Inflammation & Non-Steroidal Anti-Inflammatories in Horses

Inflammation. It’s a word commonly associated with poor health outcomes. Yet a certain amount of inflammation is absolutely crucial to health and wellbeing in our horses. Some inflammation is essential to promote normal immune function; repair muscles, bones, tendons and ligaments after exercise; and even facilitate healthy digestive function.

Problems start to occur when levels of inflammation are excessive, and/or occur for extended periods of time- beyond that which the body needs for normal healthy repair and functioning. Inhibiting the body’s own repair and defence mechanisms however, can also be problematic.

Non-steroidal anti-inflammatories (NSAIDs) are one of the most widely used classes of drugs in horses. The most commonly used NSAIDs in equines include phenylbutazone (bute), flunixin meglumine (commonly sold under brand names including Banamine, Finadyne, Flu-Nix, Flunixamine), firocoxib (Equioxx, Previcox) and meloxicam (Metacam).

How do Non- Steroidal Anti-Inflammatories Work?

When it comes to using NSAIDs in horses and ponies, understanding how these drugs work can help to make an informed approach about their appropriate use.

Non-steroidal anti-inflammatory drugs work on a chemical level. They inhibit the effects of special enzymes: specifically cyclooxygenase (COX)-1 and COX-2 enzymes. These enzymes play a key role in making prostaglandins which promote inflammation. By blocking the COX enzymes, NSAIDs reduce the production of prostaglandins and in turn inflammation. It is important to remember that other inflammatory pathways exist in the horse: COX-1 and COX- 2 are most commonly targeted.

COX-1 is expressed in nearly all tissues in the horse’s body and is necessary for proper gastrointestinal (GI) function, renal (kidney) function, and blood coagulation. COX-2 is also expressed at low levels in many tissues, contributing to normal kidney function and interestingly, playing a critical role in the healing of the gastrointestinal (GI) mucosa (cells lining the GI).

The potential risks

Most people are well aware of the deleterious effects the use of NSAIDs can have on the GI lining in our horses. Although ulcers commonly come to mind, the effects of these drugs on the digestive tract of our horses extend far beyond this. In the case of phenylbutazone and flunixin, the production of mucin (which is one of our horse’s internal mechanisms for protecting and maintaining a healthy gut lining) is stopped. This is the primary way in which damage to the GI (including the development of ulcers) can occur with NSAID use. It is critical to note that this occurs regardless of whether the NSAID is given orally or by intravenous (IV) injection. It is not the physical presence of the drug in the GI system that causes the damage, it is the changes in inflammatory pathways.

It is common practice to give ulcer medications (specifically those containing omeprazole) in conjunction with NSAIDs, with the belief that this may help to offset the detrimental effects to the GI. Research has demonstrated however, that this practice can further compound damage caused to the GI mucosa. This is likely due to changes in blood flow to the gut lining and shifts in protective microflora of the GI.

Changes to GI microflora associated with NSAID use is a lesser discussed but equally important aspect in terms of our horse’s health. Although beyond the scope of this article, specific microflora serve crucial protective and anti-inflammatory actions in the GI of our horses. Significant changes in these fine balances of microflora can occur in association with NSAID use. This in turn has significant implications on the nutritional status of our horses. To read further on this topic visit the Gastrointestinal (Gut) Health heading in ‘Article’ section of the Optim Equine website.

Research has also indicated that the use of NSAIDs following hard work, competition or training is likely to inhibit desired adaptations and proper recovery to the exercise undertaken. Changes in blood flow and cellular repair mechanisms vital for proper recovery are altered by the use of NSAIDs. The practice of giving NSAIDs as a precautionary or ‘preventative’ method after hard work, racing, competition or training may in fact work against what is trying to be achieved.

What about selective and preferential COX-2 inhibitors?

In more recent years, the use of NSAIDs that selectively or preferentially inhibit COX-2 and don’t (in theory) inhibit COX-1 may cause fewer adverse effects than nonselective NSAIDs. Examples of these drugs include firocoxib and meloxicam.

Selective COX-2 inhibitors don’t entirely spare COX-1. They also inhibit COX-1 to a small degree, but generally carry a lower risk for direct damage to the gut lining. An interesting point to note is although COX-2 selective drugs may decrease the risk of developing GI ulcers compared to non-selective NSAIDs, they can impair the healing of pre-existing ulcers.  Additionally, similar to non-selective NSAIDs, COX-2 inhibitors are associated with changes in gut microflora, which in turn can lead to adverse effects on the GI system.

It is important to note that COX-2 is involved in normal, healthy kidney and cardiovascular function (thus administration of selective COX-2 inhibitors can still cause adverse renal and hameodynamic effects in susceptible horses).

The dosage amounts of COX-2 inhibitors needs to be taken into account when evaluating their potential risks and side effects. When COX-2 inhibitors are used in higher doses, their ability to be selective in their action on COX-2 enzymes decreases. That is, higher doses may cause effects similar to those of nonselective NSAIDs. Combining NSAIDs (for example, administering firocoxib and phenylbutazone together) has also been shown to increase the risk for adverse effects, including that to the kidneys.

Takeaways

Non-steroidal anti-inflammatories have their place in illness and injury in horses and like all drugs, their use should be judicious. Selective and preferential COX-2 inhibitors may have less adverse effects on the GI system than non-selective NSAIDs, but still come with risks. Appropriate dietary, nutraceutical and supplementation practices may help to decrease detrimental effects to the GI, cardiovascular system and kidneys associated with NSAID use. Employing specific therapeutics and dietary strategies to restore gut mucosal integrity and reinstate a healthy GI microflora following NSAID use is highly advisable. In low and appropriate doses, selective COX 2 inhibitors may be a better choice in reducing adverse side effects when NSAID use is necessitated