Arthroplasty/Joint Replacement

Approximately 5.5 million patients undergo orthopedic surgery in the United States each year, and more than 1 million of the procedures are total knee arthroplasty (TKA) or total hip arthroplasty.¹ From its 2010 level, demand for joint arthroplasty is expected to double by 2020 and quadruple by 2030.²

About half the patients who have major joint arthroplasty experience severe postsurgical pain.³ Because postsurgical pain may persist for days or weeks, and inadequate treatment is associated with negative outcomes, achieving effective postsurgical analgesia is an important consideration.^4-7 Complications of inadequate postsurgical pain management include thromboembolic or pulmonary complications, development of chronic pain, and decrements in health-related quality of life.^4,8

In patients who have orthopedic surgery, the inability to adequately control postsurgical pain has been associated with increased hospital length of stay (LOS), delayed time to ambulation, and reduced capacity for exercise.^9-12 A recent study involving 4709 patients who had hip or knee arthroplasty found that postsurgical pain relief was the second most highly correlated factor with respect to overall patient satisfaction (how well surgery met patient expectations was the most highly correlated factor),¹³ suggesting that postsurgical analgesia should be a focus of surgical practice.

A prolonged-release liposomal formulation of the local anesthetic bupivacaine is now available. Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is indicated for administration into the surgical site to produce postsurgical analgesia.¹⁴ In this article, we review evidence from clinical studies regarding the potential contribution of liposome bupivacaine to improving postsurgical pain management when used as part of a multimodal analgesic regimen in patients undergoing orthopedic surgery.

Postsurgical Pain Management in Orthopedic Surgery

Frequently Used Modalities

Analgesic modalities commonly used for perioperative pain management include central (eg, epidural),^4,10,15,16 central regional (eg, neuraxial),⁴ peripheral regional (eg, peripheral nerve blocks, local/regional surgical site infiltration, intra-articular administration),^{4,10,15,17-25} and intravenous (IV) patient-controlled analgesia.^4,10,25 These pharmacologic interventions may be augmented by nonpharmacologic modalities (eg, transcutaneous electrical nerve stimulation).²⁶

Pharmacologic treatment options for perioperative pain management include opioids, local anesthetics, clonidine, ketamine, nonsteroidal anti-inflammatory drugs, acetaminophen, and calcium-channel blockers.^4,26-28 In TKA, “drug cocktails” (eg, combinations of ropivacaine, ketorolac, epinephrine, and clonidine) for regional or intra-articular injection can also provide effective immediate postsurgical analgesia.²⁵ Although opioids are the most commonly used analgesics for management of orthopedic perioperative pain,²⁵ their use is often associated with adverse effects (AEs), including constipation or ileus, nausea, sedation, dizziness, pruritus, urinary retention, and respiratory depression.⁶

Multimodal Analgesic Regimens for Postsurgical Pain Management

Current American Society of Anesthesiologists guidelines endorse use of multimodal analgesia, whenever possible, to provide effective management of acute perioperative pain.⁴ Multimodal analgesia involves applying 2 or more agents with different mechanisms of action to achieve a synergistic effect, which allows each agent to be reduced in dose^4,28 and thereby may limit the risk and severity of dose-related AEs.^4,25,28

Multimodal analgesia aims to reduce the risk for opioid-related AEs (ORAEs) and the impact of opioids on postsurgical milestones (eg, ambulation, discharge) and may reduce opioid consumption, with attendant reductions in ORAE risk.^29,30 Health economics studies have shown that postsurgical ORAEs are associated with increased hospital costs and LOS.⁶ In a study using a national hospital database, development of an ORAE (vs no ORAE) in postsurgical patients was associated with mean increases of about $4700 in hospital costs and 3.3 days in LOS.⁷ Reducing postsurgical opioid use may also help reduce the risk for opioid abuse, addiction, and diversion.^31-33

One approach to reducing opioid use involves continuous or intermittent administration of local anesthetics by elastomeric pumps to extend duration of postsurgical analgesia.^34-36 However, use of elastomeric pumps has been associated with risk for AEs, including tissue necrosis, sloughing, wound infection, and chondrolysis.^37-40 In addition, AEs related to “dose dumping” (accidental delivery of excessive doses) have been reported.^40-44 Key issues that may negatively affect rehabilitation after orthopedic surgery include consistency and accuracy of analgesic delivery and the potential for motor block–induced muscle weakness, which may lead to falls and constrain ambulation.^45-47

Liposome Bupivacaine

Description

Drug Delivery Technology. Liposome bupivacaine incorporates DepoFoam drug delivery technology (Pacira Pharmaceuticals, Inc.) to facilitate prolonged release of bupivacaine. This technology is based on creation of multivesicular liposome particles (diameter, 10-30 µm) with multiple aqueous chambers.^30,48 After administration into the surgical site, bupivacaine diffuses from chambers in the liposomal particles over time, providing analgesia and reduced opioid requirements for up to 72 hours.^29,30

Indication, Mechanism of Action, Pharmacokinetics, and Dose/Administration. Liposome bupivacaine is indicated for single-dose administration into the surgical site to produce postsurgical analgesia in patients at least 18 years old.¹⁴ Like other local anesthetics, liposome bupivacaine is thought to exert its pharmacologic effects by interacting with voltage-gated Na⁺ channels on neural membranes to raise the threshold for electrical excitability, to slow nerve impulse propagation, and to reduce the rate of rise of the action potential.^14,49

Liposome bupivacaine has dose-proportional pharmacokinetics.⁵⁰ Presence of a small amount of extra-liposomal bupivacaine in the formulation leads to a bimodal pharmacokinetic profile, with an initial peak serum concentration about 1 hour after administration, followed by a second peak within 12 to 36 hours (Figure).⁵⁰

Maximum amount of liposome bupivacaine approved for single administration is 266 mg (packaged as 20 mL of a 1.3% solution). However, product labeling includes safety data associated with doses of 532 mg or less.¹⁴ The appropriate volume to be used should be based on the amount required to cover the surgical area. Liposome bupivacaine may be expanded with preservative-free normal (0.9%) sterile saline to a total volume of 300 mL: 20 mL liposome bupivacaine plus 280 mL or less diluent, with final concentration of 0.89 mg/mL (1:14 by volume).¹⁴

A 25-gauge or larger bore needle should be used to slowly inject liposome bupivacaine into soft tissues of the surgical site, with frequent aspiration to check for blood to minimize risk for intravascular injection.¹⁴ Total volume used and fraction injected in specific regions of the surgical site depend on the procedure. For example, a TKA study used 266 mg diluted to a total volume of 60 mL, with 8 mL infiltrated to the area around the medial capsule, 8 mL around the lateral capsule, 12 mL around the posterior capsule, 8 mL around the peripatellar area, 12 mL into the capsulotomy incision, and 12 mL into the subcutaneous tissue on each side of the incision.⁵¹

Efficacy

Multiple Surgical Settings. The efficacy of liposome bupivacaine, either alone or as a component of a multimodal analgesic regimen, has been evaluated in a series of 10 phase 2 and 3 studies (8 active-controlled, 2 placebo-controlled) involving 823 patients undergoing TKA, bunionectomy, hemorrhoidectomy, inguinal hernia repair, or mammoplasty.⁵² Patients received a single liposome bupivacaine dose ranging from 66 to 532 mg.⁵²

Combined analyses of efficacy data from these studies found that liposome bupivacaine–based multimodal analgesic regimens produced postsurgical analgesia for up to 72 hours, increased time to first use of opioid rescue medication after surgery, and reduced total amount of postsurgical opioid consumption versus placebo.⁵²

Compared with standard of care, liposome bupivacaine has been shown to provide effective analgesia in open-label studies in patients undergoing open colectomy,⁵³ laparoscopic colectomy,⁵⁴ and ileostomy reversal,^55,56 as reflected in assessments of postsurgical opioid consumption, LOS, and hospital costs. It has also been studied when administered by infiltration into the transversus abdominis plane (TAP) in patients having laparoscopic prostatectomy and open abdominal hernia repair.^57,58

Orthopedic Surgery. In a phase 2 randomized, double-blind, dose-ranging study, TKA patients (N = 138) received bupivacaine HCl 150 mg or liposome bupivacaine 133, 266, 399, or 532 mg administered by local infiltration into the capsulotomy incision and on either side of the incision before wound closure.⁵¹ Postsurgical rescue analgesia was available to all patients. Cumulative pain intensity scores with activity (primary efficacy measure) were not statistically different between liposome bupivacaine groups and the bupivacaine HCl group through postoperative day 4. Mean scores in the liposome bupivacaine 266-, 399-, and 532-mg groups were numerically lower than for those treated with bupivacaine HCl on postoperative days 2 to 5, with all doses of liposome bupivacaine having a statistically significant lower pain score at rest on day 5. There were no statistically significant differences across treatment groups with respect to total amount of postsurgical opioids used.

In a phase 3 randomized, double-blind study of TKA patients (N = 245), liposome bupivacaine 532 mg administered into the surgical site was compared with bupivacaine HCl 200 mg for postsurgical analgesia.⁵² Rescue analgesia was available to all patients. No statistically significant between-group differences were found with respect to postsurgical cumulative pain scores through 72 hours (primary efficacy endpoint).

In a single-center retrospective TKA study, postsurgical outcomes in a patient cohort that received intraoperative periarticular infiltration with liposome bupivacaine 266 mg (n = 65) were compared with a cohort that received infiltration with a combination of ropivacaine 400 mg, morphine 5 mg, and epinephrine 0.4 mg (n = 85).⁵⁹ Patient-reported postsurgical pain scores were similar in the 2 treatment groups during the first 24 hours after surgery and at discharge. Mean (SD) pain scores during hospitalization after the first 24 hours until discharge were significantly (P = .04) higher in the liposome bupivacaine group, 4.9 (1.4), than in the periarticular group, 4.4 (1.6). There was no significant difference between the 2 treatment groups in postsurgical opioid use. The study demonstrated no advantage to using liposome bupivacaine injections with respect to pain relief, but it was a retrospective review in which pain scores were obtained from electronic medical records. It is essential that liposome bupivacaine be compared with intra-articular injections in well-designed randomized trials.

Another single-center, matched-cohort TKA study (N = 200) compared a liposome bupivacaine regimen with femoral nerve block.⁶⁰ Compared with patients who received femoral nerve block, patients who received liposome bupivacaine reported lower pain intensity scores after surgery and had shorter LOS, reduced costs, and improved knee flexion at follow-up.⁶⁰

Results from 2 other studies were presented at the 2014 meeting of the American Academy of Orthopaedic Surgeons (AAOS). One was a single-center, matched-cohort TKA study (N = 72) comparing infiltration of a single dose of liposome bupivacaine into the surgical site with continuous femoral nerve block.⁶¹ The 2 treatment groups had similar mean postsurgical pain intensity scores on a 0-to-10 visual analog scale, 1.8 for liposome bupivacaine and 2.3 for continuous nerve block (P = NS), but total amount of postsurgical opioids (hydrocodone-equivalent milligrams) was significantly (P < .0001) less in the liposome bupivacaine group (82 vs 177 mg).

The other study presented at the AAOS meeting was a larger, prospective case–control study comparing outcomes between 1000 patients who had total joint arthroplasty (TJA) with liposome bupivacaine and 1000 control patients who had TJA without liposome bupivacaine.⁶² For the control and liposome bupivacaine cohorts, respectively, mean postsurgical pain intensity scores were 2.41 and 1.98 (P < .0001), mean LOS was 2.83 days and 2.66 days (P < .02), and incidence of falls was 1.0% and 0.2% (P = .02). Average per-patient costs were $1246 lower in the liposome bupivacaine cohort.

A pivotal phase 3 placebo-controlled study compared liposome bupivacaine 106 mg with placebo in patients undergoing bunionectomy (N = 193).⁵ Rescue medication was available to all patients. Cumulative pain scores were significantly (P = .0005) lower in the liposome bupivacaine group (125) than in the placebo group (146) through 24 hours after surgery (primary efficacy measure) and significantly (P = .0229) lower (197 vs 220) through 36 hours. Median time to first use of rescue opioids was delayed in favor of the liposome bupivacaine group (7.2 vs 4.3 hours; P < .0001). Mean total number of opioid tablets used within 24 hours after surgery was also significantly lower (3.8 vs 4.7; P = .008), and a larger percentage of patients in the liposome bupivacaine group avoided opioid use altogether through 24 hours (7% vs 1%; P = .04).

Efficacy data for liposome bupivacaine appear promising for relief of pain after joint arthroplasty and other orthopedic procedures but have their limitations. First, no randomized trials have compared liposome bupivacaine with locally injected pain medications (intra-articular injections in TKA or hip arthroplasty). As these injections are quite common now, such analyses are essential. Second, cost-effectiveness studies are needed for orthopedic procedures. Third, most of the published studies were sponsored by the manufacturer of liposome bupivacaine—a situation that raises questions about potential bias. Non-industry-sponsored randomized trials assessing efficacy, safety, and cost-effectiveness are needed.

Safety

Local anesthetics, including liposome bupivacaine, have the potential for central nervous system (CNS) or cardiac toxicity resulting from excessive systemic absorption or inadvertent IV administration.⁶³ However, reported serious CNS or cardiac-related AEs are rare.^63,64

AE Profile. Safety data from 10 phase 2 and 3 studies involving 823 patients who received liposome bupivacaine were evaluated.⁶⁵ Of these patients, 545 received a dose of 266 mg or less (maximum dose approved by the US Food and Drug Administration [FDA]). Liposome bupivacaine was generally well tolerated. Reported AE incidence was 62% (liposome bupivacaine), 75% (bupivacaine HCl), and 43% (placebo). More than 90% of reported AEs were mild or moderate. The most frequently reported AEs were nausea, constipation, and vomiting (liposome bupivacaine, bupivacaine HCl) and nausea, dizziness, and vomiting (placebo).

Serious AEs were reported in 22 (2.7%) of the 823 patients in the liposome bupivacaine group, 24 (5.4%) of the 446 in the bupivacaine HCl group, and 2 (1.1%) of the 190 in the placebo group.⁶⁵ None of the serious AEs in the liposome bupivacaine and placebo groups were considered treatment-related. Six patients in the bupivacaine HCl group had treatment-related serious AEs (hypoglycemia, arthrofibrosis, hemarthrosis, joint swelling, scar, knee arthroplasty).

Cardiac Safety. Possible cardiac effects associated with liposome bupivacaine were evaluated with data from studies conducted during the clinical development program.⁶⁶ One hundred thirty-eight patients participated in the phase 2 safety and efficacy study in TKA. In these patients, a consistent change in mean heart rate (range, +12.2 to +16.5 beats per minute) was found across all liposome bupivacaine doses and with bupivacaine HCl. No clinically relevant changes from baseline in mean electrocardiographic parameters, including QTcF interval (QT interval adjusted using Fridericia’s correction formula), were found. In another analysis,⁶⁷ liposome bupivacaine administered in a single subcutaneous dose (266, 399, 532, or 665 mg) to healthy volunteers did not prolong (vs placebo) QTc interval.

Wound Healing. The potential effects of liposome bupivacaine on wound healing were evaluated with results from 10 phase 2 and 3 studies.⁶⁸ The assessments, which varied across studies, included clinicians’ overall satisfaction with patient wound healing, wound status assessment (categories included erythema, drainage, edema, and induration), and wound scarring (categories included pigmentation, height, pliability, and vascularity). Clinician-assessed scores reflected high satisfaction with wound healing overall. There were few statistically significant differences in wound status assessments between liposome bupivacaine and the comparators and no statistically significant differences in scarring between liposome bupivacaine and bupivacaine HCl.

The potential of liposome bupivacaine to have adverse intra-articular effects was assessed with drainage samples from patients (n = 23) who had TKA and received liposome bupivacaine (133, 266, 399, or 532 mg) or bupivacaine HCl (150 mg) by wound infiltration near the intra-articular space.^51,65 Only small amounts of bupivacaine were present in drainage fluid collected for 12 hours after liposome bupivacaine administration, comparable to bupivacaine HCl administration.⁶⁵ Currently, the product is not approved for intra-articular use.

Compatibility With Diluents, Other Medications, and Implant Materials

Liposome bupivacaine may be expanded up to a ratio of 1:14 by volume (to a final total volume of 300 mL or a concentration of 0.89 mg/mL) using preservative-free normal (0.9%) sterile saline for injection.¹⁴ It has also been shown in vitro to be compatible with lactated Ringer solution as a diluent.⁶⁹

Liposome bupivacaine should not be admixed with other medications before administration.¹⁴ No formal drug–drug interaction studies have been conducted with liposome bupivacaine, but it has been shown in vitro to be compatible with epinephrine solutions, with certain anti-infective medications (eg, bacitracin, gentamicin, cefazolin, cefuroxime), with certain analgesics (eg, ketorolac, morphine), with an antihypertensive medication (clonidine), with an antihemorrhagic medication (tranexamic acid), and with certain corticosteroids (eg, methylprednisolone, triamcinolone acetonide). These medications may be coadministered in the same location as liposome bupivacaine.⁶⁹

Topical antiseptics (eg, povidone iodine) may be used in surgical procedures involving liposome bupivacaine as long as they are not directly mixed with liposome bupivacaine and are allowed to dry before it is administered. If a topical antiseptic is used for wound irrigation, the wound should be rinsed clear before liposome bupivacaine administration.^14,69

Liposome bupivacaine may be coadministered into the same surgical site immediately after bupivacaine HCl as long as the dose ratio of liposome bupivacaine to bupivacaine HCl is 2:1 or higher. Because of the prolonged-release pharmacokinetic profile of liposome bupivacaine and the potential for increased bupivacaine exposure, bupivacaine HCl should not be administered within 96 hours after administration of liposome bupivacaine.^14,69

In vitro coincubation studies of liposome bupivacaine and other local anesthetics, including ropivacaine, lidocaine, and mepivacaine, have found rapid release of free bupivacaine from the liposome matrix. Therefore, after giving any of these other local anesthetics, surgeons should wait at least 20 minutes before administering liposome bupivacaine into the same area.^14,69

In vitro studies have shown that liposome bupivacaine is compatible with a wide range of commonly used implant materials, including polypropylene, expanded polytetrafluoroethylene, stainless steel, titanium, and smooth- and textured-type silicone.⁶⁹

Investigational Use and Ongoing Studies

A phase 2 randomized, double-masked, dose-escalating/deescalating study was conducted to evaluate the efficacy, safety, and pharmacokinetics of liposome bupivacaine (155, 199, or 310 mg) in comparison with bupivacaine HCl 125 mg for ankle nerve block in patients undergoing bunionectomy (N = 58).⁷⁰ The study medication was injected into 3 sites to reach the posterior tibial, sural, deep peroneal, superficial peroneal, and saphenous nerves. Pharmacokinetic exposure was higher for liposome bupivacaine than for bupivacaine HCl, as reflected by a significantly greater area under the curve, lower C_max (maximum serum concentration), and longer mean half-life. Mean pain intensity scores were lower in the bupivacaine HCl group than in each liposome bupivacaine group the first 12 hours after surgery. However, the liposome bupivacaine 310-mg group had similar or lower scores than the bupivacaine HCl group from 12 to 96 hours after surgery. The most common AEs in the liposome bupivacaine group were gastrointestinal and not treatment-related.⁷⁰

The efficacy and safety of liposome bupivacaine, administered as a femoral nerve block for postsurgical analgesia, were assessed in a phase 2/3 manufacturer-sponsored, placebo-controlled, multicenter, randomized, double-blind 2-part study (NCT01683071)⁷¹ in 280 TKA patients.^71,72 Part 2 of the study, comparing liposome bupivacaine 266 mg (n = 116) and placebo (n = 116), met its primary endpoint, demonstrating statistical significance in favor of liposome bupivacaine for cumulative pain scores over 72 hours (P < .0001), with decreased opioid use (P < .05) and a safety profile similar to that of placebo.⁷²

Other ongoing investigator-sponsored studies in orthopedic populations include comparisons of liposome bupivacaine and bupivacaine HCl for ultrasound-guided periarticular hip infiltration in hip arthroplasty (NTC01917191),⁷³ as femoral nerve block in TKA (NCT01977339),⁷⁴ and as interscalene brachial plexus block in arthroscopic shoulder surgery (NCT01977352).⁷⁵ The primary efficacy outcome measure in these studies was postsurgical opioid use.^73-75

Health Economics

A series of phase 4 health economics studies was conducted for gastrointestinal surgeries, including open colectomy, laparoscopic colectomy, and ileostomy reversal.^53-56,76 These studies, of similar design, showed that a liposome bupivacaine–based multimodal analgesic regimen was associated with reduced opioid use, shorter hospital LOS, and lower hospitalization costs in comparison with a traditional opioid-based regimen.^53-56 Although pooled analysis of these studies showed a cost savings of more than $2000 per patient and an LOS decrease of 1.4 days,⁷⁶ all were conducted in the gastrointestinal surgery setting. Studies are needed to fully assess the economic benefits associated with liposome bupivacaine in the orthopedic surgery setting.

Conclusion

Liposome bupivacaine represents a potentially important contributor to multimodal analgesic regimens used to manage postsurgical pain. Liposome bupivacaine has demonstrated efficacy in providing prolonged postsurgical analgesia and reducing postsurgical opioid use in most surgical settings studied. Additional data from health economics studies in gastrointestinal surgery suggest liposome bupivacaine–based multimodal analgesic regimens may also contribute to reductions in hospital LOS and hospitalization costs. Non-industry-sponsored trials are needed to answer these crucial questions in orthopedic surgery settings. Nevertheless, data on the safety and efficacy of liposome bupivacaine for postsurgical analgesia continue to accumulate, and liposome bupivacaine appears to be a feasible therapeutic option for managing postsurgical pain in orthopedic surgery.

Approximately 5.5 million patients undergo orthopedic surgery in the United States each year, and more than 1 million of the procedures are total knee arthroplasty (TKA) or total hip arthroplasty.¹ From its 2010 level, demand for joint arthroplasty is expected to double by 2020 and quadruple by 2030.²

About half the patients who have major joint arthroplasty experience severe postsurgical pain.³ Because postsurgical pain may persist for days or weeks, and inadequate treatment is associated with negative outcomes, achieving effective postsurgical analgesia is an important consideration.^4-7 Complications of inadequate postsurgical pain management include thromboembolic or pulmonary complications, development of chronic pain, and decrements in health-related quality of life.^4,8

In patients who have orthopedic surgery, the inability to adequately control postsurgical pain has been associated with increased hospital length of stay (LOS), delayed time to ambulation, and reduced capacity for exercise.^9-12 A recent study involving 4709 patients who had hip or knee arthroplasty found that postsurgical pain relief was the second most highly correlated factor with respect to overall patient satisfaction (how well surgery met patient expectations was the most highly correlated factor),¹³ suggesting that postsurgical analgesia should be a focus of surgical practice.

A prolonged-release liposomal formulation of the local anesthetic bupivacaine is now available. Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is indicated for administration into the surgical site to produce postsurgical analgesia.¹⁴ In this article, we review evidence from clinical studies regarding the potential contribution of liposome bupivacaine to improving postsurgical pain management when used as part of a multimodal analgesic regimen in patients undergoing orthopedic surgery.

Postsurgical Pain Management in Orthopedic Surgery

Frequently Used Modalities

Analgesic modalities commonly used for perioperative pain management include central (eg, epidural),^4,10,15,16 central regional (eg, neuraxial),⁴ peripheral regional (eg, peripheral nerve blocks, local/regional surgical site infiltration, intra-articular administration),^{4,10,15,17-25} and intravenous (IV) patient-controlled analgesia.^4,10,25 These pharmacologic interventions may be augmented by nonpharmacologic modalities (eg, transcutaneous electrical nerve stimulation).²⁶

Pharmacologic treatment options for perioperative pain management include opioids, local anesthetics, clonidine, ketamine, nonsteroidal anti-inflammatory drugs, acetaminophen, and calcium-channel blockers.^4,26-28 In TKA, “drug cocktails” (eg, combinations of ropivacaine, ketorolac, epinephrine, and clonidine) for regional or intra-articular injection can also provide effective immediate postsurgical analgesia.²⁵ Although opioids are the most commonly used analgesics for management of orthopedic perioperative pain,²⁵ their use is often associated with adverse effects (AEs), including constipation or ileus, nausea, sedation, dizziness, pruritus, urinary retention, and respiratory depression.⁶

Multimodal Analgesic Regimens for Postsurgical Pain Management

Current American Society of Anesthesiologists guidelines endorse use of multimodal analgesia, whenever possible, to provide effective management of acute perioperative pain.⁴ Multimodal analgesia involves applying 2 or more agents with different mechanisms of action to achieve a synergistic effect, which allows each agent to be reduced in dose^4,28 and thereby may limit the risk and severity of dose-related AEs.^4,25,28

Multimodal analgesia aims to reduce the risk for opioid-related AEs (ORAEs) and the impact of opioids on postsurgical milestones (eg, ambulation, discharge) and may reduce opioid consumption, with attendant reductions in ORAE risk.^29,30 Health economics studies have shown that postsurgical ORAEs are associated with increased hospital costs and LOS.⁶ In a study using a national hospital database, development of an ORAE (vs no ORAE) in postsurgical patients was associated with mean increases of about $4700 in hospital costs and 3.3 days in LOS.⁷ Reducing postsurgical opioid use may also help reduce the risk for opioid abuse, addiction, and diversion.^31-33

One approach to reducing opioid use involves continuous or intermittent administration of local anesthetics by elastomeric pumps to extend duration of postsurgical analgesia.^34-36 However, use of elastomeric pumps has been associated with risk for AEs, including tissue necrosis, sloughing, wound infection, and chondrolysis.^37-40 In addition, AEs related to “dose dumping” (accidental delivery of excessive doses) have been reported.^40-44 Key issues that may negatively affect rehabilitation after orthopedic surgery include consistency and accuracy of analgesic delivery and the potential for motor block–induced muscle weakness, which may lead to falls and constrain ambulation.^45-47

Liposome Bupivacaine

Description

Drug Delivery Technology. Liposome bupivacaine incorporates DepoFoam drug delivery technology (Pacira Pharmaceuticals, Inc.) to facilitate prolonged release of bupivacaine. This technology is based on creation of multivesicular liposome particles (diameter, 10-30 µm) with multiple aqueous chambers.^30,48 After administration into the surgical site, bupivacaine diffuses from chambers in the liposomal particles over time, providing analgesia and reduced opioid requirements for up to 72 hours.^29,30

Indication, Mechanism of Action, Pharmacokinetics, and Dose/Administration. Liposome bupivacaine is indicated for single-dose administration into the surgical site to produce postsurgical analgesia in patients at least 18 years old.¹⁴ Like other local anesthetics, liposome bupivacaine is thought to exert its pharmacologic effects by interacting with voltage-gated Na⁺ channels on neural membranes to raise the threshold for electrical excitability, to slow nerve impulse propagation, and to reduce the rate of rise of the action potential.^14,49

Liposome bupivacaine has dose-proportional pharmacokinetics.⁵⁰ Presence of a small amount of extra-liposomal bupivacaine in the formulation leads to a bimodal pharmacokinetic profile, with an initial peak serum concentration about 1 hour after administration, followed by a second peak within 12 to 36 hours (Figure).⁵⁰

Maximum amount of liposome bupivacaine approved for single administration is 266 mg (packaged as 20 mL of a 1.3% solution). However, product labeling includes safety data associated with doses of 532 mg or less.¹⁴ The appropriate volume to be used should be based on the amount required to cover the surgical area. Liposome bupivacaine may be expanded with preservative-free normal (0.9%) sterile saline to a total volume of 300 mL: 20 mL liposome bupivacaine plus 280 mL or less diluent, with final concentration of 0.89 mg/mL (1:14 by volume).¹⁴

A 25-gauge or larger bore needle should be used to slowly inject liposome bupivacaine into soft tissues of the surgical site, with frequent aspiration to check for blood to minimize risk for intravascular injection.¹⁴ Total volume used and fraction injected in specific regions of the surgical site depend on the procedure. For example, a TKA study used 266 mg diluted to a total volume of 60 mL, with 8 mL infiltrated to the area around the medial capsule, 8 mL around the lateral capsule, 12 mL around the posterior capsule, 8 mL around the peripatellar area, 12 mL into the capsulotomy incision, and 12 mL into the subcutaneous tissue on each side of the incision.⁵¹

Efficacy

Multiple Surgical Settings. The efficacy of liposome bupivacaine, either alone or as a component of a multimodal analgesic regimen, has been evaluated in a series of 10 phase 2 and 3 studies (8 active-controlled, 2 placebo-controlled) involving 823 patients undergoing TKA, bunionectomy, hemorrhoidectomy, inguinal hernia repair, or mammoplasty.⁵² Patients received a single liposome bupivacaine dose ranging from 66 to 532 mg.⁵²

Combined analyses of efficacy data from these studies found that liposome bupivacaine–based multimodal analgesic regimens produced postsurgical analgesia for up to 72 hours, increased time to first use of opioid rescue medication after surgery, and reduced total amount of postsurgical opioid consumption versus placebo.⁵²

Compared with standard of care, liposome bupivacaine has been shown to provide effective analgesia in open-label studies in patients undergoing open colectomy,⁵³ laparoscopic colectomy,⁵⁴ and ileostomy reversal,^55,56 as reflected in assessments of postsurgical opioid consumption, LOS, and hospital costs. It has also been studied when administered by infiltration into the transversus abdominis plane (TAP) in patients having laparoscopic prostatectomy and open abdominal hernia repair.^57,58

Orthopedic Surgery. In a phase 2 randomized, double-blind, dose-ranging study, TKA patients (N = 138) received bupivacaine HCl 150 mg or liposome bupivacaine 133, 266, 399, or 532 mg administered by local infiltration into the capsulotomy incision and on either side of the incision before wound closure.⁵¹ Postsurgical rescue analgesia was available to all patients. Cumulative pain intensity scores with activity (primary efficacy measure) were not statistically different between liposome bupivacaine groups and the bupivacaine HCl group through postoperative day 4. Mean scores in the liposome bupivacaine 266-, 399-, and 532-mg groups were numerically lower than for those treated with bupivacaine HCl on postoperative days 2 to 5, with all doses of liposome bupivacaine having a statistically significant lower pain score at rest on day 5. There were no statistically significant differences across treatment groups with respect to total amount of postsurgical opioids used.

In a phase 3 randomized, double-blind study of TKA patients (N = 245), liposome bupivacaine 532 mg administered into the surgical site was compared with bupivacaine HCl 200 mg for postsurgical analgesia.⁵² Rescue analgesia was available to all patients. No statistically significant between-group differences were found with respect to postsurgical cumulative pain scores through 72 hours (primary efficacy endpoint).

In a single-center retrospective TKA study, postsurgical outcomes in a patient cohort that received intraoperative periarticular infiltration with liposome bupivacaine 266 mg (n = 65) were compared with a cohort that received infiltration with a combination of ropivacaine 400 mg, morphine 5 mg, and epinephrine 0.4 mg (n = 85).⁵⁹ Patient-reported postsurgical pain scores were similar in the 2 treatment groups during the first 24 hours after surgery and at discharge. Mean (SD) pain scores during hospitalization after the first 24 hours until discharge were significantly (P = .04) higher in the liposome bupivacaine group, 4.9 (1.4), than in the periarticular group, 4.4 (1.6). There was no significant difference between the 2 treatment groups in postsurgical opioid use. The study demonstrated no advantage to using liposome bupivacaine injections with respect to pain relief, but it was a retrospective review in which pain scores were obtained from electronic medical records. It is essential that liposome bupivacaine be compared with intra-articular injections in well-designed randomized trials.

Another single-center, matched-cohort TKA study (N = 200) compared a liposome bupivacaine regimen with femoral nerve block.⁶⁰ Compared with patients who received femoral nerve block, patients who received liposome bupivacaine reported lower pain intensity scores after surgery and had shorter LOS, reduced costs, and improved knee flexion at follow-up.⁶⁰

Results from 2 other studies were presented at the 2014 meeting of the American Academy of Orthopaedic Surgeons (AAOS). One was a single-center, matched-cohort TKA study (N = 72) comparing infiltration of a single dose of liposome bupivacaine into the surgical site with continuous femoral nerve block.⁶¹ The 2 treatment groups had similar mean postsurgical pain intensity scores on a 0-to-10 visual analog scale, 1.8 for liposome bupivacaine and 2.3 for continuous nerve block (P = NS), but total amount of postsurgical opioids (hydrocodone-equivalent milligrams) was significantly (P < .0001) less in the liposome bupivacaine group (82 vs 177 mg).

The other study presented at the AAOS meeting was a larger, prospective case–control study comparing outcomes between 1000 patients who had total joint arthroplasty (TJA) with liposome bupivacaine and 1000 control patients who had TJA without liposome bupivacaine.⁶² For the control and liposome bupivacaine cohorts, respectively, mean postsurgical pain intensity scores were 2.41 and 1.98 (P < .0001), mean LOS was 2.83 days and 2.66 days (P < .02), and incidence of falls was 1.0% and 0.2% (P = .02). Average per-patient costs were $1246 lower in the liposome bupivacaine cohort.

A pivotal phase 3 placebo-controlled study compared liposome bupivacaine 106 mg with placebo in patients undergoing bunionectomy (N = 193).⁵ Rescue medication was available to all patients. Cumulative pain scores were significantly (P = .0005) lower in the liposome bupivacaine group (125) than in the placebo group (146) through 24 hours after surgery (primary efficacy measure) and significantly (P = .0229) lower (197 vs 220) through 36 hours. Median time to first use of rescue opioids was delayed in favor of the liposome bupivacaine group (7.2 vs 4.3 hours; P < .0001). Mean total number of opioid tablets used within 24 hours after surgery was also significantly lower (3.8 vs 4.7; P = .008), and a larger percentage of patients in the liposome bupivacaine group avoided opioid use altogether through 24 hours (7% vs 1%; P = .04).

Efficacy data for liposome bupivacaine appear promising for relief of pain after joint arthroplasty and other orthopedic procedures but have their limitations. First, no randomized trials have compared liposome bupivacaine with locally injected pain medications (intra-articular injections in TKA or hip arthroplasty). As these injections are quite common now, such analyses are essential. Second, cost-effectiveness studies are needed for orthopedic procedures. Third, most of the published studies were sponsored by the manufacturer of liposome bupivacaine—a situation that raises questions about potential bias. Non-industry-sponsored randomized trials assessing efficacy, safety, and cost-effectiveness are needed.

Safety

Local anesthetics, including liposome bupivacaine, have the potential for central nervous system (CNS) or cardiac toxicity resulting from excessive systemic absorption or inadvertent IV administration.⁶³ However, reported serious CNS or cardiac-related AEs are rare.^63,64

AE Profile. Safety data from 10 phase 2 and 3 studies involving 823 patients who received liposome bupivacaine were evaluated.⁶⁵ Of these patients, 545 received a dose of 266 mg or less (maximum dose approved by the US Food and Drug Administration [FDA]). Liposome bupivacaine was generally well tolerated. Reported AE incidence was 62% (liposome bupivacaine), 75% (bupivacaine HCl), and 43% (placebo). More than 90% of reported AEs were mild or moderate. The most frequently reported AEs were nausea, constipation, and vomiting (liposome bupivacaine, bupivacaine HCl) and nausea, dizziness, and vomiting (placebo).

Serious AEs were reported in 22 (2.7%) of the 823 patients in the liposome bupivacaine group, 24 (5.4%) of the 446 in the bupivacaine HCl group, and 2 (1.1%) of the 190 in the placebo group.⁶⁵ None of the serious AEs in the liposome bupivacaine and placebo groups were considered treatment-related. Six patients in the bupivacaine HCl group had treatment-related serious AEs (hypoglycemia, arthrofibrosis, hemarthrosis, joint swelling, scar, knee arthroplasty).

Cardiac Safety. Possible cardiac effects associated with liposome bupivacaine were evaluated with data from studies conducted during the clinical development program.⁶⁶ One hundred thirty-eight patients participated in the phase 2 safety and efficacy study in TKA. In these patients, a consistent change in mean heart rate (range, +12.2 to +16.5 beats per minute) was found across all liposome bupivacaine doses and with bupivacaine HCl. No clinically relevant changes from baseline in mean electrocardiographic parameters, including QTcF interval (QT interval adjusted using Fridericia’s correction formula), were found. In another analysis,⁶⁷ liposome bupivacaine administered in a single subcutaneous dose (266, 399, 532, or 665 mg) to healthy volunteers did not prolong (vs placebo) QTc interval.

Wound Healing. The potential effects of liposome bupivacaine on wound healing were evaluated with results from 10 phase 2 and 3 studies.⁶⁸ The assessments, which varied across studies, included clinicians’ overall satisfaction with patient wound healing, wound status assessment (categories included erythema, drainage, edema, and induration), and wound scarring (categories included pigmentation, height, pliability, and vascularity). Clinician-assessed scores reflected high satisfaction with wound healing overall. There were few statistically significant differences in wound status assessments between liposome bupivacaine and the comparators and no statistically significant differences in scarring between liposome bupivacaine and bupivacaine HCl.

The potential of liposome bupivacaine to have adverse intra-articular effects was assessed with drainage samples from patients (n = 23) who had TKA and received liposome bupivacaine (133, 266, 399, or 532 mg) or bupivacaine HCl (150 mg) by wound infiltration near the intra-articular space.^51,65 Only small amounts of bupivacaine were present in drainage fluid collected for 12 hours after liposome bupivacaine administration, comparable to bupivacaine HCl administration.⁶⁵ Currently, the product is not approved for intra-articular use.

Compatibility With Diluents, Other Medications, and Implant Materials

Liposome bupivacaine may be expanded up to a ratio of 1:14 by volume (to a final total volume of 300 mL or a concentration of 0.89 mg/mL) using preservative-free normal (0.9%) sterile saline for injection.¹⁴ It has also been shown in vitro to be compatible with lactated Ringer solution as a diluent.⁶⁹

Liposome bupivacaine should not be admixed with other medications before administration.¹⁴ No formal drug–drug interaction studies have been conducted with liposome bupivacaine, but it has been shown in vitro to be compatible with epinephrine solutions, with certain anti-infective medications (eg, bacitracin, gentamicin, cefazolin, cefuroxime), with certain analgesics (eg, ketorolac, morphine), with an antihypertensive medication (clonidine), with an antihemorrhagic medication (tranexamic acid), and with certain corticosteroids (eg, methylprednisolone, triamcinolone acetonide). These medications may be coadministered in the same location as liposome bupivacaine.⁶⁹

Topical antiseptics (eg, povidone iodine) may be used in surgical procedures involving liposome bupivacaine as long as they are not directly mixed with liposome bupivacaine and are allowed to dry before it is administered. If a topical antiseptic is used for wound irrigation, the wound should be rinsed clear before liposome bupivacaine administration.^14,69

Liposome bupivacaine may be coadministered into the same surgical site immediately after bupivacaine HCl as long as the dose ratio of liposome bupivacaine to bupivacaine HCl is 2:1 or higher. Because of the prolonged-release pharmacokinetic profile of liposome bupivacaine and the potential for increased bupivacaine exposure, bupivacaine HCl should not be administered within 96 hours after administration of liposome bupivacaine.^14,69

In vitro coincubation studies of liposome bupivacaine and other local anesthetics, including ropivacaine, lidocaine, and mepivacaine, have found rapid release of free bupivacaine from the liposome matrix. Therefore, after giving any of these other local anesthetics, surgeons should wait at least 20 minutes before administering liposome bupivacaine into the same area.^14,69

In vitro studies have shown that liposome bupivacaine is compatible with a wide range of commonly used implant materials, including polypropylene, expanded polytetrafluoroethylene, stainless steel, titanium, and smooth- and textured-type silicone.⁶⁹

Investigational Use and Ongoing Studies

A phase 2 randomized, double-masked, dose-escalating/deescalating study was conducted to evaluate the efficacy, safety, and pharmacokinetics of liposome bupivacaine (155, 199, or 310 mg) in comparison with bupivacaine HCl 125 mg for ankle nerve block in patients undergoing bunionectomy (N = 58).⁷⁰ The study medication was injected into 3 sites to reach the posterior tibial, sural, deep peroneal, superficial peroneal, and saphenous nerves. Pharmacokinetic exposure was higher for liposome bupivacaine than for bupivacaine HCl, as reflected by a significantly greater area under the curve, lower C_max (maximum serum concentration), and longer mean half-life. Mean pain intensity scores were lower in the bupivacaine HCl group than in each liposome bupivacaine group the first 12 hours after surgery. However, the liposome bupivacaine 310-mg group had similar or lower scores than the bupivacaine HCl group from 12 to 96 hours after surgery. The most common AEs in the liposome bupivacaine group were gastrointestinal and not treatment-related.⁷⁰

The efficacy and safety of liposome bupivacaine, administered as a femoral nerve block for postsurgical analgesia, were assessed in a phase 2/3 manufacturer-sponsored, placebo-controlled, multicenter, randomized, double-blind 2-part study (NCT01683071)⁷¹ in 280 TKA patients.^71,72 Part 2 of the study, comparing liposome bupivacaine 266 mg (n = 116) and placebo (n = 116), met its primary endpoint, demonstrating statistical significance in favor of liposome bupivacaine for cumulative pain scores over 72 hours (P < .0001), with decreased opioid use (P < .05) and a safety profile similar to that of placebo.⁷²

Other ongoing investigator-sponsored studies in orthopedic populations include comparisons of liposome bupivacaine and bupivacaine HCl for ultrasound-guided periarticular hip infiltration in hip arthroplasty (NTC01917191),⁷³ as femoral nerve block in TKA (NCT01977339),⁷⁴ and as interscalene brachial plexus block in arthroscopic shoulder surgery (NCT01977352).⁷⁵ The primary efficacy outcome measure in these studies was postsurgical opioid use.^73-75

Health Economics

A series of phase 4 health economics studies was conducted for gastrointestinal surgeries, including open colectomy, laparoscopic colectomy, and ileostomy reversal.^53-56,76 These studies, of similar design, showed that a liposome bupivacaine–based multimodal analgesic regimen was associated with reduced opioid use, shorter hospital LOS, and lower hospitalization costs in comparison with a traditional opioid-based regimen.^53-56 Although pooled analysis of these studies showed a cost savings of more than $2000 per patient and an LOS decrease of 1.4 days,⁷⁶ all were conducted in the gastrointestinal surgery setting. Studies are needed to fully assess the economic benefits associated with liposome bupivacaine in the orthopedic surgery setting.

Conclusion

Liposome bupivacaine represents a potentially important contributor to multimodal analgesic regimens used to manage postsurgical pain. Liposome bupivacaine has demonstrated efficacy in providing prolonged postsurgical analgesia and reducing postsurgical opioid use in most surgical settings studied. Additional data from health economics studies in gastrointestinal surgery suggest liposome bupivacaine–based multimodal analgesic regimens may also contribute to reductions in hospital LOS and hospitalization costs. Non-industry-sponsored trials are needed to answer these crucial questions in orthopedic surgery settings. Nevertheless, data on the safety and efficacy of liposome bupivacaine for postsurgical analgesia continue to accumulate, and liposome bupivacaine appears to be a feasible therapeutic option for managing postsurgical pain in orthopedic surgery.

Approximately 5.5 million patients undergo orthopedic surgery in the United States each year, and more than 1 million of the procedures are total knee arthroplasty (TKA) or total hip arthroplasty.¹ From its 2010 level, demand for joint arthroplasty is expected to double by 2020 and quadruple by 2030.²

About half the patients who have major joint arthroplasty experience severe postsurgical pain.³ Because postsurgical pain may persist for days or weeks, and inadequate treatment is associated with negative outcomes, achieving effective postsurgical analgesia is an important consideration.^4-7 Complications of inadequate postsurgical pain management include thromboembolic or pulmonary complications, development of chronic pain, and decrements in health-related quality of life.^4,8

In patients who have orthopedic surgery, the inability to adequately control postsurgical pain has been associated with increased hospital length of stay (LOS), delayed time to ambulation, and reduced capacity for exercise.^9-12 A recent study involving 4709 patients who had hip or knee arthroplasty found that postsurgical pain relief was the second most highly correlated factor with respect to overall patient satisfaction (how well surgery met patient expectations was the most highly correlated factor),¹³ suggesting that postsurgical analgesia should be a focus of surgical practice.

A prolonged-release liposomal formulation of the local anesthetic bupivacaine is now available. Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is indicated for administration into the surgical site to produce postsurgical analgesia.¹⁴ In this article, we review evidence from clinical studies regarding the potential contribution of liposome bupivacaine to improving postsurgical pain management when used as part of a multimodal analgesic regimen in patients undergoing orthopedic surgery.

Postsurgical Pain Management in Orthopedic Surgery

Frequently Used Modalities

Analgesic modalities commonly used for perioperative pain management include central (eg, epidural),^4,10,15,16 central regional (eg, neuraxial),⁴ peripheral regional (eg, peripheral nerve blocks, local/regional surgical site infiltration, intra-articular administration),^{4,10,15,17-25} and intravenous (IV) patient-controlled analgesia.^4,10,25 These pharmacologic interventions may be augmented by nonpharmacologic modalities (eg, transcutaneous electrical nerve stimulation).²⁶

Pharmacologic treatment options for perioperative pain management include opioids, local anesthetics, clonidine, ketamine, nonsteroidal anti-inflammatory drugs, acetaminophen, and calcium-channel blockers.^4,26-28 In TKA, “drug cocktails” (eg, combinations of ropivacaine, ketorolac, epinephrine, and clonidine) for regional or intra-articular injection can also provide effective immediate postsurgical analgesia.²⁵ Although opioids are the most commonly used analgesics for management of orthopedic perioperative pain,²⁵ their use is often associated with adverse effects (AEs), including constipation or ileus, nausea, sedation, dizziness, pruritus, urinary retention, and respiratory depression.⁶

Multimodal Analgesic Regimens for Postsurgical Pain Management

Current American Society of Anesthesiologists guidelines endorse use of multimodal analgesia, whenever possible, to provide effective management of acute perioperative pain.⁴ Multimodal analgesia involves applying 2 or more agents with different mechanisms of action to achieve a synergistic effect, which allows each agent to be reduced in dose^4,28 and thereby may limit the risk and severity of dose-related AEs.^4,25,28

Multimodal analgesia aims to reduce the risk for opioid-related AEs (ORAEs) and the impact of opioids on postsurgical milestones (eg, ambulation, discharge) and may reduce opioid consumption, with attendant reductions in ORAE risk.^29,30 Health economics studies have shown that postsurgical ORAEs are associated with increased hospital costs and LOS.⁶ In a study using a national hospital database, development of an ORAE (vs no ORAE) in postsurgical patients was associated with mean increases of about $4700 in hospital costs and 3.3 days in LOS.⁷ Reducing postsurgical opioid use may also help reduce the risk for opioid abuse, addiction, and diversion.^31-33

One approach to reducing opioid use involves continuous or intermittent administration of local anesthetics by elastomeric pumps to extend duration of postsurgical analgesia.^34-36 However, use of elastomeric pumps has been associated with risk for AEs, including tissue necrosis, sloughing, wound infection, and chondrolysis.^37-40 In addition, AEs related to “dose dumping” (accidental delivery of excessive doses) have been reported.^40-44 Key issues that may negatively affect rehabilitation after orthopedic surgery include consistency and accuracy of analgesic delivery and the potential for motor block–induced muscle weakness, which may lead to falls and constrain ambulation.^45-47

Liposome Bupivacaine

Description

Drug Delivery Technology. Liposome bupivacaine incorporates DepoFoam drug delivery technology (Pacira Pharmaceuticals, Inc.) to facilitate prolonged release of bupivacaine. This technology is based on creation of multivesicular liposome particles (diameter, 10-30 µm) with multiple aqueous chambers.^30,48 After administration into the surgical site, bupivacaine diffuses from chambers in the liposomal particles over time, providing analgesia and reduced opioid requirements for up to 72 hours.^29,30

Indication, Mechanism of Action, Pharmacokinetics, and Dose/Administration. Liposome bupivacaine is indicated for single-dose administration into the surgical site to produce postsurgical analgesia in patients at least 18 years old.¹⁴ Like other local anesthetics, liposome bupivacaine is thought to exert its pharmacologic effects by interacting with voltage-gated Na⁺ channels on neural membranes to raise the threshold for electrical excitability, to slow nerve impulse propagation, and to reduce the rate of rise of the action potential.^14,49

Liposome bupivacaine has dose-proportional pharmacokinetics.⁵⁰ Presence of a small amount of extra-liposomal bupivacaine in the formulation leads to a bimodal pharmacokinetic profile, with an initial peak serum concentration about 1 hour after administration, followed by a second peak within 12 to 36 hours (Figure).⁵⁰

Maximum amount of liposome bupivacaine approved for single administration is 266 mg (packaged as 20 mL of a 1.3% solution). However, product labeling includes safety data associated with doses of 532 mg or less.¹⁴ The appropriate volume to be used should be based on the amount required to cover the surgical area. Liposome bupivacaine may be expanded with preservative-free normal (0.9%) sterile saline to a total volume of 300 mL: 20 mL liposome bupivacaine plus 280 mL or less diluent, with final concentration of 0.89 mg/mL (1:14 by volume).¹⁴

A 25-gauge or larger bore needle should be used to slowly inject liposome bupivacaine into soft tissues of the surgical site, with frequent aspiration to check for blood to minimize risk for intravascular injection.¹⁴ Total volume used and fraction injected in specific regions of the surgical site depend on the procedure. For example, a TKA study used 266 mg diluted to a total volume of 60 mL, with 8 mL infiltrated to the area around the medial capsule, 8 mL around the lateral capsule, 12 mL around the posterior capsule, 8 mL around the peripatellar area, 12 mL into the capsulotomy incision, and 12 mL into the subcutaneous tissue on each side of the incision.⁵¹

Efficacy

Multiple Surgical Settings. The efficacy of liposome bupivacaine, either alone or as a component of a multimodal analgesic regimen, has been evaluated in a series of 10 phase 2 and 3 studies (8 active-controlled, 2 placebo-controlled) involving 823 patients undergoing TKA, bunionectomy, hemorrhoidectomy, inguinal hernia repair, or mammoplasty.⁵² Patients received a single liposome bupivacaine dose ranging from 66 to 532 mg.⁵²

Combined analyses of efficacy data from these studies found that liposome bupivacaine–based multimodal analgesic regimens produced postsurgical analgesia for up to 72 hours, increased time to first use of opioid rescue medication after surgery, and reduced total amount of postsurgical opioid consumption versus placebo.⁵²

Compared with standard of care, liposome bupivacaine has been shown to provide effective analgesia in open-label studies in patients undergoing open colectomy,⁵³ laparoscopic colectomy,⁵⁴ and ileostomy reversal,^55,56 as reflected in assessments of postsurgical opioid consumption, LOS, and hospital costs. It has also been studied when administered by infiltration into the transversus abdominis plane (TAP) in patients having laparoscopic prostatectomy and open abdominal hernia repair.^57,58

Orthopedic Surgery. In a phase 2 randomized, double-blind, dose-ranging study, TKA patients (N = 138) received bupivacaine HCl 150 mg or liposome bupivacaine 133, 266, 399, or 532 mg administered by local infiltration into the capsulotomy incision and on either side of the incision before wound closure.⁵¹ Postsurgical rescue analgesia was available to all patients. Cumulative pain intensity scores with activity (primary efficacy measure) were not statistically different between liposome bupivacaine groups and the bupivacaine HCl group through postoperative day 4. Mean scores in the liposome bupivacaine 266-, 399-, and 532-mg groups were numerically lower than for those treated with bupivacaine HCl on postoperative days 2 to 5, with all doses of liposome bupivacaine having a statistically significant lower pain score at rest on day 5. There were no statistically significant differences across treatment groups with respect to total amount of postsurgical opioids used.

In a phase 3 randomized, double-blind study of TKA patients (N = 245), liposome bupivacaine 532 mg administered into the surgical site was compared with bupivacaine HCl 200 mg for postsurgical analgesia.⁵² Rescue analgesia was available to all patients. No statistically significant between-group differences were found with respect to postsurgical cumulative pain scores through 72 hours (primary efficacy endpoint).

In a single-center retrospective TKA study, postsurgical outcomes in a patient cohort that received intraoperative periarticular infiltration with liposome bupivacaine 266 mg (n = 65) were compared with a cohort that received infiltration with a combination of ropivacaine 400 mg, morphine 5 mg, and epinephrine 0.4 mg (n = 85).⁵⁹ Patient-reported postsurgical pain scores were similar in the 2 treatment groups during the first 24 hours after surgery and at discharge. Mean (SD) pain scores during hospitalization after the first 24 hours until discharge were significantly (P = .04) higher in the liposome bupivacaine group, 4.9 (1.4), than in the periarticular group, 4.4 (1.6). There was no significant difference between the 2 treatment groups in postsurgical opioid use. The study demonstrated no advantage to using liposome bupivacaine injections with respect to pain relief, but it was a retrospective review in which pain scores were obtained from electronic medical records. It is essential that liposome bupivacaine be compared with intra-articular injections in well-designed randomized trials.

Another single-center, matched-cohort TKA study (N = 200) compared a liposome bupivacaine regimen with femoral nerve block.⁶⁰ Compared with patients who received femoral nerve block, patients who received liposome bupivacaine reported lower pain intensity scores after surgery and had shorter LOS, reduced costs, and improved knee flexion at follow-up.⁶⁰

Results from 2 other studies were presented at the 2014 meeting of the American Academy of Orthopaedic Surgeons (AAOS). One was a single-center, matched-cohort TKA study (N = 72) comparing infiltration of a single dose of liposome bupivacaine into the surgical site with continuous femoral nerve block.⁶¹ The 2 treatment groups had similar mean postsurgical pain intensity scores on a 0-to-10 visual analog scale, 1.8 for liposome bupivacaine and 2.3 for continuous nerve block (P = NS), but total amount of postsurgical opioids (hydrocodone-equivalent milligrams) was significantly (P < .0001) less in the liposome bupivacaine group (82 vs 177 mg).

The other study presented at the AAOS meeting was a larger, prospective case–control study comparing outcomes between 1000 patients who had total joint arthroplasty (TJA) with liposome bupivacaine and 1000 control patients who had TJA without liposome bupivacaine.⁶² For the control and liposome bupivacaine cohorts, respectively, mean postsurgical pain intensity scores were 2.41 and 1.98 (P < .0001), mean LOS was 2.83 days and 2.66 days (P < .02), and incidence of falls was 1.0% and 0.2% (P = .02). Average per-patient costs were $1246 lower in the liposome bupivacaine cohort.

A pivotal phase 3 placebo-controlled study compared liposome bupivacaine 106 mg with placebo in patients undergoing bunionectomy (N = 193).⁵ Rescue medication was available to all patients. Cumulative pain scores were significantly (P = .0005) lower in the liposome bupivacaine group (125) than in the placebo group (146) through 24 hours after surgery (primary efficacy measure) and significantly (P = .0229) lower (197 vs 220) through 36 hours. Median time to first use of rescue opioids was delayed in favor of the liposome bupivacaine group (7.2 vs 4.3 hours; P < .0001). Mean total number of opioid tablets used within 24 hours after surgery was also significantly lower (3.8 vs 4.7; P = .008), and a larger percentage of patients in the liposome bupivacaine group avoided opioid use altogether through 24 hours (7% vs 1%; P = .04).

Efficacy data for liposome bupivacaine appear promising for relief of pain after joint arthroplasty and other orthopedic procedures but have their limitations. First, no randomized trials have compared liposome bupivacaine with locally injected pain medications (intra-articular injections in TKA or hip arthroplasty). As these injections are quite common now, such analyses are essential. Second, cost-effectiveness studies are needed for orthopedic procedures. Third, most of the published studies were sponsored by the manufacturer of liposome bupivacaine—a situation that raises questions about potential bias. Non-industry-sponsored randomized trials assessing efficacy, safety, and cost-effectiveness are needed.

Safety

Local anesthetics, including liposome bupivacaine, have the potential for central nervous system (CNS) or cardiac toxicity resulting from excessive systemic absorption or inadvertent IV administration.⁶³ However, reported serious CNS or cardiac-related AEs are rare.^63,64

AE Profile. Safety data from 10 phase 2 and 3 studies involving 823 patients who received liposome bupivacaine were evaluated.⁶⁵ Of these patients, 545 received a dose of 266 mg or less (maximum dose approved by the US Food and Drug Administration [FDA]). Liposome bupivacaine was generally well tolerated. Reported AE incidence was 62% (liposome bupivacaine), 75% (bupivacaine HCl), and 43% (placebo). More than 90% of reported AEs were mild or moderate. The most frequently reported AEs were nausea, constipation, and vomiting (liposome bupivacaine, bupivacaine HCl) and nausea, dizziness, and vomiting (placebo).

Serious AEs were reported in 22 (2.7%) of the 823 patients in the liposome bupivacaine group, 24 (5.4%) of the 446 in the bupivacaine HCl group, and 2 (1.1%) of the 190 in the placebo group.⁶⁵ None of the serious AEs in the liposome bupivacaine and placebo groups were considered treatment-related. Six patients in the bupivacaine HCl group had treatment-related serious AEs (hypoglycemia, arthrofibrosis, hemarthrosis, joint swelling, scar, knee arthroplasty).

Cardiac Safety. Possible cardiac effects associated with liposome bupivacaine were evaluated with data from studies conducted during the clinical development program.⁶⁶ One hundred thirty-eight patients participated in the phase 2 safety and efficacy study in TKA. In these patients, a consistent change in mean heart rate (range, +12.2 to +16.5 beats per minute) was found across all liposome bupivacaine doses and with bupivacaine HCl. No clinically relevant changes from baseline in mean electrocardiographic parameters, including QTcF interval (QT interval adjusted using Fridericia’s correction formula), were found. In another analysis,⁶⁷ liposome bupivacaine administered in a single subcutaneous dose (266, 399, 532, or 665 mg) to healthy volunteers did not prolong (vs placebo) QTc interval.

Wound Healing. The potential effects of liposome bupivacaine on wound healing were evaluated with results from 10 phase 2 and 3 studies.⁶⁸ The assessments, which varied across studies, included clinicians’ overall satisfaction with patient wound healing, wound status assessment (categories included erythema, drainage, edema, and induration), and wound scarring (categories included pigmentation, height, pliability, and vascularity). Clinician-assessed scores reflected high satisfaction with wound healing overall. There were few statistically significant differences in wound status assessments between liposome bupivacaine and the comparators and no statistically significant differences in scarring between liposome bupivacaine and bupivacaine HCl.

The potential of liposome bupivacaine to have adverse intra-articular effects was assessed with drainage samples from patients (n = 23) who had TKA and received liposome bupivacaine (133, 266, 399, or 532 mg) or bupivacaine HCl (150 mg) by wound infiltration near the intra-articular space.^51,65 Only small amounts of bupivacaine were present in drainage fluid collected for 12 hours after liposome bupivacaine administration, comparable to bupivacaine HCl administration.⁶⁵ Currently, the product is not approved for intra-articular use.

Compatibility With Diluents, Other Medications, and Implant Materials

Liposome bupivacaine may be expanded up to a ratio of 1:14 by volume (to a final total volume of 300 mL or a concentration of 0.89 mg/mL) using preservative-free normal (0.9%) sterile saline for injection.¹⁴ It has also been shown in vitro to be compatible with lactated Ringer solution as a diluent.⁶⁹

Liposome bupivacaine should not be admixed with other medications before administration.¹⁴ No formal drug–drug interaction studies have been conducted with liposome bupivacaine, but it has been shown in vitro to be compatible with epinephrine solutions, with certain anti-infective medications (eg, bacitracin, gentamicin, cefazolin, cefuroxime), with certain analgesics (eg, ketorolac, morphine), with an antihypertensive medication (clonidine), with an antihemorrhagic medication (tranexamic acid), and with certain corticosteroids (eg, methylprednisolone, triamcinolone acetonide). These medications may be coadministered in the same location as liposome bupivacaine.⁶⁹

Topical antiseptics (eg, povidone iodine) may be used in surgical procedures involving liposome bupivacaine as long as they are not directly mixed with liposome bupivacaine and are allowed to dry before it is administered. If a topical antiseptic is used for wound irrigation, the wound should be rinsed clear before liposome bupivacaine administration.^14,69

Liposome bupivacaine may be coadministered into the same surgical site immediately after bupivacaine HCl as long as the dose ratio of liposome bupivacaine to bupivacaine HCl is 2:1 or higher. Because of the prolonged-release pharmacokinetic profile of liposome bupivacaine and the potential for increased bupivacaine exposure, bupivacaine HCl should not be administered within 96 hours after administration of liposome bupivacaine.^14,69

In vitro coincubation studies of liposome bupivacaine and other local anesthetics, including ropivacaine, lidocaine, and mepivacaine, have found rapid release of free bupivacaine from the liposome matrix. Therefore, after giving any of these other local anesthetics, surgeons should wait at least 20 minutes before administering liposome bupivacaine into the same area.^14,69

In vitro studies have shown that liposome bupivacaine is compatible with a wide range of commonly used implant materials, including polypropylene, expanded polytetrafluoroethylene, stainless steel, titanium, and smooth- and textured-type silicone.⁶⁹

Investigational Use and Ongoing Studies

A phase 2 randomized, double-masked, dose-escalating/deescalating study was conducted to evaluate the efficacy, safety, and pharmacokinetics of liposome bupivacaine (155, 199, or 310 mg) in comparison with bupivacaine HCl 125 mg for ankle nerve block in patients undergoing bunionectomy (N = 58).⁷⁰ The study medication was injected into 3 sites to reach the posterior tibial, sural, deep peroneal, superficial peroneal, and saphenous nerves. Pharmacokinetic exposure was higher for liposome bupivacaine than for bupivacaine HCl, as reflected by a significantly greater area under the curve, lower C_max (maximum serum concentration), and longer mean half-life. Mean pain intensity scores were lower in the bupivacaine HCl group than in each liposome bupivacaine group the first 12 hours after surgery. However, the liposome bupivacaine 310-mg group had similar or lower scores than the bupivacaine HCl group from 12 to 96 hours after surgery. The most common AEs in the liposome bupivacaine group were gastrointestinal and not treatment-related.⁷⁰

The efficacy and safety of liposome bupivacaine, administered as a femoral nerve block for postsurgical analgesia, were assessed in a phase 2/3 manufacturer-sponsored, placebo-controlled, multicenter, randomized, double-blind 2-part study (NCT01683071)⁷¹ in 280 TKA patients.^71,72 Part 2 of the study, comparing liposome bupivacaine 266 mg (n = 116) and placebo (n = 116), met its primary endpoint, demonstrating statistical significance in favor of liposome bupivacaine for cumulative pain scores over 72 hours (P < .0001), with decreased opioid use (P < .05) and a safety profile similar to that of placebo.⁷²

Other ongoing investigator-sponsored studies in orthopedic populations include comparisons of liposome bupivacaine and bupivacaine HCl for ultrasound-guided periarticular hip infiltration in hip arthroplasty (NTC01917191),⁷³ as femoral nerve block in TKA (NCT01977339),⁷⁴ and as interscalene brachial plexus block in arthroscopic shoulder surgery (NCT01977352).⁷⁵ The primary efficacy outcome measure in these studies was postsurgical opioid use.^73-75

Health Economics

A series of phase 4 health economics studies was conducted for gastrointestinal surgeries, including open colectomy, laparoscopic colectomy, and ileostomy reversal.^53-56,76 These studies, of similar design, showed that a liposome bupivacaine–based multimodal analgesic regimen was associated with reduced opioid use, shorter hospital LOS, and lower hospitalization costs in comparison with a traditional opioid-based regimen.^53-56 Although pooled analysis of these studies showed a cost savings of more than $2000 per patient and an LOS decrease of 1.4 days,⁷⁶ all were conducted in the gastrointestinal surgery setting. Studies are needed to fully assess the economic benefits associated with liposome bupivacaine in the orthopedic surgery setting.

Conclusion

Liposome bupivacaine represents a potentially important contributor to multimodal analgesic regimens used to manage postsurgical pain. Liposome bupivacaine has demonstrated efficacy in providing prolonged postsurgical analgesia and reducing postsurgical opioid use in most surgical settings studied. Additional data from health economics studies in gastrointestinal surgery suggest liposome bupivacaine–based multimodal analgesic regimens may also contribute to reductions in hospital LOS and hospitalization costs. Non-industry-sponsored trials are needed to answer these crucial questions in orthopedic surgery settings. Nevertheless, data on the safety and efficacy of liposome bupivacaine for postsurgical analgesia continue to accumulate, and liposome bupivacaine appears to be a feasible therapeutic option for managing postsurgical pain in orthopedic surgery.

The combination of chondroitin sulfate plus glucosamine hydrochloride has comparable efficacy to the anti-inflammatory drug celecoxib after 6 months of treatment in severe osteoarthritis, according to a recent clinical trial published online ahead of print January 14 in Annals of the Rheumatic Diseases. Specifically, it was seen that the combination of these two drugs caused a clinically relevant reduction in pain, functional disability, stiffness, swelling, and joint effusion.

MOVES (Multicentre Osteoarthritis InterVEntion Trial with Sysadoa) is a multicenter, randomized, parallel-group, double-blind controlled clinical trial that enrolled 606 patients from at 42 centers in France, Germany, Poland, and Spain. The study was sponsored by Bioibérica, suppliers of the chondroitin sulfate used in Cosamin DS. The trial was developed as an extension of the GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial) study, which showed that the combination of 1,500 mg per day of glucosamine hydrochloride and 1,200 mg per day of chondroitin sulfate was effective in a moderate to severe subgroup of patients.

Patients with primary knee osteoarthritis and moderate to severe pain were randomized to receive 1,200 mg of chondroitin sulfate (400 mg/d tid) plus 1,500 mg of glucosamine hydrochloride (500 mg/d tid) or celecoxib (200 mg) every day for 6 months.

After 6 months, patients experienced the following:

• A reduction in pain by 50.1%.

• A reduction in swelling by 53%.

• A reduction in stiffness by 46.9%.

• A reduction in functional disability by 45.5%.

• A reduction in joint effusion by 56%.

“This study confirms the efficacy of the combination of pharmaceutical-grade chondroitin sulfate and glucosamine [hydrochloride] in the long term and suggests that, considering its excellent safety profile, it may be a good alternative for patients with cardiovascular or gastrointestinal problems, for whom chronic treatment with NSAIDs cannot be recommended,” said lead author Marc C. Hochberg, MD, MPH, a Professor at the University of Maryland School of Medicine in Baltimore.

The combination of chondroitin sulfate plus glucosamine hydrochloride has comparable efficacy to the anti-inflammatory drug celecoxib after 6 months of treatment in severe osteoarthritis, according to a recent clinical trial published online ahead of print January 14 in Annals of the Rheumatic Diseases. Specifically, it was seen that the combination of these two drugs caused a clinically relevant reduction in pain, functional disability, stiffness, swelling, and joint effusion.

MOVES (Multicentre Osteoarthritis InterVEntion Trial with Sysadoa) is a multicenter, randomized, parallel-group, double-blind controlled clinical trial that enrolled 606 patients from at 42 centers in France, Germany, Poland, and Spain. The study was sponsored by Bioibérica, suppliers of the chondroitin sulfate used in Cosamin DS. The trial was developed as an extension of the GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial) study, which showed that the combination of 1,500 mg per day of glucosamine hydrochloride and 1,200 mg per day of chondroitin sulfate was effective in a moderate to severe subgroup of patients.

Patients with primary knee osteoarthritis and moderate to severe pain were randomized to receive 1,200 mg of chondroitin sulfate (400 mg/d tid) plus 1,500 mg of glucosamine hydrochloride (500 mg/d tid) or celecoxib (200 mg) every day for 6 months.

After 6 months, patients experienced the following:

• A reduction in pain by 50.1%.

• A reduction in swelling by 53%.

• A reduction in stiffness by 46.9%.

• A reduction in functional disability by 45.5%.

• A reduction in joint effusion by 56%.

“This study confirms the efficacy of the combination of pharmaceutical-grade chondroitin sulfate and glucosamine [hydrochloride] in the long term and suggests that, considering its excellent safety profile, it may be a good alternative for patients with cardiovascular or gastrointestinal problems, for whom chronic treatment with NSAIDs cannot be recommended,” said lead author Marc C. Hochberg, MD, MPH, a Professor at the University of Maryland School of Medicine in Baltimore.

The combination of chondroitin sulfate plus glucosamine hydrochloride has comparable efficacy to the anti-inflammatory drug celecoxib after 6 months of treatment in severe osteoarthritis, according to a recent clinical trial published online ahead of print January 14 in Annals of the Rheumatic Diseases. Specifically, it was seen that the combination of these two drugs caused a clinically relevant reduction in pain, functional disability, stiffness, swelling, and joint effusion.

MOVES (Multicentre Osteoarthritis InterVEntion Trial with Sysadoa) is a multicenter, randomized, parallel-group, double-blind controlled clinical trial that enrolled 606 patients from at 42 centers in France, Germany, Poland, and Spain. The study was sponsored by Bioibérica, suppliers of the chondroitin sulfate used in Cosamin DS. The trial was developed as an extension of the GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial) study, which showed that the combination of 1,500 mg per day of glucosamine hydrochloride and 1,200 mg per day of chondroitin sulfate was effective in a moderate to severe subgroup of patients.

Patients with primary knee osteoarthritis and moderate to severe pain were randomized to receive 1,200 mg of chondroitin sulfate (400 mg/d tid) plus 1,500 mg of glucosamine hydrochloride (500 mg/d tid) or celecoxib (200 mg) every day for 6 months.

After 6 months, patients experienced the following:

• A reduction in pain by 50.1%.

• A reduction in swelling by 53%.

• A reduction in stiffness by 46.9%.

• A reduction in functional disability by 45.5%.

• A reduction in joint effusion by 56%.

“This study confirms the efficacy of the combination of pharmaceutical-grade chondroitin sulfate and glucosamine [hydrochloride] in the long term and suggests that, considering its excellent safety profile, it may be a good alternative for patients with cardiovascular or gastrointestinal problems, for whom chronic treatment with NSAIDs cannot be recommended,” said lead author Marc C. Hochberg, MD, MPH, a Professor at the University of Maryland School of Medicine in Baltimore.

A fluorescent probe may make it easier to diagnose and monitor osteoarthritis, according to a study published in the February issue of Arthritis & Rheumatology. Researchers found that a fluorescent probe tracked the development of osteoarthritis in male mice, brightening as the disease progressed. Their study is the first to demonstrate that near-infared fluorescence can be used to detect osteoarthritis changes over time.

“Patients are frequently in pain by the time osteoarthritis is diagnosed. The imaging tests most frequently used, x-rays, do not indicate the level of pain or allow us to directly see the amount of cartilage loss, which is a challenge for physicians and patients,” said lead author Averi A. Leahy, BA, an MD/PhD student in the medical scientist training program at Tufts University School of Medicine (TUSM) and the Sackler School of Graduate Biomedical Sciences at Tufts in Boston.

For this study, the right knees of 54 mice were affected by injury-induced osteoarthritis and served as the experimental group. The healthy left knees of the mice served as the control group.

Over a 2-month period, the researchers took images of each knee every 2 weeks to determine if the fluorescent probe emitted a signal. The signal became brighter in the injured right knee, at every examined time point, through the early to moderate stages of osteoarthritis. The probe emitted a lower signal in the healthy left knee, and did not increase significantly over time.

According to the researchers, the fluorescent probe made it easy to see the activities that lead to cartilage breakdown in the initial and moderate stages of osteoarthritis, which is necessary for early detection and adequate monitoring of the disease.

Senior author Li Zeng, PhD, an Associate Professor in the Department of Integrative Physiology and Pathobiology at TUSM and member of the cellular, molecular, and developmental biology program faculty at the Sackler School reported that the next step is to monitor the fluorescent probe over a longer period of time to determine whether the same results are produced during the late stages of osteoarthritis.

A fluorescent probe may make it easier to diagnose and monitor osteoarthritis, according to a study published in the February issue of Arthritis & Rheumatology. Researchers found that a fluorescent probe tracked the development of osteoarthritis in male mice, brightening as the disease progressed. Their study is the first to demonstrate that near-infared fluorescence can be used to detect osteoarthritis changes over time.

“Patients are frequently in pain by the time osteoarthritis is diagnosed. The imaging tests most frequently used, x-rays, do not indicate the level of pain or allow us to directly see the amount of cartilage loss, which is a challenge for physicians and patients,” said lead author Averi A. Leahy, BA, an MD/PhD student in the medical scientist training program at Tufts University School of Medicine (TUSM) and the Sackler School of Graduate Biomedical Sciences at Tufts in Boston.

For this study, the right knees of 54 mice were affected by injury-induced osteoarthritis and served as the experimental group. The healthy left knees of the mice served as the control group.

Over a 2-month period, the researchers took images of each knee every 2 weeks to determine if the fluorescent probe emitted a signal. The signal became brighter in the injured right knee, at every examined time point, through the early to moderate stages of osteoarthritis. The probe emitted a lower signal in the healthy left knee, and did not increase significantly over time.

According to the researchers, the fluorescent probe made it easy to see the activities that lead to cartilage breakdown in the initial and moderate stages of osteoarthritis, which is necessary for early detection and adequate monitoring of the disease.

Senior author Li Zeng, PhD, an Associate Professor in the Department of Integrative Physiology and Pathobiology at TUSM and member of the cellular, molecular, and developmental biology program faculty at the Sackler School reported that the next step is to monitor the fluorescent probe over a longer period of time to determine whether the same results are produced during the late stages of osteoarthritis.

A fluorescent probe may make it easier to diagnose and monitor osteoarthritis, according to a study published in the February issue of Arthritis & Rheumatology. Researchers found that a fluorescent probe tracked the development of osteoarthritis in male mice, brightening as the disease progressed. Their study is the first to demonstrate that near-infared fluorescence can be used to detect osteoarthritis changes over time.

“Patients are frequently in pain by the time osteoarthritis is diagnosed. The imaging tests most frequently used, x-rays, do not indicate the level of pain or allow us to directly see the amount of cartilage loss, which is a challenge for physicians and patients,” said lead author Averi A. Leahy, BA, an MD/PhD student in the medical scientist training program at Tufts University School of Medicine (TUSM) and the Sackler School of Graduate Biomedical Sciences at Tufts in Boston.

For this study, the right knees of 54 mice were affected by injury-induced osteoarthritis and served as the experimental group. The healthy left knees of the mice served as the control group.

Over a 2-month period, the researchers took images of each knee every 2 weeks to determine if the fluorescent probe emitted a signal. The signal became brighter in the injured right knee, at every examined time point, through the early to moderate stages of osteoarthritis. The probe emitted a lower signal in the healthy left knee, and did not increase significantly over time.

According to the researchers, the fluorescent probe made it easy to see the activities that lead to cartilage breakdown in the initial and moderate stages of osteoarthritis, which is necessary for early detection and adequate monitoring of the disease.

Senior author Li Zeng, PhD, an Associate Professor in the Department of Integrative Physiology and Pathobiology at TUSM and member of the cellular, molecular, and developmental biology program faculty at the Sackler School reported that the next step is to monitor the fluorescent probe over a longer period of time to determine whether the same results are produced during the late stages of osteoarthritis.

New research reveals the physical and psychosocial factors that significantly increase the risk of low back pain onset. The trial results, which were published online ahead of print February 9 in Arthritis Care & Research, show that being engaged in manual tasks involving awkward positions will increase the risk of low back pain by 8 times. People who are distracted during activities or fatigued also significantly increase their risk of acute low back pain.

“Understanding which risk factors contribute to back pain and controlling exposure to these risks is an important first step in prevention,” said Manuela Ferreira, PhD, Associate Professor at the George Institute for Global Health and Sydney Medical School at the University of Sydney in New South Wales, Australia. “Our study is the first to examine brief exposure to a range of modifiable triggers for an acute episode of low back pain.”

For this case-crossover study, Dr. Ferreira and colleagues recruited 999 participants from 300 primary care clinics in Sydney, Australia, who had an acute low back pain episode between October 2011 and November 2012. Participants were asked to report exposure to 12 physical or psychosocial factors in the 96 hours prior to the onset of back pain.

The study found that:

• The risk of a new episode of low back pain significantly increased due to a range of triggers, from an odds ratio of 2.7 for moderate to vigorous physical activity to 25.0 for distraction during an activity.

• Back pain risk was highest between 7:00 am and at noontime.

• Age moderated the effect of exposure to heavy loads, with an odds ratio for individuals age 20, 40, or 60 at 13.6, 6.0, and 2.7, respectively.

“Understanding which modifiable risk factors lead to low back pain is an important step toward controlling a condition that affects so many worldwide,” said Dr. Ferreira. “Our findings enhance knowledge of low back pain triggers and will assist the development of new prevention programs that can reduce suffering from this potentially disabling condition.”

New research reveals the physical and psychosocial factors that significantly increase the risk of low back pain onset. The trial results, which were published online ahead of print February 9 in Arthritis Care & Research, show that being engaged in manual tasks involving awkward positions will increase the risk of low back pain by 8 times. People who are distracted during activities or fatigued also significantly increase their risk of acute low back pain.

“Understanding which risk factors contribute to back pain and controlling exposure to these risks is an important first step in prevention,” said Manuela Ferreira, PhD, Associate Professor at the George Institute for Global Health and Sydney Medical School at the University of Sydney in New South Wales, Australia. “Our study is the first to examine brief exposure to a range of modifiable triggers for an acute episode of low back pain.”

For this case-crossover study, Dr. Ferreira and colleagues recruited 999 participants from 300 primary care clinics in Sydney, Australia, who had an acute low back pain episode between October 2011 and November 2012. Participants were asked to report exposure to 12 physical or psychosocial factors in the 96 hours prior to the onset of back pain.

The study found that:

• The risk of a new episode of low back pain significantly increased due to a range of triggers, from an odds ratio of 2.7 for moderate to vigorous physical activity to 25.0 for distraction during an activity.

• Back pain risk was highest between 7:00 am and at noontime.

• Age moderated the effect of exposure to heavy loads, with an odds ratio for individuals age 20, 40, or 60 at 13.6, 6.0, and 2.7, respectively.

“Understanding which modifiable risk factors lead to low back pain is an important step toward controlling a condition that affects so many worldwide,” said Dr. Ferreira. “Our findings enhance knowledge of low back pain triggers and will assist the development of new prevention programs that can reduce suffering from this potentially disabling condition.”

New research reveals the physical and psychosocial factors that significantly increase the risk of low back pain onset. The trial results, which were published online ahead of print February 9 in Arthritis Care & Research, show that being engaged in manual tasks involving awkward positions will increase the risk of low back pain by 8 times. People who are distracted during activities or fatigued also significantly increase their risk of acute low back pain.

“Understanding which risk factors contribute to back pain and controlling exposure to these risks is an important first step in prevention,” said Manuela Ferreira, PhD, Associate Professor at the George Institute for Global Health and Sydney Medical School at the University of Sydney in New South Wales, Australia. “Our study is the first to examine brief exposure to a range of modifiable triggers for an acute episode of low back pain.”

For this case-crossover study, Dr. Ferreira and colleagues recruited 999 participants from 300 primary care clinics in Sydney, Australia, who had an acute low back pain episode between October 2011 and November 2012. Participants were asked to report exposure to 12 physical or psychosocial factors in the 96 hours prior to the onset of back pain.

The study found that:

• The risk of a new episode of low back pain significantly increased due to a range of triggers, from an odds ratio of 2.7 for moderate to vigorous physical activity to 25.0 for distraction during an activity.

• Back pain risk was highest between 7:00 am and at noontime.

• Age moderated the effect of exposure to heavy loads, with an odds ratio for individuals age 20, 40, or 60 at 13.6, 6.0, and 2.7, respectively.

“Understanding which modifiable risk factors lead to low back pain is an important step toward controlling a condition that affects so many worldwide,” said Dr. Ferreira. “Our findings enhance knowledge of low back pain triggers and will assist the development of new prevention programs that can reduce suffering from this potentially disabling condition.”

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts or animal products. Infection of total knee or hip arthroplasty by Brucella species is a rare complication with only 18 cases reported in the English literature.^1-12 We describe a case of an infected total hip replacement, its treatment, and 2-year follow-up and review the available literature. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 67-year-old Spanish-speaking woman, a native of Mexico, presented with a painful right total hip arthroplasty (THA) 2 years after implantation in Chihuahua, Mexico. The patient reported 1 year of increasing thigh pain with recent onset of start-up pain, and also mild groin pain. The patient reported an uneventful postoperative course without wound drainage and denied any history of fevers, chills, or night sweats after the procedure. Preoperative notes and radiographs were unavailable for review. Radiographic evaluation showed a hybrid construct with a well-fixed–appearing, uncemented acetabular component but a failed cemented femoral stem (Figures 1A, 1B). Although we discussed revision surgery, the patient elected not to proceed with surgery or to undergo evaluation to rule out infection. Nine months later, she returned with worsening pain and requested revision surgery; radiographs showed progressive bone loss around the cement mantle (Figures 2A, 2B).

Hematologic evaluation showed an erythrocyte sedimentation rate (ESR) of 54 mm/h (normal, 0-27 mm/h) and C-reactive protein (CRP) level of 0.24 mg/L (normal, <0.8). An aspiration of the hip with fluoroscopic guidance produced a small sample (0.2 mL) of yellow synovial fluid. There was not enough fluid for cell count, but fluid culture was negative.

The patient was taken to the operating room for revision THA. Because of concern about progressive bone loss and elevated infectious indices, the administration of antibiotics was delayed until we obtained sufficient deep-tissue specimens. Before opening the capsule, we introduced a syringe into the joint and aspirated 10 mL of cloudy yellow synovial fluid that was sent for cell count. Additional findings at surgery included a grossly loose stem with a fragmented cement mantle surrounded by poor bone stock with anterior cortical bone loss and a loose acetabular component with pockets of cavitary bone loss. Frozen section showed up to 5 nucleated cells per high power field, and the cell count showed 1480 nucleated cells/µL (50% polymorphonuclear cells). The equivocal intraoperative findings (cell count and frozen section) and the loose femoral and acetabular components with significant bone loss were sufficiently concerning that we removed the components and placed a cement spacer rather than proceed with revision arthroplasty (Figures 3A, 3B). The surgeon, first assistant, and scrub technician wore body exhaust suits. We performed irrigation of the wound bed with pulse lavage.

Intraoperative cultures (synovial fluid, joint capsule synovium, and femur pseudocapsule) were positive after 8 days and growing B abortus. Infectious disease consultants prescribed rifampin 300 mg twice daily and doxycycline 100 mg twice daily for 5 months. Follow-up ESR and CRP returned to normal range. A preoperative aspiration of the hip was negative as well. The patient returned to the operating room at 6 months for re-implantation using uncemented components; synovial fluid and tissue cultures taken at this time were negative. Two years after re-implantation, the patient is doing well without evidence of infection (Figures 4A, 4B). Additional follow-up will be required to monitor for infection and implant survival. Additional history taken from the patient after the culture results revealed that her development of hip pain was preceded by a febrile illness consistent with brucellosis. 

Because of the nature of the procedure (irrigation and débridement using pulse lavage), we were concerned about aerosolization of Brucella bacteria and possible transmission to all staff present during the procedure. After consulting with the New Mexico Department of Health (NMDOH) and the Centers for Disease Control and Prevention (CDC), all surgical, anesthesia, and support personnel present in the operative suite  and staff who cleaned the room after the procedure were treated prophylactically (rifampin 600 mg daily, doxycycline 100 mg twice daily for 3 weeks) to prevent development of brucellosis.¹³ All 15 operating room personnel who were exposed elected to proceed with antibiotic prophylaxis. In addition to prophylactic antibiotics, serial serologic testing for anti-Brucella antibodies was conducted at baseline and 2, 4, 6, and 24 weeks postexposure to monitor for the development of Brucella infection. There were no conversions to positive antibody status. No personnel complained of symptoms that would indicate development of brucellosis. At the recommendation of NMDOH and CDC, all staff in the operating room during and immediately after the re-implantation procedure wore properly fitting N-95 disposable respiratory masks (3M, St. Paul, Minnesota) to guard against the potential risk of further exposure.

Discussion

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts. Transmission can occur via breaks in the skin in direct contact, through the ingestion of unpasteurized dairy products or raw meat, or through ingestion of aerosolized bacteria. Transmission via aerosolization has been described during medical procedures.

Brucella is endemic in India, Middle Eastern and Mediterranean countries, Central Asia, and South America. Brucella species are gram-negative coccobacilli that are capable of surviving within phagocytic cells, making antibiotic treatment difficult. Brucellosis is a febrile illness that occurs after a 1- to 3-week incubation period and is often accompanied by headache, arthralgias, and hepatosplenomegaly. Osteoarticular infection is the most common complication, occurring in 10% to 85% of cases and usually involves the sacroiliac joint and the large joints of the lower extremity. Spondylitis, bursitis, tenosynovitis, endocarditis, colitis, meningitis, and osteomyelitis have also been described.^7,14-17

As mentioned previously, 18 cases of infected THAs and total knee arthroplasties (TKAs) in 16 patients were identified in the English literature: 9 THAs and 9 TKAs.^1-12 With the exception of 1 case reported in Texas, all others were from the Middle East or the Mediterranean region. In these patients, symptom onset occurred from 2 months to 14 years from the time of the index surgery, and symptom duration ranged from 1 month to 2 years prior to presentation. The exposure was not reported in 2 cases, but the remaining patients either ingested unpasteurized dairy products or worked closely with livestock. Laboratory evaluation revealed elevated ESR or CRP in 8 cases. In 7 cases, no laboratory results were reported, although 1 had a draining sinus. In 1 case, the ESR was normal, but a bone scan was positive. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (one aspirate yielded Acinetobacter baumanii). Only 3 cases reported a time-to-culture positivity (1 “prolonged” and 2 took 7 days).

Eight cases presented with loose components, while 1 case was not reported, and the remaining were presumed to be well-fixed. In cases that were identified as loose, 5 underwent a 2-stage revision and 2 underwent a 1-stage revision (in one of the 1-stage revisions, the infection was identified only after the revision from intra-operative cultures). Of those with well-fixed components, 7 patients with 9 infected joints (including the case where no preoperative description of the components was reported) were treated with oral antibiotics only (range, 6 weeks to 26 months) and 1 with irrigation and débridement and oral antibiotics. Among those treated only with antibiotics, there were 2 failures (2 joints) leading to revision surgery. The other 5 cases were reportedly doing well between 8 months and 5 years after treatment. There were no reports of transmission to hospital or laboratory personnel in any of these cases nor were there reports of precautions to limit exposure for operating room staff or hospital personnel. 

Failure of TKA or THA secondary to periprosthetic infection by Brucella species is rare, and this represents only the second reported case in the United States.⁴ This case highlights several important principles. Maintaining a high level of suspicion for infection in cases of failed joint arthroplasty is important. In addition, as more international travel occurs and patients are seen from areas where Brucella is endemic, the possibility of this infectious etiology should be considered. Based on reported cases, patients will usually have elevated ESR or CRP; all (except 2 cases in which no exposure was reported) had known exposure to unpasteurized dairy products or livestock. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (1 aspirate yielded Acinetobacter baumanii). In this case, ESR and CRP were elevated, and infection was suspected but joint aspiration was negative. The initial aspiration was cultured for 5 days and previous data, as well as that presented here, suggest that prolonged culture may provide diagnostic value.¹⁸ The patient had resided in an endemic area and had exposure to unpasteurized dairy products, but Brucella infection was not considered and, therefore, no precautions were taken.

Of the reported cases, only 1 met major criteria for periprosthetic joint infection (draining sinus) while 10 of the remaining 15 cases were positive for minor criteria of periprosthetic joint infection (elevated ESR or CRP, or positive culture from joint aspiration).¹⁹ Unfortunately, the available case reports did not detail the extent to which preoperative periprosthetic joint infection could be established based on minor criteria for periprosthetic joint infection (elevated joint synovial white blood cell count or neutrophil percentage, intra-articular purulence, or elevated neutrophil count on periprosthetic tissue histologic analysis).¹⁹

Periprosthetic joint infection by Brucella species is so rare that specific recommendations for this infectious etiology based on 18 reported cases would be overreaching. However, Brucella should be considered when evaluating a potentially infected joint replacement where the possibility of exposure exists (eg, travel to or previous residence in endemic areas, close contact with livestock, or ingestion of unpasteurized dairy products in endemic regions), with the potential for transmission to operating room and hospital personnel also considered. If there is concern about Brucella involvement, tissue and fluid specimens should be labeled so that laboratory personnel can take appropriate precautions. Brucella can be cultured using routine techniques on standard, nonselective media, but the culture time-to-growth may be prolonged. Culture plates should be held for 14 days before reporting no growth of Brucella if it is suspected; the New Mexico Department of Health Microbiology Laboratory holds routine cultures for 1 week after a report of no growth. Thus, a suspicion of Brucella should be communicated in order for culture time to be adjusted if the holding of culture plates after an initial report of no growth is not standard practice. If operative intervention is planned and brucellosis is known, personnel should be notified of the possibility of exposure and appropriate measures taken (ie, wearing N-95 respiratory masks during the procedure and considering other methods of irrigation less likely to aerosolize particulates). It is not known if preoperative antibiotic therapy can sufficiently lower the bacterial load to make aerosolization less likely. If brucellosis is suspected but not identified preoperatively, wearing N-95 respiratory masks should be considered during any open procedures. 

Conclusion

In cases of Brucella infection and loose components, 1- or 2-stage revision with appropriate antibiotic therapy is indicated. (There is not enough data to recommend either 1- or 2-stage revision.) Several reports comment on the ability to treat periprosthetic joint infection in the setting of well-fixed components with antibiotic therapy alone. While this appears to have been successful in 7 of 9 infected joints reported in the literature, length of follow-up ranged from 8 months to 5 years, with no report of length of follow-up in some cases. Antibiotic therapy duration ranged from 6 weeks to 26 months, and the antibiotic treatment involved combination therapy with multiple agents reported but, most commonly, doxycycline, rifampin, and streptomycin. With 2 of 9 (22%) joints failing antibiotic therapy alone and those reported to be successful having relatively short-term follow-up, this treatment strategy should be approached with caution.

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts or animal products. Infection of total knee or hip arthroplasty by Brucella species is a rare complication with only 18 cases reported in the English literature.^1-12 We describe a case of an infected total hip replacement, its treatment, and 2-year follow-up and review the available literature. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 67-year-old Spanish-speaking woman, a native of Mexico, presented with a painful right total hip arthroplasty (THA) 2 years after implantation in Chihuahua, Mexico. The patient reported 1 year of increasing thigh pain with recent onset of start-up pain, and also mild groin pain. The patient reported an uneventful postoperative course without wound drainage and denied any history of fevers, chills, or night sweats after the procedure. Preoperative notes and radiographs were unavailable for review. Radiographic evaluation showed a hybrid construct with a well-fixed–appearing, uncemented acetabular component but a failed cemented femoral stem (Figures 1A, 1B). Although we discussed revision surgery, the patient elected not to proceed with surgery or to undergo evaluation to rule out infection. Nine months later, she returned with worsening pain and requested revision surgery; radiographs showed progressive bone loss around the cement mantle (Figures 2A, 2B).

Hematologic evaluation showed an erythrocyte sedimentation rate (ESR) of 54 mm/h (normal, 0-27 mm/h) and C-reactive protein (CRP) level of 0.24 mg/L (normal, <0.8). An aspiration of the hip with fluoroscopic guidance produced a small sample (0.2 mL) of yellow synovial fluid. There was not enough fluid for cell count, but fluid culture was negative.

The patient was taken to the operating room for revision THA. Because of concern about progressive bone loss and elevated infectious indices, the administration of antibiotics was delayed until we obtained sufficient deep-tissue specimens. Before opening the capsule, we introduced a syringe into the joint and aspirated 10 mL of cloudy yellow synovial fluid that was sent for cell count. Additional findings at surgery included a grossly loose stem with a fragmented cement mantle surrounded by poor bone stock with anterior cortical bone loss and a loose acetabular component with pockets of cavitary bone loss. Frozen section showed up to 5 nucleated cells per high power field, and the cell count showed 1480 nucleated cells/µL (50% polymorphonuclear cells). The equivocal intraoperative findings (cell count and frozen section) and the loose femoral and acetabular components with significant bone loss were sufficiently concerning that we removed the components and placed a cement spacer rather than proceed with revision arthroplasty (Figures 3A, 3B). The surgeon, first assistant, and scrub technician wore body exhaust suits. We performed irrigation of the wound bed with pulse lavage.

Intraoperative cultures (synovial fluid, joint capsule synovium, and femur pseudocapsule) were positive after 8 days and growing B abortus. Infectious disease consultants prescribed rifampin 300 mg twice daily and doxycycline 100 mg twice daily for 5 months. Follow-up ESR and CRP returned to normal range. A preoperative aspiration of the hip was negative as well. The patient returned to the operating room at 6 months for re-implantation using uncemented components; synovial fluid and tissue cultures taken at this time were negative. Two years after re-implantation, the patient is doing well without evidence of infection (Figures 4A, 4B). Additional follow-up will be required to monitor for infection and implant survival. Additional history taken from the patient after the culture results revealed that her development of hip pain was preceded by a febrile illness consistent with brucellosis. 

Because of the nature of the procedure (irrigation and débridement using pulse lavage), we were concerned about aerosolization of Brucella bacteria and possible transmission to all staff present during the procedure. After consulting with the New Mexico Department of Health (NMDOH) and the Centers for Disease Control and Prevention (CDC), all surgical, anesthesia, and support personnel present in the operative suite  and staff who cleaned the room after the procedure were treated prophylactically (rifampin 600 mg daily, doxycycline 100 mg twice daily for 3 weeks) to prevent development of brucellosis.¹³ All 15 operating room personnel who were exposed elected to proceed with antibiotic prophylaxis. In addition to prophylactic antibiotics, serial serologic testing for anti-Brucella antibodies was conducted at baseline and 2, 4, 6, and 24 weeks postexposure to monitor for the development of Brucella infection. There were no conversions to positive antibody status. No personnel complained of symptoms that would indicate development of brucellosis. At the recommendation of NMDOH and CDC, all staff in the operating room during and immediately after the re-implantation procedure wore properly fitting N-95 disposable respiratory masks (3M, St. Paul, Minnesota) to guard against the potential risk of further exposure.

Discussion

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts. Transmission can occur via breaks in the skin in direct contact, through the ingestion of unpasteurized dairy products or raw meat, or through ingestion of aerosolized bacteria. Transmission via aerosolization has been described during medical procedures.

Brucella is endemic in India, Middle Eastern and Mediterranean countries, Central Asia, and South America. Brucella species are gram-negative coccobacilli that are capable of surviving within phagocytic cells, making antibiotic treatment difficult. Brucellosis is a febrile illness that occurs after a 1- to 3-week incubation period and is often accompanied by headache, arthralgias, and hepatosplenomegaly. Osteoarticular infection is the most common complication, occurring in 10% to 85% of cases and usually involves the sacroiliac joint and the large joints of the lower extremity. Spondylitis, bursitis, tenosynovitis, endocarditis, colitis, meningitis, and osteomyelitis have also been described.^7,14-17

As mentioned previously, 18 cases of infected THAs and total knee arthroplasties (TKAs) in 16 patients were identified in the English literature: 9 THAs and 9 TKAs.^1-12 With the exception of 1 case reported in Texas, all others were from the Middle East or the Mediterranean region. In these patients, symptom onset occurred from 2 months to 14 years from the time of the index surgery, and symptom duration ranged from 1 month to 2 years prior to presentation. The exposure was not reported in 2 cases, but the remaining patients either ingested unpasteurized dairy products or worked closely with livestock. Laboratory evaluation revealed elevated ESR or CRP in 8 cases. In 7 cases, no laboratory results were reported, although 1 had a draining sinus. In 1 case, the ESR was normal, but a bone scan was positive. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (one aspirate yielded Acinetobacter baumanii). Only 3 cases reported a time-to-culture positivity (1 “prolonged” and 2 took 7 days).

Eight cases presented with loose components, while 1 case was not reported, and the remaining were presumed to be well-fixed. In cases that were identified as loose, 5 underwent a 2-stage revision and 2 underwent a 1-stage revision (in one of the 1-stage revisions, the infection was identified only after the revision from intra-operative cultures). Of those with well-fixed components, 7 patients with 9 infected joints (including the case where no preoperative description of the components was reported) were treated with oral antibiotics only (range, 6 weeks to 26 months) and 1 with irrigation and débridement and oral antibiotics. Among those treated only with antibiotics, there were 2 failures (2 joints) leading to revision surgery. The other 5 cases were reportedly doing well between 8 months and 5 years after treatment. There were no reports of transmission to hospital or laboratory personnel in any of these cases nor were there reports of precautions to limit exposure for operating room staff or hospital personnel. 

Failure of TKA or THA secondary to periprosthetic infection by Brucella species is rare, and this represents only the second reported case in the United States.⁴ This case highlights several important principles. Maintaining a high level of suspicion for infection in cases of failed joint arthroplasty is important. In addition, as more international travel occurs and patients are seen from areas where Brucella is endemic, the possibility of this infectious etiology should be considered. Based on reported cases, patients will usually have elevated ESR or CRP; all (except 2 cases in which no exposure was reported) had known exposure to unpasteurized dairy products or livestock. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (1 aspirate yielded Acinetobacter baumanii). In this case, ESR and CRP were elevated, and infection was suspected but joint aspiration was negative. The initial aspiration was cultured for 5 days and previous data, as well as that presented here, suggest that prolonged culture may provide diagnostic value.¹⁸ The patient had resided in an endemic area and had exposure to unpasteurized dairy products, but Brucella infection was not considered and, therefore, no precautions were taken.

Of the reported cases, only 1 met major criteria for periprosthetic joint infection (draining sinus) while 10 of the remaining 15 cases were positive for minor criteria of periprosthetic joint infection (elevated ESR or CRP, or positive culture from joint aspiration).¹⁹ Unfortunately, the available case reports did not detail the extent to which preoperative periprosthetic joint infection could be established based on minor criteria for periprosthetic joint infection (elevated joint synovial white blood cell count or neutrophil percentage, intra-articular purulence, or elevated neutrophil count on periprosthetic tissue histologic analysis).¹⁹

Periprosthetic joint infection by Brucella species is so rare that specific recommendations for this infectious etiology based on 18 reported cases would be overreaching. However, Brucella should be considered when evaluating a potentially infected joint replacement where the possibility of exposure exists (eg, travel to or previous residence in endemic areas, close contact with livestock, or ingestion of unpasteurized dairy products in endemic regions), with the potential for transmission to operating room and hospital personnel also considered. If there is concern about Brucella involvement, tissue and fluid specimens should be labeled so that laboratory personnel can take appropriate precautions. Brucella can be cultured using routine techniques on standard, nonselective media, but the culture time-to-growth may be prolonged. Culture plates should be held for 14 days before reporting no growth of Brucella if it is suspected; the New Mexico Department of Health Microbiology Laboratory holds routine cultures for 1 week after a report of no growth. Thus, a suspicion of Brucella should be communicated in order for culture time to be adjusted if the holding of culture plates after an initial report of no growth is not standard practice. If operative intervention is planned and brucellosis is known, personnel should be notified of the possibility of exposure and appropriate measures taken (ie, wearing N-95 respiratory masks during the procedure and considering other methods of irrigation less likely to aerosolize particulates). It is not known if preoperative antibiotic therapy can sufficiently lower the bacterial load to make aerosolization less likely. If brucellosis is suspected but not identified preoperatively, wearing N-95 respiratory masks should be considered during any open procedures. 

Conclusion

In cases of Brucella infection and loose components, 1- or 2-stage revision with appropriate antibiotic therapy is indicated. (There is not enough data to recommend either 1- or 2-stage revision.) Several reports comment on the ability to treat periprosthetic joint infection in the setting of well-fixed components with antibiotic therapy alone. While this appears to have been successful in 7 of 9 infected joints reported in the literature, length of follow-up ranged from 8 months to 5 years, with no report of length of follow-up in some cases. Antibiotic therapy duration ranged from 6 weeks to 26 months, and the antibiotic treatment involved combination therapy with multiple agents reported but, most commonly, doxycycline, rifampin, and streptomycin. With 2 of 9 (22%) joints failing antibiotic therapy alone and those reported to be successful having relatively short-term follow-up, this treatment strategy should be approached with caution.

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts or animal products. Infection of total knee or hip arthroplasty by Brucella species is a rare complication with only 18 cases reported in the English literature.^1-12 We describe a case of an infected total hip replacement, its treatment, and 2-year follow-up and review the available literature. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 67-year-old Spanish-speaking woman, a native of Mexico, presented with a painful right total hip arthroplasty (THA) 2 years after implantation in Chihuahua, Mexico. The patient reported 1 year of increasing thigh pain with recent onset of start-up pain, and also mild groin pain. The patient reported an uneventful postoperative course without wound drainage and denied any history of fevers, chills, or night sweats after the procedure. Preoperative notes and radiographs were unavailable for review. Radiographic evaluation showed a hybrid construct with a well-fixed–appearing, uncemented acetabular component but a failed cemented femoral stem (Figures 1A, 1B). Although we discussed revision surgery, the patient elected not to proceed with surgery or to undergo evaluation to rule out infection. Nine months later, she returned with worsening pain and requested revision surgery; radiographs showed progressive bone loss around the cement mantle (Figures 2A, 2B).

Hematologic evaluation showed an erythrocyte sedimentation rate (ESR) of 54 mm/h (normal, 0-27 mm/h) and C-reactive protein (CRP) level of 0.24 mg/L (normal, <0.8). An aspiration of the hip with fluoroscopic guidance produced a small sample (0.2 mL) of yellow synovial fluid. There was not enough fluid for cell count, but fluid culture was negative.

The patient was taken to the operating room for revision THA. Because of concern about progressive bone loss and elevated infectious indices, the administration of antibiotics was delayed until we obtained sufficient deep-tissue specimens. Before opening the capsule, we introduced a syringe into the joint and aspirated 10 mL of cloudy yellow synovial fluid that was sent for cell count. Additional findings at surgery included a grossly loose stem with a fragmented cement mantle surrounded by poor bone stock with anterior cortical bone loss and a loose acetabular component with pockets of cavitary bone loss. Frozen section showed up to 5 nucleated cells per high power field, and the cell count showed 1480 nucleated cells/µL (50% polymorphonuclear cells). The equivocal intraoperative findings (cell count and frozen section) and the loose femoral and acetabular components with significant bone loss were sufficiently concerning that we removed the components and placed a cement spacer rather than proceed with revision arthroplasty (Figures 3A, 3B). The surgeon, first assistant, and scrub technician wore body exhaust suits. We performed irrigation of the wound bed with pulse lavage.

Intraoperative cultures (synovial fluid, joint capsule synovium, and femur pseudocapsule) were positive after 8 days and growing B abortus. Infectious disease consultants prescribed rifampin 300 mg twice daily and doxycycline 100 mg twice daily for 5 months. Follow-up ESR and CRP returned to normal range. A preoperative aspiration of the hip was negative as well. The patient returned to the operating room at 6 months for re-implantation using uncemented components; synovial fluid and tissue cultures taken at this time were negative. Two years after re-implantation, the patient is doing well without evidence of infection (Figures 4A, 4B). Additional follow-up will be required to monitor for infection and implant survival. Additional history taken from the patient after the culture results revealed that her development of hip pain was preceded by a febrile illness consistent with brucellosis. 

Because of the nature of the procedure (irrigation and débridement using pulse lavage), we were concerned about aerosolization of Brucella bacteria and possible transmission to all staff present during the procedure. After consulting with the New Mexico Department of Health (NMDOH) and the Centers for Disease Control and Prevention (CDC), all surgical, anesthesia, and support personnel present in the operative suite  and staff who cleaned the room after the procedure were treated prophylactically (rifampin 600 mg daily, doxycycline 100 mg twice daily for 3 weeks) to prevent development of brucellosis.¹³ All 15 operating room personnel who were exposed elected to proceed with antibiotic prophylaxis. In addition to prophylactic antibiotics, serial serologic testing for anti-Brucella antibodies was conducted at baseline and 2, 4, 6, and 24 weeks postexposure to monitor for the development of Brucella infection. There were no conversions to positive antibody status. No personnel complained of symptoms that would indicate development of brucellosis. At the recommendation of NMDOH and CDC, all staff in the operating room during and immediately after the re-implantation procedure wore properly fitting N-95 disposable respiratory masks (3M, St. Paul, Minnesota) to guard against the potential risk of further exposure.

Discussion

Brucellosis is a zoonotic disease transmitted to humans through contact with animal hosts. Transmission can occur via breaks in the skin in direct contact, through the ingestion of unpasteurized dairy products or raw meat, or through ingestion of aerosolized bacteria. Transmission via aerosolization has been described during medical procedures.

Brucella is endemic in India, Middle Eastern and Mediterranean countries, Central Asia, and South America. Brucella species are gram-negative coccobacilli that are capable of surviving within phagocytic cells, making antibiotic treatment difficult. Brucellosis is a febrile illness that occurs after a 1- to 3-week incubation period and is often accompanied by headache, arthralgias, and hepatosplenomegaly. Osteoarticular infection is the most common complication, occurring in 10% to 85% of cases and usually involves the sacroiliac joint and the large joints of the lower extremity. Spondylitis, bursitis, tenosynovitis, endocarditis, colitis, meningitis, and osteomyelitis have also been described.^7,14-17

As mentioned previously, 18 cases of infected THAs and total knee arthroplasties (TKAs) in 16 patients were identified in the English literature: 9 THAs and 9 TKAs.^1-12 With the exception of 1 case reported in Texas, all others were from the Middle East or the Mediterranean region. In these patients, symptom onset occurred from 2 months to 14 years from the time of the index surgery, and symptom duration ranged from 1 month to 2 years prior to presentation. The exposure was not reported in 2 cases, but the remaining patients either ingested unpasteurized dairy products or worked closely with livestock. Laboratory evaluation revealed elevated ESR or CRP in 8 cases. In 7 cases, no laboratory results were reported, although 1 had a draining sinus. In 1 case, the ESR was normal, but a bone scan was positive. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (one aspirate yielded Acinetobacter baumanii). Only 3 cases reported a time-to-culture positivity (1 “prolonged” and 2 took 7 days).

Eight cases presented with loose components, while 1 case was not reported, and the remaining were presumed to be well-fixed. In cases that were identified as loose, 5 underwent a 2-stage revision and 2 underwent a 1-stage revision (in one of the 1-stage revisions, the infection was identified only after the revision from intra-operative cultures). Of those with well-fixed components, 7 patients with 9 infected joints (including the case where no preoperative description of the components was reported) were treated with oral antibiotics only (range, 6 weeks to 26 months) and 1 with irrigation and débridement and oral antibiotics. Among those treated only with antibiotics, there were 2 failures (2 joints) leading to revision surgery. The other 5 cases were reportedly doing well between 8 months and 5 years after treatment. There were no reports of transmission to hospital or laboratory personnel in any of these cases nor were there reports of precautions to limit exposure for operating room staff or hospital personnel. 

Failure of TKA or THA secondary to periprosthetic infection by Brucella species is rare, and this represents only the second reported case in the United States.⁴ This case highlights several important principles. Maintaining a high level of suspicion for infection in cases of failed joint arthroplasty is important. In addition, as more international travel occurs and patients are seen from areas where Brucella is endemic, the possibility of this infectious etiology should be considered. Based on reported cases, patients will usually have elevated ESR or CRP; all (except 2 cases in which no exposure was reported) had known exposure to unpasteurized dairy products or livestock. Joint aspiration yielded Brucella species in 8 cases, was negative in 3, and not reported in 5 cases (1 aspirate yielded Acinetobacter baumanii). In this case, ESR and CRP were elevated, and infection was suspected but joint aspiration was negative. The initial aspiration was cultured for 5 days and previous data, as well as that presented here, suggest that prolonged culture may provide diagnostic value.¹⁸ The patient had resided in an endemic area and had exposure to unpasteurized dairy products, but Brucella infection was not considered and, therefore, no precautions were taken.

Of the reported cases, only 1 met major criteria for periprosthetic joint infection (draining sinus) while 10 of the remaining 15 cases were positive for minor criteria of periprosthetic joint infection (elevated ESR or CRP, or positive culture from joint aspiration).¹⁹ Unfortunately, the available case reports did not detail the extent to which preoperative periprosthetic joint infection could be established based on minor criteria for periprosthetic joint infection (elevated joint synovial white blood cell count or neutrophil percentage, intra-articular purulence, or elevated neutrophil count on periprosthetic tissue histologic analysis).¹⁹

Periprosthetic joint infection by Brucella species is so rare that specific recommendations for this infectious etiology based on 18 reported cases would be overreaching. However, Brucella should be considered when evaluating a potentially infected joint replacement where the possibility of exposure exists (eg, travel to or previous residence in endemic areas, close contact with livestock, or ingestion of unpasteurized dairy products in endemic regions), with the potential for transmission to operating room and hospital personnel also considered. If there is concern about Brucella involvement, tissue and fluid specimens should be labeled so that laboratory personnel can take appropriate precautions. Brucella can be cultured using routine techniques on standard, nonselective media, but the culture time-to-growth may be prolonged. Culture plates should be held for 14 days before reporting no growth of Brucella if it is suspected; the New Mexico Department of Health Microbiology Laboratory holds routine cultures for 1 week after a report of no growth. Thus, a suspicion of Brucella should be communicated in order for culture time to be adjusted if the holding of culture plates after an initial report of no growth is not standard practice. If operative intervention is planned and brucellosis is known, personnel should be notified of the possibility of exposure and appropriate measures taken (ie, wearing N-95 respiratory masks during the procedure and considering other methods of irrigation less likely to aerosolize particulates). It is not known if preoperative antibiotic therapy can sufficiently lower the bacterial load to make aerosolization less likely. If brucellosis is suspected but not identified preoperatively, wearing N-95 respiratory masks should be considered during any open procedures. 

Conclusion

In cases of Brucella infection and loose components, 1- or 2-stage revision with appropriate antibiotic therapy is indicated. (There is not enough data to recommend either 1- or 2-stage revision.) Several reports comment on the ability to treat periprosthetic joint infection in the setting of well-fixed components with antibiotic therapy alone. While this appears to have been successful in 7 of 9 infected joints reported in the literature, length of follow-up ranged from 8 months to 5 years, with no report of length of follow-up in some cases. Antibiotic therapy duration ranged from 6 weeks to 26 months, and the antibiotic treatment involved combination therapy with multiple agents reported but, most commonly, doxycycline, rifampin, and streptomycin. With 2 of 9 (22%) joints failing antibiotic therapy alone and those reported to be successful having relatively short-term follow-up, this treatment strategy should be approached with caution.

Researchers have honed in on a way to replace the meniscus, using a personalized 3D-printed implant in sheep, according to a study published online December 10, 2014, in Science Translational Medicine. The therapy, successfully tested in sheep, could provide the first effective and long-lasting repair of damaged menisci.

“At present, there’s little that orthopedists can do to regenerate a torn knee meniscus,” said lead study author Jeremy Mao, DDS, PhD, the Edwin S. Robinson Professor of Dentistry in Orthopedic Surgery at Columbia University Medical Center in New York. “In contrast, we’re jumpstarting the process within the body, using factors that promote endogenous stem cells for tissue regeneration.”

This process was tested on 11 sheep. Knees of sheep were chosen because of their close resemblance to the human knee. In this study, the sheep were randomized to have part of their knee meniscus replaced with a protein-infused 3D scaffold or a 3D scaffold without protein.

Dr. Mao’s approach starts with MRI scans of the intact meniscus in the undamaged knee, which is then converted into a 3D image. Data from the image are then used to drive a 3D printer, which produces a scaffold in the exact shape of the meniscus, down to a resolution of 10 microns. The scaffold is infused with connective growth factor (CTGF) and transforming growth factor β3 (TGFβ3). Dr. Mao’s team found that sequential delivery of these two proteins attracts existing stem cells from the body and induces them to form meniscal tissue.

After three months, treated animals were walking normally. In a postmortem analysis, the researchers found that the regenerated meniscus in the treatment group had structural and mechanical properties very similar to those of natural meniscus. In sheep, the meniscus regenerates at a rate of about 4 to 6 weeks. Eventually, the scaffold dissolves and is eliminated by the body.

Researchers have honed in on a way to replace the meniscus, using a personalized 3D-printed implant in sheep, according to a study published online December 10, 2014, in Science Translational Medicine. The therapy, successfully tested in sheep, could provide the first effective and long-lasting repair of damaged menisci.

“At present, there’s little that orthopedists can do to regenerate a torn knee meniscus,” said lead study author Jeremy Mao, DDS, PhD, the Edwin S. Robinson Professor of Dentistry in Orthopedic Surgery at Columbia University Medical Center in New York. “In contrast, we’re jumpstarting the process within the body, using factors that promote endogenous stem cells for tissue regeneration.”

This process was tested on 11 sheep. Knees of sheep were chosen because of their close resemblance to the human knee. In this study, the sheep were randomized to have part of their knee meniscus replaced with a protein-infused 3D scaffold or a 3D scaffold without protein.

Dr. Mao’s approach starts with MRI scans of the intact meniscus in the undamaged knee, which is then converted into a 3D image. Data from the image are then used to drive a 3D printer, which produces a scaffold in the exact shape of the meniscus, down to a resolution of 10 microns. The scaffold is infused with connective growth factor (CTGF) and transforming growth factor β3 (TGFβ3). Dr. Mao’s team found that sequential delivery of these two proteins attracts existing stem cells from the body and induces them to form meniscal tissue.

After three months, treated animals were walking normally. In a postmortem analysis, the researchers found that the regenerated meniscus in the treatment group had structural and mechanical properties very similar to those of natural meniscus. In sheep, the meniscus regenerates at a rate of about 4 to 6 weeks. Eventually, the scaffold dissolves and is eliminated by the body.

Researchers have honed in on a way to replace the meniscus, using a personalized 3D-printed implant in sheep, according to a study published online December 10, 2014, in Science Translational Medicine. The therapy, successfully tested in sheep, could provide the first effective and long-lasting repair of damaged menisci.

“At present, there’s little that orthopedists can do to regenerate a torn knee meniscus,” said lead study author Jeremy Mao, DDS, PhD, the Edwin S. Robinson Professor of Dentistry in Orthopedic Surgery at Columbia University Medical Center in New York. “In contrast, we’re jumpstarting the process within the body, using factors that promote endogenous stem cells for tissue regeneration.”

This process was tested on 11 sheep. Knees of sheep were chosen because of their close resemblance to the human knee. In this study, the sheep were randomized to have part of their knee meniscus replaced with a protein-infused 3D scaffold or a 3D scaffold without protein.

Dr. Mao’s approach starts with MRI scans of the intact meniscus in the undamaged knee, which is then converted into a 3D image. Data from the image are then used to drive a 3D printer, which produces a scaffold in the exact shape of the meniscus, down to a resolution of 10 microns. The scaffold is infused with connective growth factor (CTGF) and transforming growth factor β3 (TGFβ3). Dr. Mao’s team found that sequential delivery of these two proteins attracts existing stem cells from the body and induces them to form meniscal tissue.

After three months, treated animals were walking normally. In a postmortem analysis, the researchers found that the regenerated meniscus in the treatment group had structural and mechanical properties very similar to those of natural meniscus. In sheep, the meniscus regenerates at a rate of about 4 to 6 weeks. Eventually, the scaffold dissolves and is eliminated by the body.

DALLAS—Injecting long-acting liposomal bupivacaine into the tissue surrounding the knee during knee replacement surgery may provide a faster receovery and higher patient satisfaction, according to a report presented at the recent American Association for Hip and Knee Surgeons meeting.

“The pain scores for this injection technique averaged about 3/10, which is similar to the pain scores seen with our traditional method,” said Jason Davis, MD, a Henry Ford West Bloomfield Hospital joint replacement surgeon and senior study author. “Patients had pain relief for up to 2 days after surgery and better knee function compared with the traditional method.”

In the study, 216 patients were evaluated for pain control the first 2 days after surgery from October 2012 to September 2013. Half of the patients received the traditional pain control method with continuous femoral nerve blockade, in which common numbing medicine is injected into the groin area, blunting the main nerve down the front of the knee—a method that calls for a pain pump to extend pain control for two days but causes some leg weakness.

“Pain control came at the price of weakness and made patients somewhat tentative when walking during their hospital stay,” stated Dr. Davis.

The other half of patients received the liposomal bupivacaine injection at the site of the surgery. With this method, Dr. Davis says many patients were able to walk comfortably within hours after surgery.

Dr. Davis said that the injection around the knee itself “optimizes pain control early on” without the side effects of the traditional technique. “Function-wise, it was a lot easier for patients to move around more confidently,” Dr. Davis stated.

“In the past decade, we’ve made major advancements in pain control for knee replacement surgery. This option is a promising, viable one for our patients,” Dr. Davis said.

DALLAS—Injecting long-acting liposomal bupivacaine into the tissue surrounding the knee during knee replacement surgery may provide a faster receovery and higher patient satisfaction, according to a report presented at the recent American Association for Hip and Knee Surgeons meeting.

“The pain scores for this injection technique averaged about 3/10, which is similar to the pain scores seen with our traditional method,” said Jason Davis, MD, a Henry Ford West Bloomfield Hospital joint replacement surgeon and senior study author. “Patients had pain relief for up to 2 days after surgery and better knee function compared with the traditional method.”

In the study, 216 patients were evaluated for pain control the first 2 days after surgery from October 2012 to September 2013. Half of the patients received the traditional pain control method with continuous femoral nerve blockade, in which common numbing medicine is injected into the groin area, blunting the main nerve down the front of the knee—a method that calls for a pain pump to extend pain control for two days but causes some leg weakness.

“Pain control came at the price of weakness and made patients somewhat tentative when walking during their hospital stay,” stated Dr. Davis.

The other half of patients received the liposomal bupivacaine injection at the site of the surgery. With this method, Dr. Davis says many patients were able to walk comfortably within hours after surgery.

Dr. Davis said that the injection around the knee itself “optimizes pain control early on” without the side effects of the traditional technique. “Function-wise, it was a lot easier for patients to move around more confidently,” Dr. Davis stated.

“In the past decade, we’ve made major advancements in pain control for knee replacement surgery. This option is a promising, viable one for our patients,” Dr. Davis said.

DALLAS—Injecting long-acting liposomal bupivacaine into the tissue surrounding the knee during knee replacement surgery may provide a faster receovery and higher patient satisfaction, according to a report presented at the recent American Association for Hip and Knee Surgeons meeting.

“The pain scores for this injection technique averaged about 3/10, which is similar to the pain scores seen with our traditional method,” said Jason Davis, MD, a Henry Ford West Bloomfield Hospital joint replacement surgeon and senior study author. “Patients had pain relief for up to 2 days after surgery and better knee function compared with the traditional method.”

In the study, 216 patients were evaluated for pain control the first 2 days after surgery from October 2012 to September 2013. Half of the patients received the traditional pain control method with continuous femoral nerve blockade, in which common numbing medicine is injected into the groin area, blunting the main nerve down the front of the knee—a method that calls for a pain pump to extend pain control for two days but causes some leg weakness.

“Pain control came at the price of weakness and made patients somewhat tentative when walking during their hospital stay,” stated Dr. Davis.

The other half of patients received the liposomal bupivacaine injection at the site of the surgery. With this method, Dr. Davis says many patients were able to walk comfortably within hours after surgery.

Dr. Davis said that the injection around the knee itself “optimizes pain control early on” without the side effects of the traditional technique. “Function-wise, it was a lot easier for patients to move around more confidently,” Dr. Davis stated.

“In the past decade, we’ve made major advancements in pain control for knee replacement surgery. This option is a promising, viable one for our patients,” Dr. Davis said.