Nonsteroidal Antiinflammatory Drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are antiinflammatory agents that inhibit some components of the enzyme system that converts arachidonic acid into prostaglandins and thromboxane. Prostaglandin (PG) E₂ (PGE₂) is the product associated with synovial inflammation and cartilage matrix depletion and was demonstrated in the synovial fluid of horses with OA.^5,6 Phenylbutazone is the most commonly used NSAID in the horse, given at a dose of 2.2 mg/kg, once or twice daily. However, results are variable both in horses with naturally occurring OA⁷ and in experimental trials using an equine OA model developed at Colorado State University (CSU), which has been used to assess a number of commonly used medications.⁸ Lameness scores were lowest after administration of the combination of phenylbutazone with flunixin meglumine compared with phenylbutazone alone, but concerns with secondary side effects (including acute necrotizing colitis) were raised.⁸

All NSAIDs inhibit cyclooxygenase (COX) activity to some degree,^5,6 but more recently two different isoenzymes called COX-l and COX-2 were reported with potential importance in the horse. COX-l maintains the “good” or “housekeeping” portion (constitutive part) of the COX pathway.⁹ COX-1 is important in the balance of normal physiology of the gastrointestinal and renal systems but plays a lesser role in the inflammatory COX cascade. COX-2 is associated with inflammatory events, especially those driven by macrophages and synovial cells, plays a minor role in normal physiology, and is considered the “bad” or “inducible” portion of the COX pathway. Drugs that preferentially inhibit COX-2 have been developed. Although it is logical that inhibition should minimize side effects, there is some suggestion that complete inhibition of COX-2 may not be optimal for either the joint or the horse.^9-11 Whereas COX-l is mainly responsible for the protective functioning of prostaglandins, COX-2 may play an accessory constitutive role in the COX pathway.

The mainstream view is still that the beneficial effects of selective COX-2 inhibition in OA are ideal. Anecdotally, carprofen (Rimadyl, Pfizer, New York, New York, United States) was used at CSU in horses that developed high serum creatinine levels and diarrhea in association with phenylbutazone use. These side effects disappeared when horses were given carprofen; a protective effect was seen, implying there may be more preferential COX-2 inhibition than with phenylbutazone therapy. Firocoxib, a member of the class of drugs that selectively inhibits the COX-2 isoenzyme, is now approved for use in horses to control pain and inflammation associated with OA in general, and its pharmacokinetics during prolonged use have been determined.¹²

Although prostaglandin inhibition provides effective symptomatic relief, there may be long-term deleterious effects of some NSAIDs on cartilage metabolism.¹¹ In vitro work in the horse had initially shown no evidence of deleterious effects on cartilage metabolism.¹³ However, in a more recent study, phenylbutazone was given to horses for 14 days, and serum was tested on articular cartilage explants in vitro. There was decreased proteoglycan synthesis to a degree similar to that with recombinant human interleukin–1β.¹⁴ However, in the absence of any clinical associations between phenylbutazone use and articular cartilage degeneration, continued appropriate use of NSAIDs is justified.

A new, licensed topical NSAID preparation, 1% diclofenac sodium cream (Surpass, IDEXX Laboratories, Greensboro, North Carolina, United States), is now available in the United States but not in Europe. Previous research in people indicated topical NSAID could be clinically beneficial while reducing systemic side effects. Antiinflammatory effects were demonstrated experimentally using an induced subcutaneous inflammation model.¹⁵ A clinical field trial of the topically applied diclofenac liposomal cream for the relief of joint inflammation showed promising results,¹⁶ and more recently its value was demonstrated in equine OA using an osteochondral fragment–exercise model (see the section on Intraarticular Corticosteroids).⁸

Intraarticular Corticosteroids

The use of intraarticular corticosteroids for treatment of equine OA was extensively reviewed in 1996, and the benefits and deleterious side effects were more recently clarified.¹⁷ Based on my observation of an apparent lack of correlation between the previous use of betamethasone esters (Betavet Soluspan, Schering-Plough Animal Health Corp., Union, New Jersey, United States) and articular cartilage degradation during arthroscopic surgery for osteochondral chip removal, experimental studies were initiated for the three most commonly used intraarticular corticosteroids. Methylprednisolone acetate (MPA) (Depo-Medrol, Pharmacia and Upjohn Co., Kalamazoo, Michigan, United States), triamcinolone acetonide (TA) (Vetalog, Bristol Myers Squibb for Fort Dodge, Fort Dodge, Iowa, United States), and betamethasone esters (Betavet Soluspan) were evaluated using an osteochondral fragment–exercise model.^18-20 Betamethasone (Betavet Soluspan, now available as Celestone Soluspan) was tested first. Osteochondral fragments were created arthroscopically on the distal dorsal aspect of the radial carpal bone in both middle carpal joints in 12 horses, and one joint was treated with 15 mg of betamethasone at 14 and 35 days after surgery.¹⁸ The contralateral control middle carpal joint was injected with saline. No deleterious side effects on articular cartilage were demonstrated. Exercise produced no harmful effects in the presence of betamethasone.¹⁸

In subsequent studies with intraarticular corticosteroids (as well as other treatments), the research model was modified so that the contralateral joint was not used as a control. The chip fragment model was also modified to more effectively produce early osteoarthritic change. Eighteen horses were randomly assigned to three groups: MPA or TA was injected 14 and 28 days after surgery, and horses were exercised on a high-speed treadmill for 6 weeks, beginning on day 15 after surgery. Results were compared with control joints treated with corticosteroids but which had no osteochondral fragment, as well as with a second control osteochondral fragment group treated with polyionic fluid (Figure 84-1).^19,20 In joints containing an osteochondral fragment and treated with MPA, there was a trend (not statistically significant) for lower lameness scores. However, there were significantly lower synovial fluid PGE₂ concentrations and lower scores for intimal hyperplasia and vascularity (no effect on cellular infiltration in the synovium compared with placebo-treated joints) in MPA-treated joints compared with control joints. Of more importance, modified Mankin scores (a score of histopathological change in articular cartilage) were significantly increased in MPA-treated joints compared with control joints, suggesting deleterious effects of intraarticular administration of MPA.¹⁹ This is in contrast to the results with TA (Vetalog).²⁰ Horses that were given 12 mg of TA in a joint containing a fragment (TA TX) were less lame than horses in the two control groups (see Figure 84-1). Horses treated with TA had lower protein and higher hyaluronan (HA) and GAG concentrations in synovial fluid. Synovium from treated groups had less inflammatory cell infiltration, intimal hyperplasia, and subintimal fibrosis. Analysis of articular cartilage morphological parameters evaluated using a standardized scoring system was significantly better from TA control (no fragment) and TA treatment groups compared with the control placebo-treated fragment group. The results supported favorable effects of TA on lameness scores, synovial fluid, synovium, and articular cartilage morphological parameters, both with direct intraarticular administration and remote site administration compared with placebo injections.²⁰ Evaluation of intraarticular TA on subchondral bone showed no deleterious effects.²¹ In other work, repetitive intraarticular administration of MPA to exercising horses altered mechanical integrity of articular cartilage but had no effect on subchondral or cancellous bone.²³

Fig. 84-1 Design of experiments to assess the value of direct intraarticular injection of a corticosteroid into an osteoarthritic joint (ST TX), as well as injection of intraarticular corticosteroid in a remote joint (ST CNT) compared with a saline-injected control (CNT).

(Reproduced with permission. McIlwraith CW: From arthroscopy to gene therapy—30 years of looking in joints, Proc Am Assoc Equine Pract 51:65, 2005.)

Based on these and recent in vitro results demonstrating a protective effect of TA,²⁴ I recommend TA be used especially in high motion joints. Some have recommended low doses of MPA to alleviate potential negative effects. However, based on in vitro titration studies, commonly used “low doses” are unlikely to have the same clinical effects because a greater concentration of corticosteroid is needed to inhibit the catabolic compared with the anabolic effects on articular cartilage.²⁵ On the other hand, clinical improvement is seen in horses administered low doses, an observation that is more important to a clinician than are experimental data.

Despite scientific studies demonstrating the efficacy and chondroprotective properties of TA, some practitioners fear the potential of TA to cause laminitis. Laminitis did not occur in 1200 horses treated with TA when the total dose did not exceed 18 mg.²⁶ From this study, 18 mg was established as a maximum dose. A more recent study reported no association between the occurrence of laminitis and the intraarticular use of TA.²⁷ There was a recent legal case in the United Kingdom in which a horse developed catastrophic laminitis after receiving 8 mg of TA in each tarsus and 20 mg of dexamethasone into its back.²⁸ This led to a review of the literature, which revealed that there was a lack of good evidence linking laminitis to corticosteroid injection; it was suggested that a large-scale multicenter trial was needed.²⁹ A related retrospective study from one clinician^29,30 revealed that laminitis associated with intraarticular injection of corticosteroids had occurred in 3 of 2000 (0.15%) horses. TA was used the majority of the time, and the upper total dose ranged from 20 to 45 mg.³⁰ The relationship between corticosteroid use and laminitis is discussed further in Chapter 34.

Another traditional cliché is that although it is better not to use MPA in high-motion joints, using it in low-motion joints (such as the distal tarsal joints) is appropriate. This implies that we do not care about the state of the articular cartilage in these joints, and perhaps corticosteroids may promote ankylosis. There is currently no evidence that ankylosis can be promoted in this fashion. The other side of this argument is that we should preserve articular cartilage whenever we can. Intraarticular injection of MPA or TA (with or without hyaluronan [HA]) in horses with OA of the distal hock joints led to a positive outcome in only 38% of horses (suggesting to the authors that surgical treatment may lead to better long-term prognosis).³¹ There was no significant difference between treatment with either MPA or TA, thus questioning any clinical advantages of the use of MPA.³¹ However, this was a relatively small study performed on a referral population of horses, and these results may not be representative of the overall response of horses with distal hock OA to intraarticular medication.

Intraarticular corticosteroids are commonly combined with HA, and there is a perception that the HA might be protective against any deleterious effects of corticosteroids (MPA). This perception is based on tradition rather than scientific proof but has become common thinking among equine practitioners.³ Some support can be gained from a 1-year, single-blind, randomized study in which 24 human patients were treated with intraarticular HA once weekly for 3 weeks and then again at 6 months (total of six injections).³² Sixteen of these patients also had TA before the first and fourth HA injections, and using the Western Ontario and McMaster Universities Index of OA (WOMAC) scores, the results were better with the combination of these two products. There was no progression of OA as evaluated using magnetic resonance imaging in either group.³² Two in vitro equine studies evaluated whether HA might have a mitigating effect against the deleterious effects of MPA. In the first study, HA addition had little effect on MPA-induced cartilage matrix proteoglycan catabolism in cartilage explants.³³ In the second study, MPA combined with HA had beneficial effects on proteoglycan metabolism in interleukin-1 (IL-1)–treated equine chondrocytes (but there were no comparisons between HA alone and MPA plus HA).³⁴ The combination of MPA and HA increased PG synthesis compared with IL-1–treated controls.³⁴

Hyaluronan (Sodium Hyaluronate)

HA is a nonsulfated GAG, and the biological characteristics and therapeutic use of HA in equine OA were reviewed previously.^35,36 HA has modest analgesic effects,³⁷ but more emphasis is placed on its antiinflammatory effects that may be physical (steric hindrance) or pharmacological (inhibition of inflammatory cells and mediators).³⁶ Various in vitro studies have shown HA protects against IL-1–driven prostaglandin synthesis and inhibits free radicals, but the ability of HA to inhibit matrix metalloproteinase (MMP) activity is questionable.^38,39 Several inflammatory mediators can augment HA production by synovial fibroblasts in vitro; therefore elevated synthesis of HA in early OA may constitute a protective response by the synovium to joint inflammation.³⁶ While providing a rationale for exogenous administration, it may explain the elevated levels of HA in response to intraarticular injection of a number of medications.^19,20

In my opinion, HA alone is useful in horses with mild to moderate synovitis, but the adjunctive use of corticosteroids is necessary in most horses with OA. However, based on clinical evidence in people, although the immediate effects may not be dramatic, the evidence for long-term disease-modifying activity of HA is accumulating.⁴⁰ Claims that HA preparations of molecular weight exceeding 1 × 10⁶ Da may provide superior clinical results and chondroprotection than lesser-molecular-weight products remain controversial.^36,41,42

In a randomized, double-blind, and placebo-controlled clinical study, 77 Standardbred trotters with moderate to severe lameness were treated with HA, polysulfated glycosaminoglycan (PSGAG), or placebo for 3 weeks. Mean initial lameness score was significantly reduced during treatment and at the last examination in all three groups (P < 0.01).⁴³ Additionally, the prevalence of sound horses increased significantly from 1 to 3 weeks of treatment into the last examination in all three groups. Both drugs (250 mg of PSGAG intraarticularly four times or 20 mg of HA intraarticularly twice) were superior to placebo for reduction of lameness score during treatment and the total study period, time until soundness occurred, and the number of sound horses at the last examination. Thus placebo and drug therapy were effective in the treatment of naturally occurring traumatic arthritis in horses, but HA and PSGAG gave better results than placebo. In a second study, the researchers compared intraarticular saline with rest alone in 38 Standardbreds with traumatic arthritis.⁴⁴ The mean lameness was significantly lower when 2.0 mL of 0.9% NaCl solution was injected compared with control horses.⁴⁴ This raises the question: is this effect the result of withdrawing fluid and/or placing a needle in the joint?

Most recently, intraarticular HA was tested in the CSU equine OA model.⁴⁵ OA was induced by the osteochondral fragment–exercise model in one middle carpal joint of 24 horses. Eight horses received HA (20 mg) (Hyvisc, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany) and amikacin (125 mg) intraarticularly on study days 14, 21, and 28. A second group of eight horses received PSGAG (250 mg) and amikacin (125 mg) intraarticularly on study days 14, 21, and 28. The remaining eight horses were control horses. There were no adverse treatment-related problems. Synovial effusion was reduced with PSGAG compared with controls. No changes in other clinical signs (lameness, response to flexion, joint effusion, and radiological findings) were seen with PSGAG or HA compared with controls. Histologically, however, there was significantly less articular cartilage fibrillation seen with HA treatment compared with controls (despite no significant reduction in vascularity and subintimal fibrosis of the synovium). The conclusion was that HA had beneficial disease-modifying effects and was a viable therapeutic option in equine OA.⁴⁵ The result of a questionnaire survey of 20 members of the American Association of Equine Practitioners (14 responses) showed that it was uncommon for the respondents to administer intraarticular HA initially or alone, particularly in horses with established OA.³ Twelve of 14 supplemented HA injections with other forms of treatment (usually intraarticular corticosteroids).³

The use of intravenous HA (Legend [or Hyonate], Bayer HealthCare LLC, Animal Health Division, Shawnee Mission, Kansas, United States) in the treatment of OA is now common. Using intravenous HA in the experimental osteochondral fragment–exercise model, there was significant improvement in clinical lameness, decreased PGE₂, and total protein levels in the synovial fluid, as well as decreased hyperemia and cellular infiltration of the synovium.⁴⁶ However, in a survey, most clinicians were not impressed by the efficacy of intravenous HA and its short duration of action in the treatment of OA, particularly when used alone.³

Based on the reports from the manufacturing company, the majority of intravenous HA is used “prophylactically” in athletic horses with the attributed benefits being subjective. The prophylactic value of intravenous HA was studied in both Quarter Horse and Thoroughbred racehorses. One hundred and forty horses participated in the Quarter Horse study and received either intravenous saline or HA every 2 weeks for the duration of the 9-month study.⁴⁷ Trends for HA-treated horses to race longer, require an intraarticular injection of corticosteroid earlier, have a better speed index, have a higher average number of starts, and earn more money were observed when compared with placebo-treated horses. The Editors note that the better performance results could be due to earlier corticosteroid treatment in the HA-treated compared with placebo-treated horses. A second unpublished study was conducted in Thoroughbred racehorses using synovial fluid markers and starting with horses without musculoskeletal problems. No significant differences were found between HA- and placebo-treated horses. However, there are anecdotal positive reports regarding the prophylactic use of intravenous HA from trainers in various equine disciplines.

Polysulfated Glycosaminoglycan

PSGAG belongs to a group of polysulfated polysaccharides and includes, in addition to PSGAG (Adequan, Luitpold Pharmaceuticals Inc., Animal Health Division, Shirley, New York, United States), pentosan polysulfate. These drugs are DMOADs, and therefore PSGAG has been traditionally used when cartilage damage is presumed present rather than in the treatment of acute synovitis.⁴⁸ However, recent work questions this traditional approach (see below). Use of DMOADs is meant to prevent, retard, or reverse the morphological cartilaginous lesions of OA, with the major criterion for inclusion being prevention of cartilage degeneration. The principal GAG in PSGAG is chondroitin sulfate (CS), and the product is made from an extract of bovine lung and trachea modified by sulfate esterification.

Adequan was reviewed extensively in 1996.⁴⁸ One in vitro study demonstrated that PSGAG was the only drug tested (others included phenylbutazone, flunixin meglumine, betamethasone, and HA) that inhibited stromelysin.⁴⁹ There have been three other in vitro studies on the effect of PSGAG on equine cartilage that had contradictory results. PSGAG caused increased collagen and GAG synthesis in both articular cartilage explants and cell cultures from normal and osteoarthritic equine articular cartilage.⁵⁰ However, other work found a dose-dependent inhibition of proteoglycan synthesis, little effect on proteoglycan degradation, and no effect on proteoglycan monomer size.⁵¹ Various studies have supported the value of intraarticular PSGAG (250 mg) in equine OA, including a clinical study,⁵² a study using a Freund’s adjuvant-induced OA model,⁵³ and a carpal synovitis model using sodium monoiodoacetate.⁵⁴ In the latter study, there was significant reduction of articular cartilage fibrillation erosion, less chondrocyte death, and markedly improved GAG staining.⁵⁴ However, PSGAG had no benefit in healing preexisting articular cartilage lesions in the latter study⁵⁴ or in a different study in ponies.⁵⁵

I have traditionally recommended the use of intraarticular PSGAG after arthroscopic surgery when there is substantial loss of articular cartilage (most commonly in the carpus). I observed rapid resolution of synovitis and hemarthrosis after PSGAG administration that otherwise tended to be persistent after arthroscopy when there was secondary loss of articular cartilage. A recent study using the CSU equine osteochondral fragment–exercise model compared intraarticular PSGAG with either intraarticular HA or saline and revealed that synovial fluid effusion was significantly reduced with PSGAG compared with both saline and HA. The degree of vascularity and subintimal fibrosis of the synovium was significantly reduced with PSGAG treatment compared with controls.⁴⁵ The main value of intraarticular PSGAG appears to be for severe (and acute) synovitis (most commonly seen after arthroscopic surgery when there is considerable debridement of bone). However, the U.K. data sheet expressly states, “Do not inject into actively inflamed joints. In the presence of active joint inflammation, therapy with a suitable antiinflammatory drug should be given prior to intraarticular treatment with Adequan.”

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