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Home , Carprofen, Firocoxib, Phenylbutazone

IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS

Joint Therapy: Non-Steroidal Anti-Inflammatory Drugs

Michael W. Ross, DVM, Diplomate ACVS

Author’s address: New Bolton Center, 382 West Street Road, Kennett Square, PA 19348-1692; e-mail: [email protected]. © 2011 AAEP.

1. Introduction utazone (PBZ) was given to horses for 14 days and Non-steroidal anti-inflammatory drugs (NSAIDs) serum was tested in a cartilage explant model, there play an important role in the medical management was decreased proteoglycan synthesis similar in de- 5,8 of horses with (OA) and many other gree to that seen when interleukin-1␤ was given. degenerative conditions as well as horses undergo- In addition, systemic side effects of some NSAIDs ing surgery. NSAIDs are given orally, parenter- have become well-recognized, and the therapeutic ally, or topically; most have clinical sign-modifying range may be considerably more narrow than was effects, but some have disease-modifying effects. once thought (see below). NSAIDs inhibit one or more of the involved All NSAIDs work by inhibiting in the production of (PGs) and (COX), an found in the AAC that converts , the so-called arachadonic acid cas- arachadonic acid to PG or . Some cade (AAC). PGs are associated with synovitis and have non-COX effects. reduces cartilage matrix depletion, particularly those of the and effusion in horses with experimental OA, and E series, and PGE2 was identified in the synovial inhibits lipoxygenase in addition to 1–5 1,9,10 fluid of horses with OA. PGE2 is synthesized in COX. However, the predominant effect is COX synoviocytes and chondrocytes after exposure to in- inhibition. There are two isoenzymes of COX, flammatory mediators, was implicated in the ero- COX-1 and COX-2, that have important differences. sion of cartilage and adjacent bone, and may Differential inhibition of these isoforms may well modulate metalloproteinase release.1 Interest- explain not only clinical efficacy of NSAIDs but also ingly, PGE2 may be involved in regulatory functions the toxic side effects leading to narrow therapeutic within an inflamed joint, and inhibition may pro- indices. COX-1 is known as the housekeeping form duce a paradoxical response.1 Although inhibiting of the enzyme, because it is responsible for the pro- PGE2 may be advantageous in horses with OA as a duction of PGs in a constitutive manner. Constitu- clinical sign-modifying outcome, there may be long- tive activity of COX-1 helps maintain homeostasis in term detrimental sequelae.1,5,6 In horses, initial the gastrointestinal tract (gastric mucosa and vari- studies revealed no deleterious effects of NSAIDs on ous portions of the colon) and . Therefore, articular cartilage metabolism,7 but when phenylb- inhibition of COX-1 explains many of the potential

NOTES

102 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS toxic side effects associated with NSAID administra- particularly susceptible to the effects of NSAIDs, tion. COX-2 is the inducible form of COX and is particularly if the horse has other systemic diseases; principally involved in the inflammatory events although on a milligram per kilogram basis, a total leading to elevated levels of PGs found in OA and dose of 4 g may seem low, it was recommended that other inflammatory processes. Thus, COX-1 could this total dose not be exceeded and the drug be given be considered the good isoform, and COX-2 could be a maximum of 5–7 days.19 Horses, like ponies, are considered the bad isoform.5 Non-selective inhibi- at risk to develop toxic side effects as well, including tion of both COX-1 and COX-2 may indeed reduce hypoproteinemia, , neutropenia, renal pap- clinical signs associated with OA but at the risk of illary necrosis, gastric ulceration, and right dorsal potentiating toxic side effects. The ubiquitous drug colitis.18,20,21 Recently, horses given PBZ at a rel- PBZ is the best-known non-selective COX inhibitor, atively high dose of 8.8 mg/kg, q 24 h, PO, for 21 and although it is effective, it has potential for toxic days developed hypoproteinemia, neutropenia, side effects as a result of COX-1 inhibition. Selec- changes in right dorsal colon arterial blood flow, and tive inhibition of COX-2 while sparing COX-1 would changes in volatile fatty acid production.22 Al- seem ideal, and recently, the COX-2 inhibitor firo- though I have been cavalier in the past regarding coxib was approved for equine use and was shown to use of PBZ, I have adjusted my recommendations highly favor COX-2 inhibition. Concentrations of based on my own experience and that of others. firocoxib required to inhibit 50% of COX-1 activity I believe horses at risk include hospitalized horses were 384, 58, and 643 times, respectively, the con- being managed for other serious problems such as centrations required to inhibit 50% of COX-2 activ- enteritis, metritis, , and infectious arthri- ity in the dog,11 cat,12 and horse,13 and when tis; also, dehydrated horses are at substantial risk to firocoxib was given to horses with naturally occur- develop renal or gastrointestinal complications and ring OA, results compared favorably with PBZ.14 should be rehydrated before administering NSAIDs Compared with horses given firocoxib, horses given such as PBZ. Endurance horses developing ex- flunixin meglumine (FM; a non-selective COX inhib- hausted horse syndrome or severe rhabdomyolysis itor) had significantly lower transepithelial resis- are at profound risk of developing renal damage if tance and higher lipopolysaccharide permeability in NSAIDs are administered before they are given IV ischemic-injured jejunum, indicating that a specific fluid therapy.23 Horses with OA or degenerative COX-2 inhibitor may be advantageous.15 The use conditions such as navicular syndrome or horses of a combination of PBZ and FM was more effective undergoing surgery can safely receive 4.4 mg/kg, q at alleviating lameness than was PBZ alone, indi- 12 h, IV or PO for 2–3 days and then receive a cating that combining non-selective COX inhibitors tapering dose, leveling out to 2.2–3.3 mg/kg, q 12 h, had superior clinical sign-modifying ef- IV or PO. PBZ is quite effective at managing pain fects.16 However, in an earlier study, Reed et al.17 associated with chronic OA, and it is my opinion that showed the need for substantial caution in horses the potential deleterious side effects on cartilage being administered this combination therapy, be- metabolism are overrated; it is the continued use of cause one horse was euthanized likely as a result of the horse that poses the biggest risk to additional toxic side effects and other experimental horses de- deterioration of the original condition. Interest- veloped gastric ulcers.17 Beneficial effects of a com- ingly, in a recent study, PBZ administration to bination of NSAIDs may be outweighed by horses caused a significant increase in the bio- deleterious systemic side effects. marker osteocalcin, a finding suggesting that PBZ exerted an undetermined anabolic effect on periar- 2. Drugs and Clinical Use ticular bone or a transient induction of osteogenesis The most common NSAIDs used are those given in articular chondrocytes or mesenchymal subpopu- parenterally or orally (PBZ, FM, ketoprofen, lation of synoviocytes.24 In hospitalized horses un- , carprofen, and firocoxib) and a topically dergoing major orthopedic procedures, PBZ can be applied , sodium. A review of given chronically and safely at a dose of 3.3 mg/kg, q NSAIDs and additional information can be found 12 h. Clinicians often try to wean the horse off the elsewhere.1,5,18 medication or taper the dose, leading to a notable deterioration in the horse’s clinical signs. After PBZ lameness increases, the knee-jerk reaction is to re- In my opinion, horses are PBZ-deficient. This establish the original higher dose of PBZ; however, statement reflects my attitude to the administration many horses remain lame, despite receiving a level and usefulness of this ubiquitous NSAID. In my of medication on which they had previously been opinion, PBZ is the best and most cost-effective comfortable. I have no explanation for this para- NSAID available and has been used for nearly 30 yr doxical response. To combat the potential serious safely and effectively. The toxic side effects are or fatal sequelae of contralateral laminitis, I prefer well-recognized in ponies,19 which seem to be par- to risk the potential side effects of PBZ therapy and ticularly sensitive to the effects of non-selective COX often maintain horses on relatively high doses. inhibitors and caution should always be used. Cer- Others disagree and recommend no more than 2.2 tain draft breeds, such as the Clydesdale, may be mg/kg, q 12 h be administered after an initial load-

AAEP PROCEEDINGS ր Vol. 57 ր 2011 103 IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS ing dose of 4.4 mg/kg, q 12 h for no more than 2 there is risk to the development of toxic side effects days.18 In combination with intra-articular medi- (see above).17 Because the drug is more expensive cations and topical application of NSAIDs, paren- and less efficacious, I seldom recommend it in horses teral or oral PBZ therapy is quite effective in the with OA. medical management of OA. Corrective shoeing significantly increased the peak vertical ground re- Ketoprofen action force (a measure of increased weight bearing Ketoprofen inhibits both the COX and lipoxygenase expressed as the percent of the body weight force) in pathways in the AAC and thus, should be more horses with navicular syndrome; the addition of PBZ effective than COX inhibitors, because the drug therapy but not intra-articularly administered tri- should reduce leukotriene in addition to PG accumu- amcinolone acetonide produced a significant addi- lation. However, numerous studies have refuted tional increase in weight bearing.25 Drug testing this claim.18 Given that ketoprofen is poorly ab- rules often preclude use of the medication at a dose sorbed when given orally, is more expensive than sufficient to alleviate clinical signs in upper-level PBZ, and anecdotally, does not alleviate clinical sports horses and racehorses. However, PBZ ther- signs as well as PBZ, I do not recommend it. In a apy is often quite useful in racehorses in which study comparing PBZ with ketoprofen, PBZ was su- low-grade exercise is given in an attempt to work perior to ketoprofen in managing acute through mild pain, gait deficits, and poor perfor- synovitis.18,29 mance associated with mild OA or subchondral bone pain. PBZ therapy may help prevent the develop- Naproxen ment of compensatory lameness. There has long Naproxen would seem to be an ideal substitute to been an attempt to link the chronic low-grade ad- PBZ for horses being managed chronically for OA or ministration of NSAIDs, such as PBZ, FM, and other degenerative conditions, but I have little ex- naproxen, to fatal or non-fatal musculosketal inju- perience with the drug. A review can be found else- ries. In a recent study, the possible relationship of where.18 Given the half-life of 4–5 h (similar to NSAID administration and injuries in Thorough- PBZ), wide safety margin, and favorable results bred racehorses was investigated; plasma concen- compared with PBZ in an induced model of myositis, trations of PBZ and FM but not naproxen were it seems to be a useful alternative NSAID to use.18 higher in injured horses, but Dirikolu et al.26 con- The dose is 10 mg/kg, q 12 or 24 h, PO.18 Naproxen cluded that additional study was needed. A combi- may be indicated in horses that cannot tolerate PBZ nation of PBZ and other NSAIDs such as FM could because of hypoproteinemia and oral or gastric be used to manage substantial musculoskeletal pain ulceration. in horses, but potential toxic side effects must be strongly considered.16,17 Carprofen Route of administration seems to be important. Carprofen is another NSAID that inhibits both The response of horses given PBZ IV seems superior COX-1 and COX-2, although the specific mode of compared with the response of horses given the drug action has not been clearly defined.18 Anecdotal orally. Lameness is often worse in horses with sub- information suggests that the drug may preferen- stantial pain switched from IV to oral administra- tially inhibit COX-2 more than COX-1, because clin- tion (usually hospitalized horses with severe OA, ical signs of PBZ (elevated creatinine levels laminitis, or other substantial injuries). The same and diarrhea) subsided when horses were subse- dose given orally does not produce the same clinical quently given carprofen.5 The drug is quite effec- results, and it seems that bioavailability is consid- tive in dogs being managed for chronic OA and may erably less when PBZ is given by the oral route. have a role in the management of horses with chronic OA, although expense may be a limiting FM factor. Compared with , , and Half-life of FM is reported to be much less than PBZ butorphanol, dogs treated with carprofen showed (PBZ ϭ 5.5 h27 and FM ϭ 1.6–2.5 h28), and inexpli- the greatest improvement in vertical ground reac- cably, it is most often only given one time daily.18 tion forces and weight-bearing scores in an induced The medication is given orally (chronically), much synovitis model.30 Carprofen exists as two enan- like PBZ. There has been concern about possible tiomers (R and S), and although its mechanism of myonecrosis associated with IM use.18 I have occa- action may not be completely understood, in one sionally seen horses develop clostridial myositis af- study, the S-enantiomer had a greater effect than ter IM , and one of these cases was early in the R-enantiomer or hyaluronan in stimulating pro- my career; therefore, I have avoided this route of teoglycan synthesis.31 Furthermore, carprofen had administration. The drug is thought to be safer an antiarthritic effect in yet another study; the drug than PBZ and similar in effect. My experience is significantly decreased PGE2 production, antago- different, and FM does not seem to work as well as nized an interleukin-1–induced increase in PGE2 PBZ, particularly when given one time daily. I production, and increased proteoglycan synthesis.32 have used the drug in combination with PBZ in In a study evaluating postoperative analgesia in horses with severe lameness for 2 or 3 days, but horses, there was no difference in pain score be-

104 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS tween horses given carprofen, PBZ, and FM.33 turer, 1% diclofenac sodium liposomal cream re- In that study, duration of analgesia for carprofen duced lameness (as judged by owners and (11.7 h before redosing) was between FM (12.8 h veterinarians) regardless of severity or chronicity of before redosing) and PBZ (8.4 h before redosing).33 the condition.37 In a SC inflammation model using Carprofen seems well-tolerated at the recommended topically applied 1% diclofenac sodium liposomal IV or oral dose of 0.7 mg/kg, but it should not be cream, the drug was found in transudate at6hand given IM because of a risk for myonecrosis.18 I significantly decreased carrageenan-induced local 38 have no experience with the drug in horses, but production of PGE2, showing efficacy. Diclofenac given what appears to be not only clinical sign- sodium liposomal cream was compared with PBZ modifying but also disease-modifying effects, consid- and untreated control groups in an osteochondral eration for its use should be given. fragment model to induce OA of the middle carpal joint and was shown to have clinical sign- (clinical improvement in lameness scores) and disease-mod- Firocoxib is a member of a new class of NSAIDs ifying effects (increased glycosaminoglycan content known as coxibs that are essentially selective COX-2 in articular cartilage and less radial carpal bone inhibitors, because COX-2 inhibition is basically 643 sclerosis and cartilage erosion compared with PBZ) times that of COX-1 inhibition.13 Pharmacokinet- in a study supported by the drug manufacturer.39 ics and dosing recommendations for firocoxib were In that study, PBZ significantly reduced synovial 14,15,34,35 determined. In a recent study, firocoxib fluid PGE2. However, there were no differences be- was effective compared with the vehicle control in tween horses treated with topical 1% diclofenac li- horses with naturally occurring OA and navicular posomal cream and controls in lameness score, disease, and a dose of 0.25 mg/kg, q 24 h, PO was no carpal surface temperature and circumference, sy- better than 0.1 mg/kg, q 24 h, PO.35 In a multi- novial fluid cell count, total protein content, and center study, efficacy of a paste formulation of firo- biochemical markers of inflammation in an induced coxib was comparable with PBZ in horses with acute synovitis model.40 Anecdotally, at our hospi- naturally occurring OA.14 Interestingly, in that tal, topical application of 1% diclofenac sodium study, no treatment-related adverse effects of either seemed useful in reducing inflammation at regional drug were found, although the dose of PBZ was limb perfusion sites, leading to an investigation sup- modest (2.2 mg/kg, q 24 h, PO). Furthermore, the ported by the drug manufacturerb.41 In a blinded time interval between drug administration and ex- study of horses undergoing regional limb perfusion, amination was not controlled. Given the short 1% diclofenac liposomal cream significantly reduced half-life of PBZ (5.5 h) and prolonged half-life of local inflammation at perfusion sites, which was firocoxib (Ͼ36 h), some suggest that the inconsis- judged by visual assessment and ultrasonographic tency in time interval between PBZ administration score.41 This product seems useful in reducing lo- and clinical examination may have falsely lowered cal signs of inflammation. the drug’s efficacy, because PBZ is more commonly a administered q 12 h than q 24 h . Although evi- 3. Other Considerations dence-based information suggests that firocoxib is Individual responses of horses to NSAID adminis- similar to PBZ in clinical sign-modifying effects in tration may be variable, which is similar to re- horses with OA, anecdotally, the drug seems inferior sponses seen in people; some horses exhibit a more in efficacy and is much more expensive. marked response to different NSAIDs than others. Diclofenac Sodium What works in one horse may not be efficacious in another horse. Cost is an important factor. At A topically applied liposomal suspension containing our hospital, cost per day of PBZ (2.2 mg/kg, q 12 h, 1% diclofenac sodium is now approved for use in PO [for tablets; paste formulation is 10 times more horses. Topical application was reasoned to reduce expensive]), FM (1.1 mg/kg, q 12 h, PO), and firo- the chances of systemic side effects of the drug, coxib (0.1 mg/kg, q 24 h, PO), respectively, are $0.35, although the drug is used widely in people and rel- $25.00, and $11.00. Given the favorable biological atively well-tolerated. To my knowledge, diclofe- response of most horses to PBZ, I believe that it still nac sodium has not been given to horses by other is the most cost-effective and efficacious choice. routes. Topically applied diclofenac sodium is If toxic side effects are noted, a change should be slowly absorbed into SC tissues when enclosed in made. Although evidence-based information may liposomes, where there is local anti-inflammatory equate efficacy of firocoxib and PBZ, my own expe- action as a result of COX inhibition. Although the rience suggests otherwise. Diclofenac sodium drug is slowly absorbed and clinically relevant blood seems to have a place as a clinical sign-modifying and distant tissue concentrations are low, they can drug in the management of horses with OA. still be detected in both serum and urine, and these residues must be taken into account in horses un- dergoing drug testing.36 In a double-blinded place- References and Footnotes bo-controlled clinical field trial of 122 horses with 1. Caron JP. Principles and practices of joint disease treat- naturally occurring OA supported by the manufac- ment. In: Ross MW, Dyson SJ, eds. Diagnosis and man-

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Urinary and phenylbutazone in horses with naturally occurring osteoar- serum concentrations of diclofenac after topical application to thritis. J Am Vet Med Assoc 2008;232:91–97. horses. Vet Ther 2005;6:57–66. 15. Cook VL, Meyer CT, Campbell NB, et al. Effect of firocoxib 37. Lynn RC, Hepler DI, Kelch WJ, et al. Double-blinded pla- or flunixin meglumine on recovery of ischemic-injured equine cebo-controlled clinical field trial to evaluate the safety and jejunum. Am J Vet Res 2009;70:992–1000. efficacy of topically applied 1% diclofenac liposomal cream for 16. Keegan KG, Messer NT, Reed SK, et al. Effectiveness of the relief of lameness in horses. Vet Ther 2004;5:128–138. administration of phenylbutazone alone or concurrent ad- 38. Caldwell FJ, Mueller PO, Lynn RC, et al. Effect of topical ministration of phenylbutazone and flunixin meglumine to application of diclofenac liposomal suspension on experimen- alleviate lameness in horses. 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