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colic, both for management of pain and inflammation, and to aid in clinical decision-making. It is a very common field practice to refer colic cases which do not respond favourably to pain control at the farm to a secondary care facility for further assessment and treatment. Colic pain which does not relent following administration of NSAIDs and/or sedatives is commonly considered an indication that a patient may require surgical intervention (Duz 2019). However, the use of NSAIDs in critical cases of any species has always been controversial (Cook and Blikslager 2015). In fact, their use is considered contraindicated in small animals and humans with critical clinical derangements including any kind of gastrointestinal disease (Mathews 2000). This is due to the significant risk of serious renal and gastrointestinal side effects from NSAID treatment (Marshall and Blikslager 2011). Both then and now, clinicians know that treatment of endotoxaemia is dependent on first reducing or eliminating the underlying cause and cannot rely solely on anti- inflammatory drugs and supportive care. Of course, a veterinary team’s ability to eliminate the original pathology is limited by the patient’s current clinical condition and the tools and facilities available (Moore 1988).


Nonselective and selective NSAIDs


NSAIDs work by inhibiting COX enzymes. However, there are two clinically relevant isoforms of COX in horses, COX-1 and COX-2, each having important and relatively distinct physiology and expression (Vane 1971; Vane and Botting 1995). Due to these differences in COX-isoenzyme physiology, newer COX-selective drugs which allow targeted inhibition of select isoforms have been developed and are available for use in horses (Ziegler et al. 2017). It is important to understand the differences in the physiology and pathophysiology of the two main COX isoenzymes when considering use of selective NSAIDs in horses. Both COX isoforms synthesise prostaglandin H2 from arachidonic acid, which is further metabolised by tissue synthetases to active thromboxanes and prostaglandins (collectively termed prostanoids). Important for many homeostatic functions, COX-1 is constitutively expressed in most tissues and is required at low levels for normal gastrointestinal function, coagulation and renal physiology. Specifically, low-level, continuous COX-1 activity in the gastrointestinal tract and the kidneys steadily produce low concentrations of prostaglandin H2, which is rapidly converted to low levels of prostanoids required to support intestinal barrier and renal perfusion functions. Conversely, with the exception of the kidney where there is some constitutive COX-2 expression for physiological renal function, COX-2 expression is normally very low in most tissues and is induced during pro-inflammatory states. Upregulation of COX- 2 in disease massively increases production of prostaglandin H2 producing pathological amounts of downstream prostanoids, leading to systemic inflammation and pain. Traditional NSAIDs such as


flunixin meglumine,


phenylbutazone and aspirin inhibit both COX isoforms and are thus termed nonselective NSAIDs. These nonselective drugs inhibit the normal physiological functions of COX-1, which results in significant risk of adverse gastrointestinal and renal effects (Vane and Botting 1995; Cook and Blikslager 2015). Thus, COX-2-selective NSAIDs have been introduced to the market with the intention of reducing adverse effects of COX-1 inhibition (Blikslager 1999). Meloxicam, a moderately


COX-2-selective NSAID, is labelled for use in horses for the control of orthopaedic and gastrointestinal pain and inflammation in the UK. Recently, more highly COX-2-selective NSAIDs termed coxibs have entered the veterinary market,


including deracoxib, mavacoxib, robenacoxib, cimicoxib and firocoxib (Bienhoff et al. 2012; Reymond et al. 2012; Kim et al. 2014, 2015; Payne-Johnson et al. 2015). In the USA and UK, only firocoxib is commercially available, and in the USA it is labelled specifically for the management of osteoarthritis in horses at a recommended dosage of 0.3 mg/kg i.v. for a loading dose followed by 0.1 mg/kg i.v. every 24 h thereafter (Cox et al. 2013).


Potential benefits of selective NSAIDs in strangulating colic cases


Due to the COX-1 sparing activity of newer selective NSAIDs, there has been increased interest in the potential benefits of using these rather than nonselective NSAIDs like flunixin or phenylbutazone in horses with gastrointestinal clinical signs. Recent preclinical trials to test effects of nonselective NSAIDs on intestinal barrier function and repair in horses have shown that inhibition of both COX isoenzymes with flunixin meglumine causes increased intestinal permeability to LPS in horses with experimentally induced small intestinal strangulating obstruction (SISO) (Cook et al. 2009). Researchers hypothesised that COX-2 selective NSAIDs would spare COX-1 activity and thus improve barrier repair after ischaemic injury. Subsequent preclinical trials found that experimentally SISO-injured horses treated with the modestly


COX-2-selective meloxicam or the highly COX-2-selective firocoxib had significantly lower intestinal permeability versus horses treated with flunixin meglumine (Little et al. 2007; Cook et al. 2009; Naylor et al. 2013). Based on these findings, researchers conducted a randomised controlled clinical trial to test the hypothesis that treatment of actual colic cases after surgical correction of SISO with COX-2-selective firocoxib would have reduced signs of endotoxaemia as compared to nonselective flunixin while providing effective control of pain. This study of 56 cases found a decreased risk of elevated plasma sCD14 (as a marker of endotoxaemia) in horses treated with firocoxib as compared to flunixin, while providing similar effective pain control (Ziegler et al. 2019). This is presumably due to reduction of the underlying source of endotoxin by promoting gut barrier repair through preserved COX-1 activity while effectively controlling pro-inflammatory COX-2 activity. No differences were found in clinical signs of endotoxaemia or survival outcomes, but interpretation of this study is limited by relatively low numbers of horses and a lack of NSAID randomisation in the field prior to referral (which resulted in all horses receiving flunixin prior to surgery, thereby potentially lessening the apparent benefitof firocoxib) (Ziegler et al. 2019).


Important considerations for COX-2 inhibitor use in horses with colic


COX-2 inhibitors first entered the human market for the treatment of pain and inflammation associated with osteoarthritis in people with the same intended advantage of reduced adverse gastrointestinal effects as compared to nonselective NSAIDs (Simon et al. 1999; Bombardier et al. 2000). Although effective in the treatment of degenerative


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