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joint disease, two COX-2 inhibitors produced unexpected adverse thromboembolic effects and were voluntarily withdrawn from the human market. These effects in people are thought to be the result of inhibition of COX-2 (reducing vasodilatory prostaglandin E2) and a lack of inhibition of COX-1 (permitting thrombogenic thromboxane A2) (Sibbald 2004; Atukorala and Hunter 2013). In light of this history, some veterinarians have expressed concern about increased risk of thromboembolic effects in critical, possibly already pro- thrombotic horses when treated with COX-2-selective drugs (Freeman 2019). However, while horses are similarly susceptible to the gastrointestinal side effects seen in humans, they are not known to be susceptible to these prothrombotic side effects from COX-2-selective NSAIDs. Importantly, clinical trials testing COX-2-selective NSAIDs in critical equine cases reported no differences in thrombotic events such as thrombosed jugular veins (Naylor et al. 2013; Freeman 2019; Ziegler et al. 2019). COX-selective NSAIDs will have the equivalent potential


to mask signs of surgical colic pain as nonselective flunixin meglumine, and this masking effect may be prolonged by the increased half-life of 24-h-dosed firocoxib. Attending veterinarians should bear this in mind when selecting 24-h- dosed analgesics to treat a potential surgical case. In addition, COX-2-selective NSAIDs still carry some risk for renal complications due to the presence of some physiologic COX- 2 activity in the kidneys, although nonselective NSAIDs will have the same effect because of their ability to inhibit COX-2 as well as COX-1. Therefore, similar care must be taken when prescribing any NSAID to clinically ill and potentially dehydrated cases regardless of COX-selectivity. Finally, specifically with the current available formulation of intravenous firocoxib, there are minor considerations due to observed interactions of the nonaqueous vehicle with intravenous catheter tubing materials. Contrary to widespread belief, the drug does not precipitate in an aqueous solution, but rather turns the clear plastic material of an extension set white. Direct venipuncture is one possible method of administering firocoxib to avoid this, but given the risk of frequent venipuncture and jugular vein thrombosis or inadvertent perivascular injection, an extension set with a port immediately adjacent to the catheter hub can be used,


or blood can be withdrawn into the extension set, giving firocoxib with the whole blood. Both of these manoeuvres avoid any issues with the extension set.


Need for evidence-based veterinary medicine and surpassing potential clinical biases


The unfortunate reality is colic-related deaths still account for more than 30% of mortality in horses 1–20 years of age (USDA 2016). In the USA, approximately 10% of horses colic each year and about 10% of these cases will need surgical intervention to survive (Tinker et al. 1997a,b). Survival rates following surgical correction of severe colic have improved over the past 30–40 years, but complications related to endotoxaemia still claim too many lives (Proudman et al. 2002a,b). To potentially improve the prognosis for surgical cases of colic, every aspect of the Standard of Care must be scrutinised and updated as hypothesis-driven empirical evidence for superior treatment approaches emerge. This includes assessment of relevant outcomes from well designed and appropriately powered studies. In light of what is


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currently known about NSAID use in horses, the scientific veterinary community must build upon a foundation of evidence-based clinical practice and further explore the potential benefits of COX-2-selective NSAID therapy in our critical colic cases. Larger, ideally randomised studies evaluating COX-2 directed therapy in colic cases, particularly if COX-1 activity can be spared at the first NSAID dose on the farm, may reveal superior clinical outcomes and survival rates after colic attributable to SISO. Also, studies to assess the efficacy of COX-2-selective NSAIDs in treating the visceral pain of uncomplicated gas and spasmodic colics may further support use of these drugs as a first-line analgesic for simple colic cases in the field. While visceral pain independent of surgical pain has not yet been studied, it would be informative to compare these analgesics in a model of spasmodic or gas colic, such as the model utilising balloon dilation of the duodenum developed by Sanchez, Merritt and colleagues (Robertson et al. 2005; Elfenbein et al. 2009). Currently, there exists no evidence that flunixin meglumine significantly alters rates of complications or mortality in severe colic or that it provides superior pain control in simple colic, and the idea that this drug is indispensable for every colicking horse should be questioned. The veterinary community has a responsibility to ensure that the equine public are properly educated about the implications of indiscriminate use of flunixin in colic cases and to seriously consider the use of alternative NSAIDs such as COX-2-selective NSAIDs, which can be prescribed by their veterinarians.


Conclusions


It has been shown both pre-clinically and clinically, that the nonselective NSAID flunixin increases evidence of endotoxaemia in horses with severe ischaemic colic by inhibiting recovery of injured mucosa (Tomlinson et al. 2004; Tomlinson and Blikslager 2005; Little et al. 2007; Cook et al. 2008, 2009; Ziegler et al. 2019). As it stands, veterinarians must assess the current scientific evidence and their own individual cases for themselves to decide if COX-2-selective NSAIDs may be preferable for management of colic in the field and hospital. The use of selective COX-2-selective anti- inflammatory drugs in place of conventional nonselective anti- inflammatory drugs as the preferred first-line treatment for colic cases would be further supported by examining complication and survival outcomes in larger numbers of horses with drug randomisation beginning at the onset of field management. There is a COX-2-selective anti-inflammatory drug, firocoxib, labelled for use in horses which has been shown to reduce the potential complications of flunixin while providing appropriate pain control (Ziegler et al. 2019). Ultimately, these authors suggest that current Standard of Care for colic cases should be continually evaluated by hypothesis-driven research that seeks to provide evidence to support efficacy and avoid following inherently biased, anecdotal clinical opinion.


Authors’ declaration of interests No conflicts of interest have been declared.


Ethical animal research Ethical review not applicable to this article.


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