Phenylbutazone (bute) and NSAIDs

By Clare MacLeod

The benefits of non-steroidal anti-inflammatories (NSAIDs)

Non-steroidal anti-inflammatories (NSAIDs) are effective and useful drugs that are mainly used for the treatment of soft tissue inflammation in the horse (Tobin et al, 1986). Inflammation is a useful physiological response to tissue damage which aids healing, but if it persists, it becomes chronic and exacerbates damage (Higgins & Snyder, 2006). The inflammation process involves many mediators and modulators, and drugs acting on these can be useful in interrupting the cascade, breaking chronic inflammation and controlling associated pain.

The most well-known NSAID used in horses is phenylbutazone (bute), but others including flunixine, suxibuzone (Danilon), meloxicam (Metacam) and carprofen are also available for horses.

How NSAIDs work
NSAIDs are a group of drugs that are similar in chemical structure, and work in a similar way, primarily inhibiting one of the enzymes (cyclo-oxygenase, or COX) involved in the inflammatory process (Higgins & Snyder, 2006). There are likely to be other actions that are not yet understood. COX enzymes exist in different forms, and the search is on for NSAIDs that specifically inhibit each form, because most NSAIDs inhibit mostly COX-1, and have detrimental side effects linked to that action.

A certain amount of inflammation is useful and aids healing, but if it persists it is unhelpful so strategies to combat it are required.
A certain amount of inflammation is useful and aids healing, but if it persists it is unhelpful so strategies to combat it are required.

The toxicity of NSAIDs in the horse
Inhibiting inflammatory mediators to reduce chronic inflammation seems quite straightforward, but the COX enzymes produce compounds that are involved in many other body processes, so inhibiting them has a range of side effects (Higgins & Snyder, 2006).

NSAIDs inhibit a hormone that protects the stomach and gut lining, so gut irritation and ulceration are a well-known side effect for both oral and intravenous routes of NSAID administration. These side effects are well understood for phenylbutazone, which, even at moderate doses can cause stomach ulcers, and in high doses can cause colitis, and can lead to plasma-losing enteropathy (leaky gut wall), hypovolemic shock (heart problems due to fluid and blood loss) and death (Higgins & Snyder, 2006).

NSAIDS can be helpful in reducing inflammation but if over-used, some actually have detrimental effects on joint cartilage.
NSAIDS can be helpful in reducing inflammation but if over-used, some actually have detrimental effects on joint cartilage.

Many studies investigating the toxicity of phenylbutazone have been published in the past two decades, with reported side effects including anorexia, depression, colic, hypoproteinemia, diarrhoea, gut erosion and ulceration, weight loss, under-abdominal swelling, kidney and liver damage. Long term doses of phenylbutazone should be maintained under 4.4 mg/kg bodyweight or less to reduce the risk of these side effects (Higgins & Snyder, 2006). Tobin and colleagues (1986) reported that, if phenylbutazone administration was stopped in the early stages of toxicity, the outcome is favourable, but if stopped late in the stages of toxicity, there will be a delayed recovery. They also stated that death may occur up to 50 days after stopping the drug.

There is a high risk of kidney damage in NSAID-treated horses who are dehydrated so maintaining adequate hydration in horses being given these drugs is paramount.

McConnico and colleagues (2008) recommend that veterinarians should monitor certain blood parameters in horses being given high doses of phenylbutazone to check for signs of colitis, which was induced in two out of eight horses given 8.8 mg/kg phenylbutazone orally over 21 days.

Vets should monitor horses being given high doses of phenylbutazone to avoid toxic side effects.
Vets should monitor horses being given high doses of phenylbutazone to avoid toxic side effects.

Some of the newer NSAIDs available for horses may have less detrimental side effects than the older types. For example, meloxicam (e.g. Metacam) is thought to be preferential for COX-2 rather than COX-1, which might slightly reduce its ulcerogenic effects (Higgins & Snyder, 2006; Marshall & Blikslager, 2011). D’Arcy-Moskwa and colleagues (2012) found that meloxicam was associated with less detrimental effects to the integrity of the stomach lining of treated horses compared to phenylbutazone. De Grauw and colleagues (2009) found that meloxicam helped to ‘limit inflammation-induced cartilage catabolism’ in horses with induced joint inflammation, although this was only in the short term.

The manufacturers of the NSAID flunixin state:

“Flunixin meglumine is a non steroidal anti-inflammatory drug (NSAID). Untoward effects include gastrointestinal irritation, ulceration and, in dehydrated or hypovolaemic animals, potential for renal damage” (accessed on 23rd January 2013 at http://www.norbrook.com/roi/products/flunixin-25mg-g-granules-for-horses-roi/)

Other side effects
Higgins and Snyder (2006) recommend ‘judicious use’ of most NSAIDs due to their potential to ‘accelerate cartilage loss’ in joint disease, and ‘retard or prevent fracture healing’. There is some scientific evidence for both, and Beluche and colleagues (2001) reported that giving phenylbutazone in the feed for two weeks significantly decreased proteoglycan synthesis in cartilage, and recommended that ‘chronic administration (of phenylbutazone) can potentiate cartilage damage’.

Unlike most of the other NSAIDs, carprofen has a beneficial effect on joint cartilage (Higgins & Snyder, 2006).

We all want to keep our athletic horses sound, but experts recommend ‘judicious use’ of most NSAIDs to ensure their detrimental effects don't outweigh their beneficial effects.
We all want to keep our athletic horses sound, but experts recommend ‘judicious use’ of most NSAIDs to ensure their detrimental effects don’t outweigh their beneficial effects.

Conclusion
Non-steroidal anti-inflammatories are useful drugs for horses, but should be used strictly under veterinary supervision and always at the lowest possible dose. These drugs do have toxicity problems and side effects that contradict their therapeutic value so should be used with care for musculo-skeletal conditions and diseases.

References
Beluche, L. A., Bertone, A. L., Anderson, D. E. & Rhode, C. (2001) Effects of oral administration of phenylbutazone to horses on in vitro cartilage metabolism. American Journal of Veterinary Research, 62(12): 1916-1921.

D’Arcy-Moskwa, E., Noble, G. K., Weston, L. A., Boston, R. & Raidal, S. L. (2012) Effects of meloxicam and phenylbutazone on equine gastric mucosal permeability. Journal of Veterinary Internal Medicine, 26(6): 1494-1499.

De Grauw, J. C., van de Lest, C. H., Brama, P. A., Rambags, B. P. & van Weeren, P. R. (2009) In vivo effects of meloxicam on inflammatory mediators, MMP activity and cartilage biomarkers in equine joints with acute synovitis. Equine Veterinary Journal, 41(7): 693-699.

Higgins, A. J. & Snyder, J. R. (2006) The Equine Manual. 2nd edition. Elsevier Saunders, Edinburgh.

Marshall, J. F. & Blikslager, A. T. (2011) The effect of nonsteroidal anti-inflammatory drugs on the equine intestine. Equine Veterinary Journal Supplement 39: 140-144.

McConnico, R. S., Morgan, T. W., Williams, C. C., Hubert, J. D. & Moore, R. M. (2008) Pathophysiologic effects of phenylbutazone on the right dorsal colon in horses. American Journal of Veterinary Research, 69(11): 1496-1505.

Tobin, T., Chay, S., Kamerling, S., Woods, W. E., Weckman, T. J., Blake, J. W. & Lees, P. (1986) Phenylbutazone in the horse: a review. Journal of Veterinary Pharmacology and Therapeutics, 9(1): 1-25.

About Clare MacLeod

Clare MacLeod MSc RNutr is one of the UK’s few registered independent equine nutritionists who also has expertise in health and fitness. She advises private and commercial clients in all sectors of the horse world and is a hands-on horse owner herself. Clare is passionate about correct nutrition as a foundation for good health, without which peak fitness is not possible. She states “Good nutrition isn’t everything, but there’s nothing without it”.