Potential Utility of Liposome Bupivacaine 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