An Online Continuing Education ActivitySponsored By

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Infiltration of Local Anesthetics for Postoperative Analgesia

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(An Online Continuing Education Activity)

Welcome to

Infiltration of Local Anesthetics for Postoperative Analgesia

(An Online Continuing Education Activity)CONTINUING EDUCATION INSTRUCTIONSThis educational activity is being offered online and may be completed at any time.

Steps for Successful Course CompletionTo earn continuing education credit, the participant must complete the following steps:

1. Read the overview and objectives to ensure consistency with your own learning needs and objectives. At the end of the activity, you will be assessed on the attainment of each objective.

2. Review the content of the activity, paying particular attention to those areas that reflect the objectives.

3. Complete the Test Questions. Missed questions will offer the opportunity to re-read the question and answer choices. You may also revisit relevant content.

4. For additional information on an issue or topic, consult the references.5. To receive credit for this activity complete the evaluation and registration form. 6. A certificate of completion will be available for you to print at the conclusion.

Pfiedler Enterprises will maintain a record of your continuing education credits and provide verification, if necessary, for 7 years. Requests for certificates must be submitted in writing by the learner.

If you have any questions, please call: 720-748-6144.

CONTACT INFORMATION:

© 2015All rights reserved

Pfiedler Enterprises, 2101 S. Blackhawk Street, Suite 220, Aurora, Colorado 80014www.pfiedlerenterprises.com Phone: 720-748-6144 Fax: 720-748-6196

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OVERVIEWPain is a predictable consequence of surgery that can often last for several days; if left untreated, it is associated with significant adverse consequences for the patient. In addition, pain relief is a critical factor in a patient’s recovery from anesthesia and surgery. For these reasons, effective postoperative analgesia is a key component of perioperative nursing care. Because the pain management paradigm has shifted to an increasing use of multimodal analgesia, the role of local anesthetics has taken on greater significance. Infiltration of local anesthetics into the surgical site at the time of wound closure is one aspect of a multimodal approach for postoperative analgesia today. Recent advancements have led to the development of a local anesthetic with an extended duration of action and a novel delivery platform, thereby broadening its potential role as a component of some postoperative pain management regimens. This continuing education activity will provide a review of the pathophysiology of acute pain, as it relates to the surgical patient. It will review the problems and limitations associated with opioid therapy, followed by the rationale for the use of multimodal analgesia as a key strategy for effective postoperative pain management. The history and development of local anesthetics will be outlined. The pharmacodynamics of local anesthetics and common local anesthetic agents that are currently infiltrated will be reviewed. Current techniques for extending the duration of infiltrated local anesthetics will be explained, followed by the clinical benefits as documented in the literature. The clinical implications of local anesthetic toxicity will also be described. Finally, the role of local anesthetics, with a focus on wound infiltration, in multimodal analgesia will be discussed.

LEARNER OBJECTIVES After completing this continuing nursing education activity, the participant should be able to:

1. Explain the pathophysiology of acute postoperative pain as it relates to the surgical patient.

2. Identify the problems and limitations associated with opioid monotherapy for postoperative pain management.

3. Discuss the history and development of local anesthetics. 4. Describe the pharmacodynamics of local anesthetics. 5. List common local anesthetic agents that are currently infiltrated. 6. Discuss the current techniques for and clinical benefits of extending the duration of

infiltrated local anesthetics. 7. Describe the clinical implications of local anesthetic toxicity. 8. Discuss the role of local anesthetics in multimodal analgesia.

INTENDED AUDIENCE This continuing education activity is intended for perioperative registered nurses want to learn more about the infiltration of local anesthetics as a component of a multimodal analgesia regimen for effective management of postoperative pain.

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CREDIT/CREDIT INFORMATION State Board Approval for Nurses Pfiedler Enterprises is a provider approved by the California Board of Registered Nursing, Provider Number CEP14944, for 2.0 contact hours.

Obtaining full credit for this offering depends upon attendance, regardless of circumstances, from beginning to end. Licensees must provide their license numbers for record keeping purposes.

The certificate of course completion issued at the conclusion of this course must be retained in the participant’s records for at least four (4) years as proof of attendance.

IACETPfiedler Enterprises has been accredited as an Authorized Provider by the International Association for Continuing Education and Training (IACET).

CEU Statements• As an IACET Authorized Provider, Pfiedler Enterprises offers CEUs for its

programs that qualify under the ANSI/IACET Standard. • Pfiedler Enterprises is authorized by IACET to offer 0.2 CEUs for this program.

RELEASE AND ExPIRATION DATE:This continuing education activity was planned and provided in accordance with accreditation criteria. This material was originally produced in April 2015 and can no longer be used after April 2017 without being updated; therefore, this continuing education activity expires April 2017.

DISCLAIMERPfiedler Enterprises does not endorse or promote any commercial product that may be discussed in this activity

SUPPORTFunds to support this activity have been provided by Pacira Pharmaceuticals, Inc.

AUThORS/PLANNING COMMITTEE/REVIEWERRose Moss, MN, RN, CNOR Casa Grande, AZNurse Consultant/AuthorC & R Moss Enterprises

Judith I. Pfister, RN, BSN, MBA Aurora, COProgram Manager/Planning CommitteePfiedler Enterprises

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ExPERT REVIEWER:Julia A. Kneedler, RN, MS, EdD Aurora, COProgram Manager/ReviewerPfiedler Enterprises

DISCLOSURE OF RELATIONShIPS WITh COMMERCIAL ENTITIES FOR ThOSE IN A POSITION TO CONTROL CONTENT FOR ThIS ACTIVITy Pfiedler Enterprises has a policy in place for identifying and resolving conflicts of interest for individuals who control content for an educational activity. Information below is provided to the learner, so that a determination can be made if identified external interests or influences pose potential bias in content, recommendations or conclusions. The intent is full disclosure of those in a position to control content, with a goal of objectivity, balance and scientific rigor in the activity. For additional information regarding Pfiedler Enterprises’ disclosure process, visit our website at: http://www. pfiedlerenterprises.com/disclosure

Disclosure includes relevant financial relationships with commercial interests related to the subject matter that may be presented in this continuing education activity. “Relevant financial relationships” are those in any amount, occurring within the past 12 months that create a conflict of interest. A commercial interest is any entity producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients.

Activity Authors/ Planning Committee/Reviewer

Rose Moss, RN, MN, CNOR No conflict of interest

Judith I. Pfister, MBA, RN Co-owner of company that receives grant funds from commercial entities

Julia A. Kneedler, EdD, RN Co-owner of company that receives grant funds from commercial entities

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Phone: 720-748-6144

Email: registrar@pfiedlerenterprises.com

Postal Address: 2101 S. Blackhawk Street, Suite 220 Aurora, Colorado 80014

Website URL: http://www.pfiedlerenterprises.com

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INTRODUCTIONAn expected outcome for all surgical patients is that they demonstrate and/or report adequate pain control, since comfort and pain relief are critical factors in a patient’s recovery from anesthesia and surgery.1 In the United States, over 51 million inpatient surgical procedures are performed annually2; over 53 million surgical and nonsurgical procedures are performed in an ambulatory surgery setting.3 One of the most common questions asked by patients preoperatively is about the amount of pain they can expect after the procedure; pain is also a major concern for surgeons because of its close association with clinical outcomes and acute postoperative patient well-being.4 A national study assessing patients’ postoperative pain experience and the status of acute pain management found that approximately 80% of the patients surveyed had experienced acute postsurgical pain, with most patients reporting moderate, severe, or extreme pain.5

Another important consideration in regards to postsurgical pain is that can often last for several days.6 An examination of the extent and evolution of pain after commonly performed major elective noncardiac surgical procedures showed relatively high pain scores and minimum reductions in pain from Postoperative Days 1 to 3; these results emphasize the need for more effective pain management that continues into the postoperative period in order to facilitate mobilization and recovery.7

While pain is a predictable consequence of surgery; if left untreated, is associated with significant physiological, emotional, mental, and economic consequences.8 Unrelieved pain and/or ineffective pain management have been reported to be:

• One of the three most common causes of delayed discharge after ambulatory surgery (the other two are drowsiness and nausea and vomiting).9

• Associated with increased hospital length of stay (LOS), delayed ambulation, and long-term functional impairment.10

• Associated with reports of high levels of dissatisfaction when patients experience moderate to severe postsurgical pain.11

• A factor in the development of chronic pain, ie, the intensity of acute postsurgical pain is a predictor of ongoing chronic postsurgical pain, which occurs in 15% to 45% of patients after commonly performed procedures (eg, limb amputations, breast surgery, gallbladder surgery, lung surgery and inguinal hernia surgery).12

For these reasons, effective pain management remains a primary concern and area of focus in the United States today; however, despite the overwhelming rationale for effective postoperative pain control, in reality it is still unsatisfactory.13 Therefore effective postoperative pain management is an essential component of perioperative nursing care.

While opioid therapy has been the cornerstone of most postsurgical analgesic regimens, recent evidence has supported the use of multimodal therapy as a way to decrease opioid usage, minimize its concomitant opioid-related adverse events (ORAEs), and also improve economic outcomes.14

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PAThOPhySIOLOGy OF POSTOPERATIVE PAINIn order to understand the role of local anesthetics in effective management of postsurgical pain, the perioperative nurse should have a working knowledge of analgesia and the inflammatory responses to surgery; this includes knowledge of the various types and manifestations of pain and the requirements for pain production.15

Types of Pain16

There are three commonly reported types of pain: visceral, neuropathic, and nociceptive or somatic. Visceral pain is produced by activation of nociceptors in any of the visceral tissues. This type of pain is often referred to as distant pain, as it is poorly localized. An example of visceral pain is the right upper quadrant abdominal and shoulder pain associated with cholecystitis. Neuropathic pain is typically intermittent and often experienced as an area of sensory loss or numbness. An example of neuropathic pain is carpal tunnel syndrome. Nociceptive or somatic pain is well localized, described as familiar in quality, and often associated with inflammation. Somatic pain is produced by activation of nociceptors in the somatic tissues (eg, muscles, skeleton, and skin); surgical pain is an example of somatic pain.

Requirements for Pain Production17,18

All of the three types of pain have one thing in common: the four basic requirements for the production of pain, as outlined below (see Figure 1).

• Transduction is the process by which afferent nerve endings participate in translating a painful stimulus into nociceptive impulses. Transduction occurs when mediators, eg, substance P, serotonin, histamine, and bradykinin are released at the tissue injury site. These mediators then stimulate peripheral sensory afferent nerves that extend to the dorsal horn of the spinal cord. A painful or noxious stimulus is first carried by the faster A-delta fibers, and then by the slower C fibers; silent nociceptors afferent nerves that do not respond to external stimulation unless inflammatory mediators are present are also involved in transduction.

• Transmission is the process by which impulses are sent to the dorsal horn of the spinal cord, and then along the sensory tracts to the brain. Transmission occurs when ascending nerves extending from the dorsal horn of the spinal cord to the brain are stimulated by the peripheral sensory afferents.

• Modulation is the process of dampening or amplifying these pain-related neural signals. Modulation occurs when descending pathways to the dorsal horn modulate the activity of the peripheral nerves by releasing enkephalins and endorphins.

• Perception of pain occurs at the level of the brain; it refers to the subjective experience of pain resulting from the interaction of transduction, transmission, modulation, and also the psychological aspects of the individual.

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Figure 1 – Postsurgical Pain Pathway

Pain and the Inflammatory Response: The “Wind-Up” Phenomenon19,20

In surgical wounds, tissue damage stimulates an inflammatory response. After the incision is made, a cascade of hyperexcitable events occurs in the nervous system. This physiologic “wind-up” phenomenon begins at the skin, is potentiated along the peripheral nerves, and ends in a hypersensitivity response from the dorsal horn of the spinal cord and the brain. Inflammatory cells that surround the areas of tissue damage produce cytokines and chemokines, substances that are meant to mediate the process of healing and tissue regeneration. However, these substances are also irritants and change the properties of the primary sensory neurons surrounding the area of trauma. Therefore, the primary features that trigger inflammatory pain include damage to the high-threshold nociceptors (ie, peripheral sensitization), modifications and modulation of the neurons in the nervous system, and amplification of the excitability of neurons within the CNS. This represents central sensitization and is responsible for hypersensitivity, in which areas adjacent to the area of the actual injury hurt as if they are injured. These tissues also can respond to stimuli that ordinarily do not produce pain, such as a touch, clothing, light pressure, or a hairbrush, as if they are painful.

The “wind-up” phenomenon causes untreated pain to get worse, since the nerve fibers transmitting the painful impulses to the brain essentially become “trained” to deliver pain signals better and with an intensity that is over and above what is needed to get the affected person’s attention. To further complicate this situation, the brain also becomes more sensitive to the pain and as a result, the pain feels much worse even though the injury is not worsening.

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Preemptive Analgesia21,22

The concept of preemptive analgesia was first formulated about 100 years ago. It is an antinociceptive treatment which proposes that the perception of pain can be reduced with the use of analgesics capable of inhibiting CNS sensitization before the painful stimulus occurs, ie, counteracting the “wind-up” phenomenon. Preemptive analgesia is initiated before the surgical procedure in order to reduce the peripheral and central sensitization that occurs from tissue damage after surgery. Because of this “protective” effect on the nociceptive system, preemptive analgesia has the potential to be more effective than similar analgesic treatment initiated after surgery.

Pain Assessment23,24

Because effective pain management is one of the highest priorities in the post anesthesia care unit (PACU), assessment of pain and pain control in all postsurgical patients is critical. Patients should be assessed for pain on admission to the PACU and at frequent intervals. It is important to remember that pain is a subjective experience, ie, it is whatever the patient says it is and that, despite similar surgical procedures, not all patients respond to pain in the same manner. Because patients may not verbalize their pain, perioperative nurses often require objective signs of discomfort as well as subjective reports of pain from the patient.

Pain and pain control should be assessed using a validated pain scale (eg, Numeric Pain Intensity Scale, Visual Analogue Scale, the Wong-Baker FACES Pain Rating Scale); these assessments should be correlated with the patient’s self-report as the most important measure of pain intensity. In patients who cannot self-report, other assessment measures include behavioral signs, eg, restlessness or crying as well as physiologic indicators such as elevated vital signs.

OPIOID ThERAPy: PROBLEMS AND LIMITATIONS In order to appreciate the benefits of multimodal analgesia, the clinical concerns associated with opioid monotherapy should be reviewed.

Historically, monotherapy with opioids has been the mainstay of postsurgical pain management regimens and they remain a foundation of many current treatment modalities.25 While opioids are often effective, they have several idiosyncratic or dose-limiting side effects that limit their practical efficacy and also subject patients to adverse drug events. The most serious adverse events include respiratory depression and sedation, which increase the risk for aspiration, respiratory failure, impaired mobility, and falls. Moreover, more common reactions, eg, nausea, vomiting, constipation, and ileus, may occur even with low dosages of opioids, which can result in significant discomfort and increased lengths of stay. For these reasons, increasing the dose of opioids alone is neither an adequate or appropriate strategy for effective pain management in postsurgical patients. The consequences of unrelieved postoperative pain and opioid-related adverse events are outlined in Table 1.

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Table 1 – Consequences of Unrelieved Postoperative Pain and Opioid-Related Adverse Events26,27

System/Parameter Adverse EffectsCardiovascular System Decreased arterial blood pressure, increased heart rate, infarction,

myocardial ischemiaCoagulation Increased platelet aggregation, thromboembolism, venous stasis

Gastrointestinal System Decreased intestinal motility, ileus, increase secretions, nausea, vomiting

Immunologic System Increased risk for infection, impaired immune function

Musculoskeletal System Fatigue, muscle atrophy and weakness, limitations in movement

Neurologic System Increased risk for developing chronic pain syndromes

Psychological Anger, anxiety, depression, fearPulmonary System Atelectasis, diaphragmatic dysfunction, hypoventilation, hypoxemia,

impaired ventilation and coughing, reduced vital capacity, respiratory and abdominal muscle spasm (splinting)

Renal System Increased urinary sphincter tone, urinary retentionOverall Recovery Delayed recovery and discharge, increased expenses, increased use

of health care resources

Economic Considerations of Opioid Therapy28,31

In addition to the clinical consequences of opioid therapy, there are also economic and operational aspects of ineffective pain management. Hospitals consume substantial resources in direct care, equipment, supplies, and pharmaceuticals in managing pain. Because opioids are often the mainstay of pain management and are generally inexpensive, providers may not consider treatment of pain as a priority in cost reduction efforts; but these treatments have inherent risks that can lead to patient complications that that further increase the cost of care. Relatively small amounts of opioids can increase the risk of ORAEs, length of stay, and associated costs, as documented:

• One study found that ORAEs following surgery increased the median hospitalization costs by 7.4% and the median length of stay by 10.3%.29

• A retrospective study of patients undergoing elective colorectal surgery found that intravenous (IV) opioid therapy was significantly associated with postoperative ileus and prolonged length of stay, particularly when the maximum hydromorphone dose per day exceeded 2 mg.30

The risk of ORAEs increases in patient populations where opioid use is often problematic, such as sleep apneic and obese patients, the elderly and opioid-tolerant patients (eg, patients with rheumatoid arthritis, osteoarthritis, or back pain). Increasingly, providers are looking for new methods to manage pain that are more effective and minimize costly ORAE complications; therefore, alternative, non-opioid–based pain management options should be considered. A variety of non-opioid pain therapies, such as non-steroidal anti-inflammatory drugs (NSAIDs) and local analgesics, are also used to

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treat postsurgical pain, but these therapeutics also bear risks, as do the infusion methods often used for administration of opioids and non-opioids alike. Increasingly, providers are looking for new methods of managing pain that are more effective and that also minimize costly complications.

Routine therapy for pain involves several expenses in addition to the medications themselves. Beyond the resources needed for postsurgical pain management, there are significant and potentially much higher expenses arising from potential complications; one of the most costly of these is prolonged length of stay, which is a common result of opioid side effects such as nausea, ileus, and urinary retention (see Table 2).

Table 2 – Additional Length of hospital Stay (Days) due to Side Effects from Opioid-Based Pain Management (U.S.), 2011 (N=50)

Side Effect Average Mean Number of Additional DaysRespiratory Depression 3.3Nausea and/or Vomiting 2.5Ileus and/or Constipation 3.4Urinary Retention 2.8Somnolence 2.0Delirium 3.1Pruritus 1.8Delayed Ambulation 3.0

In the past, hospitals could bill for the additional costs of care associated with increased lengths of stay; however, in today’s reimbursement system of bundled payment, these additional costs are a major economic concern for hospitals. An additional length of stay of one day costs a hospital $2,095 on average for a general/colorectal surgery patient; $1,990 for an obstetrics/gynecology patient, and $1,868 for a plastic surgery patient. Hospitals are now incentivized to discharge patients sooner. Other side effects may require additional costs of medication and care, such as antihistamine for pruritus ($100 per patient stay and 1.6 hours of nurse time). While rare, respiratory depression due to opioid incurs high costs in terms of extra monitoring and treatment ($200 and 3.8 hours of nursing time). In addition, treating the delirium that results from postsurgical pain management costs $152 on average, and 3.4 hours of nursing time.

Some modalities, such as PCA entail the cost of equipment and supplies as well as pharmacy expenses to fill the order. Table 3 outlines the average costs associated with PCA. The average cost per patient stay for IV opioids by PCA is $616: $235 for the PCA pump, $179 for tubing and fittings, and $202 to fill the opioid order in the pharmacy. Additionally, opioids incur extra expenses for the hospital in terms of secure storage and tracking within the hospital. These substantial expenses are directs costs, but there are many indirect costs as well. Monitoring patients, particularly those on opioids, requires the use of monitoring equipment and nursing time for periodic evaluation of vital signs. The average time needed for nurses to initiate, maintain, document, and monitor PCA was 3.9 hours.

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Table 3 – Average Costs per Patient Stay Associated with Supplies and Services for PCA

Modality PCA

Delivery Pump $ 235

Fittings and Tubing $ 179

Pharmacy $ 202

Staff Time to Maintain, Document, and Monitor 3.9 hours

Clearly there are many direct and indirect costs associated with postsurgical pain management. Hospitals will need to establish priorities and protocols that allow them to continue to improve postsurgical pain management while reducing overall and avoidable costs.

RATIONALE FOR ThE USE OF MULTIMODAL ANALGESIAOverview of Multimodal Analgesia32

The use of multimodal analgesia involves the administration of two or more analgesic agents that act through different mechanisms with the goal of improving postsurgical pain management, decreasing the use of opioids, and consequently reducing their associated adverse drug events in postsurgical patients (see Figure 2).

Figure 2 – Mechanisms of Multimodal Analgesia

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Even though pain results from complex physiologic mechanisms that involve multiple receptors in both the central and peripheral nervous systems, as outlined above, single or monotherapy with opioids has been a foundation of postsurgical pain management. However, no single analgesic targets all types of pain receptors or signaling pathways; furthermore, the amount of opioids that can be administered is limited due the risk for adverse drug events that lead to patient discomfort, delayed recovery, prolonged LOS, and increase costs, as previously discussed.

Non-opioid alternatives, eg, NSAIDs, acetaminophen, and local anesthetics are recognized as effective components of a multimodal pain regimen postoperatively. A multimodal approach can reduce opioid use and opioid-related adverse drug events and also result in earlier patient ambulation as well as discharge.

Professional Guidelines for Multimodal Postsurgical Pain ManagementTwo key organizations recommend a multimodal approach for effective postsurgical pain management, as described below.

• Veterans Administration/Department of Defense (VA/DoD) Clinical Practice Guideline for the Management of Postoperative Pain.33 A summary of the key points of this guideline state that: ◦ Postoperative pain management should be multimodal and individualized for the

particular patient, operation, and circumstances. Understanding of both the range of available interventions and considering the type of surgical procedure are essential to safe and effective pain management.

◦ Selection of a pain management option should be determined by balancing the advantages, disadvantages, contraindications, as well as patient preference. For most patients, more than one modality will be needed for successful pain management.

◦ Interventions for postoperative pain management include both pharmacologic (ie, using the primary classes of medication: opioids, NSAIDs, and local anesthetics) and non-pharmacologic (ie, cognitive and physical modalities).

◦ Evaluation of the balance between pain control and side effects should be routine, timely, and specific. If indicated, the management plan should be modified.

◦ Incisional local anesthetic infiltration is included for specific surgical procedures, eg, thoracic (non-cardiac), upper abdominal. This guideline notes that infiltration of the incision/wound with local anesthesia improved postoperative analgesia provided by epidural bupivacaine/morphine during mobilization and also reduced the need for supplemental intramuscular morphine.

• American Society of Anesthesiologists (ASA) Guidelines Practice Guidelines for Acute Pain Management in the Perioperative Setting.34 These guidelines also state that whenever possible, multimodal pain management therapy should be used. Dosing regimens should be administered to optimize efficacy while minimizing the risk of adverse events. The selection of medication, dose, route, and duration of therapy should be individualized.

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hISTORy AND DEVELOPMENT OF LOCAL ANESThETICSIn order to understand the evolving role of local anesthetics in postsurgical pain management, it is helpful to review the history and development of these agents. As it is known today, local anesthesia is the result of both the discovery and development of suitable agents, as well as the invention of the syringe.35

After 1530, the conquest of Peru brought the properties of a plant, whose leaves were described as “stimulating” when chewed, to the attention of Europeans.36 In Peru, this plant was regarded as divine; because of its importance to their economy, it was called khoka, meaning the plant, which in Europe resulted in the term coca. In 1850, a sufficient amount of coca leaves was brought to Europe, which led to the isolation of cocaine. The first clinical procedure performed under local anesthesia, with the administration of cocaine on the eye, took place in 1884. After this, the use of cocaine for local and regional anesthesia spread quickly throughout Europe and also in America. However, soon thereafter, the toxic effects of cocaine were identified and were also associated with deaths among both patients and health care personnel who became addicted. As a result, local anesthesia was in a state of crisis until the development of modern organic chemistry, which led to the production of pure cocaine in 1891. Synthetic cocaine was developed in 1923.37

New anesthetic drugs were also being sought to replace cocaine; the initial attempts were unsuccessful until 1904, when 18 para-aminobenzoic derivatives that had been developed by a German chemist were patented.38 Of these, compound number 2, called novocaine, appeared for the first time in an article published in 1905, in which it was compared to other promising local anesthetics. The author of this article reported excellent results comparing compounds with various concentrations of novocaine and adrenaline. Because novocaine was found to be safe, it quickly became the standard local anesthetic agent. However, the anesthetic effects of the drug were weak and it required high concentrations of adrenaline, especially when used for infiltration techniques; in addition, some patients and health care professionals were highly allergic to it. These drawbacks encouraged the search for alternative drugs.

Research conducted over the next several decades continued the search for safer local anesthetic agents.39 Between 1891 and 1930, new amino ester local anesthetics, eg, tropocaine, eucaine, benzocaine, and tetracaine, were being developed.40 An important breakthrough that occurred in 1949 was the launch of a new non-ester local anesthetic agent, lidocaine.41 At the time, lidocaine was considered revolutionary because of its potential for improved patient safety; because it had a short duration of action, adverse drug events (ADEs) could be identified and managed quickly, therefore patients could be stabilized until the drug was cleared from the body.

Until 1972, safer, longer-acting amide-type local anesthetics, including articaine, bupivacaine, etidocaine, mepivacaine, and prilocaine continued to be developed.42,43 All of these agents were seemingly less toxic than cocaine, but they all had varying amounts of both central nervous system (CNS) and cardiovascular (CV) toxicity, which continued to adversely affect the use of local anesthetics.44,45

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As research has continued over the past several decades, it has focused on the development of both novel compounds, as well as on new drug delivery methods (eg, microspheres and liposomal particles that encapsulate local anesthetics) to prolong the duration of action and also improve the safety and tolerability profiles.46 For example, ropivicaine was first marketed in 1996; a novel extended-release liposomal bupivacaine injectable suspension was approved by the United States Food and Drug Administration (FDA) in 2011.47

The invention of syringes and needles was also an important development in the history of local anesthesia. Around 1845, the use of a hypodermic syringe broadened the use of local anesthetics.48

The development of the syringe permitted the administration of liquids or solutions of pharmaceutical agents; eg, the syringe was used to inject morphine or opioid solutions near where nerves were believed to be located.49 By approximately 1850, syringes were widely used; however, because these early devices were relatively large, it was impossible to administer small amounts (eg, only a few drops) of a solution to a precise location.50 In 1852, a silver hollow needle was invented and combined with a small volume (eg, approximately 1.5 mL) glass syringe.51

Until the late 1890s, syringes had to be loaded by drawing the desired amount of liquid out of a vial.52 In 1917, during World War I, an American army physician invented the anesthetic cartridge, based on the cartridges used in a gun barrel.53 In addition, the ongoing development, refinement, and use of the hypodermic syringe further expanded the route of local anesthetic administration to include subcutaneous and intramuscular injection.54

The key developments in the history of local anesthetics and syringes are summarized in Table 4.

Table 4 – historical Development of Local Anesthetics and Syringes55

Time Frame Development1845 First use of hypodermic syringes1850 Coca leaves were brought to Europe, leading to the isolation of cocaine1852 Silver hollow needle was invented and combined with a small volume glass syringe1884 First clinical procedure was performed under local anesthesia with the

administration of cocaine on the eye1891 Pure cocaine was produced1905 Novocaine use was documented in the literature1917 Anesthetic cartridge was developed 1923 Synthetic cocaine was developed1949 Lidocaine, a new non-ester local anesthetic agent, was launchedUntil 1972 Safer, longer-acting amide-type local anesthetics (eg, articaine, bupivacaine,

etidocaine, mepivacaine, and prilocaine) continued to be developed1996 Ropivacaine was first marketed2011 A novel extended-release liposomal bupivacaine injectable suspension was

approved by the United States FDA

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hOW DO LOCAL ANESThETICS WORK?56,57

In order to understand the impact of infiltration of the surgical wound with local anesthetics on postsurgical pain control, it is helpful to review their definition and mechanisms of action. Local anesthetics are defined as pharmacologic agents capable of producing a loss of sensation in an area of the body; when they are used on specific nerve pathways, analgesia can be achieved.

Nerves conduct impulses that provide information to the CNS regarding the type, degree, and magnitude of pain. Cytoplasm inside the nerve cell (including the axon) contains positively charged potassium ions and negatively charged proteins. The potassium ions can freely move in and out of the cytoplasm, whereas the proteins are not freely diffusible. The fluid outside the nerve cell and axon contains positively charged sodium ions and negatively charged chloride ions; these ions are freely diffusible in the cytoplasm. However, sodium is quickly pushed out of the nerve cell via a sodium pump. Outside the cell, the concentration of the positively charged potassium is low. Inside the cell, the concentration of potassium is high and the concentration of negatively charged chloride ions is low. The freely diffusible potassium ions are held inside the nerve cell by an excess of negatively charged ions. When a nerve impulse is conducted down the nerve fiber, the nerve membranes become permeable (due to depolarization) to the positively charged sodium ions. These sodium ions are conducted through sodium channels, or pores, in which a “gate” controls their passage to the inside of the nerve cell. Once the sodium has reached a certain ionic concentration, the gate closes in the sodium channels. The membrane permeability to potassium increases, which allows potassium back into the cytoplasm; sodium is pumped out of the nerve cell.

Because local anesthetics are quite lipid soluble, they can diffuse through the cell membrane. Therefore, most local anesthetic agents exert their analgesic effects by inhibiting depolarization of the nerve membrane and also by interfering with sodium and potassium currents. While most nerve fibers are sensitive to local anesthetics, nerves with small diameters tend to be more sensitive than those larger in diameter. There are three types of nerve fibers (types A, B, and C): type A fibers are the largest in diameter and type C are the smallest. Type A fibers transmit pressure sensation and motor commands; type C fibers transmit pain and temperature sensation. Therefore, patients who have blocked type C fibers experience analgesia and reduced pain sensation but can still feel pressure and the ability to move because the type A fibers are fully functioning. In addition to analgesic effects, most local anesthetics also have vasodilatory effects, which increase the risk of local bleeding and the rate of systemic drug absorption; these effects may also decrease the duration of analgesia. This is why epinephrine, a potent vasoconstrictor, is often combined with local anesthetic agents to prolong the duration of action and reduce bleeding at the site.

Local anesthetic agents can be divided into three groups, according to potency: • Low potency – procaine and chloroprocaine.• Intermediate potency (ie, twice the potency of procaine) – lidocaine, cocaine,

mepivacaine, and prilocaine.• High potency (ie, approximately six to eight times more active than procaine) –

tetracaine, bupivacaine (and its isomers ropivacaine and chirocaine).

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Local anesthetics are also grouped pharmacologically into two categories:• Amides (eg, lidocaine, mepivacaine, prilocaine, etidocaine, and bupivacaine) –

these agents are metabolized in the liver, have no real history of documented allergic reactions, have good penetrance, and are stable.

• Esters – except for cocaine, esters are hydrolyzed primarily in the plasma and are metabolized more rapidly than amides. Because esters are metabolized to para-aminobenzoic acid (PABA), they are associated with an increased incidence rate of allergic reactions. In general, esters have poor penetrance and fair to poor stability.

Local anesthetics are also categorized according to their duration of action: • Short-duration – procaine, chloroprocaine.• Intermediate-duration – cocaine, lidocaine, mepivacaine, prilocaine.• Long-duration – bupivacaine, etidocaine, levobupivacaine, ropivacaine,

tetracaine.

Complications associated with the use of local anesthetics include: • Allergic reactions – allergic reactions can be divided into four types: contact

dermatitis; serum sickness, including fever, lymphadenopathy, and urticarial 2 to 12 days after injection; anaphylactic reaction, characterized by dyspnea, cyanosis, and death; and atopic response, including bronchospasm, urticaria and angioneurotic edema.

• Toxicity – local anesthetic toxicity can occur as a result of inappropriate dosing, inadvertent intravascular injection of the agent, variation in the patient’s response, or injection of the agent into a highly vascular area. Local anesthetic toxicity can cause adverse effects on skeletal muscle, cardiac tissue and the neurologic system. Symptoms associated with local anesthetic toxicity are muscular twitching, cardiac electrophysiologic events (ie, QTc prolongation, heart block and possible cardiac collapse), hypotension and/or seizures.58 Toxicity will be discussed in greater detail below.

COMMON LOCAL ANESThETICS ThAT ARE CURRENTLy INFILTRATEDWound infiltration, a technique of postoperative analgesia commonly used alone or in combination with other analgesic regimens, is used across multiple surgical specialties to improve postoperative analgesia, reduce opioid consumption, and speed patient recovery.59 The use of local anesthetics instead of opioids minimizes opioid ADEs, reduces nursing time, and decreases pain while resting and on motion, which thereby facilitates patient mobility. Wound infiltration with local anesthetics is a simple and inexpensive strategy for providing effective analgesia for a variety of surgical procedures without any major side effects; moreover, local anesthetic toxicity, wound infection, and impaired wound healing do not appear to be major considerations.60

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Several local anesthetics that are currently used for infiltration of the surgical wound are briefly outlined below and summarized in Table 5.

• Bupivacaine (Marcaine™).61 Bupivacaine is available with and without epinephrine 1:200,000 for injection via local infiltration. The dilute concentration of epinephrine typically decreases the rate of absorption and peak plasma concentration of bupivacaine, thereby allowing the use of moderately larger total doses and sometimes prolonging the duration of action.The onset of action with bupivacaine is rapid. As noted above, its duration of anesthesia is significantly longer compared with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that continues after the return of sensation; during this time, the need for strong analgesics is reduced.

• Lidocaine hydrochloride (HCl).62 Lidocaine hydrochloride injection is indicated for the production of local or regional anesthesia by infiltration techniques, eg, percutaneous injection. Lidocaine is completely absorbed after parenteral administration; its rate of absorption depends on several various factors, including the site of administration and the presence or absence of a vasoconstrictor agent. With the exception of intravascular administration, the highest blood levels are obtained after intercostal nerve block and the lowest levels are obtained following subcutaneous administration.

• Ropivacaine hydrochloride (Naropin®).63 The systemic concentration of ropivacaine is dependent on several factors, including the total concentration and dose administered, the route of administration, the patient’s hemodynamic/circulatory condition, and the vascularity of the administration site. In studies conducted to evaluate local infiltration of ropivacaine for anesthesia during surgery and analgesia in postoperative pain management, with infiltration of 100 to 200 mg, the time to first request for analgesic was 2 to 6 hours. When compared to a placebo, ropivacaine resulted in lower pain scores and a decrease in analgesic consumption.

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Table 5 – Pharmacokinetics and Maximum Dose of Injectable Local Anesthetics64

Local Anesthetic

(Trade) Name

Equivalent Concentration

Onset (minutes)

Duration(hours)

Maximum Dose

(mg/kg)

Maximum Dose

(mL/70 kg)Moderate Duration Agents

Lidocaine 1% or 2% Less than 2 1.5 to 2 4mg/kg, not to exceed 280 mg

1%: 28 mL2%: 14 mL

Mepivacaine 1% 3 to 5 0.75 to 1.5 4mg/kg, not to exceed 280 mg

28 mL

Prilocaine 1% Less than 2 Over 1 7 mg/kg, not to exceed 500 mg

50 mL

Long Duration AgentsLidocaine with epinephrine

1% or 2% lidocaine, 1:100,000 or 1:200,000 epinephrine

Less than 2 2 to 6 7 mg/kg, not to exceed 500 mg

Based on lidocaine:

1%: 50 mL2%: 25 mL

Bupivacaine 0.25% 5 2 to 4 25 mg/kg, not to exceed 175 mg

50 mL

Etidocaine 0.5% to 1% 3 to 5 2 to 3 4 mg/kg, not to exceed 300 mg

50 mL, 0.5%

Very Long Duration AgentsBupivacaine liposome injectable suspension

1.3%, not bioequivalent to other bupivacaine formulations

5 Up to 24 1.3 % (13.3 mg/mL), not to exceed 266 mg per surgical site

ExTENDING ThE DURATION OF INFILTRATED LOCAL ANESThETICS Overview65

Because the pain management paradigm has shifted to an increased use of multimodal analgesia, the role of local anesthetics has come to the forefront. However, since postsurgical pain can often last for several days, the use of local anesthetics is limited due to their relatively short duration of action (ie, minutes to hours); therefore, alternate delivery methods are needed in order to extend their duration for use in postsurgical pain management. Several strategies have been used to prolong the effects of local anesthetics, including the concomitant use of epinephrine or clonidine and the use of

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catheters and elastomeric pumps for continuous administration of the drug; however, the duration of action is still relatively short (ie, hours or days). Recently, advances in therapeutic approaches have substantially improved postsurgical pain control over past several years; one of these advancements is the development of a novel liposomal delivery platform that encapsulates the local anesthetic and releases it over an extended period of time, thereby broadening its use in acute postsurgical pain management. Each of these methods for extending the duration of local anesthetics is explained in greater detail below.

Epinephrine66,67

As noted above in Table 6, some local anesthetics contain a dilute concentration of epinephrine, which is a vasoconstrictor. Vasoconstrictors extend both the duration and intensity of a local anesthetic agent through two mechanisms. First, vasoconstriction slows the uptake of the drug, which also reduces its toxicity. Second, vasoconstrictors may exert a direct antinociceptive effect by acting on a1- and a2-receptors, thereby modulating action in the dorsal horn action, which has a dose-dependent analgesic effect.

Clonidine68

Clonidine has also been shown to extend the action of local anesthetics when used for peripheral nerve blocks, most likely by direct peripheral action. While the exact mechanism of peripheral action is unknown, it may act on peripheral a2-receptors or reduce the vascular uptake of the local anesthetic agent by its vascular adrenergic effects. Clonidine may also exert a peripheral analgesic action due to the release of enkephalin-like compounds.

Elastomeric Pumps69,70

Recently, new methods and devices have been developed to not only extend the duration of local anesthetics, but also expand their use for both hospitalized and ambulatory patients. Various types of disposable elastomeric continuous infusion pumps can be used efficiently to deliver local anesthetic infusion. Continuous infusion pumps that are specially designed for postoperative PCA are more flexible, allow for in-process dose adjustment; they also permit the delivery of continuous drug doses that provide sufficient analgesia for rest periods as well as supplemental drug doses for the performing daily activities.

Several studies evaluating the administration of local anesthetics via continuous infusion pump systems across multiple surgical specialties (eg, cardiothoracic, orthopedic, general, and gynecologic/urologic) found a reduction in pain scores as well as an improvement in patient satisfaction. The primary disadvantage of these devices is their inability to provide sufficient analgesia for painful periods during patient mobilization. Other disadvantages include dislodgement, infection, cumbersome for the patient, and uncertainty of the dose of drug given.

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The use of an elastomeric pump also entails the cost of equipment, supplies, pharmacy expenses to fill the order, and nursing time to monitor the patient, as outlined in Table 6. The average cost per patient stay for local anesthetic via continuous nerve block is $646: $284 for the elastomeric pump, $166 for the tubing and fittings, and $196 to fill the order in the pharmacy. Monitoring these patients requires the use of equipment and nursing time for periodic evaluation of vital signs. The average time needed for nurses to initiate, maintain, document, and monitor nerve block patients is typically 3.4 hours. As noted above, hospitals should consider whether the time required for these tasks could be otherwise be given to other interventions that facilitate patient recovery and throughput.

Table 6 – Average Costs per Patient Stay Associated with Supplies and Services for Elastomeric Pumps

Modality Elastomeric Pump

Delivery Pump $ 284

Fittings and Tubing $ 166

Pharmacy $ 196

Staff Time to Maintain, Document, and Monitor 3.4 hours

Liposomal BupivacaineToday, a long-acting anesthetic that may provide effective postsurgical pain control and reduce the need for opioids can be a valuable component of a multimodal pain management regimen.71 Long duration local anesthetic agents are preferred for infiltration of a surgical wound; as noted above, bupivacaine provides a rapid onset of action and is one of the longest-acting local anesthetics because of its high lipid soluble and protein-binding properties.72 However, the use of bupivacaine for postoperative pain control is limited by its short duration of analgesic efficacy (in general, about 6 to 8 hours), which is inadequate to effectively manage postsurgical pain, which lasts for 24 to 48 hours.73

The development of a novel long-acting liposomal bupivacaine injectable suspension may provide analgesia and reduce the need for opioids in the acute postoperative period; as outlined above, it was approved by the United States FDA in October 2011.74 This product combines bupivacaine and a novel drug delivery system that is composed of multivesicular liposomes that consist of microscopic, spherical, lipid-based particles composed of a honeycomb of numerous nonconcentric, internal aqueous chambers that contain the encapsulated drug (see Figure 3). The nonconcentric characteristic of the liposomes allows for progressive breakdown and reorganization of the lipid bilayer; thus, this preparation extends the duration of the local anesthetic action by slow release from the liposome over an extended time period, which delays the peak plasma concentration in comparison to plain bupivacaine administration.75,76

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Figure 3 – Multivesicular Liposomes

In regards to it indications and injection techniques, liposomal bupivacaine is indicated for single-dose infiltration into the surgical site to produce postsurgical analgesia.77 It should be injected slowly into soft tissues of the surgical site (see Figure 4), using a 25 gauge or larger bore needle, with frequent aspiration to check for blood and minimize the risk of intravascular injection. The maximum dosage should not exceed 266 mg (20 mL, 1.3% of undiluted drug). It can be administered undiluted or diluted to up to 0.89 mg/mL (ie, 1:14 dilution by volume) with normal (0.9%) sterile saline for injection or lactated Ringer’s solution. The vials should be inverted to re-suspend the particles immediately prior to withdrawal from the vial; multiple inversions may be necessary to re-suspend the particles if the contents of the vial have settled. The medication should be used within 4 hours of opening.

Figure 4 – Infiltration of Liposomal Bupivacaine

Liposomal bupivacaine is contraindicated in obstetrical paracervical block anesthesia.78 The patient’s cardiovascular and neurological status, as well as vital signs should be monitored during and after injection of liposomal bupivacaine, as with other local anesthetics. Because bupivacaine is metabolized by the liver, this agent should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Other formulations of bupivacaine should not be administered within 96 hours after administration of liposomal bupivacaine. This agent

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should not be admixed with lidocaine or other non-bupivacaine-based local anesthetics; it may be administered after at least 20 or more minutes following local administration of lidocaine. Adverse reactions following administration of liposomal bupivacaine include nausea, constipation, and vomiting. Its safety and effectiveness in pediatric patients under the age of 18 have not been established.

The pharmacokinetics of liposomal bupivacaine was determined by several Phase I, II, and III studies that measured bupivacaine plasma concentrations at different time points after local administration in several surgical specialties that included bunionectomy, inguinal hernia repair, hemorrhoidectomy, and total knee arthroplasty (see Figure 5).79 Liposomal bupivacaine exhibits dose-proportional pharmacokinetics with a bimodal release profile after a single administration via infiltration of the wound. The small amount of extra-liposomal bupivacaine is believed to contribute to an initial peak plasma concentration within 1 hour of administration, followed by a second peak which occurs 12 to 36 hours after administration. The systemic plasma concentrations of bupivacaine can persist up to 96 hours, which reflects the gradual release of the local anesthetic from the liposomes.

Figure 5 – Pharmacokinetic Curves of Liposomal Bupivacaine in Various Surgical Sites*80

*Reprinted with permission.

Efficacy and Safety Data for Liposomal BupivacaineStudies have demonstrated liposomal bupivacaine to be an effective tool for postsurgical pain relief, which may reduce or eliminate the need for opiods; it has also been found to have an acceptable adverse effect profile.81 Three relevant studies demonstrating the clinical benefits of this agent are discussed below and summarized in Table 7.

• Dasta et al assessed the comparative efficacy of liposomal bupivacaine administered at doses ≤266 mg and bupivacaine HCl administered at doses ≤200 mg for postsurgical analgesia.82 The authors analyzed the pooled efficacy and safety data from nine controlled multimodal analgesia studies using a single dose of liposomal bupivacaine or a placebo, administered into the surgical site before the end of surgery (in patients undergoing inguinal hernia repair, total

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knee arthroplasty, hemorrhoidectomy, breast augmentation, or bunionectomy).The results demonstrated that liposomal bupivacaine administered at doses ≤ 266 mg in a multimodal setting was associated with statistically significant and clinically meaningful lower cumulative pain score at 72 hours, delayed and less consumption of opioids, and fewer ORAEs than bupivacaine HCl.

• Gorfine et al conducted a multicenter study to compare the magnitude and duration of postoperative analgesia from a single dose of liposomal bupivacaine extended-release injection with a placebo administered intraoperatively in patients undergoing hemorrhoidectomy.83 The results demonstrated that in the group receiving liposomal bupivacaine extended-release: ◦ Pain intensity scores were significantly lower; ◦ More patients remained opioid-free from 12 hours to 72 hours after surgery; ◦ The mean total amount of opioids used through 72 hours was lower; ◦ The median time to first opioid use was longer; and ◦ A greater proportion of patients were satisfied with their postsurgical analgesia.

• Viscusi and Sinatra analyzed the pooled safety profile of liposomal bupivacaine in a total of 823 patients in wound infiltration studies in five different surgical procedures (ie, hemorrhoidectomy, bunionectomy, breast augmentation, total knee arthroplasty, and hernia repair).84 In those studies, 446 control patients received bupivacaine HCl (at doses ranging from 75 mg to 200 mg) and 190 received placebo; the patient demographics were similar between treatment groups within each study. Adverse events were collected for up to 36 days after administration of study drug. The results demonstrated that, across all studies, liposomal bupivacaine was well tolerated. The types of treatment-emergent adverse events (TEAEs) reported and the incidence rates were similar between the liposomal bupivacaine and bupivacaine HCl groups. Across all study pools, most of the TEAEs were assessed as mild or moderate in severity and unrelated to study drug. The incidence of cardiovascular and nervous system TEAEs was low and similar between the liposomal bupivacaine and bupivacaine HCl groups. Two deaths, one in each group, were reported; both were assessed as unlikely related to study drug. In doses up to 750 mg of liposomal bupivacaine, no signal of any kind concerning the CNS or the CV system; it did not cause significant QTc prolongation, even in doses up to 750 mg, the maximum feasible volume for subcutaneous administration. The authors concluded that liposomal bupivacaine demonstrated an acceptable safety profile across 823 patient exposures; moreover, this analysis supports that the use of liposomal bupivacaine may be a well-tolerated adjunct for the management of postsurgical pain across various surgical specialties.

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Table 7 – Results of Studies Pertaining to the Efficacy and Safety of Liposomal Bupivacaine

Study Author(s) Study Description Results/ConclusionsDasta et al Analysis of the pooled efficacy and

safety data comparing the liposomal bupivacaine and bupivacaine HCl administered into the surgical site before the end of surgery in patients undergoing inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, or bunionectomy

Liposomal bupivacaine (≤266 mg doses) in a multimodal setting was associated with:

- Statistically significant and clinically meaningful lower pain score at 72 hours- Delayed and less consumption of opioids- Fewer ORAEs

Gorfine et al 186 hemorrhoidectomy patients receiving (via wound infiltration intraoperatively) either

- A single dose of liposomal bupivacaine; or

- Placebo

Wound infiltration with extended-release liposomal bupivacaine resulted in:

- Significantly lower pain intensity scores - More patients remained opioid-free from 12 - 72 hours after surgery- A lower total amount of opioids used through 72 hours- A longer time to first opioid use- Greater patient satisfaction with postsurgical analgesia

Viscusi and Sinatra

Analysis of the pooled safety profile of wound infiltration studies using liposomal bupivacaine in 823 patients in five surgical procedures (hemorrhoidectomy, bunionectomy, breast augmentation, total knee arthroplasty, and hernia repair)

Across all studies, liposomal bupivacaine was well tolerated

Liposomal bupivacaine demonstrated an acceptable safety profile across 823 patient exposures

This analysis supports that the use of liposomal bupivacaine may be a well-tolerated adjunct for the management of postsurgical pain across various surgical specialties

LOCAL ANESThETIC TOxICITyAs noted above, toxicity is a rare but potentially lethal adverse consequence associated with the use of local anesthetics.85 Therefore, perioperative nurses should be aware of the potential for local anesthetic toxicity and appropriate strategies to reduce the risk.

Local anesthetic toxicity results when an unsafe amount of a local anesthetic agent has been absorbed into the patient’s bloodstream.86 This may occur slowly from systemic absorption of a local anesthetic that is correctly injected into the tissue or immediately

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and tragically if the anesthetic agent is injected directly into a blood vessel. The signs of local anesthetic toxicity generally progress in the following order: the patient may initially complain of perioral numbness, a metallic taste in the mouth, tinnitus, visual disturbances, and/or dizziness. If the toxicity is immediate or progresses, the patient will most likely experience seizures, respiratory arrest, and/or cardiac arrest. Other symptoms associated with local anesthetic toxicity include muscular twitching, cardiac electrophysiologic events (ie, QTc prolongation, heart block and possible cardiac collapse and hypotension.87

Local anesthetic blood levels are influenced by the site of injection and also the dose; factors that can increase the likelihood of local anesthetic systemic toxicity include88:

• Advanced age;• Heart failure; • Ischemic heart disease;• Conduction abnormalities;• Metabolic (eg, mitochondrial) disease;• Liver disease; • Low plasma protein concentration;• Metabolic or respiratory acidosis; and • Medications that inhibit sodium channels.

Patients who have severe cardiac dysfunction, especially very low ejection fraction, are more sensitive to local anesthetic systemic toxicity (LAST) and also more prone to “stacked” injections, which result in elevated tissue concentrations of the agent because of the slowed circulation time.89

All members of the perioperative team should take appropriate measures to reduce the risk of LAST, such as90:

• Being sensible: ◦ Use the lowest dose of the local anesthetic needed to achieve the desired

extent and duration of action. ◦ Consider using a pharmacologic marker and/or test dose of the local

anesthetic; know the expected response, onset, duration, and limitations of a test dose in identifying intravascular injection.

◦ Aspirate the syringe prior to each injection while observing for blood. ◦ Inject incrementally, while observing for signs of toxicity between each

injection.

• Being prepared: ◦ Establish a plan to manage local anesthetic toxicity, including a kit and posted

instructions for it use.

• Being vigilant: ◦ Monitor the patient during and after completion of the injection, since clinical

toxicity may be delayed for up to 30 minutes.

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◦ Consider LAST in any patient who develops an altered mental status, any neurological symptoms, or cardiovascular instability.

It is important to note that standard, prolonged resuscitation efforts are not always successful in cases of local anesthetic cardiotoxicity; however, animal studies have demonstrated that hemodynamic stability can be restored after local anesthetic-induced cardiac arrest with the administration of intravenous lipid emulsion.91 The American Society of Regional Anesthesia and Pain Medicine has developed a checklist for the treatment of Local Anesthetic Systemic Toxicity, which includes the use of a 20% lipid emulsion (LipidRescue™) to bind the local anesthetic and reverse local anesthetic toxicity according to the following protocol92:

• Get help.

• Initial focus parameters: ◦ Airway management – ventilate the patient with 100% oxygen. ◦ Suppress seizures – the use of benzodiazepines is preferred; AVOID using

propofol in patients with signs of cardiovascular instability. ◦ Alert the nearest facility that has cardiopulmonary bypass capability.

• Management of cardiac arrhythmias: ◦ Basic and Advanced Cardiac Life Support will require an adjustment of the

medications and perhaps a prolonged effort. ◦ AVOID the use of vasopressin, calcium channel blockers, beta blockers, or

local anesthetics. ◦ REDUCE individual epinephrine doses to <1 mcg/kg.

• Lipid Emulsion (20%) Therapy (the values in parenthesis are for a 70 kg [154 pound] patient): ◦ Bolus 1.5 mL/kg (lean body mass) intravenously over 1 minute (approximately

100 mL). ◦ Continuous infusion 0.25 mL/kg/min (approximately 18 mL/min; adjust by roller

clamp). ◦ Repeat the bolus once or twice for persistent cardiovascular collapse. ◦ Double the infusion rate to 0.5 mL/kg/min if the patient’s blood pressure

remains low. ◦ Continue the infusion for at least10 minutes after circulatory stability is

attained. ◦ The recommended upper limit is approximately 10 mL/kg lipid emulsion over

the first 30 minutes.

• Post LAST events at www.lipidrescue.org and report the use of lipid to www.lipidregistry.org. Liposomal bupivacaine was shown to be safe, ie, demonstrated a good cardiac safety profile, as documented in the literature.

• Naseem et al conducted a study to characterize the effect on the corrected QT interval (QTc) of single subcutaneous administration of liposomal bupivacaine in

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various doses compared with a placebo.93 The results of this study demonstrated that various doses of liposomal bupivacaine did not show any clinically significant effect on QTc; a slight shortening of the QTc interval was observed (more than in the placebo group), which appeared to be dose dependent; the clinical significance of shortening the QTc interval is not known but is not considered a clinical concern, as QTc shortening has also been described in published data for other medicines. The authors concluded that this study shows that bupivacaine given subcutaneously as a new extended-release formulation in doses of up to 750 mg does not prolong the QT interval and raises no cardiac concerns.

• In a review of the cardiac safety profile of liposomal bupivacaine conducted by Bergese et al findings from paired electrocardiograms (ECGs), corresponding pharmacokinetic assessments, and cardiovascular adverse events (AEs) of extended-release bupivacaine (in 150, 300, 450, or 600 mg) or bupivacaine HCl 150 mg with epinephrine administered intraoperatively via wound infiltration in 138 patients undergoing total knee arthroplasty were assessed for potential causality.94 The results demonstrated that the mean change from baseline in QRS duration and QTcF duration across dose levels of the extended-release bupivacaine was similar compared with bupivacaine HCl. The mean change from baseline in heart rate, PR interval, and QRS interval was similar between treatment groups as well. No clinically relevant ECG changes or cardiac adverse events with extended-release bupivacaine were observed in the other clinical studies. The investigators concluded that this focused assessment of ECG data and cardiac findings and adverse event data from other studies in the extended-release bupivacaine development program did not demonstrate any cardiac safety issues.

ThE ROLE OF LOCAL ANESThETICS AS A COMPONENT OF MULTIMODAL ANALGESIA As previously discussed, wound infiltration is a method of postoperative analgesia commonly used alone or in combination with other analgesic regimens; in this regard, over the past several years, wound infiltration and the role of local anesthetics have become important components of multimodal analgesia in which the combination of various postoperative analgesic techniques maximizes the benefits of each method while minimizing adverse reactions.95

As part of a multimodal analgesia regimen, local anesthetics are used in several ways for postoperative pain control.96 These strategies include the use of local anesthetics in epidural anesthesia, for various types of peripheral nerve blocks, as well as through continuous infusion with the use of either elastomeric or electronic pumps. However, continuous infusion of local anesthetics through indwelling catheters can be associated with various complications (eg, bleeding, accidental dislodgement or migration, infection, paresthesias, dysesthesias, and pain not related to the surgical procedure).

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As previously discussed, local anesthetics can also be used for infiltration of the wound during the final stages of an operative procedure; this can be used alone or in combination with other analgesic regiments.97 Because this mode of delivery does not require an indwelling catheter, it has several advantages, such as effective postoperative pain control and earlier discharge from the hospital. Moreover, the use of local anesthetics/ analgesics instead of opioids precludes the risk for opioid-induced adverse events and also decreases nursing staff workload. Since the analgesic action of the agent can control pain both at rest and on motion, earlier patient mobility is also fostered.

While almost all local anesthetics can be used effectively for wound infiltration, those with a longer duration of action are preferred.98 As discussed above, the high lipid solubility of bupivacaine lends itself to the treatment of postsurgical pain; in particular, bupivacaine provides a rapid onset of action and also a longer duration of activity compared with many of the commonly used extended-duration analgesic agents. Moreover, a multivesicular liposomal bupivacaine formulation can extend the duration of action and therefore, it is more suitable to address the natural time frame of postsurgical pain and thus achieve both clinical and economic benefits.

Studies have demonstrated liposomal bupivacaine to be an effective tool for postsurgical pain relief, which may help reduce the need for opioids; it has also been found to have an acceptable adverse effect profile.99 Both the clinical and economic benefits associated with the use of wound infiltration with local anesthetics across multiple surgical specialties, as part of a multimodal analgesia regimen, have also been documented in the literature. Four relevant studies are summarized below.

• A study conducted by Kerr et al demonstrated the benefits of local infiltration analgesia (LIA) for controlling pain after knee and hip surgery in 325 patients over a 2-year period.100 This technique is based on the systematic infiltration of a mixture of ropivacaine, ketorolac, and adrenaline into the tissues around the operative field to achieve satisfactory pain control with little physiological disturbance; it also allows nearly immediate mobilization and earlier discharge from hospital. In this open, nonrandomized study, the authors used LIA to manage postoperative pain in all 325 undergoing elective hip resurfacing, primary total hip arthroplasty (THA), or primary total knee arthroplasty (TKA). The patients’ pain scores, mobilization times, and morphine usage for the entire group were recorded. The results demonstrated that pain control was generally satisfactory (the numerical pain rating scores ranged from 0 to 3); no morphine was required for postoperative pain control in two-thirds of the patients; most of the patients were able to walk with assistance between 5 and 6 hours postoperatively; and independent mobility was achieved in 13 to 22 hours after surgery. Orthostatic hypotension, nausea, and vomiting were reported occasionally when standing for the first time, however, other side effects were unremarkable. A total of 230 (71%) of the 325 patients were discharged directly home after a one night stay in the hospital. The authors concluded that LIA is practical, safe, simple, and effective for pain management following knee and hip surgery.

• Candiotti et al demonstrated the benefits of liposomal bupivacaine for postsurgical analgesia in patients undergoing laparoscopic colectomy.101 Noting that opioid-

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based postsurgical analgesia exposes these patients to an increased risk for gastrointestinal motility problems and other ORAEs, this study was conducted to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, using a single administration of liposome bupivacaine and other analgesics that act by different mechanisms. The authors analyzed the combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received either opioid-based intravenous PCA or multimodal analgesia that included intraoperative administration of liposomal bupivacaine. The primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs; secondary measures included time to first rescue opioid use, patient satisfaction with analgesia, and ORAEs. The results of this study demonstrated that the patients in the liposomal bupivacaine-based multimodal analgesia group, in comparison to the PCA group, had significantly lower mean total postoperative opioid consumption (32 mg versus 96 mg, respectively); shorter postoperative hospital lengths of stay (3.0 versus 4.0 days); and lower mean costs ($11,234 versus $13,018, respectively). The median time to first use of rescue opioids was longer in the multimodal analgesia patients versus those in the PCA group (1.1 hours compared to 0.6 hours, respectively); ORAEs were experienced by 41% of the patients in the PCA group and 8% of the patients in the multimodal analgesia group. The authors concluded that in patients undergoing laparoscopic colectomy, a liposomal bupivacaine-based multimodal analgesia regimen, compared to intravenous opioid PCA, reduced postoperative opioid use, hospital length of stay, and ORAEs, and may also lead to improved postsurgical outcomes.

• Barrington et al reported their results using a bupivacaine liposome injectable suspension, a non-opioid method for pain management, in patients undergoing total hip and knee arthroplasty.102 The authors noted that pain following orthopedic surgery is common and often inadequately managed, as many patients complain of acute moderate to severe pain postoperatively. While opioids are often used to manage this pain, this can result in significant side effects and complications. The use of multimodal therapy that includes surgical site infiltration with extended release local anesthetic has been seen as a new way to reduce postoperative pain for these patients, which can result in a shorter length of hospital stay and also an improved quality of life. The use of liposomal bupivacaine can also result in earlier postoperative ambulation: this report noted that a patient with a femoral nerve catheter generally required two-person assistance, crutches, and a knee immobilizer to ambulate; in contrast, a patient who received liposomal bupivacaine could ambulate without crutches or a knee immobilizer and needed minimal assistance from one person. In another example regarding the clinical benefits of liposomal bupivacaine infiltration, a patient with severe osteoarthritis who had a total knee replacement never reported a pain score higher than 3 in the 72-hour postoperative period, even after physical therapy; in addition, within 3 months, the patient returned to full activity without pain and130° range of motion.

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The issues of economic efficiency and patient outcomes associated with the use of liposomal bupivacaine cannot be overlooked, since hospitals continue to face pressure to contain costs while improving care. Today, pain management is an economic consideration when patient satisfaction is tied to hospital reimbursement; therefore, strategies that help to decrease the expenses related to pain management will optimize the hospital’s reimbursement level. An example of one hospital’s preliminary cost analysis (based on 2012 TKA data) comparing the use of liposomal bupivacaine versus a femoral nerve catheter in patients undergoing TKA is outlined in Table 8.

Table 8 – Preliminary Cost Savings: Use of Liposomal Bupivacaine versus a Femoral Nerve Catheter

Cost of Liposomal Bupivacaine $273Reduced Costs

- Anesthesia Professional Fees- Anesthesia Technician- Full-time Equivalent Physical Therapist- Femoral Nerve Catheter Drug

Administration

Total Reduced Costs

$ 1,450$ 230$ 180$ 148

$ 2,008

Total Savings- Additional costs of using liposomal

bupivacaine

- Reduced costs

$ 273

($2,008)

TOTAL SAVINGS ($ 1,735) per case

The authors concluded that a multimodal pain management approach that includes infiltration of the surgical site with a local anesthetic is becoming a more accepted practice because of the effectiveness of this technique. The use of liposomal bupivacaine, as the local anesthetic agent of choice, permits the development of a new protocol for postoperative pain management, with a reduced reliance on the use of opioids and fewer associated side effects that extend hospital stays, increase costs, reduce patient satisfaction and result in higher readmission rates.

• Bilgin et al conducted a study to assess the impact of wound infiltration with bupivacaine and intramuscular (IM) diclofenac administration on PCA tramadol consumption and postoperative pain in patients having radical retropubic prostatectomy (RRP) under general anesthesia.103 This study included 96 men undergoing RRP, who were randomized into two groups of 48: one group received wound infiltration with 0.5% bupivacaine during closure and 75mg of diclofenac IM; the other group received wound infiltration with saline during closure and IM saline. In both groups, PCA with IV tramadol was used for postsurgical

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analgesia. The patients’ PCA tramadol consumptions and pain scores were measured at 1, 2, 6, 12, and 24 hours postoperatively. The results demonstrated significant differences for all parameters measured; for the patients who received bupivacaine and diclofenac, mean cumulative tramadol consumption was significantly lower at 24 hours, their pain scores were significantly lower, the number of patients who required rescue antiemetic and analgesia was also lower, and their satisfaction scores were significantly higher compared to the patients who received saline.

SUMMARyPain is a predictable consequence of surgery; if left untreated, it is associated with undesirable clinical and economic consequences. One of the expected outcomes for all surgical patients is they demonstrate and/or report adequate pain control; therefore effective postoperative pain management using a multimodal approach is an essential component of surgical patient care. The administration of a local anesthetic via infiltration of the surgical wound is one component of a multimodal approach that allows for minimally invasive exposure and also results in immediate pain relief, which has been proven to increase patient satisfaction.104 Recent advancements have led to the development of a long-acting formulation of bupivacaine that is designed to allow drug diffusion to occur over time following a single administration, which matches the time frame of postsurgical pain. Today, infiltration of the surgical wound with a long-acting local anesthetic has the potential to become a foundation of multimodal pain management.105 Therefore, perioperative nurses should be aware of the important role of wound infiltration of local anesthetics in order to manage postoperative pain more effectively.

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GLOSSARyBupivacaine A high-potency, long-duration, amide local

anesthetic agent.

Corrected QT Interval (QTc) The measured QT interval that is transformed by various heart rate correction formulas; it is independent of heart rate.

Dysesthesia Impairment of sensation short of anesthesia; abnormal sensations experienced without stimulation.

Endorphin Any of a group of peptide hormones, found primarily in the brain, that bind to opiate receptors; they reduce the sensation of pain and also trigger a positive feeling in the body, similar to that of morphine and therefore, are often referred to as endogenous morphine.

Liposome A microscopic spherical vesicle consisting of an aqueous core enclosed in one or more phospholipid layers; it is used to transport drugs, enzymes, or other substances to targeted cells or organs.

Modulation The process of dampening or amplifying pain-related neural signals; it occurs when descending pathways to the dorsal horn modulate the activity of the peripheral nerves by releasing enkephalins and endorphins.

Multimodal Analgesia The administration of two or more analgesic agents that act via different mechanisms with the goal of improving postsurgical pain management and reducing the use of opioids and consequently the associated adverse drug events in postsurgical patients.

Nociceptors A group of cells that acts as a sensory receptor for painful stimuli.

Paresthesia An altered sensation often experienced as burning, tingling, or pin pricks.

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Perception The subjective experience of pain resulting from the interaction of transduction, transmission, modulation, and the psychological aspects of the individual; it occurs at the level of the brain.

Preemptive Analgesia An antinociceptive treatment intended to prevent CNS sensitization to counteract the “wind-up” phenomenon and alter the overall pain response.

Somatic Pain Pain that originates in muscles, skeleton, or skin; pain in the parts of the body other than the viscera. Surgical pain is an example of somatic pain.

Transduction The process by which afferent nerve endings participate in translating a painful stimulus into nociceptive impulses; it occurs when mediators, eg, substance P, serotonin, histamine, and bradykinin are released at the tissue injury site.

Transmission The process by which impulses are sent to the dorsal horn of the spinal cord, and then along the sensory tracts to the brain; it occurs when ascending nerves extending from the dorsal horn of the spinal cord to the brain are stimulated by the peripheral sensory afferents.

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104. Gorfine SR, Onel E, Patou G, KrivokapicZV. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011; 54(12): 1552-1559.

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