EQUINE VETERINARY EDUCATION Equine vet. Educ. (2020) 32 (11) 611-616 doi: 10.1111/eve.13189


Hypothesis Article


Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic


A. L. Ziegler†‡ and A. T. Blikslager‡* †Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina; and ‡Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North


Carolina, USA


*Corresponding author email: Anthony_blikslager@ncsu.edu Keywords: horse; NSAIDs; COX-selective; colic; endotoxaemia; gut barrier


Summary Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1- driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.


NSAID use in horses


Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in horses to alleviate pain and inflammation associated with a wide range of disease. Most commonly, NSAIDs are used to treat soft tissue injury, degenerative joint disease and colic (Clark and Clark 1999; Goodrich and Nixon 2006; Knych 2017). There are currently six NSAIDs labelled for use in horses approved by the United States Food and Drug Administration (FDA), and numerous others are often used off-label in the USA and other countries (Knych 2017). For example, though not approved by the FDA for use in horses in the USA, meloxicam is routinely used for the treatment of orthopaedic pain in other countries (Knych 2017). NSAIDs reduce inflammation by inhibiting cyclo-oxygenase (COX) enzymes to prevent the production of pro-inflammatory eicosanoids (such as thromboxane, prostacyclin and prostaglandin E2) from arachidonic acid during injurious events including colic (Fig 1). However, due to their potent efficacy in blocking these COX enzymes, there are also important and potentially serious side effects associated with their use (Fig 1). This is because metabolites of the arachidonic acid pathway are critical for maintaining homeostasis. Furthermore, eicosanoid production is a normal response to tissue injury, playing


important roles in initiating signalling for tissue repair. Overall, the benefits of NSAID therapy must be carefully weighed against potential risks, particularly with long-term use, or in cases with comorbidities affecting coagulation, renal or gastrointestinal function.


Endotoxaemia in colic


Injury to the intestinal mucosa during a severe ischaemic colic event can lead to leakage of luminal bacteria and their highly inflammatory and injurious products, including lipopolysaccharide (LPS), into the systemic circulation due to breakdown of the epithelial barrier. Veterinarians have appreciated this presence of LPS, termed endotoxin, in horses with severe colic since the 1960s (Moore et al. 1981a). The development of techniques to isolate and study specific inflammatory mediators in the 1970s and 1980s made it possible to carefully examine the induction and implication of discrete molecules in inflammatory events like colic. In early work to understand endotoxaemia, thromboxane was thought to be the cause of deleterious effects while prostacyclin’s vasodilatory effects were thought to be protective (Hardee et al. 1986). The former was refuted by a 1987 study in which no clinical improvement was seen in endotoxin-challenged ponies when treated with a thromboxane synthetase inhibitor (Semrad and Moore 1987a,b). Researchers realised that, while COX-derived products are implicated in causing the pathological effects of endotoxaemia, endotoxin has the unique ability to induce nearly every host immune response, and the complex litany of clinical signs is likely attributable to a wide variety of effector molecules (Moore 1988). This is captured well by the following quote:


Our [physiological] arsenals for fighting off bacteria are so powerful and involve so many different defense mechanisms, that we are in more danger from them than from the invaders.. . The [endotoxin] macromolecules are read by our tissues as the very worst of bad news. When we sense lipopolysaccharide, we are likely to turn on every defense at our disposal. Lewis Thomas 1974


The challenge of better understanding the complex inflam- matory signalling cascades in endotoxaemic horses is further complicated by the dynamic and fleeting existence of individual mediators. While initial attempts were made to measure LPS in the blood as a biomarker of endotoxaemia to


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