Dr. Masataka Enomoto is a research associate in the Translational Research in Pain program at North Carolina State University. He obtained his veterinary medicine degree from Azabu University in Japan. His research focuses on orthopedic surgery, cartilage regeneration/restoration, and pain management in comparative models.Read Articles Written by Masataka Enomoto
Dr. Hiroko Enomoto is a postdoctoral research scholar in the Molecular Biomedical Sciences department at North Carolina State University. She obtained her veterinary medicine degree from Nippon Veterinary and Animal Science University in Japan. Her research focuses on the pharmacokinetics and pharmacodynamics of analgesic drugs in veterinary species and the delivery and transit profiles of orally dosed, locally acting gastrointestinal therapeutics in animal models.Read Articles Written by Hiroko Enomoto
DVM, PhD, DACVAA, DACVCP
Dr. Messenger is an assistant professor of pharmacology at North Carolina State University. She is board-certified in both veterinary anesthesia and analgesia and veterinary clinical pharmacology. Her research focuses on the pharmacokinetics and pharmacodynamics of analgesic drugs in veterinary species.Read Articles Written by Kristen Messenger
B. Duncan X. Lascelles
BSc, BVSc, PhD, FRCVS, CertVA, DSAS(ST), DECVS, DACVS
Dr. Lascelles is a professor of small animal surgery and pain management at North Carolina State University. He is board-certified in small animal surgery by the Royal College of Veterinary Surgeons, the European College of Veterinary Surgeons, and the American College of Veterinary Surgeons. His research program (Translational Research in Pain) develops methods to measure pain associated with spontaneous disease in animals and seeks to understand the underlying neurobiology. His work improves pain control in companion animals and facilitates analgesic development in human medicine.Read Articles Written by B. Duncan X. Lascelles
Effective, appropriate perioperative and postdischarge analgesia in surgical patients is paramount not only from an ethical perspective but also for avoiding negative consequences associated with pain (e.g., delayed functional recovery, increased postsurgical complications, chronic postoperative pain).1 The inflammatory phase of wound healing typically lasts approximately 72 hours, which is recommended as the minimum amount of time analgesics should be provided following surgery.2 While an animal is hospitalized, postsurgical pain can generally be well controlled with a multimodal approach using injectable opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and local anesthetics. However, most veterinary surgical patients are discharged from the veterinary hospital within 24 hours after surgery, and the tools for providing effective postoperative analgesia in the home environment are very limited.
An extended-release formulation of the local anesthetic bupivacaine (Exparel; Pacira Pharmaceuticals, pacira.com) became available for humans in 2011, and its counterpart (Nocita; Elanco, elanco.com) was recently approved for use in dogs and cats. A single injection of this bupivacaine formulation provides analgesia for up to 72 hours.3 This drug may therefore have significant utility in addressing the unmet need for effective postoperative analgesia in the home environment.
Overview of Local Anesthetics
Local anesthetics block cell membrane sodium channels on neurons, thus preventing membrane depolarization, nerve excitation, and propagation of nociceptive signals. The use of local anesthetics is one of the most effective means of providing analgesia. Indeed, the only available analgesics that can completely block perioperative pain are local anesthetics, which are used via various routes, such as wound/tissue infiltration, regional nerve blocks, neuraxial injection (intrathecal, epidural), and injection through catheters (soaker, perineural).4-7 Local anesthetics have been shown to provide enhanced multimodal analgesia with little risk for untoward effects.8 Therefore, the routine use of local anesthetics is recommended, as outlined in recent veterinary pain management guidelines.1,9
However, single injections of currently available local anesthetics have a relatively short duration of action, limiting their ability to sufficiently cover the postoperative time period. Bupivacaine is one of the longest-acting local anesthetic drugs, but its duration of action is generally considered to be 6 to 8 hours.10 The placement of a catheter and intermittent administration of local anesthetic through the catheter has been described as a technique to extend the duration of local anesthetic-attributable analgesia.6 Although this technique has been reported to be very effective, home management of the catheter is of understandable concern. The availability of an extended-release formulation of bupivacaine is an important recent advance in clinical medicine.
Bupivacaine Liposome Injectable Suspension
Indications and Injection Techniques
Bupivacaine liposome injectable suspension (BLIS) comprises multivesicular liposomes. Each vesicle is composed of a phospholipid bilayer encapsulating an aqueous core and bupivacaine (FIGURE 1). After injection, these vesicles break down, gradually releasing bupivacaine over an extended period of time to provide analgesia for up to 72 hours.2 Although data have not been reported in animals, the onset of action of BLIS in humans is considered to be within 2 to 5 minutes.11
The technique for instilling BLIS differs from that used for traditional bupivacaine formulations. BLIS can be injected into tissue layers or around nerves to provide analgesia, but it may not be effective for blocks that require migration of local anesthetics (e.g., testicular block). This is because the liposomes are too large (10 to 30 µm) to move throughout the tissue. Once released from the vesicles, the bupivacaine moves through tissue as other bupivacaine solutions do. However, because it is initially locked into the vesicles of the liposomes and released slowly, the recommendation is to instill BLIS close to where the effect is required.
The BLIS product Nocita has been approved by the U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine for use in dogs and cats. In dogs, BLIS is approved for single-dose (5.3 mg/kg) infiltration into the surgical site at the time of incisional closure for cranial cruciate ligament (CCL) surgery. A “moving needle technique” is used to inject the BLIS into all tissue layers within the surgical field12 (FIGURE 2). In this technique, the needle is inserted approximately 0.5 to 1 cm into the tissue plane, and BLIS is injected while the needle is slowly withdrawn. A 25-gauge or larger needle should be used for injection, as a smaller diameter can disrupt the liposomes.
If a larger volume of drug is required, BLIS may be diluted, according to the package insert, with an equal amount of sterile 0.9% normal saline or lactated Ringer’s solution to ensure adequate coverage of the area to be infiltrated.
In cats, BLIS is approved for use as a peripheral nerve block before onychectomy (5.3 mg/kg per forelimb, for a total dose of 10.6 mg/kg/cat). BLIS must be deposited close to the targeted nerve; otherwise, limited diffusion of local anesthetic across tissue layers may decrease the efficiency of the block. Although the on-label use of BLIS is currently limited, it is commonly used off-label in both dogs and cats for tissue infiltration in other surgeries and nerve blocks.13,14
Two published clinical trials evaluated the efficacy of BLIS in dogs.3,15 In the placebo-controlled, randomized, multicenter pilot study, 46 dogs were randomly assigned to receive surgical site tissue infiltration of either BLIS or saline before wound closure following CCL surgery.3 A subjective pain score was used to evaluate pain at multiple time points postoperatively. This study demonstrated that BLIS provided pain relief that was significantly superior to saline over a 72-hour period.
A recently published paper compared the efficacy of BLIS and 0.5% bupivacaine for the control of postoperative pain in dogs undergoing tibial plateau leveling osteotomy.15 The dogs were evaluated at multiple time points using subjective pain scales and pressure algometry, and rescue analgesia (opioid) was administered if necessary. This study found that dogs receiving BLIS were significantly less likely to require rescue analgesia and received significantly fewer opioid doses than dogs administered 0.5% bupivacaine, demonstrating superior efficacy of BLIS over 0.5% bupivacaine for postoperative analgesia.
Published trials on the use and efficacy of BLIS in cats are sparse. In a noninferiority study, cats received an incisional block using BLIS or bupivacaine hydrochloric acid (HCl) followed by daily NSAID injection after an ovariohysterectomy.13 Pain was assessed at multiple time points postoperatively and compared between groups up to 42 hours after surgery. The authors concluded that the BLIS incisional block was as efficacious as 0.5% bupivacaine, but the median pain score at all times was 0, with mean pain scores being very low (<0.5 on a scale of 0 to 20) and group differences were very small, tending to favor BLIS. The low pain scores suggest that the patients experienced insufficient pain to test the 2 treatments or that there were problems with the assessment of pain.
Other descriptive information for the efficacy of BLIS in cats is available from the package insert. In the randomized, placebo-controlled, multicenter study, a 4-point perineural block was used to evaluate the analgesic effect of BLIS in cats undergoing an onychectomy. Pain was assessed at multiple time points following surgery, and cats were classified as treatment success/failure based on the score. The results demonstrated that the percentage of treatment success for the BLIS-treated group was significantly greater than that for the placebo-treated group.
BLIS is preservative free, and, according to the label, the contents of the vial should be used within 4 hours following the first withdrawal from a vial. However, a recent study evaluated bacterial and fungal growth over a 5-day period of repeated, daily withdrawal of BLIS from single-use vials.16 The results showed that when aseptic technique was used, BLIS remained sterile for 5 days when stored under both refrigerated and room-temperature conditions. Additionally, neither condition resulted in a significant change in the concentration of free, unencapsulated bupivacaine for 4 days. Thus, it appears the single-use BLIS vials may be used for up to 4 days as multidose vials as long as aseptic technique is used.
BLIS should not be administered intravascularly. Consequently, aspiration should be used to confirm the absence of intravascular needle positioning before BLIS injection and repeated when the needle is repositioned. If accidental intravascular administration occurs, subjects should be monitored for adverse cardiovascular (dysrhythmias, hypotension, hypertension) and neurologic (tremors, ataxia, seizures) reactions.
Currently, intra-articular injection of BLIS is not recommended, as bupivacaine HCl is toxic to chondrocytes.17 However, recent studies in other species showed that a single injection of BLIS appears to have minimal toxicity to chondrocytes, which is presumably due to the slower release over time resulting in lower overall exposure to bupivacaine.18,19 Additionally, BLIS has not been evaluated for use in dogs younger than 5 months or dogs that are pregnant, lactating, or intended for breeding. The extralabel administration of BLIS as an incisional block in lactating bitches after cesarean section has been used at the authors’ institution.
BLIS Side Effects and Precautions
The safety of BLIS has been extensively studied in dogs as part of the development of BLIS for human use.20-22 These studies have centered on the local and systemic safety and tolerability of the drug (up to 30 mg/kg) after tissue infiltration and perineural injection. Although a minor inflammatory response at the injection site was observed, no clinically meaningful side effects associated with BLIS were seen. Of note, across all these studies, plasma concentrations following injection of BLIS were approximately 3- to 6-fold lower than those seen after an equivalent dose of bupivacaine HCl solution, with an average (± standard deviation) maximum plasma concentration (Cmax) of approximately 500 (±500) ng/mL after a 9 mg/kg dose. For context, seizures have been reported to occur at bupivacaine Cmax of 18,000 ng/mL.23
In another study, BLIS was injected via various routes (intravascular, intrathecal, epidural) in dogs to evaluate local and systemic safety and tolerability. The results indicated that BLIS has a favorable safety profile compared with bupivacaine HCl via any of these routes.24 However, these routes are not recommended. Indeed, from this work, it appears that if 9 mg/kg of BLIS is injected intravenously, systemic side effects can occur. Interestingly, less motor blockade is reported with BLIS than an equivalent dose of bupivacaine HCl in dogs when used epidurally.24
Clinicians should always anticipate that extralabel perineural injection of BLIS could cause motor and sensory blockade after surgery. Other reported side effects in dogs following the use of BLIS during the clinical studies performed for approval include incisional discharge and inflammation, bradycardia, and vomiting.3 In cats, other reported side effects from the clinical studies performed for approval include elevated body temperature and injection site erythema.21
Generally, cats are more sensitive to local anesthetics, with toxic doses being approximately half those in dogs.23,25 Safety studies of BLIS have been performed in cats, as reported in the package insert/Freedom of Information summary.26 Up to 31.8 mg/kg of BLIS was injected using a suprainguinal approach for a femoral nerve block. In this study, there were no clinically relevant treatment-related effects on electrocardiograms, bloodwork, or urinalysis. A minor local inflammatory response was observed in dogs; however, no clinically meaningful treatment-related findings were observed on histopathology of soft tissue and the femoral nerve at the injection sites.
BLIS Interactions With Other Drugs
As BLIS may not release adequate bupivacaine concentrations to desensitize the surgical site at the initial time of administration, coadministration of BLIS with bupivacaine HCl has been proposed to decrease the time to onset of efficacy when using BLIS in humans.27 However, this technique is unlikely necessary, since the onset time of BLIS is very fast.11 If used, it is recommended that BLIS should only be mixed with 0.5% bupivacaine HCl up to an equal volume. The FDA-approved label states that BLIS should not be mixed with other local anesthetics (lidocaine, ropivacaine, mepivacaine), as this has been shown to result in substantial disruption and release of free bupivacaine from liposomes.28 It also cautions there is potential for toxicosis when these drugs are used simultaneously; however, at the authors’ institution, preoperative local or regional blocks are routinely performed, followed by BLIS the time of closure. Interactions between BLIS and other drugs (e.g., epinephrine, corticosteroids, antibiotics, NSAIDs, opioids) and implant materials (e.g., polypropylene, stainless, titanium) have been studied, but no clinically meaningful interactions were found.28 Therefore, BLIS may be safely coadministered with these agents, and a multimodal approach to analgesia is recommended.
Effects of Physical Treatments on Release of BLIS
The lipid bilayers are dynamic, and they can be destabilized by several factors, including pH and temperature. Such destabilization can disrupt the desired release profiles by causing leakages or burst release of the encapsulated drug. However, the effects of physical therapy (therapeutic ultrasound, cold therapy, hot therapy) on bupivacaine release from liposomes remains unknown at this time.
BLIS is an extended-release formulation of bupivacaine, and a single injection of BLIS can provide up to 72 hours of analgesia. Although few clinical studies have been published, BLIS appears to be a very useful and safe method of providing effective postoperative pain relief in dogs and cats.
1. Epstein M, Rodan I, Griffenhagen G, et al. 2015 AAHA/AAFP pain management guidelines for dogs and cats. JAAHA 2015;51:67-84.
2. Lascelles BDX, Shaw KK. An extended release local anaesthetic: potential for future use in veterinary surgical patients? Vet Med Sci 2016;2(4):229-38.
3. Lascelles BDX, Rausch-Derra LC, Wofford JA, Huebner M. Pilot, randomized, placebo-controlled clinical field study to evaluate the effectiveness of bupivacaine liposome injectable suspension for the provision of post-surgical analgesia in dogs undergoing stifle surgery. BMC Vet Res 2016;12(1):168.
4. Grubb T, Lobprise H. Local and regional anaesthesia in dogs and cats: descriptions of specific local and regional techniques (part 2). Vet Med Sci 2020;6(2):218-234.
5. Marolf V, Luyet C, Spadavecchia C, et al. Use of a perineural coiled catheter at the sciatic nerve in dogs after tibial plateau levelling osteotomy – preliminary observations. Vet Med Sci 2015;1(2):39-50.
6. Abelson AL, McCobb EC, Shaw S, et al. Use of wound soaker catheters for the administration of local anesthetic for post-operative analgesia: 56 cases. Vet Anaesth Analg 2009;36(6):597-602.
7. Sarotti D, Rabozzi R, Franci P. Comparison of epidural versus intrathecal anaesthesia in dogs undergoing pelvic limb orthopaedic surgery. Vet Anaesth Analg 2015;42(4):405-413.
8. Dickerson DM, Apfelbaum JL. Local anesthetic systemic toxicity. Aesthet Surg J 2014;34(7):1111-1119.
9. Mathews K, Kronen PW, Lascelles D, et al. Guidelines for recognition, assessment and treatment of pain: WSAVA Global Pain Council members and co-authors of this document. J Small Anim Pract 2014;55(6):E10-E68.
10. Lerche P, Aarnes TK, Covey-Crump G, Taboada FM. Handbook of Small Animal Regional Anesthesia and Analgesia Techniques. Chichester, West Sussex, UK: John Wiley & Sons; 2016:10-19 .
11. Apseloff G, Onel E, Patou G. Time to onset of analgesia following local infiltration of liposome bupivacaine in healthy volunteers: a randomized, single-blind, sequential cohort, crossover study. Int J Clin Pharmacol Ther 2013;51(5):367-73.
12. Joshi GP, Janis JE, Haas EM, et al. Surgical site infiltration for abdominal surgery: a novel neuroanatomical-based approach. Plast Reconstr Surg Glob Open 2016;4(12):e1181.
13. Gordon-Evans WJ, Suh HY, Guedes AG. Controlled, non-inferiority trial of bupivacaine liposome injectable suspension. J Feline Med Surg 2019:1098612X19892355 [online ahead of print].
14. Grubb T, Lobprise H. Local and regional anaesthesia in dogs and cats: overview of concepts and drugs (part 1). Vet Med Sci.
15. Reader RC, McCarthy RJ, Schultz KL, et al. Comparison of liposomal bupivacaine and 0.5% bupivacaine hydrochloride for control of postoperative pain in dogs undergoing tibial plateau leveling osteotomy. JAVMA 2020;256(9):1011-1019.
16. Carlson AR, Nixon E, Jacob ME, Messenger KM. Sterility and concentration of liposomal bupivacaine single-use vial when used in a multiple-dose manner. Vet Surg 2020;49(4):772-777.
17. Hennig GS, Hosgood G, Bubenik-Angapen LJ, et al. Evaluation of chondrocyte death in canine osteochondral explants exposed to a 0.5% solution of bupivacaine. Am J Vet Res 2010;71(8):875-883.
18. Shaw KA, Moreland C, Jacobs J, et al. Improved chondrotoxic profile of liposomal bupivacaine compared with standard bupivacaine after intra-articular infiltration in a porcine model. Am J Sports Med 2018;46:66-71.
19. Knych HK, Mama KR, Moore CE, et al. Plasma and synovial fluid concentrations and cartilage toxicity of bupivacaine following intra-articular administration of a liposomal formulation to horses. Equine Vet J 2019;51(3):408-414.
20. Richard BM, Rickert DE, Newton PE, et al. Safety evaluation of EXPAREL (DepoFoam bupivacaine) administered by repeated subcutaneous injection in rabbits and dogs: species comparison.
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21. Richard BM, Newton P, Ott LR, et al. The safety of EXPAREL® (bupivacaine liposome injectable suspension) administered by peripheral nerve block in rabbits and dogs. J Drug Deliv 2012;2012:962101.
22. Richard BM, Ott LR, Haan D, et al. The safety and tolerability evaluation of DepoFoam bupivacaine (bupivacaine extended-release liposome injection) administered by incision wound infiltration in rabbits and dogs. Expert Opin Investig Drugs 2011;20(10):1327-1341.
23. Feldman HS, Arthur GR, Covino BG. Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog. Anesth Analg 1989;69(6):794-801.
24. Joshi GP, Patou G, Kharitonov V. The safety of liposome bupivacaine following various routes of administration in animals. J Pain Res 2015;8:781-789.
25. de Jong RH, Ronfeld RA, DeRosa RA. Cardiovascular effects of convulsant and supraconvulsant doses of amide local anesthetics. Anesth Analg 1982;61(1):3-9.
26. Freedom of Information Summary for Supplemental Approval of NADA 141-461 NOCITA®. animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/3952. Accessed April 6, 2020.
27. Eppstein AC, Sakamoto B. The novel use of different bupivacaine preparations with combined regional techniques for postoperative pain management in non-opioid-based laparoscopic inguinal herniorrhaphy. J Clin Anesth 2016;34:403-406.
28. Kharitonov V. A review of the compatibility of liposome bupivacaine with other drug products and commonly used implant materials. Postgrad Med 2014;126(1):129-138.