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A Novel Local Anesthetic: Nocita (bupivacaine liposome injectable solution)

By Stephanie Krein, DVM, DACVAA
angell.org/anesthesia
anesthesia@angell.org
617-541-5048

Perioperative analgesia has become recognized as one of the most important parts of providing superior care for dogs and cats before and after surgical procedures. The mainstays of perioperative analgesia include opioids, alpha-2 agonists, ketamine, NSAIDs, and local anesthetics. Each of these drug classes, while providing pain relief, also present their own unique side effects and affect each patient differently. Opioids, for example, are the most commonly used analgesic drugs in veterinary medicine due to their superior safety profile and excellent analgesic properties but are fraught with adverse effects such as dysphoria, vomiting, ileus, nausea, and regurgitation. Local anesthetic drugs, such as bupivacaine and lidocaine, are unique in that they can be used locoregionally instead of systemically, thereby providing analgesia while minimizing side effects. Local anesthetics work by blocking sodium channels along nerves, inhibiting excitation and blocking conduction and nerve transmission. Local anesthetics have both a peripheral effect on the nociceptors at the site of injury as well as a central effect in the spinal cord. They not only act on nociceptors (pain receptors) but also on vascular smooth muscle, nerves, and the heart. Local anesthetics can be administered via several routes, including topical application, spinal anesthesia, epidural injection, intravenous infusion, and regionally by nerve blocks. Many consider local anesthetics to be the only true analgesic due to the fact that they provide pre-emptive analgesia by actually blocking pain transmission vs. the treatment of pain after it occurs.

Recently NOCITA®, bupivacaine liposome injectable suspension, was introduced into the veterinary market by Aratana Therapeutics. This novel therapeutic is approved for use in dogs undergoing stifle surgery and intended to provide 72 hours of post-operative pain relief.  It is labeled for single dose administration and uses within 4 hours. NOCITA acts by releasing the local anesthetic bupivacaine slowly over 72 hours from the injection site. The liposomal technology, named DepoFoam® bupivacaine, has been used with much success in human medicine since 2011.1 DepoFoam technology involves multivesicular liposomes that encapsulate aqueous bupivacaine. The liposomes are made up of nonconcentric lipid bilayers and as these bilayers are broken down by enzymes the bupivacaine is gradually released over 72 hours (Figure 1).2  During the FDA approval of DepoFoam, liposomal bupivacaine was extensively studied in dogs and was found to be well tolerated and have an acceptable safety profile.3,4

Figure 1. Microscopic structure of a liposome. https://www.researchgate.net/figure/Cross-sectional-diagram-of-DepoFoam-containing-bupivacaine-Image-supplied-courtesy-of_232226382

 

Figure 2. The moving needle technique. http://nocita.aratana.com/dosingandadministration-2

 

NOCITA is administered by the surgeon at the site of surgery using the moving needle technique (Figure 2).5 Once the bupivacaine is released from the liposome after the lipid bilayers are broken down, its pharmacokinetics and pharmacodynamics are expected to be similar to bupivacaine HCL.6 Bupivacaine elimination depends largely on binding to plasma proteins in systemic circulation and hepatic metabolism. Excretion of bupivacaine is mainly performed by the kidneys. In patients with marked hepatic disease or dysfunction, NOCITA should be used with caution as they may be more prone to toxicities of local anesthetics such as seizures, tremors, or circulatory collapse. Many surgeons worry about delayed wound healing with local anesthetics but studies have shown this not to be a problem with the use of NOCITA.7  Another study showed that local irritation or tissue damage was mild with the use of liposomal bupivacaine, but that swollen or thickened injection sites can be seen.8  Overall it seems that the adverse effects noted with the use of NOCITA are minimal in comparison to the excellent analgesia provided by the drug.

Although at this time NOCITA is approved only for use in dogs undergoing stifle surgery, it is also used off label in both dogs and cats. NOCITA is prescribed for use in procedures associated with severe post-operative pain such as thoracotomies or amputations. Prior to the use of NOCITA in these procedures, diffusion catheters were placed at the surgical site allowing infusion of local anesthetic to provide post-operative analgesia for 24 hours. Adverse effects of diffusion catheters included seroma formation, irritation at the catheter site, infection at the site, or accidental intravascular injection. The use of NOCITA avoids the need for a diffusion catheter at the surgical site, also avoiding the adverse effects noted with diffusion catheter use. Subjectively, patients receiving NOCITA have seemed very comfortable and have required fewer systemic analgesics. It is of the author’s opinion that these patients also seem to eat sooner after the procedure and are more mobile than the patients prior to the use of NOCITA. Other procedures in which NOCITA can be used off label include mastectomies, mass removals, or fracture repairs in both dogs and cats.

The introduction of NOCITA into the veterinary market has allowed us to greatly improve how we provide post-operative analgesia to our patients. Unlike locoregional anesthesia techniques, including epidurals or peripheral nerve blocks, the proper use of NOCITA can be easily learned and used by all practitioners. Although expensive, the benefits of adding NOCITA to a practice’s arsenal of available analgesic drugs will greatly outweigh the costs when it comes to patient comfort and client satisfaction. Hopefully in the future, the label use of NOCITA will be expanded for use in both dogs and cats and in many different surgical procedures.

 

References:

  1. Chahar P, Cummings KC. Liposomal bupivacaine: a review of a new bupivacaine formulation. J Pain Res. 2012;5(257):264.
  2. Lascelles BDX, Rausch-Derra L, 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.
  3. 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.
  4. Richard BM, Newton P, Ott LR. The safety of EXPAREL (bupivacaine liposome injectable suspension) administered by peripheral nerve block in rabbits and dogs. J Drug Deliv. 2012;2012:96210.

5 .www.aratana.com/therapeutics/post-operative-pain/

  1. Spector MS, Zasadzinski JA, Sankaran MB. Topology of multivesicular liposomes, a model biliquid foam. Langmuir. 1996;12(20): 4704-4708.
  2. 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.
  3. Richard BM,Rickert DE, Newton PE. Safety evaluation of EXPAREL (DepoFoam bupivacaine) administered by repeated subcutaneous injection in rabbits and dogs: Species comparison. J Drug Deliv. 2011; 2011:467429.
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