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Nocita packaging and drug

NocitaⓇ is fairly new drug on the veterinary market. It is composed of a liposomally encapsulated bupivacaine that confers a slow release of local anesthetic over time, reportedly allowing for 72 hours of pain relief. The initial labeling for dogs is for cranial cruciate ligament surgery and for cats for forelimb onychectomy, as part of a four point block of the forelimbs to be “declawed”.

A similar drug has been on the human market, which is known as ExparelⓇ or DepoFoamⓇ. These drugs are designed to encapsulate the bupivacaine molecules with a special liposomal structure that provides a slow but consistent release of bupivacaine, a long acting local anesthetic, to afford locoregional analgesia for up to 72 hours.

The veterinary formulation is provided as a 13.3 mg/mL solution with a recommended dosing of 5.3 mg/kg or 0.4 ml/kg for injection into the tissue layers during closure for dogs, and the same dosing, (5.3 mg/kg or 0.4 ml/kg) PER forelimb, for a total dose of 10.6 mg/kg or 0.8 ml/kg for cats. The label insert provides a clear diagram of the locoregional technique recommended for cat declaws. Officially dilution of the NocitaⓇ is not recommended, but anecdotally a 1:1 dilution has been used and there are multiple reports in the human literature of various strengths of dilution. Currently it is not recommended to mix another local anesthetic with NocitaⓇ or other liposomal bupivacaine formulations, as there is concern that there may be an impact on the concentration gradient and it may no longer favor release of the bupivacaine if the concentration of bupivacaine is higher outside the liposomes. Again, some anesthesia practices do combine a local anesthetic such as bupivacaine with the NocitaⓇ, which in theory will work to provide a more immediate blockade as well as a delayed release of bupivacaine. Vandepitte et al. 2017 is an example of such a technique and is listed below for further reading. The on-label use is described as above, but there has been some investigation into providing NocitaⓇ into various other locoregional techniques with varying degrees of success.

This brings us to some more recent literature involving the human formulations of liposomal bupivacaine. There are multiple meta-analyses coming from human literature comparing liposomal bupivacaine to non-liposomal local anesthesia provided by various routes in clinical settings that appear to show liposomal bupivacaine not conferring an advantage to non-liposomal local anesthetics or standard bupivacaine formulations. This will be an interesting space to watch as more evidence is gathered about the advantages/disadvantages of liposomal local anesthetics. Though care must be used in the interpretation of these results, as the results from the human literature and the clinical outcomes in our patients may be quite different. Based on the current level of evidence, NocitaⓇ does appear to be useful as a part of a multi-modal analgesia regimen. As in all instances, each patient should have their pain individually and regularly assessed and treated appropriately following any procedure that may cause the patient pain.

On a more optimistic note, NocitaⓇ has been evaluated by multiple studies as to its efficacy and sterility when used in a multi-dose fashion and, if the vial is handled aseptically, the results appear to be quite positive leading to some practices using it off label in a multidose fashion.

NocitaⓇ is contraindicated for intravascular (arterial or venous) injection, as well as intra-articular injection due to chondrotoxicity. Though there is some literature in equine species of intra-articular injection of NocitaⓇ, which suggests it may be a viable therapeutic modality, further studies are needed to determine its effect on chondrocytes and long term outcomes in these patients (Kynch et al. 2018).

Recently there is some published evidence evaluation NocitaⓇ as part of locoregional technique. When used in a tap block, NocitaⓇ provided similar analgesic profile compared to using a mixture of dexmedetomidine and bupivacaine (Campoy, Martin-Flores, Boesch, et al. 2022). When used as part of sciatic nerve block, NocitaⓇ was shown to have a longer duration compared to bupivacaine and dexmedetomidine, though there was some inconsistency in the degree of blockade over time (Campoy, Martin-Flores, Gleed et al. 2022). Though the authors do speculate the lack of difference in analgesia may be related to how the analgesic requirements changed over time in these patients. It may be that the longer duration of analgesia provided by NocitaⓇ may not be required as they get further out from the painful stimulus of surgery.

Overall, NocitaⓇ shows a lot of promise as a part of a mutli-modal anesthesia regimen, along with systemic drugs, but should not be used as a sole postoperative analgesic. It represents a good adjunct for post-operative pain management, particularly in patients where an NSAID may not be appropriate. It will be interesting to see how the literature continues to evolve on the place for NocitaⓇ in our patients. Below are some resources that discuss in greater details some of the points highlighted in this post.

Diagram included in the Nocita package insert

Campoy, L., Martin-Flores, M., Boesch, J. M., Moyal, M. N., Gleed, R. D., Radhakrishman, S., Pavlinac, R. M., Sieger, J. L., Colon, C. S., & Magidenko, S. R. (2022). Transverse abdominis plane injection of bupivacaine with dexmedetomidine or a bupivacaine liposomal suspension yielded lower pain scores and requirement for rescue analgesia in a controlled, randomized trial in dogs undergoing elective ovariohysterectomy. American Journal of Veterinary Research, 83(9).

Campoy, L., Martin-Flores, M., Gleed, R. D., Taylor, L. C., Yant, J. E., & Pavlinac, R. (2022). Block duration is substantially longer with a liposomal suspension of bupivacaine than with 0.5% bupivacaine HCl potentiated with dexmedetomidine following an ultrasound-guided sciatic nerve block in Beagles. American Journal of Veterinary Research, 83(8).

Carlson, A. R., Nixon, E., Jacob, M. E., & Messenger, K. M. (2020). Sterility and concentration of liposomal bupivacaine single‐use vial when used in a multiple‐dose manner. Veterinary Surgery, 49(4), 772-777.

Hussain, N., Brull, R., Sheehy, B., Essandoh, M. K., Stahl, D. L., Weaver, T. E., & Abdallah, F. W. (2021). Perineural liposomal bupivacaine is not superior to nonliposomal bupivacaine for peripheral nerve block AnalgesiaA systematic review and meta-analysis. Anesthesiology, 134(2), 147-164.

Knych, H. K., Mama, K. R., Moore, C. E., Hill, A. E., & McKemie, D. S. (2019). Plasma and synovial fluid concentrations and cartilage toxicity of bupivacaine following intra‐articular administration of a liposomal formulation to horses. Equine veterinary journal, 51(3), 408-414.

Kolade, O., Patel, K., Ihejirika, R., Press, D., Friedlander, S., Roberts, T., ... & Virk, M. S. (2019). Efficacy of liposomal bupivacaine in shoulder surgery: a systematic review and meta-analysis. Journal of shoulder and elbow surgery, 28(9), 1824-1834.

Kuang, M. J., Du, Y., Ma, J. X., He, W., Fu, L., & Ma, X. L. (2017). The efficacy of liposomal bupivacaine using periarticular injection in total knee arthroplasty: a systematic review and meta-analysis. The Journal of arthroplasty, 32(4), 1395-1402.

Vandepitte, C., Kuroda, M., Witvrouw, R., Anne, L., Bellemans, J., Corten, K., ... & Hadzic, A. (2017). Addition of liposome bupivacaine to bupivacaine HCl versus bupivacaine HCl alone for interscalene brachial plexus block in patients having major shoulder surgery. Regional Anesthesia & Pain Medicine, 42(3), 334-341.

Wang, A. Y., Malavasi, L., & Craft, R. (2021). Evaluation of bupivacaine liposome injectable suspension efficacy in single-use vials over five days of multiple use. Veterinary Anaesthesia and Analgesia, 48(6), 956-961.

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