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COX Inhibitors: Making the Best Choice for the Laminitic Case
CLINICAL TECHNIQUES COX Inhibitors: Making the Best Choice for the Laminitic Case Thomas J. Divers, DVM, Dipl ACVIM, ACVECC INTRODUCTION Cyclo-oxygenase (COX) inhibitors have anti-inflammatory, analgesic, and anti-pyretic properties. Some have the ability to inhibit platelet activity. Two or more cyclooxygenase enzyme systems (COX-1 and COX-2) control the production of different prostanoids (prostaglandins and thromboxane) from arachidonic acid being released from cell membrane phospholipids. COX-1 enzyme is considered a constitutive enzyme responsible for the production of a variety of cytoprotective prostanoids, which are important for normal gastrointestinal, renal, vascular, and other body system physiologic functions. COX-2 enzymes are induced by inflammatory cytokines and produce prostaglandins involved in inflammation, pain, and fever.1 COX activity has now been further divided, by some, into COX-3 activity, which appears to act centrally (brain).2 The most commonly used COX inhibitors are nonsteroidal anti-inflammatory drugs (NSAIDs). Choosing the most appropriate COX inhibitor for laminitic horses based on current information is not straightforward. Considerations for choosing an NSAID must include relative importance of each of the following: (1) the need to inhibit ongoing systemic inflammatory mediators, such as endotoxemia; (2) the level of concern for intestinal and renal injury from the COX inhibitor; (3) possible administration routes, such as intravenous, orally, intramuscularly, transdermally; (4) whether platelet inhibition is desirable; (5) what level of analgesia is needed, in other words, how painful the horse is; and (6) expense. The choice of COX inhibitor is further complicated by our lack of experience with the new COX-2 selective drug firocoxib (Equioxx) on many of these points. For horses being treated for laminitis and having significant risk for intestinal or renal injury from prolonged NSAID use, firocoxib could be a medically sound selection and, in a study of naturally occurring equine osteoarthritis, pain reduction with firocoxib was comparable to phenylbutazone.3 Use of the drug in horses already having intestinal From the Cornell University College of Veterinary Medicine, Department of Clinical Sciences, Ithaca, NY. Reprint requests: Thomas J. Divers, DVM, Dipl ACVIM, ACVECC, Cornell University College of Veterinary Medicine, Department of Clinical Sciences, Tower Road, Ithaca, NY 14853. 0737-0806/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2008.04.006
Journal of Equine Veterinary Science Vol 28, No 6 (2008)
disease raises some questions; firocoxib is only available for oral administration and intestinal disease might interfere with absorption and the ability of the drug to reach therapeutic levels. Additionally, prostaglandin E2 (PGE2) is thought to be important for intestinal repair and both selective COX-2 inhibitors, and general COX inhibitors have been shown to interfere with intestinal repair after ischemia in the horse.4,5 The only other relatively ‘‘selective’’ COX-2 inhibitor that has been evaluated in horses is meloxicam.6-8 Meloxicam treatment provided analgesia comparable to flunixin and had recovery of transepithelial barrier equal to saline and better than flunixin in an experimental equine jejunal ischemic model.8 It is available for intravenous and oral administration, but expense in the United States would prevent its use in most cases. Another NSAID that may have some relatively selective COX-2 inhibition is carprofen (there are conflicting data regarding its COX-2 selectivity in the equine),6,9 which is available for oral and intravenous administration and could be used when intestinal injury/repair is a concern. In my experience, carprofen works well as an analgesic in foals with arthritis, but I have no experience with it in adult horses with laminitis, and the intravenous form would be very expensive. Nonselective COX inhibitors (flunixin, phenylbutazone, and ketoprofen) have been the standard of care for inhibiting inflammatory mediators and controlling pain in the laminitic horse for 3 decades. In my opinion, the best and most consistent pain control is with phenylbutazone treatment, although one report found that ketoprofen relieved foot pain better than phenylbutazone at a single time point.10 If systemic toxemia is still present (fever, band neutrophils, or toxic neutrophils) in the laminitic patient, I prefer to use flunixin, because it has shown the greatest effects against several endotoxic-induced inflammatory mediators, such as thromboxane,11 and may have anti-inflammatory effects (inhibits production of nitric oxide and pro-inflammatory transcription factor (nuclear factor kappa-B) not directly related to COX inhibition. Additionally, a ‘‘low’’ dose of flunixin (0.25 mg/kg) can inhibit thromboxane.12 If the horse/pony can be systemically stabilized, treatment with firocoxib could then be used for more long-term and presumably less toxic NSAID treatment, assuming the pain relief is acceptable. Combining NSAIDs for improved analgesia is not generally recommended and may increase intestinal toxicity, as
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was demonstrated in normal horses given normal doses of both phenylbutazone and flunixin for 5 days.13 For shortterm effects (1 3 days) in horses with acute laminitis and continuing endotoxemia, I will often administer 4 to 6 mg/kg phenylbutazone once or twice daily for analgesic effects and simultaneously give low doses of flunixin, 0.25 mg/kg every 8 hours, for its ‘‘anti-endotoxic/inflammation’’ effect. For these patients, I pay strict attention to their hydration status and plasma albumin concentration. It is very important to maintain normal hydration in horses/ponies being treated with NSAIDs, because dehydration enhances their toxic effects. This can be a significant problem in laminitic horses that spend large amounts of time in recumbency. Feeding a moderate protein diet (low starches and sugars, of course) with added corn oil and glutamine may help protect against the intestinal and renal injury sometimes associated with NSAIDs. I would not recommend intramuscular flunixin administration if there are alternatives, because of the relatively high incidence of clostridial myositis that follows intramuscular injections of this drug.14 Occasionally, I will combine ‘‘low-dose’’ aspirin (10 mg/kg given per rectum or by mouth every 2 3 days) with moderate doses of phenylbutazone in subacute to chronic laminitis in hopes of providing pain relief (phenylbutazone) and platelet inhibition (aspirin).15 All NSAIDs have little effect on equine platelet function during endotoxemia.16 The combination of firocoxib and aspirin might also be worth considering in subacute or chronic laminitis without endotoxemia. In acute laminitic cases, I believe it is important to administer NSAIDs at a dose that provides appropriate analgesia. Inhibiting pain might be important in normalizing some of the pathophysiology taking place in the foot and might prevent a ‘‘windup’’ neuropathic pain cycle that may occur in the spinal cord, in addition to its humane benefits. I believe response to high-level (6 mg/kg) treatment with phenylbutazone can be used as a prognostic guide. I have always believed that acute laminitis caused by systemic inflammation could be divided clinically into two groups: (1) those that respond within 6 to 24 hours to 4 to 6 mg/kg of phenylbutazone—fair to good prognosis, and (2) those that have minimal or no noticeable response to the same treatment—guarded to poor prognosis. Consideration also must be given to the different pharmacodynamics of NSAIDs in ponies and donkeys when compared with horses. In mules and donkeys, the metabolism and elimination of most NSAIDs is faster and might require more frequent administration of the drugs (3/ day of some NSAIDs).17,18 Some NSAIDs, such as phenylbutazone, appear to be more toxic to the intestine of ponies than the intestine of horses at similar mg/kg dosages19; therefore, firocoxib might be particularly indicated in ponies with chronic laminitis. Further clinical experience
with firocoxib will help answer this and other questions regarding the use of the drug. Ketoprofen, another nonselective NSAID, is approved for use in the horse, and one study demonstrated better analgesic effect with hoof pain when compared with phenylbutazone, whereas another study found it less toxic than phenylbutazone and flunixin. My experience is somewhat limited with ketoprofen use in treating laminitis, and I cannot comment further on its use. REFERENCES 1. Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem 2007;42:3–27. 2. Burdan F, Chalas A, Szumilo J. Cyclooxygenase and prostanoids: biological implications. Postepy Hig Med Dosw 2006;60:129–141. 3. Doucet MY, Bertone AL, Hendrickson D, Hughes F, Macallister C, McClure S, et al. Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. J Am Vet Med Assoc 2008;232:91–97. 4. Tomlinson JE, Blikslager AT. Effects of cyclooxygenase inhibitors flunixin and deracoxib on permeability of ischaemic-injured equine jejunum. Equine Vet J 2005;37:75–80. 5. Tomlinson JE, Wilder BO, Young KM, Blikslager AT. Effects of flunixin meglumine or etodoiac treatment on mucosal recovery of equine jejunum after ischemia. Am J Vet Res 2004;65:761–769. 6. Beretta C, Garavaglia G, Cavalli M. COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxican: an in vitro analysis. Pharmacol Res 2005;52:302–306. 7. Sinclair MD, Mealey KL, Matthews NS, Peck KE, Taylor TS, Bennett BS. Comparative pharmacokinetics of meloxican in clinically normal horses and donkeys. Am J Vet Res 2006;67:1082–1085. 8. Little D, Brown SA, Campbell NB, Moeser AJ, Davis JL, Blikslager AT. Effects of cyclooxygenase inhibitor meloxicam on recovery of ischemiainjured equine jejunum. Am J Vet Res 2007;68:614–624. 9. Brideau C, Van Staden C, Chan CC. In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats. Am J Vet Res 2001;62:1755–1760. 10. Owens JG, Kamerling SG, Stanton SR, Keowen ML. Effects of ketoprofen and phenylbutazone on chronic hoof pain and lameness in the horse. Equine Vet J 1995;27:296–300. 11. Moore JN, Hardee MM, Hardee GE. Modulation of arachidonic acid metabolism in endotoxic horses: comparison of flunixin meglumine, phenylbutazone, and a selective thromboxane synthetase inhibitor. Am J Vet Res 1996;47:110–113. 12. Semrad SD, Hardee GE, Hardee MM, Moore JN. Low dose flunixin meglumine: effects on eicosanoid production and clinical signs induced by experimental endotoxaemia in horses. Equine Vet J 1987;19:201–206. 13. Reed SK, Messer NT, Tessman RK, Keegan KG. Effects of phenylbutazone alone or in combination with flunixin meglumine on blood protein concentrations in horses. Am J Vet Res 2006;67:398–402. 14. Peek SF, Semrad SD, Perkins GA. Clostridial myonecrosis in horses (37 cases 1985-2000). Equine Vet J 2003;35:86–92.
TJ Divers Vol 28, No 6 (2008)
15. Cambridge H, Lees P, Hooke RE, Russell CS. Antithrombotic actions of aspirin in the horse. Equine Vet J 1991;23:123–127.
369
oxyphenbutazone in clinically normal horses and donkeys. Am J Vet Res 1997;58:53–55.
16. Jarvis GE, Evans RJ. Platelet-activating factor and not thromboxane
18. Coakley M, Peck KE, Taylor TS, Matthews NS, Mealey KL. Pharma-
A2 is an important mediator of endotoxin-induced platelet aggrega-
cokinetics of flunixin meglumine in donkeys, mules, and horses. Am J
tion in equine heparinised whole blood in vitro. Blood Coag Fibrinolysis 1996;7:194–198. 17. Mealey KL, Matthews NS, Peck KE, Ray AC, Taylor TS. Comparative pharmacokinetics of phenylbutazone and its metabolite
Vet Res 1999;60:1441–1444. 19. Snow DH, Douglas TA, Thompson H, Parkins JJ, Holmes PH. Phenylbutazone toxicosis in equidae: a biochemical and pathophysiological study. Am J Vet Res 1981;42:1754–1759.
Journal of Equine Veterinary Science Vol 28, No 6 (2008)
disease raises some questions; firocoxib is only available for oral administration and intestinal disease might interfere with absorption and the ability of the drug to reach therapeutic levels. Additionally, prostaglandin E2 (PGE2) is thought to be important for intestinal repair and both selective COX-2 inhibitors, and general COX inhibitors have been shown to interfere with intestinal repair after ischemia in the horse.4,5 The only other relatively ‘‘selective’’ COX-2 inhibitor that has been evaluated in horses is meloxicam.6-8 Meloxicam treatment provided analgesia comparable to flunixin and had recovery of transepithelial barrier equal to saline and better than flunixin in an experimental equine jejunal ischemic model.8 It is available for intravenous and oral administration, but expense in the United States would prevent its use in most cases. Another NSAID that may have some relatively selective COX-2 inhibition is carprofen (there are conflicting data regarding its COX-2 selectivity in the equine),6,9 which is available for oral and intravenous administration and could be used when intestinal injury/repair is a concern. In my experience, carprofen works well as an analgesic in foals with arthritis, but I have no experience with it in adult horses with laminitis, and the intravenous form would be very expensive. Nonselective COX inhibitors (flunixin, phenylbutazone, and ketoprofen) have been the standard of care for inhibiting inflammatory mediators and controlling pain in the laminitic horse for 3 decades. In my opinion, the best and most consistent pain control is with phenylbutazone treatment, although one report found that ketoprofen relieved foot pain better than phenylbutazone at a single time point.10 If systemic toxemia is still present (fever, band neutrophils, or toxic neutrophils) in the laminitic patient, I prefer to use flunixin, because it has shown the greatest effects against several endotoxic-induced inflammatory mediators, such as thromboxane,11 and may have anti-inflammatory effects (inhibits production of nitric oxide and pro-inflammatory transcription factor (nuclear factor kappa-B) not directly related to COX inhibition. Additionally, a ‘‘low’’ dose of flunixin (0.25 mg/kg) can inhibit thromboxane.12 If the horse/pony can be systemically stabilized, treatment with firocoxib could then be used for more long-term and presumably less toxic NSAID treatment, assuming the pain relief is acceptable. Combining NSAIDs for improved analgesia is not generally recommended and may increase intestinal toxicity, as
367
TJ Divers Vol 28, No 6 (2008)
368
was demonstrated in normal horses given normal doses of both phenylbutazone and flunixin for 5 days.13 For shortterm effects (1 3 days) in horses with acute laminitis and continuing endotoxemia, I will often administer 4 to 6 mg/kg phenylbutazone once or twice daily for analgesic effects and simultaneously give low doses of flunixin, 0.25 mg/kg every 8 hours, for its ‘‘anti-endotoxic/inflammation’’ effect. For these patients, I pay strict attention to their hydration status and plasma albumin concentration. It is very important to maintain normal hydration in horses/ponies being treated with NSAIDs, because dehydration enhances their toxic effects. This can be a significant problem in laminitic horses that spend large amounts of time in recumbency. Feeding a moderate protein diet (low starches and sugars, of course) with added corn oil and glutamine may help protect against the intestinal and renal injury sometimes associated with NSAIDs. I would not recommend intramuscular flunixin administration if there are alternatives, because of the relatively high incidence of clostridial myositis that follows intramuscular injections of this drug.14 Occasionally, I will combine ‘‘low-dose’’ aspirin (10 mg/kg given per rectum or by mouth every 2 3 days) with moderate doses of phenylbutazone in subacute to chronic laminitis in hopes of providing pain relief (phenylbutazone) and platelet inhibition (aspirin).15 All NSAIDs have little effect on equine platelet function during endotoxemia.16 The combination of firocoxib and aspirin might also be worth considering in subacute or chronic laminitis without endotoxemia. In acute laminitic cases, I believe it is important to administer NSAIDs at a dose that provides appropriate analgesia. Inhibiting pain might be important in normalizing some of the pathophysiology taking place in the foot and might prevent a ‘‘windup’’ neuropathic pain cycle that may occur in the spinal cord, in addition to its humane benefits. I believe response to high-level (6 mg/kg) treatment with phenylbutazone can be used as a prognostic guide. I have always believed that acute laminitis caused by systemic inflammation could be divided clinically into two groups: (1) those that respond within 6 to 24 hours to 4 to 6 mg/kg of phenylbutazone—fair to good prognosis, and (2) those that have minimal or no noticeable response to the same treatment—guarded to poor prognosis. Consideration also must be given to the different pharmacodynamics of NSAIDs in ponies and donkeys when compared with horses. In mules and donkeys, the metabolism and elimination of most NSAIDs is faster and might require more frequent administration of the drugs (3/ day of some NSAIDs).17,18 Some NSAIDs, such as phenylbutazone, appear to be more toxic to the intestine of ponies than the intestine of horses at similar mg/kg dosages19; therefore, firocoxib might be particularly indicated in ponies with chronic laminitis. Further clinical experience
with firocoxib will help answer this and other questions regarding the use of the drug. Ketoprofen, another nonselective NSAID, is approved for use in the horse, and one study demonstrated better analgesic effect with hoof pain when compared with phenylbutazone, whereas another study found it less toxic than phenylbutazone and flunixin. My experience is somewhat limited with ketoprofen use in treating laminitis, and I cannot comment further on its use. REFERENCES 1. Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem 2007;42:3–27. 2. Burdan F, Chalas A, Szumilo J. Cyclooxygenase and prostanoids: biological implications. Postepy Hig Med Dosw 2006;60:129–141. 3. Doucet MY, Bertone AL, Hendrickson D, Hughes F, Macallister C, McClure S, et al. Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. J Am Vet Med Assoc 2008;232:91–97. 4. Tomlinson JE, Blikslager AT. Effects of cyclooxygenase inhibitors flunixin and deracoxib on permeability of ischaemic-injured equine jejunum. Equine Vet J 2005;37:75–80. 5. Tomlinson JE, Wilder BO, Young KM, Blikslager AT. Effects of flunixin meglumine or etodoiac treatment on mucosal recovery of equine jejunum after ischemia. Am J Vet Res 2004;65:761–769. 6. Beretta C, Garavaglia G, Cavalli M. COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxican: an in vitro analysis. Pharmacol Res 2005;52:302–306. 7. Sinclair MD, Mealey KL, Matthews NS, Peck KE, Taylor TS, Bennett BS. Comparative pharmacokinetics of meloxican in clinically normal horses and donkeys. Am J Vet Res 2006;67:1082–1085. 8. Little D, Brown SA, Campbell NB, Moeser AJ, Davis JL, Blikslager AT. Effects of cyclooxygenase inhibitor meloxicam on recovery of ischemiainjured equine jejunum. Am J Vet Res 2007;68:614–624. 9. Brideau C, Van Staden C, Chan CC. In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats. Am J Vet Res 2001;62:1755–1760. 10. Owens JG, Kamerling SG, Stanton SR, Keowen ML. Effects of ketoprofen and phenylbutazone on chronic hoof pain and lameness in the horse. Equine Vet J 1995;27:296–300. 11. Moore JN, Hardee MM, Hardee GE. Modulation of arachidonic acid metabolism in endotoxic horses: comparison of flunixin meglumine, phenylbutazone, and a selective thromboxane synthetase inhibitor. Am J Vet Res 1996;47:110–113. 12. Semrad SD, Hardee GE, Hardee MM, Moore JN. Low dose flunixin meglumine: effects on eicosanoid production and clinical signs induced by experimental endotoxaemia in horses. Equine Vet J 1987;19:201–206. 13. Reed SK, Messer NT, Tessman RK, Keegan KG. Effects of phenylbutazone alone or in combination with flunixin meglumine on blood protein concentrations in horses. Am J Vet Res 2006;67:398–402. 14. Peek SF, Semrad SD, Perkins GA. Clostridial myonecrosis in horses (37 cases 1985-2000). Equine Vet J 2003;35:86–92.
TJ Divers Vol 28, No 6 (2008)
15. Cambridge H, Lees P, Hooke RE, Russell CS. Antithrombotic actions of aspirin in the horse. Equine Vet J 1991;23:123–127.
369
oxyphenbutazone in clinically normal horses and donkeys. Am J Vet Res 1997;58:53–55.
16. Jarvis GE, Evans RJ. Platelet-activating factor and not thromboxane
18. Coakley M, Peck KE, Taylor TS, Matthews NS, Mealey KL. Pharma-
A2 is an important mediator of endotoxin-induced platelet aggrega-
cokinetics of flunixin meglumine in donkeys, mules, and horses. Am J
tion in equine heparinised whole blood in vitro. Blood Coag Fibrinolysis 1996;7:194–198. 17. Mealey KL, Matthews NS, Peck KE, Ray AC, Taylor TS. Comparative pharmacokinetics of phenylbutazone and its metabolite
Vet Res 1999;60:1441–1444. 19. Snow DH, Douglas TA, Thompson H, Parkins JJ, Holmes PH. Phenylbutazone toxicosis in equidae: a biochemical and pathophysiological study. Am J Vet Res 1981;42:1754–1759.