Clinical efficacy and tolerance of meloxicam

in dogs with chronic osteoarthritis

Paul A. Doig, Kimberly A. Purbrick, Jonathan E. Hare, Donal B. McKeown

Abstract - A clinical trial was conducted to evaluate the safety and efficacy of the nonsteroidal
anti-inflammatory drug meloxicam in dogs with chronic osteoarthritis. Forty clinical cases were
enrolled in the 2-phase study. Phase 1 compared therapeutic efficacy and tolerance of meloxicam or
placebo for 1 week. Phase 2 involved a 4-week evaluation of the drug's clinical efficacy and tolerance.
Clinical efficacy was evaluated by using a scoring system that assessed specific lameness, general
stiffness, painful rise, exercise intolerance, and behavior. Evaluations demonstrated significant reduc-
tions (P < 0.05) in clinical signs of osteoarthritis following 4 weeks of drug therapy. Side effects were
minimal in extent and duration. The drug was accepted without problems in the majority of cases.
The findings of this investigation suggest that the efficacy, tolerance, and formulation of meloxicam
oral suspension make it well suited for the treatment of chronic osteoarthritis in the dog.

Resume - Efficacite clinique et tolerance au meloxicam chez des chiens atteints d'osteoarthrite
chronique. Une etude clinique a ete effectuee afin d'evaluer la securite et l'efficacite du meloxicam,
un anti-inflammatoire non-steroidien, chez des chiens presentant une osteoarthrite chronique.
Quarante cas cliniques ont ete inclus dans cette etude en 2 phases. Dans la phase 1, qui s'etendait sur
1 semaine, le meloxicam et le placebo ont ete compares aux points de vue de l'efficacite therapeu-
tique et de la tolerance. La phase 2 impliquait une evaluation du medicament par rapport 'a l'efficacite
clinique et la tolerance pendant une periode de 4 semaines. L'efficacite clinique a ete evaluee par
un systeme de cotation qui evaluait la boiterie specifique, la raideur generale, le leve douloureux,
l'intolerance a l'exercice et le comportement. Les evaluations ont demontre une reduction significative
(P < 0,05) des signes cliniques de l'osteoarthrite apres 4 semaines de therapie medicamenteuse.
L'importance et la duree des effets secondaires etaient minimes. Le medicament a ete accepte sans
problemes dans la majorite des cas. Les resultats de cette etude suggerent que l'efficacite, la
tolerance et la presentation du meloxicam en suspension orale sont bien appropriees au traitement
de l'osteoarthrite chronique chez le chien.
(Traduit par docteur Andre Blouin)
Can Vet J 2000;41:296-300

Introduction currently available for veterinary use is, however, lim-

Canine osteoarthritis (OA) is commonly encoun- ited. Furthermore, where treatment of OA is frequently
tered in veterinary practice. It is a syndrome char- life-long, very few NSAIDs are approved for long
acterized by deterioration of articular cartilage, bone term use.
remodeling and osteophyte formation, changes to the tis- Meloxicam is an NSAID recently approved for use in
sues surrounding the joint, and inflammation and pain. dogs in Canada. Meloxicam is indicated for the treatment
Curing canine OA, once it becomes clinically evident, of inflammation and pain associated with acute and
is not currently possible. Current treatment strategies are chronic musculoskeletal disease. The label dosage is
directed towards slowing the progression of the dis- 0.2 mg/kg body weight (BW) on day 1 followed by
ease and improving the general mobility, exercise tol- 0.1 mg/kg BW once daily (1).
erance, and quality of life of the dog. Nonsteroidal Meloxicam is widely recognized as being one of the
anti-inflammatory drugs (NSAIDs) are widely used for first commercially available cyclooxygenase type 2
the treatment of OA. The number of approved NSAIDs (COX-2) selective NSAIDS (2-6). While COX-2 selec-
tive NSAIDs are believed to inhibit many of the inflam-
matory aspects of arachidonic acid metabolism, they are
also believed to spare the "housekeeping" functions of
prostaglandins and thromboxanes. The housekeeping
Boehringer Ingelheim Vetmedica, 5180 South Service Road, duties of these arachidonic acid metabolites include
Burlington, Ontario L7L 5H4 (Doig), International Bio- the regulation of gastrointestinal blood flow and gas-
Institute Corp., R.R. #3, Fergus, Ontario NIM 2W4 (Purbrick, troprotective mechanisms, the regulation of renal blood
McKeown), Janssen Animal Health, 19 Green Belt Drive,
Toronto, Ontario M3C lL9 (Hare). flow, control of platelet aggregation and clot formation,
and a host of other physiologic functions. The objective
Correspondence and reprint requests to Dr. Jonathan Hare. of the current study was to investigate the therapeutic
This study was supported by Boehringer Ingelheim (Canada) efficacy and tolerance of meloxicam suspension in dogs
Ltd. suffering from chronic OA.
296 Can Vet J Volume 41, April 2000
 Materials and methods Table 1. Scoring system for assessment of clinical
Animals efficacy parameters
Forty dogs of mixed age, gender, breed, and body Clinical Parameter Scoring System
weight were enrolled in the trial. All animals were Specific lameness 1 - No lameness
household pets and were initially selected from the
case records of 7 veterinary practices in southwestern 2 - Mild (slight weight shift observed)
Ontario. All dogs included in the study had clinical 3 - Moderate (marked weight shift
signs of chronic OA (any or all of specific lameness, gen- observable, head shaking during
walking)
eral stiffness, painful rise, or exercise intolerance).
These clinical signs had been apparent within 2 wk 4 - Severe (severe lameness with
intermittent toe touching or non-
preceding entry to the study. The dogs included in the weight bearing)
trial had not been administered any medication other than General stiffness 1 - None (normal gait, stride length,
heartworm and flea prophylaxis in the 2 wk preceding the no arching of back)
study. Furthermore, the dogs had not received any long- 2 - Mild (slight disturbance of gait, stride
acting corticosteroids within a 2-month period prior to length, and/or slight arching of back)
study commencement. Informed consent was obtained 3 - Moderate (moderate disturbance of
from all owners prior to their dogs being entered in gait, stride length, and/or moderate
the study. arching of back)
Dogs with clinical signs suggestive of the follow- 4 - Severe (severe disturbance of gait,
ing conditions were excluded: spinal disk disease, gas- extreme reduction in step length,
trointestinal ulceration, impaired renal function, diabetes and/or marked arching of back)
mellitus, osteoporosis, fracture, pregnancy, pyrexia, Painful rise 1 - Rises normally
and myositis. 2 - Mild, rises slowly
3 - Moderate, rises with difficulty
Study design 4 - Severe, rises reluctantly or only
The study consisted of 2 phases. Phase 1 compared the with assistance
therapeutic efficacy and tolerance of meloxicam or Exercise intolerance 1 - Normal
placebo under controlled conditions for 1 wk. Phase 2 2 - Mild, refuses to jump
involved further evaluation of the drug' s clinical ther-
apeutic efficacy and tolerance. 3 - Moderate, refuses to climb stairs
Phase I - Dogs were assigned to either drug or 4 - Severe, reluctance to walk
placebo treatment groups by using a computer-generated Behavior 1 - No abnormality (dog is willing and
randomization table. Animals in the drug group were able to exercise without any signs of
treated with meloxicam at a dosage of 0.2 mg/kg BW, lameness or stiffness)
PO, on day 1, followed by a reduction to 0.1 mg/kg BW, 2 - Minor abnormality (dog is willing
PO, q24h for a further 6 d. Animals in the placebo and able to exercise but slight signs
of lameness and/or stiffness are
group were administered an equal volume of placebo by occasionally observed)
using the same dosing scheme. The study was blinded, 3 - Moderate abnormality (dog is
so that neither the investigators nor the animal owners reluctant to exercise, obvious signs
were aware of the dogs' treatment group. The drug of lameness or stiffness observed)
(or placebo) was administered PO to all dogs on a small 4- Severe abnormality (dog is not able
quantity of food. to do any exercise, permanent obvious
Phase 2- Following the initial 7 d of treatment, dogs signs of lameness and/or stiffness)
assigned to the drug group continued to receive meloxi-
cam at a dosage of 0.1 mg/kg BW, PO, q24h for a total parameters detailed in Table 2. Assessments were per-
of 28 d. Dogs assigned to the placebo group during formed following 28 d of meloxicam therapy.
Phase 1 were treated with meloxicam at a dosage of Blood from each animal was collected and analyzed
0.2 mg/kg BW, PO, on day 1, followed by a reduction to for hematologic and serum chemistry parameters. These
0.1 mg/kg BW, PO, q24h for a further 27 d. included red blood cell (RBC) count, differential white
blood cell (WBC) count, total platelet count, packed cell
Data parameters volume (PCV), hemoglobin, mean corpuscular volume
Efficacy of the treatment was assessed by means of a (MCV), mean corpuscular hemoglobin concentration
clinical scoring system that assessed the animal's spe- (MCHC), serum urea, serum creatinine, total serum
cific lameness, general stiffness, painful rise, exercise protein, serum albumin/globulin (A/G) ratio, and serum
intolerance, and behavior (Table 1). Clinical scoring was potassium. Analyses were performed for all animals
performed by the investigating veterinarian prior to preceding treatment, following 7 d of treatment with
treatment, following 7 d of meloxicam or placebo meloxicam or placebo, and following 28 d of treatment
administration, and following 4 wk of meloxicam with meloxicam.
administration.
The overall palatability of the drug, overall toler- Test article
ance of drug treatment, and overall assessment of the Dogs assigned to the drug group received an oral sus-
dogs' quality of life were evaluated according to the pension of meloxicam (Metacam, 1.5 mg/niL meloxicam
Can Vet J Volume 41, April 2000 297
Table 2. Scoring system for the assessment of the
overall efficacy of meloxicam therapy and the overall
palatability of meloxicam oral suspension 12.0 -

Clinical
Parameter Score Scoring System *~~~~~~2.
I10.0 -
0
Overall Excellent The clinical signs observed U
quality of life at the first examination have CO) 1.9
i 8.0-
disappeared. The physical '1
condition is excellent.
6.0-
Good Quality of life has improved.
Obvious response to treatment.
Moderate Quality of life has slightly improved 4.0 -
in comparison with the initial
examination; minimal clinical
2.0 -
improvement.
Poor The general clinical condition of
the dog has remained unchanged or It~ l~I~
__n- 7dl_ 7dlm-
has worsened during the course of Pbembo DnPg Dnug
treatment. Day of Trl/alratment Group
Overall Good The drug was accepted without
palatability problems. CH * *rb * -
iseues im BP
M usum
Satisfactory The drug was accepted with some i
problems.
Figure 1. Clinical efficacy of meloxicam suspension for dogs
Poor The dog refused to take the product. in the drug and placebo groups following 7 d treatment.
Numbers within bar refer to mean clinical scores for individ-
ual parameters. *Significantly different from pretreatment
oral suspension, Boehringer Ingelheim Vetmedica, global score (P < 0.05), n = 19 for each group.
Burlington, Ontario). Dogs in the placebo group received
the meloxicam oral suspension vehicle.
golden retriever (6/40). The most common diagnosis was
Statistical analysis hip dysplasia (28/40); the remainder suffered from a
Data generated by the study were analyzed by Sapientia range of arthritides involving the stifle, elbow, and/or
Scientific Services, Guelph, Ontario, using appropriate shoulder joints.
statistical tests. Associations were considered significant Of the original 40 clinical cases, 38 animals suc-
if P < 0.05. cessfully completed the study. One animal died fol-
Phase I - Clinical symptoms including specific lowing 3 d of treatment with placebo. One dog's records
lameness, general stiffness, painful rise, exercise intol- and evaluation forms were retained by the animal's
erance, and quality of life, for the 2 treatment groups, owner, who declined to pass them along to the investi-
placebo and drug, were tested by using an F-test with gators for inclusion in the trial.
1 degree of freedom for the treatment effect (equivalent Clinical assessments for specific lameness, general
to a t-test). This test was done for data on day 1 and on stiffness, painful rise, exercise intolerance, and behav-
day 7. ior made following 7 d of meloxicam or placebo treat-
Phase 2 - The clinical scores for the clinical signs ment were compared with initial pre-drug assessments
mentioned above were subjected to a regression analy- (Figure 1). Significant reductions (P < 0.05) in the
sis where the independent variable was duration (day 0, severity of clinical signs of disease were reported only
day 7, and day 28). Regression coefficients were used to for the drug group and not for the placebo group.
estimate scores for pre- and post-drug therapy. Evaluations performed following 28 d of meloxicam
Data for hematologic and serum chemistry parame- therapy, using an initial dose of 0.2 mg/kg BW fol-
ters (dependent variables) were split into 2: ratio of lowed by a maintenance dose of 0.1 mg/kg BW, q24h,
responses below the normal reference range and ratio of demonstrated significant (P < 0.05) reductions in the
responses above the normal reference range. These severity of clinical signs of OA (Figure 2). Clinical
ratios were tested by using the linear logistic model and scores for exercise intolerance were reduced by 26% and
estimates of regression coefficients were obtained painful rise decreased by 29%; there was a 25% reduc-
using the method of maximum likelihood (Logistic tion in both general stiffness and specific lameness,
procedure, SAS/Stat 6th ed, SAS Institute, Cary, North while scores for behavior improved by 24%. It should be
Carolina, USA). The independent variable was time noted, however, that these measures were based on
(day 0, day 28). The model was tested for goodness of fit day 0 evaluations as a historical control group, and
and chi-squared analysis on the estimates was performed. that a control cohort was not used in this phase of
the study.
Data for the overall palatability of the drug, overall tol-
Results erance of drug treatment, and overall assessment of
The average age of the 40 dogs selected for entry to the the drug's clinical efficacy are reported in Table 3.
trial was 9.2 y, s = 3.3. The most prevalent breeds were There were no signs of intolerance to the drug or
Labrador retriever (9/40), German shepherd (7/40), and placebo in the first 7 d of the study. Data for the overall
298 Can Vet J Volume 41, April 2000
 Table 3. Overall clinical efficacy, palatability and
tolerance of meloxicam treatment. Results are
reported as percent of clinical cases
Following 28 d
Clinical Parametera Score Meloxicam therapy
Overall quality Excellent 5%
of life Good 82%
Moderate 5%
'E 1.6 mmb
powu~~~ Poor 8%
i) 6.0- _H Overall palatability Good 84%
.2 of drug Satisfactory 13%
Poor 3%

3.0 -- Overall tolerance Excellent 89%

of drug treatment Good 11%
Moderate 0%
Poor 0%
IyoTram- an = 38 for each parameter

Day of Treatment
and painful conditions of the locomotor system. Non-
Figure 2. Clinical efficacy of meloxicam suspension for dogs steroidal anti-inflammatory drugs are inhibitors of
administered 28 d therapy by using an initial loading dose of cyclooxygenase, the enzyme that ultimately converts
0.2 mg/kg BW followed by a maintenance dose of 0.1 mg/kg arachidonic acid to prostanoids (thromboxane, prosta-
BW q24h. Numbers within bar refer to mean clinical scores cyclin, and prostaglandins), compounds that mediate
for individual parameters. *Significantly different from pre- inflammation (9).
treatment global score (P < 0.05), n = 38.
Meloxicam is a selective COX-2 inhibitor derived from
enolic acid (10). It has been documented to be effective
tolerance of meloxicam therapy revealed that on com- in decreasing the local inflammatory response in a
pletion of 28 d of treatment, 4 of 38 dogs showed signs shoulder synovitis model in dogs ( 11) and in attenuating
of possible mild intolerance to the drug, including iso- stifle synovitis and associated lameness induced by
lated episodes of inappetence, diarrhea, vomiting, and sodium urate in this species (12). This investigation
fecal blood. One dog, however, had a history of occa- demonstrates the effectiveness of meloxicam in treating
sional episodes of colitis/vomiting and another was chronic locomotive disorders in the dog. Meloxicam
prone to periodic diarrhea. It was not necessary to dis- significantly reduced specific lameness, general stiffness,
continue treatment or reduce the dosage of meloxicam painful rise, and exercise intolerance of the dogs par-
administered in any of the dogs. ticipating in the study, while greatly improving their qual-
Hematologic values and serum chemistry measure- ity of life. It should be noted, however, that a negative
ments were presented as falling within, above, or below control group was used for only the first 7 d, after
the normal reference range (Table 4). Pre-drug treatment which humane concerns made this option untenable.
data were tested against post-drug treatment data to At the owner's insistence, 17 dogs were maintained on
determine if there was a change in parameters associated meloxicam treatment following the conclusion of the
with prolonged meloxicam treatment. There were no study. At the time of writing, efficacy has been main-
definitive tendencies or trends in hematological or tained for at least 22 mo with no adverse effects noted.
serum chemistry measurements. For all the parameters Dogs are quite susceptible to the adverse effects of
tested (RBC, WBC, total platelet count, PCV, hemo- NSAIDs and safety data from other species, especially
globin, MCV, MCHC, serum urea, serum creatinine, total humans, cannot be extrapolated to the dog (8). The use
serum protein, serum albumin/globulin ratio, and serum of NSAIDs approved only for human use can carry
potassium), there were no statistically significant changes appreciable risk when these drugs are administered to
above or below their respective normal reference ranges dogs (13). These drugs are recognized to induce specific
(P > 0.05). side effects in animals and humans by virtue of their
mode of action. Inhibition of the production of endoge-
nous gastric prostaglandin E2 (PGE2) can affect gastric
Discussion mucus production, mucosal blood flow, and acid secre-
During the past decade, there has been an increased tion, which may give rise to gastrointestinal irritation and
awareness of the medical importance of pain manage- ulceration (14). Inhibition of vasodilatory PGE2 and
ment in veterinary medicine (7,8). Nonsteroidal anti- PGU2 production in the kidney, particularly in hypo-
inflammatory drugs are among the most widely used volemia, can lead to compromised renal perfusion (15).
drugs in human medicine and have been used for decades A host of other possible side effects have been reported
for management of chronic pain. They have been widely but are much less common than are gastrointestinal
and successfully employed in a variety of therapeutic and renal effects.
applications in both man and animals; their primary Meloxicam was well tolerated by the dogs in this
use being in the treatment of inflammatory, degenerative, trial. Of the 4 dogs that experienced adverse effects, all
Can Vet J Volume 41, April 2000 299
 Table 4. Hematologic and serum chemistry data for animals (n = 38)
treated with meloxicam using an initial dose of 0.2 mg/kg BW followed
by a maintenance dose of 0.1 mg/kg BW q24h for 28 d in total.
Results are reported as percent of clinical cases falling within the
normal reference range per assessment point
% of cases within
normal reference range
Hematology Time of Assessment
or serum
chemistry Normal reference Following 28 d
parameter range Pre-treatment oftherapy
RBC count 5.5-8.2 X 1012/L 100% 85%
WBC count 6.6-18.4 X 109/L 90% 80%
Total platelet count 150-450 X 1012/L 90% 90%
PCV 0.37-0.55 L/L 95% 90%
Hemoglobin 126-194 g/L 95% 95%
MCV 65-75 fl 95% 95%
MCHC 320-360 g/L 75% 90%
Urea 2.1-8.9 mmol/L 95% 95%
Creatinine 53-145 mol/L 90% 90%
Total protein 54-76 g/L 95% 95%
A/G ratio 0.6-1.3 85% 80%
RBC - red blood cell; WBC - white blood cell; PCV - packed cell volume; MCV -mean corpus-
cular volume; MCHC - mean corpuscular hemoglobin concentration; A/G - albumin/globulin

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300 Can Vet J Volume 41, April 2000