conclusion, comparing two multimodal pain management protocols for primary

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TKA, no clinically significant improvement was observed with use of liposomal

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bupivacaine compared with bupivacaine HCl in terms of 96 hour-postoperative pain

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scores, narcotic consumption, and related side effects and satisfaction level, as well as

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complication rates and functional outcomes at 4-6 week follow-up.

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References:

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[1] Tali M, Maaroos J. Lower limbs function and pain relationships after unilateral total knee arthroplasty. Int J Rehabil Res Int Z Für Rehabil Rev Int Rech Réadapt. 2010;33(3):264-267. doi:10.1097/MRR.0b013e3283352126. [2] Brokelman RBG, van Loon CJM, Rijnberg WJ. Patient versus surgeon satisfaction after total hip arthroplasty. J Bone Joint Surg Br. 2003;85(4):495-498.

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[3] Loeser JD, Melzack R. Pain: an overview. Lancet. 1999;353(9164):1607-1609. doi:10.1016/S0140-6736(99)01311-2.

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[6] Buvanendran A, Kroin JS, Valle CJ Della, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg. 2010;110(1):199-207. doi:10.1213/ANE.0b013e3181c4273a.

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[10] Goyal N, McKenzie J, Sharkey PF, Parvizi J, Hozack WJ, Austin MS. The 2012 Chitranjan Ranawat award: intraarticular analgesia after TKA reduces pain: a randomized, double-blinded, placebo-controlled, prospective study. Clin Orthop Relat Res. 2013;471(1):64-75. doi:10.1007/s11999-012-2596-9.

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[12] Abrisham SMJ, Ghahramani R, Heiranizadeh N, Kermani-Alghoraishi M, Ayatollahi V, Pahlavanhosseini H. Reduced morphine consumption and pain severity with transdermal fentanyl patches following total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc Off J ESSKA. 2014;22(7):1580-1584. doi:10.1007/s00167-012-22879. [13] Lonner J. Role of liposomal bupivacaine in pain management after total joint arthroplasty. J Surg Orthop Adv. 2014;23(1):37-41.

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[14] Kharitonov V. A review of the compatibility of liposome bupivacaine with other drug products and commonly used implant materials. Postgrad Med. 2014;126(1):129138. doi:10.3810/pgm.2014.01.2733.

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[15] Gorfine SR, Onel E, Patou G, Krivokapic ZV. 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):1552-1559. doi:10.1097/DCR.0b013e318232d4c1.

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[16] Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: a randomized, double-blind, active-control study. Aesthetic Surg J Am Soc Aesthetic Plast Surg. 2012;32(1):69-76. doi:10.1177/1090820X11430831. [17] Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. 2011;28(9):776-788. doi:10.1007/s12325-011-0052-y. [18] 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

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[20] 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. doi:10.1016/j.arth.2014.03.034.

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[21] Quality improvement guidelines for the treatment of acute pain and cancer pain. American Pain Society Quality of Care Committee. JAMA. 1995;274(23):1874-1880. [22] Main CJ, Wood PL, Hollis S, Spanswick CC, Waddell G. The Distress and Risk Assessment Method. A simple patient classification to identify distress and evaluate the risk of poor outcome. Spine. 1992;17(1):42-52.

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[23] Opioid Equivalents: Overview. June 2015. http://emedicine.medscape.com/article/2138678-overview. Accessed July 21, 2015. [24] Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994;23(2):129-138.

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[25] Todd KH, Funk KG, Funk JP, Bonacci R. Clinical Significance of Reported Changes in Pain Severity. Ann Emerg Med. 1996;27(4):485-489. doi:10.1016/S01960644(96)70238-X. [26] Kelly AM. Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad Emerg Med Off J Soc Acad Emerg Med. 1998;5(11):1086-1090. [27] Kelly AM. The Minimum Clinically Significant Difference in Visual Analogue Scale Pain Score Does Not Differ with Severity of Pain. Emerg Med J. 2001;18(3):205207. doi:10.1136/emj.18.3.205. [28] Tsukada S, Wakui M, Hoshino A. Postoperative epidural analgesia compared with intraoperative periarticular injection for pain control following total knee arthroplasty

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[29] Marques EMR, Jones HE, Elvers KT, Pyke M, Blom AW, Beswick AD. Local anaesthetic infiltration for peri-operative pain control in total hip and knee replacement: systematic review and meta-analyses of short- and long-term effectiveness. BMC Musculoskelet Disord. 2014;15:220. doi:10.1186/1471-2474-15-220.

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[30] Viscusi ER, Sinatra R, Onel E, Ramamoorthy SL. The safety of liposome bupivacaine, a novel local analgesic formulation. Clin J Pain. 2014;30(2):102-110. doi:10.1097/AJP.0b013e318288e1f6.

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[31] Baxter R, Bramlett K, Onel E, Daniels S. Impact of local administration of liposome bupivacaine for postsurgical analgesia on wound healing: a review of data from ten prospective, controlled clinical studies. Clin Ther. 2013;35(3):312-320.e5. doi:10.1016/j.clinthera.2013.02.005.

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[32] Mullaji A, Kanna R, Shetty GM, Chavda V, Singh DP. Efficacy of periarticular injection of bupivacaine, fentanyl, and methylprednisolone in total knee arthroplasty:a prospective, randomized trial. J Arthroplasty. 2010;25(6):851-857. doi:10.1016/j.arth.2009.09.007.

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[33] Schroer WC, Diesfeld PG, LeMarr AR, Morton DJ, Reedy ME. Does ExtendedRelease Liposomal Bupivacaine Better Control Pain Than Bupivacaine After TKA? A Prospective, Randomized Clinical Trial. J Arthroplasty. doi:10.1016/j.arth.2015.01.059.

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[34] Issa K, Banerjee S, Kester MA, Khanuja HS, Delanois RE, Mont MA. The Effect of Timing of Manipulation Under Anesthesia to Improve Range of Motion and Functional Outcomes Following Total Knee Arthroplasty. J Bone Joint Surg. 2014;96(16):13491357. doi:10.2106/JBJS.M.00899. [35] Bawa HS, Wera GD, Kraay MJ, Marcus RE, Goldberg VM. Predictors of range of motion in patients undergoing manipulation after TKA. Clin Orthop Relat Res. 2013;471(1):258-263. doi:10.1007/s11999-012-2591-1. [36] Kester BS, Merkow RP, Ju MH, et al. Effect of post-discharge venous thromboembolism on hospital quality comparisons following hip and knee arthroplasty. J Bone Joint Surg Am. 2014;96(17):1476-1484. doi:10.2106/JBJS.M.01248.

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37] Duchman KR, Gao Y, Pugely AJ, Martin CT, Noiseux NO, Callaghan JJ. The Effect of Smoking on Short-Term Complications Following Total Hip and Knee Arthroplasty. J Bone Joint Surg Am. 2015;97(13):1049-1058. doi:10.2106/JBJS.N.01016.

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[38] Bolognesi MP, Greiner MA, Attarian DE, et al. Unicompartmental Knee Arthroplasty and Total Knee Arthroplasty Among Medicare Beneficiaries, 2000 to 2009. J Bone Joint Surg. 2013;95(22):e174. doi:10.2106/JBJS.L.00652.

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[39] Menendez ME, Memtsoudis SG, Opperer M, Boettner F, Gonzalez Della Valle A. A nationwide analysis of risk factors for in-hospital myocardial infarction after total joint arthroplasty. Int Orthop. August 2014. doi:10.1007/s00264-014-2502-z.

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Figure Legend Figure 1. The flow diagram of recruited patients through various stages of the study

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Figure 2. Mean postoperative pain scores (average, least, and worst daily pain) for experimental and control groups. POD: postoperative day

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Figure 3. Box and whisker plots representing overall and by-day narcotic consumption (in mg of oral morphine equivalent) in experimental and control groups during the first 96 hours postsurgery. POD: postoperative day

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Table - 1 Comparison of characteristics of patients in the experimental and control groups.

Bupivacaine HCl (Control, N=59)

p Value

64.3 (60.2 – 71.7)

64.9 (60.8 – 70.4)

0.95

30 / 29

32 / 27

0.85

32.3 (27.4 – 34.6)

28.7 (26.4 – 34.7)

0.10

37 / 18 / 4

45 / 13 / 1

0.16

32 / 27

1.0

40 / 10 / 6 / 3

42 / 8 / 5 / 4

0.77

54 / 5

52 / 7

0.76

2 (1 – 2)

2 (1 – 2)

0.35

85.9 (±17.8)

85.6 (±16.7)

0.92

Average daily

38 (19 – 46)

42 (30 – 50)

0.09

Least daily

14 (6 – 30)

18 (3 – 32)

0.53

Worst daily

53 (33 – 72)

62 (47 – 72)

0.06

Loading conditions †

38 (22 – 60)

45 (34 – 59)

0.36

8 (3 – 18)

13 (3 – 30)

0.13

2 (1–2)

2 (1–2)

0.18

53 (41 – 63) 8 (4 – 13)

46 (34 – 57) 8 (5 – 15)

0.06 0.56

6 (10%)

11 (19%)

0.29

1 (0 – 3)

2 (0 – 3)

0.35

Short Form 12–MCS (Preoperative) *

58.3 (53.8 – 63.3)

59.4 (53.7 – 63.9)

0.77

Short Form 12–PCS (Preoperative) *

30.7 (28.3 – 38.2)

31.7 (25.8 – 40.2)

0.97

Gender (female/male) BMI (Kg/m2) * Ethnicity (White / black / others)

33 / 26

Side (right/left) Charlson Comorbidity Index (0 / 1 / 2 / ≥ 3)

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Thromboprophylaxis (Aspirin / Warfarin)

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Age (years) *

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Liposomal Bupivacaine (Experimental, N=59)

Length of Hospital Stay (days) * Operative Duration (min) ǂ

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Preoperative Pain (mm) *

Unloading conditions ‡

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Frequency of Moderate to Severe Pain *§ Knee Society Score (Preoperative) *

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Preoperative DRAM–DI *

Patients at risk of depression (DRAM–DI ≥ 17) Preoperative DRAM–SP *



* The values are given as median with interquartile range in parentheses. The other variables are presented as frequency of the events.

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ǂ The values are given as mean with standard deviation in parentheses. † The average pain during getting out of bed, walking and physical therapy.

§ The values

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‡ The average pain during rest, sleep, cough, bathroom and eating. are presented based on Likert scale (0: never, 1: almost never, 2: often, 3: almost

always and 4: always).

patients with somatization anxiety (preoperative DRAM–SP ≥ 12).

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There were no

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BMI: body mass index, DRAM–DI: distress and risk assessment method–depression index), DRAM–SP (distress and risk assessment method–somatic perception), LOS: length of hospital

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stay, MCS: mental composite scale, PCS: physical composite scale

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Table 2- Postoperative potentially narcotic-related adverse effects

0.2 (0 – 0.5) 0 (0 – 0) 1 (0 – 1.8) 0 (0 – 0.2) 0 (0 – 0.3) 0.3 (0.2 – 1.0) 0 (0 – 0.5) 0 (0 – 0) 0.5 (0 – 1.0) 0 (0 – 0.5) 0.7 (0 – 1.3) 0 (0 – 0.3)

0 (0 – 0.5) 0 (0 – 0) 0.8 (0.2 – 1.7) 0 (0 – 0.2) 0 (0 – 0) 0.3 (0 – 0.8) 0 (0 – 0.4) 0 (0 – 0) 0.5 (0 – 1.0) 0.5 (0 – 0.7) 0.8 (0.1 – 1.2) 0 (0 – 0.2)

p Value

0.32 0.64 0.87 0.89 0.26 0.45 0.72 0.15 0.72 0.94 0.73 0.84

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Bupivacaine HCl (Control)

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Nausea * Vomiting Constipation Difficulty Passing Urine Difficulty Concentration Drowsiness Dizziness Confusion Fatigue Itchiness Dry Mouth Headache

Liposomal Bupivacaine (Experimental)

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* The values are given as median with interquartile range in parentheses. They are presented based on Likert scale (0: none, 1: mild, 2: moderate, 3: severe and 4: very severe).

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Table 3- Postoperative complications based on intention-to-treat analysis (n=162)

1 2

1 0

Neurologic Complications

2

0

Thromboembolic Complications

1

Periprosthetic Joint Infection

0

Wound Healing Complications Cutaneous Eruptions

1 2

Spinal Abscess

0

1

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1

0 0

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1

10/87 (11)

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Total (percentage)

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Hematoma Ischemic Cardiac Complications

Considerations Indicated based on range of motion during the 4-6 week follow-up assessment. Both patients required surgical intervention. Case #1 had myocardial infarction 5 days after surgery. The patient had history of coronary artery disease. Case #2 had unstable angina 3 weeks after surgery. The patient had history of coronary artery disease. Case #1 developed foot drop. Case #2 had persistent plantar pain and numbness. Case #1 (experimental group) had deep vein thrombosis diagnosed 2 weeks after surgery. Case #2 (control group) was diagnosed with postoperative atrial fibrillation and pulmonary embolus. Plaque of skin necrosis with subsequent skin defect and exposure of soft tissues. The patient underwent revision surgery due to periprosthetic joint infection 5 months after the index surgery. The pathogen was methicillin sensitive Staphylococcus aureus. Delayed wound healing without need for surgery. Case one developed peri-incisional eruptions with pruritus Case two had eruptions in the medial aspect of leg and thigh Unremarkable immediate postoperative course. Patient’s narcotic consumption was equivalent to 15 mg of morphine. Symptoms started 2 weeks after surgery. Abscess was drained in another institution. p value = 1.0

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Liposomal Bupivacaine (Experimental) n=87 1

8/74 (11)

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Table 4- Functional outcomes

Bupivacaine HCl (Control, N=53)

Postoperative

80 (61 – 88)

75 (61 – 86)

0.53

∆

25 (14 – 41)

30 (9 – 53)

0.34

56.3 (47.8-62.5)

55.9 (49.2 – 62.5)

0.82

-4.1 [(-9.2) – (+1.3)]

-3.2 [(-10.4) – (+3.4)]

0.79

Knee Society Score

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∆

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Short Form 12-MCS Postoperative

Short Form 12-PCS Postoperative ∆

37.8 (32.3 – 45.2)

37.9 (29.5 – 47.0)

0.66

2.9 [(-2.1) – (+9.3)]

2.9 [(-4.0) – (+13.5)]

0.77

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All variables are presented as median with interquartile range in parentheses.

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MCS: mental composite scale, PCS: physical composite scale

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p Value

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Liposomal Bupivacaine (Experimental, N=51)

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