IntroductionAs a slowly progressive, degenerative and incapacitating

disease, osteoarthritis is a common cause of morbidity indogs. Currently available treatments are mostly symptomaticones largely relying on anti-inflammatory / analgesic drugs.Over the past decade, veterinary medicine has seen a numberof effective non-steroidal anti-inflammatory drugs(NSAIDs) introduced into practice with different modes ofaction, therapeutic targets, and with wide ranging efficacies,cyclooxygenase (COX)-2 selectivities, and adverse reactionprofiles.

Nimesulide is a member of NSAIDs and has a COX2-selectivity of 5-20 on human as well as canine COX-1 and -2 isozymes [2, 7, 9, 12, 14-16]. COX2 is known to be invol-ved in the production of prostaglandins (PGs), especiallyPGE2, the key mediator of pain, vasodilatation and oedema.In contrast, COX1 induces PGs and thromboxanes that playan important role in platelet aggregation and cytoprotectionof stomach mucosa. COX1 inhibitory drugs have thus beenimplicated in the frequently observed adverse reactions suchas gastrointestinal mucous bleeding and renal dysfunction,whereas COX2-selective NSAIDs are considered to havehighly effective and yet relatively safe analgesic, anti-inflammatory and antipyretic effects. Among the COX2-

selective NSAIDs, carprofen and meloxicam have beenextensively studied and their therapeutic efficacies in canineosteoarthritis have been evaluated [1, 3, 4, 8]. In the presentsynovitis model study in dogs, we aimed to evaluate theanalgesic, anti-inflammatory potential and tolerability ofnimesulide in comparison with carprofen and meloxicam.

Materials and methods

ANIMALS

Eight beagle dogs (4 males, 4 females) aged 1 - 5 years andweighing 9.8 - 13.6 kg were employed for the study. Thedogs were kept in a controlled animal housing (18°C, 55%humidity, and 12h light/dark cycle), fed once a day with adiet, Vet Complex Adult (Virbac Nutrition, Carros, France),and given free access to water. The dogs had not receivedmedication during the 2 weeks preceding the study, had noknown history of lameness, and were considered clinicallynormal based on complete physical examination.

PRODUCTS

Nimesulide (Zolan® or Sulidene®, 50 mg tablets), carpro-fen (Rimadyl®, 20 mg tablets) and meloxicam (Metacam®,

Analgesic efficacy of nimesulide in a canineosteoarthritis modelS. BONNEAU, W. NAJBAR, A. SANQUER, H.M. EUN*, D. GROUSSON and L. MAYNARD

R&D Department, Virbac S.A., B.P.27, 06511 Carros Cedex, France

* Corresponding author : E-mail : teun@virbac.fr

RÉSUMÉ

Efficacité antalgique du nimésulide sur un modèle d’arthrite expéri-mental chez le chien. Par S. BONNEAU, W. NAJBAR, A. SANQUER,H.M. EUN, D. GROUSSON et L. MAYNARD.

L’efficacité antalgique du nimésulide a été évaluée en comparaison avec2 produits de référence (le carprofène et le méloxicam) sur un modèle d’ar-thrite expérimentale sur 8 chiens. Une synovite réversible a été induite parinjection intrasynoviale de cristaux d’urate. Chaque animal a ensuite reçuchacun des 3 traitements ou n’a pas été traité (contrôle) suivant un protoco-le de cross-over complet sur 4 périodes. L’efficacité antalgique a été évaluéesur la base de 5 paramètres cliniques.

Les 3 traitements (nimésulide, carprofène et méloxicam) ont présenté uneactivité antalgique significative par rapport à l’absence de traitement(p < 0,0001). Durant la période d’observation de 4,5 heures après inductionde l’arthrite, le carprofène et le méloxicam ont montré des activités antal-giques modérées avec un profile sensiblement identique, tandis que le nimé-sulide présentait une activité rapide et plus forte (environ 4 fois) que les 2autres médicaments.

Dans le cadre de cette étude, les 3 produits ont été bien tolérés.

Mots-clés : Arthrite canine - anti-inflammatoire - carpro-fène - méloxicam - nimésulide - synovite.

Revue Méd. Vét., 2005, 156, 4, 179-181

SUMMARY

The analgesic efficacy of nimesulide was evaluated in comparison withtwo reference drugs (carprofen and meloxicam) using an experimentalmodel of osteoarthritis in 8 dogs. Reversible synovitis was induced byintrasynovial injection of sodium urate crystals. Each dog was then treatedwith each of the 3 drugs or none according to a 4-period crossover design.The analgesic effects were evaluated on the basis of 5 clinical parameters.

The 3 test drugs (nimesulide, carprofen and meloxicam) exhibited signi-ficant analgesic activities compared with the unmedicated control (p <0.0001). Within the observation period of 4.5 hours after synovitis induc-tion, carprofen and meloxicam showed moderate analgesic activities with asimilar profile, whereas nimesulide showed a rapid, substantially strongeractivity (approximately 4-fold) than the 2 other drugs.

Within the frame of this work, all 3 test drugs were well tolerated.

Keywords : Canine osteoarthritis - anti-inflammatorydrug - carprofen - meloxicam - nimesulide - synovitis.

Revue Méd. Vét., 2005, 156, 4, 179-181

1.5 mg/ml suspension) were obtained from Virbac S.A.(Carros, France), Pfizer S.A. (Orsay, France), andBoehringer Ingelheim (Reims, France), respectively.Sodium urate crystals (U2875) were purchased from SigmaChemicals (St. Louis, MO, USA) and propofol (Rapinovet®)was obtained from Schering Plough Veterinary (Levallois-Perret, France).

SYNOVITIS INDUCTION

Acute synovitis was induced by intrasynovial injection ofsodium urate crystals [5, 6, 13]. Briefly, urate crystals weredispersed in a physiologic saline at 17 mg/ml, sonicated, andthe suspension sterilized by autoclave (20 min at 120°C).One ml of the suspension was injected under strict asepticconditions into the left and right stifle joints alternately oncea week. Prior to the injection, dogs were briefly anesthetizedby intravenous administration of propofol at a dose of6.5 mg/kg. All experiments, including animal handling,were carried out strictly abiding by the protocols approvedby the Ethics committee (Virbac S.A.).

TREATMENT AND FOLLOW-UP

The study followed a 4-period crossover design composedof four treatment groups : an unmedicated control, nimesu-lide (NM), carprofen (CP) and meloxicam (MC).

In this study design, each dog received the four treatmentsseparated by a one-week washout period. The sequence oftreatments was randomly allocated to dogs according to aLatin square model.

The treatment consisted of a single dose of NM (5 mg/kg),CP (4 mg/kg), or MC (0.2 mg/kg or 0.13 ml/kg), which wasgiven orally during the meal 15 minutes after synovitisinduction.

CLINICAL EXAMINATION AND SCORING

Lameness was evaluated at four time points, i.e., 1.5 h, 2.5h, 3.5 h and 4.5 h after sodium urate injection, by two inves-tigators in a blinded and independent manner. The scoringwas based on 5 parameters with graded severity from 0 to 3(table I) ; (i) general behavior (mood), (ii) standing lame-ness, (iii) trotting lameness, (iv) response to contralaterallimb lift, and (v) response to limb flexion/extension. A clini-cal score was defined as the sum of the 5-parameter values.

STATISTICAL ANALYSIS

Data were analyzed using an ANOVA on such variables astreatment sequence, test drug, time and animal as well astheir interactions. In case of a significant difference, furtheranalyses were performed by use of the Newman-Keuls mul-tiple-comparison test. Statistical significance was set atP < 0.05.

ResultsIn this model of induced synovitis, the arthritic condition

reached peak intensity at around 3 h post-injection and thendecreased steadily from 4 to 8 h. Dogs recovered normal sta-tus generally within 24 h and occasionally in 36 h after thesynovitis induction.

Compared with the control, all test drugs demonstratedsignificant treatment effects (P < 0.0001) and time effects(P < 0.0001) between the 0 and 4.5 h time period (figure 1).CP and MC presented similar profiles of moderate but statis-tically significant analgesic activity. In contrast, NM dis-played a prompt, significantly stronger analgesic activitythan the other two drugs.

At the 2.5 h time point, NM demonstrated a maximal dif-ference (4.7-fold) in analgesic activity from CP and MC.The analgesic potency calculated from the data (area-under-curve in figure 1) ranks in the order of NM (6.02) > CP(1.58) > MC (1.39) compared with the control.

Throughout the study period, no adverse reactions (diar-rhoea or vomiting) were observed with any of the test drugs.

DiscussionIn this study, acute synovitis was induced by intrasynovial

injection of urate crystals, reproducing the characteristic andconsistent clinical signs of lameness, which was reversible in24 h - 36 h after induction [5, 10, 11, 13]. Our scoring system(table I) used for the evaluation of clinical signs was a sub-jective one based on variables related to locomotion as well

180 BONNEAU (S.) AND COLLABORATORS

TABLE I. — Scoring scheme for the assessment of lameness.

Revue Méd. Vét., 2005, 156, 4, 179-181

NIMESULIDE IN A CANINE OSTEOARTHRITIS MODEL 181

as behaviour/demeanour. The locomotion variables wereidentical to those described by CROSS et al. [3] and shownto have strong correlations with the ground-reaction-forcevariables measured by means of a biomechanical force plate.The blinded assessments by two independent investigators inour study were meant to render the evaluations as bias-freeas possible, which turned out to be fairly coherent. Withinthe experimental design and especially under the conditionswhere the 3 drugs (carprofen, meloxicam and nimesulide)were used according to the doses and routes recommendedby the suppliers, the therapeutic potentials of the analgesic /anti-inflammatory drugs can be reasonably compared. Underthese circumstances, our data suggest in a statistically signi-ficant manner that nimesulide had a roughly 4-fold highertherapeutic potency than carprofen or meloxicam.

Perhaps important to be mentioned here is the fact that, asa fundamental feature of the synovitis model, the therapeuticeffects observed here are relevant only to the acute phase ofthe symptoms. Thus the present data do not address the pro-perties related to long-term efficacy or tolerability of any ofthe drugs tested. Nonetheless, we would like to note that,according to our unpublished observations, the therapeuticprofiles of the 3 drugs (figure 1) could generally be extendedin a continuous manner to up to 8 h post-synovitis induction.Regarding nimesulide in particular, TOUTAIN et al. [13]have observed under a similar treatment regimen a maximalanalgesic activity (measured by lameness reduction) up to 12h in dogs with Freund adjuvant-induced chronic arthritis.

Within the frame of this study, therefore, our data confirmthe utility of nimesulide as a highly effective analgesic / anti-inflammatory drug for managing the acute pain associatedwith canine osteoarthritis.

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FIGURE 1. — Time courses of clinical scores (Mean ± SEM) of four measu-rements after the synovitis induction, where Cont (◆) : unmedicatedcontrols, NM (■) : nimesulide, CP (▲) : carprofen and MC (✕) : meloxi-cam.